DE2548955A1 - NEW CYCLOPENTAN DERIVATIVES - Google Patents

Description

Dr. F. Zumstein Sr. - Dr. E. Assmann - Dr. R. Koenigsberger Dipl.-Phys. R. Holzbauer - Dipl.-Ing. F. Klingselsen - Dr. F. Zumstein jun.

PATENT LAWYERS -

TELEPHONE: COLLECTIVE NO. 22 5341

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CHECK ACCOUNT: MUNICH 91139-809. BLZ 70O10O8O BANK ACCOUNT: BANKHAUS H. AUFHÄUSER ACCOUNT NO. 397997. BLZ 7OO 306 00

8 MUNICH 2.

BRAUHAUSSTRASSE 4

Case 786

MAY & BAKER LIMITED, Dagenham, Essex, England

New cyclopentane derivatives

The present invention relates to new cyclopentane derivatives with pharmacological properties.

According to the invention are new cyclopentane derivatives of the general formula

(CH ₂ ) _n COOR ^J : ~ ya ~ zr ²

[where R is a hydrogen atom or a straight or branched chain alkyl group of 1 to 12 (e.g. 1 to 4

ο or 7 to 12) carbon atoms, R represents an aryl group or a heterocyclic group (for example a phenyl, naphthyl, furyl or thienyl group and preferably a phenyl, naphthyl or thienyl group) which may be substituted by one or more substituents can, selected from halogen (for example fluorine, chlorine or bromine) atoms, straight or branched chain. Alkyl groups with 1 to 4 carbon atoms, trihalomethyl

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(e.g. trifluoromethyl) groups, alkenyl groups with 2 to 4 carbon atoms, phenyl groups, alkoxy groups with 1 to 4 carbon atoms, hydroxyl groups, nitro groups, cyano groups, carboxy groups, alkoxycarbonyl groups, in which the alkoxy part contains 1 to 4 carbon atoms, hydroxymethylene groups, = alkoxymethylene groups, in which the alkoxy part contains 1 to 4 carbon atoms, sulfide groups, alkylsulfonyl groups with 1 to 4 carbon atoms in the alkyl part and sulfamoyl, carbamoyl, N-aminocarbamoyl ,. Amidino, amino, hydroxyimino groups, each such nitrogen-containing group optionally being substituted by one or more alkyl groups each having 1 to 4 carbon atoms, η 5, 6, 7 or 8, preferably 6, and either (i) A is straight or branched alkylene chain with up to 12, preferably 1 to 7, carbon atoms, X is an ethylene or transethylene group, Y is a carbonyl group or a group -CH (OPr) - (in which Bp is a hydrogen atom or a carboxylic acyl group , for example a straight or branched alkanoyl group with 1 to 6 carbon atoms or a benzoyl group) and Z is a direct bond or an oxygen or sulfur atom or also (ii) A and Z are both direct bonds and X and Y are ethylene and at the same time Carbonyl, transvinylene and carbonyl, or ethylene and -CH (OIr) groups, (where for has the meaning given above)]
and when R represents a hydrogen atom, nontoxic salts.

The structure shown in the general formula I has, as is evident to the person skilled in the art, at least two centers of activity, these two centers of chirality on the ring carbon atoms sit in positions 1 and 2 respectively. In addition to these two centers of chirality, there is another center of chirality if Y represents a -CH (OR ^) - group and still

1 2 further chiral centers can be found in groups A, R, R and

R ^ occur. The presence of centers of chirality is known to result to the presence of isomers. However, the compounds of the formula I according to the invention all have such a

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term configuration that the ring carbon atoms in the side chains bound to positions 1 and 2 are trans to one another. Accordingly, all isomers belong to general formula I and mixtures thereof, the side chains of this type linked to ring carbon atoms in positions 1 and 2 have and have a transconfiguration, the Scope of the invention.

The compounds of the formula I and, when R represents a hydrogen atom, their nontoxic salts have valuable salts pharmacological properties, e.g. properties common to related series of natural products known as prostaglandins are typical including, for example, the generation of hypotension, bronchodilation, the inhibition of gastric acid secretion, the Lightening of gastric ulcers, stimulating luteolysis and stimulating uterine contraction. The connections are particularly useful in the inhibition of gastric acid secretion and the healing of gastric ulcers and their utility is characterized by its remarkably low activity in terms of causing the undesirable side effect aggravated by diarrhea.

Preferred classes of compounds of formula I according to the invention include:

(a) Compounds of the formula I in which R is an alkyl group as defined above and the other symbols are those above have given meaning;

(b) Compounds of the formula I in which R is a substituted or represents an unsubstituted heterocyclic group or aryl group (other than phenyl) or a substituted phenyl group, wherein the substitution is as defined above and the other symbols have the meanings given above;

(c) Compounds of the formula I in which η is 5, 7 or 8, where the other symbols have the meanings given above;

(d) Compounds of the formula I in which X represents an ethylene group and the other symbols correspond to the above

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5Λ89

have meaning;

(e) Compounds of the formula I in which Y is a carbonyl group represents, wherein the other symbols have the meanings given above;

(f) Compounds of the formula I in which A is a direct bond and the other symbols are those given above Have meaning and

(g) Compounds of the formula I in which Z represents an oxygen or sulfur atom, the other symbols being those above have given meaning.

Compounds of the formula I in which R is a hydrogen atom and

2 Y represents a carbonyl or hydroxymethylene group and R n, X, A and Z have the meaning given above, are prepared according to the invention by hydrolysis of compounds the general formula

II

XYAZR ²

2
(where R η, X, Y, A and Z have the meanings given above

and the symbols R represent identical alkyl groups or together an unsubstituted or substituted by identical alkyl groups on each carbon atom ethylene bond form, the symbols R preferably together representing an unsubstituted ethylene bond) by using known methods for converting a ketal group into a ketone group.

The hydrolysis is generally carried out under acidic conditions, for example by reaction with a dilute inorganic acid, for example dilute hydrochloric acid, preferably at a temperature above room temperature, for example between 50 and 70 ^° C. or

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with the aid of an organic acid in the presence of water, for example aqueous acetic acid, for example 60 to 80 % vol / vol. aqueous acetic acid or p-toluenesulfonic acid in acetone, which contains a small amount of water, preferably at a temperature between 5 and 100 ⁰ C, in particular between 15 and JO ⁰ C. Alternatively, the ketal of formula II can be converted into the ketone of formula I by if it is subjected to a chromatographic treatment, preferably using an eluent containing an organic acid, for example glacial acetic acid or formic acid}. This causes cleaning at the same time as hydrolysis.

According to a further feature of the invention, compounds of the formula I in which R represents a hydrogen atom and Y

2 denotes a carbonyl or hydroxymethylene group, R, n, X, A and Z have the meanings given above, in others Compounds of the formula I and their salts by using for the preparation of salts from acids, for the preparation of esters from acids or alcohols, for the production of Alcohols from ketones or for the reduction of carbon-carbon -Converted double bonds known methods.

For example, compounds of the formula I in which Y represents an acyloxymethylene group are acylated according to the invention of compounds of the formula I in which Y represents a hydroxymethylene group. The acylation can be carried out, for example, by Reaction with the appropriate acid anhydride, preferably in the presence of a base, e.g. pyridine, preferably at room temperature, optionally in the presence of an inert organic solvent such as an aromatic hydrocarbon (e.g. Benzene).

Compounds of the formula I in which R represents an alkyl group having 1 to 12 carbon atoms are prepared according to the invention, starting from the corresponding acids of the formula I, in which R represents a hydrogen atom, by using for the

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Esterification of acids by known methods, e.g. by reacting the acid with a suitable alcohol, with an excess of the same can be used as a solvent medium, in the presence of an inorganic acid, e.g. hydrochloric acid or sulfuric acid, preferably at a temperature between 50 and 110 ° C and suitably at the reflux temperature of the reaction mixture or with a suitable diazoalkane in an inert one organic solvent medium, preferably a dialkyl ether (e.g. diethyl ether), preferably at room temperature.

The term "non-toxic salt", as used in the present case, is to be understood as meaning salts whose cations are used for the organism of the animal or living being are relatively harmless when used in therapeutic doses, such that the valuable pharmacological properties of the acidic parent compound of general formula I due to these cations attributable .. side effects are not impaired. The salts are preferably water-soluble. Suitable salts include the alkali metal salts, e.g. sodium and potassium and ammonium salts and pharmaceutically acceptable (i.e. non-toxic) Amine salts.

According to the invention, the nontoxic salts are obtained from the acids of formula I prepared using known methods, e.g. by reacting stoichiometric amounts of the compounds of Formula I (in which R represents a hydrogen atom) and the appropriate ones or associated base, e.g. an alkali metal hydroxide or carbonate, ammonium hydroxide, ammonia or an amine in a suitable solvent, which is preferred in the case of manufacture of alkali metal salts is water and in the case of amine salts Is water or isopropanol. The salts can be obtained by lyophilizing the solution or, if there are enough insoluble components present in the reaction medium, isolated by filtration, if necessary after removing part of the solvent will.

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As well as themselves as pharmaceutically acceptable compounds Are useful are salts of the compounds of formula I, wherein R represents a hydrogen atom, for the purpose the purification of the parent acids of the formula I, for example by utilizing the solubility differences between the Salts and the parent acids in water and in organic solvents can be used by techniques known to those skilled in the art. The parent acids of the formula I can be prepared from their salts by known methods, for example by treatment with an inorganic Acid, e.g. dilute hydrochloric acid, can be regenerated.

It will be understood that reference to the compounds of formula I is intended where the context allows allows the salts of the compounds of the formula I in which R is a hydrogen atom to be included.

As it can be easily seen by the person skilled in the art, the isomeric forms of the compounds according to the invention, which are ' from the aforementioned centers of chirality, can be separated using known methods, e.g. diastereoisomeric forms by chromatography using selective absorption from solution or from the vapor phase separated in suitable absorbents.

The expression “known methods” as used in the present case means methods which have been used up to now or have been described in the chemical literature.

Compounds of the formula II in which Y is a carbonyl or hydroxy

2 4
represent methylene group (R, R, n, X, A and Z have the meaning given above), in which, however, X and Y do not simultaneously denote a transvinylene group or a carbonyl group (hereinafter referred to as "compounds of the formula Ha"), are reduced by reduction prepared from compounds of formula II wherein Y is a carbonyl or hydroxymethylene group

2 4
represents (wherein R, R, n, X, A and Z are those given above

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Have meaning), but in which X and Y do not simultaneously represent an ethylene group or a hydroxymethylene group (hereinafter referred to as "compounds of the formula Hb"). Thus:

(a) Compounds of the formula Ha, wherein X represents an ethylene or transvinylene group and Y represents a hydroxymethylene group, prepared by reducing the corresponding compounds of the formula Hb, wherein X represents an ethylene or transvinylene group and Y represents a carbonyl group, using methods and conditions capable of reducing carbonyl groups to hydroxymethylene groups without affecting the carbon-carbon double bonds. The reduction is preferably carried out using a metal borohydride (e.g. sodium borohydride or potassium borohydride). usually in an aqueous, alcoholic or aqueous-alcoholic medium at a temperature between -40 and + 5O ⁰ C, preferably between -5 and +15 ⁰ C, optionally in the presence of a base, for example an alkali metal hydroxide (such as an aqueous or aqueous Natriumhydroxyds Kaliumhydroxyds ) or specifically, if potassium borohydride is used, under aqueous or aqueous-alcoholic conditions buffered to a pH of 7 to 9 *, for example pH 8, (for example by adding an aqueous citric acid solution). Alternatively, the reduction is carried out by reaction with aluminum isopropoxide in the presence of isopropanol, preferably as a solvent medium at an elevated temperature, advantageously at the reflux temperature of the reaction mixture.

(b) Compounds of the formula Ha, in which X is an ethylene group and Y represent a carbonyl or hydroxymethylene group are prepared by reducing the corresponding compounds of the formula Hb, wherein X is a transvinylene group and Y represent a carbonyl or hydroxymethylene group using means and conditions suitable for the reduction of carbon-carbon double bonds without impairment

the carbonyl groups are capable. The reduction is preferably carried out by hydrogenation in the presence of a hydrogenation catalyst, e.g. rhodium on carbon or activated carbon or palladium on activated carbon in the presence of an inert organic solvent, for example a lower alcohol such as ethanol, generally at room temperature and under elevated pressure, e.g.

at a hydrogen pressure of 2 to 15 kg / cm.

(c) Compounds of the formula Ha in which X is an ethylene group and Y is a hydroxymethylene group are prepared by reducing the corresponding compounds of the formula Hb, using agents and conditions which lead to the reduction every carbonyl group present into a hydroxymethylene group and every transvinylene group present into an ethylene group are capable. The reduction is preferably carried out by hydrogenation in the presence of a hydrogenation catalyst, e.g. Raney nickel or palladium on activated carbon, in the presence of an inert organic solvent, e.g. a lower alcohol, e.g. ethanol, preferably under increased pressure, e.g. at a

Hydrogen pressure of 2 to 15 kg / cm.

Compounds of the formula II in which X is a transvinylene group and Y is a carbonyl group (hereinafter referred to as "compounds of the formula Hc "), can be prepared by Use the following sequence of reactions:

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■ + R ³ O (CH ₂ J _n CHO

III

(CH,) CH ₉ OH

Enamine

ο Ύ

[CH ₂ J _n CH ₂ OH

CHO

VII

VIII

wherein R is a hydrogen atom or a suitable acid labile

2 4
Group represents R, R, n, A and Z those given above

Have meaning and the double bond shown in the side chain of formula VIII and lic is trans. Suitable acid-labile groups represented by R- ^ are those _(Δ which are easily removed by acid hydrolysis and do not cause any side reactions, e.g. the 2-tetrahydropyranyl group, which can be ο unsubstituted or substituted, for example, by at least one lower alkyl group.

° The reaction of an aldehyde of formula III and an enamine (e.g. morpholine amine) of cyclopentanone to give an alcohol of formula IV is carried out in an inert organic

Solvent, eg an aromatic hydrocarbon (eg benzene) with continuous removal of water, preferably at 60 to 120 ⁰ C and subsequent hydrolysis under aqueous acidic conditions (eg with hydrochloric acid), preferably at room temperature and with subsequent heating with an acid (eg concentrated hydrochloric acid ), preferably at about 100 ^° C. and preferably in an inert organic solvent such as an alcohol (e.g. butanol), causing the double bond to migrate from the exocyclic to the endocyclic position.

The alcohols of general formula IV are reacted with a source of hydrogen cyanide (e.g. acetone cyanohydrin), preferably in the presence of a base, e.g. an alkali metal carbonate (e.g. sodium carbonate) in an aqueous organic solvent, e.g., an aqueous lower alcohol (e.g. aqueous methanol), preferably at 50 to 110 ° C, advantageously under the reflux temperature of the solvent used Achievement of ketone! Triles of the formula V.

The ketals of the general formula VI are prepared from the ketonitriles of the formula V by using for the preparation of ketals from ketones known conditions, for example by reacting a compound of the formula V with a suitable one Alcohol or diol in the presence of an acidic catalyst, e.g. p-toluenesulfonic acid with continuous removal of Water. Advantageously, the reaction is carried out in the presence of an inert organic solvent such as an aromatic Hydrocarbons (e.g. benzene) at elevated temperature with continuous removal of water using a Dean-Starck apparatus performed.

The ketals of the general formula VI can be reduced in an inert organic solvent, eg a lower dialkyl ethers (for example diethyl ether), preferably at a temperature between -8o ° C and +30 ⁰ C, to form compounds of the formula VII using methods known Komplexmetallreduk -

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tion agents, preferably using a dialkyl aluminum hydride (e.g. diisobutyl aluminum hydride) in an inert organic solvent such as an aromatic hydrocarbon (e.g. benzene).

Compounds of formula VIII are prepared by reacting compounds of formula VII, either with compounds of general formula

• (R ⁶ ), P = CHCO-AZR ² IX

(in which R, A and Z are as defined above and R is an alkyl group or an unsubstituted or substituted phenyl group and advantageously a phenyl or n-butyl group) preferably in the presence of an inert organic solvent and preferably at a temperature between 20 and 100 C, for example in the presence of tetrahydrofuran as a solvent, at Rückflüßtemperatur the reaction mixture or in the presence of Hexamethylphosphornäuretrisamid as a solvent, at a temperature between 95 and 100 ⁰ C, optionally under an inert atmosphere (eg nitrogen) or with compounds of the general formula

, 2

(R ⁷ O) ₂ P (O) CH ₂ CO-AZ ^

(where R, A and Z are as defined above and R 'is an alkyl group having 1 to 4 carbon atoms, preferably a methyl group, means)) in the presence of a strong Base, e.g. sodium hydride, preferably in the presence of an inert organic solvent, e.g. an ether (e.g. Tetrahydrofuran), preferably at or near room temperature and optionally under an inert atmosphere (e.g. nitrogen atmosphere).

The compounds of formula VIII are then oxidized, preferably in an inert organic solvent, with the aid of one for converting a terminal hydroxymethyl group into a Carboxy group without affecting the carbon-carbon

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Double bonds or the group -C (OR) ₂ ~ known agent (for example chromium trioxide and sulfuric acid in dimethylformamide, preferably at a temperature of -5 to ■ of the compounds of the formula lic.

preferably at a temperature of -5 to +10 ⁰ C), with formation

Compounds of Formula IX can be prepared using known methods, e.g., by reacting compounds the general formula

QCH ₂ CO-AZR ² XI

(in which R, A and Z have the meanings given above and Q means a bromine or chlorine atom) .and one suitable trialkyl- or triphenylphosphine in a suitable organic solvent (e.g. chloroform), under a nitrogen atmosphere, for example under anhydrous conditions and at a temperature of 20 to 100 ° C and advantageously at reflux temperature of the reaction mixture, followed by a reaction of the 2-0xo-alkylphosphonium halide obtained formula

[(R ⁶ ), PCH ₂ -CO-AZR ² ] ⁺ Q "XII

(wherein R, R, A, Z and Q have the meanings given above own) with a base (e.g. aqueous sodium carbonate or achanolic sodium ethoxide) at room temperature.

Compounds of formula X can be prepared using known methods, for example by treating a Compound of the general formula

(R ⁷ O) ₂ P (O) CH, XIII

• 7

(where R 'has the meaning given above) with butyllithium at low temperature, for example between -45 and -6O ⁰ C and in an inert organic solvent, for example a mixture of tetrahydrofuran and hexane, preferably under an inert atmosphere (for example nitrogen) and under anhydrous conditions, followed by treatment of the mixture obtained, which is a compound of the general formula

(R ⁷ O) ₂ P (O) CH ₂ Li XIV

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(where R '· has the meaning given above) contains ^ with a compound of the general formula

R ⁸ OOC-AZR ² XV

ο
(where R, A and Z are as defined above

and R is an alkyl group, preferably the ethyl group) at a temperature which is initially between -70 and -55 ° C and then rises to room temperature.

Compounds of formulas XI, XIII and XV can be prepared using known methods.

The following examples illustrate the invention.

example 1

(i) 7- [5- (3-0xoalk-i-enyl) -2-oxocyclopentyl] -heptanoic acids

A mixture of 7- £ ¹ * 4-Dioxa-7- (j5-oxo-5-phenylpent-1-enyl) -

spiro [4.4] non-6-YL2-heptanoic acid [1.0 g prepared as described below in Example 1 (ii) above] and 20 ml of 2N hydrochloric acid were stirred at 60 to 65 ⁰ C -2 hrs. and then extracted with diethyl ether. The ethereal solution was extracted with 2N aqueous sodium bicarbonate solution and the aqueous extract obtained was acidified to pH by adding dilute hydrochloric acid (2N), saturated with sodium chloride and extracted with diethyl ether. This essential extract was washed with water, dried over anhydrous magnesium sulfate and the diethyl ether was evaporated. The residue obtained was purified by preparative thin layer chromatography on silica gel using a mixture of ethyl acetate, cyclohexane and 90% formic acid (200: 200: 5 by volume) as the eluent to give 0.5 S 7- [5- (j5- Oxo-5-phenylpent-1-enyl) -2-oxocyclopentylj-heptanoic acid in the form of a pale yellow oil.

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Analysis. C ₃₅ H ₅₀ O ₄
Calculated: C 74.6j H 8.2 Ji
found: 74, S; 8.6 %

\ 990 cm " ¹ , 1625 cm" ¹ , 1670 cm " ¹ , 17ΟΟ cm" ¹ , 1730 cm " ¹ .

■ max
The nuclear magnetic resonance spectrum (NMR spectrum) of a 10 ^ solution in deuterochloroform showed the following peaks: Multiplets at 7.26 δ, 2.94 S, 2.0 - 2.6 £, 1.0 - 2.0 5 " , Doublet of doublets at £ 6.78 (J = 15.5 and 7.5 Hz), doublet at 6.15 5 * singlet at 10.5 <£.

The same procedure was followed, but the 7- {i, 4-Dioxa-7- (3-oxo-5-phenylpent-1-enyl) used as starting material spiro [4,4] non-6-yl (-heptanoic acid replaced by a suitable one Sets of

7-ii, 4-Dioxa-7- (3-oxo-4-phenylbut-1-enyl) sspiro [4,4] non-6-yl? - heptanoic acid,

7- ^ 1,4-Dioxa-7- (3-oxo-3-phenylprop-1-enyl) spiro [4,4] non-6-yl? - heptanoic acid,

7- ^ 1,4-Dioxa-7- (3-oxo-6-phenylhex-1-enyl) spiro [4,4] non-6-yl? - heptanoic acid,

7-? 1,4-Dioxa-7- (3-oxo-4-phenylhept-1-enyl) spiro [4,4] non-6-yljheptanoic acid,

7- £ 1,4-Dioxa-7- (3-oxo-4-phenyloct-1-enyl) spiro [4,4] non-6-ylvheptanoic acid,

7-ii, 4-Dioxa-7- (4-benzyl-3-oxooct-1-enyl) spiro [4,4] non-6-ylV-heptanoic acid

7- (1,4-Dioxa-7- (4-p-chlorobenzyl-3-oxooct-1-eny1) spiro [4,4] non-6-ylf-heptanoic acid,

7- [1,4-Dioxa-7- (4-p-methylbenzyl-3-oxooct-1-enyl) spiro [4,4] non-6-ylj-heptanoic acid,

7- ^ 1,4-Dioxa-7- (3-p-bromophenyl-3-oxoprop-1-enyl) spiro [4,4] non-6-yl} -heptanoic acid and

7-ii, 4-Dioxa-7- (3-0x0-3-thien-2'-yl-prop-1-enyl) spiro [4,4] non-6-yl ^ -heptanoic acid, all as described below in Example 1 (ii), were manufactured. The following were produced:

7- [5- (3-0xo-4-phenylbut-1-enyl) -2-oxocyclopentyl] -heptanoic acid analysis C ₂₂ H ₂ g0 ₄ calc .: C 74.1 H 7.9 % found : 75.7 8.2 % $ " _ev 985 cm" ¹ , 1620 cm " ¹ , 1665 cm" ¹ , 1700 cm " ¹ , 1730 cm" ¹ .

NMR (about 10 % w / v solution in deuterochloroform): broad singlet at 10.3 ί , singlet at 3.88 S ₁ doublet at 6.23 <T (J = 15.5 Hz), doublet of doublets at 6.9 / (J = 15.5 and 7.5 Hz), multiplets at 7.3 <i and 1.0 - 2.9 o ~, 7- [5- (j5-Oxo-3-phenylprop-1 - enyl) -2-oxocyclopentyl] -heptanoic acid analysis C ₂₁ H ₂₅ O ₄ calc .: C 73.7 H 7.65 % found : 73.7 7.8 % ^ 995 cm " ¹ , 1620 cm" ¹ , 1690 cm " ¹ , 17ΟΟ cm" ¹ , 17.20 cm " ¹ , 1730cnf ¹ '.

NMR (about 10 % w / v solution in deuterochloroform): Multiplets at 7.8 - 8.2 S, 7.35 - 7.8 S, 6.8 - 7.3 cT and 1.9 -

7- [5- (3-0xo-6-phenylhex-1-enyl) -2-oxocyclopentyl] -heptanoic acid analysis C ₃₄ H ^ ₂ O ₄ calc .: C 75.0 H 8.4 % found : 75, 3 8.5 %

^ ™ * _v 990 cm " ¹ , 1625 cm" ¹ , 1665 cm " ¹ , 17ΟΟ cm" ¹ , 173Ο cm " ¹ , max

NMR (about 10% w / v solution in deuterochloroform): broad singlet at 10.5 cT, doublet at 6.18 cT (J = 16 Hz), doublet of doublets at 6.76 cT (j = 8 and 16 Hz), Multiplets at 7.24 <£ and 1.0-2.9 S, 7- [5- (3-0xo-4-phenylhept-1-enyl) -2-oxocyclopentyl1-heptanoic acid analysis C ₂₅ H ₅₄ O ₄ calc. : C 75.3 H 8.6 % Found: 75.4 8.9 % ^ _mQV 995 cm " ¹ , 1630 cm" ¹ , 1665 cm " ¹ , 1705 cm ^-1 , 1725 cm" ¹ .

IiIcL-X.

NMR (about 10 % w / v solution in deuterochloroform):

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Broad singlet at 10.2 <£, singlet at 7.2 cT, doublet at 6.1 <f (-J = 15.5 Hz), doublet of doublets at 6.8 S (J = 15.5 and 7 Hz ), Multiplets at 3.8 cT, 1.0-2.6ef and 0.9 cf, 7- [5- (3-0xo-4-phenyloct-1-enyl) -2-oxocyclopentyl] -heptanoic acid

Analysis ^C 26 ^H 36 ° 4
calc .: C 75.7 H 8.8 %
found: 76.1 9.1 %

^ « _QV 980 cm" ¹ , 1615 cm " ¹ , 1655 cm" ¹ , 1695 cm " ¹ , 1725 cm" ¹ .

NMR (about 10% solution in deuterochloroform): broad singlet at 9.6 cf, doublet at 6.15 J ¹ (J = 15.5 Hz), doublet of doublets at 6.8 cf (J = 15.5 and 7.5 Hz) and 3.77 cf (J = 7 Hz), triplets at 2.31 <and 0.85 <f, multiplets at 7.1 - 7.4 cf, 1.05 - 2.8 (P. ,

7- [5- (4-Benzyl-3-oxooct-1-enyl) -2-oxocyclopentyl] -heptanoic acid analysis C ₂₇ H-ZgO ₄

calc .: C 76.0 H 9.0 %
found: 76.4 9.0 %

^ ~ O _V 990 cm ^"1, 1625 cm" ^1, 1660 cm ^"1, 1705 em" ^1, 1730 cm ^'1.

Πι ä X

NMR (about 10 % w / v solution in deuterochloroform): broad singlet at 10.8 cf, doublet at 6.12 S (J = 16 Hz), doublet of doublets at 6.67 cT (J = 7 and 16 Hz ), Triplet at 0.88 cf, multiplets at 7.18 cf, 2.6-3.2 cf, 2.0-2.6 <T, 1.5-2.0 cf, 7- [5- ( 4-p-Cilobenzyl-3-oxooct-1-enyl) -2-oxocyclopentyl] -heptanoic acid
Analysis C ₂₇ H ^ ₇ ClO ₄

calc .: C 70.3 H 8.1 %
found: 70.2 8.4 %

^ ™ o ^ 990 cm " ¹ , 1620 cm" ¹ , 1660 cm " ¹ , 17OO cm" ¹ , 1730 cm " ¹ , max

NMR (about 10% solution in deuterochloroform): broad singlet at 9.8 cf, doublet at 6, 14cf (J = 16 Hz), doublet of doublets at 6.7cf (J = 16 and 8 Hz), triplet at 0 , 86 S, multiplets

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at 6.9 - 7.35 pounds, 2.6 - 3.2 «f, 1.05 - 2.6 <f, 7- [5- (4-p-Methylbenzyl-3-oxooct-1-enyl) -2-oxocyclopentyl] -heptanoic acid

Analysis CggH ^ O ^

calc .: C 76.3 H 9.7 %
found: '76.2 9.5 %

$ ™ _ö "990 cm", 1625 cm " ¹ , 1660 cm" ¹ , 1705 cm " ¹ , 1730 cm" ¹ , max

NMR (about 10 % w / v solution in deuterochloroform): broad singlet at 9.43 <£, doublet at 6.13 S (J = 15.5 Hz), doublet of doublets at 6.68 S ( J = 15.5 and 7Hz), triplet at 0.88 <Γ, multiplets at 7.03 cT, 2.6 - 3.2 <T, 2.3 <f, 2.1 - 2.6 <T, 1, 05 -

7- [5- (3-p-bromophenyl-3-oxoprop-1-enyl) -2-oxocyclopentyl] -heptane

Analysis C ₂₁ H ₂₅ BrO ^

calc .: C 59.9 H 6.5 #
found: 60.1 6.5 ^

990 cm " ¹ , 1070 cm" ¹ , 1615 cm " ¹ , 1665 cm" ¹ , 17ΟΟ cm " ¹ ,

1730 cm " ¹ .

NMR (about 10 % w / v solution in deuterochloroform): broad singlet at 10.65 S, multiplets at 7.88 cf, 7.65 J ", 6.8 $ 7.2, 2.0 - 2, 9cf, 1.0-2, OcT and

7- [5- (3-0xo-3-thien-2'-ylprop-1-enyl) -2-oxocyclopentyl] -heptane

Analysis C ^ H ^ O ^ S

calc .: C 65.5 H 6.9 %
found: 65.3 7.2 %

^ ^ 985 cm " ¹ , 1415 cm" ¹ , 1515 cm " ¹ , 1605 cm" ¹ , 1645 cm "" ¹ , max

1690 cm " ¹ , 1720 cm" ¹ ,

max ² ? ⁸ ^ - ^ ax ¹¹ «°% χ ^ " ¹ H- ^ _3x 11100 NMR (about 10 % w / v solution in deuterochloroform) j broad singlet at 9.3, multiplets at 7.6 - 7.9 ^ , 6.7 - 7.35 &, 1.9 - 3.0 & and 1.0 - 1.9 &.

SQ9820 / 1130

(ii) 7-1,4-Dioxa-7- (3-oxoalk-1-enyl) splrof4,41non-6-yl? -heptanoic acids

4.4 g of anhydrous chromium trioxide were partially stirred into a solution of 5 * 85 g of 6- (7-hydroxyheptyl) -7- (3-ox ° -5-phenylpent-i-enyl) -1,4-dioxaspiro [4 , 4inonane [prepared as described below, in Example 1 (iii)] is added to 60 ml of anhydrous dimethylformamide at a temperature below 10 ^° C. A solution of 1.4 ml of concentrated sulfuric acid in 60 ml of dimethylformamide was added and the mixture was stirred ^{below 10 ° C. for 1 hour.} 200 ml of diethyl ether and then 100 ml of water were then added and the ethereal layer was separated off and then extracted with a 2N aqueous sodium carbonate solution. The aqueous solution obtained was acidified to pH 4 by adding dilute 2N hydrochloric acid and then saturated with sodium chloride and extracted with diethyl ether. The resulting ethereal solution was washed with water, dried over anhydrous magnesium sulfate, and dried to obtain 2.0 g of 7- / 1,4-dioxa-7- (3-oxo-5-phenylpent-1-enyl) spiro [4,4 ] evaporated non-6-yl? -heptanoic acid in the form of a yellow oil.

950 cm ¹ , 990 cm " ¹ , 1620 cm" ¹ , 1665 cm " ¹ , 1700 cm" ¹ ).

This material was used for subsequent steps without any further purification required.

The procedure was analogous, but this was replaced as the starting material used 6- (7-hydroxyheptyl) -7- (3-oxo-5-phenylpent-1-enyl) -1,4-dioxaspiro [4,4] nonane by appropriate amounts of

6- (7-Hydroxyheptyl) -7- (3-oxo-4-phenylbut-1-enyl) -1,4-dioxaspiro- [4,4] nonane,

6- (7-Hydroxy.heptyl) -7- (3-oxo-3-phenylprop-1-enyl) -1,4-dioxaspiro [4,4] nonane,

6- (7-Hydroxyheptyl) -7- (3-oxo-6-phenylhex-1-enyl) -1,4-dioxaspir.o [4,4] nonane,

6- (7-Hydroxyheptyl) -7- (j5-oxo-4-phenylhept-1-enyl) -1,4-dioxaspiro [4,4] nonane,
6- (7-Hydroxyheptyl) -7- (3-oxo-4-phenyloct-1-enyl) -1,4-d <fcoxa-

6Q8820 / 1130

spiro [4,4] nonane,

6- (7-Hydroxyheptyl) -7- (4-benzyl-3-oxo-oct-1-enyl) -1,4-dioxaspiro [4,4] nonane,

6- (7-Hydroxyheptyl) -7- (4-p-chlorobenzyl-3-oxooct-1-enyl) -1,4-dioxaspiro [4,4] nonane, 6- (7-hydroxyheptyl) -7- (4-p-methylbenzyl-3-oxooct-1-enyl) -1,4-dioxaspiro [4,4] nonane, 7 - ^ - p-bromophenyl - ^ - oxoprop-i-enyl) -6- (7- hydroxyheptyl) -1,4-dioxaspiro [4,4] nonane and 6- (7-hydroxyheptyl) -7- (3-oxo-3-thien-2 ^f -ylprop-1-enyl) -1,4-dioxaspiro [ 4,4] nonane [all compounds were prepared as described in Example 1 (iii) below]. The following were produced:

7- | l, 4-i> icra: a-7 ~ (3 ~ oxo-4-phenylbut ~ l-enyl) spiro [4, 4] -non-6-yll ~ heptanoic acid (V ^ _10x 950 cm, 985 can, 1625 cm " ¹ , 1675 can" ¹ , 1710 can " ¹ ), 7- jfl, 4 ~ dioxa ~ 7 ~ (3-oxo ~ 3-phenylprop- * l ~ enyl) spiro- [4,4] non -6-yl} heptanoic acid ^ maac 1620 on "* ¹ , 1660 can" ¹ , 1700 ση " ¹ ), 7- £ l, 4-Dio: ca-7 ~ (3-oxo- 6-phenylliex-l-- enYl) spiro [4,4 J-non ~ 6-yl ^ heptane acid ■ ma ^ c ^{955 0} ^ ¹ »

1625 can "* ¹ , 1670 cm"" ¹ , 1700 cm" ¹ ), 7- | 1,4-DiOMa -? - (3-oxo ~ 4-phenylhept-1-enyl) spiro- [4,43non-6 -yi? heptanoic acid (V "_ _v 955 can, 990 cm,

1620 cm " ¹ , 1660 cm"" ¹ , 1700 cm" ¹ ),

non-6-yl ^ heptanoic acid ^ max ⁹⁵⁵ ^ ¹ »1625 cm" ¹ , 1665 cm " ¹ , 1690 craT ¹ , 1705 era" ¹ ), 7- ^ l, 4-D io: ca-7 «(4- benzyl-3 ~ o3coct-i-enyl) spiro [4.4] non-6-yl ^ _S äure heptan ^ max ⁹⁵⁰ ^ ¹ "* ^1" '° cm ^"1, 1620 cm" ^1, 1660 cm ^"1, 1705 cn "" ¹ ),

25A8955

7 ~ £ 1,4-dioxa ~ 7- (4- »p ~ chlorobenzyl-3-oxooct-1-enyl) spiro

[4,4] non ~ 6-yl? ~ Heptanoic acid (^ _m ^ 950 cm " ¹ ,

985 cm " ¹ , 1625 cm" ¹ , 1665 cm " ¹ , 1710 to" ¹ ),

7- | l, 4 ~ Dioxa-7- (4-p-xnetliylben2yl-3-oxooct ~ l ~ enyl) spiro-

[4,4] non-6-yl ^ heptanoic acid A may ^{950 cm} ' ⁹⁹⁰ ^ ® *
1620 cm " ¹ , 1660 cm" ¹ , 1705 cm " ¹ ,)

⁹⁵ ° ^ ¹ "" ¹ »" ° cm " ¹ »

1070 cm "" ¹ , 1620 cm " ¹ , 1665 cm *" ¹ , 1705 cm "* ¹ ) and

7- £ l, 4- ~ Dioxa-7 ~ (3-oxo-3-thien-2'-ylprop-1-enyl) spiro-

[4,4] non-6-yl} heptanoic acid ^ mas- ⁹⁵ ° ^ ¹¹ "" ¹ * ⁹⁹⁰ cm "

1415 cnT ¹ , 1515 cm " ¹ , 1605 cm" ¹ , 1645 cm " ¹ , 1695 OtT ¹ )

(iii) 6- (7-Hydroxyheptyl) -7- (3-oxoalk-1-enyl) -1,4- dioxaspiro [4,4] -nonanes

(a) A solution of 2.5 g of dimethyl 2-oxo-4-phenylbutylphosphonate (prepared as in Example 9 below
described) added in 50 ml of anhydrous tetrahydrofuran to a stirred suspension of 0.24 g of sodium hydride in 20 ml of tetrahydrofuran. The mixture was stirred at room temperature under a nitrogen atmosphere for 24 hours and then added dropwise with a solution of 2.7 g of 7-formyl-6- (7-hydroxyheptyl) -1,4-dioxaspiro [4,4] nonane [prepared as follows described in Example 1 (iv)] in 30 ml of tetrahydrofuran and stirred for a further 2 hours under a nitrogen atmosphere. The mixture was then acidified to pH 4 by adding glacial acetic acid, the solvents were removed in vacuo and the residue was extracted with diethyl ether. The ethereal solution was 10 % w / v. aqueous sodium bicarbonate solution and then washed with water and dried over anhydrous magnesium sulfate. Evaporation of the solution gave J5i9 S 6- (7-hydroxyheptyl) -7- (3-oxo-5-phenylpent-1-enyl) -1,4-dioxaspiro [4,4] nonane in the form of a yellow oil.

some / mo

955 cm " ¹ , 990 cm" ¹ , 1625 cm " ¹ , 1665 cm" ¹ , 1690 cm " ¹ ).

By proceeding in an analogous manner, but using the dimethyl 2-oxo-4-phenylbutylphosphonate used as starting material by the appropriate or suitable amount of dimethyl 2-oxo-j5-phenylpropylphosphonate (prepared as follows described in Example 9), 6- (7-Hydroxyheptyl) -7- (3-oxo-4-phenylbut-1 -enyl) -1,4-dioxaspiro [4,4] nonane manufactured

(* L « _V 955 cm" ¹ , 990 cm " ¹ , 1625 cm" ¹ , 1665 cm " ¹ , 1685 cm" ¹ ), max

(b) A mixture of 4.0 g of 7-formyl-6- (7-hydroxyheptyl) -1,4-dioxaspiro [4,4] nonane was heated and 5.6 g of benzoylmethylene triphenylphosphorane (prepared according to the method of F. Ramirez and S. Dershowitz, J. Org. Chem., 1957 * .22, 41) in 35 ml of hexamethylphosphoric trisamide on a steam bath under an atmosphere of dry nitrogen for 48 hours and then poured into 200 ml of water. The mix was extracted with diethyl ether and the ethereal solution was washed with water, dried over anhydrous magnesium sulfate and evaporated. The residue became with a mixture of petroleum ether (boiling point 40 to 60 ° C) and diethyl ether treated, left to stand at 0 C and then filtered to remove triphenylphosphine oxide. The Piltrat was to obtain 6-C7-hydroxyheptyl) -7- (3-phenyl-3.-oxoprop-1-enyl) -1,4-dioxaspiro [4,4] nonane evaporated.

0Lo _V 950 cm " ¹ , 985 cm" ¹ , 1615 cm " ¹ , ΐββθ cm" ¹ , 3380 cm " ¹ ).

IHClJt

By proceeding in an analogous manner, but using the benzoylmethylene triphenylphosphorane used as the starting material by the appropriate amount of 4-phenylbutanoylmethylene triphenylphosphorane [prepared as described below in Example 8 "(1)], 6- (7-Hydroxyheptyl) -7- (3-oxo-6-phenylhex-1-enyl) -1,4-dioxaspiro [4,4] nonan manufactured.

950 cm " ¹ , 990 cm" ¹ , 1620 cm " ¹ , 1680 cm" ¹ , 3335 cm " ¹ ).

009820/1130

The procedure was analogous, except that the benzoylmethylene triphenylphosphorane used as the starting material was used replaced by suitable amounts of ct-phenylpentanoylmethylene triphenylphosphorane, a-phenylhexanoylmethylene triphenylphosphorane, a-Benzylhexanoylmethylene triphenylphosphorane, a-p-chlorobenzylhexanoylmethylene triphenylphosphorane, a-p-Methylbenzylhexanoylmethylene triphenylphosphorane [these latter five compounds were prepared as described below in Example 8 (i)], p-Brombenzoylmethylene triphenylphosphorane (prepared according to the procedure of A.V. Dombrovskii and M.I. Shevchuk, Zh. Obshch. Khim. 196 ?, 33, 1263, Chem. Abstr. 1963, 59, 10113b) and Thien-2-oylmethylene triphenylphosphorane [prepared according to Procedure by A.V. Dombrovskii, M.I. Shevchuk and A.A. Grigorenko, Metody Poluch, Khim. Reaktivov Prep. 1966, no. H, 147 (Chem. Abstr. 1967, 67, 43889X)]. The following were produced:

6- (7 ~ Hyäroxyheptyl) -7- (3-oxo ~ 4 ~ phenylhept-l-enyl) -l, 4-dioxaspiro [4.4] nonane (V CNT ^{950, 1} 990 cm ^'1.

1625 on "" ¹ , 1690 can " ¹ , 3400 cm" ¹ ), 6- (7-hydroxyheptyl) -7 ~ (3-oxo-4 ~ phenylpct-1-enyl) ~ 1,4-dioxaspiro [4.4 ] nonane (^) "950 esa" ^1, 980 cm ^"1, 1615 cm"^"1, 1675 CNT ^1, 3335 cm" ^1), 7- (4-Bensyl-3-o; iooct-l-enyl} ~ 6- (7-hydroxyheptyl) -l ·, 4-

äioxaspiro [4,4] nonane (S) 950 cm * " ¹ 990 cm" ¹ .

1620 cnT ¹ , 1660 er " ¹ , 3400 era" ¹ ), 7- (4-p-ChloÄ> enzyl-3-oxooct-1-enyl) -6- (7-hydroxyheptyl) -1, 4-oxaspiro [4 , '4] nonaR (S) 955 to " ¹

995 era " ¹ , 1615 cm" ¹ , 1680 cm " ¹ , 3335 cm" ¹ ),

-H.hydro3cyheptyl) -7- (4-p-methylbenzyl-3-oxooct-lenyl) -1, 4-dioxasp ± ro [4,4] nonane (^ _max ⁹ $ 5 ση ", 990 em"" ¹ , 1625 cm " ¹ , 1685 cm" ¹ , 3400 cm " ¹ ),. 7- (3-p-Bromophenyl-3-oxoprop-1-enyl) -6- (7-hydroxyheptyl) -1, 4-dioxaspiro [4,4] nonari 'CV ₅₁₃₃ . 950 cm, 99Ο cm "" ¹ , 1070 cm " ¹ , 1615 cm *" ¹ , 1665 cm " ¹ , 3400 cm *" ¹ ), and '-'. "■ ..- '." , 'ν' ¹ · '■' ■

6- (7-Hydroxyheptyl) -7- (3-oxo-3-thien-2 '-ylprop-1-enyl) -1, 4-dioxaspiro [4,4] nonane. (^^ χ ⁹⁶⁰ cm " ¹ , 995 cm" * ¹ , 1425 cm "" ¹ , 1525 cm " ¹ , 1610 on" ¹ ,. 1655 cm "* ¹ , 3335 cm *" ¹ ),

(i ^v) 7-Formyl-6- (7-hydroxyheptyl) -1 »4 dloxaspiro- [4,4jnonan

(a) Preparation of 2- (7-hydroxyheptyl) cyclopent-2-en-1-one

A mixture of 22 g of 7- (2-tetrahydropyranyloxy) -heptanal was obtained and 21.4 g of 1-morpholinocyclopentene, i.e. the morpholinenamine of cyclopentanone, in 25 ml of benzene under Heated to reflux for 12 hours under nitrogen and the released water continuously through a Dean-Stark head removed. 10 ml of benzene and then 28 ml of 18 # hydrochloric acid were added dropwise, and the mixture was during Stirred for 2 hours. The organic layer was separated and evaporated. 72 ml was concentrated to the residue Hydrochloric acid and 300 ml of butanol were added. The mixture was heated to 100 ° C for 1 hour and the solution then became concentrated to obtain an oil. Diethyl ether was added and the ether solution was made with aqueous sodium bicarbonate and then washed with water and dried over sodium sulfate. The solvent was evaporated and the residue under reduced pressure to give 11.7 g

60SI20 / T130

2- (7-Hydroxyheptyl) -cyclopent-2-en-i-one distilled,

Bp. 125 - 170 ° C / 0.15 mm Hg, n ^ ^{5 1} ^ 90, ^ _max 228 mu (ethanol)

The 7- (2-tetrahydropyranyloxy) -heptanal used as starting material in the above procedure was prepared as follows:

272 g of 3,4-dihydro-2H-pyran were added dropwise at 40 ° C. with stirring to a mixture of 284 g of 7-hydroxyheptanenitrile and 10 drops of concentrated hydrochloric acid. The temperature was allowed to rise to 65 ^° C. and held at this level for 1 hour. The solution was cooled and 500 ml of benzene was added. The solution was washed with aqueous sodium bicarbonate and then with water and dried over sodium sulfate. The solvent was removed in vacuo and the residue was distilled under reduced pressure to give 411 g of 7- (2-tetrahydropyranyloxy) heptanenitrile, bp 100-130 ° C./0.1 mm Hg, njp 1.455.

19 * 4 g of diisobutylaluminum hydride in 50 ml of dry benzene were added dropwise at 10 ° C. to a stirred solution of 20.6 g of 7- (2-tetrahydropyranyloxy) -heptanenitrile in 200 ml of dry diethyl ether. The solution was stirred for 30 min. At 10 ° C and then added out of 2N aqueous sulfuric acid at 0 ⁰ C to 300 ml. The mixture was ^{heated to 30 °} C. for 30 min and then saturated with sodium chloride and the layers separated. The aqueous layer was extracted with diethyl ether and the combined organic layers were washed with aqueous sodium bicarbonate and then with aqueous sodium chloride and dried over sodium sulfate. The solvent was evaporated and the residue was distilled under reduced pressure to give 12.7 g of 7- (2-tetrahydropyranyloxy) heptanal, bp 78-106 ° C / 0.1 mm Hg, ⁵ 1.456.

609820/1130

(b) Preparation of 2- (7-hydroxyheptyl) -5-oxocyclopentanecarbonitrile

A mixture of 17 g of 2- (7-hydroxyheptyl) cyclopent-2-en-i-one, 8.5 g of acetone cyanohydrin, 8 ml of 6 ^ iges, aqueous sodium carbonate and 50 ml of methanol and stirred for 4 hours Heated to reflux. Methanol was removed in vacuo, 100 ml of water were added and the mixture was extracted with diethyl ether and dried over magnesium sulfate. The solvent was removed by evaporation and the residue under reduced pressure Pressure to obtain 13 * 5 g of 2- (7-hydroxyheptyl) -3-oxocyclopentanecarbonitrile distilled, bp 144 - 182 ° C / O, 15 mm Hg,

H) 1.4795-

( ^c ) Preparation of 7-cyano-6- (7-hydroxyheptyl) -1,4-dioxaspiro [4,4] nonane

A mixture of 20 g of 2- (7-hydroxyheptyl) -j5-oxocyclopentanecarbonitrile, 5.6 g of ethylene glycol, 1 g of p-toluenesulfonic acid and 160 ml of benzene was heated under reflux for 210 minutes with the continuous removal of water. The mixture was cooled to room temperature, anhydrous sodium carbonate was added and, after filtration through a bed of sodium carbonate, the solvent was removed under reduced pressure. The residue was distilled under reduced pressure to give 19.3 g of 6-cyano-6- (7-hydroxyheptyl) -1,4-dioxaspiro [4.4] nonane, bp 166 182 ° C / 0.1 mm Hg This material was used as the starting material for the next stage, an aliquot being redistilled for elemental analysis at a bp of 177-179 ° C./0.1 mm Hg.
Analysis C ₁ ^ H ₂₅ NO ₅

calc .: C 67.37 H 9.42 N 5.24 %
found: 67.1 9.2 4.89 %

10 ** 20/1130

(d) Preparation of 7-formyl-6- (7-hydroxyheptyl) -1,4-dioxaspiro [4,43nonane

With rapid stirring, a solution of 53 g of diisobutylaluminum hydride in 145 ml of dry benzene was added to a solution of 43.2 g of 7-cyano-6- (7-hydroxyheptyl) -1,4-dioxaspiro [4,4] nonane in 432 ml added dry diethyl ether at 10-15 ° C. Stirring was continued at room temperature for 90 min. And the mixture was added to one liter of 2N aqueous acetic acid at a temperature lower than 15 ° C. The organic phase was separated and the aqueous layer was extracted with diethyl ether. The combined organic phases were washed with aqueous sodium bicarbonate, dried over sodium sulfate, the solvents were removed in vacuo and the residue was removed under reduced pressure to give 25.3 S 7-formyl-6- (7-hydroxyheptyl) -i, 4- dioxaspiro [4.4] nonane distilled, bp 164-200 ° C / 0.05 mm Hg.O _v 1710 cm " ¹ , 2700 cm" ¹

(liquid film).

Example 2

(i) 7-i 5- [4- (2-phenylethyl) -3-oxooct-1-enyl] -2-oxoeyclopentyl] -heptanoic acid

A solution of 0.4 g of 7-U , 4-dioxa-7- [4- (2-phenylethyl) -3-oxooct-1-enyl] spiro [4,4] non-6-ylj-heptanoic acid [ prepared as described below in Example 2 (ii)] in 10 ml of acetic acid and 5 ml of water at room temperature for 4 hours and then evaporated at a temperature below 50 ° C. in vacuo. The residue was dissolved in diethyl ether and the ethereal solution was extracted with water and then with 2N aqueous sodium carbonate solution. This aqueous solution was then acidified to pH 3 by adding 2N dilute hydrochloric acid, saturated with sodium chloride and with diethyl ether

6Ö9820 / 1130

extracted. The ethereal solution was washed with water, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by preparative thin layer chromatography on silica gel using a mixture of ethyl acetate, cyclohexane and 90% formic acid (200: 200: 5 by volume) as the eluent to give 0.12 g of 7- £ 5- [4- (2 -Phenyläthyl) -3-oxooct-1 -enyl] -2-oxocyclopentyl Ί, - heptanoic acid purified,
Analysis C ₃₈ H ₄₀ O ₄

calc .: C 76.5 H 9.2 %
found: 76.1 9.5 %

^ _mQV 995 cm "" ¹ , 1630 cm " ¹ , 1665 cm" ¹ , 1710 cm " ¹ , 1735 cm" ¹ .

Ill S. JC

NMR (about 10 # solution in deuterochloroform): broad Singlet at 10.5 «T, singlet at 7 * 25 <f, doublet at 6.2 J" (J = 16 Hz), doublet of doublets at 6.8 cT (j = 16 and 7.5 Hz), Triplet at 0.87 <f, multiplet at 1.05 - 3 * 0 ^.

(ii) 7-f 1,4-DiOXa -? - Γ4- (2-phenylethyl) -3-oxooct-1-enyl1-spiro [4,4] non-6-yl | -heptanoic acid

By proceeding in an analogous manner to that described in Example 1 (ii), but using the 6- (7-hydroxyheptyl) -7- (3- ° ^x ° -5-phenylpent-1-enyl) -1 used as starting material , 4-dioxaspiro [4,4] nonane with the appropriate amount of 6- (6-hydroxyheptyl) -7- [4- (2-phenylethyl) -3-oxooct-1-enyl] -1,4-dioxaspiro [4 , 4] nonane prepared [as described below in example 2 (iii)] replaced, 7- £ ^1, 4-dioxa-7 [4- (2-phenylethyl) -3-oxooct-1-enyl] spiro [4, 4] non-6-yl | - heptanoic acid produced,

^ _mev 950 cm " ¹ , 990 cm" ¹ , 1625 cm " ¹ , 1660 cm" ¹ , 1710 cm " ¹ .

(iii) 6- (7-Hydroxyheptyl) -7-Γ4- (2-phenylethyl) -3-oxooct-1,4-dioxaspiro [4,4] nonane

By proceeding in a manner analogous to that described in Example 1 (iii) (a) proceeded, but using that as the starting material

used dimethyl 2-oxo-4-phenylbutylphosphonate by the suitable amount of dimethyl 2-oxo-3- (2-phenylethyl) heptylphosphonate replaced (prepared as follows in Example 9 described) was 6- (7-hydroxyheptyl) -7- [4- (2-phenylethyl) -3-oxooct-1 -enyl] -1,4-dioxaspiro [4,4] nonane

("L ,,, 950 cm" ¹ , 990 cm " ¹ , 1620 cm" ¹ , 1655 cm ~ ¹ , 168O cm " ¹ ), max

Example 3

(i) 7- [5- (3-Hydroxyalk: -1-enyl) -2-oxocyclopentyl] -heptanoic acid

By in a manner analogous to Example 1 (i) for the preparation of 7- [5- (3-0xo-5-phenylpent-1-enyl) -2-oxocyclopenty.l] -heptanoic acid proceeded described, but using the 7- £ 1,4-dioxa-7- (3-oxo-5-phenylpent-1-enyl) spiro [4,4] -non-6-yl | -heptanoic acid used as starting material by the appropriate amount of 7- £ 1,4-dioxa-7- (3-hydroxy-4-phenyloct-1-enyl) -spiro [4,4] non-6-yl] -heptanoic acid, 7- £ i, 4-Dioxa-7- (4-p-chlorobenzyl-3-hydroxyoct-i-enyl) spiro [4,4] non-6-ylr-heptanoic acid and 7- £ 1,4-Dioxa-7- (4-p-methylbenzyl-3-oxooct-1-enyl) spiral 4,4] non-6-yl ^ -heptanoic acid replaced [all three compounds were prepared as described below in Example 3 (ü)], the following compounds were prepared: 7- [5- (3-Hydroxy-4-phenyloct-1-enyl) -2-oxocyclopentyl] -heptanoic acid,

analysis ^C 26 ^H 38 ° 4 c- / O 1730 cm " ¹ , 3450 cm " ¹ ber .: C 75.3 H 9, 5% found: 75.2 9, cm ", ) 98O
max ^y cm ", 1705

NMR (about 10 % w / v solution in deuterochloroform): broad singlet at 6.7 <f, triplet at 0.81 S (J = 6 Hz), multiplets at 6.9 - 7.4 cT, 5, 25 to 5.7 cT, 4,2cf, 2.0 to 2.6 cT, from 1.0 to 2.0 J ^1, 7- [5- (4-p-chlorobenzyl-3-hydroxyoct-1-enyl) -2-oxocyclopentyl] heptanoic acid,

601820/1130

Analysis C ₂ ~ H, gCl0 ^

calc .: C 70.0 H 8.5 %
found: 69.7 8.8 #

^ _mQV 975 cm " ¹ , 1700 cm" ¹ , 1725 cm " ¹ , 3 ² K) O cm" ¹ .

NMR (about 10 % w / v solution in deuterochloroform): multiples at 7.0-7.3i, 5.4-5.7 cT, 4.1 cf, 1.0-2.05 <£ and 0 , £ 87 and

7- [5- (4-p-methylbenzyl-3-hydroxyoct-1-enyl) -2-oxo-cyclopentyl] -heptanoic acid,
Analysis ^C 28 ^H 42 ° 4
calc .: C 76.0 H 9.6 %
found: 76.0 9.6 %

" ¹

^ max ^{975 cm} " ^{1 '17} ° ^{5 cm} ~ ¹ ' ¹⁷⁵ ° ^cm " ¹ x 3450 cm. NMR (about 10 % w / v solution in deuterochloroform): singlets at 6.45 "f, 2.3 cf, triplet at 0.88 J", multiplets at 7.1 c /, 5.55-5, 75 (T, 4.15 cT, 2.0-2.9 / and 1.1-2, OcT.

(ii) 7-fi, 4-dioxa-7- (3-hydroxyalk-1-enyl) spiro [4,4] non-6-yl-heptanoic acids

A solution of 0.8 g of 7-1,4-dioxa-7- (3-oxo-4-phenyloct-1-enyl) spiro [4,4] non-6-ylj-heptanoic acid [prepared as above in Example 1 (ii)] in 12 ml of methanol was added to 160 ml of a 2 % w / v. given aqueous sodium citrate solution and cooled to -5 ° C. 2.4 g of potassium borohydride were partially added with stirring over a period of 30 minutes while maintaining a temperature of -5 ° C. and maintaining a pH of 8 by adding small amounts of 10 % w / v. Citric acid solution added. The solution was stirred for 2 hours at -5 to ⁰ ° C. at pH 8, 24 ml of acetone were added and then a further amount of citric acid solution was added,

109820/1130

- 31 - 25A8955

until the solution reached pH 4. The mixture was saturated with sodium chloride and extracted with diethyl ether. The ethereal solution was washed with water, dried over anhydrous magnesium sulfate and obtained of 0.8 g of 7- £ 14-dioxa-7- (j5-hydroxy-4-phenyloct-1-enyl) spiro [4,4] non-6-ylj-heptanoic acid evaporated in the form of a yellow oil.

^ max 955'cm " ¹ , 975 cm" ¹ , 1705 cm " ¹ ,? 440 cm" ¹ ).

By proceeding in an analogous manner, but using the 7- £ 1,4-dioxa-7- (3- ° ^x ° -4-phenyloct-1-enyl) spiro [4,4] non-6- yl? -heptanoic acid by suitable amounts of 7-f 1,4-dioxa-7- (4-p-chlorobenzyl-j5-oxooct-1-enyl) ~ spiro [4> 4] non-6-yl ^ -heptanoic acid and 7-fi ^ -Dioxa - ^ - ^ - p-methylbenzyl ^ -oxooct-i-eny ^ spiro ^^ jnon-o-ylj-heptanoic acid [both were prepared as described in Example 1 (ii) above], the following compounds were prepared: 7- £ ¹ i4-dioxa-7- (4-p-chlorobenzyl-3-hydroxyoct-1-enyl) spiro [4.4] non-6-heptanoic acid YLJ

i ^ _mav 950 cm " ¹ , 975 cm" ¹ , 1705 cm " ¹ , 3400 cm" ¹ ) and 7-ί (1,4-dioxa-7- (3-hydroxy-4-p-methylbenzyloct-1-enyl ) -spiro [4,4] non-6-yl ^ -heptanoic acid

950 cm " ¹ , 975 cm" ¹ , 1700 cm ~ ¹ , 3400 cm ~ ¹ ).

Example 4

(i) 7-f 5-r3-hydroxy-4- (2-phenylethyl) oct-1-enyl'l-2-oxocyclopentyl'l -heptanoic acid

A solution of 0.77 g of 7,4-dioxa-7- [3-hydroxy-4- (2-phenylethyl) oct-1-enyl] spiro [4,4] non-6-yl was kept ^ -heptanoic acid [prepared as described hereinafter in example 4 (ii) above] in 16 ml of acetic acid and 8 ml of water for 4 hrs. at room temperature and then evaporated in a vacuum at a temperature below 50 ⁰ C. The residue was dissolved in diethyl ether and

130

the ethereal solution was washed with water and then extracted with 2N aqueous sodium carbonate solution. These Solution was made up by adding 2N dilute hydrochloric acid acidified to pH 3 and then saturated with sodium chloride and extracted with diethyl ether. The essential Solution was washed with water, dried over anhydrous magnesium sulfate and evaporated to give 0.6 g of crude 7- £ 5- [3-hydroxy-4- (2-phenylethyl) oct-1-enyl] -2-oxocyclopentylj-heptanoic acid in the form of a mixture of the diastereoisomers.

The mixture was purified and partially using preparative thin layer chromatography on silica gel a mixture of ethyl acetate, cyclohexane and 90% formic acid (200: 200: 5 by volume) as the eluent separated to form two different diastereoisomeric components.

In analogy to known prostaglandins, the material more remote from the starting material ("component. 4a") (O * ¹ 3 δ) was kept as a 1: 1: 1: 1 mixture of the isomers

COOH 0 and

, COOH

and their enantiomers. Analysis ^c ₂ 8 ^ 42 ° 4
calc .: C 76.0 H 9.6 % found : 76.1 9.8 %

ν max ^{975 cm} ~ "^'17 °° ^cm ~'' ^{1725 cm} ~''^ 50 cm

609820/1130

NMR (about 10 % w / v solution in deuterochloroform): singlet at 7.23 cT> 6.4 S, triplets at 2, β7 <Γ, 2.30 S, 0.90 S and multiplets at 5.55 - 5.7 cf, 4.19 <T, 1.05 - 2.7 <f Similarly, the material closer to the starting material ("component 4b") (0.07 g) was considered to be a 1p1: 1: 1 mixture of the isomers

CX) OH

and their enantiomers.
Analysis C 75.7 H 9.8 %

As usual, the symbol means a tie below

the level of the formula and the symbol Ny a bond above the level of the formula. The infrared and NMR spectra of component 4b were virtually identical to those of component 4a.

(ii) 7-1,4-Dioxa-7- [3-hydroxy-4- (2-phenylethyl) oct-1-enyl] spiro [4,4] non-6-ylj-heptanoic acid

By reacting, in an analogous manner as described in Example 3 (ii) for the preparation of 7- £ ^1, 4-dioxa-7- (3-hydroxy-4-phenyloct-1-enyl) spiro [4.4] non-6 -ylj-heptanoic acid proceeded, but the 7- £ 1,4-dioxa-7- (3-oxo-4-phenyloct-1-enyl) spiro [4,4] non-6-yl ^ - used as starting material heptanoic acid by the appropriate amount of 7-1,4-dioxa-7- [4- (2-phenylethyl) -3-oxooct-i-enyl) spiro [4,4] non-6-ylJ-heptanoic acid [prepared as described above in Example 2 (ii)], 7- £ i, 4-Dioxa-7- [3-hydroxy-4- (2-phenylethyl) -oct-1-enyl] spiro [4,4] non- 6-ylj-heptanoic acid produced;

£ 89 * 20/1130

(^ Lo _V 955 cm " ¹ , 980 cm" ¹ , 1710 cm " ¹ , 3450 cm" ¹ ).

Example 5

(i) 7- [5- (3-Hydroxy-5-phenylpent-T-enyl) -2-oxocyclopentyl] -heptanoic acid

A solution was maintained from 1.0 g of 7 ~ V. "4-dioxa-7- (3-hydroxy-5-phenyl-pent-1-enyl) spiro [4.4] non-6-YLJ-heptanoic acid [prepared as described hereinafter in example 5 (ii) above] in 10 ml acetic acid and 5 ml of water for 4 hrs. at room temperature and then evaporated in a vacuum at a temperature below 50 ⁰ C. The residue was dissolved in diethyl ether and the ethereal solution was washed with water and then extracted with 2N aqueous sodium carbonate solution. This solution was acidified to pH 3 by adding 2N dilute hydrochloric acid and then saturated with sodium chloride and extracted with diethyl ether. The ethereal solution was washed with water, dried over anhydrous magnesium sulfate and treated to give 0.8 g of crude 7- [5- (3-hydroxy-5-phenylpent-1-enyl) -2-oxocyclopentyl] heptanoic acid ("*> · 975 cm ^"1, 17ΟΟ cm" ^1, 1720 cm ^"1) and

Max

Evaporated mixture of diastereoisomers in the form of an oil. The mixture was purified and analyzed by preparative thin layer chromatography on silica gel using a mixture of ethyl acetate, cyclohexane and 90% formic acid (200: 200: 5 in volume) as the eluent, with the plates were eluted twice, partly separated into the diastereoisomeric components.

In analogy to known prostaglandins, the material more removed from the starting material (126 mg) ("component 5a") for a 1: 1 mixture of the isomer

COOH

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and its enantiomers, while that of the starting material closer material (112 mg) ("component 5b") for a 1: 1 mixture of the isomer

COOH

and held its enantiomers

(ii) 7-f.1,4-Dioxa-7- (3-hydroxy-5-phenylpent-1-enyl) -spiro [4,4] non-6-ylf-heptanoic acid

A solution of 1.0 g of 7-1,4-dioxa-7- (3-oxo-5-phenylpent-1-enyl) spiro [4,4] non-6-ylj-heptanoic acid [prepared as above was added described in Example 1 (ii)] in 10 ml of methanol to 16O ml of a 2 % w / v. aqueous sodium citrate solution and cooled to -5 ° C. Partially 3.2 g of potassium borohydride were added with stirring over a period of 30 minutes, the temperature being kept at -5 ° C. and the pH value at a value by adding small amounts of 10% w / v aqueous citric acid solution of 8. The solution was stirred for 2 hours at -5 to 0 C at a pH of 8 and 25 ml of acetone were added and then a further amount of the aqueous citric acid solution until the solution reached a pH of 4 The mixture was saturated with sodium chloride and extracted with diethyl ether, the ethereal solution was washed with water, dried over anhydrous magnesium sulfate and dried to give 0.8 g of 7-1,4-dioxa-7- (3-hydroxy-5 ~ phenylpent-1-enyl) spiro [4,4] non-6-yl ^ -iheptanoic acid evaporated in the form of a yellow oil.

955 cm ^"1, 975 cm" ^1, 17oo cm ^"1, 3400 cm" ^1).

Example 6 7- [5- (3-Hydroxy - ^ - phenylpropyl) -2-oxoGyGlopentyl} -heptanoic acid

(i) Preparation of 7-U , 4-dioxa-7- (3-hydroxy-3-phenylpropyl) spiro [4,4] non-6-ylj-heptanoic acid

A solution of 1.0 g of 7- [i, 4-dioxa-7- (3-phenyl-3-

oxoprop-1-enyl) spiro [4,4] non-6-ylj-heptanoic acid [prepared as described above in Example 1 (ii)] in 50 ml of ethanol and 0.25 g of palladium-activated carbon catalyst together with hydrogen (2 , 8 kg / cm ² ) for 1 hour at 25 ° C. The catalyst was filtered off and evaporation of the solvent gave 0.95 g of 7-1,4-dioxa-7- (3-hydroxy-3-phenylpropyl) -spiro [4,4] non-6-ylj-heptanoic acid,

(° _max 955 cm " ¹ , 1705 cm" ¹ , 1715 cm " ¹ , 3 ^ 50 cm" ¹ ).

This material was used for the next stage, namely manufacturing of 7- [5- (j5-Hydroxy-3-phenylpropyl) -2-oxocyclopentyl] -heptanoic acid used without further purification required.

(ii) Preparation of 7- [5- (3-Hydroxy-3-phenylpropyl) -2-oxocyclopentyl] -heptanoic acid

A solution of 0.5 g of 7-fi, 4-dioxa-7- (3-hydroxy-3-phenylpropyl) spiro [4,4] non-6-yl? -Heptanoic acid was kept in 10 ml of acetic acid and 5 ntl of water for 4 hours at 25 C and steamed then in a vacuum below 50 C.

The residue was dissolved in diethyl ether and the ethereal solution was washed with water over anhydrous magnesium sulfate dried and evaporated. The residue was purified by preparative thin-layer chromatography on silica gel using a mixture of ethyl acetate, cyclohexane and 90% formic acid (200: 200: 5 in volume) as elution

£ 09820/1130

medium to obtain 0.2 g of 7- [5- (3-Hydroxy-3-phenylpropyl) -2-oxocyclopentyl] -heptanoic acid cleaned in the form of an almost colorless oil

Analysis C ₂₁ E ₅₀ O ₄

calc .: c 72.8 H 8.7 %
found: 73.0 8.7 %

>) _mo 1705 cm " ¹ , 1730 cm" ¹ , 3450 cm " ¹ .

NMR (about 10 % w / v solution in deuterochloroform): singlet at 7.35 pounds, multiplets at 4.67 S and 1.0-2.45 S.

Example 7

Acetates

A solution of 0.35 g of 7- [5- (3-hydroxy-4-p-methylbenzyloct-1-enyl) -2-oxocyclopentyl] -heptanoic acid [prepared as described in Example 3 (i) above] in 10 was kept ml of anhydrous pyridine and 10 ml of acetic acid for 43 hours at 25 ° C. and poured into a mixture of ice and water (approx. 30 ml). The obtained mixture was extracted with diethyl ether and the ethereal extracts were washed with 2N dilute hydrochloric acid and then with water and dried over anhydrous magnesium sulfate. The solution was evaporated and the residue was purified by preparative thin layer chromatography on silica gel using a mixture of ethyl acetate, cyclohexane and 90% formic acid (200: 200: 5 by volume) as the eluent to give 0.18 g of 7- [5- ( 3-Acetoxy-4-p-methylbenzyloct-1-enyl) -2-oxocyclopentyl] -heptanoic acid in the form of a yellow oil. Analysis C ₅₀ H ₄₄ O ₅

calc .: C 74.3 H 9.15 %
found: 74.5 9.5 %

^ max ^{12lf0 cm} ~ ¹ ' ^{1710 cm} " ¹ ·
NMR (about 10 % w / v solution in deuterochloroform): broad

§09820 / 1130

Singlet at £ 10.6, singlet at 7, θ8 £, 2.33 £, 2.04 £, triplet at 0.87 S, multiplet at 5.2-5.8.5, 2.0-2.8J ¹ and 1.05 - 2.0 p. - '

By proceeding in an analogous manner, but using that as the starting material used 7- [5- (3-hydroxy-3-phenylpropyl) -2-oxocyclopentyl] -heptanoic acid by the appropriate amount of 7- [5- (3-hydroxy-4-p-methylbenzyloct-1-enyl) -2-oxocyclopentyl] -heptanoic acid (prepared as described above in Example 6) replaced 7- [5- (3-acetoxy-3-phenylpropyl) -2-oxocyclopentyl] -heptanoic acid here;

Analysis Cg-xH,

calc .: C 71/1 H 8.3 %
found: 71.5 £ 8.6

^ _mav 1240 cm " ¹ , 1705 cm" ¹ , 1725 cm " ¹ .

NMR (about 10 % w / v solution in deuterochloroform): broad singlet at 10.25 S ₉ singlet at 2.10 cf, multiplets at 7.37 <T / 5.78 c ?, 2.0-2.6 <f, 1.0-2, OcT.

By again proceeding in an analogous manner, but with 7- [5- (3-Hydroxy-4-p-methylbenzyloct-1-enyl) -2-oxocyclopentyl] -heptanoic acid used as starting material by the appropriate amount of 7- ^ 5- [3-hydroxy-4- (2-phenylethyl) oct-1-enyl] -2-oxocyclopentylj-heptanoic acid [Crude mixture of diastereoisomers prepared as in Example above 4 (i)] was replaced by 7-15- [3-acetoxy-4- (2-phenylethyl) oct-1-enyl] -2-oxocyclopentylj-heptanoic acid manufactured,

Analysis C ^ qH ^ O, -

Calcd .: C 74.3 H 9.2 ^
found: 74.2 9.4 %

^ 1235 cm ^"1, 17oo cm" ^1, 1710 cm ^'1.

§63820 / 1130

Example 8 Acylmethylene triphenylphosphoranes

(i) Preparation of acylmethylene triphenylphosphoranes

(a) A solution of 0.1 g of sodium in 3.8 ml of anhydrous was added Ethanol to a solution of 1.0 g of 4-phenylbutanoylmethyltriphenylphosphonium chloride [prepared as described below in Example 8 (ii)] in 10 ml of anhydrous ethanol and the obtained mixture was allowed to stay at room temperature

Stand for 4 hours. The mixture was concentrated to half its amount by removing ethanol in vacuo and then with Diluted 50 ml of water and extracted with chloroform. The combined chloroform extracts were washed over with water Dried sodium sulfate and evaporated to dryness. The remaining oil was treated with light petroleum ether (bp 40 to 60 ° C) and then from cyclohexane to give 0.6 g 4-phenylbutanoylmethylene triphenylphosphorane in the form of a white crystalline pesticide with a melting point of 93-95 ° C recrystallized.

Analysis of CggHgyOP

calc .: C 82.4 H 6.4 P 7.3 %
found: 82.8 6.5 7.6 %

^ Lo ^ ¹¹ ° 0 c ^m ~ ¹ » ¹² K) O cm" ¹ , 1440 cm " ¹ , 1485 cnf ¹ , 1540 cm" ¹ .

(b) 7.9 grams of a-phenylhexanoylmethyltriphenylphosphonium chloride [prepared as described in Example 8 (ii) below] was added to 80 ml of a stirred 10 % w / v. aqueous sodium carbonate solution at room temperature. The mix was

Stirred for 5 hours and then extracted with diethyl ether. The essential Solution was washed with water, dried over anhydrous magnesium sulfate and given a yellow The oil was evaporated, from which a white solid was obtained by treatment with light petroleum ether (boiling point 40-60 ° C.). Recrystallization of this material from light petroleum ether (Bp. 60 to 80 ° C) gave 4.0 g of a-phenylhexanoylmethylene

600820/1130

triphenylphosphorane in the form of colorless prisms, melting point 89-91 ° C.

Analysis CZ ₁ KU ₁ OP

calc .: C 82.6 H 6.9 P 6.9 %
found: 83.0 6.9 7.0 %

) 1100 cm " ¹ , 1380 cm" ¹ , 1435 cm " ¹ , 148O cm" ¹ , 1450 cm " ¹ ).

By proceeding in an analogous manner, but using as. Starting materials using the appropriate acylmethyltriphenylphosphonium chlorides [all prepared as described below in Example 8 (ii)] the following compounds were prepared:
α-phenylpentanoylmethylene triphenylphosphorane (\) 1105 cm " ¹ , 1385 cm" ¹ , 1440 cm " ¹ , 1485 cm" ¹ , 1550 cm " ¹ ),

α-Benzylhexanoylmethylene triphenylphosphorane (ν 1110 cm " ¹ , 1395 cm" ¹ , 1440 cm " ¹ , 1485 cm" ¹ , 1545 cm " ¹ ),

IiI el X

α-p-chlorobenzylhexanoylmethylene triphenylphosphorane (^ L * ¹¹¹⁰ cm " ¹ , 1395 cm" ¹ , 1445 cm " ¹ , 1485 cm" ¹ , 1550 cm " ¹ ) and

a-p-Methylbenzylhexanoylmethylene triphenylphosphorane Melting point 111-115 ° C.

Analysis ^C 33 ^H 35 ^0p

calc .: C 82.8 H 7.4 P 6.5 %
found: 82.7 7.4 6.7 %

^ ^_10/11 10 cm ^"1, 1395 cm" ^1, 144O cm ^"1, 1485 cm" ^1, 1545 cm ^"1).

(ii) Preparation of Acylmethyltriphenylphosphonium Chlorides

A solution of 6.55 g of 1-chloro-2-oxo-5-phenylpentane [prepared as described below in Example 8 (iii)] was added] in 30 ml of dry chloroform to a solution of 8.7 g of triphenylphosphine in 30 ml of dry chloroform and heated in a

109820/1130

dry nitrogen atmosphere for 4 hours under reflux. The solution was then evaporated under reduced pressure and the remaining oil was treated with a mixture of light petroleum ether (bp 40 to 60 ° C.) and diethyl ether to give a white solid. Recrystallization of this material from a mixture of dichloromethane and diethyl ether gave 11.2 g of 4-Phenylbutanoylmethyltriphenylphosphoniumchlorid in the form of a white crystalline solid, melting point 192-195 ⁰ C.

Analysis C ₂ qH ₂ qC10P

calc .: C 75.9 H 6.2 %
found: 76.0 6.2 %

^ max ¹¹¹ ° ^cm ~ ¹ ' ¹ ^ 5 cm " ¹ , 1490 cm" ¹ , 1695 cm " ¹ .

By proceeding in an analogous manner, but replacing the 1-chloro-2-oxo-5-phenylpentane used as starting material with suitable amounts of
1 -Chlor - ^ - oxo ^ -phenylheptane,
1 -Chlor ^ -oxo - ^ - phenylhexane,
3-benzyl-1-chloro-2-oxoheptane,
1-chloro-Jp-chlorobenzyl - ^ - oxoheptane and 1-chloro-3-p-methylbenzyl-2-oxoheptane

2-0xo-3-phenylheptyltriphenylphosphoniumchlorid melting point 185-187 ⁰ C. [all as hereinafter prepared as described in Example 8 (iii)], the following compounds were prepared

analysis ^C 31 H ₅₂ ClOP, 1445 0 ,1 CH ₂ C ¹ 2 6th % ber .: C. 75 5 H. 6th , 5 Cl 8th, 9 % found: 75 1 6th , 6 8th, cm ", O cm cm" , 14 90

max I69O cm " ¹ ,

2-0xo-3-phenylhexyltriphenylphosphonium chloride, 3-benzyl-2-oxoheptyl triphenylphosphonium chloride

I0982Ö / 1130

^, o "1115 cm" ¹ , 1445 cm " ¹ , 1485 cm" ¹ , 1690 cm " ¹ ),

5_p_Chlorbenzyl-2-oxoheptyltriphenylphosphonium chloride ¹¹¹ ° cm " ¹ , 1445 cm" ¹ , 1495 cm " ¹ , 1690 cm" ¹ ) and

3-p-methylbenzyl-2-oxoheptyltriphenylphosphonium chloride mo cm " ¹ , 1445 cm" ¹ , 1490 cm " ¹ , 1695 cm" ¹ ).

Production of chloroketones

14.7 g of 4-phenylbutanoyl chloride were added dropwise to a stirred solution of 7.5 g of diazomethane in 340 ml of diethyl ether at 0 ° C. The solution was stirred in an ice bath for an additional hour and then confirmed with anhydrous hydrogen chloride gas. After one hour at 0 ^° C., dry nitrogen was passed through this solution, which was then poured onto approx. 500 ml of crushed ice. The ethereal layer was separated off and the aqueous phase was diluted with 150 ml of water, saturated with sodium chloride and extracted with diethyl ether. The combined ethereal solutions were washed with water, 2N aqueous sodium carbonate solution and then again with water and dried over anhydrous magnesium sulfate. The solution was evaporated and the residue was distilled to give 11.5 g of 1-chloro-2-oxo-5-phenylpentane, bp 150-151 ° C./10 mm Hg.

Analysis C ₁₁ H ₁

calc .: C 67.2 H 6.7 Cl 18, O %

found: 67.4 7.1 18.0 % ^

^ _M i455 cm ^"1, 15OO cm" ^1, 1725 cm ^'1.

By proceeding in an analogous manner, but using the 4-phenylbutanoyl chloride used as starting material by suitable amounts of 2-phenylhexanoyl chloride, 2-phenylpentanoyl-

§09820 / 1130

Chloride, 2-benzylhexanoylechloride, 2-p-chlorobenzylhexanoylchloride and 2-p-methylbenzylhexanoyl chloride replaced [this the last three compounds were all prepared as described in Example 8 (iv) below] became the following Compounds made: 1-chloro-2-oxo-3-phenylheptane, bp 146-148 ° C / 8 mm Hg.

Analysis C ₁ -, H ₁ ^

calc .: C 69.5 H. Found .: 1.6 69.0 7.9 ^cm ~ ^{1 '150} ° ^C

1-chloro ^ -oxo ^ -phenylhexane

-3 _me "14OO cm" ¹ , 1455 cm " ¹ , 1495 cm" ¹ , 1720 cm " ¹ , max

5-benzyl-1-chloro-2-oxoheptane, b.p. 172 - 177 ° C / 14 mm Hg.analysis C ^ H ^ CIO calc .: C 70.4 H 8.0 % found : 70.6 8, 3 % \> ™ ~ _ν ¹ 400 cm " ¹ , 1455 cm" ¹ , 15ΟΟ cm " ¹ , 1715 cm" ¹ ,

Iu el X

1-chloro-3-p-chlorobenzyl-2-oxoheptane, bp 196-2OO ° C / 13 mm Hg.

0 " _ov 1410 cm" ¹ , 1465 cm " ¹ , 1495 cm" ¹ , 1715 cm " ¹ and max

1-chloro-3-p-methylbenzyl-2-oxoheptane, b.p. 182-19O ° C / 13 mm Hg. Analysis C ₁₅ H ₂₁ ClO calc .: C 71 * 2 H 8.4 % found : 70.8 8.4% ^ ¹ 595 cm ^"1, 1455 cm" ^1, 1515 cm ^"1, 1715 cm ^'1.

(iv) Production of Acid Chlorides

25.0 g of 2-benzylhexanoic acid and 50 ml of thionyl chloride were added refluxed together for 5 hours. The excess thionyl chloride was then removed by evaporation and the residue obtained 23.6 g of 2-benzylhexanoylechloride in the form of a yellow oil, melting point 147-149 C / 10 mm Hg j distilled.

109820/1130

Analysis C ₁ ^ H ₁

calc .: C 69.5 H 7.6 Cl 15 * 8 %
found: 69.4 7.8 Cl 15.7 %

»? _ _A _ 15OO cm" ¹ , 1605 cm " ¹ , 1780 cm" ¹ .

ΙΠ el A.

By proceeding in an analogous manner, however, the 2-benzylhexanoic acid by 2-p-chlorobenzylhexanoic acid and 2-p-methylbenzylhexanoic acid replaced [both prepared as described below in Example 8 (v)] the following compounds were prepared: 2-p-chlorobenzylhexanoyl chloride, bp 179-181 ° C / 10 mm Hg.

Analysis C ₁ ^ H ₁ 5Cl ₃ O

calc .: C 60.2 H 6.4 %
found: 60.4 6.4 %

Ο ~ "" ¹ 495 cm " ¹ , 1595 cm" ¹ , 1785 cm " ¹ and ms χ

2-p-methylbenzylhexanoyl chloride, bp 160-162 ° C / 10 mm Hg. 0 _aY 1390 cm " ¹ , 1520 cm" ¹ , 1790 cm " ¹ .

(v) manufacture of acids

(a) Preparation of diethyl 2-p-chlorobenzyl-2-butylmalonate

88.0 grams of p-chlorobenzyl chloride was added to a stirred solution of 108.0 g of diethyl 2-butyl malonate in 500 ml of dry ethanol, which contained 11.5 g of sodium. The mixture was refluxed for 6 hours and then filtered and the piltrate became concentrated in vacuo to remove the ethanol. 150 ml of water was added to the residue and the obtained Mixture was extracted with diethyl ether. The ethereal solution was dried over anhydrous magnesium sulfate and then evaporated and the residue was purified to give 110.0 g of diethyl 2-p-chlorobenzyl-2-butylmalonate as a colorless oil, bp. 180-182 ° C / 1.0 mm Hg, distilled.

009020/1130

Analysis C ^ H ^^

calc .: C 63.4 H 7.4 Cl 10.4 %

found: 63.3 7.5 10.5 %

(b) Preparation of 2-p-chlorobenzylhexanoic acid

A mixture of 110 g of diethyl 2-p-chlorobenzyl-2-butylmalonate was stirred and 103 g of sodium hydroxide in 100 ml of water and 400 ml of ethanol and refluxed for 21 hours. The ethanol was removed under reduced pressure, water was added to the residue and the resulting solution was washed with diethyl ether. The aqueous solution was adjusted to pH by adding concentrated hydrochloric acid brought from 1 and the separating oil was with diethyl ether extracted. After washing with water, the ethereal solution was dried over anhydrous magnesium fullfate and then evaporated and the remaining oil was in a metal bath at 200 ° C for 20 min. Until complete evolution of carbon dioxide heated. The residue became colorless to obtain 63.6 g of 2-p-chlorobenzylhexanoic acid Oils, bp 212-214 ° C / 12 mm Hg, distilled.

Analysis C ₁ , H ₁₇₂

calc .: C 64.9 H 7.1 Cl 14.7 %
found: 65.4 7.3 14.7 *

By proceeding in an analogous manner, but using the p-chlorobenzyl chloride used as starting material

Replacing p-methylbenzyl chloride, the following compounds were made:
2-p-methylbenzyl-2-butylmalonate, b.p. 196-198 ° C / 10 mm Hg.

Analysis C ₁₉ H ₂₃ O ^

calc .: C 71.2 H 8.8 %
found: 71.3 9.0 % and
2-p-methylbenzylhexanoic acid, bp 195-198 ° C / 10 mm Hg.

analysis C ₁₄ H ₂₀ O, 9 9.5 %. ber .: C ι found: 76.3 H 9.15 % Dimethyl 2-oxoalkyl phosphonates example 76.7

A solution of 9.6 g of butyl lithium in hexane and 97 l ^ 16O mL of anhydrous diethyl ether were added during 20 min. To a stirred solution of 18.6 g> dimethyl methylphosphonate in 80 ml of anhydrous tetrahydrofuran at -50 ⁰ C in a nitrogen atmosphere. The solution was further 15 min. Stirred at -6Q ⁰ C and then there was added a solution of 1J, 4 g of ethyl-.beta.-phenylpropionate in 60 ml of anhydrous tetrahydrofuran over 10 min. Was added at -60 ° C. This solution was stirred for 90 minutes at -60 ° C. and then for 150 minutes at room temperature. 14.2 ml of glacial acetic acid was added and the solvents were evaporated. 75 ml of water was added to the gelatinous residue and the mixture was then extracted with diethyl ether. The ethereal extracts were washed with water, dried over anhydrous magnesium sulfate and the ether was then removed in vacuo.

The residue was purified to give 10.0 g of dimethyl 2-oxo-4-phenylbutylphosphonate distilled in the form of a colorless oil with a bp of 155-158 ° C / 0.1 mm Hg. Analysis C ^ H ^ O ^ P

calc .: C 56.25 H 6.7 P 12.1 %
found: 56.4 6.9 11.8 %

^ r, ^ ⁸ 35 cm " ¹ , 1035 cm" ¹ , II80 cm " ¹ , 1260 cm" ¹ , 1455 cm " ¹ , 1710 cm" ¹ .

By proceeding in an analogous manner, but using the ethyl ß-phenylpropionate used as the starting material suitable amounts of ethylphenyl acetate and ethyl-2- (2-phenyl-

80 * 120/1130

The following compounds were substituted for ethyl) hexanoate manufactured:

Dimethyl 2-oxo-3-phenylpropylphosphonate with a b.p. 143 - 150 ° C / 0.1 mm Hgj

Analysis C ₁₁ H ₁₁ -O ^ P

calc .: C 5 ^, 5 H 6.2 %
found: 54.6 6.3 %

^ max ^ ⁵ cm " ¹ , 1035 cm" ¹ , 118O cm " ¹ , 1260 cm" ¹ , 1455 cm " ¹ , 1710 cm" and

Dimethyl 2-oxo-3- (2-phenylethyl) heptylphosphonate • with a bp of 162 - 172 ° C / 0.15 mm Hg.

Analysis C ^ Hg ^ O ^ P

calc .: C 62.6 H 8.3 P 9.5 %
found: 62.6 8.6 9.3 %

^ max ⁸¹ ° ^cm ~ ¹ ' ¹⁰⁵ ° ^cm ~ ¹ ' ¹¹⁸ ° ^{cn 1} "1 '12 ^{β0 cm} ~ ¹ * ¹ ^ ^{55 cm} ~ ¹ ' 1700 cm" ¹ .

The ethyl 2- (2-phenylethyl) hexanoate used as the starting material was refluxed for 18 hours by a solution of 17.0 g of 2- (2-phenylethyl) hexanoic acid in 15.5 ml of anhydrous ethanol and 1.5 ml of concentrated sulfuric acid. The solution was then added to 150 ml of water and the oil which separated out was extracted with diethyl ether. The ethereal solution was washed successively with water, 2N aqueous sodium carbonate solution and water and then dried over anhydrous magnesium sulfate and evaporated. The residue was distilled to give 15.25 g of ethyl 2- (2-phenylethyl) hexanoate in the form of a colorless oil with a boiling point of 158-160 ° C./7 mm Hg.
Analysis CjgHphOg

calc .: C 77.4 H 9.7 %
found: 77.5 9.9 %

130

Example 10

The procedure described above in Example 5 (i) and (ii) was followed, but using the 7- £ i, 4-dioxa-7- (3-oxo-5-phenylpent-1-enyl) used as starting material spiro [4,4] -non-6-ylj-heptanoic acid by the appropriate amount of
7-f1,4-Dioxa-7- (3-oxo-4-phenoxybut-1-enyl) spiro [4,4] non-6-yljheptanoic acid (prepared as described below) replaced and prepared the following compounds:
7- £ 1,4-Dioxa-7- (3-hydroxy-4-phenoxybut-1-enyl) spiro [4,4] non-6-ylJ-

heptanoic acid (** _v 950 cm " ¹ , 975 cm" ¹ , 1700 cm " ¹ , 3400 cm" ¹ ) and max

7- [5- (3-Hydroxy-4-phenoxybut-1-enyl) -2-oxocyclopentyl] -heptanoic acid

Analysis ^C 22 ^H 30 ° 5
calc .: C 71 * 0 H 8.0 %
found: 70.6 8.1 %
V ™ ^ 970 cm " ¹ , 1700 cm" ¹ , 1720 cm " ¹ .

NMR (about 10 % w / v solution in deuterochloroform):
Multiplets at 1.0 - 2, OcT, 2.0 - 2.8 /, 3.8 - 4.1 cT, 4.4 -
4.7 J, 5.7 - 5.9 / and 6.8 - 7.6 /.

0.55 g of 7- [5- (3-Hydroxy-4-phenoxybut-1-enyl) -2-oxocyclopentyl] -heptanoic acid were determined by preparative thin layer chromatography on silica gel plates using>. a mixture of ethyl acetate, cyclohexane and 90% formic acid (200: 200: 5 in volumes) as the eluent, eluting each plate four times to form two diastereoisomeric components severed.

In analogy to well-known prostaglandins, this was held to be the case
Starting material approaching material (80 mg) (component
"10a") for a 1: 1 mixture of the isomers

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COOH

and its enantiomers,
analysis

C 70.8 H 8.0 %

while the material more remote from the starting material (105 mg) ("component 10b") for a 1: 1 mixture of the Isomers

COOH

and its enantiomer was maintained. analysis

C 70.4 H 8.4 %.

The used as starting material 7 "C ^1, 4-dioxa-7- (3-oxo-4 ~ phenoxybut-1-enyl) spiro [4.4] non-6-YLJ-heptanoic acid was prepared by in a manner analogous proceeded as described above in Example 1 (ii) and (iii) (b), except that the benzoylmethylene triphenylphosphorane used as starting material was used to form 6- (7-hydroxyheptyl) -7- (3-oxo-4-phenoxybut-1 -enyl) -1,4-dioxaspiro [4,4] nonane and 7-1,4-dioxa-7- (3-oxo-4-phenoxybut-1-enyl) »piro [4,4] non-6 -yl | heptanoic acid replaced.

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The phenoxyacetylmethylene triphenylphosphorane used as the starting material was made as follows:

A solution of 6.8 g of 1-chloro-3-phenoxyacetone was saturated and 12 g triphenylphosphine in 16 ml chloroform with nitrogen and refluxed overnight. An excess of dry diethyl ether and the solvents were added were then decanted from the resinous mass that separated out. The remaining solvent was in vacuo to obtain 10.35 g of crude 2-0xo-3-phenoxypropyltriphenylphosphonium chloride removed. This was vigorously with a solution of 18 g of sodium carbonate in 18O ml of water during Stirred for 24 hours. The solution was extracted with diethyl ether and the ethereal extracts were dried over sodium sulfate. The solvent was removed by evaporation to give 5 * 3 S phenoxyacetylmethylene triphenylphosphorane removed in the form of a sticky solid.

The 1-chloro-3-phenoxyacetone used as the starting material was made as follows:

100 ml of 8N Jones reagent was added dropwise to a stirred solution of 28.3 S 1-chloro-2-hydroxy-3-phenoxypropane in 100 ml Acetone added over the course of 1 hour, the reaction temperature to 20 ° C. was held. The mixture was then stirred for 4 hours and there was then sufficient water to dissolve the added precipitated chromium salts. The mixture was extracted three times with diethyl ether and the combined ethereal extracts were dried over sodium sulfate, concentrated under reduced pressure, again dried over sodium sulfate and further narrowed and achieving 13 * 9 S 1-chloro-3-phenoxyacetone with a bp of 150-155 ° C / 20 mm Hg distilled.

By proceeding in a manner analogous to above ^ .B. in the previous Examples described ^ proceeding were the following Compounds of formula I prepared:.

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7- [5- (3-0xo-6-phenylhex-1-enyl) -2-oxocyclopentyl] -heptanoic acid ^ max ' ^{975 cm} ~ ¹ * ^{1625 cm} " ¹ ' ^{1665 cm} ~ ^{1 '17} °° ^cm " ¹ ' ¹⁷⁵ ° ^cm " ¹ ) i 7- [5- (3-oxo-4-phenylbut-1-enyl) -2-oxocyclopentyl] -heptanoic acid (> i, _ev -99O cm ¹ , 1625 cm" ¹ , 1700 cm " ^1, 1730 cm ^"1); 7-15- [5- (2,4-dichlorophenyl) -3-oxopent-1-enyl] -2-oxocyclopentyl-4-heptanoic acid

(^ o _v 985 cm " ¹ , 1625 cm ~ ¹ , 1665 cm" ¹ , 17ΟΟ cm " ¹ , 1730 cm" ¹ );

7- [5- ( ¹ I-p-bromophenyl-3-oxobut-1-enyl) -2-oxocyclopentyl] heptanoic acid

(^ _mav 9S5 cm " ¹ , 1620 cm" ¹ , 17ΟΟ cm " ¹ , 1725 cm" ¹ );

7-15- (4-p-trifluoromethyl-pentyl-3-0x0 but-1-enyl) -2-oxocyclopentyl ] -heptanoic acid

990 cm " ¹ , 1335 cm" ¹ , 1630 cm " ¹ , 1710 cm" ¹ , 17 ^ 0 cm " ¹ );

7-ip- [3- (N.aphth-2-yl) -3-oxoprop-1-enyl) -2-oxocyclopentyljheptanoic acid,

Analysis Cg ^ HggO ^

calc .: C 7β, 5 Η 7.2 %
found: 76.7 7.5 %

^ _Mev 990 cm " ¹ , 1620 cm" ¹ , 1660 cm " ¹ , 1700 cm" ¹ , 1730 cm " ¹ , max

NMR (about 10 % w / v solution in deuterochloroform): singlets at 9.2 J "and 7, 16cT, doublet at 7.1 (T (J = 2 Hz), multiplets at 7.5-8.6 S, 2.0-2.6 / and 1.0-2.0 /; 7- ^ 5- [3-hydroxy-3- (naphth-2-yl) propyl] -2-oxocyclopentyljheptanoic acid,

Analysis C ₂ JBU ₂ O ^

calc .: C 75.7 H 8.1 %
found: 75A 8.3 %

^ ¹⁷ ° ^{5 cm} ~ ¹ » ¹ ^ ²⁰ cm" ¹ , 3400 cm " ¹ .

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NMR (about 10 % w / v solution in deuterochloroform): · · Singlet at 6.73 cf, multiplets at 7.3-8, Oc ^, 4.82 ef, 1.6-2.6 cT, 1 , 0 - 2.0 cTj 7- [5- (3-acetoxy-5-phenylpent-1-enyl) -2-oxocyclopentyl] heptanoic acid,

Analysis Cg ^ H ^ O ^ calc .: C 72.4 H 8.3 % found : 72.6 8.3 ^ \) _max 1240 cm " ¹ , 1705 cm" ¹ , 1730 cm " ¹ .

NMR (about 10 % w / v solution in deuterochloroform):

Singlet at 7.24 <T, multiplets at 5.5-5.8 / ^{, 5.0-5.5 (T, 1.0-3.0 cf and 2.05 c / 1} ; 7- ^ 5- [ 3-acetoxy-3- (naphth-2-yl) propyl] -2-oxocyclopentyljheptanoic acid,

Analysis 0 ₂ γΗ ^ 0 ^ calc .: C 73.9 H 7.8 % found : 74.3 8.0 %

>} _β 1240 cm " ¹ , 1705 cm" ¹ , 1720 cm " ¹ , max

NMR (about 10 % w / v solution in deuterochloroform): singlets at 9.4 $ and 2.1 cT, triplet at 5.93 cT (J = 6 Hz), multiplets at 7.3-8, OcT, 1 , 8 - 2.6 </ and J ₁ O - 2.0 c / j

Undecyl 7- [5- (3-acetoxy-3-phenylpropyl) -2-OXOCyClOPe ^ yI] -heptanoate,

Analysis C * 2 | Hc2 | Oiber .: C 75.2 H 10.0 % found : 75.5 10.3 % ^ max ¹²⁵ ° ^cm " ¹ ' ¹⁷²⁵ cm"^1; NMR (about 10 % w / v solution in deuterochloroform): singlets at 7.37 <f and 2.1OcT, triplets at 5.8 ^ (J = 6 Hz), 4.08 cf (J = 6.5 Hz), 0.9 ^ (J = 5 Hz), multiplets at 1.0-2, methyl 7- [5- (3-oxo-4-phenylbutyl) -2-oxocyclopentyl] heptanoate

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Analysis C ₃₅ H ₅₂ O ₄ calc .: C 7 ^, 2 H 8.7 % found : 73.9 9.1 £

NMR (about 10 % w / v solution in deuterochloroform): singlets at 7.24 ^, 3.69 cps, and 3.64 cps, multiples at 1.0-2.8 cps;
7- [5- (3-0xo-4-phenylbutyl) -2-oxocyclopentyl] heptanoic acid

cm " ¹ , 1730 cm" ¹ );

A 1: 1 mixture of 11-deoxy-16- (4-methylbenzyl) -prostaglandin E., and its enantiomers (^ 975 cm ", 1705 cm", λ · λ max

1730 cm ", 3400 cm");

A 1: 1 mixture of 15-epi-11-deoxy-16- (4-methylbenzyl) -prostaglandin E ₁ . and its enantiomers (IR spectrum practically identical to that of the above epimeric material);

A 1: 1 mixture of 11-deoxy-16- (4-propoxyphenoxy) -tetranorprostaglandin E ₁ and its enantiomers NMR (about 10 % wt. A ^ oI. Solution in deuterochloroform): triplet at £ 1.0 (J. = 7 Hz), multiples at ^{1.1-2.7 J 1} , 3.8-4, OcT, 4.3-4.7 cf, 5.7-5.9cT and a singlet at 6.85 /;

A 1: 1 mixture of 15 ~ epi-11-deoxy-16- (4-propoxyphenoxy) -tetranorprostaglandin E ₁ and its enantiomers, analysis C ₃₅

calc .: C 69.4 H 8.4 % found : 69.5 9.0 %

NMR spectrum practically identical to that of the above epimeric material;

A 1: 1 mixture of 11-deoxy-16- (3-trifluoromethylphenoxy) -tetranorprostaglandin E ₁ and its enantiomers, analysis C ₂₅ H ₃₉ O ₅ F ₅ calculated: C 62.4 H 6.61 ^ found: 62.8 6.85 %

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NMR (about 10 % w / v solution in deuterochloroform); Multiplets at 1.1 - 2.7 (0.3.9 - 4.1 <f, 4.4 - 4.7 /, 5.7 - 5.9 <f, broad singlet at 6.0 - 6, 3 / and multiplet at 7.0 -

Sine 1: 1 mixture of 15-epi-11-deoxy-16- (2-trifluoromethylphenoxy) -tetranorprostaglandin E ₁ and its enantiomers, analysis C 62.1 H 6.81 $

NMR spectrum practically identical to that of the above epimeric material;

A 1: 1 mixture of 11-deoxy-16- (4-chlorophenoxy) -tetranorprostaglandin E ₁ and its enantiomers, analysis C ₂₂ H ₂ QClO ₅

calc .: C 64.6 H 7.1 Cl 8.7 %
found: 64.6 7.3 %

NMR (about 10 w / v solution in deuterochloroform): Multiplets at 1.1-2.7 cf, 3.7-4.2 d \ 4.4-4.8 /, 5.7 5.9 J *, 6.6 - 7.5 cT;

A 1: 1 mixture of 15-Epi-11 -deoxy-16- (4-chlorophenoxy) tetranorprostaglandin E ₁ and its enantiomers, analysis C 64.2 H 7.3 Cl 9.0 %

NMR spectrum essentially identical to that of the above epimeric material;

A 1: 1 mixture of 11-deoxy-16- (3-chlorophenoxy) -tetranorprostaglandin E ₁ and its enantiomers,. NMR (about 10 % w / v solution in deuterochloroform): multiplets at 0.9-2.5 3.7-4.1 /, 4.2-4.7 cf, 5.0 5.9 6 , 7 - 7.2 Si

A 1: 1 mixture of 15-epi-11-deoxy-16- (3-chlorophenoxy) -tetranorprostaglandin E ₁ and its enantiomers, NMR spectrum practically identical to that of the above epimeric material;

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A 1: 1 dilution of 11-deoxy-16- (2-methylphenoxy) -tetranorprostaglandin E ₁ and its enantiomers, analysis C ₂ -HZ ₂ ⁰ G

calc .: C 71 * 1 H 8.3 % '
found: 71.1 8.5 %

NMR (about 10 % w / v solution in deuterochloroform); . Multiplets at 0.5 - 2.8 J, 3.7 - 4.0 cf, 4.2 - 4.7 J ¹ , 4.8 5.3 J ¹ , 5.6 - 5.9 cT, 6.6 - 7.3 &;

A 1: 1 mixture of 15 epi-11-deoxy-16- (2-methylphenoxy) -tetranorprostaglandin E ₁ and its enantiomers, NMR spectrum practically identical to that of the above epimeric material;

A 1: 1 mixture of H-deoxy-16-phenoxytetranorprostaglandin E ₁ -ftiethyl ester and its enantiomers, analysis C ₂ 3 ^H 32 ° 5

calc .: C 7M H 8.3 %

found: 71.0 8;,. 3 %

NMR (about 10 % w / v solution in deuterochloroform): singlet 3.7 cf, multiples at 1.2-2.8 cf, 3.9-4.1 A 4.3-4.6 <f, 5.7-5.9cT, 6.8-7.5 Λ

A 1: 1 mixture of ^ -Epi-H-deoxy-iö-phenoxytetranorprostaglandin-E ^ methyl ester and its enantiomers, analysis C 71.4 H 8.7 %

NMR spectrum practically identical to that of the above epimeric material;

7- J5 ~ [3- (3-trifluoromethylphenyl) -3-oxopent-1-enyl] -2-oxocyclopentylj-heptanoic acid

^ ⁸⁰ ° ^cm ~ ¹ * 985 cm " ¹ , 1125 cm" ¹ , 1165 cm " ¹ , 1330 cm" ¹ , 1630 cm " ¹ , 1740 cm" ¹ and 1740 cm "¹;

60S820 / 1130

7-ξβ- [5- (4-fluorophenyl) -I-oxopent-i-enyl] -2-oxoeyclopentyl> heptanoic acid

\) 830 cm " ¹ , 985 cm" ¹ , 1630 cm " ¹ , 1705 cm" ¹ and 1740 cm ~ ¹ .

The present invention also includes pharmaceutical compositions, which contain at least one compound of the invention together with a pharmaceutical carrier or coating. In In clinical practice, the compounds of the invention will normally be administered orally, rectally, vaginally or parenterally.

Solid compositions for oral administration include compressed tablets, pills, dispersible powders and granules.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, Syrups and elixirs.

The compositions of the invention for oral administration also include capsules made of absorbable material,. such as gelatin, the one or more compounds according to the invention contain. '·

Solid compositions for vaginal administration include pessaries.

Solid compositions for rectal administration include suppositories.

Preparations according to the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. .

The compounds according to the invention can alternatively be administered orally each for administration by inhalation of active substances, which are not gaseous even under the usual conditions for administration, are administered known methods.

g09820 / 1130

- 51 -

Thus a solution of the active component in a suitable pharmaceutically acceptable solvent, e.g. Water, through a mechanical nebulizer such as a Wright Nebulizer, to form an aerosol of finely divided liquid Particles suitable for inhalation are atomized. The active ingredients can also be taken orally administered by inhalation in the form of aerosols formed by self-propelling pharmaceutical compositions will.

Methods for the administration of pharmaceutically active compounds are known from the prior art and are suitable The carrier can be provided by a physicist, pharmacist or veterinarian, depending on factors such as the desired effect, the size, age, sex and condition of the patient and, in veterinary applications, the species to be treated Animal and can be determined depending on the physical properties of the active ingredient. The compositions can also, as is customary according to the prior art, materials such as solid or liquid diluents, wetting agents, protective substances, contain flavoring and coloring agents and the like.

The percentage of active ingredient in those of the invention Compositions can be varied, it being necessary that it represent such a proportion that a suitable dosage for the desired therapeutic effect is obtained. Obviously, several can be done at the same time Unit dosage forms can be administered.

In general, the compositions should normally contain at least 0.025% by weight of active substance, if it is necessary for administration by injection. For oral administration, the preparations usually contain at least 0.1% by weight of active substance. The dose used depends on the desired therapeutic effect, the mode of administration and the duration of the treatment. In the adult

£ 09820/1130

the doses are generally, for example, between 0.02 "and 2.0 mg at of aerosol administration and between 0.0002 _- 2.0 mg / kg body weight for intravenous administration, and between 0.001 and t ', 0 mg / kg body weight oral administration. If necessary, the doses can be repeated as necessary.

The following example illustrates pharmaceutical compositions according to the invention.

Example 11

300 mg of 7- [5- (3-hydroxy-4-phenoxybut-1-enyl) -2-oxocyclopentyl] heptanoic acid was dissolved in 1 ml of ethanol, and the resulting solution was added to 12 ml of an aqueous solution containing 50 ml of sodium carbonate. 2 ml of aqueous sodium chloride solution (0.9 % w / v) was then added to make the final volume 15 ml. The solution was then sterilized by passing it through a filter to be retained by bacteria and placed in 1 ^ 5 ml portions in 5 ml ampoules, giving 30 mg of heptanoic acid derivative (in the form of its sodium salt) per ampoule. The contents of the vials were freeze-dried and the vials were closed. Dissolving the contents of an ampoule in a suitable volume, for example 2 ml of sterile water or physiological saline solution, provided a ready-to-use solution for administration by injection.

609820/1130

Claims (1)

Claims 1 J) Cyelopentane derivatives of the general formula XY-Ä-ZR ² wherein R is a hydrogen atom or a straight or branched chain Represents an alkyl group having 1 to 12 carbon atoms, ρ
R denotes an aryl group or a heterocyclic group which can be substituted by one or more substituents selected from halogen atoms, straight or branched chain alkyl groups with 1 to 4 carbon atoms, trihalomethyl groups, alkenyl groups with 2 to 4 carbon atoms, phenyl groups, alkoxy groups with 1 to 4 Carbon atoms, hydroxy groups, nitro groups, cyano groups, carboxy groups, alkoxycarbonyl groups in which the alkyl part contains 1 to 4 carbon atoms, hydroxymethylene groups, alkoxymethylene groups in which the alkyl part contains 1 to 4 carbon atoms, sulfino groups, alkylsulfonyl groups in which the alkyl part contains 1 to 4 carbon atoms and sulfamoyl, Carbamoyl, N-aminocarbamoyl, amidino, amino and hydroxyimino groups, each such nitrogen-containing group optionally being substituted by one or more alkyl groups each having 1 to 4 carbon atoms, η being 5, 6, 7 or 8 and either ( i) A is a straight or branched chain alkylene group. With 1 to 12 carbon atoms, X is an ethylene or trans -vinylene group, Y is a carbonyl group or a group -CH (OR) - (where R- ^ is a hydrogen atom or a carboxylic acyl group) and Z is a direct bond or represents an oxygen or sulfur atom or also (ii) A and Z both represent direct bonds and X and Y 60982Ό / Τ130 at the same time ethylene and carbonyl, trans-vinylene and carbonyl or ethylene and -CH (OIr) - represent (where R ^ has the meaning given above)
and, if R
see salts. and, when R is a hydrogen atom, its non-toxic 2 2.) Cyclopentane derivatives according to claim 1, wherein R represents an aryl or heterocyclic group which is substituted can be through one or more substituents selected from halogen atoms, straight or branched chain alkyl groups with 1 to 4 carbon atoms and trihalomethyl groups and R, n, A, X, Y and Z have the meaning given in claim 1 have and, when R is a hydrogen atom, their non-toxic salts. 3 ·) Cyclopentane derivatives according to claim 1 or 2, wherein η 6 means. 4.) Cyclopentane derivatives according to claim 1, 2 or 3, wherein R a straight or branched chain alkyl group of 1 to 12 Represents carbon atoms. 5.) Cyclopentane derivatives according to one of claims 1 to 4, wherein R is a substituted or unsubstituted heterocyclic Represents a group or aryl group (other than the phenyl group) or a substituted phenyl group, wherein the substituents present on said heterocyclic and aryl (including phenyl) groups are those in claim 1 or 2 have given meaning. 6.) Cyclopentane derivatives according to claim 1, 2, 4 or 5> wherein η is 5, 7 or 8. 7.) Cyclopentane derivatives according to one of the preceding claims, wherein X is an ethylene group. 8.) Cyclopentane derivatives according to one of the preceding claims, wherein Y is a carbonyl group. 809820/1130 9.) Cyclopentane derivatives according to one of the preceding claims, where A is a direct bond. 10.) Cyclopentane derivatives according to one of the preceding claims, wherein Z is an oxygen or sulfur atom. 11.) Cyclopentane derivatives according to one of the preceding p
Proverbs in which R is phenyl, naphthyl, furyl or thienyl. represents a group which can be unsubstituted or, as indicated in claim 1 or 2, substituted. 12.) Cyclopentane derivatives according to one of claims 1 to 10, ρ
wherein R is a phenyl, naphthyl or thienyl group which can be unsubstituted or, as indicated in claim 1 or 2, substituted. ¹ 3 ·) Cyclopentane derivatives according to any one of claims 1 to 8, 10, 11 and 12, wherein A represents a straight or branched-chain alkylene group having 1 to 7 carbon atoms. 14-.) Cyclopentane derivatives according to any one of claims 1 to 7 9 to 13, wherein Y represents a group -CH (OR-O-, wherein R ^ a hydrogen atom or a straight or branched chain Alkanoyl group with 1 to 6 carbon atoms or a benzoyl group means. 15.) alkali metal, ammonium and non-toxic amine salts of a cyclopentane derivative according to any one of claims 1 to 14, wherein R represents a hydrogen atom. 16 \ -) 7- [5- (3-Oxo-5-phenylpent-l-enyl) -2-oxocyciopentyl] heptaric acid e _t - ¹ 7.) - 7- [5- (3-Oxo-4-phenylbut-1-enyl) -2-oxocyclopentyljhsptanoic acid. 18.) 7- [S- {3-Oxo-3-phenylprop ~ l-enyl) -2- 609820/1130 oxocyclopentyl heptanoic acid. 19.) 7- [5- (3-Oxo-6-phenylhex-1-enyl) -2-oxocyclopentyl] heptanoic acid. 20 "). 7- [5- (3-Oxo-4-phenylhept-1-enyl) -2-oxocyclopentyl] heptanoic acid. - 21 ·.) ■ 7- [5- (3-Oxo-4-pnenyloct-1-enyl) -2-oxocyclopentyl ] heptanaic acid e. 22.) 7- [5- (4- Benzyl-3-oxooct-1-enyl) -2-oxocyclopentyl] hept acidic. 23.) 7- [5- (4-p ~ chlorot? Enz.yi -> - oxooct-i -enyl) 2-oxocyclopentyl] heptanoic acid. -.- ^ 24.) 7- [5- (4-p-Methyll-benzyl-3-oxooGt. ~ L-enyl} -2-oxocyclopentyl] heptanoic acid ... ' i ·· 25 1) 7- [5- (3-p ~ broinplienyl-3-oxoprop-1 -eilyl) 2-oxocyclopentyl] heptanoic acid. -_ 26.) 7- [5- (3-Oxo-3-thien-2 ^! -Ylprop-1-enyl) -2-oxocyclopeHityljheptanoic acid. 27.) 7 ~ ^ 5- [4- {2-Phenylatliyl) -3-oxooct-1-enyl] -2-oxocyclopentyl3 heptanoic acid .t- <W 28.) 7- [5- (3-hydroxy-4-p2ienyloct-1-enyi) -2-oxocyclopentyl ] heptanoic acid. 29.) 7- [5- (4- £ -chlorobenzyl ^ -3 ^ hy dr oxyo ct -1 enyl) -2 ~ oxocyclopentyljheptanoic acid. 30.) 7- [5- (4-p-Methylbenzyl-3-hydroxyoct-ienyl) -2-oxocyclopentyl] heptanoic acid. -r-- "' 609820/1130 31.) 7-45- C 3-hydroxy-4- (2-phenylethyl) oc t-1-enyl 3-2-OXOCyClOPeIItYlJiIePtSnSaUrS. - 32.) 7- [5- (3-Hydroxy-5- phenylpent-1-enyl) -2- oxocyclopenty ^ heptanoic acid. 33.) 7- [5- (3-Hydroxy-3-phenylpropyl) -2-oxocyclopentyljhept acidic. 34.) 7- [5- (3-Aceto3ry-4-p-methylbenzyloct ~ l- enyl) -2-0303CyClOPeIItYl] leptanoic acid. 35.) 7- [5- (3-Acetoxy-3-phenylpropyl) -2- ' oxocyclopentyl] heptanoic acid. 36.) 7 - ^. 5- [3 ~ acetoxy-4- (2-pheny3ethyl} oct-1-enyl ] -2-oxocyclopentyl-lieptaric acid. 37 ..) 7- [5- (3 ~ hyaroxy-4-phenoxybut-1-enyl} - 2-oxocyclopentyl] heptanoic acid. ■ 38.) 7-O5- (3-0xo-6-phenylhex-1-enyl) -2-oxocyclopentyl] beptanoic acid. 39.) 7- [5- (3-Oxo-4-phenylbut-1-enyl) -2-oxocyclopentyl] heptanoic acid. 40.) 7- ^ 5- [5- (2,4-dichlorophenyl) -3-oxopent-1-enyl ] ■ - 2-oxocyclopentyli heptanoic acid. 41.) 7- [5- (4-yn-5rlfluoromethylphenyl-5-oxobut-1-enyl) -2-oxocyclopentyl] heptanoic acid. 42.) 7- ^ 5- [3- (Naphth-2-yl) -3-oxoprop-1-enyl] -2-oxocyclopentyl-3heptanoic acid. 43.) 7- £ 5- [3-Kydroxy-3- (naphth-2-yl) propyl3-2- 809820/1130 - 6k - ■ oscocyclopenxiyljneptanic acid. 44.) 7- [5- (3-Acetoxy-5-phenylpent ~ 1-enyl) -2- O2: ocyclopentyl] heptanoic acid. 45.) 7- £ 5- [3 ~ aeto: xy-3- (naphth-2-yl) propyl] - 2 ~ oxocydopentyljheptanoic acid. 46,) 7 ~ [5- (3- »O3K> -4 ~ phenylbutyl) -2-ojsocyclo- pentylheptanoic acid. 47.) 7- [5- (4-β-Briiphenyl-3-oxobut-1-enyl) -2-oxocydopentyljheptanoic acid. " 48.) II-Deoxy-16- (4-methylbc £ n2yl) prostaglandin 49.) IS-'Bpi-II-dGoxy-ie- (4-methylbenzyl) prostaglandin S ,. '' 50.) 11-Deoxy-16- (4-propo ^ jyphenoxyjtetranor- prostaglandin E ^. 51.) 15 ~ Bpi-II-eeo: ^ - 16- (4-propossyphenoxy) - tetranorprostaglandin E .. 52.) ll ~ Deocy-16- (3-trifluoromethylphenoxy) tetranorprostaglandin Ξ ,. 53.) 15r-Epi-II-aeo2iy ~ 16- (3-trifluoxmethylpheno: cy) tetranorprostaglandin E ₁ ,, 54,) II-Deo3cy-16 ~ (4-cIalorphenoxy) -tetranorprostaglandin E ^. 55.) 15 ~ Spi-II-dc5o: cy-16- (4 ~ chlorophenoXy) tetranorprostaglandin E ... 609820/1130 5.6. ) li-Deo: ^ y-16 ~ (3-chlorophenoxy) tetranorprostaglandin E-. S7 ") 15-2pi-li ~ deoxy-16- (3-chlorophenoxy) tetranorprostaglandin 3- _φ .. · - .. 5.8. ) 11-Deoxy-l 6- (2-methylpheno3jy) t etranor- · prostaglandin E .., 59.) 15-3pi-ll-doo3! Y ~ l & -C2-inethylphenosy} - tetranorprostaglandin Ξ- _# 60.) 7- | 5- [3- (3-trifluorinylphenyl) -3-oxopent-1-enyl] -2-oxocyclopentyljheptanoic acid. 61 ,.) 7- £ 5- [5- (4-fluorophenyl) -3-oxopent-i-enyl} ~ 2- o ^ socyclopentyljüeptens aur e. 62,) Undecyl-7- [5- (3-acetoxy-3-phenylpropyl) - 2 ~ o2rocyclopent: yl jlieptanoate 63 ^) KGthyl-7- [5- (3-o: co-4-phenylbutyl) -2- O2S0 cyclopentyl] liGptanoate 64.) 11 — Decwry — Lö-phenoicytetranorprostaglandin - E, methyl ester. 65,) 15 ~ £ pi — ll-deojcy — lö — plaenoiiytetranor— pro staglandin-E - rnefchyl-ester. 66.) enantiomer of a cyclopentane derivative according to one of claims 48 to 59 * 64 or 65 · 67.) A mixture of a cyclopentane derivative according to one of claims 48 to 59 * 64 or 65 with their enantiomers. 68.) Non-toxic salts of a cyclopentane derivative. according to any one of claims 16 to 61. 609820/1130 69.) Process for the preparation of a cyclopentane derivative of the general formula given in claim 1, wherein R is a hydrogen atom, Y is a carbonyl or hydroxy p
represents methylene group and R, n, X, A and Z have the meaning given in claim 1, characterized in that a compound of the general formula (CH ₂ J _n COOH ρ
hydrolyzed, wherein R, n, X, Y, A and Z are those in claim 1 4 and the symbols R represent the same alkyl groups or together form an ethylene bridge which is unsubstituted or substituted by the same alkyl groups on each carbon atom, methods known per se being used for converting a ketal group into a ketone group. 70.) Method according to claim 69 » characterized in that the symbols R represent an unsubstituted ethylene bridge. 71 ·) Method according to claim 69 or 70j, characterized in that that the hydrolysis is carried out under acidic conditions. 72.) The method according to claim 69 or 70, characterized in that the hydrolysis with a dilute inorganic Acid or with an organic acid in the presence of water. 73.) The method according to claim 69, 70, 71 or 72, characterized characterized in that a stage is followed in which, by methods known per se, the symbol Y in the cyclo- 609820/1130 pentane product of the general formula given in claim 1 represented by hydroxymethylene group for the Acylation of alcohols known per se methods is converted into a carboxylic acyloxymethylene group. 7 ^.) Method according to one of claims 69 to 73 * thereby characterized by the fact that a stage is followed in which the Cyclopentanoic acid product of the general formula given in claim 1, in which R is a hydrogen atom methods known per se for the esterification of acids are converted into a corresponding compound in which R is an alkyl group represents having 1 to 12 carbon atoms. 75 ·) Method according to one of claims 69 to 73 * thereby characterized in that a stage is followed in which the cyclopentanoic acid product by methods known per se Formula given in claim 1, in which R is a hydrogen atom, is converted into a non-toxic salt, 76.) Pharmaceutical compositions, characterized in that they contain as active ingredient at least one cyclopentane derivative according to one of claims 1 to 66 or, if desired, a non-toxic salt thereof together with a pharmaceutical carrier or coating. r
609820/1130