DE2422512A1 - PROSTANIC ACID DERIVATIVES AND PROCESS FOR THE PREPARATION - Google Patents

Description

PATENT LAWYERS

_D Π. I. MAAS

DH. Ο .. C '"- ^Tl

0000, ··. Wl ^ 40

8CHLEISSHElViSiSTR.

TEL. 3592201/205

CAS3: 24 011 tM / ΐΛ

AI-BRIG ¹ AIT CYAiIAIiID COMPAlTY, V.'ayne, Eew Jersey / USA

"Frostic acid derivatives and processes for their production

The invention relates to 11-alkoxy substituted prostanoic acids and their derivatives as well as processes for their production and intermediate products obtained in the process.

P: .3 compounds according to the invention correspond to the following (3 en general 3? orn: el

R ₇

^N CR ₃
J
OR ₂ - 2 -

409847/1159

in the

3.J, a low molecular alkoxy group, ■ an ω-hydroxy-substituted low molecular alkoxy group or a ^ -tetrahydropyranyloxy-substituted low molecular alkoxy group,

H- a ^ 'aesers toff atom, a low molecular weight alkyl group or a triphenylilethyl group,

E ^ a straight-chain alkyl group with 2 to 10 carbon atoms, a straight-chain alkyl group with 2 to carbon atoms substituted with one or two low molecular weight alkyl groups, a straight-chain alkenylmethyl group with 3 to 10 carbon atoms, a straight-chain alkenyl group substituted with one or two low molecular weight alkyl groups 'tiiylgruppe with ~ j to 10 carbon atoms, a cycloalkyl group: 3IT 4- atoms to 9 carbon atoms, substituted with a niedriguiolekularen alkyl group Cycloalkylgrii ppe atoms with 5 to 10 carbon, one having a Cycloaikjlgruppe substituted lower alkyl group having 6 to 12 carbon atoms, whose Cycloalkyl group possibly substituted with a low molecular weight alkyl group, an oyoloalkenyl group with 5 to 9 carbon atoms, a cycloalkenyl group with 6 to 10 carbon atoms substituted with a low molecular weight alkyl group, a low molecular weight group substituted with a cycloalkenyl group ekuiare alkyl group with 6 to 12 carbon atoms, the cycloalkene group of which is optionally substituted with a low molecular weight alkyl group, an adamantyl group or a straight chain alkyl group substituted with an adamantyl group,

R ^, a hydroxyl group, an alkoxy group having 1 to 12 carbon atoms or a tetrahydropyranyloxy group,

Έ-rj a water atom or a low molecular weight alkyl group with up to 3 carbon atoms,

409847/1159

Y is a divalent group of the following formulas

PIO, H ■ ■ H, 0E

Z is a two-valued group of the following general formulas

- (CTIg) _n -, - (C: i ₂ ) _n -C-CH ₂ -, - (CHg) _n -CH-,

Rr-

HH
and -CH ₂ -C = C- (CH ₂ ) -

in which η is an integer with a value from 3 "to 8, incl., ρ is an integer with a fourth from 2 "to 6 inclusive, R- an alkyl group with up to 3 carbon atoms and

H ^ an alkyl group of "up to 3 carbon atoms Represent fluorine atom or a phenyl group and

the 'group -C ^^ - C ^^ - an ethylene or trans-yinylene group t-means, with the!' let that the group Rp ^e ^ - ⁿ hydrogen atom "means when the group R ^ is a low molecular weight alkyl group represents, so / ie the optical isomers' of these compounds.

The invention "also relates to a method of manufacture the optical antipodes, enantiomers, diastereomers,

409847/1159

Dia-stereo tables, racemates and racemic mixtures of the Compounds of the following general formula:

V /

0 Y ZCR ₂ ,

h L r "

R ₁ - '\ p c I'

ι ³

OR ₂

v / orin R 1, E ₀ , R _{1, R 1, R 7} , Y and Z have the abovementioned Be i c- 0 ¹ TI

Own interpretations, which is characterized by the fact that one a compound of the general formula

in the R ^f . a low molecular weight alkoxy group or a W-tetrahydropy-ranyloxy-substituted low molecular weight alkoxy group and

E ' _{A represent} a tetrahydropyranyloxy group or an alkoxy group having 1 to 12 carbon atoms and

Z has the meanings just given, with a Lithium alanate of the following general formula

Li ©

H CH-R- ^ C = C

RRR

409847/1159

in the ·

Il is an alkyl group with 1 to 7 carbon atoms,

R 'is a low molecular weight alkyl group or a triphenylethyl group mean and

Ι · Ι _{η has} the oloen absnen meanings to a compound of the following general formula

¹ I '

Il t

ZCR ₁ ,

^ C = C-CH-R.

H-

■ /

OR.

in which R ^{1 is} a hydroxyl group, an alkoxy group having 1 to carbon atoms or a tetrahydropyranyloxy group and

R '. ,, E.'p, I'v and Ti have the meanings given above, converts, then blocking the ether and ester groups · -? Group with a weak acid to form a compound of the following general formula

R.

κ it

"Z-C-R,

H
, C = C-CHR-

I »U

OR ₀

409847/1159

in the R ". a low molecular weight alkoxy group or a «- • —hydroxy — substituted low molecular weight alkyl group,

R ' ^: ., A "fass only off atom or a low-molecular alkyl group, ■. *

H ^l:. denote a hydroxyl group or an alkoxy group having 1 to carbon atoms and

Z and E, which have the meanings given above, are split off and, if desired, the compound obtained is treated with an egg hydride as a reducing agent and the 9 <t- or 9β-compounds obtained are isolated and, if desired, selectively a 9,15-Mhydroxy-A -trans-prostanoate- A compound with 2,3-2ichlor-5f6-dicyano-1,4-benzenequinone or kangan dioxide is oxidized to the corresponding 15-ketone, all free hydroxyl groups are blocked with a Grignard-resistant group, the compounds with a low molecular weight "Ikyjinagnesiurahe.lo ^. enide, the hydroxyl groups are freed from their protective group and, if desired, the ester is converted into the corresponding carboxylic acid and, if desired, the 9-hydroxyl group is oxidized into a 9-oxo group and the products obtained are isolated and, if necessary, the C ₁ ^ -C J ₁ -vinylene group is added hydrogenated an ethylene group and isolated the products obtained.

The invention also relates to the non-toxic, pharmaceutically acceptable salts of the invention Compounds in which the group R 1 represents a hydroxy group. The cations in these salts are, for example, non-toxic metal cations, such as sodium ions, Ealiuniionen, Calciuraions and Kagnesiuaionen or organic Aninkationon, such as tri- (lower alkyl) -aininka1; ioneii (e.g. triethylamine-, iriethanolaniin, procaine cations and the like. ) contains «n.

The compounds of the invention are in the form of yellow oils

4Q9847 / 1159

with characteristic absorption spectra, available. They are relatively insoluble in Vacser, but relatively readily soluble in common organic solvents such as ethanol, ethyl acetate, dimethylformamide and the like. The cationic salts of the compounds whose group R . represents a hydroxyl group, are generally white his'gelbe 'rz?: LstE.ll ± ne solids with characteristic melting points and absorption spectra. They are relatively easy to read in water, methanol and ethanol, but relatively insoluble in Eenzcl, diethyl ether and petroleum ether.

The ProEtag2 andinc a Eamilie represent closely-related compounds which have been isolated from various animal tissues and which stimulate the smooth musculature, the Arterient.Iu- ^1; lower pressure, counteract the Kofcilisierung of free fatty acids caused by epinephrine and ^f; Ir acids develop further pharsiacological and autopharmacological effects. For this purpose, reference should be made to the publications of Bergström et al )) and the references cited therein. The so-called natural prostaglandins are derivatives of proctanoic acid of the following formula:

ιί

COOH

/ CH ₂ ^ CH ₂ CH ₃ CH ₂ ^N CH ₂ "CH ₂

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Pie bound to the C-8 and the C-12 carbon atom Hydrogen atoms are in the trane configuration. the natural prostaglandins represent only one of the possible optical isora. However, the invention is asleep all possible optical isomers.

The compounds according to the invention can easily be prepared from large cyclopentenone intermediates which are substituted in the 4-position and which have the following general formula

correspond in the

R \ a low molecular weight alkoxy group or an by a FII Tetra.hydrop3 ^T ranylo>: ygruppe substituted low molecular Allroxygruppe and

R ¹ . represent a tetrahydropyranyloxy group or an alkoxy group having 1 to 12 carbon atoms and

Z has the meanings given above.

Certain 4-oxycyclopentenone intermediates can accordingly that in the Heaktionsschema A, in which Z 'the meanings of Z with the exception of the group of the formula

ice cream

-CH ₂ -CH = CH- (CH ₂ )

has given reaction from the corresponding, in 4-position unsubstituted cyclopentenones of the general Formula (i) can be prepared.

409847/1159

The necessary cyclopentenones are in ΒΞ-PS No. 736 215 (published January 15, 1973) "or can be prepared analogously to the procedures mentioned therein will.

In Reaction Scheme A below, the groups have Z ', R' .. and H '. the meanings given above, while R a low molecular weight allyl group, R ". A hydroxyl group or an alkoxy group having 1 to 12 carbon atoms and m is an integer from 2 to 5 inclusive.

.409847 / 1159

REACTION SCHEME Λ

Br

E0- (CH ₂ ) ₄ -0 HO- (CH ₂ VO

Z'-C-H%

R '

ο Il

Z'-C-

(V)

Ii

Z'-C-R ' ₄

(VI)

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The introduction of the 4-oxy function into the cyclopentenones of the general formula (I) unsubstituted in the 4-position is achieved by first treating the compounds in the "" position with an allylic halogenating agent, preferably "T -Bromosuccinimide, halogenated. The resulting 4-BrOiOCyCl op ent enones (II) are then solvolyzed to introduce the oxy-J function. This process step is preferably accomplished in the presence of a silver salt to facilitate the displacement of the ealide ions. The particular 4-oxy derivative formed depends on the nature of the solvent systeria. The treatment of the 4-bromocycloper.tenon old siloerfluoroborate in a water-acetone solution (for reasons of solubility) leads to the 'i.-i ^ / drorcj'cyclopeRtenon. If a VaE'ser-tetrahydrofuran mixture is used as the solvent system, one obtains the 4'-hydroxybutyloxy derivative (the Fo-o . \ el III). If only tetrahyarofuran is used as the solvent, only the latter compound is formed. If the tetrahydrofuran is replaced by alcohols, e.3. Methanol, ethanol, isopropanol, butanol and dorrueichen, 30 one obtains the corresponding 4-alkoxycyclopentenones (of the formula IV). The corresponding 4- (w-substituted-Eydroj.yalkoyy) -cyclopentenones (of the formula V) are formed with ethylene glycol or propylene glycol, etc. It is preferred for the three last-mentioned procedures, one with the compounds of the general formula II is not reacting proton acceptor, for example syia-Kcllidin, to add.

In general, these processes can be carried out either with the free carboxylic acid or with the corresponding one, depending on the requirements Carboxylic acid alkyl esters are carried out. Any alkyl carboxylate can be used which is not covered by the general Formula (I) is given by hydrolysis of this compound

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to the acid and its usual esterification, e.g. with the appropriate Alcohol, or with isobutylene to give the corresponding tert-butyl ester. In the subsequent However, alanate conjugate addition requires a Use cyclopentanone, its carboxylic acid group as also whose free hydroxyl groups are blocked. A group particularly suitable for blocking both groups is the setrahydropyranyl group, since "this group is easily associated with a weak acid can be split off under conditions which are subsequently produced, relatively unstable 11-0xy-9-keto compounds (ß-oxyketone) do not affect. Thus it is not possible to obtain a satisfactory one chemical hydrolysis of an alkyl ester or an O-alkanoyl group of a 1 i-oxy-9-ketopro'stanoic acid derivative under conditions in which this system is stable (although enzymatic hydrolysis is possible is). Of course, these stability considerations do not apply to the "5" 'pure (9-hydroxy compounds).

The 9-keto-13 ~ trans-prostate acids according to the invention and their esters can be prepared with the aid of the new conjugate addition process given in Reaction Scheme B below. In the following reaction scheme B, the groups R ~, R '^, R ¹ ^ ,, R% and Z have the meanings given above, while the group R _{8 is} a low molecular weight alkyl group (the three groups Rg bonded to aluminum not necessarily being the same must be), R'p a low molecular weight alkyl group or a triphenylmethyl group, R "a hydrogen atom or a low molecular weight alkyl group and R" _? mean a low molecular alkoxy group or a cj-hydroxy-substituted low molecular alkoxy group.

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REACTION 0
Il
+ CR ₃ I. CHEiMA B. 2422512 • CHiCH Cl
) (VIII)
0
- ii
tmnn, CR _n
~ C
\
H AlCl ₃ (VII
V!
Cl > I " trans : c = c, 0
ii
, CR ₃
lh

(IX)

OR ' a

I H trans CH-R ₃ /

(XI)

OH I

H trans CH-R ₃

R ₃ CKO ■ + LiC = CH ^ R ₃ -CH-C = CH

(XIII) (XIV) ι (XV)

OR'2 ι

H trans CH-R ₃

'C = (Γ Li ^ ^ H

OR'ζ

IR ₃ -CH-C = CH

(XVI) OR'2 \

ν Η trans "CH-R ₃ / \ /

N.

(XVII)

R ₈ -Al-R ₈ Ro

Li

(XVIII)

409847/1159

2A22512

REACTION SCIENTIFIC B (continued):

O +; OR ¹ 2 ZCR ¹ * / "^ -C =
/
H C
\
CH-R ₃
I.
OR% XVIII Γ ι 0 (XVIIIa) O
Il
^ ZCR ¹¹ * r ~ ——
*
R ¹ I H
I. (XIX) Ii l /
^ -C = C
/ \
H CH-R ₂ \ Γ ρ U ''

(XX)

A09847 / 11B9

According to the reaction given in reaction 3-scheme B, acetylene (formula "VIl) is converted with a suitable acid chloride (of general formula VIII) in the presence of aluminum: niiiiumtriehlorid to the corresponding i-chloro-3-ketotrana-i-alkene (of formula IX) implemented. By exchanging some lithium iodide, which is preferably carried out in a ketone solvent such as acetone, the corresponding trans-vinyl iodide (of the general formula X) is obtained. The reduction of the ketofunction of the compounds of the general formula (X) rait ITodium borohydride gives the corresponding alcohol of the formula (XII), which then blocks with a triphenylmethyl group or a triphenylmethyl group substituted with one or two methoxy, '-; groups or in the one O -lower alkyl group is introduced. The hydroxyl group can also be blocked with the aid of a ürialZ-: yl8iIyIgru -pp e.

The protected trans-vinyl iodide can also be obtained by conventional treatment of the corresponding aldehyde (the general Pcirnel ICIII) with lithium acetylide (formula XIV), blocking the; 3-hydroxy-1-alkyne obtained as a product (of the general formula XV) and reaction of the compound of the general formula (XVI) obtained in one process by successive treatment with disiamylborane, trimethyl amine-IT-oxyc. and iodine in aqueous sodium hydroxide to form the compound of general formula (XI). This latter method is preferred when the group H _{7 represents} an adamantyl group, contains an unsaturated group, a cyclopropyl ring or some other relatively sensitive group.

The protected or blocked vinyl iodide of the general Forasl (XI) is then subjected to metal exchange with a Alkyllithiuinverbindung, for example n-butyllithium, at very low temperatures, for example -78 ⁰ C, subjected to give the

409847/115

.ithium derivative of the general ...or "si (XVII), which retains the tran3-formation of the double bond - 'remains, According to 1 to A- £ -td., the addition of a T-ri alkyl-gluninium compound (of the formula ( Rg) -Al)), for which ruaii before-possibly uses irimethylaluminiuin, see below the Lb "sue /: lee litiiiumderivatg of the general formula (XVII) to the idthium alanate product of the general formula (XTU"".;v; obei again the trans configuration of the double bond remains unchanged. Then one adds dissolved cyoloalkenone of the general formula (III) to the alanate solution or to another non-prototropic solvent. The resulting solution is then allowed to warm to r .vj-eirperattir - and is kept at about 6 to 1 stU.

: ■. ::: 'J (XVIIIa) contains potential hydroxy- o: k- ^f ' carboxylic acid groups in the form of ethers or esters, .-.,? .. with tetrahydropyrcjij '. ".- and / or trialkylsilyl -G:? -; p (? · .. >> ^Ί .cchiert. The exchange, of the alanate the more general: Ιοτ.ζ. '. "■ -. -'. '.""I) with the cyclo' vlkenorj the general formula \ IYI11 C : Τ ^ λ. '^ ur ^ - ^ r Eoioexialt ^ Jig ler trans-iZonfiguration τ, " oiner"",:''■■kr.'nfu-'.'ized transfer of the trans —1-Alkenylli7an.ä ^: i ■ i-? R 7; :: 'vin ^ -. Ng of the general formula (X ^ / III) on ': \. Zi eic.?.".iieiion of the general formula ( XVIIIa) what 7ia3li de ^. On the other hand, the correction solution gives the! '5s • j .'- t ν; n' -.- deutun ^ .Cests'-ε divide that the trans-alkenyl- . ^ {■■ ^: ^ of the compound of the general formula (XVIII) in the craxia position at the 4-3 ".:. bstituenten der Verbirtdung der yj. Igaraeir.en Trrr,;?! (XVlIIa) is added. Regarding the relative confi ^ r; .- ε. lic η dc ^: f- side chains of connexion? '"der- general ^ eire:. Pc τη el 'XI7) there is, however, no SiCl-IV - meaning that this IV / böache in general. Fo ^ i'-v- (XIZ) through the ¹ ^ A · \ '"- üjini ·? I-sclmv-ng gQ trag · ?.". wi :: ir ■■

A098A7 / 1159

BATH ORIGINAL

π
-ZC-R '

is present and in the nomenclature of the compounds of these Kind by, the designation 8? is specified. In feathers Pall gives when the protective groups are split off Formation of the compounds of the general formula (XX), which can be achieved with an acid, e.g. by treatment with an acetic acid-tetrahydrofuran-water mixture takes place with a ratio of 3: 1: 1- at 35 to 45 ° C for 3 to 48 hours, -a trans configuration of the chains. This process leads to a cleavage of the O-trityl group as well as a Hydrolysis of the tetrahydropyranyl and trialkylsilyl groups. The allyl esters are not split off as a result, however, can -but by enzymatic ^ or microbiological known per se Procedure Irydrolyzed.

To ensure the trans configuration of the compounds of the general formula (XIX), these products can be reacted under the conditions described in the literature for the equilibration of the 8-1So-PG-E ₁ compounds to form a mixture containing about 90% of the trans -Product contains. These conditions include treatment with potassium acetate in aqueous methanol for 96 hours at room temperature.

As an alternative process route in the following reaction scheme C conjugate addition · described a Alants to a Cycloalfcenon. In the following Reaktionsscherra C, R,., Rq, Z, R ¹ .., R ¹ are, and R ". The above given meanings.

409847/11 * 9

• REACTION SCHEME C

(XV)

OC (C _e H ₅ ) ₃

H-CiC-CH

(XXI)

CH ₃ -CK-CH ₃

CH ₂ -Al-H ι

CH ₂ CH CH ₃ CH

CH ₃ "\ _c

^ CHCH ₂ -Al '' Γ CH ₂

.CH

CH ₃ CH,

(XXII)

(XXIV)

(XXIII)

O-C (C _e H ₅ ) ₃ OH

CH ₃

409847/1159

iiEM / i C

Il

^ Z-C-R '.

CH CH-R ₃

trans I.

(XXVI)

JZ-C-R "*

trans

CH-R ₃

(XXVII)

AÖ98A7 / 1

According to the reaction indicated in reaction scheme C, the triphenylmethoxy-substituted 1-alkyne of the general formula (XXI) obtained by O-triphenylmethylation of the corresponding 1-Alki2i-3-ol8 (general formula XV of reaction scheme B) with diisobutylaluminxum hydride (compound of Formula XXII) treated, whereby the alan of the general formula (XXIII) having the trans double bond is obtained, which in an inert solvent, such as 3erzene, toluene and the like, at temperatures in the range from 4-0 to 6O ⁰ C for several Hours.

The reaction can also be carried out in a solvent such as tetrahydrofuran or in an approximately 2: 1 mixture of benzene or hexane, for which somewhat more severe conditions are required, which usually consist of heating to approximately 70 to 75 ° C. for approximately 18 hours. The subsequent reaction with methyl or n-butyllithiuro (lU-Li) is preferably carried out in a mixture of the above solvents with an ether solvent such as diethyl ether, dibutyl ether, tetrahydrofuran and the like. This reaction proceeds rapidly and is preferably carried out under cooling at 0 to -10 ⁰ C. The conjugated 1,4-addition of the resulting alanate salt of the general formula (XXV) to the 4-oxy-cyclopent-2-en-1-one of the general formula (XXIV) is preferably carried out at room temperature for a period of 12 to 24 hours. accomplished. This reaction is also advantageously carried out in an ether solvent such as diethyl ether, dibutyl ether, tetrahydrofuran and the like. The alanate-enolate adduct obtained as an intermediate is then carefully hydrolyzed in situ with dilute hydrochloric acid with cooling, after which the product of the general formula (XXVI) is isolated in the customary manner. The tetrahydropyranyl protective groups and the iriphenylmethyl protective group can then be removed by treatment with a weak acid. A preferred method is to keep the material at 45 ° C during

409847/1159

3.5 hours in a solvent system consisting of an acetic acid-tetrahydrofuran-Vfessei'-mixture in a ratio of 4: 2: 1 to srhitsen. ¥ enn as a compound of the general formula (XXVI) a tetrahydropyranyl ester is used, the Irosteneic acid (compound of the general formula XXVII, in which represents the group R "., a hydroxyl group).

The invention. 9-keto derivatives of the general formula (XXYIII) can be converted into the corresponding 9-hydroxy derivatives ■ be convicted. If this conversion with sodium borohydride takes place, the product obtained is a mixture of the 9Grund 93-IIydroxy derivatives of the general formulas (XXIX and XXX), v / as also in the following reaction scheme D is specified. -

AO9847 / 1159

RiSAKTICVSSCHEMA D

(XXIX)

OH

Il

ZCR ₄

ORg

409847/1159

Ir, the Eeaktionsschema D own the groups

Ii ,, IU, Z and -C -, - CM- üie meanings given above .. Who · ::, can the reaction with Lithiu ^ i-.perhydro-9'b.-borarheriylyl-hycrid (HC Brown and V, ^r .C. Dickason, Journ. Aner. -Chora. Sec, 92, 709 (1970)), the product consists predominantly of the 9 <x -hydroxy derivative of the general romel (ΧΣΙΧ), ΐη which is the 9-hydroxy group in cis Position to the side chain bonded to the Cq atom and the 1 - oxy group.

The compounds according to the invention which have the -CH _O -CH _O group as the group -C - C ₁ - can be prepared by catalytic reduction sus the corresponding Δ derivatives obtained by the alanate process, preferably at low pressure with the aid of a noble; metal catalyst in an inert solvent at Rc.uTStenrpera / bur. ^

According to a general convention, the ct-substituent is in the 8-, 9-, 11- or 12-position behind the plane of the paper ^{in a: n or: r.el, while the ß-substituent at this point "is above"} This is usually indicated by an oc substituent

a dashed bond (), in the case of a ß-substituent

through a soaked bond () and if both

jo ^ should just be verden, indicated by a serpentine line (-—- ^). "Thus the 9-hydroxy derivatives can be prepared as follows • 1 ar'cf:

^H v

9a-hydroxy 93-hydroxy 9a / β-hydroxy

4098A7 / 115

The compounds of the invention are hypotensive agents, {stimulate the ulcer-forming smock, means for Treatment of gastric irypersecretion and gastric erosion, bronchiodiladatbren, antimicrobial agents, anticoivulant agents Means, abortion drugs, means to induce childbirth, means to induce menstruation, Means of controlling fertility, means of regulating the central nervous system, analgesic means, Salt- and water-retaining agents, diuretics, the metabolism regulating agents, gowns that lower the serum cholesterol level, anti-inflammatory agents Agents and agents for inhibiting platelet aggregation for the treatment of periodontal diseases, G-luccmen, for uveitis. sickle cell anemia and psoriasis. Certain of the new inventive compounds are as Intermediates for the preparation of other compounds according to the invention are suitable.

The compounds according to the invention also result in a Schute against the ulcerogenic properties of certain non-steroidal anti-inflammatory. acting agents, e.g. Indomethacin, aspirin, and phenylbutazone.

The agents according to the invention are suitable as hypotensive agents, their hypotensive effects can be demonstrated using the following test procedure. This method i -.-. t a modification of the Pike et al. described Technique (Prostaglandins, Nobel Symposium 2, Stockholm, June 1966, p. 165).

Male rats (Wistar strain, Royal Hart Parais) are attached to boards with a ¹ ? Then lidocaine infiltrates the thigh area subcutaneously and exposes the iliac artery and vein

409847/1159

introduces Ka.mileil. The (syOtolic / diastolic) arterial blood pressure is _{measured using an appropriate measuring device (Statham P?} ~ Db), the animals being anesthetized intravenously with 30 mg pentobarbital / kg body weight and at the same time intravenously treated with 2 mg hexariethoxiurabitartrate / kg body weight before use. The 'lestverbindungen are produced by ultrasound dispersion in a saline solution-polyoxyethylene sorbitan monooleate carrier material (Twesn 00). At a constant
The compounds to be examined are administered in doses of 0.1 to 10.0 mg / kg of body weight to a dose volume of 0.5 ml introduced intravenously. Depending on the effect achieved, increasing or decreasing doses are given.

The compounds according to the invention, such as 9-0xo-1 la-methoxy-15-hydroxy-13-trans-prostenic acid, 9-0xo-1ia-methoxy-15-hydroxy-15-methyl-13-trans-prostenic acid, 9-0xo- 11a-methoxy-15-hydroxy-i6, i6-dimethyl - 1;> - trans ~ prostenic acid, 9-0xo-1 la-niethoxy-15-hydroxy-1 ^ -trans-IT-cis-prostadic acid,
"9-OxO- ^ - OXa-1 .ia-niethoxy-15-hydroxy-16,1'6-dimethyl-13-trans-prostenoic acid, 9-0xo-11a-methoxy-" [5-hydroxy-15-methyl -17 »IS-cis-methano-13-trans-prostenic acid, 9-Οχο-11α-nethoxy-15-hydroxy-15-hydroxy-16,19-trans-ethano-13-transprostic acid, 9-0xo-1ia- ( 2-hydroxyethoxy) -15-hydroxy-13-trans-prostenic acid, 9-0xo-11a- (2-hydroxyethoxy) -15-hydroxy-16,16 ~ dimethyl-13-trans-prostenic acid and 9-0xo-11Ck- ( 2-hydroxyethoxy) -15-hydroxy-13-trar.s-17-cis-proatadienoic acid results in a decrease in diastolic blood pressure of about 10 πα at a dosage of 0.5 mg to about 2.0 mg / kg body weight .

The active ingredients according to the invention can be in the form of tablets verv-ends, the essential active ingredient with common tableting ingredients, such as corn starch, lactose,

409847/1159

Sucrose, sorbitol, talc, stearic acid, magnesium stearate, Dicalcurrent phosphate, rubber3 or similar, non-toxic, pharmaceutically acceptable diluents or carrier materials vsruiiacht will. Those in the form of tablets or pills present new compositions can be coated or otherwise formulated to provide a dosage form which has the benefit of a prolonged or delayed effect or a predetermined sequence of the effects of the included Medicines -possessed. For example, the tablet or Pills contain an inner and an outer dosage component, the latter in a porin shell and in the the former is arranged around. The two components can be separated by a layer to prevent decomposition resists in the stomach and allows the internal component to pass intact into the duodenum is released or is delayed. Various types of intestinal layers or coatings can be used to form such intestinal layers Materials are used, e.g. a series of polymeric acids or mixtures of polymeric acids with Materials such as shellac, shellac and cetyl alcohol, cellulose acetate and the like. A particularly "beneficial" one This type of coating comprises a styrene-maleic acid copolymer as well as materials that give the coating the intestinal properties.

The liquid formulations in which the compositions according to the invention can be administered include suitably flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil and the like as well as elixirs and similar pharmaceutical vehicles. Sterile suspensions can be used for parenteral use or solutions are prepared. Isotonic preparations containing suitable preservatives are also available desirable for injections.

409847/1159

The term "dosage form" as used in the present context stands for physically discrete units that can be administered to warm blood as a single dose, with each unit containing a predetermined amount of an active ingredient calculated in such a way as to that the desired therapeutic effect results in connection with the required pharmaceutical diluent, carrier material or vehicle Wirkstoffe.für the therapy indicated Ύοη warm-blooded animals existing restrictions in the specification. Examples of suitable oral erfindungsgemäS Dosierungsforraen 3ind tablets, capsules, pills, powder packets, granules, Via.fein, cachets, teaspoonfuls, Tropfflascheniü'.lungen, ibipullen, separate multiple units of penaniite forms of bias as well as e other proxy cases described. . .

The bronchodilatoric effect was determined in guinea pigs against bronchial spasms which were induced by intravenous injections of 5-kydroxytryptamine, histamine and acetyl chloride according to the method of Konzett v / vu. den (see J. Juli ing, P. Li evens & El Sayed and J. Pri;:; not, Arzneimittel-Forschung, J _- G, 995 (1968)).

9-Oxo-i 1a-: cethoxy-15-hydroxy-13-trans-pro "stanoic acid shows - :; o _c " er the three spasmodic agents have a bronchodilatoric effect, expressed as ED ^ ₀ in mg / kg of 0.149, C, COS-. tsw ... .0.0936, whereby these values were determined with the help of three intravenous doses that were cumulative in an intravenous way,

The following examples are intended to further illustrate the invention

tern.

409847/1159

In the following examples, unless otherwise indicated, the products obtained include all possible optical isomers.

Beis-niel

Production of 2- (6-carboxy-6-fluorohexyl) -cyclopent-2-en-

1 -cn

This cyclic pentenone is obtained according to the BS-PS 786 215 described preparation of 2- (6-carboxyoctyl) -cyclopent-2-en-1-one by replacing the ethylmalonic acid di-ethyl ester through the fluoromalonic acid diethyl ester.

Example2

Production of 2- (6-carboxy-6-phenylhexyl) -cyclopent-2-

en-1-on

This cyclopentenone is obtained according to that in the BE-PS 786 215 "for the preparation of 2- (6-carboxyoctyl) -cyclopent-2-en-1-one by replacing the ethyl alcoholic acid diethyl ester by phenylmalonic acid diethyl ester.

Example 3

ng of 2- (6-carboxyheptyl) -cyclopent-2-sn-1 «-one

This Ö3 * clopenteron obtained by the process described in the BS-PS 736 2 ^ 5 procedure for preparing vcn 2- (6-Carboxyheptyl) -cyclcpent-2-en-1-one by replacing dfi £ Athylinalonsäure-diäthylesters by the Methylmalonoäure- diets ter.

A09847 / 1159

B is ρ ie 1 4

Preparation of 2- (6-carbo-n-butoxyhexyl) -cyclopent-2-en-

1-ΟΊΐ

A solution of 50 g of 2- (6-carboxyhexyi) -cyclopent-2-en-1-one (Bagli et al., Tetrahedron Letters, No. 5, 465 ("1966)) in 1400 is left in a closed flask ml of n-butanol containing 2.7 g of p-toluenesulfonic acid monohydrate stand for about 24 hours at room temperature, then the solution is evaporated to dryness, the residue is taken up with ether and the ethereal solution is washed several times with a salt solution, dried with anhydrous magnesium sulfate, concentrated to dryness and obtained the desired butyl ester.

Examples

5-7

Treatment of 2- (6-carboxyhexyl) -cyclopent-2-en-1-one following the procedure of Example 4 with the appropriate alcohols results in those given in Table I below Ester:

TABLE Σ

example

alcohol

Isopropanol

Methanol

1-kydroxy-ndecane

Ester product

2- (6-Carboisopropoxyhexyl) cyclopent-2-en-1-one

2- (6-carbomethoxyhexyl) cyclopent-2-en-1-one

2- (6-Garbo-n-decyloxyhexyl) -cyclopent-2-en-i-one

409847/1159

Example- 8

Preparation of 4-bromo-2- (6-carboxyhexyl) -cyclopent-2-en-1-one

A mixture of 35.9 g (0.171 mol) of 2- (6-carboxyhexyl) -cyclopent-2-en-1-one is kept (Bagli et al., Tetrahedron Letters, Ko. 5, 465 (1966)), 35.0 g. (0.197 mol) n-bromine- ' succinimide and 600 ral carbon tetrachloride for 35 min. with stirring at reflux. Then you cool the mixture 5 C and filtered it. The! Filtrate is made with cold water washed, dried over magnesium sulfate and evaporated to dryness to form an oil.

i ^ ^H = 225 m / rev (885C);

max. = 1705 (cartonyl groups) and 1625 cm (olefin group).

Example 9-32

In the same way as described in Example 8, the The cyclopentenones given in Table I-A below are converted into the corresponding 4-bromo derivatives:

409847/1159

TABLE I-A-

Example

Starting cyclopent-2-en-1-one

2- (6-Carbethoxyhexyl) -cycIopent-2-en-i-one *

2- (6-Carboinethoxyhexyl) -cycloperit-2-en-1-one
(Example 6)

2- (4-Carbethoxybutyl) -cyclopent ^ -en-i-one *

2- (3-Carbätlaoxypropyl) cyclopent-2-en-i-one *

2- (4-carbon oxybutyl) -cyclopent-2-en-i-one *

2- (3-Garboyypropyl) -cyclopont-2-en ~ 1-one *

2- (8-Garboxyoctyl) -cyclopent-2-en-1-one *

2- (e-Carbethoxycctyl) · cyclopent-2-en-1-one *

2- (6-Carboxyoctyl) -c; / "clopent-2-en-1 -on *

2- (6-Carbethoxyo c tyl) ■ cyclopent-2-en-1-one *

2- (6-carboxy-5,5-di-Eiethj / iliexyl) -cyclopent-2-en-1-one *

2- (6-carbethox; / - 5.5-. diinethylhexyl) -cyclop ent-2-en-1-on *

2- (6-carboxy-5-oxahexyl) -cyclopent-2-

en-1 — on *

4-bromocyclopentenone product

4-3rom2- (6-carbethoxyhexyl) ■ cyclopent-2-en-1-one

4 ^ Βγοιπ-2- (6-carbomethoxyhexyl) ~ cyclopent-2-en-1-one

4-Bromo-2- (4-carbethoxybutyl) cyclopent-2-en-1-one

4-bromo-2- (3-carbethoxy-

propyl) -cyclopent-2-en-1-

4-Bromo-2- (4-carboxybutyl) cyclopent-2-en-i-one

4-Bromo-2- (3-ca'boxypropyl) cyclopent-2-en-1-one

4-3rora-2- (8-carboxyoctyl) -cyclopent-2-en-1-one

4-Bromo-2- (8-carbethoxyoctyl) cyclopent-2-en-1-one

4-broin-2- (6-carboxyoc tyl) eyclopent-2-en-i-one

4-3rom-2- (6-carbethoxyoctyl) cyclopent-2-en-1-one

4-Broai-2- (6-carboxy-5,5-dimethylhexyl) -cyclopent-2-en-1-one

4-bromo-2- (6-carbethoxy-5,5-

dimethylhexyl) cyclopent-2-en-1-one

4-3roE-2- (6-carboxy-5-oxahexyl) -cyclcopent-2-en-1-one

Α098Α7 / Π59

TABLE I-A (continued):

example

Starting

cyciopent-2-en-1-one

2- (6 ~ Car "bethoxy-5-oxah.e: cyl) -cyclopent-2-en-

1 -on *

2- (6-Carboxy-6-fluorohycxyl) -cyclopent-2-en-1-one
(Example 1)

2 - (5-G art ο xyp entyl) -C3'clopent-2-en-1-one *

2- (5-carbonyl type ent jri) C7 / clopent-2-en-1 -on *

2- (7-carboxyheptyl) -C3'clopent-2-en-1 -on *

2- (7-Carbethoxyheptyl) -cvclooent-2 ~ en-1-one *

2- (6-Carboxy-6-phenylhexyl) -cyclopent-2-en-1-one
(Baiepiel 2)

4-bromocyclopentenone product

4-3rom-2- (6-carbethoxy-5-oxahexyl) -cyciopent-2-en-1-one-

4-Broin2- (6-carboxy-6-

riuorhexyl) cyclopent-2-en-1-one

4-bromo-2- (5-carfccxypentyl) cyclopent-2-en-i-one

4-bromo-2- (5-car "ethoxy-

pentyl) cyclopent-2-en-1-

4-bromo-2- (7-carboxyheptyl) cyclopent-2-en-1-one

4-Bromo-2- (7-carbethoxyheptyl) -cyclopent-2-en-1-one

4-bromo-2- (6-carboxy-6-

phenylliexyl) -cyelopent-2-en-1-one

2- (G-Carbo-n-butoxyhexyl) -4-bromo-2- (6-carbo-n-butoxy-

cyclcper-.t-2: -9n-1 -cn (Example 4)

2- (6-Oarbo-isopropoxy hezrjl ) -cyclopent-2-en-1-one
Beiopiel "5)

2- (6-Carbo-n-decy3.ox3 '• -hexyl) -cyclopent-2-en-1-cn
(Example 7)

c- (ö-CarbojryTiep tyl) cyc-.lopent-2-en-i -one (l 3)

hexyl) cyclopent-2-en-1-one

4-Broni-2- (6-carbo-isopropoxyhexyl) -cyclopent-2-en-1-one

4-Broiü-2- (6-carbo-n-decyloxyhexyl ) -cyc.lopent-2-en-1-one

4-broin-2- (6-carboxyheptyl) cyclopent-2-en-1-one

* ■■ BeLg. Patent lir. 783 215 (January 15, 1973).

40 9847/1159

Example 33

Production of 4-methoxy-2- (6-carboxyhexyl) -cyclopent-2-

en-1 -on

To a stirred solution of 5.30 g of crude 4-bromo-2- (6-earboxyhexyl) ~ cyclopent-2-en-1-one (Example 8) in 85 ml of methanol are added at 0 to 3 ° C in one portion of 4.40 g (22.6 DiMoI) silver fluorate. After 2 minutes you treat the Mixture with 2.66 g (24.8 mmol) 2,6-lutidine. After 50 minutes Allowing to stand at 0 to 3 ° C., the mixture is stirred for 45 minutes. Room temperature. Then you remove that Silver bromide by filtration and the filtrate is concentrated Volume of 40 ml. The solution becomes saturated with Treated sodium chloride solution and extracted with ether. The extract is successively mixed with 0.5N hydrochloric acid solution, Washed water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The partition chromatography of the residue over a filter aid (Gelite®) leads to. an oil * ■

= ²² ° ^ra / ^u (™ ⁵⁰ >'
^) max, = 1715 (carbonyl groups) and 1095 cm ~ (methoxy groups).

B ei s ρ i e 1 e 34 .- 61

The alcoholysis of the 4-bromocyclopentenones given in Table II below with the corresponding alcohol the manner given in Example 33 leads to the 4-alkoxycyclopentenones given in Table II below:

409847/1159

TABLE II

example

34

36 37 38

40 41 42 43 44 45 A6 47

Starting brqracyclopentenone of example

10 11 12 13 14 15 16 17 18 19 20 21 22 -Z-SH-I-On-Prοdukt

4-Ätlioxy-2- (6-carbethoxyhexyl) cyclopent-2-en-1-orL

4-Methoxy-2- (6-carbomethoxyh.exyl) cyclopent-2-en-i-one

4-propoxy-2- (4-carbethoxybutyl) cyclopent-2-en-i-one

4-Isopropoxy-2- (3-carbethoxypropyl) -cyclopent-2-en-1-one

4-Kethoxy-2- (4-carl> oxybutyl) -cyclopenta-en-1-one

4-A * thoxy-2- (3-carboxypropyl) -cyclopent-2-en-1-one

4-Hethoxy-2- (8-carl3Oxyoctyl) -cyclopent-2-en-1-one

4-Isopropoxy-2- (8-carbethoxyoctyl) cyclopent-2-en-i-one

4-methoxy-2- (6-carboxyoctyl) -cyclopent-2-en-1-one

4-n-Butoxy-2- (6-carboxyoctyl) -cyclopent-2-en-1-one

4-methoxy-2- (6-carboxy-5,5-dimethylhexyl) -cyclopent-2-en-1-one

4-Kethoxy-2- (6-carbethoxy-5,5-dimethylhexyl) -cyclopent-2-en-1-one

4-Ethoxy-2- (6-carboxy-5-oxah.exyl) -cyclopent-2-en-1-one

4-ltlioxy-2- (6-carbath.oxy-5-oxah.exyl) -cyclopent-2-en-1-one

4098A7 / T159

TABSLLB II (continued):

When starting 4 alcohol: ycyclopent-2-en-1-one product game Ercaicyclo-

pentenon of.

example

23-4-methoxy-2- (6-carboxy-6-fluoro} iexyl) -

cyclopent-2-en-1-one

24 4-methoxy-2- (5-carboxypentyl) -cyclo-

pent-2-en-1-one

4-sec-butoxy-2-(5-carbäth.oxypentyl) -cyclopent-2-en-1-one

4-methoxy-2- (7-carboxyheptyl) -cyclopent-2-en-1-one

A-methoxy-2- (7-carT-ethoxyh.eptyl) -cyclopent-2-en-1-one

4-l'ietlioxy-2- (6-carboxy-6-ph.enylh.exyl) -cyclopent-2-en-i-one

4-riethox.y-2- (6-car'boxyh.eptyl) -cyclopent-2-en-1-one

4-Kethoxy-2- (6-car'bo-n-'butoxyhexyl) -cyclopent-2-en-1-one

4-Iethoxy-2- (6-carbo-isopropoxyhexyl) -cyclopGnt-2-en-t-one

4-24ethoxy-2- (6-carbo-n-a-ecyloxyhexyl) -cyclopent-2-en-1-one

4-Ethox3 '- 2- (6-carboxyh.exyl) -cyclopent-2-en-1-one

. & • 4-Propo: -: y-2- (6-carboxyh.exyl) -cyclo-

pent-2-en-1-one

£ 0 8 4-isopropoxy-2- (6-carboxyh.exyl) -cyclo-

pent-2-en-1-one

O 4-n-3utO3: y-2- (6-carboxyhexyl) -cyclo-. . υβηΐ-2-βη-1-οη

50 25th 51 26th 27 53 28 32 he, 29 56 30th 57 31 58 8th

409847/1159

B e is ρ ie 1 62

Production of 4-tert-butoxy-2- (6-carbethoxyhexyl) -cyclo pent-2-en-1-one

A mixture of 6.35 g (20 mmol) of 4-bromo (2-carbethoxyhexyl) cyclopent-2-en-1-one is heated (Example 9), 3.01 g (11 mmol) of silver carbonate and 40 ml of tert-butanol with stirring to 70 ° C. for 17 hours. Then the mixture is cooled and filtered. After the tert-butanol, the residue is mixed with an aqueous sodium chloride solution treated and with an ether-hexane mixture (3: 1) extracted. The extract is washed with saturated sodium chloride solution and dried over magnesium sulfate and narrowed. The crude product is purified by silica gel chromatography, which is followed by the sequence the elution receives the following compounds:

The title compound in the form of an oil (AlffS = 219 m / rev (0860);

^N ) n: ar. = 1735 (ester carbonyl group), 1725 (ketone carbonyl group) and 1365 cm (tert-butyl group)) and

4-Hydroxy-2- (6-carbethoxyhexyl) -cyclopent-2-enTi-one, the also occurs in the form of an oil.

Example 63

Production of 4- (2-hydroxyethoxy) -2- (6-carboxyhexyl) - cyclopent-2-en-1-one "

To a stirred solution of 19 »1 g of crude 4-bromo-2- (6-carboxyhexyl) -C3rclopent-2-en-1-one (Example 8) in 310 ml of ethylene glycol are added in the course of 2 minutes. 15.6 g (30 mmoles) silver fluorate. The exothermic reaction is controlled so that a temperature of 29 ° C results, after which the mixture after 1 min. For 1 min. With

409847/1159

0.6 g (80 nmoles) of 2,6-lutidine. Then you stir them ! ■ mixture for 2 hours at room temperature, dilute it with Water and filter it. The filtrate is diluted with a saturated sodium chloride solution and extracted with ether. The extract is mixed with a half-saturated sodium chloride solution containing a small amount of hydrochloric acid contains, and washed saturated sodium chloride solution. The extract is dried over magnesium sulfate and concentrated. Column chromatography of the residue over silica gel gives an oil:

V max. = 3340 (hydroxyl groups), 1700 (carbonyl groups) and

_ -ι
1620 ca (olefin group).

Examples 64-85

Following the procedure described in Example 63, the in the following Table III indicated various 4-Bromcyclopentenone with the corresponding diol in the corresponding 4- (q-hydroxyalkyl) -cyclopentenones of Table III transferred:

409847/1159

- pa -

TABLE III

en-1-on product

4-ß-Hydroxyethoxy-2- (6-carbethoxyhexyl) -cyclopent-2-en-1-one

4-ß-Hydroxyethoxy-2- (6-carbomethoxyhexyl) -cyclopent-2-en-1-one

4-Y-hydroxypropoxy-2- (4-carbätnoxybutyl) -cyclopent-2-en-1-one

4-ß-Hydroxyethoxy-2- (3-carbethoxypropyl) -cyclopent-2-en-i-one

4-ß-Hydroxyethoxy-2- (4-carboxybutyl) -cyclopent-2-en-1-one

4-ß-Hydroxyethoxy-2- (3-carboxypropyl) -cyclopent-2-en-1-one

4-ß-Hydroxyethoxy-2- (8-carboxyoctyl) -cyclopent-2-en-1-one

4-ß-Hydroxyethoxy-2- (8-carbethoxyoctyl) -cyclopent-2-en-1-one

4-ß-Hydroxyethoxy-2- (6-carboxyoctyl) -cyclopent-2-en-1-one

4-Y-hydroxypropoxy-2- (6-carbethoxyoctyl) -cyclopent-2-en-1-one

4-ß-Hydroxyethoxy-2- (6-carboxy-5,5-dimethylhexyl) -cyclopent-2-en-1-one

75 20. 4-ß-hydroxyethoxy-2- (6-carbethoxy-

5,5-dimethylhexyl) cyclopent-2-en-1-one

76 21 4-ß-hydroxyethoxy-2- (6-carboxy-5-

oxahexyl) cyclopent-2-en-i-one

at
game Starting 4-bromo
cyclopentenone
of example 64 9 65 10 66 11 67 12th 68 13th 69 14th 70 15th 71 16 72 17th 73 18th 74 · 19th

409847/1159

TABLE III (continued):

Example starting 4-broin-4- (ω-hydroxyalkoxy) -cyclopent-2-game cyclopentanone en-1-one product of example

77 22 4-y-hydroxypropoxy-2- (6-carb-

ethoxy-5-oxahexyl) cyclopent-2-en-1-one

4-ß-Hydroxyethoxy-2- (6-carboxy-6-fluorohexyl) -cyclopent-2-en-1-one 4-ß-Hydroxyethoxy-2- (5-carboxypentyl) -cyclopent-2-en-1-one, 4-ß-Hydroxyethoxy-2- (7-carboxyheptyl) -cyclopent-2-en-i-one 4-ß-Hydroxyethoxy-2- (6-carboxy-6-phenylhexyl) -cyclopent-2-en-1-one 4-ß-Hydroxyethoxy-2- (6-carbo-n-butoxyhexyl) -cyclopent-2-en-i-one 4-ß-Hydroxyethoxy-2- (carbo-isopropoxyhexyl) -cyclopent-2-en-1-one 4-ß-hydroxyethoxy-2- (6-carbo-

n-decyloxyhexyl) -cyclqpent-2-en-

1-on

35 .8 4-ß-Hydroxypropoxy-2- (6-carbo-

hexyl) cyclopent-2-en-1-one

73 23 79 24 80 26th 81 28 82 29 83 30th 84 31

409847/1159

S e i s ρ i e 1 86

Of 4-.beta.-tetrahydropyran-2'-yl-oxy-ethoxy-2- (6-carbotetrahydrcpyran-2'-yl-OX5 ^r hexyl) cyclopent-2-en-1-one Prepared

To a stirred solution of 5-59 g of 4- (2-hydroxyethoxy) -2- (6-carboxyhexyl) cyclopent-2-en-1-one (Example 63) and 20.7 g (246 mmol) of dihydropyran in 100 ml of methylene chloride are added at 20 ⁰ O in one portion 47 mg (0.246 mmol) of p-toluenesulfonic acid-MOE-ohydrat. The temperature is maintained by cooling at 20 to -25 ° C. and stirred for 1 hour at this temperature. The solution is then diluted with 200 ml of ether and poured into a mixture of 40 ml of saturated sodium bicarbonate solution, 40 ml of saturated sodium chloride solution and 80 ml ml of water. Han separates the phases and extracts the aqueous phase with further ether. The combined extracts are washed successively with water and saturated sodium chloride solution, dried over potassium carbonate and freed of volatile materials by evaporation under reduced pressure to form an oil VO ?!

= 223 nyu (9500);

"^ max. 1730 (ester carbonyl group), 1705 (ketone carbonyl group) and 1030 cm "(tetrahydropyranyloxy groups).

Examples 87-102

Following the procedure given in Example 86, the 4-alkoxycyclopentenone carboxylic acids given in Table IV below are obtained converted into the corresponding listed tetrahydropyran-2'-yl esters:

409847/1159

TABLE IV

Example of starting 4-alkoxy-tetrahydropyran-2'-ylcyclopentencn-carbon ester product of the acid of Example ⁱ l-alkoxycyclopent ~ 2-ene-

1-on

p; ₇ vo 4-methoxy-2- ( ⁱ i-carbote-

^J trahydropyran-2'-yloxy-

butyl) cyclopent-2-en-1- -on

4-ethoxy-2- (3-carbote-

^bd 39 trahydropyran-2 ^l -yloxy-

propyl) cyclopent-2-en-1 -on

4-M.ethoxy-2- (8-carbote-

"2 ^ ⁰ trahydropyran-2 ^l -yloxy-

octyl) cyclopent-2-en-1- -on

4-methoxy-2- (6-carbote-

^ ² trahydropyran-2'-yloxy-

octyl) cyclopent-2-en-1- -on

4-methoxy-2- (6-carbote-

^ ¹ ^ trahydropyran-2'-yloxy-

-5,5-dimethylhexyl) cyclopent-2-en-1-one

4-methoxy-2- (6-carbote-

^ 6 trahydroxypyfan-2'-yl-

oxy-5-oxahexyl) cyclopent-2-en-1-one

4-methoxy-2- (6-carbote-

48 trahydropyran-2'-yloxy-

-6-fluorohexyl) cyclopent-2-en-1-one

4-methoxy-2- (5-carbote-

49. trahydropyran-2'-yloxy-

-pentyl) cyclopent-2-en- -1-on

4-methoxy-2- (7-carbote-

5i trahydropyran-2'-yloxy-

heptyl) cyclopent-2-en-1- -on

4-methoxy-2- (6-carbote-

53 trahydropyran-2'-yloxy-

-6-phenylhexyl) eyelopent-2-en-1-one

A09847 / 1159

2A2251 2

TABLE IV (continued):

Example starting - ^ - alkoxy-

cyclopentenone carboxylic acid of Example tetrahydropyran-2'-yl ester product des it-alkoxycyclopent-a-en-1-one

97

58

98

99

100

101

59

60

6l

33

102

5 ** ⁱ t-Xthoxy-2- (6-carbotetrahydropyran-2 '-yloxyhexyl) cyclopent-2-en-1-one

4-propoxy-2- (6-carbotetrahydropyran-2'-yloxyhexyl) cyclopent-2-en-1- -on

^ -Isopropoxy - ^ - (6-carbotetrahydropyran-2 '-yloxyhexyl) eyelopent-2-en- -1-on

¹ fn-Butoxy-2 ~ (6-carbotetrahydropyran-2 '-yloxyhexyl) eyelopent-2-en-1-one

4-methoxy-2- (6-carbotetrahydropyran-2'-yloxyhexyl) eyelopent-2-en-1- -on

4-methoxy-2- (6-carbotetrahydropyran-2'-yloxyheptyl) cyclop ent-2-en-l- -one

Α09847 / Ί159

■ Examples 10? - 124

i) The treatment of those given in Table V. 4- (ω-Hydroxyalkoxy) -cyclopentenones with dihydropyran in the procedure given in Example 86 gives the 4 - («I-tetrahydropyranyloxyalkoxy) cyclopentanone esters given in Table T below:

409847/1159

TABLE V

Example output 4- (ω game hydroxyalkoxy) -cyclopentenone from BeiSOiel

• 103 104 105 106 '107

108

109 110

111

112

64

65

66 ·

67

68

69

71

70

72

73 4- (ω-Tetrahydropyran-2. -Yl-oxyalkoxy) -cyclopent-2-en-1-one ester product

4-ß-Tetrahydropyran-2 ^l -yl-oxyethoxy-2- (6-carbethoxyhexyl) -cyclopent-2-en-1-one

4-ß-Tetrahydropyran-2 ^f -yl-oxyethoxy-2- (6-carbomethoxyhexyl) -cyclopent-2-en-1-one

4-y-Tetrahydropyran-2'-yl-oxypropoxy-2- (4-carbethoxybutyl) -cyclopent-2-en-i-one

4-β- ⁱ tetrahydropyran-2 '-yl-oxyethoxy-2- (3-carbethoxypropyl) -cyclopent-2-en-1-one

4-ß-Tetrahydropyran-2-yoxyethoxy-2- (4-carbotetrahydropyran-2'-yl-oxybutyl) -cyclopent-2-en-1-one

4-ß-tetrahydropyran-2'-yl-oxyäthoxy-2- (3-carbotetrahydropyran-2 ^J-oxypropyl -yl) cyclopent-2-en-1-one

4-ß-Tetrahydropyran-2'-yl-oxyethoxy-2- (8-carbethoxyoctyl) -cyclopent-2-en-1-one

4-ß-Tetrahydropyran-2. -Yl-oxyethoxy-2- (8-carbotetrahydropyran-2 "-Yl-oxyoctyl) -cyclopent-2-en-1-one

4-ß-Tetrahydropyran-2. -Yl-oxyethoxy-2- (6-carbotetrahydropyran-2 * -yl-oxyoctyl) -cyclopent-2-en-1-one

4-γ-Tetrahydropyran-2'-yl-oxypropoxy-2- (6-carbethoxyoctyl; -cyclopent-2-en-i-one

A098A7 / 1159

TABLE V (continued):

Example from 4- (ω game hydroxyalkoxy) -cyclopentenone of example

114

115

116

117

118

119

120

121

- 74

75

76

77

78

80

81

82 4- (w-Tetrahydropyran-2'-yl-oxy-

alkoxy) cyclopent-2-en-1-one ester product

4-ß-Tetrahydropyran-2 »-yl-oxyethoxy-2- (6-carbotetrahydropyran-2'-yl-oxy-5,5-diraethylhexyl) -cyclopent-2-en-i-one

4-ß-tetrahydropyran-2'-yl-oxyethoxy-2- (6-carbethoxy-5,5-diraethylhexyl) -cyclopent-2-en-i-one

4-ß-Tetrahydropyran-2'-yl-oxyethoxy-2- (6-carbotetrahydropyran-2 »-yl-oxy-5-oxahexyl) -cyclopent-2-en-1-one

4-γ-Τβtrahydropyran-2'-yl-oxypropoxy-2- (6-carbethoxy-5-oxanexyl) -cyclopent-2-en-1-"On

4-ß-Tetrahydropyran-2'-yl-oxyethoxy-2- (6-carbotetrahydropyran-2'-yl-oxy-6-fluorohexyl) -cyclopent-2-en-1-one ··

4-ß-Tetrahydropyran-2'-yl-oxyethoxy-2- (5-carbotetrahydropyran-2'-yl-oxypentyl) -cyclopent-2-en-1-one

4-ß-Tetrahydropyran-2'-yl-oxyethoxy-2- (7-carbotetrahydropyran-2'-yl-oxyheptyl) -cyclopent-2-en-1-one

4-ß-Tetrahydropyran-2 »-yl-oxyethoxy-2- (6-carbotetrahydropyran-2 · -yl-oxy-6-phenylhexyl) -cyclopent-2-en-1-one

4-ß-Tetrahydropyran-2-yoxyethoxy-2- (6-carbo-n-butoxyhexyl) -cyclopent-2-en-1-one

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TAB5LLE V (continued):

At- starting 4- (tospiel hydroxyalkoxy) cyclopentenone of Example 4- (ω-tetrahydropyran-2'-yl-oxyalkoxy) -cyclopent-2-en-i-one ter product

122

123

124

84

85 4-ß-tetrahydropyran-2 ^! -yl-oxyethoxy-2- (5-carbo-isopropoxyhexyl) · cyclopent-2-en-i-one

4-ß-Tetrahydropyran-2'-yl-oxyethoxy-2- (δ-carbo-n-decyloxyhexyl; -cyclopent-2-en-1-one

4-ß-Tetrahydropyran-2'-yl-oxypropoxy-2- (6-carbotetrahydropyran-2 * -yl-oxyhexyl) -cyclopent-2-en-1-one

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B e i s ρ i e 1 125

Preparation of 4- (4-hydroxybutoxy} -2- (6-carbpxyhexyl) -cyclopent -2-en-1-one

To a solution of 56.0 g of crude 4-bromo-2- (6-carboxyhexyl) -cyclopent-2-en-1-one (Example 8) in 400 ml of tetrahydrofuran and 133 ml of water is added with stirring at 3 ° C im Over the course of 25 minutes, 44.1 g (0.226 mol) of silver fluoborate were added. The mixture is stirred for 60 minutes at 0-5 ^° C., diluted with water and ether and filtered. The aqueous portion of the filtrate is saturated with solid sodium chloride and extracted with further ether. The combined organic phases are washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. Column chromatography of the residue gives the title compound in the form of a mixture with 4-hydroxy-2- (6-carboxyhexyl) -cyclopent-2-en-1-one. KIO spectrum (CDCl *) 3.60 (multiplet, O-methylene protons) and 4.60 γ (multiplet, O-methine proton).

Example ■ '* 126

Preparation of 4- (4-tetrahydropyranyloxybutoxy) -2- (6- tetrahydropyranylcarboxyhexyl) -cyclopent-2-en-1-one

In the procedure given in Example 86, the mixture of 4-hydroxy-2- (6-carboxyhexyl) -cyclopent-2-en-1-one and 4- (4-hydroxybutoxy) -2- (6-carboxyhexyl) - cyclopent-2-en-1-one (Example 125) with dihydropyran and p-toluenesulfonic acid monohydrate in methylene chloride in a mixture of the title ^{compound and 4-tetrahydropyranylox3 r} -2- (6-tetrahydropyranylcarboxyhexyl) -cyclopent-2-en-1 -on.

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Example 127

Preparation of 3-iriphenylmethoxy-1-octyne

Heating a mixed breed of 1.26 g (10.0 mmol) of i-octyn-3-ol, 4 j 85 g (15.0 mmol) of triphenylmethyl bromide and 50 ml of dry pyridine for 60 min. With occasional agitation at 95 ⁰ C The solution is cooled, treated with water and extracted with ether. The extract is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The crude product is purified chromatofraphisch over a highly selective absorbent (Magnesiuinsilikatgel, Plorisil ^) and recrystallization from petroleum ether to give white crystals occur with a melting point of 65-66 ⁰ C.

\Max. (KBr) 3280 (acetylenic hydrogen), 1605, 1030 and 702 cm ~ (triphenylmethoxy group).

Example 128

Production of i-iodo-3-triphenylmethoxy-trans-i-octene

To a mixture, cooled to -5 ° C., of 0.650 g (16.91 mmol) of sodium borohydride and 3.17 g (45.2 mmol) of 2-methyl-2-butene in 40 ml of diglyme is added under an inert atmosphere in the course of 15 min. 3.24 g (22.6 mmol) of boron trifluoride etherate and the mixture obtained is stirred for 2 hours at ⁰ ° C. 8.32 g (22.6 mmol) of 3-triphenylmethoxy-icctin (Example 127) in 10 ml of diglyme, after which the cooling bath is removed and the mixture is stirred for 1.5 hours at room temperature. The mixture is ^{cooled to 0} ° C., after which 6.0 g of finely divided anhydrous trimethylamine oxide are added in the course of 10 minutes. You remove that

409847/1 159

Cooling wheel and stir the mixture for 0.5 hours at room temperature. Then the mixture is poured into 200 ml of a 15 "iifjen riatrium hydroxide solution and immediately a solution of 16 g (65 ml) iodine in 20 ml tetrahydrofuran is added and the mixture is stirred the mixture obtained for 0.5 hours. The organic phase is then separated off and the aqueous phase is washed with ether. The combined organic phases and washing liquids are decolorized with a 5% sodium thiosulphate solution, washed with saturated salt solution, dried over ITa _? SO. dried and evaporated. The residue is subjected to dry column chromatography over aluminum oxide using hexane as the eluant, after which the. Title compound is isolated in the form of an oil.

Examples "129-138

Following the procedure given in Example 127 are the various 3-hydroxy-1-alkynes given in Table VI below by treatment with triphenylmethyl bromide converted into the corresponding 3-triphenylmethoxy-1-alkynes :

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TABLE VI

At- starting 3-hydroxy-l-3-triphenylmethoxy-l-alkyne game alkyne-l-heptyne-3-ol product

129 l-heptin-3-ol 3-triphenylmethoxyhept in-1 130 l-hexyne-3-ol 3-triphenylmethoxyhept in-1 131 1-penta-3-oil 3-tripheny.lmethoxypentine-l 132 l-nonin-3-ol ^a 3-triphenylmethoxynonin-1 133 l-decyne-3-ol ^b 3-triphenylmethoxydec in-1 134 M-ethyl-1-octyn-3-ol 3-triphenylmethoxy-4-ethyl
octyne-1 135 4-methyl-l-heptine-3-
ol - 3-triphenyl methoxy-4-methy 1-
heptin-1- 136 7-methyl-6-en-1-octyne
3-ol ^c 3-triphenylmethoxy-7-methy1-
6-en-octyne-l 137 5,9-dimethyl-9-en-l-
decin-3-ol ^d 3-triphenylmethoxy-5,9 ~ di-
methyl-9-en-decyne-l 138 cis-5-en-l-octyne-3-
ol ^e 3-triphenylmethoxy-cis-5-en-
octyne-1

a- - M. Bertrand, Bull.Soc.Chim. France, 461 (1956).

b - F. Bohlmann and D. Ratz, Chem. Ber., 90, 2265 (1957).

c - U.S. Patent 3,452,105 (June 24, 1969); Chem. Abs., 71, 60678 (1969).

d - Sequin, Bull.Soc.Chim. France, £ 1, 948 (1945).

e - J. Fried et al., Jour.Amer.Chem.Soc. £ 4,44342 (1972).

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B. Eigpiel 13SA Manufacture of 3-methoxy-1-octyne

To an ice-cold solution of 63 g of i-octyn-3-ol in 300 ml of dimethoxyethane, 312 ml of a 1.6 M n-butyllithium solution in hexane are added dropwise under an inert atmosphere over the course of 1 hour then 145 g of methyl iodide and the mixture obtained is stirred for 24 hours hot
Room temperature and then heated for 1 hour
60 ⁰ C. The mixture is cooled and poured into dilute cold
Poured hydrochloric acid. Then the organic
Phase separated, washed with water and saturated salt solution, over KapSO. dried and evaporated to an oil. Fractional distillation of the oil in vacuo gives the product in the form of a colorless oil.

Examples 139-148

The treatment of the "1-alkynes given in the following Table VII" with (prepared in situ from 2-methyl-2-butene, sodium borohydride and boron trifluoride) disimylborane, trimethylamine oxide, iodine and aqueous sodium hydroxide according to the example
123, the 3-triphenylmethoxy-1-iodotrans-1-alkene products given in Table VII below are obtained:

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TABLE VII

Example starting

1-alkyne by example.

1-iodine-trans-l-alkene product

139

129

130

141 131 142 132 143 133 144 134 145 135 me 136 147 137 148 138 148A 133a

l-iodo-3-triphenylmethoxy-trans-1-heptene

l-iodo-3-triphenylmethoxy-trans-1-hexene

l-iodo-3-triphenylmethoxy-trans-1-pentene

l-iodo-3-triphenylmethoxy-trans-1-nonene

l-iodo-3-triphenylmethoxy-trans-1-decene

l-iodo-3-triphenylmethoxy-4-ethyl-trans-1-octene

1-iodo-3-triphenylmethoxy-4-methyltrans-1-heptene

l-iodo-3-triphenylmethoxy-7-methyl-trans-l, 6-octadiene

1-iodo-3-triphenylmethoxy-5,9-dimethyl-trans-1,9-decadiene

1-iodo-3-triphenylmethoxy-transl-cis-5- octadiene

l-iodo-3-methoxy-trans-l-octene

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Example 149

Preparation of 4,4-dimethyl-1-octyn-3-ol

To a solution of 20.2 g (0.220 mol) of a Lithiumacetylidätliylenediamine complex in 100 inl dry dimethyl sulfoxide gilit Kan (with cooling) 25.6 g (0.200 mol) 2,2-dimethyl-1-hexanal (which is prepared by the method of G. Stork and S. R. Dowd, J. Amer. Chem. Soc., 8jj, 2178 (1963) hat) in 25 ml of dimethyl sulfoxide as quickly

(Cooling) to maintain a temperature of 25 ° C. The mixture is then ^{kept at 25 °} C. for 2 hours and then poured onto ice and excess hydrochloric acid. The mixture is extracted with ether and the organic phase washed with water and saturated brine, over Na ₂ SO. dried and evaporated to an oil. -Distillation in vacuo gives the product in the form of a colorless oil.

Example 150

Preparation of 4,4-dimethyl-3-tetrahydropyranyloxy-1-octyne

To a solution of 23.1 g (0.150 mol) 4,4-dimethyl-1-octyn-3-ol (Example 149) one drop of phosphorus oxychloride is added to 126 g of freshly distilled dihydropyran and left the solution in a tightly closed flask for 20 hours at room temperature. Then 5 drops of triethylamine are added and the mixture is evaporated to an oil in vacuo. The oil is chromatographed over 600 g of silica gel, the product with a 5? igen solution of ethyl acetate eluted in benzene, resulting in a colorless oil.

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Example 151

Preparation of 4,4-dimethyl-1-; iodo-trans-1-octen-3-ol

233 to a ⁰ on O G O cooled, 43n solution of disiamylborane ml in.Diglyme are added under an inert atmosphere · 23.8 g (0.100 mol) of 4,4-dimethyl-3-tetrahydropyranyloxy-1-octyne (Example 150) . The mixture is allowed to warm to room temperature and is stirred for 3 hours at room temperature. Then, the solution is cooled to O ⁰ C and treated portionwise "with 22.5 g (0.30 mol) Triäthylaminoxyd in the V / else added, that a temperature of 0 to 5 ° 0 is maintained The mixture is then for 1 hour. Stirred at ⁰ ° C. and then poured into 150 ml of a 1N sodium hydroxide solution, whereupon a solution of 25.4 g (0.100 mol) of iodine in 60 ml of tetrahydrofuran is immediately added Then pour it into 500 ml of water. The mixture is decolorized by adding sodium thiosulphate and extracted with ether. The organic phase is washed with water and the solvent is removed in vacuo. The residue is stirred at room temperature for 20 hours with 900 ml of tetrahydrofuran / Acetic acid / water mixture (3: 1: 1) The solution is then evaporated in vacuo and the residue is chromatographed on silica gel using benzene containing 10 to 20 μl of ethyl acetate as the eluent.

Be. Game 152

Preparation of 4,4-dimethyl-1-iodo-3-triphenylmethoxy - trans- 1-octene

By treating 11.2 g (0.396 moles) of 4,4-dimethyl-i-iodotrans-1-octen-3-ol (Example 151) with 12.8 g of triphenyl bromide in 50 ml of pyridine and cleaning with a highly selective

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2A22512

tive absorbent (Kagensiumsilikatgel, Florisil ^) after the In the manner described in Example 127, the vanity compound is obtained.

Example 153

Preparation of 5,5-dimethyl-1-octyn-3-ol

The title compound is obtained by treating 20.2 g (0.220 mol) of the lithium acetylide-ethylenediamine complex in 100 ml of dimethyl sulfoxide with 25.6 g (0.200 mol) of 3,3-dimethylhexanol (which is prepared by the method of A.W. Burstahler, J.Amer.Chem.Soc., 82, 4681 (1960) hat) and distillation of the product according to the manner described in Example 149.

Example 154

Preparation of 5,5-dimethyl-3-tetrahydropyranyloxy-1-octyne

By treating 23.1 g (0.150 moles) of 5,5-dimethyl-1-octyn-3-ol (Example 153) with 126 g of dihydropyran and 1 drop of phosphorus oxychloride according to that in Example 150 indicated manner gives the title compound.

Example '155

Preparation of 5,5-dimethyl-1-iodo-trans-1-octen-3-ol

By gradually treating 23.8 g (0.100 moles) of 5,5-dimethyl-3-tetrahydropyranyloxy-i-octyne (Example 154) with 233 mg of a 0.43 M disiamylborane solution in diglyme, 22.5 g trimethylamine oxide, 150 ml 1N sodium hydroxide solution,

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25.4 g of iodine and 900 LiI of a tetrahydrofuran / acetic acid / water mixture (3: 1: 1) according to the method described in Example 151, the title compound is obtained.

Example 156

Hex-substitution of 5,5-dimethyl-1-; iodo-3-triphenylniethoxytraris-1-octene

By treating 6.0 g of 5 »5-dimethyl-i-iodo-trans-i-octene-1-.ol (Example 155) with 6.9 g triphenylraethylbroinide in 30 1.11 pyridine and purification over a highly selective Absorbent (magnesium silicate gel, Florisil '^) is obtained according to the procedure of Example 127, the title

cxnaung.

Example 157

Preparation of 1,1-dimethoxy-cis-3,4-ioethano-hexane (cis-1-ethyl-2- (2, 2-dimethoxyethyl) cycloprcpan)

Su an ethereal suspension of a zinc-silver pair, which nan according to the deia method of JM Danis, CG-irand and JM Conia. (Synthesis, 1974, 549) from 0.400 g of silver acetate, 400 ml of acetic acid, 68 g of zinc granules, full syllables and 6CO ml of ether is added dropwise to 136 g of Dij οdaethane at such a rate that the mixture comes to a moderate reflux. The mixture is then stirred at room temperature for 1 hour and over the course of 20 kins. 57.7 g of 1,1-dimethoxy-cis-3-hexene (M. Winter, Helvetica Chimica Acta, 46>, 1792 (1963)) are added, after which the mixture is refluxed for 5 hours. The mixture is then cooled to 0 ⁰ C, was added iither ml at 600, after which is added in the course of 1 hour. Dropwise 50.5 g of pyridine. The precipitate obtained is

A098A7 / 1159

filtered off -and washed with ether. The filtrate and the Wash liquids are combined and evaporated, after which the residue is fractionally distilled at a pressure of 12 Torr the title compound is obtained in the form of a colorless oil.

example

Production of cis-3,4-methano-1-hexanol

To a vigorously stirred solution of 31.6 g of 1,1-dimethoxycis-3,4-methano-he2can (Example 157), 75 mg of hydroquinone and 6 g of oxalic acid in 150 ml of acetone are added at 45 ° C. an inert atmosphere in the course of 0.5 hours. 700 ml of water. The mixture is cooled and extracted applies with Ether. The organic phase is separated off, washed with saturated sodium bicarbonate solution and saturated salt solution, via NapSO. dried and evaporated. The residue is distilled at a pressure of 30 torr, whereby the title compound is obtained.

Example 159

Preparation of cis-5,6-methano-1-octyn-3-ol

16.8 g (0.150 mol) of cis-3,4-methano-1-hexanol (Example 158) are added to a solution of 15.2 g (0.165 mol) of the lithium acetylide-ethylenediaain complex in 1.00 ml of dry dimethyl sulfoxide 25 ml of dimethyl sulfoxide at such a rate (with cooling) that a temperature of 25 ⁰ C is maintained. The mixture is then ^{left at 25 °} C. for 2 hours and then poured onto Sis and excess hydrochloric acid. The mixture is extracted with ether, the organic phase is washed with water and saturated salt solution, dried over EapSO and evaporated

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a Cl a. Distillation in vacuo gives the title compound in the form of a colorless oil.

■ Example 160

Preparation of 3-triphenylmethoxy-cis-5,6-methano-i-octyne

Mari heated a mixture of 13.8 g of cis-5,6-methano-1-octyn-3-ol (Example 159) and 33.0 g of triphenylmethyl bromide in 100 ml of pyridine for 1.5 hours under an inert atmosphere to 100 ⁰ C. The mixture is then cooled and filtered. Da3 Piltrat is distributed between ice water and ether. The organic phase is washed with cold dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated brine, over HapSO. dried and evaporated to an oil. The oil is dissolved in hexane and passed through 400 g of a highly selective absorbent (magnesium silicate gel, Florisil ^), after which the title compound is obtained in the form of a colorless oil after evaporation.

Example 161

Preparation of 1-iodo-3-triphenylmethoxy-cis-5,6-methano trans-1-octene

To. 160 ml of a ^{0.50 m solution of disiamytborane in diglyme, cooled to 0} ° C., are added under an inert atmosphere to 28.6 g (0.075 mol) of 3-triphenylmethoxy-cis-5,6-methano-1-octyne (Example 160) . The mixture is allowed to warm to room temperature and is stirred for 3 hours at room temperature. Then-the solution is cooled to, 0 ⁰ C, and are added in portions 16.9 g (0.225 mol) Triäthylaminox3rd to such that a temperature of 0 to 5 ° C results. The mixture is then stirred at 0 ° C. for 1 hour

409847/1159

and then pour it into 3OC ml of a 1N sodium hydroxide solution, after which a solution of 57 g (0.225 mol) of iodine in ISO ml of tetrahydrofuran is added. The mixture is then stirred for 0.5 hours at liaurateraperatur and then pours it in 1000 ml of water. The mixture is decolorized by adding Tatriurathi 0 sulfate solution and with ether extracted. The organic phase is washed with water and the solvent is removed in vacuo. The residue is determined by dry column chromatography on 1.5 kg of alulainium oxide purified using hexane as a solvent. The title compound is obtained in the form of a Oil.

Examples 162-168

The treatment of the Cax'boxaldehydes given in Table VIII below with lithium acetylide according to the in Example 159 followed by treatment of the resulting 3-hydroxy-1-alkynes with i'i.-iphenylraethylbromide following the procedure of Example 160 the 3- ^ riphenylmethoxy-1-alkyne products given in Table VIII below are obtained:

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TABLE VIII

Example starting carboxaldehyde

162 (2-cyclohexenyl) -
acetaldehyde- 163 (3-cyclohexenyl) -
acetaldehyde* 164 Adamantane-1-carbox-
aldehyde 165 2-cyclohexene-carbox-
aldehyde 166 3-cyclohexene
carboxaldehyde 167 Adamantane-2-carbox-
aldehyde** 168 (Adaraantyl-1 -) - acet
aldehyde

3-triphenylmethoxy-1-alkyne product

4- (2-cyclohexenyl) -3-triphenylme thoxy-1-but in

4- (3-cyclohexenyl) -3-triphenylmethoxy-1-butyne

3- (1-Adamantyl) -3-triphenylmethoxy-1-propyne

3- (2-Cyclophexenyl) -3-triphenylmethoxy-1-propyne

3- (3-Cyclohexenyl) -3-triphenylmethoxy-1-propyne

3- (2-Adamantyl) -3-triphenylmethoxy-1-propyne

4- (1-adamantyl) -1-butyne

* C.W. Whitehead et al., J.Org.Chem., 26, 2814 (1961)

** AH. Alberto, H. Wynberg and J.Strating, Synthetic Communications, £, 79 (1972).

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Examples 169-175

By treating those given in Table IX below 3-triphenylmethoxy-i-alkynes with disiamylborane, trimethylamine oxide, Iodine and aqueous sodium hydroxide according to the example 161, the 3-triphenylmethoxy-1-iodo-1-trans-alkene products given in Table IX below are obtained:

TABLE IX example

Starting 3-triphenylmethoxy-1-alkynes from Example 3-triphenylmethoxy-1-iod-1
trans-alkene products

169

170

162

163

171 164 172 165 173 166 174 167 175 168

4- (2-Cyclohexenyl) -3-triphenylmethoxy-1-iodo-1-trans-butene

4- (3-cyclohexenyl) -3-triphenylmethoxy-1-;} od-1-transbutene

3- (1-Adainantyl) -3-triphenylmethoxy-1-j od-1-trans-propene

3- (2-cyclohexenyl) -3-triphenylmethoxy-1-3 od-1-trans-propene

3- (3-Cyclohexenyl) -3-triphenylmethoxy-1-iodo-1-trans-propene

3- (2-Adamantyl) -3-triphenylmethoxy-1-iodo-1-trans-propene

4- (1-Adamantyl) -3-triphenylmethoxy-1-j od-1-trans-butene

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Example 176

Production of cyclopentylacetyl chloride

• To a solution of 50 g of cyclopentane acetic acid, which contains 2.9 ml of! {, !! - dimethylformamide, 51 U of thionyl chloride are added dropwise with stirring over the course of 15 minutes. After further stirring for 60 minutes removed the excess thionyl chloride in vacuo and distilling the remaining residue as the oil to give 55.4 g (97%) of the product obtained boiling point = 57-58 ⁰ C / 10 mm Hg.

Example 177

Preparation of 1-chloro-4-cyclopentyl-1-trans-buten-3-one

Place a three-necked flask fitted with a stirrer, a gas inlet tube, and one with a calcium chloride tube provided gas outlet tube is provided in an ice-water bath. Then you flush the system during 3 min. With acetylene. 150 ml of tetra-chlorinated carbon are then added to the flask and passed during 3 min. Acetylene on high speed. Then 59 g of aluminum chloride are added and the mixture is passed for 5 min. Acetylene through the mixture. The gas inlet tube is then protected with a calcium chloride drying tube Dropping funnel replaced. 55.4 g of cyclopentane acetyl chloride are then added over a period of about 20 minutes with stirring (Example 176) to the reaction mixture. Then replace the dropping funnel with the gas inlet tube and introduces acetylene gas with stirring at a rate greater than the saturation rate. To about 15 minutes the rate of absorption of the acetylene becomes very great, after which the acetylene is introduced so quickly becomes how it is absorbed. The introduction of acetylene

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. - 63 -

becomes during 45 minutes after the end of the rapid absorption (which lasts about 1 hour) continued.

The reaction mixture is then poured, with stirring, onto 430 g of ice + 180 ml of saturated sodium chloride solution. then the aqueous phase is extracted three times with ether, after which the combined extracts are washed with anhydrous magnesium sulfate dries and evaporates to dryness in vacuo. After adding 1.5g of hydroquinone, the oil obtained as a residue is distilled, 57 g (89%) of an oil being obtained. Boiling point = 67 to 69 ° C / 0.14 mm Hg.

Example 178

Preparation of 4-cyclopentyl-1-; iodo-1-trans-buten-3-one

A solution of 57 g of 1-chloro-4-cyclopentyl-1-trans-buten-3-one is stirred (Example 177) in 360 ml of acetone containing 55 g of sodium iodide for 18 hours at reflux. The mixture obtained is cooled and filtered, after which the mother liquor is evaporated to dryness The resulting oil is dissolved in ether, successively with water, dilute sodium thiosulphate solution and saturated sodium chloride solution, dried with anhydrous magnesium sulfate and dried to give 87 g (99/0 of an orange-colored oil evaporated to dryness. The vapor phase chromatography shows a peak.

Example 179

Production of 4-cyclopentyl-1-; iod-1-tran3-buten-3-ol

To a solution of 7.1 g of sodium borohydride in 60 ml of absolute ethanol is added with stirring in an ice bath and drop white in the course under a nitrogen atmosphere

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of about 2 hours of a solution which contains 87 g of 4-cyclopentyl-1-iodotran-buten-5-one (Example 178) in 160 ml of absolute alcohol. The temperature is maintained at 5 to 10 ⁰ C. The solution is then poured into 850 ml of ice water, after which the mixture obtained is extracted three times with ether. The combined extracts are washed with a dilute sodium bisulfite solution and a saturated sodium chloride solution, dried with anhydrous magnesium sulfate and evaporated to dryness, 81 g of a yellow oil being obtained. Column chromatography of the oily product over a column filled with 1 kg of silica gel using benzene as the eluant gives 75 g (68 #) of the oily product.

Example 180-199

The treatment of the carboxylic acids listed in the following Table X with thionyl chloride according to the procedure described in Example 176 method, followed by treatment of the acid chloride obtained with acetylene by the method of Example 177 _f of the performed thereafter treating the resulting 1 -Chlor'- 1-trans -alken-3-one with sodium iodide according to the method of Example 178 and similarly by treating the 1-iodo-i-transalken-3-one obtained with sodium borohydride according to the method of Example 179, the 3- Hydroxy-i-i-i-i-i-trans-alkene products:

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TABLE X

At the starting carboxylic acid 3 ~ hydroxy-l-iodine-l-tran3-alkene play product

Cyclobutylacetic acid *

3 ~ cyclopentylpropion-

iJ-Cyclopentylbutyric acid ^

5-cyclopentylpentanoic acid 2

6-cyclopentylhexane-2

2-methyl-3-cyclopentylpropanoic acid ^

2-ethyl-4-cyclopenty! Butyric acid ^

(2-trans-methylcyclopentyl) acetic acid

Cyclohexyl acetic acid

3-cyclohexylpropionic acid

4-cyclohexylbutyric acid

• 7 cycloheptylacetic acid

Cyclooctyl acetic acid ⁸ 9

(4-methylcyclohexyl) -

(3-Methylcyclohexyl) acetic acid * ¹ ^ J-Cyclobutyl-3-hydroxy-ljod-1-trans-butene

5-cyclopentyl-3-hydroxy-1-iodo-1-trans-pentene

6-Cyclopentyl-3-hydroxy-1-iodo-1-trans-hexene

7-cyclopentyl-3-hydroxy-1-iodo-1-trans-heptene

8-Cyclopentyl-3-hydroxy-1-iodo-1-trans-octene

5-Cyclopentyl - ^ - methyl-3-hydroxy-1-iodo-1-trans-pentene

6-Cyclopentyl-4-ethyl-3-hydroxy-i-j, od-l-trans-hexene.

¹ l- (2-trans-methylcyclopentyl) -3-hydroxy-1-j od-1-trans-butene

4-Cyclohexyl-3-hydroxy-1-iod-1-trans-butene

5-cyclohexyl-3-hydroxy-1-iodo-1-trans-pentene

6-Cyclohexyl-3-hydroxy-1-iodo-1-trans-hexene

^f l-Cycloheptyl-3-hydroxy-1-iodo-1-trans-butene

4-Cyclooctylr3-hydroxy-1-iodo-1-trans-butene

4- (i | -Methylcyclohexyl) -3-hydroxy-1-iodo-1-trans-butene

4- (3-methylcyclohexyl) -3-hydroxy-1-j od-1-trans-butene

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TABLE X '(continued):

example

Starting carboxylic acid 3-hydroxy-1-iodo-1-transalkene product.

196 197

198 199

trans-2-methylcyclopentane carboxylic acid! 2

Cyclohexanecarboxylic acid

trans -4-methylcyclohexanecarboxylic acid ¹ ^

Cyclooctane carboxylic acids ^

Cyclopentanecarboxylic acid 3- (trans-Z-Kethylcyclopenty1) -3-hydroxy-1-iodo-1-trans-propene

3-Cycohexyl-3-hydroxy-1-iodo-1-trans-propene

3- (trans-4-Hethylcyclohexy1) -3-hydroxy-1-iodo-1-transpropene

3-Cyclooctyl-3-hydroxy-1-iodo-trans ~ propene

3-Cycloheptyl-3-hydroxy-1-iodo-1-trans-propene

409847/1159

LITEFiATURE POINTS for TABLE X:

1. CG. Overberger et al., J. Polymer Sci., PiA; " 2, 755

(1954) '

2. M.I. Goryeav et al., Chem. Abs., 69, 1742, no. 186462 (1968).

3 CD. Nenitzescu and G.C. Vantu, Bull.Soc.Chim.France (5), 2, 2209 (1935).

4. G.R. Yoke and R. Adams, J.Amer.Chem.Soc., 50, 1503 (1928). ~

5. W. Herz, J.Org.Chem., 20, 1062 (1955).

6. G.S. Hlen and R. Adams, J.Amer.Chem. Soc, 48, 2385 (1926). ~ "

7. E.E. Royais and A.N. Neal, J.Org.Chem., 21, 1448 (1956).

8. F.F. Views and W.K. Johnson, J.Am.Pharm.Assoc.Sci.Ed., 15, 443 (1956).

9. L. Ruzicka and H.A. Boekenogen, Helv.Chim.Acta, 14, 1319 (1931).

10. A.N. Burgstahler and I.C. Nordin, "J.Amer.Chim.Soc., 83, 198 (1961). .

11. J. von Braun "and W. Teuffert, Ber., ^ 8B, 2210 (1925).

12. M. Julia and F. LeGaffie, Bull.Soc.Chim.Fr., 1550 (1965).

13. 'VN Ipatieff et al., J. Amer. Chem. Soc, 75, 6222 (1953).

14. A.T. Blomquist and F.W. Schlaefer, J.Amer.Chem.Soc, 83, 4547 (I96I).

409847/1159

Example 200

Production of ^ cyclopentyl-i-i-iodine ^ -triphenylmethoxy-itrans-butene

A mixture of 21.4 4-cyclopentyl-i-iodo-itrans-buten-3-ol is heated (Example 179) in 17Q ml of dry pyridine containing 31 g of Tx'iphenylmethylbromid, for 2 hours. on a steam room. The dark mixture comes in 850 ml Poured ice water, after which the resulting solution is extracted three times with ether. The combined extracts are Rait ice-cold 2% hydrochloric acid solution, "bis the wash waters are acidic and eventually with saturated Sodium chloride solution washed over anhydrous magnesium sulfate dried and evaporated to dryness. That Trituration of the residue followed by filtration removes the triphenyl carbinol. The mother liquor becomes Evaporated dry and the resulting syrup over 400 g of a highly selective absorbent (magnesium silicate gel, Plorisilv £)) using hexane chromatographed, resulting in 32 g (78 ^) of a syrup, which solidifies when standing. Recrystallization from hexane gives white crystals with a melting point of 87 to 88 ° C.

Example 201 Preparation of 4-cyclopentyl-1-; iodo-3- (p-methoxyphenyl diphenyl) methoxy-1 -trans-butene -

Han heats a solution of 20 g of 4-cyclopentyl-1-iodo-1-trans-buten-3-ol (Example 179) and 25 g'p-anisylchlorodiphenyliaethane in 170 ml of dry pyridine for 18 hours at 60 ° C and then for 3 hours at 70 ° C. The then cooled Solution is poured into 850 ml of ice water. The solution obtained is distributed between ether and water, where-

4098A7 / 1159

after the ether layer is washed with water, dried with anhydrous magnesium sulfate and evaporated to dryness. The remaining pyridine is removed by further evaporation with toluene. The oil obtained is chromatographed over 300 g of a hpch-selective absorbent (magnesium silicate gel, Florisil Q * J ), 22.3 g of the product being obtained. The material is homogeneous according to thin-layer chromatography.

Examples 202-221

The treatment of the 3-kydroxy-1-3 od-trans-1-alkenes given in Table XI below with triphenylmethyl bromide according to the process described in Example 200, the 3-triphenylnethoxy-i-iodo-trans-i-alkene products given in Table XI below are obtained:

409847/1159

TABLE XI

Example starting

l-iodine-l-transalkene of Example 3-triphenylmethoxy-1-iodo-trans-1-alkene product

202
203
204

205
20-5

207
208

209
210

212

213
214

215

18O 181 182 183 134

185 186 187 188 189 190 191 192 193 4-cyclobutyl-3-triphenylmethoxy-1-j od-1-trans-butene

5-Cyclopentyl-3-triphenylmethoxy-1-iodo-1-trans-pentene

ö-Cyclopentyl ^ -triphenylmethoxy-1-j od-1-trans-hexene

T-Cyclopentyl ^ -triphenylmethoxy-1-iodo-1-trans-heptene

S-Cyclopentyl ^ -triphenylmethoxy-1-iodo-1-trans-octene

S-Cyclopentyl-A-methyl - ^ - triphenylmethoxy-i-iodo-1-trans-pentene

o-Cyclopentyl-ii-ethyl ^ -triphenyl-, methoxy-1-iodine-l-trans-hexene

4- (2-trans-Hethylcyclopentyl) ~ 3 ~ triphenylmethoxy-1-iodo-1-trans-butene

4-Cyclohexyl-3-triphenylniethoxy-1-iodo-trans-butene

5-Cyclohexyl-3-triphenylπlethoxy-lj od-1-trans-pentene

ö-Cyclohexyl ^ -triphenylmethoxy-lj od-1-trans-hexene

4-Cycloheptyl-3-triphenylπlethoxy-1-iodo-1-trans-butene

4-Cyclooctyl-3-triphenylmethoxy-1-iodo-1-trans-butene

4- (4-Methylcyclohexyl) -3 ~ tripheny1-methoxy-1-iodo-1-trans-butene

409847/1159

IABELLEXI (continued):

Example starting

1-iodine-1-transalkene of Example 3-triphenylmethoxy-1-od-trans-1-alkene product

216

217

194

195

218 196 219 197 220 198 221 199

4- (3-Methylcyclohexy1) -3-tripehnylmethoxy-1-j od-1-transbutene

3- (trans-2-methylcyclopentyl) -3-

triphenylmethoxy-1-iodine-l-trans-

propene 3-cyclohexyl-3-triphenylmethoxy-1-j od-1-trans-propene

3- (trans-4-Methy! .Cyclohexyl) -3-triphenylmethoxy-1-iodo-1-transpropene

3-Cyclooctyl-3-tΓiphenylmethoxy-1-j od-1-trans-propene

S-Cycloheptyl ^ -triphenylmethoxy-1-iodo-1-trans-propene

A098A7 / 1159

Example 222 Preparation of 1-chloro-trans-1-octen-3-one

To a slurry of 233.5 g (1.75 moles) of aluminum chloride in 390 ml of carbon tetrachloride, which is saturated with acetylene and cooled in an ice bath, is given in the Course of 20 min. 201.9 g (1.5p KoI) hexanoyl chloride. To When the addition is complete, acetylene is introduced into the mixture as quickly as it is absorbed, with the absorption slows down after 1 hour. The mixture is then poured into .1700 g of Sis and 720 ml of saturated saline solution. The organic Phase is separated off and the aqueous phase is washed with ether. The combined organic phases and Wash waters are washed with saturated saline solution, viaex 'NapSO. dried and evaporated. That as a residue accruing oil is mixed with 10 g of hydroquinone and distilled to form a colorless oil, boiling point 51 to 52 ° C / 0.10 torr.

Example 224

Production of i-iodine-trans-i-octen-3-one

A mixture of 54.5 g (0.364 mol) of sodium iodide is stirred and 40 g (0.249 mol) of i-chloro-trans-i-octen-3-one (Example 222) in 360 ml of acetone for 24 hours at reflux. The reaction mixture is then cooled, filtered and concentrated. The residue is partitioned between water and ether, whereupon the organic phase is washed with dilute sodium bicarbonate solution and brine washes over MgSO. dries and evaporates to an oil. This material comes straight away with no purification used.

409847/1159

Example 225 Preparation of 1-J "od-trans-1-octen-3-ol

A solution of 78.2 g (0.310 mol) of i-iodo-trans-i-octen-3-one (Example 224) in 150 ml of absolute ethanol is added dropwise over 2 hours to a slurry cooled in an ice bath of 6.49 g (0.172 mol)
ITodium borohydride in 50 ml of absolute ethanol. When the addition is complete, the mixture is stirred for 2 hours with ice cooling and then poured into 1 liter of water. The mixture is extracted with benzene and the organic phase is washed with saturated brine, over Na ₂ SO. is dried and evaporated '. The oil obtained is dissolved in 4OO ml of absolute ethanol and v for the elimination of the residual ketone / hile 1.5 hrs. With 5 mol # p-carboxyphenylhydrazine treated at "70 ⁰ C. Then the mixture is cooled and evaporated, and the residue is dissolved in 400 ml of ether and filtered. The filtrate is washed with dilute sodium bicarbonate solution and saturated salt solution, dried over lic.pSO. and evaporated to an oil. This oil is poured over 2 kg of a highly selective absorbent (magnesium silicate gel, packed in hexane). Florisil ^ Q) ) chromatography, the product being obtained by elution with benzene. Distillation of the product gives a colorless oil, boiling point = 74 to 76 ° C / O, OO5 Torr.

Example 226

Production of 1-iodo-3- (p-anisyldiphenylmefhoxy) -trans-toctene

Kan heats a mixture of 14.92 g (0.0588 mol) of 1-iodotrans-1-octen-3-ol (Example 225) and 16.2 g (0.0588 mol)

409847/1159

p-Anisyldiphenylmethylchlorid in 165 ml of dry pyridine in an inert atmosphere for 18 hrs. at 60 ⁰ C. Then the mixture is cooled and the solvent evaporated in vacuo. The residue is partitioned between ether and water and the organic phase is washed with water and saturated salt solution, over MgSO. dried and evaporated. The residue is chromatographed over 300 g of a highly selective absorbent packed in hexane (magnesium silicate gel, FlorisilCÜy), the product being eluted with hexane and a hexane / 3enao1 mixture (4: 1), a colorless oil being obtained as the product.

Example 227

Manufacture of 9-0xo-1 la prostensilure

To a cooled to -78 ⁰ C solution of 6.030 g (0.01215 mol) of 1-iodo-3-triphenylmethoxy-trans-1-octene (Example 128) in 8 ml of toluene are added under inert atmosphere 5.2 ml of a 2 , 34 m solution of n-butyllithium in hexane .. Man the resulting solution allowed to warm to -40 ⁰ C and leaving it for 1 hr. at this temperature. 5.0 ml of a 2.44 m (0.0122 mol) solution of trimethylaluminum in heptane are then added to the solution containing 3-triphenylmethoxy-trans-1-octenyllithium and the mixture is allowed to warm to -10.degree. The mixture containing the lithium trimethyl (3-triphenylmethoxy) trans-1-octenyl) alanate is then cooled to -78 ° C. and treated with a solution of 3.94 g (0.01215 mol) of 4-methoxy-2- ( 4-carbotetrahydropyran-2 ^l -yl-oxy-hexyl) -cyclopent-2-en-1-one (Example 101) was added to 10 ml of diethyl ether. The mixture is then allowed to warm to room temperature and is stirred for 18 hours at the edge temperature. Then the mixture is poured on ice and diluted chlorine water

409847/1159

poured chemical acid and extracted with ither. The organic ' Phase is washed with water and saturated saline solution, over Na ^ SO, dried and evaporated to a colorless oil.

The obtained crude 9-oxo-1 Xa- methoxy-15-triphenyl-icethoxy-8 £ -13-trans-prostenic acid is dissolved in 100 ml of a glacial acetic acid-tetrahydrofuran-water mixture (4: 2: 1) and for 7 hours heated. at 45 ⁰ C. The mixture is then cooled, diluted with aqueous sodium chloride solution and extracted with ether. The extract is washed with water and the aqueous acetic acid is eliminated by ezeotropic distillation using toluene. The residue is chromatographed on silica gel, the vanity compound being obtained in the form of the 15-epimer.

Examples 228-393

Treatment of those given in Table XII below 1-iodo-3-triphenylmethoxy (or 3-niethoxy) trans-1-alkenes with n-butyllithiuni followed by a treatment of the self resulting trans-1-alkenyllithium derivatives with trimethylaluiuiniuia and the subsequent treatment of the lithium (trans-1-alkenyl) trimethylalanates obtained with the blocked JJ-Oxy-cyclopent - ^ - en-l-ones according to the in Example 227 also indicated in Table XII given procedure results, with the exception of the 15-kethoxy derivative, ' the 15-0-triphenylmethyl-8 ^ - corresponding to the products given in Table XII below Derivatives. Further treatment of these intermediates with an acetic acid-tetrahydrofuran-water mixture the procedure given in Example 227 leads to the products given in Table XII:

409847/1159

TABLE XII

at
game Starting-4-oxy-
cyclopent-2-en-
1-on from Bei
game 228 101 409847 / 229
230 101
101 1159 231
232 101
101 233 101 234 101 235 101

From gangs -1 - j ο d-1-trans-alken of example

9-Oxo-i 1-o: r / -15-hydro: r / - (methoxy) -13-transprogeneic acid product

148A

148

152

156

161

171 9-Oxo-llα-nethoxy-15-hydroxy-20-ethyl-13-trans-

-prostenic acid

9-oxo-lla-methoxy- 15-hydroxy-16- ethyl-13-1 i * ans-
-prostenic acid

9-Oχo-lla-methoxy-15-methoxy-13-trans-prosten-1

acid. _j

g-Oxo-lla-methoxy-lS-hydroxy-l ^ -trans-rr-cis-pros- 1 tadienoic acid

-trans-prostenic acid

9-0 xo-llct-methoxy- 15-hydroxy-17,17- d ime thyl-13-
-trans-prostenic acid

- ^, l8-cis-methano-13-

-trans-prostenic acid

9-Oxo-Ila-methoxy-15-hydroxy-16,17,18,19,20-penta- ^ nor-15- (I-adamantyl) -trans-prostenic acid, ^ ₀

TABLE XII (continued):

At- output 4-oxy game cyclopent-2-en-

1-on from

example

Starting ^ -iodo-1-trans-alkene of Example 9 "0xo-11 -oxy-15-hydroxy- (mexhp: r /) -1 ^" - transpros acid product

236
237
238
239
240
241
242
243
244

101

101

101

87

87

88

88

89

89

172

221

219

140 '

210

202

141.

143

152 -trans, 17-prostadic acid

9-Oχo-llα-methoxy-15-hydroxy-16,20-ethano-13- -trans-prostenic acid

9-0xo-lla-methoxy ~ 15-hydroxy-l6,19-trans-ethano- -13-trans-prostenic acid

-ö, · ?, 19.20-tetranor-

-13-trans-prostenic acid

9-oxo-lla-methoxy-15-hydroxy-6,7-dinor-17> 20-ethano-13-trans-prostenic acid

9-Oxo-lla-ethoxy-15-hydroxy-5 * 6.7 * 20-1etranor-17 » -IJ-trans-prostenic acid

9-Oxo-lla-ethoxy-15-hydroxy-5 * 6,7,18,19, '20 -hexanor-13-trans-prostenic acid

9-oxo-lla-inethoxy-15-hydroxy-7a, 7b-bishomo-20- -ethyl-13-trans-prostenic acid

9-Oxo-lla-methoxy-15-hydroxy-7a, 7b-bishoIno-l6, l6- -dimethyl-13-trans-prostenic acid '

TABLE XII (continued):

At starting 4-oxyspiol cyclopen.t-2-en-

1-on from

example

Starting 1-iodine-1-trans-alkene of Example 9-0x0-11-oxy-15-hydroxy- (methoKy) ~ 13-transprostic acid product

245
246
247
248

249
250
251
252

253.

89 90 90 91

91 92 92 92 92

220 139 173 175

142 128 148A. 152

169 9-Oxo ~ lla-methoxy-15-hydroxy-7a, 7b-bishcmo-16,20- - (1,3-propane) -13-trans-prostenic acid

9-0xo-llα-methoxy-15-hydroxy-2-ethyl-20-noΓ-13- -trans-prostenic acid

9-0xo-llcx-methoxy-15-hydroxy-2-ethyl-16,20-πlethano-13-trans, 18-prostadic acid

9-oxo-lla-methoxy-15-hydroxy-3,3-dimethyl-16- (l- -adamantyl) -17,18,19,20-tetranor-13-trans-prostenic acid ·

-J, ^, 2O-trim.ethyl-lj5-

-trans-prostenic acid

9-0.χo-llα-Inethpxy-15-hydroxy-, 3-oxa-13-tΓans-prostenic acid

9-oxo-lla, lS-acid

-13-trans-prosten acid.

9-oxo-llα-methoxy-15-hydroxy-3-oxa-17,20-ethano- -! ^ -, trans, 18-prostadic acid

TABLE XII (continued):. .

At- starting-4-oxy- starting-1-iodo- 9-0xo-11-oxy-15-hydroxy- (methoxy) -13-trans-

play cyclopent-2-en-1-trans-alkene prostenic acid product

1-on from of example

example

254 92 218 255 93 203 256 93 145 257 94 139 258 94 214 ' . 259 95 142 260 95 161 261 95 206 262 96 156

g-Oxo-lla-methoxy-lS-hydroxy - ^ - oxa-lö ^ O-methano- -13-trans-prostenic acid

_ 9-oxo-lla-methoxy-15-hydroxy-2-fluoro-18.20-eth-

^ ₀ ^C "^{> J 7} ^ *" ^w "ano-13-trans-prostenic acid

• c * _nr .r _n ^ -1 /, κ 9-Oxorllct-methoxy-15-hydroxy-2-fluoro -16-raethyl-

-20-nor-13-trans-pros acid

_ 9-Oxo-llα-methoxy-15-hydroxy-7,20-dinor-13-trans-

& ^C ~ ^JI ^ '* " -prostenic acid

9-0xo-lla-methoxy-15-hydroxy-7-nor-17> 20- (1,4- -butah) -13- trans-pros acid

9-0xo-llα-methoxy-15-hydroxy-7a-homo-20-methyl- -13-trans-prosten acid

9-0xo-llα-methoxy-15-hydroxy-7a-homo-17,18-cis- -methano-13-trans-prostenic acid

9-0xo-llα-lnethoxy-15-hydroxy-7a-homo-20-cyclopen- - ¹ ^ tyl-13-trans-prostenic acid ¹ ^ ⁰

9-C> xo ~ lla-methoxy-15-hydroxy-2-phenyl-17,17-di- ^ methyl-13-trans-prostenic acid 'K)

TABLE XII (continued):

At- Auspangs-4-oxy- Aus-angs-1 -iodine- 9-0;: o-11 -oxy-15-hydroxy- (ethoxy) -13-trans

play cyclopont-2-ori- 1-trans ~ alcon prostenic acid product

1-on from of example

Example »^ _- _M _-« ---

263 96 211 * "-
O 264 97 152 CO OO
4>
-J 265 97 207 266 97 146 cn CO 267 97 148 '268 98 152 269 98 139
• 270 98 128 271 98 174

9-oxo-lla-methoxy-15-hydroxy-2-phenyl-18,20- (1,3- -propano) -13-trans-prostenic acid

9-oxo-11α-ethoxy-15-hydroxy-16,16-dimethyl-13- -trans-prostenic acid

9-oxo-llα-ethoxy-15-hydroxy-16-methyl-18,20-ethano-13-trans-prostenic acid

9- ° xo-lla-ethoxy-15-hydroxy-19-methyl-13-trans-l8- -prostadienic acid

g-Oxo-lla-ethoxy - ^ - hydroxy-l ^ -trans, ^ - cis-

-prostadienic acid

9-oxo-lla-propoxy-15-hydroxy-16,16-dimethyl-13- -trans-prostenic acid

9-oxo-lla-propoxy-15-hydroxy-20-nor-13-trans-

-prostenic acid

9-oxo-lla-propoxy-15-hydroxy-13-trans-prosten-

9-oxo-lla-propoxy-15-hydroxy-16,17,18,19,20-pentanor-15- (2-adamantyl) -13-trans-prostenic acid

TABSLLS XII (continued);

At- _. _

game cyclopent-2-en-

1-on from

example

Output 3 ~ 1- _V iodine 1-trans-alkene from example

272 98 170 409847 273
274 99
99 148
148A 275 99 152 cn
CO 276 99 200

277

99

278 100 279 100 280 100

281

100

9 ~ Qxo-11 -oxy-15-hydroxy- (nethoxy) -13-trans process acidic product

9 ^ 0xo-lla-propoxy-15-hydroxy-17,20-ethano-13- - trans, 19-prostadic acid

9-oxo-lla-isopropoxy-15-hydroxy-13-trans, 17-cis- -prostaic acid

9-OxΌ-llα-isopropoxy-15-methoxy-13-trans-prostenic acid

9-oxo-lla-isopropoxy-15-hydroxy-16,16-dimethyl- -13-trans-prostenic acid

9-oxo-lla-isopropoxy-15-hydroxy-17 * 20-- -methano-13-transr-prostenic acid

9-0xo-lla-isopropoxy-15-hydroxy-13-trans-pro3-tic acid

SyS
- trans-p rusting acid

9-oxo-4-n-butoxy-15-hydroxy-13-trans-prosten-

9-0xo- ¹ ^ -n-butoxy-15-hydroxy-16-methyl-20-nor-13- -trans-prostenoic acid

gylS-hydroxy-16-ethyl-J.9.20- (1.3- -propano7-13-trans-prostenic acid

K). KJ

TABLE XII (continued):

at
game Starting-4-oxy-
cyclopent-2-en-
1-on from
example 282 100 283 102 284 102 285 102 286 34 287 34
• 288 35 289 35 290 36 291 37

Starting 1-iodine 1-trans-alkene from example

9-0x0-11-oxy-15-hydroxy- (methoxy) -13-transprostic acid product

9-0xo-4 ~ n-butoxy-15-hydroxy-16,20-ethano-13-trans-prostenic acid

9-0x0-11a-methoxy-15-hydroxy-2,17-dimethyl-20-. nor-16,19-trans-aiethano-13-trans-prosteiic acid

9-Oxo-i 1 rr-methoxy-15-hydroxy-2,16,16-trimethyl-13-trans-prosteiic acid

9-Oxo-i 1 a-methoxy-15-hydroxy-2-ynethyl-13-transprostic acid

9-0x0-11a-ethoxy-15-hydroxy-13-trans-prostenic acid ethyl ester

9- "OXO-11 a-ethoxy-15-hydroxy-20-methyl-17,20-ethano-13-trans-prostanoic acid ethyl ester

9-0x0-11 a-methoxy-15-hydroxy-16,16-dimethyl-1,3-trans-prostenoic acid, ethyl ester

9-0x0-11a-methoxy-15-hydroxy-16,17,18,19,20-pentanor-15- ( 2-adamantyl) -13-trans-prostenic acid methyl ester

9-0x0-11a-propoxy-15-hydroxy-6,7-dinor-13-transprostic acid ethyl ester

9-0x0-11a-isopropoxy-15-hydroxy-5,6,7-trinor-13-trans- ^ prostenic acid ethy ! ester

4 ^ ro ro cn ν

TA3SLLE XII (continued):

At- starting-4-oxy- starting-1-iodine- 9-0xo-11-cxy-15 ~ hydroxy- (methoxy) -i3-trans-

play cyclopent-2-en-1-trans-alkene prostene acid product

1-on from of example

example

ö
co
OO
-J 293
294 41
43 '11 59 295
296 43
■ 45 297 45 298 47 299 47

292 41 147 9-0x0-1ia-isopropoxy-15-hydroxy-7a, 7b-bis-horao-

Ethyl 17-niethyl-20- (2-propenyl) -13-trans-prostenoate

148 9-0x0-11a-isopropoxy-15-hydroxy-7a, 7b-bis-homo-13-

trans-17-prostadienoic acid ethyl ester

148A 9-0x0-11a-butoxy-15-methoxy-2-ethyl-13-trans-pro-

stenic acid ethyl ester cd

9-0x0-11a-butoxy-15-hydroxy-2-ethyl-16,16-di- ' methyl-13-rrans-prostenic acid ethyl ester

9-0x0-11a-methoxy-15-hydroxy-3,3-dimethy1-13-trans-prostenic acid ethyl ester

9-0x0-1 la-methoxy - ^ - hydroxy ^, 3,16,16-tetramethyl- -13-trans-prostenic acid ethyl ester

. 9-0x0-11a-ethoxy-i5-hydroxy-3-oxa-20-ethyi-13-

trans-prostenic acid ethyl ester 'ro

9-0x0-11a-ethoxy-i5-hydroxy-3-oxa-19-, 20- (1,3- ro propane) -13-trans-prostenic acid ethyl ester ro

9-0x0-1 la-sec-butoxy-IS-hydroxy ^ -no ^ O-methyl- - '13-trans-prostenic acid ethyl ester. · ¹ ^

TABiSLLIS XII (continued):

At- Ausftaiirn-h-ozzy- output a-I-iodine 9-0; co-11-oxy-i5-hydroxy- (iu'2thoxy) -13-trans-

spiol cyclopont-2-en ~ i-trnnG-nlkon proctonsiäiuOprodukt

1-on from of example

example

301 50 212 * »· 302 52 213 O
CO
OO 303 52 1", 304 55 205 cn
CO 305 55 152 306 55 128 307 56 152 308 56 128 309 56, 216 310 56 161

Ethyl 9-0x0-11α-sec-butoxy-15-hydroxy-7-nor-19,20- (1,4-butane) -13-trans-protoate

9-0x0-11fr-raethoxy-15-hydroxy-7 (. «- homo-17,20- (1,3-propane) -13-trans-prostanoic acid ethyl ester

9-0x0-11a-mothoxy-15-hydroxy-7a-homo-13-trans-17-prostadienic acid ethyl ester

9-0x0-11α-methoxy-1 5-hydroxy-20,20- (1,4-butane) -13-trans-prostenic acid butyl ester

9-0x0-11 a-methoxy-15-hydroxy-16,16-dimethyl-13-tranG-proGtonic acid-butylene door

9-Oxo-i1a-mothoxy-15-hydroxy-13-tranfi-prostonic acid butyl ester

9-Oxo-i1a-methoxy-15-hydroxy-16,16-dimothyl-13-tranG-prostenic acid isopropyl ester

9-Oxo-i1a-methoxy-15-hydroxy-13-trans-prosten- J ^

acid isopropyl ester j ^

9-0x0-11a-methoxy-15-hydroxy-i7,19- (1,3-propane) - ^ 13-tran3-prostenic acid isopropyl ester __ ^

9-0XO-11a-methoxy-15-hydroxy-17,18-cis-mG-13- than ¹ ^ Trang prostensäureiGopropylester

.tawoi.i.: ·: χιτ

Bei- Aur, r.anfcr.-h-oz-zy ispiel cyc'lopcnt-2-on-1-on of

Boin game

Output! 3-1 -, iodine-1 -1 r an s -al ke η of Example 9-oxo-i 1 -oxy-1 ^ -hydroxy- (mothoxy) -13-trani; -procycic acid product

311 57

312 57

313 57

314 57

315 57

316 62

317 62

318 62

319 86

120 152 143 213 201

152

209 128 9-Oxo-i 1 a-methoxy-15-hydroxy-1 .j-trans-pros t decyl ester

9-0x0-11 (x-methoxy-1 5-hydroxy-i 6,16-diine thyl-13-tranG-proatensäui ^ decylestcr

9-Oxo-i1a-methoxy-15-hydroxy-20-ethyl-13-transprosteric acid docyl ester

9-0x0-11a-methoxy-15-hydroxy-17.20- (1,3-propane) - ^U1 ^ -trans-prostencauredecylester ι

9-0x0-11α-methoxy-15-hydroxy-17 »20-methane-13-trans-prostenoic acid decyl ester

9-0x0-11α-tert-butoxy-15-hydroxy-13-transprost acid ethyl ester

9-0x0-11α-tert-butoxy-15-hydroxy-16,16-dimethyl-13-trans-prostenic acid ethyl ester

9-0x0-11α-tert-butoxy-15-hydroxy-2O-nor-17,18- 'trans- (1,3-propane) -13-trans-prostenic acid ethyl ester J ^ 9-0x0-11α- (2 -hydroxyethoxy) -15-hydroxy-13-trans- [^ prostenic acid q-,

TABBIJJi XII (continued)?

Bo i-Au3ßan <* s-4-oxysspiel cyclopent-2-one

1-on from

example

1-trana-alkon of example 9-0x0-11-oxy-15-hydroxy- (methoxy) -13-transprostons aurcproduct

320

321
322

323
324
325
326
327
328

86 86 86

86

86

86

86

107

152 161 171

143

144

221

148A

148 9-Oxo-LLA (2-hydroxyethoxy) -15-hydroxy-l6 l6 _{J-dimethyl-13-trans-prostensäurG}

9-üxo-lla- (i5-hydroxyethoxy) -15-hydroxy-17 »IS-cis- -methano-13-trans-prosten acid

9-Oxo-llo- (2-hydroxyethoxy) -15-hydroxy-l6,17il8, -19, SO-pentanor-LS (l-adamantyl) -13-trans-pronten- ü äure

9-oxo-lla- (2-hydroxyethoxy) -15-hydroxy-20-ethyl- -13-trans-prostensäiiro

9rOxo-lla- (2-hydroxyethoxy) -15-hydroxy-16-ethyl- * ■ 13- trans-pros ton acid

9-Oxo-Ila- (2-hydroxyethoxy) -15-hydroxy-16,20-ethano-13-trans-prosten acid

9-0xo-lia- (2-hydroxyethoxy) -15 ~ methoxy-13-trans- -prostenic acid

9-Oxo-Ila- (2-hydroxyethoxy) -15-hydroxy-13-tran3 17-cis-prostadienoic acid

9-0χο-11α- (2-hydroxyethoxy) -15-hydroxy-6,7,19,20- -tetranor-13-trans-prosten acid

I ¹ ABKI .LiO X11 (Vo r ts ο t ζ un /):

At- Au.sßangr.-4-oxy- Ausgan / T> -1 -.iod- 9-Oxo-11 -oxy-'l ij-rhy

game cyclopont-2-en- 1-trnnr.-al3wn prontonoriuroprodukt

1-on from from Do.ifspißl

Example '

: cy- (υιό bhoxy) -13-trann-

329 107 210 O 330 103 141 co
CD
jr-
-J 331 108 221 "^. 332 110 143 cn
co 333 110 152 334 110
• 128 335 110 220 336 111 206 337 111 148

9- (2-hydroxyethoxy) -15-hydroxy-6,7-dinor-

-17.20 -; -! Thano-12-tranc-prostensauro

9-Oxo-Ila- (2-hydroxyothoxy) -15-hydroxy-5 _> 6, 7, 18, -19,20-hexanor-Ij5-trans-pros ton ': H.

9-Οχο-11α- (2-hydroxycthoxy) -15-hydroxy-5,6,7-trinor-16,20-3thano-13-trans-prostenGaurs

9-0xo-lla- (2-hydroxyethoxy) -15-hydroxy-7a, 7b-bishomo-20-ethyl-13-trans-prostenic acid

9-oxo-lla- (2-hydroxyethoxy) -15-hydroxy-7a, 7b-bishomo-l £, l6 -iimethyl-13-trans-prostenic acid

9-0xo-lla- (2-hydroxyethoxy) -15-hydroxy-7a, 7b-bishomo-13-trans-prostatic acid

9-Οχο- 11α- (2-hydroxyethoxy) -lS-hydroxy ^ n-, 7b-bishomo-16,20- (1,3-propano) -13-trans-prostene; iure

9-oxo-lla- (2-hydroxyethoxy) -15-hydroxy-2-ethy1-20-

-cyclopentyl - ^ - trans-pros tens acid

9-oxo-lla- (2-hydroxyethoxy) -15-hydroxy-2-ethyl-13- -trans, 17-cis-prostadic acid. '

TABLE XII (continued) ι

Bel- AuHjrjahßs-4-o: x: y- Auf ^ an ^ a-i-i-iodine- 9-Oxo-11-oxy-15-hydroxy- (m '? Thoxy) -i3-trana> -'

game cyciopont-S-on-1-trans-alken prostenaäurtproclukt

1-on from of example

example

338 113 128 O
CO
GO 339
340 113
113 144
213 341 115 128 cn
CO . 342 115 , 152 343 115 219 344 *
115 148A 345 115 148 346 115 ' 172 347 117 152

9-Üxo-IIIa- (2-hydroxyethoxy) -15-hydroxy-3, j5-dij> icthyl-13-trans-prostenic acid

9-Oxo-IIIa- (2-bydroxyethoxy) -15-hydroxy-3,3-dlmethyl-16-ethyl-13-trans-prosten acid

9-0xo ~ lla- (2-hydroxyethoxy) -15-hydroxy-3,3-dlmethyl-17 »20- (1,3-propano) -13-trans-prosten acid

9-Oxo-Ila- (2-hydroxyethoxy) -15-hydroxy-3-oxa-13- ^ -trans-prostatic acid °°

9-Oxo-lla- (2-hydroxyethoxy) -15-hydroxy-3-oxa-16 l6-dimethyl-13-trar ^ s-prosten acid

9-oxo-llo- (2-hydroxyethoxy) -15-hydroxy-j5-oxa-16, -19-trans-ethano-13-trans-prosten acid

9-OXo-lla- (2-hydroxyethoxy) -15-methoxy-3-6xa-13- -trans-prostenic acid

9-oxo-lla- (2-hydroxyethoxy) -15-hydroxy-3-oxa-13- -trans-17-prostadic acid J ^

9-0xo-lla- (2-hydroxyethoxy) -15-hydroxy-3-oxa-16 -, S ₀ 20-methano-13-trans-17-ci _s _p _ros t _ac ji _en yau _r e cn

9-Oxo-IIIa- (2-hydroxyethoxy) -15-hydroxy-2-fluoro-Ki -16, 16-dimethyl-13-trans-prostenic acid

TABLE XII (continued):

at
game From gangs-4-oxy-
cyclopent-2-en-
1-on from
example Starting-1-iodine-
1-tranu-alken
of example 348 117 128 O 349 ii7 214 9847 350 118 139 - * 351 118 145 cn 352 119 142 • 353 119
• 152 354 119 174 355 120 128 356 124 128

9-Oxo-i1-0X7-15-hydroxy- (methqxy) -13-transprostic acid product

9- oxo-lla- (2-hydroxy ethoxy) -15-hydroxy-2-fluorine- -13-trans-prcsten acid

9-0xo-lla- (2-hydroxy ethoxy) -15-hydroxy-2-fluorine- -17.20- (1,4-butano) -13-trans-prootic acid

9-0xo-lla- (2-hydroxyethoxy) -15-hydroxy-7,20-bisnor-13-trans-prosten acid

9-0xo-lla- (2-hydroxyethoxy) -15-hydroxy-7,20-bisnor-16-methyl-13-trans-pros ten acid

9-Oxo- 11α- (2-hydroxy ethoxy) -lS-hydroxy ^ a-homo- -20-iiiekhv; 2-17-lrans-prostenic acid

9-oxo-lla- (2-hydroxy ethoxy) -15-hydroxy-7a-homo- -lo ^ lo-dimethyl- ^ - trans-prostenic acid

9-0xo-lla- (2-hydroxyethoxy) -15-hydroxy-7a-homo- -l6,17,18,19,20-pentanor-15- (2-adamantyl) -15- -trans-pröstenic acid

9-oxo-lla- (2-hydroxyethoxy) -15-hydroxy-2-phenyl- -13-trans-prostenic acid

9-0xo-lla- (2-hydroxypropoxy) -15-hydroxy-13-trans- -p rostic acid

TABLE XII (port setting):

At- from ^ angs-4-oxy- from-1-iodine-
apiel cyclopent-2-ene-1-trans-alkene
1-on from of example
example 124 152 357 124 • 207 358 124
126 148 O
CO
00
* · »■ 359
360 126
103 152
152 1159 361
. 362 103 147 363 103 217 364 103 212 365

9-0x0-11-oxy-15-hydroxy- (mothoxy) -13-transpros tents liuroprodulct

9-0x0-11 α- (2-hydroxypropoxy) -15 ~ hydroxy-16,16-dim ethyl-13 ~ trans-prostenic acid

9-0x0-11a- (2-hydroxypropoxy) -15-hydroxy-16-. methyl-18,2O-ethano-13-trans-prostensauro

9-0x0-11 cc- (2-hydroxypropoxy) -15-hydroxy-13-trans-17-cis-prostadic acid

9-0x0-11a- (4-hydroxybutoxy) -15-hydroxy-13-transprostic acid

9-0x0-11a- (4-hydroxybutoxy) -15-hydroxy-16,16-dimethyl-13-trans-prostenic acid

9-0yo-'i i.a> r ('X ^ bydroxyethoxy) -i5-hydroxy-16,16-dimethy1-13-trans-prostenic acid ethyl ester

9-0x0-11a- (2-hydroxyethoxy) -15-hydroxy-17-methyl-20- (2-propenyl) -13-trans-prostenic acid ethyl ester

9-0x0-11 α- (2-hydroxyethoxy) -15-hydroxy-19,20-dinor-16,17- (1,3-propane) -13-trans-prostenic acid ethyl ester

9-0x0-11a- (2-hydroxyethoxy) -15-hydroxy-19.20- (1,4-butane) -13-trans-pros tens acid ethyl ester

TABLE XII (continued):

At-T output 4-oxy game cyclopent-2-en-

1-on from

example

366

367

368

369

104

104

105

106

Output-i-i-iodine-1 trans-alken by example

139

148A

202

208

cn.
(O 370 109 161 371 109 148 372 109 169 373 112 148 374 112 203

9-0x0-11-oxy-15-hydroxy- (methoxy) -13-transprostic acid product

9-0x0-11 a- (2-hydroxyethoxy) -15-hydroxy-20-nor-13-trans-prostgic acid methyl ester

9-Oxo-i Ια- (2-hydroxyethoxy) -13-methoxy-13-transpros methyl ester

9-0XO-11η: - (3-hydroxypropoxy) -15-hydroxy-6,7 , 20-trinor-17, 19-iaothan-13-trans-prostenic acid ethyl ester>

9-0x0-11 α- (2-hydroxyethoxy) -15-hydroxy-5,6,7-trinor-16-ethyl-19,20- (1,3-propane) -13-trans-prostenoic acid ethyl ester

- ⁿ '.i ~ {' 1 -hydroxyethoxy) -15-hydroxy-7a, 7t> -bishomo- ^ fiS-cis-methane-iS-trans-prostenic acid ethyl ester

9-0x0-11 α- (2-hydroxyethoxy) -15-hydroxy-7a, 7b- "bishomo-13-trans-17-cis-prostadic acid ethyl ester

9-0x0-11 α- (2-hydroxyethoxy) -15-hydrpxy-7a, 7b ~ bishomo-17,20-ethano-13-trans-18-prostadienoic acid ethyl ester

9-Oxo-i 1 α- (3-hydroxypropoxy) -15-hydroxy-2-ethyl-1 trans-17-cis-prostadienoic acid ethyl ester

9-0x0-11 oc- (3-hydroxyporpoxy) -i5-hydroxy-2-ethyl-18,20-ethano-13-trans-prostenic acid ethyl ester

T ADBLLB XII (continued):

At- Ausgo.ng5-4 ~ oxy
game cyclopont-2-en
1-on from

example

gsj trans-alken of example

375

376

114

114

CD
03 377 116 -ν 378 116 1 159 379 121 380 121 381 121 382 121

i *., ■

383

121

156 215

> i. 152

218 128 152 161 216 173 9 ~ 0xo ~ 11-oxy-15-hydro ;; y- (nGthoxy) ~ 13 ~ trans ~ Prostic acid product

9-0XO-11 α- (2-hydroxyethoxy) -15-hydroxy-3,3,17,17-tetramethyl-13-trans-pros tens acid ether.

9-0XO-11 α- (2-hydroxyethoxy) -15-hydroxy-3,3,20-triinothyl-17,20-ethano-13-trans-pros tens acid ethyl ester

9-0x0-11a- (3-hydroxypropoxy) -i5-hydroxy-3-oxa-16,16-dimethyl-13-trans-pros tens acid ethyl ester

9-0x0-11 et- (3-hydroxypropoxy) -15-hydroxy-3-oxa-16,20-methano-13-trans-prostenoic acid ethyl ester

9-0x0-11a- (2-hydroxyethoxy) -15-hydroxy-13-transpros butyl ester

9-0x0-11 α- (2-hydroxyethoxy) -15-hydroxy-16,16-dimethyl-13-trans-prostenic acid butyl ester

9-0x0-11a- (2-hydroxyethoxy) -15-hydroxy-17,18-cismethano-13-trans-prostenic acid butyl ester

9-0x0-11a- (2-hydroxyethoxy) -15-hydroxy-17,19- (1,3-propane) -13-trans-butyl prostenoate

9-0x0-11 α- (2-hydroxyethoxy) -15-hydroxy-16,20-methano-13-trans-18-prostadienoic acid butyl ester

TABLE XII (continued):

at
game Starting-4-oxy- starting-1-iodine-
cyclopent-2-ene-1-trans-alkene
1-on from of example
example 148 384 121 148 385 122 146 386 122 152 387 122 175 388 122 128 389 123 152 390 123 148A 391 . 123 209 392 123

9-0x0-11-oxy-15-hydroxy- (methoxy) -13-transprostic acid product

9-Oxo-i1 α- (2-hydroxyethoxy) -15-hydroxy-13-trans-17-cis-prostadienoic acid butyl ester

9-0x0-11 α- (2-hydroxyethoxy) -15-hydroxy-13-trans-17-cis-prostadienoic acid isopropyl ester

9-0x0-11 α- (2-hydroxyethoxy) -15-hydroxy-19-methyl-13-trans-18-prostadienoic acid isopropyl ester

9-0x0-11 α- (2-hydroxyethoxy) -15-hydroxy-16,16-dimethyl-13-trans-prostenic acid isopropyl ester

9-0x0-11 oc- (2-li / hydroxyethoxy) -15-hydroxy-17,18,19,20 tetranor-16- (1-adamantyl) -13-trans-prostenic acid isopropyl ester

9-0x0-11 α- (2-hydroxyethoxy) -15-hydroxy-13-transprostic acid decyl ester

9-0x0-11 α- (2-hydroxyethoxy) -15-hydroxy-16,16-di- N) methyl-13-trans-prostenic acid decyl ester ■ *> ·

K) '9-0x0-11 α- (2-hydroxyethoxy) -15-methoxy-i3-trans-K)

decyl prostate ^ ¹

9-0XO-11α- (2-hydroxyethoxy) -15-hydroxy-20-nor- ¹ ^ ⁰ 17,18-trans- (1,3-propane) -13-trans-prostenic acid decyl ester

TABLE XII (continued):

At- starting-4-oxy- starting-1-iodo-9-oxo-11-oxy-15-hydroxy- (mothoxy) -13- transspiel cyclopent-2-en-1-trans-alkene prostenic acid product

1-on from of example

example

5 393 123 148 9 ~ Oxo-11a ~ (2-hydroxyethoxy) -i5-hydroxy-i3-

<x> trans-1 y-cis-prostadienoic acid decyl ester

Example 394

Manufacture of 9α, 15-dihydroxy-1icf-methoxy-13-trans-prostenic acid

To a solution, stirred in an ice bath under a nitrogen atmosphere, of 433 mg of 9-Όχο-11a-metho: xy-15-hydroxy-13-trans-prostenic acid (Example 227) in 4.5 ml of tetrahydrofuran is added dropwise 3.7 ml of 0 , 76 m lithium perhydro-9b-boraphenylyl hydride. After ^{4 ° C. at 0} ° C., 1.62 ml of a 3N L'atriuni hydroxide solution and then 1.62 ml of 30 # hydrogen peroxide are added. Then ether is added and the resulting solution is acidified with 2N hydrochloric acid solution. The ether layer is washed several times with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to dryness, the title compound being obtained in the form of a chloride.

Examples 395-560

The treatment of the 9-oxo derivatives given in Table XIII below with lithium perliydro-9b-bora-phenalyl-hydride the procedure given in Example 394 gives those given in Table XIII below 9a-Hydroxy-11-oxy-15-hydroxy (or methoxy) -13-transprostic acid products.

409847/1159

TABLE XIII example

Starting 9-oxo derivative from Example 9ct-Hydroxy-11-oxy-15 ~ hydroxy- (methoxy) -13-trans-prostenic acid product

395
396

3-97
398

399
400

401
402

403

404

405

228

229

230 231

232 233 234 235

236

237

238 9 <2-hydroxy-11a-methoxy-15 hydroxy-20-ethyl-13 ~ trans prostenic acid

9a-hydroxy-lla-methoxy-15 hydroxy-16-ethyI-13-trans prostenic acid

methoxy-13-trans-prostenic acid

9a-hydroxy-lla-methoxy-15-hydroxy-13 ~ trans-17-cis- prostadic acid

9 <* - Hydroxy-llct-inethoxy-15-hydroxy-löjlö-dime trans-prostenic acid

hydroxy-17,17-dimethyl-13-trans-prostenoic acid ·

9 "-Hy droxy-1 lQc-methoxy-15-hydroxy-17,18-cis-methano-13-trans-prostenic acid

9ot-Hydroxy-IIIa> methoxy-15-hydroxy-16,17,18,19,20-pentanor-15- (1-adamanty1) -13-transprostic acid ·

9a-Hydroxy-loc-methoxy-15-hydroxy-16,20-methano-13-trans-17-prostadienoic acid

9 ", 15 ~ dihydroxy-11a-methoxy-16 ^ O-ethanol - ^ - trans-prostenic acid

9α-hydroxy-llα-methoxy-15-hydroxy-l6,19-trans-ethano-13- trans-prostenic acid

409847/1159

_ 9 * 7 -

TABLE XIII (continued):

example

Starting 9-oxo derivative of Example 9a-hydroxy-11-oxy-15-hydroxy- (methoxy) -13-trans-prostenic acid product

4o6

"407

408

409

410

411

412

413

414

415

416

239

240

241

242

243

244

245

246

247

248

249 9 <2r-Hydroxy-IIQ: -methoxy-15-hydroxy-6,7,19,20-tetranor-13-trans-prostenic acid

9 ^a -hydroxy-lla-methoxy-15-hydroxy-6,7-dinor-17,20-ethano-13-trans-prostenic acid

gyyyS hydrox.V-5,6,7,20-tetranor-17,19-n "9thano-13-trans-prostenic acid

9a-Hydrb :: y-lia-ethoxy-15-hydroxy-5 > 6,7,18,19,20-hexanor-13-trans-prostenoic acid

9a-hydroxy-llcc-inethoxy-15-hydroxy-7a, 7b-bis-homo-20-ethyl- 13-trans-prostenic acid

9α-Hydroxy-11α-n-ethoxy-15-hydroxy-7a, 7b-bis-hoino-16,16-dimethyl-13-trans-prostenic acid

9a-hydroxy-lla-ynethoxy-15-hydroxy-7a, 7b-bis-homo-16,20- (1,3-propane) -13-trans-prostenic acid

9a-Hydre-ky-iia: -methoxy-15-hydroxy '"3-ethyl-20-nor-13-trans- prostenic acid

9α-Hydroxy-11αr-methoxy-15-hydroxy-2-ethyl-16,20-methano-13-trans-18-prostadic acid

9a-Hydroxy-11a-methoxy-3,3-dimethyl-16- (1-adamantyl) -17,18,19,20-tetranor-13-trans-prostenic acid

9a-hydroxy-lla-methoxy-15-hydroxy-3,3,20-trimethyl-13-trans-prostenic acid

409847/1159

TABLE XIII (continued):

example

Starting 9-0x0 derivative of Example 9a-Hydroxy-ll-oxy-15-hydroxy- (methoky) -13-trans-pro3ten- acid product

417

4l8
419

420
421
422

423
424

425
426
427

250

251 252

253 254 255 256 257 258

259 260 9tf-Hydroxy-lla-methoxy-15-hydroxy - ^ - oxa - ^ - trans-prosten acid

9a-Hydroxy-llct, 15-dimethoxy-3-oxa-13-trans-prostenic acid

9a-Hydroxy-II <x-methoxy-15-hydroxy-3-oxa-16,16-dimethyl-13-trans-prostenic acid

9a-hydraxy-lla-methoxy-15-hydroxy "3-oxa-17,20-ethano-13- trans-18-prostadic acid

yyy hydroxy-3-oxa-16,20-methano-13 trans-prostenic acid

hydroxy-2-fluoro-18,20-ethano-13-trans-prostenic acid ·

9a-Hydroxy-II <x-methoxy-15-hydroxy-2-fluoro-16-raethyl-20-nor-13-trans-prostenic acid

9a-Hydro.Yy-II <7.-methoxy-15 ~ hydroxy-'f, 20-'dinor-13-transprostic acid

9a-Hydroxy-11E-methoxy-15-hydroxy-7-nor-17,20- (1,4-butane) -13-trans-prostenic acid

9tt-Hydroxy ~ lla.-methoxy-15-hydroxy ^ Ä-homo ^ O-methyl - ^ -. trans-prostenic acid

9a-Hydroxy-llct-ynethoxy-15-hydroxy-7a-homo-17,18-cismethano-13-trans-prostenic acid

409847/1159

TASSLLE XIII (continued):

example

Starting 9-oxo derivative of Example 9a-hydroxy-11-oxy-15-hydroxy- (methoxy) -13-trans-prostenic acid product

428

429

430

431

432

433

261

262

263

264

265

266

434 26? 435 268 436 269 437 270 43d 271

9rt-Hydroxy-ll <i-methoxy-15-hydroxy ^ a-homo ^ O-cyclopentyl- 13-trans-prostenic acid

9a-Hydroxy-11a-methoxy-15-hydroxy-2-phenyl-17,17-dimethyl 13-trans-prostenic acid

9oc-Hydroxy-IIIX-methoxy-15-hydroxy-2-phenyl-18,20- (1,3-propane) -13-trans-prostenic acid

9 "-Hydroxy-IIIa-ethoxy-15-hydroxy-16, 16-dimethyl-13-, trans-pi'ostenic acid

yyy 16-methyl-18,20-ethano-13-transprostic acid

gyyyy 19-methyl-'13-transT18-prostadic acid

9o.-Hydroxy-llo; -ethoxy-15-hydroxy-13-trans-17-prostadic acid

9a-Hydrr.vy-lla-propoxy-l6, l6-dimethyl-iS-trans-prostenic acid

9 <z-Hydroxy-lla-propoxy-15-hydroxy-20-nor-13-tran3-prosten- acid

hydroxy-13-trans-prostenic acid

9 # ~ Hydroxy-1 la-propoxyl6,17 _J 18,19,20-pentanor-15- (2-adamantyl) -13-trans-prostenoic acid

409847/1159

TABLE XIII (continued):

example

Output 970x0 derivative of Example 9a-Hydroxy-II-oxy-15-hydroxy (methoxy) ~ 13-trans-prostenic acid product

4-39

44o

441
442

443
4th

446
447
443

449
450

272

273

274 275

276

277 278

279 280 231

282 283 9A-Hydroxy-11O: -propoxy-15-hydroxy-17,20-ethano-13-trans- 19-prostadic acid

hydroxy-13-trans-17-prostadiene acid

g hydroxyllaisopropoxyl S. methoxy-13-trans-prostenic acid

9a-hydroxy-11σ-isopropoxy-15-hydroxy-l6, l6-dimethyl-13-trans- prostenic acid

9 ^ -Hydroxy-lla-isopropoxy-15-hydroxy-17,20-methano-13-trans- prostenic acid

9a-hydroxy-lla-isopropoxy-15-hydroxy-13-trans-prostenoic acid

9a-Hydroxy-4-n-butoxy-15-hydroxy-16 ₃ 16-dimethy1-13-transprostic acid

9 "-Hydroxy-4-n-butoxy-15-hydroxy-13-trans-prostenoic acid

9a-Hydroxy-4-n-butoxy-16-methyl-20-nor-13 ~ trans-prostenic acid

9 - ^ - Hydroxy-4-n-butoxy-16-ethyl-19 ₃ 20- (1,3-propane) -13-trans-prostenoic acid

9 ^Q -Hydroxy-4-n-butoxy-15-hydroxy-16,20-ethano-13-trans-prostenic acid

9a-Hydroxy-lia-methoxy-15-hydroxy ■ 2,17-diniethyl-20-nor-16,19-trans-methano-13-trans-prostenic acid

409847/1159

L ¹ TABLE XIII (amendment):

example

451

Λ52 453 454 5 5 456

457 458 459

460 461

Ausgar.gs-9-oxoderivat of example

284

285

286

287

288

289 9a-Hydroxy-II-oxy-: L5-hydroxy- (methoxy) -13-trans-prostenic acid product

290

291

292

293

294 yyy hydroxy-2, 16, 16-trircethyl-13-trans-prostenic acid

9 ^ -Hydroxy-llo £. -Methoxy-15-hydroxy-2-ynethyl-13-tran3-prostenic acid

9a-Hydrc: cy-llot-ethoxy-15-hydroxy-'i3-trans-prostenic acid ethyl ester

Ethyl 20-methyl-17,2ü-ethano-13-transpr03tenate

9ct-Kydroxy-II <r-metnoxy-15-hydroxy-16, 16-dimethyl-13-transprostenic acid ethyl ester

9or-hydroxy-llo-methoxy-15-hydroxy 16,17,18,19,20-pentanor-15- (2-adamantyl) -13-trans-prostenoic acid methyl ester

9Λ-hydroxy-lla-propoxy-15-hydroxy 6,7-dinor-13-trans-prostenic acid ethyl estersr

9-i-HydrJ>'y-lla-isopropoxy-15-hydroxy-5,6,7-t ^r i ^nor ~ 13 prostensäureäthylester

hydroxy-7a, 7b-bis-homo-17-methyl 20- (2-propenyl) -13-trans-prosten acid ethyl ester

9 <^ - Hydroxy-ll ^ -isoprcpoxy-15-hydroxy-7a, 7b-bis-homo-13-trans- 17-prostadienoic acid ethyl ester

ethyl-13-trans-prostenic acid ethy1 ester

409847/1159

TABLE XIII (continued):

example

462

463

464

465

466

467

463

469

470

471

472

Starting 9-oxo derivative of example

295

296

297

298

299

300

301

302

303

304

305 9a-Hydroxy-II-oxy-15-hydroxy- (methoxy) -13-trans-prostenic acid product

9 * -Hydroxy-II <* - butoxy-15-hydroxy-2-ethyI-16, 16-dimethyl-13-trans-prostenic acid ethyl ester

9 ^ .- Hydroxy-lla-methoxy-15-hydroxy-3j3 ~ dimethyl-13-transprostic acid ethyl ester

9 <? - Hydroxy-llcx-methoxy-15-hydroxy-3,3,16,16-tetramethyl-13-trans-prostenic acid ethyl ester

■ 9a-Hydroxy-IIIa-ethoxy-15-hydroxy-3-oxa-20-ethyl-13-transprostic acid ether

9a-hydroxy-loc-ethoxy-15 ~ hydroxy-. 3-oxa-19,20- (1,3-propane) -13-trans-prostenoic acid ethyl ester

9'i-Hydroxy-lia-sec-butoxy-15- hydroxy-7 ~ nor-20-ynethyl-13-trans- " Prostic acid ester

9 <i-Hydroxy-11a-sec-butoxy-15-hydroxy-7-nor-19,20- (1,4-butane) -13-trans-prostenoic acid ethyl ester

9 <α-Hydroxy-llix-methoxy-15-hydroxy-7a-homo-17,20- (1,3-propane) -13-trans-prostenic acid ethy1-ester

g ^ -Hydroxy-lia-methoxy-IS-hydroxy- Ia -homo - ^ - trans-ilJ-prostadienoic acid ethyl ester

9 ^ -Hydroxy-11a-methoxy-15 ~ hydroxy-20, 20- (1,4-butane) -13-trans-butyl ester

9 <i-Hydroxy-II <* - methoxy-15-hydroxy-16,16-dimethyl-13-trans-prostenic acid butyester

409847/1159

TABLE XIII (continued):

Example starting 9-oxo-9 ^ -hydroxy-II-oxy-15-hydroxy derivative of (methoxy) -13-trans-prosten example acid product

^ 73 306 9 <-T-Hydroxy-lla-methoxy-15-

butyl hydroxy-13-trans-prostenoate

307 'gotyyS

hydroxy-16, 16-dimethyl ~ 13-trans. isopropyl prostate

475 308 9fr-Hydr-j * y-llqr-methoxy-15-

isopropyl hydroxy-13-trans-prostenoate

gayyyS hydroxy-17,19- (1,3-propane) -13-trans-prostenic acid.-isopropyl ester

ga-hydroxy-llcr-methoxy-lS-hydroxy

17,18-cis-methano-13-trans-prostenic acid isopropyl ester

9ft-Hydroxy-lia-methoxy-15-hydroxy-13-trans-prostenic acid decyl ester

9-3-hydroxy-1: La-niethoxy-15-hydroxy-

Ib, Ifa-dimethyl-13-trans-prostenic acid decy lester

9a-Hydrc ^ v-llcc-methoxy-15-hydroxy

20-ethyl: 13-trans-prostenic acid decyl ester

^{1) 81} 31 ^ '■ 9o-hydroxy-11a-methoxy-15-hydroxy

17,20- (1,3-propane) -13-transprostic acid decyl ester

^ ³²³¹⁵ 9α-HydΓoxy-ilα-methoxy-i5-hydroxy

17,20-methano-13-trans-decyl prostate

316 9a-hydroxy-lla-tert-butoxy-15-

ethyl hydroxy-13-trans-prostenoate

409847/1 V59

'- 104 -

TABLE XIII (continued):

example

Starting 9-oxo derivative of Example ga-hydroxy-ll-oxy-lfj-hydroxy- (methoxy) -13-trans-prosten- sSure product

484

485

486
467

488
489

490
491
492

493
494

317 318

319, 320

321 322

323 324

325

326 327 9 ^a -Hydroxy-II * -tert-butoxy-15-hydrpxy-16, 16-dimethyl-13-transprostic acid ethyl ester

9 "-Hydroxy-IIOL-tert. -butoxy-20-nor-17,18-trans-1,3-propane-13- trans-prostenic acid ethyl ester

yyc- (2-hydroxyethoxy) 15-hydroxy-13-trans-prostenic acid

9ö-Hydroxy-lia- (2-hydroxyethoxy) -15 ~ hydroxy-16, 16 ~ dimethyl-13-transprostic acid

y- (2-hydroxyethoxy) 15-hydroxy-17,18-cis-methano-13-trans-prostenic acid

9 ^ -Hydroxy-lia- (2-hydroxyethoxy) -15-hydroxy-16,17,18,19,20-pentanor-15- (1-adamantyl *) - 13-transprostic acid

9a-hydroxy-lla- (2-hydroxyethoxy) -15 ~ hydroxy-20-ethyl-13-trans- prostenic acid

9o.-Hydroxy-lla- (2-hydroxyethoxy) -

15-hydroxy-16-ethyl-13-transprostic acid

9a-Hydroxy-IIIa- (2-hydroxyethoxy) -15-hydroxy-16,20ethano-13-transprostic acid

9a-hydroxy-llor- (2-hydroxyethoxy-) 15-methoxy-13-trans-prostenic acid

9 "-Hydroxy-lia- (2-hydroxyethoxy) -15-hydroxy-13-trans-17-cis-prosta dienic acid

409847/1159

TABLE XIII (adjustment):

example

Starting 9-oxo derivative of Example 9a-Hydroxy-II-oxy-15-hydroxy- (methoxy) -13-trans-prostenic acid product

496

497
ή 9-8
499
500

501
502

503
504

505

328

329

330

331

332

333

334

335

336

337

338 9'J-hydroxy-llcr- (2-hydroxyethoxy) 15-hydroxy-6,7 _J 19,20-tetranor-13-trans-prostenoic acid

9or-hydroxy-lla- (2-hydroxyethoxy) 6,7-dinoi-17,20-ethano-13-transprostic acid

9 ^ -hydroxy-lla- (2-hydroxyethoxy) 15-hydroxy-5,6,7,18,19,20-hexanor-13-trans-prostenic acid

gyyr- (2-hydroxyethoxy) -

15-hydroxy-5,6,7-trinor-16,20-ethano-13-trans-prostenic acid

91-Hydroxy-llcr- (2-hydroxyethoxy) -15-hydroxy-7a, 7b-bis-homo-20- ethyl-13-trans-prostenic acid

9'X-Hydroxy-1 la- (2-hydroxyethoxy) -IShd ^^ ioo

Syry ^ a ^ bbishomolojlo dimethyI-I3-trans-prostenic acid '

9 <X-Hydroxy- 11α- (2-hydroxyethoxy) 15-hydroxy-7a, 7b-bis-homo-13- trans-prostenic acid

9a-Hydroxyrllce- (2-hydroxyethoxy) 15-hydroxy-7a, 7b-bis-homo-16,20- (1,3-propane) -13-trans-prostenic acid

9a-Hydroxy-liaT (2-hydroxyethoxy) - • IS-hydroxy ^ -ethyl ^ O-cyclopentyl-13-trans-prostenic acid

9 * -Hydroxy-lla- (2-hydroxyethoxy) - 15-hydroxy-2-ethyl-13-transprostenoic acid

9 ° t-Hydroxy-llcr- (2-hydroxyethoxy) -15-hydroxy-3,3-dimethyl-13-trans- prostenic acid

409847/1159

TABLE XIII (continued):

example

506

507

508

509

510

511

512

513

514

515

Starting 9-oxo derivative of example

339

340

341

342

343

344

345

346

347

348 Qa-Hydroxy-II-oxy-IS-hydroxy- (methoxy) -13-trans-prostenic acid product

9tt-Hydroxy-11 α- (2-hydroxyethoxy) -15-hydroxy-3,3-dimethyl-16-ethyl-13-trans-prostenic acid

9a-hydroxy-11 α- (2-hydroxyethoxy) -15-hydroxy-3,3-didiraethyl-17,20- (1,3-propane) -13-trans-prostenic acid

9a-Hydroxy-11α- (2-hydroxyethoxy-15-hydroxy-3-oxa-13-transprostic acid

9a-hydroxy-11 α- (2-hydroxyethoxy) -15-hydroxy-3-oxa-16,16- ^ dimethyl1-13-trans-prostenic acid

9a-hydroxy-11 a- (2-hydroxyethoxy) -15-hydroxy-3-oxa-16,19-trans-13-trans-äthano pro'stensäure

• 9a-Hydro xy-11 a- (2-ihydroxyethoxy) -15-raethoxy-3-oxa-13-trans-prostenic acid

9 <x-hydroxy-11 α- (2-hydroxyethoxy) 15-hydroxy-3-oxa-13-trans-17-cisprostadienoic acid

9a-Hydroxy-11 oc- (2-hydroxy- · ethoxy) -15-hydroxy-3-oxa-16,20-methano-13-trans-17-prostadiene acid

9a-Hydroxy-11α- (2-hydroxyethoxy) -15-hydroxy-2-fluoro-16,16-dimethyl-13-trans-prostenic acid

9a-Hydroxy-11α- (2-hydroxyethoxy) -15-hydroxy-2-fluoro-13-transprostic acid

409S47 / 1159

TA = ELLE XIII (continued)

example

Starting 9-oxo derivative from BeisDiel

9a-Hydroxy-II-oxy-15-hydroxy- (methoxy) -13-trans-prostatic acid product

516 517 518

519 520

521

349

350

351

352

353

354

522

523 524

355

358 357 9a-hydroxy-11 α- (2-hydroxyethoxy) -15-hydroxy-2-fluoro-17,20- (1,4-butane) -13-trans-prostenic acid

9a-hydroxy-11 a- (2-hydroxyethoxy) -1 S-hydroxy ^^ O-bisnor-i 3-trans-prostenoic acid

9a-hydroxy-11cc- (2-hydroxyethoxy) -15-hydroxy-7,20-msnor-16-methyl-13-trans-prostenic acid

9 «-Hydroxy-11 α- (2-hydroxyethoxy) -15-hydroxy-7a-homo-20-methy1-13-trans-prostenic acid

9a-hydroxy-11 α- (2-hydroxyethoxy) -15-hydroxy-7a-homo-16,16-dimethyl-13-transprostic acid

9a-hydroxy-11 α- (2-hydroxyethoxy) -15-hydroxy-7a-homo-16,17,18,19,20-pentanor-15- (2-adamantyl) -13-trans-prostenic acid

9a-Hydroxy-11α- (2-hydroxyethoxy) - ' 15-hydroxy-2-phenyl-13-transprostic acid .

9oc-Hydroxy-11 a- (2-hydroxypropoxy) -15-hydroxy-13-trans-prostenic acid

9a-Hydroxy-11cc- (2-hydroxypropoxy) -15-hydroxy-16,16-dimethyl-13-trans-prostenic acid

409847/1159

TABLE XIII (continued):

example

Starting 9-oxo derivative of Example 9a-hydroxy-.ll-oxy-15-hydroxy- (methoxy) -13-trans-prostenic acid product

525

526 527 528 529

530

531

532 533

358

359 360

361 362

363

364

365 366 9a-Hydroxy-11α- (2-hydroxypropoxy) -15-hydroxy-16-methyl-18,20-ethano-13-trans-prostenic acid

9a-Hydroxy-11a- (2-hydroxypropoxy) -15-hydroxy-13-trans-17-cis-prostadienoic acid

9a-Hydroxy-11a- (4-hydroxybutoxy) -15-hydroxy-13-transprostic acid

9oc-Hydroxy-11α- (4-hydroxybutoxy) -i5-hydroxy-16,16-dimethyl-13-trans-prostenic acid

9cc-hydroxy-11 α- (2-hydroxyethoxy) -1 5-hydroxy-16,16-dimethyl-13-trans-prostenoic acid ethyl ester

9a-hydroxy-11α- (2-hydroxyethoxy ) -15-hydroxy-17-raethyl-20- (2-propenyl) -13-trans-prostenic acid - äthyIe s te r

9a-Hydroxy-11α- (2-hydroxyethoxy) 15-hydroxy-19,20-dinor-16,17- (1,3-propane) -13-trans-prostenic acid ethyl ester

9a-Hydroxy-11 a- (2-hydro> ^ rethoxy) -

15-hydroxy-19,20- (i _f 4-butane) -i3-trans-prostenic acid ethyl ester

9a-Hydroxy-11α- (2-hydroxyethoxy) -15-hydroxy-20-nor-13-transprostic acid methyl ester

A09847 / 11B9

TABLE XIII (continued):

For example

Starting 9-oxo derivative of example 9a-hydroxy-11-oxy-15-hydroxy- (methoxy) -13-trans-prostenic acid product

534

535

536

367

363

369

537

538

539

540

541

370

371

372

.373

374 9a-Hydroxy-11 «- (2-hydroxyethoxy) -15-methoxy-13-transprostic acid methyl ester

9a-Hydroxy-11α- (3-hydroxypropoxy) -15-hydroxy-6,7,20-trinor-17,19-iae thano-13-trans prostenic acid ethyl ester. .

9a-Hydroxy-11α- (2-hydroxyethoxy) -15-hydroxy-5,6,7-trinor-16-ethyl-19,20- (1,3-propane) -13-trans-prostenic acid ethyl ester

5''12

375 y / - 11 a- (2-hydroxyethoxy) -15-hydroxy-7a, 7b-bishomo-17,18-cis-methano-i3-trans-prostenic acid ethyl ester

9a-Hydro> ^ - 11 «- (2-hydroxyethoxy) -15-hydroxyt-7a, 7b-bishoino-13-trans-17-cis-prostadienoic acid ethyl ester

9a-Hydroxy-11α- (2-hydroxyethoxy) -15-hydroxy-7a, 7b-bishomo-17 , 20-ethano-13-trans-18-prostadic acid ethyl ester

9a-Hydroxy-11 -α- (3-hydroxypropoxy) -15-hydroxy-2-ethyl-13-trans-17-cis-prostadienoic acid ethyl ester

9a-Hydroxy-11α- (3-hydroxypropoxy) -15-hydroxy-2-ethyl-18,20-ethano-13-trans-prostenic acid ethyl ester

9c <-hydroxy-11 <* ■ - (3-hydroxyethoxy) ■ 3 _J 3 _J 17 _J 17-tetraniethyl-13-transprostensriureäthylester

A098A7 / 1159

TABLE XIII (continued):

example

Starting 9-oxo derivative of Example 9a-Hydroxy-II-oxy-15-hydroxy- (methoxy) -13-trans-prosten- acid product

543

544

545

546

547

548

549

376

377

378

379

380

381

382

550

551

333

384 9a-Hydroxy-1 1 ct- (2-hydroxyethoxy) -15-hydroxy-3,3,20-trimethy1-17,20-ethano-13-transprostic acid ethyl ester

9a-hydroxy-11 α- (3-hydroxypropoxy) 15-hydroxy-3-oxa-16,16-dimethyl-13-trans-prostenic acid ethyl ester

9 <x-hydroxy-11 α- (3-hydroxypropoxy) -15-hydroxy-3-oxa-16, 2O-raethano-13-ti: "AnsprostensäureäthylesteGr

9a-Hydroxy-11a- (2-hydroxyethoxy) -15-hydroxy-13-transprostanoic acid butyl ester

9a-Hydroxy-11α- (2-hydroxyethoxy) -15-hydroxy-16 , 16-dimethyl-13-trans-prostenic acid butyl ester

9a-hydroxy-11 a- (2-hydroxyethoxy) -15-hydroxy-17,18-cismethano-13-trans-prostensäurebutyle s ter

9a-hydroxy-11a- (2-hydroxyethoxy) -15-hydroxy-17,19-0,3-propane) -13-tr * ans-butyl prostenoate

9a-Hydroxy-11a- (2-hydroxyethoxy) -15-hydroxy-16,20-methano-13-trans-18-prostadienoic acid butyl ester

9a-Hydroxy-11 oc- (2-hydroxyethoxy) -15-hydroxy-13-trans-17-cis-prostenic acid butyl ester

4098A7 / 1159

TABLE XIII (adjustment):

Beiooiel

Output ~ 9 ~ oxoderivat of Example gct-hydroxy-II-oxy-IS-hydroxy- (methoxy) -13-trans-prostenic acid product

552 553 554 555

385

.386

387

388

556

557 558

559 560

389

390

391

392

393 9rc-hydroxy-11 α- (2-hydroxyethoxy) -15-hydroxy-13-trans-1 7- cis-prostadienoic

9 "-Hydroxy-11α- (2-hydroxyethoxy) -15-hydroxy-19-methyl-13-trans-18-isopropyl prostate ester

9a-Hydrcy-11α- (2-hydroxyethoxyj - ^: 15 ~ hydroxy-16,16-dimethyl-13-trans-prostenic acid isopropyl ester

9 (i-Hydroxy-11α- (2-hydroxyethoxy) -15-hydroxy-17,18,19,20-tetranor-16- (1-adamantyl; -13-trans-isopropylic acid ester

9a-Hydroxy _r 11 cc- (2-hydroxyethoxy) -15-hydroxy-13-transprostic acid decyl ester

9a-Hydroxy-11 oc ~ (2-hydroxyethoxy) -15-hydroxy-16,16-dimethyl- * ¹ 3-trans-prostenic acid decyl ester

9a-Hydroxy-11 & - (2-hydroxyethoxy) -15-methoxy-13-transp ro s tens acid de cyle s te r

9a-Hydroxy-11a- (2-hydroxyethoxy) -15-hydroxy-20-nor-17,18-trans- (1,3-propane) -13-transprostic acid decyl ester

9a-hydroxy-11α- (2-hydroxy-

ethoxy) -i5-hydroxy-13-trans-17-cis-prostadienoic acid decyl ester

4098.47 / 1 159

Be i s ρ i e 1 56I

To 2.2 equivalents Lithiumperhydro-9b-bora-phenalyl hydride in tetrahydrofuran at -78 ⁰ C is added a solution of 9-oxo-11 * -methoxy-15-hydroxy-13-trans-prostenoic acid (Example 227). After 30 minutes, the solution is diluted with water and extracted with Xther. The aqueous phase is then acidified, saturated with sodium chloride and extracted with ether. The combined ether extracts are dried (over magnesium sulfate) and concentrated in vacuo, 9%; The crude acid mixture is dissolved in methylene chloride and added to a refluxing solution of 1.2 equivalents of 2,3-dichloro-5j6-dicyano-benzoehinone (DDQ) in P4ethylene chloride the solution was cooled and filtered. the filtrate is concentrated in vacuo and the residue purified by column chromatography, where 9 <X. -hydroxy-hoC -ethoxy obtained 15-oxo-13-trans-prostenoic acid. This material is dissolved in benzene ₄ after which 2.2 equivalents (each of trinethylsilyl chloride and trimethylamine) of triethylamine hydrochloride are filtered off and the solution is concentrated in vacuo to 9 ° C-trimethylsiloxy-11 / X-methoxy-15-0x0-13-trans-prostenic acid trimethylsilicate.

The siloxy derivative is ^{dissolved in ether at 0} ° C. and 1.05 equivalents of methyl magnesium bromide are added. After the reaction has ended, the solution is poured into a saturated aqueous ammonium chloride solution and extracted with ether. The ether is dried and evaporated to an oil in vacuo. The oil is dissolved in a methanol-water-acetic acid mixture (approx. 10: 1: 1). After standing for about 3 hours at room temperature, the solution is diluted with water, saturated with sodium chloride and extracted with ether. The ether extracts are dried and concentrated in vacuo, whereby one

409847/1159

9 α, 15 <x -dihydroxy-15β-methyl-11a-methoxy-13-trans-prostenic acid and 9a, 15β-dihydroxy-15a.-meth.yl-11a-methoxy-13-transprostic acid is obtained, the column chromatography v / earth separately.

Treatment of a solution of "9a, 15 # -dihydroxy-15β-methyl-1 ia-methoxy-13-trans-prostenic acid with chromic acid-pyridine in methylene chloride (Collins reagent) followed by addition of dilute acid and extraction with ether gives the 9-0xo-11 <X-methoxy-15a-hydroxy-15ß-methyl-13-trans-prostenic acid.

A similar treatment of the corresponding 15β-hydroxy acid gives 9-oxo-1ict-methoxy-15β-hydroxy-15′-methylprostenic acid.

Examples 562-605

The treatment of the 9-0x0-15-hydroxy-prostenic acids given in Table XIV below in accordance with the reaction sequence given in Example 561 leads to the 9-0xo-15-hydroxy-15-methyl products given in Table XIV below. In the course of this The reaction sequences are also the 9a-hydroxy derivatives corresponding to the products given in the table, the 15-keto derivatives of the 9a and 9ß-hydroxy compounds corresponding to the 9-oxo starting compounds and the 9a- or 9ß-trimethylsilyloxy-trimethylsilyl esters of the 15-keto and IS-hydroxy 15-niethyl compounds · formed. In the case of the 1 ία- (ω-hydroxyalkoxy) derivatives, the silylation takes place with 3.3 equivalents of trimethylsilyl chloride and triethj'iamine, resulting in a silylation. the G / hydroxy group is reached. In all cases, both the 15 ^ -hydroxy-15ß-methyl and the 15ß-hydroxy-15a: methyl products and their intermediate products are obtained. The epimers can be separated chromatographically.

409847/1159

TABLE XIV example

562

563

564

565

Starting 9-oxoll-oxy-15-hydroxyprostenoic acid of example

228

231

239

242

566

243

567

568

569

570

246

249

250

253 9-Oxo-II-oxy-15-hydroxy-15-methy 1-13-trans-proscenic acid product

-hydroxy-l'S-methyl- ^ O -ethyl-13-trans-prostenic acid

-hydroxy-IS-methyl-ljJ -trans-17-cis-prostadic acid

9- ° xo-lla-raethoxy-15- -hydroxy-IS-methyl-ö, 7 * 19.20-tetranor-13- -trans-prostenic acid

9-0xo-llα-ethoxy-15-. -hydrόxy-15-methyl-5ί 6,7,18 ^ 19 20-hexanor ~ -15-trans-prostenoic acid

-hydroxy-15-niethyl-

-ethyl-15-trans-pros tens acid

9-Oχo-llα-ethoxy-15 -hydroxy-15-methyl-2

-pros tens aur-e

-hydroxy-15-raethyl- - ^^, SO-trimethyl-l ^ -trans-prostenic acid

9-0xo-lla-methoxy-15-hydroxy-IS-raethyl-? -oxa-15-trans-prostenic acid

-hydroxy-IS-methyl-} -oxa-17i20-ethano-13 -trans-18-prostadienoic acid

409847/1159

TABLE XIV (continued):

Example starting 9-oxoll-oxy-15-hydroxyprostenic acid of example methyl-13-trans-prostenic acid product

571

572

573

575

576

577

578

579

580

581

255

257

258

259

260

261

263 '

266

267

269

270 9-oxo-llct-methoxy-15-hydroxy-15-methyl-2-fluoro-18,20-ethano-13-trans-prostenic acid

9-Oxo-llα-methoxy-15-hydΓoxy-15-methyl-7,20-dinor-13-trano-prosten- acid

yyy methyl-7-nci «-17.20- (1,4-butane) -13 trans-prostenic acid

9rOxo-lla - irii? Thoxy-15-hydroxy-15-

inethyl-7a-ivDmo-20 ~ methyl-13-trans prostenic acid

yy methyl-7a-homo-17,18-cis-methano-13-trans-prostenic acid

methyl-20-cyclopentyl-7a-homo-13 " trans-prostenic acid

gOxolamethoxylShydroxylS methyl-2-pheny 1-18,20- (1,3-propane) '- 13 ~ trans-prostenic acid

9-oxo-llß-ethoxy-15-hydroxy-15-methyl-19-methyl-13-trans-18- prostadic acid

9-oxo-lW-ethoxy-l5-hydroxy-15-methy1-13-trans-17-cis-prostadiene- acid

9-oxo-11O'-propoxy-15-hydroxy-15-methyl-20-nor-13-trans-prosten- acid

9-Oxo-II «X-propoxy-15-hydroxy-15-methyl-13-trans-proxy acid

4098A7 / 1159

TABLE XIV (continued):

Example starting 9-oxo-II-

oxy-15-hydroxyprostenic acid of example

582

583
584

585

586
587

588

■

590

591

273

277

279

285

319

321

323

327

328

330

9-Oxo-II-oxy-15-hydroxy-15-rne thy 1-13-tranG-prostatic acid eproduct

9-Qxo-lla-isopropoxy-

-13-trans-17 -eis -prostadienoic acid

9- ° xo-lla-i s opr opoxy-15- -hydroxy-IS-methyl-IJ- -trans-prostenic acid

9-0xo-4-ri-butoxy-15- -hydroxy-15-methy1-13- -trans-prostenic acid

9-oxo-lla-methoxy-15-

-methyl-13-trans-ρ rostenic acid

9-oxo-lla- (2-hydroxyethoxy ) -15-hydroxy-15- -methyl-13-trans-prostenoic acid

9-oxo-lla- (2-hydroxyethoxy) -15-hydroxy-15-lÖ

-methano-13-trans-rostenic acid

9-oxo-lla- (2-hydroxyethoxy) -15-hydroxy-15- -methyl-20-ethyl-13- -trans-prostic acid

9-Οχο-ΙΙα- (2-hydroxyethoxy) -15-hydroxy-15- -methyI-I3-trans-17-cis -prostadienic acid

9-0χο-11α- (2-hydroxyethoxy ) -15-hydroxy-15- -methyl-6,7,19,20-tetranor-13-trans-prostenic acid

9-Oxo-Ila- (2-hydroxyethoxy) -15-hydroxy-15-methyl-5,6,7,18,19,20 -'-hexanor-13-trans-prostenic acid

409847/1159

TABLE XIV (continued)

example

592

Aus.g & ngs-9-oxo-ll-oxy-15-hydroxyprostenic acid of example

593

33-4

594

336

ς ο -

337

595

338

597

341

598

599

600

601

345

348

9-Oxo-II-oxy-15-hydroxy-15-me thy .1-13 -trans-pros acid product

9-0χο-11α- (2-hydroxy-

jithoxy) -15-hydroxy-15- ' -methyl-7a, 7t) -bishomo- -20- ethyl-13-trans- prostic acid

9- Qxo-lla ~ (2-hydroxyethoxy ) -15-hydroxy-15-hlTTbih

-13-trans-prostenic acid

9-Oxo-Ila- (2-hydroxygthoxy) -15-hydroxy-15 thla

- • cyclopentyl-15-trans »-Prostenic acid

5-0xo-lla- (2-hydroxyethoxy ) -15-hydroxy-15 -methyl-S-ethyl-U- -trans-17-cis-prostadic acid

9-0xo-lla- (2-hydroxy-

ethoxy) -15-hydroxy-15-methyl "" 3,3-diinethyl- -13-trans-prosten-Sciure

9-oxo-lla- (2-hydroxyethoxy ) -15-hydroxy-l5- -methyl-3-oxa-13-trans- -prostengic acid

9-Oxo-Ila- (2-hydroxy-ethoxy) -15-hydroxy-15 -methyl-3-oxa ~! 3-trans -prostadienic acid

350

352

409847/1159 9-Qxo-Ila- (2-hydroxyethoxy) -15-hydroxy-15- -methyl-2-fluoro-13- -trans-prostenic acid

9-Qxo-IIIa- (2-hydroxyethoxy) -15-hydroxy-15-methyl-7Jι "20-tιisnor-13 -trans-prostenic acid

9-oxo-lla- (2-hydroxyethoxy ) -15-hydroxy-15- methyl-7ct-hoao-20- -methy1-13-trans-prο stenic acid

TABLE XIV (continued):

Example starting 9-oxoll-oxy-15-hydroxyprostenoic acid. From Example me thy 1-13 ~ trans- _{proste v} acid product

602

003

004

605

355

356

359

360 9-Oxo-IIIa- (2-hydroxy-ethoxy) -15 ~ hydroxy-15-diethyl-2-phenyl-13-trans-prostenic acid

9-Oxo-IIIa- (2-hydroxy-propoxy) -15-hydroxy-15-methyl-13-transprostic acid

9-oxo-lloro- (2-hydroxy-propoxy) ■ 15-hydroxy-15-raethy1-13-trans 17-cis-prostadienoic acid

9-Oxo-11a-- (4-hydroxy-butoxy) 15-hydroxy-15-methy1-13 "trans Prostenic acid

409847/1159

Example 606

Production of ö.er 9-0xo-11a-niethoxy-15-hydroxy7prostanoic acid

One hydriert2 g 9-0xo-1 la-inethoxy-IS-hydroxy - ^ - trans-prostenoic acid (Example 227) using 700 'G fi Paliadiuh-aui-carbon mg in 50 ml of absolute alcohol. The catalyst is filtered off and the mother liquor is evaporated to dryness, 2 g of the title compound being obtained in the form of an oil .

Examples 607-634

The catalytic ^ hydrogenation of those in the following table ZV specified 13-trans prostate acids and their esters according to the method described in example 606 results in the in the prostanoic acids and their esters given in Table XV below.

409847/1159

- 120 - TABLE XV example Output-13-trans-
prostenic acid or
-Ester by example 607 228 608 229 609 230 610 232

611 612 613

233

235

611 615 616 617 618

237

238

239

242

243

11-0xy-15-oxy-prostanoic acid or -Ester product

9-oxo-lla-methoxy-15- -hydroxy-20-ethyl-prostanoic acid

9-oxo-lla-methoxy-15- -hydroxy-16-ethyl-prostanoic acid

9-oxo-lla-methoxy-15- -methoxy-prostanoic acid

9-oxo-lla-methoxy-15- -hydroxy-16,16-dimethyl-prostanoic acid

9-Oxo-Ila-methoxy-15-hydroxy-17,17-dimethyl-prostanoic acid

9-oxo-lla-methoxy-15- -hydΓoxy-17, l8-cis- -methano-ρ ros tan's acid

9-oxo-lla-methoxy-15- -hydroxy-16,17,18,19,20-

J ^ Cld

pJ ^ C, tyl) -prostanoic acid

9-oxo-lla-methoxy-15- -hydroxy-16,20-ethano- -ρrostanoic acid

9-oxo-lla-methoxy-15- -hydroxy-16,19-trans- -ethano-prostanoic acid

9-0 xo-lla-methoxy-15- -hydroxy-6,7,19,20-tetranor-prostanoic acid

9-0x0-lla-methoxy-15- -hydroxy-5,6,7,18,19,20- -hexanor-prostanoic acid

9-oxo-lla-methoxy-15- -hydroxy-7a, 7b-bishomo- -20-ethyl-prostanoic acid

619

244 9-oxo-lla-methoxy-15- -hydroxy-7a, 7b-bishomo-16,16-dimethyl-prostanoic acid

409847/1159

62

524
625

TABLE XV (continued):

Example starting 13-tranoprostenic acid or -Ester by example

620

621

622

246

243

250

251 252

11-0xy-15-oxy ~ prostanoic acid or -Ester product

-hydroxy-7a, 7b-bishomo- -16.20- (1,3-propane) - -prostanoic acid

9-Oxo-lla-methoxy-15- -hydroxy-S-ethyl-SO-nor- -prostanoic acid

9-Oxo-lla-methoxy-15- -hydroxy-3, j5-dimethyl-16 (1-adamantyl) -17,18, -19,20-tetranor-prostanoic acid

9-0 xo-lla-methoxy-15- -hydroxy-3-oxa-prostanoic acid

9-oxo-lla, 15-dimethoxy- -5- oxa-ρrostanoic acid

-dimethyl prostanoic acid

62Ö

627

628

629

254

255

257

259

■ 26ο

631

262 9-0 xo-lla-methoxy-15- -hydroxy-17, 20-ethano- -prostanoic acid

gyS -hydroxy-2-fluoro -18.20- -ethaiio-prostanoic acid

9-0x0 * lla-rae thoxy-15- -hydroxy-7j 20-dinor- -prostanoic acid

9-0 xo-lla-methoxy-15- -hydroxy-7a-homo-20- -methyl-prostanoic acid

9-Oxo-lla-methoxy-15- -hydroxy-7a-homo-17,18- -cis-methano-prostanoic acid

9-Oxo-lla-methoxy-15- -hydroxy-2-phenyl-17,17- -dimethyϊ-ρ rostanic acid

409847/1159

TABLE XV (continued):

example Output-13-trans-
prostenic acid or
-Ester by example • 632 264 633 268 634 270 635 271 636 274 537 275 638 277 639 278 640 279 641 282 642 284 643 285 644 286 645 288

11-oxy-15-oxy-prostanoic acid or -Ester product

SJ-O-xo-lla-ethoxy-lS-hydroxy-

16,16-dimethyl-prostanoic acid

9-oxo-lla-propoxy-15-hydroxy 16,16-dinethyl prostanoic acid

9-oxo-lla-propoxy-15-hydroxy-prostanoic acid

hydroxy-16,17,18,19,20-pentanor-15- (2-adamanty1) prostanoic acid

9-Oxo-IIq-isopropoxy-15-methoxy-prostanoic acid

ppy hydroxy-löjlö-dimethylprostanoic acid

9-oxo-lla-isopropoxyprostanoic acid

9-Oxo-4-n-butoxy-15-hydroxy-16,16-dimethyl-prostanoic acid

9-oxo-4-n-butoxy-15-hydroxyprostanoic acid

9-Oxo-4-n-butoxy-15-hydroxy-16,20-ethano-prostanoic acid

9-oxo-lla-methoxy-15-hydroxy-2,16,16-trimethylprostanoic acid

g-Oxo-lia-methoxy-IS-hydroxy 2-methyl-prostanoic acid

Q-Oxo-lloro-ethoxy-lS-hydroxyprostanoic acid ethyl ester

ySyy 16,16-dimethyl-prostanoic acid methyl ester

A09847 / 1159

ΤΑΏΓ, ΙΙΕ XV (port setting):

Example starting 13-trans- 'prostenic acid or -Ester by example

11-oxy-i5-oxy-prostanoic acid or -Ester-Produlct

646
64.7
648
649
650
651
652
653

295

296

297

298

300

302

304

305

654 306 655 307 656 308 657 310

Ethyl 9-oxo-lla-butoxy- * 15-hydroxy-2-ethyl-16,16-dimethylprostanoate

3,3-dimethyl-prostanoic acid ethyl ester

9-Oxo-II «-methoxy-15-hydroxy-3,3,16,16-tetramethyl-prostanoic acid eäthy he reads

3-oxa-20-ethyl-prostanoic acid ethyl ester

9-0xo-lla-sec-butoxy-15-hydroxy-7-nor-20-methyl- ethyl prostanoate

yy 7a-homo-17.20- (l _> 3-propane) -prostanoic acid ethyl ester

9-oxo-lla-methoxy-15-hydroxy 20,2O- (1,4-butane) -prostanoic acid butyl ester

ySyroxy 16,16-dimethyl-1-prostanoic acid butyl ester

g-Oxo-IIIa-methoxy-IS-hydroxy butyl prostanoate

S-Oxo-IIIa-methoxy-IS-hydroxy 16,16-dimethyl-prostanoic acid isopropyl ester

g-Oxo-IIIa-methoxy-IS-hydroxy isopropyl prostanoate

ySyo 17,18-cis-methano-prostanoic acid-isopropyl ester

4098A7 / 1159

TABLE Ύ.Ύ (continued):

Example of starting o-13-trans- 1i-oxy-15-oxy-prostanoic acid- • - Prostenic acid or ester product -Ester by example

659

660

311 312

661 316 662 317 663 319 664 320

665

666

321

322

667

668

669

323

325

326 9-Oxo-lltx-methoxy-15-hydroxyprostane acid decyl ester

9-Oxo-II'X-methoxy-15-hydroxy-Ib.16-dinethyl-prostanoic acid decyl ester

9-Oxo-II ^a -methoxy-15-hydroxy-17,20- (1,3-propane) -prostanoic acid decyl ester

9-Oxo-IIOL-tert-butoxy-15-hydroxy-prootanoic acid ethyl ester

9-0xo-llo - tert-butoxy-15-hydroxy-16,16-dimethylprostanoic acid ethyl ester

9-Oxo-lia- (2-hydroxyethoxy) -15-hydroxy-prostanoic acid

9-Oxo-IIIa- (2-hydroxyethoxy) -15 ~ hydroxy-16, 16-dimethylprostanoic acid

9-Oxo-IIIa- (2-hydroxyethoxy) -15 ~ hydroxy-17,18-cis-methanoprostanoic acid

9-Oxo-Ila- (2-hydroxyethoxy) -15-hydroxy-16,17,18,19,20-pentanor-15- (1-adamanty1) -prostanoic acid

9-oxo-lla- (2-hydroxyethoxy) -15-hydroxy-20-ethyl-prostanoic acid

9-0xo-lla- (2-hydroxyethoxy) -15-hydroxy-l6,20-ethano- prostanoic acid

9-0xo-lla- (2-hydroxyethoxy) -15-methoxy-prostanoic acid

A09847 / 1159

TABLE XV (continued):

example

Output — 1 iJ-ir

oiler

-int-s-r "vo

6 "/ O

328

671 672 673

330

332

'> Ί ^ι

SV 676 677

678

679 680

333

334

335

336

338

341 -Oxy-15-oxry-pro st anic acid e- or -Ester-Prodiikt

9-oxo-11α- (2-hydroxyethoxy) -15-hydroxy-6, 1, 19, 20-tetranoropropanoic acid

9-oxo-11α- (2-hydroxyethoxy) -15-hydroxy-5,6,7, 18,19,20-hexanor-ρrostanoic acid

9-oxo-lla- (2-hydroxyethoxy) -15-hydroxy-7a, "b- -bishomo-20-ethyl-prostanoic acid

9-oxo-lla- (2-hydroxyethoxy) -15-hydroxy-7a, 7b-

yl-prostanoic acid

9-oxo-lla- (2-hydroxyethoxy) -15-hydroxy-7a, 7b- -bishomo-prostanoic acid

9-0χο-11α- (2-hydroxyethoxy) -15-hydroxy- 7a, 7b- -bishomo-l6,20- (1,3-propane) -prostanoic acid

9-oxo-lla- (2-hydroxyethoxy) -15-hydroxy-2-ethyl- - ^ O-cyclopentyl-prostanoic acid

9-Oxo-Ha- (2-hydroxy ether

oxy) -15-hydroxy-3,3-dimethyl-prostanoic acid

9- Oxo-Ha- (2-hydroxyeth-

oxy) -15-hydroxy-j5-oxa- -prostanoic acid

9- oxo-Ha- (2-hydroxy ethoxy) -15-hydroxy-3-oxa ^{-16,16-dimethyl-prospering:} tansäure

9-oxo-lla- (2-hydroxyethoxy) -15-hydroxy-3-oxa- -16,19-trans-ethano- -prostanoic acid

A09847 / 1159

TABLE XV (continued):

example

prοstensaure or -E3ter -son example

-Oxy-1fj-oxy-prostanoic acid ■ or ester product

681 682

34

347

683 684

685

686 687 688

689 690

350

352

353

355

356

357

360

361 9-Qxo-lla- (2-hydroxyethoxy) -IS-methoxy - ^ - oxa- -prostanoic acid

9-Oxo-11α- (2-hydroxyethoxy) -15-hydroxy-2-fluoro-16,16-dimethyl-prostanoic acid

9-oxo-lla- (2-hydroxyethoxy) -15-hydroxy-7.20- -bisnor-prostanoic acid

9-oxo-lla- (2-hydroxyethoxy) -15-hydroxy-7ahomo- -20-methyl-prostanoic acid

9-oxo-lla- (2-hydroxyethoxy) -15-hydroxy-7a-homo- -16,16-dimethyl-prostanoic acid

9-Oxo-Ila- (2-hydroxyethoxy) -15-hydroxy-2-phenyl-prostanoic acid

9-Oxo-Ila- (2-hydroxypropoxy) -15-hydroxy-prostanoic acid

9-oxo-lla- (2-hydroxypropoxy) -15-hydroxy-16,16- -dimethyl prostanoic acid

9-Oxo-Ila- (4-hydroxybutoxy) -15-hydroxy-prostanoic acid

9-oxo-lla- (J | -hydroxybutoxy) -15-hydroxy-16,16- -dimethyl-prostanoic acid,

A09847 / 1159

TABJ] LLrJ ZV (port setting):

Example starting 1] 5-trans-1i-oxy-15-oxy-prostanoic acid

prostencic acid or or ester product "· —Ester by example

'691 362 9-oxo-lla- (2-hydroxyethoxy) -

15-hydroxy-1b, 16-dimethylprostanoic acid ethyl ester

366 9-oxo-lla- (2-hydroxyethoxy) -

. 15 ~ hydroxy-20-nor-prostanoic acid methyl ester

367 9-oxo-lla- (2-hydroxyethoxy) -

15-methoxy-prostanoic acid ethyl ester

69Ί 370 9-Oxo-lla- (2-hydroxyethoxy) -

15-hydroxy-7a, 7b-bishomo-17,18-cis-methano-prosta-acid-ethy-ester

377 9-Oxo-Ila- (2-hydroxypropoxy) -. '15-hydroxy-3-oxa-16, 16-di-

methyl methyl prostanoate

379 9-oxo-aliar- (2-hydroxyethoxy) -

15-hydroxy-prostanoic acid butyl ester

380 9-Oxo-lla- (2-hydroxyethoxy) -

15-hydroxy-16,16-dimethylprostanoic acid butyl ester

38I 9-oxo-lia- (2-hydroxyethoxy) -

15-hydroxy-17,18-cis-methanoprostanoic acid butyl ester

387 9-Oxo-II <z- (2-hydroxyethoxy) -

IS-hydroxy-iejlo-dimethylprostanoic acid isopropyl ester

389 9-oxo-lla- (2-hydroxyethoxy) -

15-hydroxy-prostanoic acid decyl ester

390 9-oxo-lla- (2-hydroxyethoxy) -

15-hydroxy-16,16-dimethylprostanoic acid decyl ester

9-Oxo-llo :-( 2-hydroxyethoxy) -

15-methoxy-prostanoic acid decyl ester

9 847/1159

TAE5LLB XY (continued):

Example Ausgancs-IJS-trans-1 i-Ox.y-15-oxy-prootan.säureprostenäure or or-ester product -3ster of example

703

704 705

706 707 708 709

392

710 711 712 713

395

397 399

401 402

404 405 406 410 9-OXO-IIcC- (2-hydroxyethoxy) -15-hydroxy-20-nor-17,18-trans- (1, S-propani-prostaric acid decyl ester

9a-Hydroxy-llar-ir.ethoxy-15-hydroxy-20-ethyl-prostanoic acid

9cc-Hydroxy-llo: -methoxy-15-hydroxy-16-ethyl-prostanoic acid

methoxy prostanoic acid

9a-Kydroxy-11a-methoxy-15 ~ hydroxy-16,16-dimethylprostanoic acid

9or-hydroxy-lla-methoxy-15-hydroxy-17,18-cis-methanoprostanoic acid

9 <i-Hydroxy-11a-methoxy-15-hydroxy-16,17,18, 19,20-pentanor-15- (1-adamantyl) -prostanoic acid

9a-hydroxy-lla-methoxy-15-hydroxy-16,20-ethanoprostanoic acid

9ίZ-hydroxy-llα-methoxy-15-hydroxy-16,19-trans-ethano prostanoic acid

9a-hydroxy-lla-methoxy-15-hydroxy-6 _} 7,19,20-tetranor prostanoic acid

hydroxy-7a, 7b-bis-homo-20-ethyl-prostanoic acid

409847/1159

TABLE XV (port setting):

Example exit-13-trausprosteiLsäar3 or -Ester by example

11-0xy-15-oxy-prostanoic acid β- or -Ester product

71U 9a-hydroxy-lla-piethoxy-

715

716

718 719 720

721 722 723

724

417

419

422

424

426

429

431

432 homo-16,16-dinethyl- -prostanoic acid

• 9a-hydroxy-lla-methoxy- -IS-hydroxy-a-ethyl- -20-nor-prostanoic acid

9a-hydroxy-lla-methoxy- -15-hydroxy -;?, 3.20- trimethyl prostanoic acid

9a-Hydroxy-Ila-methoxy- - ^ - hydroxy-J-oxa- -prostanoic acid

9a-hydroxy-lla-methoxylShd

-16,16-dimethyl-prostanoic acid

9a-hydroxy-lla-methoxy- -lS-hydrbxy ^ -fluoro- -18.20-ethano-prostanoic acid

9a-hydroxy-lla-methoxy- -15-hydroxy-7,20-dinor- -prostanoic acid

9a-hydroxy-lla-methoxy-

SyyT
-20-methyl-prostanoic acid

9a-hydroxy-lla-methoxy- -15-hydroxy-2-pheny1- -17,17-dimethyl-prostanoic acid

9a-hydroxy-lla-ethoxy-15-hydroxy-16,16-dimethyl-prostanoic acid

ga-hydroxy-lla-ethoxy- '

Syy
-18.20-ethano-prostanoic acid

409847/1159

TABLE XV (continued):

Example starting 13-trans-r 1i-oxy-15-oxy-prostanoic acid prostenic acid or or-Sster-Produkt -Ester von BeisOiel

725

435

726 437 727 441 728 44 2

729

735

736

443

453

454

9a ~ hydroxy-lla-propoxy-15-hydroxy-l6, l6-dimethyl- prostanoic acid

gcr-hydroxy-lia-propoxy-15-hydroxy-prostanoic acid

9a-Hydroxy-110i-propoxy-15-methoxy-prostanoic acid

ypy hydroxy-16,16-dimethylprostanoic acid

9-2-Hydroxy-llir-isopropoxy-15-hydroxy-20-nor-16,19-raethano-prostanoic acid

730 444 9 ^a "-Hydroxy-llo.-isopropoxy
15-hydroxy-prostanoic acid 731 445 9a-hydroxy-4-n-butoxy-15-
hydroxy-16,16-dimethyl
prostanoic acid 732 446 9 ^ -hydroxy-4-n-butoxy-15-
hydroxy-prostanoic acid 733 451 9x-hydroxy-II-methoxy-15
hydroxy-2,16,16-trimethyl
prostanoic acid 734 452 9 ^'1 X-Hy droxy-ll <x-methoxy-15
hydroxy-2-methyl-prostane
acid

ethyl hydroxy-prostanoate

hydroxy-20-methyl-17,20-ethano -prostanoic acid ethyl ester

409847/1159

TABLE Σ7 (continued):

Example starting 13-trans-11-oxy- "15-oxy-prostanoic acid prGstenic acid or or-eater product -Ecter by example

737 733 739

7 ^ 0 741

4 ₅ 5

463

743 744

745 746 7U7

465

467

469

472

473

474 9'T-Hydroxy-11a-methoxy-15-hydroxy-16,16-dimethylprostanoic acid methyl ester

9o.-Hydroxy-lla-butoxy-15-methoxy-2-ethyl-pro3tanoic acid-ethy he reads

9a-Hydroxy-lloro-butoxy-15-hydroxy-2-ethyl-16, 16-dimethyl-prostanoic acid-ethyl ester

9cr-Hydroxy-II ^ -methoxy-15-hydroxy-3,3-dimethyl-prostane acid ethyl ester

gyymthoxylS hydroxy-3,3> 16, 16-tetramethyl ~ prostanoic acid ethyl ester

9 a-Hydroxy-II <r ~ ethoxy-15 ethyl hydroxyl-3-oxa-20-ethylprostanoate

9cr-Hydroxy-llate-sec-butoxy-15-hyd.roxy-7-nor-20-methylprostanoic acid acetyl ester

9of-Hydroxy-11ör ~ methoxy-15-hydroxy-7a-homo-17,20- (1,3-propane) -prostanoic acid ethyl ester

9a-Hydroxy-llir-methoxy-15-hydroxy-16,16-dimethylprostanoic acid butyl ester

butyl hydroxy-prostanoate

9 = i-Hydroxy-lia-methoxy-15-hydroxy-16,16-dimethylprostanoic acid isopropyl ester

A0B8A7 / 1159

TABSLLS XV (continued):

Example Ausgaiign-1 3-tranp-11-0xy-1 5-oxy-px'ostajic acid prostenic acid or or -stex'-product -ester of example

• 'ι 7 5

477 isopropyl hydroxy-prostanoate

9a-Hydroxy-lld-; nethoxy-15 hyörcxy-17 _s iS-cis-riethanoprostanoic acid isopropyl ester

^ .- Hydroxy-lla-riethoxy-15-hydroxy-pro s t ans acid ο οy1-ester

752

753

754

755

ii γ ο

430

451

434

486 lo, lD-iiir.ethylprostanoic acid decyl ester

9a-hydroxy-lla-.iiethoxy-15 hydroxy-20-ethyl-prstansäuredecy Ie st he

ga-Hydroxy-Ila-methoxy-IS-hydroxy-17,20- (1,3-propane) -prstanoic acid decyl ester

Qcf-Hydroxy-ll ^ -tert. -butoxy 15-hydroxy-prostajis acid ethyl ester

9a-Hydroxy-lia-tert-tautoxy 15-hydroxy-16,16-dimethylprostanoic acid ethyl ester

9a-hydroxy-lla- (2-hydroxyethoxy) -15-hydroxy-prostane

acid

757

753

759

487

488

489 9a-Hydroxy-11O [.- (2-hydroxyethoxy) -15-hydroxy-16, 16 ~ - dimethyl prostanoic acid

90-Hydroxy-lla- (2-hydroxyethoxy) -15-hydroxy-17,18-cis-methano-prostanoic acid

9a-Hydroxy-llcc- (2-hydroxyethoxy) -15-hydroxy-1 €, 17,18, -19,20-pentanor-15 ~ (1-adamantyl) prostanoic acid

A09847 / 1159

TABLE XV (continued):

£ <5 game starting 13 tranoproatensjlure or -Ester by example

11-0xy ~ 15-oxy-prostanoic acid ~ or ester products

760 761 762 763 761

765

490 -491.

492 493

495

497

766

767

499

500 9a-hydroxy-lla- (2-hydroxyethoxy) -25-hydroxy- --20-ethyl-prostanoic acid

9et-hydroxy-lla- (2-hydroxy ethoxy) -15-hydroxy- -16- ethyl-prostanoic acid

9a-hydroxy-lla- (2-hydr oxy ethoxy) -15-hydroxy-, -16,20-ethano-prostanoic acid

9a-hydroxy-lla- (2-hydroxyethoxy) -15-methoxy- -prostane acid

9a-Hydroxy-IIIa- (2-hydroxyethoxy) -15-hydroxy-6,7,19,20-tetranor-pros tan acid

o ^ t-Hydroxy-IIIa- (2-hydroxyethoxy) -15-hydroxy-531

9
nor-prostanoic acid

9a-hydroxy-IIIa- (2-hydroxyethoxy) -15-hydroxy -7a, 7b-bishomo-20-ethyl -prostanoic acid

9a-hydroxy-IIIa- (2-hydroxyethoxy) -15-hydroxy -7a, 7b-bishomo-16,16- -dimethyl prostanoic acid

768

502

7.69

770

505

508 9a-Bydroxy-IIIa- (2-hydroxy ethoxy) -15-hydroxy -7 &, 7b-bishomo-16.20- - (1,3-propano) -prostan acid

9a-hydroxy-11α- (2-hydroxy ethoxy) -15-hydroxy -3,3-diraethy1-prostanoic acid

9a-hydroxy-lla- (2-hy-

hydroxyethoxy) -15-hydroxy -3-oxa-pro8 tajic acid

4098 47/1159

{TABLE XV (continued):

Example of starting 13-trans-11-0}: y-15-oxy-prostanoic acid

Prostenic acid or or ester product 'ester of example

771 772

509

510

773

774

511

775 776 777 773 779

515

517

519

520

522

780

781

523

524 9a-hydroxy-lla- (2-hydroxy ethoxy) -15-hydroxy- -5-oxa-ie, 16-dimethyl- -prostanoic acid

9cc-hydroxy-lla- (2-hydroxyethoxy) -15-hydroxy- -J-oxa-ie ,, 19-trans- -ethano-prostanoic acid

9a-hydroxy-lla- (2-hydroxyethoxy) -15-methoxy- -3-oxa-prostanoic acid

9a-hydroxy-lla- (2-hydroxyethoxy) -15-hydroxy-

methyl prostane acid

9a-Hydroxy-11α- (2-hydroxyethoxy) -15- hydroxy- -2-fluoro-prostanoic acid

9a-hydroxy-lla- (2-hydroxyethoxy) -15-hyd roxy-7,20-bisnor-prostanoic acid

9a-hydroxy-lla- (2-hydroxy ethoxy) -15-hydroxy- ^ a-homo ^ O-methyl- -prostane acid

9a-Hydroxy-lla- (2-hydroxy ethoxy) -15-hydr oxy- -7a-horao-16j, 16-dimethyl-prostanoic acid

9a-hydroxy-lla- (2-hydroxy ethoxy) -15-hydroxy- -2-pheny1-prosanoic acid

9a-Hydroxy-IIIa- (2-hy d roxyprop oxy) -15-hydr oxy-pros tanic acid

9a-hydroxy-lla- (2-hydroxypropoxy) -15-hydroxy-16,16-dimethyl-

4098A7 / 115-8 ^{rostanic acid}

I ABSELB XV (continued)

.Example

^ ci 3-trans-11-oxy-15-oxy-prostansäxirepro-ßenic acid or or ester product • litter \ ^r on example

732 733 734

735

786 787 768

789

790

527

528

529

531

533

537

791 792

545

546

547 9J-Hy droxy -1 lot - (4-hydroxybutoxy) -15-hydroxy-prostane siiure

92-Hydroxy-11a- (4-hydroxybutoxy) -15-hydroxy-16,16-dimethy1-prostanoic acid

9 ^ -Hydroxy-II> i- (2-hydroxyethoxy) -15-hydroxy-16, 16-dimethy1-prostanoic acid ethyl ester

9a-Hydroxy-11a '- (2-hydroxyethoxy) -15-hydroxy-19,20-dinor-16,17- (1,3-propane) -prostanoic acid ethyl ester

9a-Hydroxy-IIIa- (2-hydroxyethoxy) -15 ~ hydroxy-20-norprostanoic acid methyl ester

9 <7 - Hydroxy-llcr- (2-hydroxyilthoxy) -15-methoxy-prostane acid r. Ethyl ester

9c - Ky droxy- llor- (2-hydroxyethoxy) -15-hydroxy-7a _a 7bbishomo-l ^ jlß-cis-methanoprostanoic acid ethyl ester

9a-Kydroxy-IIIa- (3-hydroxypropoxy) -15-hydroxy-3-oxa-16,16-dimethyl-prostanoic acid ethyl ester ·

9 a-Hydroxy-IIIa- (3-hydroxypropoxy) -15-hydroxy-3-oxa-16,20-methano-prostanoic acid ethyl ester

9 <i-Hydroxy-IIIa- (2-hydroxyethoxy) -15-hydroxy-prostenic acid butyl ester

9 <^ - Hydroxy- II> t- (2-hydroxyethoxy) -15-hydroxy-16,16-dir.et hy 1-prost butyl ester

09 8A7 / 1159

TABSLLB ZY (Port Tune):

Example starting 15-trans- 1 i-Oxy - ^ - oxy-prcstansäureproÜterLcäu.re o & sr or -E
'· -Ester from Biil

5 ^l iÖ. 9a-IIydroxy-lla- (2-hydroxy-

etho>: y) -15 ~ hydroxy-17, 18-cis-

methano-prostanoic acid butyl

ester

• 794 5 ^ 9 9a-Hydroxy-lia- (2-hydroxy-

ethoxy) -15 ~ hydroxy-17,19- (I ₁ 3-propane) -prostanoic acid butyl ester

554 9a-hydroxy-llo .- (2-hydroxy-

ethoxy) -15-hydroxy-lo, 16-dime thy1-prostanoic acid isopropyl ester

556 9a-Hydroxy-ll! X- (2-Hydroxy-

ethoxy) -15-hydroxy-prostaiic acid decyl ester

557 9 - Hydroxy-lla- (2-hyaroxy-

ethoxy) -15-hydroxy-l6, l6-

dimäthy1-prostanoic acid decyl ester

558 9a-hydroxy-lla- (2-hydroxy-

ethoxy / -15-methoxy-prstanoic acid edecyl ester

559 9a-hydroxy-lla- (2-hydroxy-

ethoxy) -15-hydroxy-20-nor-17j18-trans- (1,3-propane) -prostanoic acid decyl ester

& 00 562 g

15-methy1-20-ethyl-prostanoic acid

801 564 gyyy

15-methy1-6,7,19,20-tetranorprostanoic acid

802 565 9-Oxo-lla-ethoxy-15-hydroxy-

15-: ethyl-5,6,7,18,19,20-hexa nor-prostanoic acid

803 566 9-oxo-lloc-methoxy-15-hydΓoxy-

15-methyl-7a _> 7b-bishomo-20-ethyl-prostanoic acid

A098A7 / 1159

(Continuation):

Example Ans ^ an ^ sI p-trans- 1 1-0x3 ^ -15-oxy-pro stansäur eprorte.isäure odor or ester product
-i'yuer of l "; eir: .Oiel

9-oxo-lla-methoxy-15-80m 567 ~ hydroxy-15-ir.etKyl-2 ~

-ethyl-20-nor-prostanoic acid

805 568. -hydroxy-15 -nie thyi-3, 3>'

20-trimethyl prostanoic acid

9-0xo-lla-methoxy-15-

806 569 -hydroxy-15-methy1-3-,

-oxa-prostane acid

9-oxo-lla-methoxy-15-

3 ^ 7 57i -hydroxy-IS-methyl-a-

-fluoro-18.20-ethano- -prostane acid

9-0xo-lla-methoxy-15-

8ü8 572 -hydroxy-15-methyl-

-7> 20-dinor-prostane ;: acid

9-oxo-lla-methoxy-15-

573 . ~ hydroxy-15-methyl-7-

-nor-17.20- (l, 4- -butano) -prostanoic acid

9- CKo-lla-methoxy-15-

810 574 -hydroxy-IS-methyl-Ta-

-homo-20-methyl-prostanoic acid

9-0xo-lla-niethoxy-15-

811. 575-hydroxy-IS-methyl-Ta-

-homo-17, l8-cis-

-methano-prostan-

acid

9- oxo-lla-methoxy-15-

812 575 -hydroxy-IS-methyl ^ a-

-horao-20-cyclopentyl- -prostanoic acid

9- Qxo-lla-methoxy-15-

577 -hydroxy-IS-methyl ^ -

phenyl-l8 2Ö- _J (l, 3- '-propano) -prostansäure

409847/1159

TABLE XY (continued):

Example ^ ucgan £; s-13-fransprosieiic acid or -Dater of example

814 580 815 '58:

816. 583 617 534 818 585

i-Oxy-15-oxy-prostanoic acid- or -Ester product

-hydroxy-15-methyl-
-20-nor-prostanoic acid

9-Oxo-lla-propoxy-15- -hydr oxy-15 rcie thyl-
-pfostanoic acid

9-oxo-lla-isopropoxy- -15-hydroxy-.r? -me thyl ^ -prostanoic acid

9-Oxo-4-n_-butoxy-15-
-hydroxy-15-methyl-
-prostanoic acid

-methyl prostanoic acid

819

586 9-Oxo-lla- (2-hydroxyethoxy} -15-hydroxy-15- -methyl prostanoic acid.

820

587

821

322

588

590

823

824

591

592 9-0xo-lla- (2-hydroxyethoxy) -15-hydroxy-15- -methyl-17,18-cis-
-methano-prosanoic acid

9-Oxo-lla- (2-hydroxyethoxy-15-hydroxy-15- -rae thy 1-2 0-a thy 1-
-prostanoic acid

9-Oxo-lla- (2-hydroxyethoxy-15-hydroxy-15- -Bethy1-6,7,19 ₃ 20-
-tetranor-prostanoic acid

9-Oxo-IIIa- (2-hydroxyethoxy) -IS-hydroxy-IS- -methyl-5,6,7,18,19,
2 O-hexanor-pros tan-

acid

9-0 xo-lla- (2-hydroxy- - ethoxy) -15-hydroxy- -15-methyl-7a, 7b-bis-

homo-2O-ethyl-pro _s tanoic acid A09847 / 1159

S / J3SLLE: r / (continued):

Example starting 13-trans-11-0xy-15-oxy-prostanoic acid prostanoic acid or or -EatCr-Pdlt -Eater "by 13cioT) iel

825

326

827 328 € 29 & 30 831

832 833 834

593

59 '

506

597

599

600

601

602

603

605 9- ° xo-lla- (ß-hydroxy- ethoxy) -15-hydroxy-

SyT ^ T horao-prostanoic acid

9-Oxo-lla- (2-hydroxyethoxy) -15-hydroxylSthl ^ t

yySO -cyclopentyl-prostanoic acid

9-oxo-lla- (2-hydroxyethoxy) - ^ - hydroxy- ^ -methyl-3,35-dimethyl- -prostanoic acid

9-0xo-Ha- (2-hydroxyethoxy) - ^ - hydroxy-IS -methyl-3-oxa-prostanoic acid

9-0xo-lla- (2-hydroxyethoxy) -lS-hydroxy- ^ -Methyl-2-fluoro- -prosta'n3 acid

9-Oxo-IIIa- (2-hydroxy-ethoxy) -IS-hydoxy-IS -methyl-7.20-bi8nor- -prostanoic acid

9-Oxo-Ila- (2-hydroxyethoxy) -15-hydroxy-15-thly

-methyl prostanoic acid

9-oxo-lla- (2-hydroxyethoxy) -IS-hydroxy- ^ -methyl-2-phenyl- -prostanoic acid

9-oxo-lla- (2-hydroxypropoxy) -15-hydroxy- -15-methyl-prostanoic acid

9-0xo-lla- (4-hydroxy- -butoxy) -15-hydroxy-15-methy1-prostanoic acid

409847/1159

example

Preparation of 9 <x / ß, 15-dihydroxy-1 1a-methoxy-13-transprostenic acid

A solution is stirred which contains 200 mg of 9-0xo ~ 1ia-methoxy-15-hydroxy-13-trans-prosteneure (Example 227) and contains 20 mg of sodium borohydride in 1 ml of absolute alcohol, while 18 hours at room temperature. The solution is then diluted with 30 ml of water and acidified with 2N hydrogen chloride acid solution and extracted several times with ether. The combined extracts are washed with a saturated solution of sodium chloride washed, dried with anhydrous magnesium sulfate and evaporated to dryness, being as oily product a mixture of the 9a and 9β-hydroxy derivatives obtained, which are separated by chromatography 3: 0ml en.

Example '836

Preparation of 4,4-Diniethyl-3-triphenylmethoxy-'1-octyne

By treating 23.1 g (0.150 mole) 4,4-dimethyl-1-octyn 3-ol (3eicniel 149) with 56.5 g triphenylmethyl bromide in 150 irl pyridine and cleaning the product with the help of a highly selective absorbent (magnesium silicate gel, Plorisil QEv according to the procedure given in example 127 by dex *, the title compound is obtained. P = 75 to 77 ° C.

409847/1159

Example 857

Preparation of 4 _i 4-dimethyl ~ 1-; iodo-3-triphenylmethoxy-trans-1-octene

To 256 ml of a cooled to ⁰ ° C O, 43n solution of di- siamylboran in Diglyiae are added under an inert atmosphere 39.6 g (0.10 mol) of 4,4-dimethyl-3-triphenylraethoxy T-octyne (Example 837). Then you remove. the mixture is stirred for 3 hours at room temperature. The mixture is then cooled to 0 ° C. and 26.3 g (0.35 mol) of finely divided trimethyl join oxide are added over the course of 10 minutes. The cooling bath is then removed and the mixture is allowed by exothermic reaction, but not more than 40 ⁰ C, warm, after which the cooled mixture to room temperature, poured into 800 ml of a 15 ^ strength liatriumhydroxydlösung and immediately added to a solution of 38.1 g iodine in 100 ml of tetrahydrofuran. The mixture is then stirred for 0.5 hours at room temperature and then partitioned between water and ether. The organic phase is decolorized with a 5% sodium thiolphate solution, washed with water and saturated salt solution, dried over calcium carbonate and evaporated The residue is purified by passing it through a column filled with a highly selective absorbent (magnesium silicate gel, Plcrisil '-), with a 5 to 15% (v / v) solution eluted from benzene in Eexan and the title compound is obtained.

409847/1159

Claims (2)

R. a low molecular alkoxy group, a t ^ -hydroxy-substituted low molecular alkoxy group or an ij-tetrahydropyranyloxy-substituted low molecular alkoxy group, Ep is a hydrogen atom, a low molecular weight alkyl group or a triphenyliaethyl group, R_ is a straight-chain alkyl group with 2 to 10 carbon atoms, a straight-chain alkyl group substituted with one or two low molecular weight alkyl groups 2 to 10 carbon atoms, a straight-chain alkenyl 409847/1159 methyl group with 3 to 10 carbon atoms, one with. substituted one or two low molecular weight alkyl groups straight-chain alkenylmethyl group with 3 "to IC carbon atoms, a cycloalkyl groupB of 4 "to 9 carbon atoms, one with a low molecular weight Alkyl group substituted cycloalkyl group with 5 to 10 carbon atoms, a low molecular weight alkyl group with 6 substituted by a cycloalkyl group up to 12 carbon atoms, the cycloalkyl group thereof optionally with a low molecular weight alkyl group is substituted, a cycloalkenyl group with 5 to 9 Carbon atoms, one with a low molecular weight Alkyl group-substituted cycloalkenyl group with 6 to 10 carbon atoms, one with a C 3 -C 10 alkenyl group substituted low molecular weight alkyl group with 6 to 12 carbon atoms, its cycloalkenyl group is optionally substituted with a low molecular weight alkyl group, an adaiaantyl group or one with low molecular weight substituted by an adamantyl group Alkyl group, Typically a hydroxyl group, an alkoxy group with 1 to 12 Carbon atoms or a tetrahydropyranyloxy group, E _{7 is} a hydrogen atom or a low molecular weight alkyl group with up to 3 carbon atoms, Y is a divalent group of the following formulas O HO ,H C. and H \ Il \ / / 409847/1159 Z is a divalent group of the following general formulas R ₅ R ₀ I 1 , - (CHa) _n -C-CH ₂ -, R ₅ H . H \ SlS./ - (CH ₂ ) -0-CH ₂ - and -CH ₂ -C = C- (CH ₂ ) _p - . in which η is an integer with a value from 5 to 8 including, ρ is an integer with a value from 2 to 6 inclusive, R _{5 is} an alkyl group with up to 3 carbon atoms and Rg is an alkyl group with up to 3 carbon atoms, represent a fluorine atom or a phenyl group and the group ~ ^c -] 3 ~ ^c -j / ~ mean an ethylene or trans-vinylene group, with the proviso that the group Rp means a hydrogen atom when the group R _{7 represents} a low molecular weight alkyl group and the optical isomers and racemates of these Links. 2. Process for the preparation of the compounds according to claim 1, characterized in that a compound the general formula 409847/1 159 in the R ¹ .. a low molecular weight alkoxy group or
a «u-tetrahydropyranyloxy-substituted low molecular weight alkoxy group and R 'is a tetrahydropyranyloxy group or an alkoxy group represent having 1 to 12 carbon atoms and Z has the meanings given above, with a lithium anate of the following general formula. H ⁰ AL
RRR in the R is an alkyl group with 1 to 7 carbon atoms, R'2 is a low molecular weight alkyl group or a triphenylmethyl group mean and R has the meanings given above, to one Compound of the following general formula rV ZCR ₁ H B ₁ '* ^ C = C-CK-R. HI ι Α098Α7 / Ί159 in which R ', a hydroxyl group, has an alkoxy group 1 to 12 carbon atoms or a tetrahydropyranyl oxy group means and R ', R' ₂ > Π · 3 and. Z have the meanings given above, then reacts the group which blocks the ether and ester groups with a weak acid to form a compound of the following general formula O, Il Il ZCR ₁₁ ^X ^ CC-CHR, H » 3 Π ti in which R ¹ 'is a low molecular alkoxy group or an ω-hydroxy-substituted low molecular alkoxy group, R "is a hydrogen atom or a low molecular weight alkyl group, R ". Denotes a hydroxyl group or an alkoxy group having 1 to 12 carbon atoms and Z and R ^ have the meanings given above, splits off and if desired treated the compound obtained with a hydride as a reducing agent and the obtained 9 <x or 9β compounds isolated and 409847/1159 If necessary, a 9.15-hydroxy-A tx-ans-prostanoate compound is selectively oxidized with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone or manganese dioxide to give ^the corresponding 15-ketone, with all free hydroxyl groups a Grignard-resistant group "blocks, which reacts compounds with a low molecular weight alkyl magnesium halide, frees the hydroxyl groups from their protective group and, if desired, converts the ester into the corresponding carboxylic acid and, if desired, oxidizes the 9-hydroxyl group into a 9-oxo group and isolates the products obtained, if desired the C., -C ..- vinylene group is hydrogenated to an ethylene group and the products obtained are isolated. 409847/1159