CH621773A5 - Process for the preparation of novel 9-oxo-15zeta-hydroxy-20-alkylideneprost-13(trans)enoic acid derivatives - Google Patents

Description

The present invention relates to a process for the preparation of new prostaglandin derivatives, namely 9-oxo-15 | -hydroxy-20-alkylidene-prost-13 (trans) -enoic acid derivatives.

The prostaglandin derivatives 15 obtainable according to the invention correspond to the following general formula:

(I)

35

wherein the symbol A is the ethylene group or the cis-vinylene group, the symbols R1 and R2, which are the same or different, hydrogen atoms or alkyl radicals having 1 to 3 carbon atoms, the symbols R3 and R4, which are the same or different, alkyl radicals with 1 to 3 carbon atoms and the symbol R5 denote the hydrogen atom or the hydroxyl group. Furthermore, pharmaceutically acceptable salts of these compounds can also be prepared according to the invention.

The prostaglandin derivatives of the formula I are valuable antiulcer agents and bronchodilator agents.

In the above formula I, the symbols R1 and R2 can have the same or different meanings, each of these symbols preferably denoting the hydrogen atom, the methyl group, the ethyl group, the n-propyl group or the isopropyl group. The symbols R3 and R4, which can be the same or different, are preferably methyl, ethyl, n-propyl or isopropyl radicals.

In the above general formula I and in the present description, a bond which adheres to the cyclopentane core and is in the a configuration, i.e. is below the level of the cyclopentane ring, represented by a dashed line, while a bond which is in the β configuration, i.e. is above the level of the cyclopentane ring, is represented by a solid line. The wavy line indicates that it is any steric configuration.

The compounds of the general formula I mentioned above, in which R 2 denotes the hydrogen atom, can be converted into pharmaceutically acceptable salts in a manner known per se. The pharmaceutically acceptable salts can, for example, be salts of alkali or alkaline earth metals, e.g. Sodium-,

Potassium, magnesium and calcium salts, ammonium salts, quaternary ammonium salts, e.g. a salt of tetramethylammonium, tetraethylammonium, benzyltrimethylammonium and 65 phenyltriethylammonium, a salt of a lower aliphatic, alicyclic or aromatic-aliphatic amine, e.g. Methylamine, ethylamine, dimethylamine, diethylamine, trimethyl

45

50

55

thylamine, triethylamine, N-methylhexylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, a-phenylethylamine and ethylenediamine, a salt of a heterocyclic amine or a lower alkyl derivative thereof, e.g. Piperidine, morpholine, pyrrolidine, piperazine, pyridine, 1-methylpiperazine and 4-ethylmorpholine, or a salt of an amine containing a hydrophilic group, e.g. Monoethanolamine, ethyl-diethanolamine and 2-amino-l-butanol.

The prostaglandin derivatives of the general formula I mentioned above are new compounds which have not yet been disclosed in the literature. They are structurally related to certain naturally occurring prostaglandins, in particular prostaglandin E2 (The Merck Index, 9th edition, 1976, page 7665). The latter connection has undesirable side effects, including an antihypertensive and inflammatory effects, it causes diarrhea and, above all, a severe bronchoconstrictive effect in the cat.

Based on extensive tests, it was found that the prostaglandin derivatives of the formula I have an excellent inhibitory effect on gastric secretion and excellent bronchodilator effects. It should be noted that the new compounds have none of the above-mentioned side effects, in particular no or practically no hypotensive and contracting effect on the intestinal tract.

The inhibitory effect on gastric secretion and the bronchodilatory effect of prostaglandin derivatives of the formula I results from the following pharmacological comparative test data.

(1) Inhibition of gastric secretion

method

The method used is practically the same as that described by M. N. Ghosh and H. O. Schild in British Journal of Pharmacology and Chemotherapy, Vol. 13, 54-61 (1958).

621 773

Physiological saline containing a small amount of sodium hydroxide was infused through the stomach of a male rat (Donryu strain) which had been anesthetized by the administration of urethane, this infusion taking place at a rate of 1 ml / minute 5. Thereby, 10 [xg / kg / hour of an agent stimulating gastric secretion, namely tetra-gastrin, was continuously injected into the vein of this rat until the pH of the outflowing liquid was approximately 3 and remained at this value. A certain amount of the i0 test compounds was then administered into the vein at a certain speed over a period of 30 minutes and the pH of the outflowing liquid was measured. This measurement was repeated with different addition amounts.

Result 15

The following Table 1 shows the amounts required to increase the pH by 1.0 when administered intravenously.

20th

Table 1

Drug dose (mg / kg / hour)

Compound A 0.074

Compound B 0.070

PGEj 0.086

Compound A: 9-oxo-l 1 et, 15a-dihydroxy-l 7ß-methyl-20-iso- 25

propylidenprost-13 (trans) -enoic acid.

Compound B: 9-oxo-lla, 15a-dihydroxy-17β-methyl-20-iso-propylidene-prost-5 (ice), 13 (trans) -dienoic acid.

Compounds A and B are either similar or higher in gastric secretion inhibition than prostaglandin Ej (PGE [), as shown in the table above. Based on experiments, it was found that the compounds according to formula I are only about V200 stronger than prostaglandin 35 Ej in terms of uterine contraction. This means that the compounds obtainable according to the invention have properties which are not present in natural prostaglandins.

(2) Bronchodilator effect 40

method

The test compounds were administered by intravenous injection to guinea pigs (body weight: 400 to 600 g) which had been anesthetized by administration of sodium pentobarbital, whereby 2 to 3 [xg / kg histamine 45 were administered by intravenous injection. The inhibition ratio of the increase in trachea resistance was determined by the method according to the Konzett-Rössler method [Archive for Experimental Pathology and Pharmacology, Vol. 195.71 (1940)].

Result 50

The tested prostaglandins showed a bronchodilator effect in guinea pigs. Table 2 below shows the results.

Table 2 55

50% inhibitory dose (IDS0) in the increase in airway resistance in guinea pigs drug ID50 (y / kg i.r.)

Compound A 0.019 (0.026 - 0.015) *

Compound B 0.014 (0.019 - 0.010) 6 "

Compound C 0.032 (0.048 - 0.022)

Compound D 0.021 (0.035 - 0.013)

Compound E 0.039 (0.056 - 0.028)

PGEj 0.14 (0.19 - 0.11)

PGE2 0.21 (0.28-0.16) ft5

Isoproterenol 0.08 (0.14 - 0.05)

Salbutamol 0.042 (0.058 - 0.031)

Connection A: as above

Connection B: as above

Compound C: 9-oxo-15a-hydroxy-20-isopropylidene

prost-13 (trans) -enoic acid,

Compound D: 9-oxo-15a-hydroxy-20-isopropylidene

prost-5 (cis), 13 (trans) -dienoic acid. Compound E: 9-oxo-l la, 15a-dihydroxy-20-isopropyli-

denprost-5 (eis), 13 (trans) -dienoic acid. * 95% confidence limit

Based on experiments, it was found that the bronchodilatory effect of the compounds of the formula I is not inhibited by a β-adrenergic blocker which inhibits the action of sulbutamol and isoproterenol.

The compounds of the formula I are therefore valuable medicaments both for the inhibition of gastric secretion and for the inhibition of bronchodilation. To combat gastric secretion, the compounds can be administered parenterally, e.g. administered by intravenous, subcutaneous or intramuscular injections, or orally, using tablets, granules, capsules, etc. The dose to be administered varies depending on the conditions such as age, body weight, route of administration, etc. Generally, the dosage is in a range of about 0.1 mg to 15 mg per day in adults. Administration for bronchodilation is usually in the form of an aerosol. The dose to be administered in these cases depends on the conditions such as age, body weight, etc., but is generally between 20 [xg and 150 | xg per day in adults.

Specific examples of compounds of the general formula I mentioned above can be found below. The following compounds are particularly suitable for this.

(1) 9-oxo-lla, 15a or ß-dihydroxy-20-isopropylidene-prost-13 (trans) -enoic acid and the methyl, ethyl, n-propyl and isopropyl esters thereof,

(2) 9-oxo-l la, 15a- or -ß-dihydroxy-20-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid and its methyl, ethyl, n-propyl and isopropyl esters,

(3) 9-oxo-lla, 15a- or -β-dihydroxy-17ß-methyl-20-iso-propylidenprost-13 (trans) -enoic acid and the methyl, ethyl, n-propyl and isopropyl esters thereof,

(4) 9-oxo-lla, 15a- or -ß-dihydroxy-17ß-methyl-20-iso-propylidenprost-5 (cis), 13 (trans) -dienoic acid and its methyl, ethyl, n-propyl- and isopropyl ester,

(5) 9-oxo-l la, 15 a- or -ß-dihydroxy-17ß-methyl-20- (l'-methyl) -isopropylidene-prost-13 (trans) -enoic acid and its methyl, ethyl, n- Propyl and isopropyl esters,

(6) 9-oxo-lla, 15a- or -β-dihydroxy-17ß-methyl-20- (l'-methyl) -isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid and the methyl, ethyl , n-propyl and isopropyl esters thereof,

(7) 9-oxo-l la, 15a- or -ß-dihydroxy-17ß-methyl-20- (1 ', 3' -dimethyl) -isopropylidene-prost-13 (trans) -enoic acid and its methyl, ethyl, n-propyl and isopropyl esters,

(8) 9-oxo-lla, 15a- or -β-dihydroxy-17ß-methyl-20-

(1 ', 3' -dimethyl) -isopropylidene-prost-5 (ice), 13 (trans) -dienoic acid and its methyl, ethyl, n-propyl and isopropyl esters,

(9) 9-Oxo-lla, 15a- or -β-dihydroxy-20- (l'-methyl) -isopropylidenprost-13 (trans) -enoic acid and its methyl, ethyl, n-propyl and isopropyl esters ,

(10) 9-oxo-l la, 15a- or -ß-dihydroxy-20- (l'-methyl) -isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid and its methyl-, ethyl-, n- Propyl and isopropyl esters,

(11) 9-oxo-l la, 15a- or -ß-dihydroxy-20- (l ', 3' -dimethyl) -isopropylidene-prost-13 (trans) -enoic acid and its methyl, ethyl, n- Propyl and isopropyl esters,

(12) 9-oxo-l la, 15a- or -β-dihydroxy-20- (l ', 3'-dimethyl) -isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid and its methyl, Ethyl, n-propyl and isopropyl esters,

(13) 9-oxo-15a or β-hydroxy-20-isopropylidene prostate

621 773

13 (trans) -enoic acid and its methyl, ethyl, n-propyl and isopropyl esters

(14) 9-oxo-15a or -β-hydroxy-17ß-methyl-20-isopropylprost-13 (trans) -enoic acid and its methyl, ethyl, n-propyl and isopropyl esters,

(15) 9-oxo-15a or β-hydroxy-20-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid and its methyl, ethyl, n-propyl and isopropyl esters,

(16) 9-Oxo-15a or -ß-hydroxy-17ß-methyl-20-isopropyl-p-yeast-5 (cis), 13 (trans) -dienoic acid and its methyl, ethyl, n-propyl and isopropyl esters .

According to the invention, the compounds of the general formula I mentioned above are prepared by using a compound of the general formula:

(II)

wherein A, R1, R2, R3 and R4 have the above meanings, R5 'to a compound of the following general formula in which the hydrogen atom or a group -OR6 and R6 are a protective group for the hydroxyl group, oxidized to get:

r-

coor "3

n

/

(III)

VR

wherein A, R1, R2, R3, R4, R5 'and R6 have the above meanings, whereupon the protective group (s) which may be present are removed from the hydroxyl group or hydroxyl groups 45 of the product obtained.

There is no limit to the protecting groups for the hydroxyl group, as long as the removal of such protecting groups does not affect the rest of the compound. The protective groups can be, for example, 5- or 6-membered cyclic groups which contain an oxygen or sulfur atom in the ring and can be substituted by alkoxy radicals, such as e.g. 2-tetrahydrofuranyl, 2-tetrahydropyranyl, 2-tetra-hydrothienyl, 2-tetrahydrothiopyranyl and 4-methoxytetra-hydropyran-4-yl radicals; straight-chain or branched alkyl groups with 1 to 5 carbon atoms, e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl and isopotyl groups, straight-chain or branched alkyl groups having 1 to 5 carbon atoms which carry alkoxy substituents, e.g. Methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, isobutoxymethyl, n-pentoxymethyl, isopentoxymethyl, 1-ethoxymethyl, 1-ethoxypropyl, 2-ethoxybutyl and 1-ethoxypentyl straight-chain or branched dialkylsilyl groups with 1 to 5 carbon atoms, e.g. Trimethylsilyl, triethylsilyl, tri-n-propylsilyl, triisopropylsilyl, tri-n-butylsilyl, triisobutylsilyl and tri-n-pentylsilyl radicals; and carboxylic ester residues of the formula:

XOCO-

(IV)

50

55

60

wherein X represents a straight-chain or branched alkyl group having 1 to 5 carbon atoms, e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and n-pentyl groups, an ethyl group containing 1 to 3 halogen atoms in the β-position, such as e.g. 2,2,2-trichloroethyl, 2,2-dibromoethyl and 2-iodoethyl groups, phenyl groups which can carry substituents, e.g. the phenyl group, 4-nitrophenyl group, 2-chlorophenyl group and 2,4-dichlorophenyl group, and aralkyl groups which contain substituted or unsubstituted aromatic rings and an alkylene component having 1 to 5 carbon atoms, e.g. Benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, 4-nitrobenzyl and chlorophenylethyl groups. Instead of the protective groups mentioned above, other protective groups can also be used.

In the process according to the invention, the oxidation of a compound of the formula II mentioned above is carried out by using an oxidizing agent in the presence or absence of a solvent. Chromic acid, e.g. Chromic acid, chromic anhydride, a chromic anhydride-pyridine complex (Collins reagent), a mixture of chromic anhydride, concentrated sulfuric acid and water (Jones reagent), sodium dichromate and potassium dichromate, active halogenated

621 773 6

organic compounds, e.g. N-bromoacetamide, N-bromo type of protective group. If the protecting group for the hydroxyl group succinimide, N-bromophthalimide, N-chloro-p-toluenesulfonamide, for example a heterocyclic and N-chlorobenzenesulfonamide, aluminum alkoxides, e.g. Group, e.g. the 2-tetrahydropyranyl group, an alkoxy sub-

Aluminum tertiary butoxide and aluminum isopropoxide, an alkyl group having substituents, e.g. the methoxymethyl mixture of dimethyl sulfoxide and dicyclohexylcarbodiimide 5 group, or a cycloalkyl group carrying alkoxy substituents and a mixture of dimethyl sulfoxide and acetic acid group, e.g. is the 1-methoxycyclohexyl group, use the drid. Unless you use a solvent to react easily by intending to combine it with an acid, there are no contact restrictions. However, if the condition is that these solvents are used in the reaction, organic acids such as e.g. Formic acid, vinegar-do not participate. Preferred solvents are, however, the 10 acid, propionic acid, butyric acid, oxalic acid and malonic acid, solvents listed below. If one or mineral acids such as hydrochloric acid, hydrobromic acid or chromic acid are used, then an organic acid, sulfuric acid, is preferably considered. The reaction can be carried out in the presence or a mixture of an organic acid and an organic or in the absence of a solvent, e.g. Acetic acid or a mixture of vinegars. However, one will preferably use a solvent, acid and acetic anhydride, or a halogenated carbon to make the reaction go smoothly. Regarding the hydrogen, e.g. Dichloromethane, chloroform or tetra choice of solvent are no special chlorinated carbon, use. If you use a reaction fancy. However, the solvent must react with halogenated organic compounds, so you will prefer not to participate. Examples of such solvents are water, such as an aqueous organic solvent, e.g. aqueous alcohols, such as methanol or ethanol, and ethers, such as tetrahy-tert-butanol, aqueous acetone or aqueous pyridine, use 20 drofuran, dioxane. One is preferably a mixture of the. If, on the other hand, an aluminum alkoxide is used, such an organic solvent and water are used, an aromatic hydrocarbon is preferably used. The reaction temperature is likewise of no importance, such as benzene, toluene or xylene. In the case of the compounds, however, the reaction is preferably carried out at a temperature of a mixture of dimethyl sulfoxide and dicyclature between room temperature and the reflux temperature hexylcarbodiimide or dimethyl sulfoxide and acetic acid solvent of the solvent. The reaction takes place usually when an excess is used, preferably at room temperature. In those cases where there is no other solvent on dimethyl sulfoxide. If the protective group for the hydroxyl group uses an alkyl group, if an aluminum alkoxide is used, it is preferred to use e.g. is the methyl group, the reaction of slightly hydrogen-binding agent takes place in excess of a ketone, by reacting the compound with a boron halide, e.g. Acetone, methyl ethyl ketone, cyclohexanone or benzo-30 e.g. Boron trichloride or boron tribromide. The quinone reaction, in addition to the solvent mentioned above, can be carried out in the presence or absence of one. This reaction requires that the water be solvent. However, it is advantageous to be thoroughly removed from the reaction system. Use solvent to smooth the reaction to a mixture of dimethyl sulfoxide and dicyclohexyl carbonate. The choice of solvent is also not of bodiimide, so you will get a Catalan amount of an acid, e.g. 35 Significance, but it must be sought that this solution phosphoric acid and acetic acid, and this does not take part in the reaction in a known manner. Use preferred solution. Halogenated hydrocarbons, such as dichloromethane, are usually used as the most preferred oxidizing agent or chloroform in the reaction in question. The reaction temperature is not of any of the chromic acids, especially a chromic anhydride meaning, but one will preferably work at a relatively low pyridine complex (Collins reagent) or a mixture of 40 temperature in order to concentrate side reactions to chromic anhydride in this way. Sulfuric acid and water (avoid Jones. The preferred temperature ranges are reagens). The reaction temperature is not important - 30 ° C and room temperature. In those cases in which the protective group for the hydroxyl group is preferably, for example, a trial work at a relatively low temperature, in order to avoid side reactions in this way. kylsilyl group, e.g. is the trimethylsilyl group, the reaction temperature is usually in a range of 45. The reaction can easily be carried out by connecting between -20.degree. C. and room temperature and preferably in water or with either an acid or a base in a range between 0 ° C and room temperature. The containing water in contact. As acid and

The reaction time mainly depends on the reaction temperature bases, which may be present in the water, come on and the type of oxidizing agent used. There are organic acids such as formic acid, acetic acid, propion-

but generally in a range between 5 minutes and 50 acid, butyric acid, oxalic acid and malonic acid, and as a mine-2 hours. raisic acids, for example hydrochloric acid, hydrobromic acid and

When the reaction is complete, sulfuric acid can be used for the oxidation. Furthermore, a desired compound obtained in a hydroxide can also be obtained in a manner known per se of an alkali or alkaline earth metal, e.g. Potassium hydroxide or isolated from the reaction mixture. For example, calcium hydroxide, or a carbonate of an alkali or alkaline earth metal, for example after the reaction has ended, can be an organic potassium metal, e.g. Potassium carbonate or calcium carbonate, ver

Solvents, e.g. Add ether, to the reaction mixture and turn. If water is used as the solvent, the insoluble constituents need to be filtered off. The resulting organic no other solvents. Other solvents are see solvent part can be washed and dried and mixtures of water with an organic solvent,

then the solvent from the organic solvent such as e.g. an ether, e.g. Tetrahydrofuran or dioxane, or layer can be distilled off; in this way the 60 is washed with an alcohol e.g. a methanol or ethanol. Also get the desired connection. The desired reaction temperature obtained in this way is not a limitation. If necessary, the compound can be prescribed in a manner known per se. Usually, however, the reaction will be carried out in a manner, for example by column chromatography or by room temperature. In those cases where thin layer chromatography continues to purify. Protecting group for the hydroxyl group either a carbonic acid

65 residue of an ester, e.g. is the ethoxycarbonyl radical, the reaction for removing the protective group from the hydroxyl reaction can easily be carried out by contacting the compound group of the compounds of the above-mentioned general with an acid or a base. One too

Formula III used reaction depends on the acid or base used is preferably a mineral

621 773

acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, or a hydroxide of an alkali or alkaline earth metal, e.g. Sodium hydroxide, potassium hydroxide or calcium hydroxide,

or a carbonai of an alkali or alkaline earth metal, e.g. Sodium carbonate, potassium carbonate or calcium carbonate. The reaction can preferably be carried out under basic conditions. It can be carried out in the presence or absence of a solvent, but the solvent will preferably be such that the reaction can be carried out smoothly. There are no restrictions on the solvent to be used. However, it should not participate in the implementation. Examples of such solvents are preferably water, alcohols, such as methanol or ethanol, and also ethers, such as tetrahydrofuran and dioxane, and mixtures of water and one of the organic solvents just mentioned. No particular restrictions are required with regard to the reaction temperature either. The reaction can be carried out at a temperature in the range between room temperature and the reflux temperature of the solvent. The reaction time mainly depends on the type of protective group to be removed.

In the case of the compounds of the general formula I mentioned above which can be obtained according to the invention, those compounds in which the symbol R2 represents the hydrogen atom can be converted into the corresponding salts in a conventional manner.

In addition, the compounds obtainable according to the invention are normally mixtures of the various geometric isomers and / or optical isomers which can be isolated or split up in a manner known per se.

The compounds of the general formula II mentioned above, which are used as starting materials for the present process, are also new compounds and can be prepared according to the following reaction schemes.

{1) Preparation of the starting compounds of the above formula II, in which the symbol A denotes the ethylene group and the symbol R5 denotes a protected hydroxyl group:

cor '

(ch2) 6coor

10th

coor-

(v)

1st stage

■ ->

r7-c = z i (ch2) 6c00r

10th

r110

coor

9

(vi) 4 2nd stage r7-c = z r110

(ch2) 6coor

13

R7-C = Z

ch2oh

3rd stage

xch2) 6c00r

12th

coor-

(viii)

(vii)

4th stage

(ch2) 6coor15

• 5th stage ch2oh

OCOR '

(ch2) 6coor

13

ch20h

(ix)

(x)

621773

8th

6th stage

H'

(xiii) (xiv)

10th stage of

Oh

(ii)

In the above formulas, the symbols A, R1, R2, R3 have protective groups. But they should not have the usual components R4, R5 'and R6 the meanings above. affect and at a later point in time through a

Have the R6 protecting group for the hydroxyl group replaced with a hydrogen atom. Such protective groups are those which cannot be removed simultaneously, for example hydrocarbon groups, such as Methyl-,

when R7CO- is a protecting group for the hydroxyl group 55 ethyl, n-propyl, isopropyl, n-butyl, isobutyl, phenyl or. R7 is a straight-chain or branched alkyl group, benzyl radicals, halogenated alkyl radicals, such as e.g. 2,2,2-trichloro e.g. the methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-ethyl radicals or heterocyclic radicals, such as e.g. 2-tetrahydro-butyl, tert-butyl or n-pentyl radical. The symbols Rs and Ru pyranyl-, 2-tetrahydrothiopyranyl-, 2-tetrahydrofuranyl- and are protective groups for the hydroxyl groups. Regarding these 4-methoxytetrahydropyran-4-yl groups. The protective groups mentioned above are not restricted, provided they are protective groups but are not the only ones which can be used and become inert with respect to the other components. The symbol R12 is the hydrogen atom or this protective group later becomes a group through the hydrogen atom, as previously as a protective group for the carboxyl

can be replaced. Such protecting groups are, for example, the group that has been mentioned. The symbol Z represents a protection - as they have been mentioned for the symbol R5. The symbol R9 represents group for the carboxyl group. Regarding the protecting group there is a straight or branched alkyl group, e.g. of the 6y for the carbonyl group there are no restrictive mass methyl, ethyl, n-propyl and isopropyl radical. The symbols R10 took, but this protective group should also the other compounds R13 are protective groups for the carboxyl groups. For the nenten of the compound and in a carboxyl group there are no restrictions on the later points in time. Such a protecting group

9

621 773

is, for example, a hydroxyimino group which forms an oxime, a dialkoxy group, e.g. the dimethoxy or dieth-oxy group, an alkylenedioxy group, e.g. the methylenedioxy or ethylenedioxy group, or an alkylenedithio group, e.g. the trimethylene dithio group. With regard to these protecting groups, other groups can also be used.

Each of the above-mentioned stages will be described in detail below, referring to known compounds of the general formula V as disclosed in Japanese Patent Laid-Open No. 57 958/73 10.

The first step relates to the preparation of a compound of the general formula VI and can be carried out by protecting the carbonyl group of a compound of the general formula V and, if necessary, replacing such a protective group with the hydroxyl group.

The order of implementation with regard to the introduction of a protective group or the introduction of a substituent mentioned above can be varied. The reaction to protect the carbonyl group of a compound of the general formula V is carried out by contacting such a compound with a compound which is capable of forming a protective group for the carbonyl group in the presence or in the absence of a solvent. For example, the compound used to form a protecting group for the carbonyl group can be a hydroxylamine-forming oxime, e.g. Hydroxylamine, methylhydroxylamine or sodium hydroxylamine sulfate, a ketal forming an orthoformate, e.g. Methyl orthoformate or ethyl orthoformate, a cyclic ketal forming an alkylene glycol, e.g. Methylene glycol or ethylene glycol, or a cyclic thioketal forming an alkylene dithioglycol, e.g. Ethylenedithioglycol or trimethylene thioglycol. The reaction varies depending on the kind of the compound used for the formation of the protecting group for the carbonyl group. 35

The substitution reaction for the symbol R8, namely the protective group for the hydroxyl group of a compound of the general formula V, can take place by removing the protective group R8 from the hydroxyl group and bringing this compound into contact with a compound which forms a preferred protective group can

The second stage relates to the preparation of a compound of the general formula VII mentioned above. This reaction stage comprises a reaction which, if necessary, removes the protective group R10 from the carboxyl group of a compound 45 of the general formula VI. This implementation will be carried out depending on the case. In the subsequent third stage, namely the reduction reaction, a higher yield will be achieved if the protective group for the hydroxyl group, namely R10, is removed before the reduction. This reaction varies depending on the kind of the protective group for the hydroxyl group.

The third step relates to the preparation of a compound of general formula VIII and can be carried out by reducing a compound of general formula VII mentioned above and, if necessary, protecting the carboxyl group in those cases in which the symbol R12 represents the hydrogen atom . The reduction is generally carried out using a reducing agent in the presence of a solvent.

The fourth stage relates to the preparation of a compound of the general formula IX above and can be carried out by removing the protective group from the carbonyl group of a compound of the general formula VIII. The implementation for removing the protecting group from the protected carbonyl group varies depending on the kind of the protecting group.

The fifth step relates to the preparation of a compound of general formula X and can be carried out by oxidizing a compound of general formula IX mentioned above. This reaction can be carried out by contacting such a compound with a peroxide in the presence or in the absence of a solvent. The peroxide used is preferably an organic peracid, e.g. Performic acid, peracetic acid, perpropionic acid, perlauric acid, percamphoric acid, trifluoroperacetic acid, perbenzoic acid, m-chloroperbenzoic acid or monoperphthalic acid or hydrogen peroxide. The reaction can take place in the presence or in the absence of a solvent.

The sixth stage relates to the preparation of compounds of the general formula XI and can be carried out by oxidizing a compound of the general formula X mentioned above. The reaction takes place in the presence of an oxidizing agent. Both the oxidizing agent used and the reaction conditions are the same as those mentioned above for the implementation of the preparation of a compound of general formula III, in which a compound of general formula II is oxidized.

The seventh step relates to the preparation of a compound of the above-mentioned general formula XII and can be carried out by preparing a compound of the above-mentioned general formula XI with a Wittig reagent of the following general formula:

1 Ii (r 0).

(XV)

wherein R1, R3 and R4 have the above meanings, R14 is an alkyl radical, e.g. the methyl radical, or an aryl radical, e.g. the phenyl radical, and Mj® a metal ion, e.g. which mean sodium, potassium or lithium ion. Any solvent can be used for this, as has been described for the customary Wittig reactions.

The eighth stage relates to the preparation of a compound of the general formula XIII and can be carried out by reducing a compound of the above-mentioned general formula XII. This reaction is carried out by using a reducing agent in the presence or in the absence of a solvent. Any reducing agent can be used for this, provided that they are able to convert the carbonyl group into a hydroxyl group and this without reducing the double bond. Such reducing agents are preferably metal hydrides such as

621 773

10th

Sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, lithium tri-tert-butoxy aluminum hydride, lithium trimethoxy aluminum hydride, sodium cyanoborohydride and lithium 9b-boraperhydrophenalenhydride. This reaction can be carried out in the presence or in the absence of a solvent.

The ninth stage leads to the preparation of compounds of the general formula XIV and can be carried out in such a way that the substituent Rn of the protective group is converted into a hydroxyl group of a compound of the general formula XIII and this hydroxyl group is protected. There is no restriction on this protecting group, provided that it is not removed if the protecting group for the hydroxyl group, namely the R7CO- group, is subsequently removed. This reaction is carried out by removing the protective group R11 and then bringing the compound thus obtained into contact with a compound which is capable of forming a preferred protective group. The compound capable of forming a protecting group for the hydroxyl group and the reaction conditions used are the same as those described above for the first step.

The tenth stage relates to the preparation of a compound of the general formula II mentioned above and can be carried out by removing the protective groups R7CO and R13 from the hydroxyl or carboxyl groups of a compound of the general formula XIV and, if necessary, esterifying the carboxyl groups. In certain cases, the

Reaction for the removal of the protective group R13 from the carboxyl group after the reaction for the removal of the protective group R7CO- from the hydroxyl group may not be necessary and is because in certain cases the protective group R13 is simultaneously removed from the carboxyl group when the Reaction to remove the protective group R7CO from the hydroxyl group is carried out.

The reaction for removing the protective group R7CO- from the hydroxyl group can easily be carried out by treating the compound with an acid or a base.

The reaction for removing the protective group R13 from the carboxyl group varies depending on the type of the protective group.

15 The reaction for the esterification of the carboxyl group, which is carried out if necessary, is carried out by treating such a compound with an esterifying agent in the presence or in the absence of a solvent. There are no restrictions on the esterification agent to be used, provided that it is an esterification agent used in the reaction for converting a carboxyl group to an alkoxycarbonyl group.

25 (2) Preparation of the starting compounds of the above general formula II, in which the symbol A denotes the ice-vinylene group and the symbol R5 'denotes a protected hydroxyl group:

15

E J0 CHO

OR6 R1

(XX)

(II)

11

621 773

In the above formulas, the symbols A, R1, R2, R3, R4, R5 and R6 have the meanings mentioned above. The symbol R15 denotes a protective group for the hydroxyl group,

no specific limitation is imposed on this protecting group, provided that it does not interfere with other 5 components of the compound if the reaction to replace the protecting group with the hydrogen atom takes place at a later time. This protecting group is the same as that previously described for the symbol R6. 10th

Each of the stages is described with reference to the known compounds of general formula XVI as described in J. Am. Chem. Soc. 91, 5675 (1969).

The first stage relates to the preparation of a compound of the above general formula XVII and can be carried out in such a way that a compound of the above-mentioned general formula XVI is reacted with a Wittig reagent of the above-mentioned general formula XV. These reaction conditions are the same as those in the seventh step in the preparation of a compound of the general formula XII mentioned above.

The second stage relates to the preparation of a compound of the general formula XVIII mentioned above and can be carried out by reducing a compound of the general formula XVII mentioned above. The same reaction conditions will be used as described in the eighth step for the preparation of a compound of the general formula XIII mentioned above.

The third stage relates to the preparation of a compound of the above-mentioned general formula XIX and can be carried out by converting the residue Rls of the protective group into a hydroxyl group of a compound of the above-mentioned general formula XVIII and protecting the hydroxyl group of the compound thus obtained . The same reaction conditions as those in the ninth stage are used for the preparation of a compound of the general formula XIV mentioned above.

The fourth stage relates to the preparation of a compound of the above general formula XX and can be carried out by reducing a compound of the above general formula XIX.

The fifth stage relates to the preparation of a compound of the above-mentioned general formula II and can be carried out by preparing a compound of the above-mentioned general formula XX with a Wittig reagent of the following general formula:

(Ri6) 3p @ - © CH- (CH2) 3-COOM2 (XXI)

wherein R16 is a hydrocarbon group, e.g. an aryl group, such as the phenyl group, or an alkyl group, for example the n-butyl group, and M2 an alkali metal, e.g. Sodium or potassium, means, the compound thus obtained is converted into a free acid by treatment with an acid in a manner known per se and, if necessary, the carboxyl group of the free acid obtained is esterified.

The reaction for the esterification of the carboxyl group of the free acid obtained, which is carried out if necessary, is carried out by treating the free acid with an esterifying agent. The reaction conditions used for this are the same as in the tenth step for the preparation of a compound of the general formula II mentioned above.

621 773

12

(3) Preparation of starting compounds of the above formula! Wherein A is the ethylene group and R5 'is the hydrogen atom:

0

M

1st stage ch2oh

(xxii)

or

18th

0

fi ch20r

(xxvt)

2nd stage

->

16

ch20r (xxiii)

coor

17th

^. Level oh oh

H

16

ch2or

(xxiv)

3rd stage ch or 2nd

(xxv)

coor

17th

5th stage or

18th

coor

17th

ch2oh

(xxvii)

6th stage or

18th

ch20h coor

17th

(xxviii)

13

621 773

Y

7th stage

OR

18th

OR

18th

COOR

8th stage

COOR

17th

OR

18th

V

9th stage

OR

18th

COOR

17th

OK. Step )

OR6 R1

11th stage

COOR

In the above formulas, the symbols R1, R2, R3, R4 and R6 have the meanings mentioned above. However, the symbol R6, which means the protective group for the hydroxyl group, should remain unchanged, while the remainder R18 of the protective group for another hydroxyl group is removed. Each of the symbols R16 and R18 means a protective group for the respective hydroxyl groups. These can be any protective groups for the hydroxyl groups, provided that they do not adversely affect the other components if the said protective group is later replaced by a hydrogen atom. Such protective groups are, for example, those as previously for the

(II)

Symbol R6 have been mentioned. The protecting group R18 is preferably an acyl group, e.g. the acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, benzoyl, 4-nitrobenzoyl, 2-chlorobenzoyl, 2,4-dichlorobenzoyl and phenylacetyl radical. The symbol R17 represents a protective group for the carboxyl group. There are also no restrictions in this regard with regard to the protective group for the carboxyl group, provided that the other components are not impaired during the later replacement of said protective group by the hydrogen atom. Such protecting groups are, for example, hydrocarbon residues, e.g. the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, phenyl or

621 773

14

Benzyl radical, halogenated alkyl radicals, such as e.g. the 2,2,2-trichloroethyl radical, or heterocyclic radicals, such as e.g. the 2-tetrahy-dropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl and 4-methoxytetrahydropyran-4-yl group. However, the invention is in no way limited to the protective groups just mentioned.

Each of the above-mentioned working steps is explained in more detail below, with reference being made to known compounds of the general formula XXII, as described in Tetrahedron Letters, 1972, 115. 10th

The first step relates to the preparation of a compound of formula XXIII and comprises the reaction for the preparation of a compound of general formula XXII mentioned above, wherein the hydroxyl group is protected. The second stage relates to the preparation of a compound of the above-mentioned general formula XXIV and can be carried out by reducing a compound of the above-mentioned general formula XXIII. This reaction takes place in the presence of a reducing agent. A metal hydride, e.g. Use diisobutyl aluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride, lithium tri-tert-butoxy aluminum hydride or lithium trimethoxy aluminum hydride.

The third stage relates to the preparation of a compound of the above-mentioned general formula XXV and 25 can be carried out by preparing a compound of the above-mentioned general formula XXIV with a Wittig reagent of the following general formula:

apply a catalytic reduction using hydrogen in the presence of a catalyst, e.g. Palladium-on-carbon or platinum oxide.

The seventh stage relates to the preparation of a compound of the above general formula XXIX and can be carried out by oxidizing a compound of the above general formula XXVIII. This reaction takes place in the presence of an oxidizing agent. In this reaction, the same oxidizing agents and the same reaction conditions are used as described above for the reaction for the oxidation of a compound of the above-mentioned general formula II to form a compound of the above-mentioned general formula III.

The eighth stage relates to the preparation of the above-mentioned general formula XXX and can be carried out by preparing a compound of the above-mentioned general formula XXIX with a Wittig reagent of the following general formula:

(R19) 3P® - © CH- (CH2) 3-COOM3

(XXXIII)

wherein the symbol R19 represents a hydrocarbon group, e.g. an aryl group such as the phenyl group or an alkyl group such as e.g. the n-butyl group, and the symbol M3 an alkali metal, e.g. Sodium or potassium, mean what you put them on

35

compound obtained in this way is converted into the free acid by treatment with an acid in a manner known per se and protects the carboxyl group of the free acid obtained.

The reaction to protect the carboxyl group is carried out in the presence or absence of a solvent by contacting the compound with a compound capable of forming a protecting group for the carboxyl group.

The fourth step relates to the preparation of a compound of general formula XXVI 45 above and can be carried out by protecting the hydroxyl group of a compound of general formula XXV mentioned above.

The fifth step relates to the preparation of a compound of the above general formula XXVII 50 and can be carried out by removing the protecting group R16 from the hydroxyl group of a compound of the above general formula XXVI. The acids as well as the bases and the reaction conditions for this reaction are the same as those described above for the reaction regarding the removal of the protective group from the hydroxyl group of a compound of the general formula III mentioned above.

The sixth stage relates to the preparation of a compound of the above general formula 6Q XXVIII and can be carried out by reducing a compound of the above general formula XXVII. This reaction is carried out using a reducing agent in the presence of a solvent. Any reducing agent can be used as the reducing agent (, 5, provided that they are of such a type that they are able to convert the double bond into an ethylene group, but without reducing the carbonyl group. Preferably in which the symbols R1, R3 and R4 are those mentioned above Have meanings and R20 is an alkyl group, for example the methyl group, or an aryl group, for example the phenyl group, and the symbol M® is a metal ion, for example the sodium, potassium or lithium ion.

The ninth stage relates to the preparation of a compound of the above general formula XXXI and can be carried out by reducing a compound of the above general formula XXX. This reaction is carried out using a reducing agent in the presence or in the absence of a solvent. Any reducing agent can be used for this, provided that they are of such a type that they are able to convert the carbonyl group into a hydroxyl group, but without reducing the double bond. Such reducing agents are preferably metal hydrides, e.g. Borohydride, potassium borohydride, lithium borohydride, zinc borohydride, lithium tri-tert-but-oxyaluminium hydride, lithium trimethoxyaluminium hydride, sodium cyanoborohydride or lithium 9b-boraperhydrophenene hydride.

The tenth stage relates to the preparation of a compound of the above general formula XXXII and can be carried out by protecting the hydroxyl group of a compound of the above general formula XXXI. Any protecting group can be used to protect the hydroxyl group, provided that it is not removed at the same time that the protecting group symbol R18 for another hydroxyl group is later removed. The compound capable of forming the protecting group and the reaction conditions are the same as those described above in connection with the first working step.

The eleventh stage relates to the preparation of the general formula II mentioned above and can be carried out by removing the protective groups R18 and R17 from the hydroxyl and carboxyl groups of compounds of the above-mentioned general formula XXXII and then, if necessary, the carboxyl group of the thus obtained Connection esterified. In certain cases, the reaction may be for the distance

15

621 773

The protective group R17 from the carboxyl group may not be necessary after the reaction for removing the protective group R18 from the hydroxyl group has been carried out, because in certain cases the protective group R17 is simultaneously removed from the carboxyl group while the reaction for the Removal of the protective group R18 from the hydroxyl group is carried out.

The reaction for removing the protective group R18 from the hydroxyl group can easily be carried out by treating the compound with either a base or an acid.

The reaction for removing the protecting group R17 from the carboxyl group varies depending on the kind of the protecting group.

The implementation for the esterification of the carboxyl group? which is carried out, if necessary, is carried out by treating such a compound with an esterifying agent in the presence or in the absence of a solvent.

(4) Preparation of starting compounds of the above formula II, in which the symbol A denotes the ice-vinylene group and the symbol R5 'denotes the hydrogen atom:

ch20h

00R

17th

1st stage coor17

(XXVII)

■ V / x / "'

.cook

4th stage of

(XXXV)

3rd stage

2nd stage

17th

or

18th

\ T \ = / nv / ncoor17

Ty ^ v

0

(xxxvi)

(XXXVIII)

(II)

In the above formulas, the symbols R1, R2, R3, R4 have general formula XXVII which, in the above-mentioned R6, R17 and R18, has the meanings mentioned above. (, 5 fifth stage of work can be obtained.

Each of the work steps just mentioned is described below. The first work step relates to the preparation of, in which, with regard to the compounds of the above general formula XXXV, and starting compounds on compounds of the above are all carried out in such a way that one compound the one above

621 773 16

general formula XXVII mentioned oxidized. The Reak- Oxo-1 la, 15a-di- (2-tetrahydropyranyloxy) -17ß-methyl-20-iso-

tion conditions are the same as those obtained in the seventh stage for propylidenprost-13 (trans) -enoic acid as an oil.

Preparation of a compound of the above-mentioned general IR spectrum (liquid film) vmax cm-1: 1745.1712.

Formula XXIX. NMR spectrum (CC14) ôppm:

The second stage relates to the production s 0.90 (3H, doublet, J = 6 Hz),

a compound of the general formula 5.0 mentioned above (1H, triplet, J = 6 Hz),

XXXVI and can be carried out in such a way that one connects 5.55 (2H, multiplet).

of the above-mentioned general formula XXXV with (2) 652 mg of 9-oxo-l la, 15a-di-XXXIV are reacted in a mixture of 15 ml of acetic acid, 15 ml of water, a Wittig reagent of the above-mentioned general formula and 5 ml of tetrahydrofuran. The reaction conditions are the same as iq (2-tetrahydropyranyloxy) -17ß-methyl-20-isopropylidene-prost-dissolved in the above-mentioned eighth step for the preparation of 13 (trans) -enoic acid, whereupon the obtained solution of a compound of the above-mentioned general formula during Stirred for 472 hours at 35 ° C. After the conversion

XXX. Tung the reaction mixture after the addition of water

The third stage relates to the production of extracted with ethyl acetate. The extract is seen with water Gewa compounds of the general formula mentioned above and dried over anhydrous sodium sulfate. The

XXXVII and can be carried out by evaporating a solvent from the extract, whereby compound of the above-mentioned general formula XXXVI 640 mg of a residue is obtained. This backlog is reduced here. The reaction conditions are the same as those purified on a column loaded with silica gel, with the ninth step for the preparation of a compound of 210 mg 9-oxo-l la, 15a-dihydroxy-17β-methyl-20-isopro-general mentioned above Formula XXXI. 20 pylidenprost-13 (trans) -enoic acid in the form of an oil.

The fourth stage relates to the preparation of the IR spectrum (liquid film) vmax cm "1: 3380.1735.1710. Above mentioned general formula XXXVTII and can thus NMR spectrum (CDC13) ôppm:

be carried out by changing the hydroxyl group of a ver o, 90 (3H, doublet, J = 6 Hz),

binding of the above-mentioned general formula XXXVII \; 5g (3H, singlet),

protects. The reaction conditions are the same as in Figure 25 (3H, singlet),

tenth stage of work for the connection of the 4 ^ 0 (2H, multiplet),

general formula XXXII mentioned above. 5.57 (2H, multiplet).

The fifth stage relates to the preparation (3) of the potassium salt of a compound of the above-mentioned general formula II. 408 mg of the 108% strength 30% aqueous alcohol are added and can be carried out in such a way that the protective groups 30 obtained as described above are dissolved . This R18 and R17 from the hydroxyl or carboxyl group of a solution is then in with 100 mg of potassium hydrogen carbonate

Compound of the above-mentioned general formula XXXVIII 10 ml of 30% aqueous methanol are added and the resultant is removed and, if necessary, the carboxyl group of the mixture obtained is stirred for 1 hour at room temperature, the compound is esterified. After the reaction has ended, the solvent is evaporated at a lower temperature than in the eleventh stage for the preparation of a low temperature, 507 mg of the potassium sal compound of the above-mentioned general formula II. Zes of 9-oxo-lla, 15 <x-dihydroxy-17ß-methyl-20-isopropyli-

In the above-mentioned work steps, each of the denprost-13 (trans) -enoic acid can be obtained as an oil.

isolate the desired compounds by looking at the IR spectrum (liquid film) vmax cm-1: 1595. Reaction mixture treated in the usual way after completion of the reaction. The desired compounds 40 thus obtained

can then be carried out by methods known per se, such as e.g. Column chromatography or thin-layer chromatography-9-oxo-11a, 15β-dihydroxy-17ß-methyl-20-, sopropylidene prostate, can be purified. 13 (trans) -sdure

In addition, the desired compounds obtained in this way are obtained. ^ TP * ^ ß-Hydroxy-l la, 15ß-di- (2-tetrahydropyranyl-

In the form of mixtures of different geometrical 45 oxy) -17ß-methyl-20-isopropylidene-prost-13 (trans) -enoic acid, isomers and / or optical isomers are obtained which are obtained in the same manner as in Example 1- above ( 1) isolate or split up and treated by a suitable synthetic step, 750 mg of 9-oxo-l lex, 15β-tane being di- (2-tetrahydropyranyloxy) -17ß-methyl-20-isopropylden-

The invention gives prost-13 (trans) -enoic acid as an oil by the following examples.

explained. 50 IR spectrum (liquid film) vmax cm!: 1739.1708.

NMR spectrum (CC14) ôppm:

Example 1 0.90 (3H, doublet, 3 = 6 Hz),

9-oxo-l la, 15a-dihydroxy-17ß-methyl-20-isopropylidene prost- 5.03 (1H, triplet, J = 6 Hz),

13 (trans) -enoic acid 5.50 (2H, multiplet).

(1) 766 mg of 9β-hydroxy-lla, 15a-55 (2) 750 9.0x0-i 1 a, 15ß-di- (2-tetrahydropyranyloxy) -di (2-tetrahydropyranyloxy) -17ß are dissolved in 20 ml acetone -methyl-20-isopropyliclen-I7ß-methyl-20-isopropylidenprost-13 (trans) -enoic acid

Pr ° tl3 tra ^ 'enSaUre- Dl, eSeJ V0SU "gg! BtAmc £! N bel ~ 11 blS implemented in the same way as in the above example l- (2) -13; C, Lml Jonesreagens (obtained by dissolving and treated with 163 9.0xo.1 lajl5ß.dihydroxy.

Mix 26.72 g of chromic acid anhydride in 23 ml of sulfuric acid and l7ß-methyl-20-isopropylidene-prost-13 (trans) -enoic acid as an oil with a certain amount of water until the total amount has reached 100 ml) and stir obtained mixture for 20 minutes. After the IR spectrum (liquid film) has ended vmax cm-1: 3400.1730, 968.

Reaction is the excess of the reactant by NMR spectrum (CDC13) ôppm:

Addition of isopropyl alcohol decomposes and the solution after 0.91 (3H, doublet, J = 6 Hz),

Add water extracted with ethyl acetate. The extract fi.s 1.58 (3H, singlet),

is washed with water and over anhydrous sodium sulfate 1.64 (3H, singlet),

fat dried. Then the solvent is reduced under 4.10 (2H, multiplet),

The pressure evaporated from the extract, giving 652 mg of 9-5.66 (2H, multiplet).

17th

621773

Example 3

9-Oxo-l la, 15a-dihydroxy-l 7β-methyl-20-isopropylidene-prost-13 (trans) -enoic acid methyl ester

(1) 351 mg of 9β-hydroxy-lla, 15a-di- (2-tetrahydropyranyl-oxy) - 17ß-methyl-20-isopropylidene-prostate-13 (trans) -enoic acid methyl ester are prepared in the same manner as in Example 1- above (1) reacted and treated, whereby 298 mg of 9-oxo

11 a, 15 a-di- (2-tetrahydropyranyloxy) -17 ß-methyl-20 -isopro-

pylidenprost-13 (trans) -enoic acid as an oil.

IR spectrum (liquid film) vmax cm-1: 1746.

NMR spectrum (CC14) ôppm:

0.91 (3H, doublet, J = 6 Hz),

3.68 (3H, singlet),

5.01 (1H, triplet, J = 6 Hz),

5.55 (2H, multiplet).

(2) 280 mg of 9-oxo-l la, 15a-di- (2-tetrahydropyranyloxy) -17β-methyl-20-isopropylidene-prost-13 (trans) -enoic acid methyl ester are prepared in the same manner as in the above example 1- (2) reacted and treated to obtain 71 mg of 9-oxo-1 la, 15a-dihydroxy-17β-methyl-20-isopropylidene-prost-13 (trans) -e .isäu-remethylester as an oil.

IR spectrum (liquid film) vmaxcm-1: 3380.1735.

NMR spectrum (CD3COCD3) ôppm:

0.90 (3H, doublet, J = 6 Hz),

3.67 (3H, singlet),

5.57 (2H, multiplet).

Example 4

9-oxo-l 1 a, l 5a-dihydroxy-l 7β-methyl-20-isopropylidene-prost-5 (ice), 13 (trans) -dietioic acid

(1) 750 mg of 9a-hydroxy-lla, 15a-di- (2-tetrahydropyranyloxy) -17ß-methyl-20-isopropylidenprost-5 (cis), 13 (trans) -dienoic acid are dissolved in 20 ml of acetone, whereupon the resulting solution is stirred at about -13 ° C for 20 minutes after the addition of 1 ml of Jones reagent. When the reaction has ended, the excess reactant is decomposed by adding isopropyl alcohol. The solution is then extracted with ethyl acetate after the addition of water. The extract is washed with water and dried over anhydrous sodium sulfate. Then the solvent is evaporated from the extract, 631 mg of 9-oxo-lla, 15a-di- (2-tetrahydropyranyloxy) -17β-methyl-20-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid as Receives oil.

IR spectrum (liquid film) vmax cm-1: 1745.1710. NMR spectrum (CC14) ôppm:

0.91 (3H, doublet, J = 6 Hz).

(2) 625 mg of 9-oxo-lla, 15a-di- (2-tetrahydropyranyloxy) -17ß-methyl-20-isopropylidene-prostate-5 (cis) is dissolved in a mixture of 15 ml of acetic acid, 15 ml of water and 5 ml of tetrahydrofuran. , 13 (trans) -dienoic acid, whereupon the solution is stirred at 35 ° C. for 4 hours. After the reaction has ended, the reaction mixture is washed with water and dried over anhydrous sodium sulfate. The solvent is evaporated from the extract, leaving 610 mg of residue. This residue is then purified in a column loaded with silica gel, 203 mg of 9-oxo

11 a, 15 a-dihydroxy-17 β-methyl-20-isopropylidene prostate

5 (cis), 13 (trans) -dienoic acid as an oil.

IR spectrum (liquid film) vmax cm "1: 3380.1740.1710.

NMR spectrum (CD3COCD3) ôppm:

0.91 (3H, doublet, J = 6 Hz),

1.59 (3H),

1.65 (3H),

4.11 (2H, multiplet),

5.38 (2H, multiplet),

5.65 (2H, multiplet).

Example 5

9-Oxo-l 1 a, 15β-dihydroxy-l 7ß-methyl-20-isopropylidene-prost-5 (ice), 13 (trans) -dienoic acid

(1) 9a-Hydroxy-11 a, 15β-di- (2-tetrahydropyranyloxy) -5 17ß-methyl-20-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid are prepared in the same manner as in Example 4 - (l) reacted to give 9-oxo-11a, 15β-di- (2-tetrahydropyranyloxy) -17ß-methyl-20-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid as an oil.

io IR spectrum (liquid film) vmax cm-1: 1745.1710. NMR spectrum (CC14) ôppm:

0.91 (3H, doublet, J = 6 Hz).

(2) 9-oxo-l la, 15β-di- (2-tetrahydropyranyloxy) -17ß-methyl-20-isopropylidene-prost-5 (eis), 13 (trans) -dienoic acid is 15 in the same manner as in Example 4- (2) reacted to give 9-oxo-11 a, 15β-dihydroxy-17β-methyl-20-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid as an oil.

IR spectrum (liquid film) v ^ cm "* 1: 3380.1730.1710.

NMR spectrum (CD3COCD3) ôppm:

20 0.91 (3H, doublet, J = 6 Hz),

1.59 (3H, singlet),

1.63 (3H, singlet),

4.15 (2H, multiplet),

5.43 (2H, multiplet),

5.69 (2H, multiplet).

25th

Example 6

9-Oxo-l la, 15a-dihydroxy-l 7ß-methyl-20-isopropylidene-prost-5 (ice), 13 (trans) -dienoic acid methyl ester 30 (1) 751 mg 9a-hydroxy-l la, 15a-di- (2nd -tetrahydropyranyl-oxy) -17ß-methyl-20-isopropylidene-prost-5 (cis), 13 (trans) -diene acid methyl ester are reacted in the same manner as in Example 4- (1), 630 mg of 9-oxo lla, 15a-di- (2-tetrahydropyranyloxy) -17ß-methyl-20-isopropylidene-prost-35 5 (cis), 13 (trans) -dienoic acid methyl ester is obtained as an oil. IR spectrum (liquid film) vmax cm-1: 1745.

NMR spectrum (CC14) ôppm:

0.90 (3H, doublet, J = 6 Hz),

3.67 (3H, singlet).

40 (2) 610 mg of 9-oxo-l la, 15a-di- (2-tetrahydropyranyloxy) -17ß-methyl-20-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid methyl ester are prepared in the same manner as in Example 4 ~ (2), giving 190 mg of 9-oxo-llla, 15a-dihydroxy-17β-methyl-20-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid 45 methyl ester as an oil.

IR spectrum (liquid film) vmax cm-1: 3400.1736. NMR spectrum (CD3COCD3) ôppm:

0.90 (3H, doublet, 6 Hz),

1.58 (3H, singlet),

50 1.60 (3H, singlet),

3.67 (3H, singlet),

5.38 (2H, multiplet),

5.65 (2H, multiplet).

55 Example 7

9-oxo-l la, 15a-dihydroxy-20-isopropylidene-prost-13 (trans) -enoic acid and 9-oxo-l la, 15β-dihydroxy-20-isopropylidene-prost-13 (trans) -enoic acid

(1) 1.01 g of 9β-hydroxy-lla, 15-di- (2-tetrahydropyranyl- "o oxy) -20-isopropylidene-prost-13 (trans) -enoic acid are prepared in the same manner as in Example 1- (1) implemented to obtain 910 mg of 9-oxo-l la, 15-di- (2-tetrahydropyranyloxy) -20-isopropylidenprost-13 (trans) -enoic acid as an oil.

IR spectrum (liquid film) vmax cm-1: 1710,1040,1020. h5 NMR spectrum (CC14) ôppm:

5.54 (2H, multiplet).

(2) 910 mg9-oxo-lla, 15-di- (2-tetrahydropyranyloxy) -20-isopropylidene-prost-13 (trans) -enoic acid are used in the same

621 773

18th

Implemented and treated as in Example 1- (2) above to obtain a crude product. The crude product thus obtained is purified by preparative thin layer chromatography using a mixture of benzene, dioxane and acetic acid (mixing ratio 18: 12: 1) as the developer solvent. In this way, 9-oxo-lla, 15a-dihydroxy-20-isopropyl-i-denprost-13 (trans) -enoic acid is obtained in the form of an oil from the more polar portion and 9-oxo-l la, 15β from the less polar eluates -dihydroxy-20-isopro-pylidenprost-13 (trans) -enoic acid.

15a isomer:

IR spectrum (liquid film) vmax cm-1:

3360.1735.1710.970.

NMR spectrum (CD3COCD3) ôppm:

1.58 (3H, singlet),

1.66 (3H, singlet),

5.58 (2H, multiplet).

15ß isomer:

IR spectrum (liquid film) vmax cm-1:

3370, 1735, 1710, 980.

NMR spectrum (CD3COCD3) ôppm:

1.59 (3H, singlet),

1.66 (3H, singlet),

5.64 (2H, multiplet).

Example 8

9-Oxo-l la, 15a-dihydroxy-20-isopropylidene-prost-5 (ice), 13 (trans) -dienoic acid

(1) 12.9 g9a-hydroxy-lla, 15a-di- (2-tetrahydropyranyloxy) -20-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid are dissolved in 300 ml of acetone. 25 ml of Jones reagent are added to this solution at −20 ° C. The mixture is then stirred at −20 ° C. for 1 hour. When the reaction has ended, the mixture is poured into 2 liters of ice water. Then the mixture is extracted with ether and the extract is dried over anhydrous sodium sulfate. The solvent is distilled off to obtain 10.3 g of an oil. This oil is purified by column chromatography using 100 g of silica gel, 8.41 g of 9-oxo-lla, 15a-di- (2-tetrahydro-pyranyloxy) -20-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid obtained as an oil.

IR spectrum (liquid film) vmax cm-1: 1745, 1710, 1135, 1020, 970.

NMR spectrum (CDC13) ôppm:

4.7 (2H, multiplet),

5.0-5.8 (5H, multiplet).

(2) 8.41 g of 9-oxo-l la, 15a-di- (2-tetrahydropyranyloxy) -20-isopropylidene prost-5 (cis) are dissolved in a mixture of 100 ml of acetic acid, 100 ml of water and 30 ml of tetrahydrofuran. 13 (trans) dienoic acid. This solution is stirred at 40 ° C. for IV2 hours. After the addition of 100 ml of water, the solution is heated to 40 ° C. for 11/1 hours. Then it is diluted with 500 ml of saturated aqueous sodium chloride solution and extracted with a mixture of ethyl acetate and benzene (mixing ratio 1: 1). The extract is washed with an aqueous saturated saline solution and the solvent is distilled off to obtain 6.9 g of an oil. This oil is purified by column chromatography using 100 g of silica gel to obtain 2.8 g of crystals. These crystals are recrystallized from a mixture of ethyl acetate and hexane, 2.1 g of 9-oxo-l la, 15a-dihydroxy-20-iso-propylidenprost-5 (cis), 13 (trans) -dienoic acid in the form of crystals (Melting point 64 to 66 ° C).

IR spectrum (liquid paraffin) vmax cm-1: 3380, 1730, 1705, 1160, 970.

NMR spectrum (CD3COCD3) ôppm:

4.08 (2H, multiplet),

5.17 (1H, triplet),

5.42 (2H, multiplet),

5.68 (2H, multiplet).

Mass spectrum m / e: 392.

Example 9

9-Oxo-I la, l 5ß-dihydroxy-20-isopropylidenprost-5 (eis), 13 (trans) -dienoic acid

(1) If the procedure is the same as in Example 10 8- (l) above, but the 9a-hydroxy-l la, 15a-di- (2-tetra-

hydropyranyloxy) -20-isopropylidene-prost-5 (ice), 13 (trans) -diene-acid by 6.5 g of 9a-hydroxy-lla, 15ß-di- (2-tetrahydropyra-nyloxy) -20-iso-propylidene-prost-5 (cis ), 13 (trans) -dienoic acid, 4.1 g of 9-oxo-lla, 15ß-di- (2-tetrahydropyranyloxy) -15 20-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid are obtained in the form an oil.

IR spectrum (liquid film) vmax cm-1: 1745, 1710, 1135, 1020, 970.

NMR spectrum (CDC13) ôppm:

2ü 4.7 (2H, multiplet),

5.0-5.8 (5H, multiplet).

(2) If the procedure according to Example 8- (2) is followed, but with the replacement of 9-oxo-lla, 15a-di- (2-tetrahydropyra-nyloxy) -20-isopropylidene-prost-5 (cis), 13 (trans ) -dienoic acid

25 by 4.2 g of 9-oxo-lla, 15ß-di- (2-tetrahydropyranyIoxy) -20-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid, 1.2 g of 9-oxo-l are obtained la, 15β-dihydroxy-20-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid as an oil.

IR spectrum (liquid film) vmax cm "1:

30 3380, 1730, 1160, 970.

NMR spectrum (CH3 COCD3) ôppm:

4.07 (2H, multiplet),

5.15 (1H, triplet),

5, 4 (2H, multiplet),

35 5.68 (2H, multiplet).

Mass spectrum m / e: 392.

Example 10

9-Oxo-15a or 15ß-hydroxy-20-isopropylidene-prost-40 13 (trans) -enoic acid methyl ester

(1) 9-Oxo-15- (2-tetrahydropyranyloxy) -2 0-isopropylidene-prost-13 (trans) -enoic acid

2.6 g of 9a-hydroxy-15- (2-tetrahy-dropyranyloxy) -20-isopropylidene-prost-13 (trans) -enoic acid are dissolved in 80 ml of acetone, followed by 45 ml of 5 ml of Jones reagent for oxidation at −20 ° C. stir in down to -10 ° C. It is then stirred at -20 ° C to -10 ° C for a further 30 minutes until the reaction is complete. Then the reaction mixture is diluted with 200 ml of ice water and extracted with ether. The ether extract is washed with water and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, 2.6 g of the desired compound are obtained in the form of an oil.

IR spectrum (liquid film) vmax cm-1: 55 3200, 2750, 1740, 1710, 1200, 1130, 1110, 1020, 970. NMR spectrum (CDC13) ôppm:

5.55 (2H, multiplet),

5.10 (1H, multiplet),

4.70 (1H, multiplet).

60

(2) 9-Oxo-15a or 15β-hydroxy-20-isopropylidene prost-13 (trans) -enoic acid methyl ester

In a 50% aqueous acetic acid solution, 2.6 g of 9-oxo-15- (2-tetrahydropyranyloxy) -20-isopropylidene-prost-e, 5 13 (trans) -enoic acid are dissolved, and the solution is kept at IV for 4 hours Temperature of 50 ° C stirred until the reaction is complete. Then the reaction mixture is diluted with 200 ml of ice water and extracted with ethyl acetate. The

19th

621 773

The extract is washed with water and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, 2.2 g of an oily residue are obtained. An ethereal solution of diazomethane is added to this residue until a yellow color 5 of the added diazomethane remains in the residue. The ether is then evaporated to give 2.23 g of an oily residue. The residue thus obtained is isolated and purified by column chromatography and by thin layer chromatography, whereby 730 mg of the desired 10 15a-hydroxy derivative and 680 mg of the desired 15β-hydroxy derivative are each obtained in the form of an oil.

15a-Hydroxy dérivât:

IR spectrum (liquid film) vmax cm-1:

3480, 1740, 1200, 1170, 970. i5

NMR spectrum (CDC13) ôppm:

3.65 (3H, singlet),

4.10 (1H, multiplet),

5.10 (1H, multiplet),

5.60 (2H, multiplet). ;O

Mass spectrum m / e: 392.

15ß-Hydroxydérivât:

IR spectrum (liquid film) vmax cm-1: 3480.1740,1200,1170,970.

Nuclear Magnetic Resonance Spectrum (CDCI3) ôppm: 25

3.65 (3H, singlet),

4.10 (1H, multiplet),

5.13 (1H, multiplet),

5.60 (2H, multiplet).

Mass spectrum m / e: 392. 30

Example 11

0- oxo-15a-hydroxy-2 O-isopropylidene-prost (13) (trans) -enoic acid In 15 ml of methanol, 730 mg of 9-oxo-15 <x-hydroxy-20-isopropylidene-prostate-13 (trans) -enoic acid methyl ester are dissolved, whereupon 35 after the addition of 10 ml of a 5% aqueous sodium hydroxide solution, the solution obtained is stirred for 2 hours at room temperature. When the reaction has ended, the reaction solution is diluted with 150 ml of ice water. The solution is then neutralized with 7% aqueous hydrochloric acid and then extracted with ethyl acetate. The extract is washed with water and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, 730 mg of an oily residue are obtained. The residue obtained in this way is crystallized from a mixture of ether and n-hexane, 524 mg of the desired compound being obtained in the form of crystals of melting point 40 to 45 ° C. IR spectrum (liquid film) vmax cm-1: 3400, 2670, 1740, 1720, 1460, 1410, 1280, 1220, 1160, 970. 50 NMR spectrum (CD3COCD3) ôppm:

4.08 (IH, multiplet),

5.16 (IH, triplet),

5.64 (2H, multiplet),

6.50 (2H, multiplet). 55

Mass spectrum m / e: 378.

IR spectrum (liquid paraffin) 3400.1735.1580 to 1560.

,cm

Example 12

Potassium 9-oxo-15a-hydroxy-2 O-isopropylidene prost-13 (trans) -enoate 60

150 mg of 9-0xo-15a-hydroxy-20-isopropylidene-prost-13 (trans) -enoic acid are dissolved in a mixture of 8 ml of methanol and 2 ml of water, after which the solution thus obtained is added for 1 hour at room temperature after the addition of 28 mg of potassium carbonate stirs. When the reaction is complete, the solvent is evaporated off under reduced pressure, giving 170 mg of the desired compound in the form of a powder.

Example 13

9-oxo-l 5β-hydroxy-20-isopropylidene prost-l 3 (trans) -enoic acid

680 mg of 9-oxo-l 5β-hydroxy-20-isopropylidene-prost-13 (trans) -enoic acid methyl ester are reacted and treated in the same manner as in Example 11 above to obtain 650 mg of the desired compound in the form of an oil. IR spectrum (liquid film) vmax cm-1: 3400, 2680, 1740, 1720, 1270, 1160, 970.

NMR spectrum (CD3COCD3) ôppm:

4.08 (IH, multiplet),

5.12 (IH, triplet),

5.60 (2H, multiplet).

Mass spectrum m / e: 378.

Example 14

9-Oxo-15a or -β-hydroxy-20-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid methyl ester

(1) 9-Oxo-15- (2-tetrahydropyranyloxy) -2 O-isopropylidene-prost-5 (ice), 13 (trans) -dienoic acid

2.5 g of 9a-hydroxy-15- (2-tetrahydropyranyloxy) -20-isopropylidenprost-5 (cis), 13 (trans) -dienoic acid are reacted and treated in the same manner as in Example 10- (1), whereby the desired compound is obtained as an oil.

IR spectrum (liquid film) vmax cm-1: 3200, 2650, 1740, 1710, 1130, 1015, 970.

(2) 9-Oxo-l5a or -β-hydroxy-20-isopropylidene-prost-5 (ice), l 3 (trans) -dienoic acid methyl ester

2.34 g of 9-oxo-l 5- (2-tetrahydropyranyloxy) -20-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid are reacted in the same manner as in Example 10- and treated, giving 0.70 g of 15a-hydroxy derivative and 0.77 g of 15β-hydroxy derivative as an oil.

15a-hydroxy isomer:

IR spectrum (liquid film) cm-1: 3450.1740.1435,1200,1155,1010,970.

NMR spectrum (CDC13) ôppm:

3.65 (3H, singlet),

4.08 (1H, multiplet),

5.08 (1H, triplet),

5.33 (2H, multiplet),

5.56 (2H, multiplet).

15ß-hydroxyisomer:

IR spectrum (liquid film) vmax cm-1: 3480.1740.1430.1240.1215.1155.970.

NMR spectrum (CDC13) ôppm:

3.65 (3H, singlet),

4.08 (1H, multiplet),

5.10 (1H, multiplet),

5.35 (2H, multiplet),

5.56 (2H, multiplet).

Example 15

9-Oxo-15a-hydroxy-2 O-isopropylidene prost 5 (ice), 13 (trans) -dienoic acid

In 15 ml of methanol, 690 mg of 9-oxo-15cx-hydroxy-20-isopropylidene-prost-5 (ice), 13 (trans) -dienic acid methyl ester are dissolved, after which 15 ml of a 5% strength aqueous sodium hydroxide solution are added Stir solution for 1 hour at room temperature. When the reaction has ended, the reaction solution is diluted with 100 ml of ice water. Then it is neutralized with 7% aqueous hydrochloric acid and extracted with ethyl acetate. The extract is washed with water and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, the oily residue is removed by column chromatography

621773

20th

purified, with 511 mg of the desired compound in

Takes the form of an oil.

IR spectrum (liquid film) vraax cm-1:

3400.2650.1740.1710.1400.1230.1150.1060.960.

Nuclear Magnetic Resonance Spectrum (CD3COCD3) ôppm: 5

4.04 (IH, multiplet),

5.12 (IH, multiplet),

5.32 (2H, multiplet),

5.57 (2H, multiplet).

Mass spectrum m / e: 376. io

Example 16

9-Oxo-15β-hydroxy-2 0-isopropylidene prost-5 (cis), 13 (trans) -dienoic acid

765 mg of 9-0xo-15β-hydroxy-20-isopropylidene-prost-5 (cis), 15 13 (trans) -dienoic acid methyl ester are reacted and treated in the same manner as in Example 15 above, giving 667 mg of the desired compound in the form of an oil receives. IR spectrum (liquid film) vmax cm-1:

3400.2650.1740.1710.1400, 1230, 1150, 1000.960. 20th

NMR spectrum (CD3COCD3) ôppm:

4.03 (IH, multiplet),

5.10 (IH, multiplet),

5.36 (2H, multiplet),

5.60 (2H, multiplet). 2s

Mass spectrum m / e: 376.

The starting compounds can be obtained according to the examples below:

Example A 30

9ß-hydroxy-lla, 15a- or -15ß-di- (2-tetrahydropyranyloxy) -17ß-methyl-20-isopropylidene-prostate-13 (trans) -enoic acid (II)

(1) 7 a-acetoxy-2ß-methoxycarbonyl-3a- (6-ethoxycarbononylhexyl) -4a (1,1'-ethylenedithioethyl) cyclopentane (VI)

22.14 g of la-acetoxy-2β-3s methoxycarbonyl-3a- (6-ethoxycarbonylhexyl) -4a-acetylcyclopentane (V) are dissolved in 50 ml of dichloromethane. This solution is mixed with ice-cooling with 80 ml of ethylene dithioglycol and 16 ml of a bread rifluoride-ethyl ether complex and the mixture is stirred for 1 hour. When the reaction is complete, ice water is added to the reaction mixture and the mixture obtained is extracted with ether. The extract is washed successively with water, an aqueous potassium hydrogen carbonate solution and water and dried over anhydrous sodium sulfate. After drying, the solvent is evaporated, leaving a gummy product. This product is then purified in a column containing silica gel, the developer used being a mixture of benzene and a 5% ethyl acetate-containing benzene solution. The eluates are combined and evaporated to remove the solvent, leaving 23.0 g of the desired compound in the form of an oil.

IR spectrum (liquid film) vmax cm-1: 1738.

NMR spectrum (CDC13) ôppm:

1.23 (3H, triplet), 55

1.78 (3H, singlet),

2.02 (3H, singlet),

3.70 (3H, singlet).

(2) 1 a-Hydroxy-2ß-methoxycarbonyl-3 a ~ (6-methoxycarbonylhexyl) -4a- (l, 1'-ethylenedithioethyl) -cyclopentane (VI) 6o

In 250 ml of methanol, 23.0 g of la-acetoxy-2ß-meth-oxycarbonyl-3a- (6-ethoxycarbonylhexyl) -4a- (1,1'-ethylenediothioethyl) cyclopentane and 10 g of potassium carbonate are dissolved, followed by the solution is stirred for 2 hours at room temperature. After the reaction has ended, the reaction mixture is extracted with ether after the addition of aqueous acetic acid. The extract is washed with water and dried over anhydrous sodium sulfate. After drying it will

Solvent evaporates, leaving a rubbery product. This product is purified in a column loaded with silica gel and developed with a mixture of benzene and a benzene solution containing 30% ethyl acetate. The eluates are combined and evaporated to remove the solvent. In this way, 20.4 g of the desired compound are obtained in the form of an oil.

IR spectrum (liquid film) vmax cm-1: 1730.3450. NMR spectrum (CDCI3) Ôppm:

3.66 (3H, singlet),

3.70 (3H, singlet).

(3) la- (2-tetrahydropyranyloxy) -2ß-methoxycarbonyl-3a- (6-methoxycarbonylhexyl) -4a (1,1'-ethylenedithioethyl) cyclopentane (VI)

20.4 g of la-hydroxy-2β-methoxy-carbonyl-3a- (6-methoxycarbonylhexyl) -4a- (l, l'-ethylenediothioethyl) cyclopentane is dissolved in 120 ml of benzene. 70 ml of dihydropyran and a catalytic amount of picric acid are added to this solution while cooling with ice, and the mixture is stirred for 15 minutes. After the reaction has ended, the solvent is evaporated from the reaction mixture, leaving a rubber-like product. This product is purified on a column with neutral aluminum oxide (Woelm Co. product fineness II 350 g) and developed with a hexane solution containing 10% benzene and a benzene solution containing 5% ethyl acetate. The eluates are combined and evaporated to remove the solvent, containing 21.44 g of the desired compound in the form of an oil.

IR spectrum (liquid film) vmax cm-1: 1030.1730. NMR spectrum (CC14) <5ppm:

3.60 (3H, singlet),

3.65 (3H, singlet).

(4) la- (2-tetrahydropyranyloxy) -2ß-methoxycarbonyl-3a- (6-carboxyhexyl) -4a- (l-ethylenedithioethyl) cyclopentane (VII)

In 200 ml of a 30% aqueous methanol solution containing 5% potassium carbonate, 3.4 g of la- (2-tetrahydro-pyranyloxy) -2ß-methoxycarbonyl-3a- (6-methoxycarbonylhe-xyl) -4a- (l , l'-ethylenedithioethyl) cyclopentane, whereupon the solution is stirred for 4 hours and 40 minutes at room temperature. When the reaction has ended, the water is added to the reaction mixture and the mixture obtained is extracted with hexane. The aqueous part is then acidified with acetic acid and extracted with ether. The extract is washed with water and dried over anhydrous sodium sulfate. After drying, the solvent is evaporated from the extract, whereupon 2.4 g of the desired compound remain in the form of an oil.

IR spectrum (liquid film) vmax cm-1: 1710.1730. NMR spectrum (CC14) ôppm:

3.70 (3H, multiplet).

(5) la- (2-tetrahydropyranyloxy) -2ß-hydroxymethyl-3a- (6-methoxycarbonylhexyl) -4a- (1,1 '-ethylenedithioethyl) -cyclopen-tan (VIII)

The potassium salt of the starting material, which is obtained from 2.7 g of la- (2-tetrahydropyranyloxy) -2ß-methoxycarbonyl-3a- (6-carbonylhexyl) -4a- (l, l'-ethylenedithioethyI) cyclopentane and 1.3 g of potassium hydrogen carbonate received is dissolved in 200 ml of anhydrous tetrahydrofuran. This solution is then added dropwise at room temperature with 3.2 g of lithium borohydride. After the addition has ended, the reaction mixture is stirred at room temperature for 15 hours and then stirred at reflux temperature for 5 1/2 hours. When the reaction has ended, the reaction mixture is poured into ice water, acidified with dilute hydrochloric acid and acetic acid and extracted with ether. The extract is washed with water and over anhydrous sodium sulfate

21st

621 773

dried. The extract is then subjected to an esterification reaction using diazomethane. When the reaction is complete, the solvent is evaporated, leaving a residue. The residue thus obtained is purified on a column of 41 g of neutral aluminum oxide j (Woelm Co. product fineness III), using benzene and a benzene solution containing 3% ethyl acetate for the elution. The combined eluates are evaporated to remove the solvent, leaving 1.58 g of the desired compound as an oil. 10th

IR spectrum (liquid film) vmaxcm "': 1735.3460. NMR spectrum (CC14) ôppm:

1.75 (3H, singlet),

3.59 (3H, singlet).

(6) la- (2-tetrahydropyranyloxy) -2ß-hydroxymethyl-3a- (6-15 methoxycarbonylhexyl) -4a-acetylcyclopentane (IX)

In 300 ml of a 15% aqueous tetrahydrofuran solution, 14.0 g of mercury (II) oxide and 9.2 g of a boron trifluoride / ethyl ether complex are suspended. 5.0 g of la- (2-tetrahydropyranyl-20 oxy) -2β-hydroxymethyl-3a- (6-methoxycarbonylhexyl) -4a- (1,1'-ethylenedithioethyl) -cyclopentane are stirred into this suspension while cooling with ice the mixture continues to stir for 25 minutes. When the reaction is complete, the reaction mixture is mixed with ether and filtered. The filtrate is washed with an aqueous sodium hydrogen carbonate solution and then with water and then dried over anhydrous sodium sulfate.

Then the solvent is evaporated from the extract,

leaving a backlog. This residue is eluted in a column charged with 100 g of aluminum oxide using benzene and a benzene solution containing 1 to 40% ethyl acetate. The eluates are combined and evaporated to remove the solvent to give 3.421 g of the desired compound in the form of an oil. IR spectrum (liquid film) vmax cm-1: 35

1705.1738.3450.

NMR spectrum (CCI4) ôppm:

1.12 (3H, singlet),

3.62 (3H, singlet).

40

(7) la- (2-tetrahydropyranyloxy) -2ß-hydroxymethyl-3a- (6-methoxycarbonylhexyl) -4ß-acetylcyclopentane (IX)

In 300 ml of an aqueous 50% methanol solution containing 2.5% potassium carbonate, 3.421 g of la- (2-tetrahy-dropyranyloxy) -2ß-hydroxymethyl-3cx- (6-methoxycarbonylhe- 45 xyl) -4a-acetylcyclopentane is dissolved which according to example A- (6)

has been obtained. Then this solution is stirred for 2 V2 hours at 50 ° C. When the reaction has ended, the methanol is evaporated from the reaction mixture. The remaining solution is extracted with 50 ethyl acetate after acidification with acetic acid. The extract is dried over anhydrous sodium sulfate and evaporated to remove the solvent. The residue thus obtained is purified in a column charged with 30 g of aluminum oxide (Woelm Co. product fineness III) and eluted using benzene 5J and a benzene solution containing 1 to 40% ethyl acetate. The eluates are combined and evaporated to remove the solvent to give 3.40 g of the desired compound in the form of an oil.

IR spectrum (liquid film) vmax cm-1: h0

1705, 1738, 3460.

NMR spectrum (CDC13) ôppm:

1.14 (3H, singlet),

3.62 (3H, singlet).

(8) la- (2-tetrahydropyranyloxy) -2ß-hydroxymethyl-3a- (6 - ,, 5 methoxycarbonylhexyl) -4ß-acetoxycyclopentane (X)

3.2 g of la- (2-tetrahydro-pyranyloxy) -2ß-hydroxymethyl-3a- (6-methoxycarbonylhexyl) - are dissolved in 70 ml of dichloromethane.

4β-acetylcyclopentane. 5.3 g of solid sodium hydrogen carbonate and 5.3 g of m-chloroperbenzoic acid are added to this solution, and the mixture is stirred at room temperature for 15 hours. When the reaction has ended, the reaction mixture is treated in the same manner as in Example A- (I) above, giving 1.658 g of the desired compound in the form of an oil.

(cm_1: 1740.3470.

IR spectrum (liquid film) v "

NMR spectrum (CC14) ôppm:

1.98 (3H, singlet),

3.62 (3H, singlet).

(9) la- (2-tetrahydropyranyloxy) -2ß-formyl-3a- (6-meth-oxycarbonylhexyl) -4ß-acetoxycyclopentane (XI)

In 300 ml of dichloromethane, 1.53 g of la- (2-tetrahy-dropyranyloxy) -2ß-hydroxymethyl-3a- (6-methoxycarbonylhe-xyl) -4ß-acetoxycyclopentane is dissolved. This solution is mixed with 17 g of a chromic anhydride-pyridine complex and the mixture is stirred for 15 minutes while cooling with ice. After the reaction has ended, ether and cooled dilute hydrochloric acid are added in succession. The ethereal part is washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. After drying, the reaction mixture is evaporated to remove the solvent, giving 1.63 g of the desired compound in the form of an oil. IR spectrum (liquid film) vmax cm-1: 1740, 2700. NMR spectrum (CDC13) ôppm:

1.93 (3H, singlet),

3.58 (3H, singlet),

9.69 (1H, broad doublet).

(10) 2-Oxo-4,8-dimethyl-7-noneylphosphoric acid dimethyl ester

41 ml of a hexane solution containing 15.1% n-butyllithium are stirred dropwise at -60 ° C in an argon atmosphere in 80 ml of a tetrahydrofuran solution containing 10.2 g of dimethyl methylphosphonate to obtain the dimethylmethylphosphonate carbanion. The carbanion thus obtained is added dropwise with 30 ml of a tetrahydrofuran solution containing 7.227 g of methyl 3,7-dimethyl-6-octenate at a temperature of less than

- 50 ° C added. The mixture thus obtained is then at a temperature of 3 hours and 10 minutes

- 50 ° C to - 60 ° C, whereupon you continue to stir after removing the cooling bath until the internal temperature has reached 0 ° C. When the reaction has ended, acetic acid and water are added to the reaction mixture in succession and the mixture is extracted with ether. The extract is washed with water, dried over anhydrous sodium sulfate and evaporated to remove the solvent. The remaining solution is at 124 to

Distilled 127 ° C / 0.1 mm Hg to obtain 4.858 g of the desired compound in the form of an oil.

IR spectrum (liquid film) vmax cm-1: 1715.

NMR spectrum (CC14) ôppm:

0.90 (3H, doublet, J = 6 Hz),

1.57 (3H, singlet),

1.64 (3H, singlet),

2.89 (2H, doublet, J = 23 Hz),

3.66 (6H, doublet, J = 11 Hz),

4.96 (1H, triplet, J = 7 Hz).

(11) 9ß-Acetoxy-lla- (2-tetrahydropyranyloxy) -15-oxo-17ß-methyl-20-isopropylidene-prost-13 (trans) -enoic acid methyl ester (XII)

292 mg of 52.9% oily sodium hydride are washed with dry petroleum ether to remove the oil and then suspended in 20 ml of dimethoxyethane. Into this suspension are added dropwise with ice cooling in an argon atmosphere

621773

22

1.85 g of 2-oxo-4,8-dimethyl-7-nonenylphosphonic acid dimethyl ester stirred in 20 ml of dimethoxyethane. After stirring for a further 2 hours, 10 ml of dimethoxyethane are added. 2.35 g of la- (2-tetrahydropyranyloxy) -2ß-formyl-3a- (6-methoxycarbonylhexyl) -4ß-acetoxycyclopentane in 30 ml of dimethoxyethane are then added dropwise to this solution, while cooling with ice, and the mixture is stirred for 25 minutes. When the reaction has ended, acetic acid and an excess amount of ether are added to the reaction mixture in succession. Then the organic solvent part is washed with water and dried over anhydrous sodium sulfate. The solvent is evaporated to give 4.08 g of a residue. The residue thus obtained is purified on a column charged with aluminum oxide, whereby 2.018 g of the desired compound are obtained in the form of an oil.

IR spectrum (liquid film) vmax cm-1:

1740.1695.1670.1630.1035.1025.

NMR spectrum (CC14) ôppm:

0.90 (3H, doublet, J = 6 Hz),

1.60 (3H, singlet),

1.64 (3H, singlet),

1.98 (3H, singlet),

3.59 (3H, singlet),

4.90 (2H, multiplet),

6.31 (2H, multiplet).

(12) 9ß-acetoxy-l 1 a- (2-tetrahydropyranyloxy) -15-hydroxy-17ß-methyl-20-isopropylidene-prostate-13 (trans) -enoic acid methyl ester (XIII)

1.5 g of sodium borohydride in small amounts with ice cooling to 2.025 g of 9ß-acetoxy-11 a- (2-tetrahydropyranyIoxy) -15-oxo-17ß-methyl-20-isopropylidenprost-13 (trans) -enoic acid methyl ester in 50 ml anhydrous methanol was added and the mixture was stirred for 20 minutes. When the reaction is complete, acetic acid is added to decompose the excess sodium borohydride. Then the mixture is extracted with ethyl acetate after the addition of water. The extract is washed with water and dried over anhydrous sodium sulfate. The solvent is then evaporated from the extract, giving 2.2 g of a residue. The residue thus obtained is then purified over a column loaded with silica gel, giving 1.989 g of the desired compound in the form of an oil. IR spectrum (liquid film vmax cm-1: 3480.1740. NMR spectrum (CC14) ôppm:

0.91 (3H, doublet, J = 6 Hz),

1.57 (3H, singlet),

1.64 (3H, singlet),

1.95 (3H, singlet),

3.60 (3H, singlet,

5.49 (2H, multiplet).

(13) 9ß-acetoxy-l la, 15a- or -15ß-dihydroxy-l 7ß-methyl-20-isopropylidenprost-13 (trans) -enoic acid methyl ester (XIII)

In a mixture of 40 ml of acetic acid, 17 ml of water and 8 ml of tetrahydrofuran, 1.987 g of 9β-acetoxy-lla- (2-tetrahy dropyranyloxy) -15 -hydroxy-17β-methyl-20-isopropylidene-prostate-13 (trans) is dissolved. -enoic acid methyl ester, whereupon the solution is stirred at about 35 ° C. for 4 1/2 hours. When the reaction is complete, water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is washed with water and dried over anhydrous sodium sulfate. The solvent is evaporated from the extract, leaving 2.11 g of a residue. The residue thus obtained is purified over a column charged with silica gel. Elution with a benzene solution containing 15 to 20% ethyl acetate gives 418 mg of the 15β-

Hydroxyisomers of the desired compound. Elution with a benzene solution containing 20 to 30% ethyl acetate gives 419 mg of a mixture of the isomers in the 15-position. Further elution with a benzene solution containing 30 to 80% ethyl 5-acetate gives 326 mg of the 15a-hydroxyisomer of the desired compound.

15a-hydroxy isomer:

IR spectrum (liquid film) vmaxcm-1: 3380.1735. NMR spectrum (CDC13) ôppm:

io 0.91 (3H, doublet, J = 6 Hz),

1.57 (3H, singlet),

1.64 (3H, singlet),

3.60 (3H, singlet),

4.95 (2H, multiplet),

15 5.45 (2H, multiplet).

15ß-hydroxy isomer:

IR spectrum (liquid film) vmax cm-1: 3430.1735. NMR spectrum (CDC13) ôppm:

1.57 (3H, singlet),

20 1.68 (3H, singlet),

1.98 (3H, singlet),

3.63 (3H, singlet),

4.92 (2H, multiplet),

5.58 (2H, multiplet).

25 (14) 9β-acetoxy-lla, 15a-di- (2-tetrahydropyranyloxy) -17ß-methyl-20-isopropylidene-prostate-13 (trans) -enoic acid methyl ester (XIV)

5 ml of dihydropyran are added at room temperature to 510 mg of 9β-acetoxy-lla, 15a-dihydroxy-17ß-methyl-20-iso-30 propylidenprost-13 (trans) -enoic acid methyl ester. The mixture thus obtained is then left under ice cooling for 2½ hours after the addition of a catalytic amount of picric acid. When the reaction has ended, the reaction mixture is purified directly in a column charged with aluminum oxide, giving 1.491 g of the desired compound in the form of a crude oil.

IR spectrum (liquid film) vmax cm-1: 1735,1030,1020. NMR spectrum (CC14) ôppm:

0.91 (3H, doublet, J = 6 Hz),

40 1.93 (3H, singlet),

3.57 (3H, singlet),

5.43 (2H, multiplet).

(15) 9β-acetoxy-1 la, 15ß-di- (2-tetrahydropyranyloxy) -17ß-methyl-20-isopropylidene-prostate-13 (trans) -enoic acid methyl ester (XIV)

555 mg of 9β-acetoxy-lla, 15β-dihydroxy-17ß-methyl-20-isopropylidene-prost-13 (trans) -enoic acid methyl ester are reacted and treated in the same manner as in Example A- (14) above, giving 1.30 g a crude product of the desired 50 compound.

IR spectrum (liquid film) vmax cm-1: 1735,1030,1015. NMR spectrum (CC14) ôppm:

0.89 (3H, doublet, J = 6 Hz),

1.98 (3H, singlet),

55 3.58 (3H, singlet),

5.41 (2H, multiplet).

(16) 9β-hydroxy-lla, 15a-di- (2-tetrahydropyranyloxy) -17ß-methyl-20-isopropylidene-prost-13 (trans) -enoic acid (II)

60 In a solution of 15 ml of water and 35 ml of methanol, which contains 1.5 g of potassium hydroxide, 1.491 g of crude 9β-acetoxy-11 al 5 a-di- (2-tetrahydropyranyloxy) -17 ß-methyl-20-isopropylidene cheers Suspended -13 (trans) -enoic acid methyl ester and this suspension was stirred vigorously at room temperature 65, with intermittent heating. After 17 hours and 45 minutes have elapsed, water is added to the reaction mixture. The resulting mixture is then extracted with a hexane solution containing 50% ether to make up the

45

23

621 773

to remove neutral materials, after which the aqueous part is extracted with ethyl acetate after acidification with acetic acid. The extract is washed with water and dried over anhydrous sodium sulfate. The solvent is then removed from the extract by evaporation, whereby; 766 mg of the desired compound is obtained as an oil. IR spectrum (liquid film) vmax cm-1: 3400.1710. NMR spectrum (CCI4) ôppm:

0.91 (3H, doublet, J = 6 Hz),

5.03 (1H, triplet, J = 6 Hz), ok

5.47 (2H, multiplet).

(17) 9β-hydroxy-1 la, 15ß-di- (2-tetrahydropyranyloxy) -I7ß-methyl-20-isopropylidene-prostate-13 (trans) -enoic acid (II)

1.3 g of crude 9β-acetoxy-lia, 15ß-di- (2-tetrahydropyranyl-oxy) -17ß-methyl-20-isopropylidene-prostate-13 (trans) -enoic acid 15-methyl ester are prepared in the same manner as in Example A above - (16) reacted and treated to give 764 mg of the desired compound in the form of an oil.

IR spectrum (liquid film) vraax cm "1: 3400.1710. NMR spectrum (CC14) ôppm: 20

0.84 (3H, doublet, J = 6 Hz),

4.98 (IH, triplet, J = 6 Hz),

5.38 (2H, multiplet).

Example B 25

9ß-Hydroxy-lla, 15a-di- (2-tetrahydropyranyloxy) -17ß-methyl-20-isopropylidenprost-l 3 (trans) -enoic acid methyl ester (II) diazomethane in ether is mixed with 125 mg of 9ß-hydroxy-11a, 15a-di - (2-tetrahydropyranyloxy) -17ß-methyl-20-isopro-pylidenprost-13 (trans) -enoic acid in 5 ml ether until the reaction mixture has turned pale yellow. When the reaction is complete, the solvent is evaporated under reduced pressure to give 127 mg of the desired compound in the form of an oil.

IR spectrum (liquid film) vmax cm-1: 3400.1730.

35

Example C

9a-Hydroxy-lla, 15a or 15β-di- (2-tetrahydropyranyloxy) -17ß-methyl-20-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid

(II) 40

(1) 3-Oxo-6-syn- (3-oxo-5,9-dimethyldeca-1,8-dienyl) -7-anti-acetoxy-2-oxabicyclo [3,3,0] octane (XVII )

321 mg of 52.9% oily sodium hydride are washed with dry petroleum ether to remove the oil, followed by suspension in 20 ml of dimethoxyethane. The solution thus obtained is added dropwise with ice cooling in the presence of an argon atmosphere in 20 ml of a dimethoxyethane solution which contains 2.035 g of 2-oxo-4,8-dimethyl-7-nonenylphosphonic acid di-methyl ester, which is obtained according to Example A- (10), stirred in. After stirring for 3 hours, a further 10 ml of dimethoxyethane are added. Then this solution is added dropwise with ice cooling with 1.35 g of 3-oxo-6-syn-formyl-7-anti-acetoxy-2-oxabicyclo [3,3,0] octane (XVI) in 30 ml of dimethoxyethane and the mixture was stirred for a further 2 hours. After the reaction has ended, acetic acid and ether are added in succession. The organic solvent portion is then washed with water, dried over anhydrous sodium sulfate and evaporated to remove the solvent. The residue thus obtained is purified in a column charged with silica gel, giving 60 1.69 g of the desired compound in the form of an oil. IR spectrum (liquid film) vmax cm-1: 1770.1740.1695.1670.1630.

NMR spectrum (CDC13) ôppm:

0.90 (3H, doublet, J = 6 Hz), "5

1.61 (3H, singlet),

1.65 (3H, singlet),

2.03 (3H, singlet).

(2) 3-oxo-6-syn- (3a- or -3ß-hydroxy-5,9-dimethyl-deca-1,8-dienyl) -7-anti-acetoxy-2-oxabicyclo- [3,3, 0] octane (XVIII)

0.8 ml of a 0.55 molar zinc borohydride dimethoxy methane solution is converted into 270 mg of 3-oxo-6-syn- (3-oxo-5,9-dimethyl-deca-1,8-dienyl) -7-anti under ice cooling -acetoxy-2-oxabicyclo [3,3,0] octane in 4 ml of dimethoxyethane was added and the mixture was stirred for 1 hour. When the reaction is complete, acetic acid is added to the reaction mixture to decompose the excess reactant, and the mixture is extracted with ethyl acetate after adding water. The extract is washed with water, dried over anhydrous sodium sulfate and evaporated to remove the solvent. The resulting residue is subjected to preparative thin layer chromatography and purified by developing with ether. This gives 89 mg of the 3a isomer of the desired compound from the less polar portion and 80 mg of the 3β isomer of the desired compound from the more polar portion.

3 a-hydroxy isomer:

IR spectrum (liquid film) vmax cm-1: 3500.1780. NMR spectrum (CDC13) ôppm:

0.91 (3H, doublet, J = 6 Hz),

1.58 (3H, singlet),

1.65 (3H, singlet),

5.51 (2H, multiplet).

3 ß-hydroxy isomer:

IR spectrum (liquid film) vmax cm-1: 3500.1780. NMR spectrum (CDC13) ôppm:

0.90 (3H, doublet, J = 6 Hz),

1.57 (3H, singlet),

1.64 (3H, singlet),

5.51 (2H, multiplet).

(3) 3-oxo-6-syn-3a-hydroxy-5,9-dimethyl-deca-1,8-di-enyl) -7-anti-hydroxy-2-oxabicyclo- [3,3,0] - octane (XVIII)

In 2 ml of anhydrous methanol, 120 mg of 3-oxo-6-syn- (3a-hydroxy-5,9-dimethyl-deca-1,8-dienyl) -7-anti-acet-oxy-2-oxabicyclo- [ 3,3,0] -octane, whereupon the solution is stirred for 20 minutes after the addition of 65 mg of anhydrous potassium carbonate. After the reaction has ended, acetic acid and water are added in succession, and the mixture is extracted with ethyl acetate. The extract is washed with water and dried over anhydrous sodium sulfate. The solvent is removed from the extract by evaporation, leaving 93 mg of the desired compound in the form of an oil.

IR spectrum (liquid film) vmax cm-1: 1770.

NMR spectrum (CDC13) ôppm:

0.91 (3H, doublet, J = 6 Hz),

1.58 (3H, singlet),

1.68 (3H, singlet),

5.54 (2H, multiplet).

(4) oxo-6-syn-3ß-hydroxy-5,9-dimethyl-deca-1,8-di-enyl) -7-anti-hydroxy-2-oxabicyclo (3,3,0] octane ( XVIII)

3-Oxo-6-syn- (3ß-hydroxy-5,9-dimethyl-deca-1,8-dienyl) -7-anti-acetoxy-2-oxabicyclo [3,3,0] octane is used in the reacted and treated in the same manner as in Example C- (3), whereby the desired compound is obtained as an oil.

IR spectrum (liquid film) vmax cm-1: 1770.

NMR spectrum (CDC13) ôppm:

0.90 (3H, doublet, J = 6 Hz),

1.57 (3H, singlet),

1.68 (3H, singlet),

5.54 (2H, multiplet).

(5) 3-Oxo-6-syn- [3a- (2-tetrahydropyranyloxy) -5,9-dimethyl-deca-1,8-dienyl] -7-anti- (2-tetrahydropyranyloxy) -2-oxabi -cyclo- [3,3,0J-octane (XIX)

150 mg 3-oxo-6-syn- (3a-hydroxy-5,9-dimethyl-deca-l, 8-

621773

24th

dienyl) -7-antihydroxy-2-oxabicyclo [3,3,0] octane are reacted and treated in the same manner as in Example A- (14) to obtain 301 mg of the desired compound as a crude product.

IR spectrum (liquid film) vmax cm-1: 1770.1030. 5

NMR spectrum (CDC13) ôppm:

0.91 (3H, doublet, J = 6 Hz).

(6) 3-Oxo-6-syn- [3ß- (2-tetrahydropyranyloxy) -5,9-dimethyl-deca-1,8-dienyl] -7-anti- (2-tetrahydropyranyloxy) -2-oxabi-cyclo - [3,3,0] octane (XIX) 10

3-Oxo-6-syn- (3ß-hydroxy-5,9-dimethyl-deca-1,8-dienyl) -7-anti-hydroxy-2-oxabicyclo [3,3,0] octane is used in the reacted and treated in the same manner as in Example A- (14), whereby the desired compound was obtained as a crude product.

15

IR spectrum (liquid film) vmax cm-1: 1770.1025. NMR spectrum (CDC13) ôppm:

0.90 (3H, doublet, J = 6 Hz).

(7) 3-Hydroxy-6-syn- [3a- (2-tetrahydropyranyloxy) -5,9-dimethyl-deca-1,8-dienyl] -7-anti- (2-tetrahydropyranyloxy) -2-20 oxabicyclo- [3,3,0] octane (XX)

190 mg of 3-oxo-6-syn- [3a- (2-tetra-hydropyranyloxy) -5,9-dimethyl-deca-1,8-dienyl] -7-anti- (2-tetrahydropyranyloxy) is dissolved in 5 ml of toluene ) -2-ocabicyclo- [3,3,0] octane, whereupon the solution is cooled to -60 ° C. 190 mg of 2s diisobutylaluminum hydride in 1 ml of toluene are stirred into this solution and the mixture is stirred for 30 minutes. When the reaction has ended, 1 ml of methanol and water are added to the reaction mixture, and the mixture is then extracted with ethyl acetate. The extract is washed with water and dried over anhydrous sodium sulfate. The solvent is evaporated from the extract, leaving 170 mg of the desired compound in the form of an oil.

IR spectrum (liquid film) vraaxcm_1: 3420.1030. Nuclear Magnetic Resonance Spectrum (CDC13) ôppm: 35

0.91 (3H, doublet, J = 6 Hz).

(8) 3-Hydroxy-6-syn- [3ß- (2-tetrahydropyranyloxy) -5,9-dimethyl-deca-1,8-dienyl] -7-anti- (2-tetrahydropyranyloxy) -2-oxabicyclo- [ 3,3,0] octane (XX)

3-oxo-6-syn- [3ß- (2-tetrahydropyranyloxy) -5,9-dimethyl-40 deca-1,8-dienyl] -7-anti- (2-tetrahydropyranyloxy) -2-oxabicyclo [ 3,3,0] octane is reacted and treated in the same manner as in Example C- (7) to obtain the desired compound as an oil.

IR spectrum (liquid film) vmax cm-1: 3410.1030. 45

NMR spectrum (CDC13) ôppm:

0.90 (3H, doublet, J = 6 Hz).

(9) 9a-hydroxy-lla, 15a-di- (2-tetrahydropyranyloxy) -17ß-methyl-20-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid (II)

624 mg of triphenylcarboxybutylphosphonium bromidine 2 ml of 50 dimethylsulfoxide are stirred dropwise at a temperature of −20 ° C. in an argon atmosphere in 1.3 ml of 2 molar sodium methylsulfinylcarbanion in dimethylsulfoxide to obtain a ylide solution with a red color. This solution is then treated with 220 mg of 3-hydroxy-6-55 syn- [3a- (2-tetrahydropyranyloxy) -5,9-dimethyl-deca-1,8-die-nyl] -7-anti- (2-tetrahydropyranyloxy ) -2-oxabicyclo- [3,3,0] octane in 5 ml of dimethyl sulfoxide and the mixture was stirred for 20 hours at room temperature. When the reaction has ended, the dimethyl sulfoxide is evaporated under reduced pressure, leaving a residue. An aqueous sodium hydrogen carbonate solution is added to this residue and the mixture is then washed with ethyl acetate in order to remove the neutral constituents. The aqueous part is adjusted to a pH of approximately 3 by adding oxalic acid and then extracted with a mixture of hexane and ether (mixing ratio 1: 1). The extract is washed with water and anhydrous

Dried sodium sulfate. The solvent is evaporated from the extract to give 198 mg of the desired compound in the form of an oil.

IR spectrum (liquid film) vmax cm-1: 3400.1708. NMR spectrum (CC14) ôppm:

0.91 (3H, doublet, J = 6 Hz),

5.01 (1H, triplet, J = 6 Hz).

(10) 9a-Hydroxy-lla, 15β-di- (2-tetrahydropyranyloxy) -17ß-methyl-2 0-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid

(II)

3-hydroxy-6-syn- [3ß- (2-tetrahydropyranyloxy) -5,9-dimethyl-deca-1,8-dienyl] -7-anti- (2-tetrahydropyranyloxy) -2-oxa-bicyclo- [3,3,0] octane is reacted and treated in the same manner as in Example C- (9) to obtain the desired compound as an oil.

IR spectrum (liquid film) vmax cm-1: 3400.1710. NMR spectrum (CC14) ôppm:

0.91 (3H, doublet, J = 6 Hz),

5.02 (1H, triplet, J = 6 Hz).

Example D

9a-hydroxy-lla, 15a-di- (2-tetrahydropyranyloxy) -l 7ß-methyl-20-isopropylidene-prost-5- (cis), 13 (trans) -dienoic acid methyl ester (II)

An ethereal solution of diazomethane is 730 mg 9ct-hydroxy-1 la, 15a-di- (2-tetrahydropyranyloxy) - 17ß-methyl-20-isopropylidene-prost-5 (ice), 13 (trans) -dienoic acid in 5 ml ether added until the reaction mixture turned pale yellow. When the reaction is complete, the solvent is evaporated under reduced pressure to give 728 mg of the desired compound in the form of an oil.

IR spectrum (liquid film) vmax cm-1: 3400.1730. NMR spectrum (CC14) ôppm:

0.91 (3H, doublet, J = 6 Hz),

5.01 (1H, triplet, J = 6 Hz).

Example E

9β-Hydroxy-l la, l 5-di- (2-tetrahydropyranyloxy) -20-isopropyl-lidenprost-13 (trans) -enoic acid

(1) 9ß-acetoxy-lla- (2-tetrahydropyranyloxy) -l5-OXO-20-isopropylidene-prost-13 (trans) -enoic acid (XII)

117.4 mg of 52.9% oily sodium hydride, 1 g of 2-oxo-8-methyl-7-nonenylphosphonic acid dimethyl ester, which was obtained according to the instructions in Example A- (10), and 680 mg of la- (2-tetrahydropyranyloxy) -2ß-formyl-3a- (6-meth-oxycarbonylhexyl) -4ß-acetoxycyclopentane are reacted and treated in the manner described in Example A- (II) to give 898 mg of the desired compound as an oil. IR spectrum (liquid film) vmax cm-1: 1735,1695,1670,1625,1035.

NMR spectrum (CC14) ôppm:

1.48 (3H, singlet,

1.58 (3H, singlet),

1.87 (3H, singlet),

3.48 (3H, singlet),

6.22 (2H, multiplet).

(2) 9ß-acetoxy-lla- (2-tetrahydropyranyloxy) -! 5-hydroxy-2O-isopropylidenprost-13 (trans) -enoic acid methyl ester (XIII)

898 mg of 9β-acetoxy-l la- (2-tetrahydropyranyloxy) -15-oxo-20-isopropylidene-prost-13 (trans) -enoic acid methyl ester are reacted and treated in the same manner as in Example A- (12), giving 851 mg receives the desired compound as an oil.

IR spectrum (liquid film) vmaxcm_1: 3420.1735.

(3) 9β-acetoxy-1 la, l5-di- (2-tetrahydropyranyloxy) -20-isopropylidene-prost-13 (trans) -enoic acid methyl ester (XIV)

25th

621773

851 mg of 9β-acetoxy-lla- (2-tetrahydropyranyloxy) -15-hydroxy-20-isopropylidene-prost-13 (trans) -enoic acid methyl ester are reacted and treated in the same manner as in Example A- (14), giving 1.55 g of the desired compound is obtained in the crude state. 5

(4) 9β-hydroxy-lla, l5-di- (2-tetrahydropyranyloxy) -20-isopropylidene prost-13 (trans) -enoic acid (II)

1.55 g of crude 9β-acetoxy-l la, 15-di- (2-tetrahydropyranyl-oxy) -20-isopropylidene-prost-13 (trans) -enoic acid methyl ester are reacted in the same manner as in Example A- (16) and io treated to obtain 1.01 g of the desired compound as an oil.

IR spectrum (liquid film) vmax cm-1:

3380.1710.1035.1020.

Nuclear Magnetic Resonance Spectrum (CC14) ôppm: 15

5.44 (2H, multiplet).

Example F

9a-hydroxy-lla, 15a- or -15ß-di- (2-tetrahydropyranyloxy) - 20 20-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid (II)

(1) 3-oxo-6-syn- (3-oxo-9-methyl-deca-l, 8-dienyl) -7-anti- (p-phenylbenzoyloxy) -2-oxa-cis-bicyclo- [3, 3.0] octane (XVII)

346 mg of 52.9% oily sodium hydride are washed with dry petroleum ether to remove the oil, after which 25 are suspended in 20 ml of dimethoxyethane. 20 ml of a dimethoxyethane solution, which contains 2.075 g of 2-oxo-8-methyl-7-nonenylphosphonic acid dimethyl ester and has been obtained as described in Example E- (1) 30, is added dropwise to the suspension with ice cooling and in an argon atmosphere, whereupon 30% is added the mixture is stirred for a further 3 hours. Then the suspension is mixed with 10 ml of dimethoxyethane, whereupon 30 ml of a dimethoxyethane solution containing 1.22 g of 3-oxo-6-syn-formyl-7-anti- (p-phenylbenzoyloxy) -2-oxa-cis are added dropwise with ice cooling -bicyclo- [3,3,0] octane 35 (XVI) contains. The mixture is stirred for 2 hours. When the reaction has ended, the mixture is treated in the same manner as in Example C- (I) above, giving 1.37 g of the desired product in the form of an oil. 40

IR spectrum (liquid film) vmax cm-1: 1783, 1723, 1680, 1635, 1280, 1185, 1120, 755.

NMR spectrum (CDC13) ôppm:

5.0 -5.5 (3H, multiplet),

6.28 (IH, doublet), 45

6.8 (1H, quartet),

7.3 -8.2 (9H, multiplet).

(2) 3-Oxo-6-syn- (3a- or 3ß-hydroxy-9-methyl-l, 8-di-enyl) -7-anti- (p-phenylbenzoyloxy) -2-oxa-cis-bicyclo - [3,3,0] octane (XVIII) 50

290 mg of 3-oxo-6-syn- (3-oxo-9-methyl-deca-l, 8-dienyl) -7-anti- (p-phenylbenzoyloxy) -2-oxa-cis- are dissolved in 5 ml of dimethoxyethane. bicyclo- [3,3,0] octane. 1 ml of a 0.55 molar zinc borohydride-dimethoxyethane solution is added to this solution while cooling with ice, and the whole mixture is stirred for 1 55 hours. After the reaction is completed, the mixture is treated in the same manner as in Example C- (2) above. The product obtained in this way is subjected to preparative thin-layer chromatography and developed with ether, 95 mg of the 3a isomer of the 60 desired product being obtained from the less polar part and 77 mg of the 3β isomer of the desired product from the more polar part.

3a-hydroxy isomer:

IR spectrum (liquid film) vraax cm-1: 3500.1780.1720.1615, 1280, 1185, 1120.975, 750. 6S

NMR spectrum (CDC13) ôppm:

4.13 (IH, multiplet),

4.9 -5.4 (3H, multiplet),

5.64 (2H, multiplet),

7.3 -8.2 (9H, multiplet).

3ß-hydroxy isomer:

IR spectrum (liquid film) vraax cm-1: 3500.1780.1720.1615, 1280, 1185, 1120.975, 750. NMR spectrum (CDCI3) ôppm:

4.13 (IH, multiplet),

4.9 -5.4 (3H, multiplet),

5.64 (2H, multiplet),

7.3 -8.2 (9H, multiplet).

(3) 3-oxo-6-syn- (3a-hydroxy-9-methyl-deca-1,8-dienyl) -7-anti-hydroxy-2-oxa-cis-bicyclo- [3,3,0] -octane (XVIII)

140 mg of 3-oxo-6-syn- (3a-hydroxy-9-methyl-deca-l, 8-dienyl) -7-anti- (p-phenyl-benzoyloxy) -2-oxa are dissolved in 3 ml of anhydrous methanol -cis-bicyclo- [3,3,0] octane and 75 mg of anhydrous potassium carbonate, followed by stirring for 35 minutes. When the reaction is complete, the mixture is treated in the same manner as in Example C- (3) above to obtain 99 mg of the desired product as an oil.

IR spectrum (liquid film) vmax cm-1: 3400.1760, 1175, 1080.970.

NMR spectrum (CDC13) ôppm:

1.60 (6H, doublet),

3.8 -4.2 (2H, multiplet),

4.8 -5.3 (2H, multiplet),

5.55 (2H, multiplet).

(4) 3-oxo-6-syn- (3ß-hydroxy-9-methyl-deca-1,8-dienyl) -7-anti-hydroxy-2-oxa-cis-bicyclo- [3,3,0] -octane (XVIII)

If you work according to the instructions in Example F- (3), but you replace the 3-oxo-6-syn- (3a-hydroxy-9-methyl-deca, l, 8-dienyl) -7-anti- (p- phenylbenzoyloxy) -2-oxa-cis-bicyclo [3,3,0] octane by 91 mg of 3-oxo-6-syn- (3ß-hydroxy-9-methyl-deca-l, 8-dienyl) -7-anti- (p-phenylbenzoyloxy) -2-oxa-cis-bicyclo- [3,3,0] octane, the desired product is obtained.

IR spectrum (liquid film) vmax cm

-1.

3400.1760, 1175, 1080.970.

NMR spectrum (CDC13) ôppm:

1.6 (6H, doublet),

3.8 -4.2 (2H, multiplet),

4.8 -5.3 (2H, multiplet),

5.55 (2H, multiplet).

(5) 3-Oxo-6-syn- [3a- (2-tetrahydropyranyloxy) -9-methyl-deca-1,8-dienyl] -7-anti- (2-tetrahydropyranyloxy) -2-oxa-cis-bicyclo - [3,3,0] octane (XIX)

To 15 ml of a benzene solution which contains 3.08 g of 3-oxo-6-syn- (3a-hydroxy-9-methyl-deca-l, 8-dienyl) -7-antihydroxy-2-oxa-cis-bicyclo- [ Contains 3,3,0] octane, 1.85 g of dihydropyran are added at room temperature and then a catalytic amount of picric acid is added while cooling with ice, whereupon the reaction mixture is left to stand for 3 hours. When the reaction has ended, 200 ml of ether are added to the reaction mixture. The mixture is neutralized with a 10% aqueous sodium bicarbonate solution, washed with water and dried over anhydrous sodium sulfate. The solvent is then distilled off and the residue is purified by column chromatography in the presence of silica gel, giving 4.3 g of the desired product in the form of an oil.

IR spectrum (liquid film) vmax cm-1: 1775,1130,1070,1015,970.

NMR spectrum (CDC13) ôppm:

4.7 (2H, multiplet),

4.8-5.2 (2H, multiplet),

5.0 (2H, multiplet).

(6) 3-Oxo-6-syn- [3ß- (2-tetrahydropyranyloxy) -9-methyl-deca-1,8-dienyl] -7-anti- (2-tetrahydropyranyloxy) -2-oxa-cis-bicyclo - (3,3,0] octane (XIX)

621 773

26

If one works according to the same procedure which was described in example F- (5), but uses instead of 3-oxo-6-syn- (3a-hydroxy-9-methyl-deca-1,8-dienyl) -7 -anti-hydroxy-2-oxa-cis-bicyclo- [3,3,0] -octane 2.7 g 3-oxo-6-syn- (3ß-hydroxy-9-methyl-deca-1,8-dienyl ) -7-anti-hydroxy-2-? oxa-cis-bicyclo [3,3,0] octane, 3.5 g of the desired product are obtained in the form of an oil.

IR spectrum (liquid film) vmax cm-1: 1775,1130,1070,1015,970.

Nuclear Magnetic Resonance Spectrum (CDC13) ôppm: io

4.7 (2H, multiplet),

4.8-5.2 (2H, multiplet),

5.0 (2H, multiplet).

(7) 3-Hydroxy-6-syn- [3a- (2-tetrahydropyranyloxy) -9-methyl-deca-1,8-dienyl] -7-anti- (2-tetrahydropyranyloxy) -2- 15 oxa-cis- bicyclo- [3,3,0] octane (XX)

If one works according to example C- (7), but instead of 3-oxo-6-syn- [3a- (2-tetrahydropyranyloxy) -5,9-dimethyl-deca-l, 8-dienyl] -7-anti- (2-tetrahydropyranyloxy) -2-oxa-cis-bicyclo [3,3,0] octane 4.3 g 3-oxo-6-syn- [3a- (2-tetra-20 hydropyranyloxy) -9-methyl -deca-1,8-dienyl] -7-anti- (2-tetra-hydropyranyloxy) -2-oxa-cis-bicyclo [3,3,0] octane, 4.1 g of the desired product are obtained in the form of an oil.

IR spectrum (liquid film) vmax cm 1:25

3400,1130,1070,1015,970.

NMR spectrum (CDC13) ôppm:

4.7 (2H, multiplet),

5.15 (1H, triplet),

5.6 (2H, multiplet). 30th

(8) 3-Hydroxy-6-syn- [3ß- (2-tetrahydropyranyloxy) -9-methyl-deca-1,8-dienyl] -7-anti- (2-tetrahydropyranyloxy) -2-oxa-cis-bicyclo - [3,3,0] octane (XX)

One works according to example C- (7), but uses instead of 3-oxo-6-syn- [3a- (2-tetrahydropyranyloxy) -5,9-dimethyl-3s deca, 1,8-dienyl] -7-anti - (2-tetrahydropyranyloxy) -2-oxa-cis-bieyclo [3,3,0] octane 3.5 g 3-oxo-6-syn- [3ß- (2-tetrahydropyranyloxy) -9-methyl -deca-1,8-dienyl] -7-anti- (2-tetrahydropyra-nyloxy) -2-oxa-cis-bicyclo- [3,3,0] -octane, 3.3 g of the desired product are obtained in the form of an oil. 40

IR spectrum (liquid film) vmax cm "1: 3400,1130,1070,1015,970.

NMR spectrum (CDC13) ôppm:

4.7 (2H, multiplet),

5.15 (1H, triplet), 45

5.6 (2H, multiplet).

(9) 9a-hydroxy-lla, 15a-di- (2-tetrahydropyranyloxy) -20-isopropylidene-prost-5 (cis), l3 (trans) -dienoic acid (II)

If you work according to the information in example C- (9), but instead of 3-hydroxy-6-syn- [3a- (2-tetrahydropyra-50 nyloxy) -5,9-dimethyl-deca-l, 8-dienyl] -7-anti- (2-tetrahydropyranyloxy) -2-oxa-bicyclo- [3,3,0] octane 4.1 g 3-hydroxy-6-syn- [3a- (2-tetrahydropyranyloxy) -9 -methyl-deca-1,8-dienyl] -7-anti- (2-tetrahydropyranyloxy) -2-oxa-cis-bicyclo [3,3,0] octane, 3.6 g of the desired product are obtained in the form of a 55 oil.

IR spectrum (liquid film) vmax cm-1: 3450,3200,2750,1715,1160,1105,1020.

NMR spectrum (CDC13) ôppm:

4.73 (2H, multiplet), 60

5.17 (1H, triplet),

5.5 (4H, multiplet).

(10) 9a-hydroxy-lla, l5ß-di- (2-tetrahydropyranyloxy) -20-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid (II)

One works in the same way as in example C- (9), 65 but uses instead of 3-oxo-6-syn- [3a- (2-tetrahydropyranyloxy) -5,9-dimethyl-deca-1,8 -dienyl] -7-anti- (2-tetrahydro-pyranyloxy) -2-oxa-cis-bicyclo- [3,3,0] -octane 3.3 g 3-hydroxy-

6-syn- [3ß- (2-tetrahydropyranyloxy) -9-methyl-deca-l, 8-die-nyl] -7-anti- (2-tetrahydropyranyloxy) -2-oxa-cis-bicyclo- [3.3 , 0] octane, 3.0 g of the desired product are obtained in the form of an oil.

IR spectrum (liquid film) vmax cm "" 1: 3450,3200,2750,1715,1160,1105,1020.

NMR spectrum (CDC13) ôppm:

4.73 (2H, multiplet),

5.17 (1H, triplet),

5.5 (4H, multiplet).

Example G

9a-hydroxy-15- (2-tetrahydropyranyloxy) -20-isopropylidene-prost-13 (trans) -enoic acid (II)

(1) 3-oxo-6-syn- (2-tetrahydropyranyloxymethyl) -2-oxa-bicyclo- [3,3,0] octane (XXIII)

3.35 g of 3-oxo-6-syn-hydroxymethyl-2-oxa-bicyclo [3,3,0] octane are dissolved in 15 ml of anhydrous 2,3-dihydropyran, and 15 mg of p-toluenesulfonic acid are added. The solution thus obtained is then stirred at room temperature for 20 minutes. When the reaction is complete, the solution is diluted with 200 ml of ethyl acetate and washed with three portions of 100 ml of a saturated aqueous saline solution. After drying over anhydrous sodium sulfate, the solvent is evaporated to give 5.95 g of the desired compound in the form of an oil.

IR spectrum (liquid film) vmax cm-1: 1780,1165,1125,1035.

(2) 3-hydroxy-6-syn- (2-tetrahydropyranyloxymethyl) -2-oxa-bicyclo- [3,3,0] octane (XXIV)

5.9 g of 3-oxo-6-syn- (2-tetrahydropyranyloxymethyl) -2-oxa-bicyclo- [3,3,0] -octane are dissolved in 100 ml of anhydrous toluene. (l) received. The solution thus obtained is then stirred in an argon atmosphere at -70 ° C. The solution is then slowly added with 21 ml of a diisobutylaluminum hydride solution (25 g / 100 mln-hexane) and this solution is stirred at -70 ° C. for 30 minutes. When the reaction has ended, 180 ml of a mixture of tetrahydrofuran and water (mixing ratio 2: 1) are slowly added to the solution. After the temperature of the mixture obtained has risen to room temperature, the precipitated, insoluble substance is filtered off through Celite. The filtrate is diluted with a saturated aqueous saline solution and extracted with ethyl acetate. The organic part is then washed with water and dried over anhydrous sodium sulfate. After evaporation of the solvent, 5.89 g of the desired compound are obtained in the form of an oil.

IR spectrum (liquid film) vmax cm-1: 3450.1125.1065.1025.

NMR spectrum (CDC13) Ôppm:

4.6 -4.8 (2H, multiplet),

5.58 (1H, multiplet).

(3) la-hydroxy-2a- (6-methoxycarbonyl-2-cis-hexenyl) -3ß- (2-tetrahydropyranyloxymethyl) cyclopentane (XXV)

A sodium methylsulfonylcarbanion solution prepared from 7.10 g of sodium hydride containing 50% of an oil and 200 ml of dimethyl sulfoxide is mixed with 32 g of triphenylphosphonium bromide at a temperature of less than −20 ° C. in an argon atmosphere in order to obtain a red-colored ylide solution . This solution is then mixed with 20 ml of dimethyl sulfoxide, which contains 5.8 g of 3-hydroxy-6-syn- (2-tetrahydropyranyloxymethyl) -2-oxa-bicyclö- [3,3,0] octane, and the mixture during Stirred for 30 minutes at room temperature. After the reaction has ended, the reaction mixture is diluted with 500 ml of cold 15% aqueous hydrochloric acid (0 ° C.) and extracted with ether. The ether extract is washed with water

27

621 773

and dried over anhydrous sodium sulfate. The solvent is evaporated, leaving an oily residue of the carboxylic acid.

The residue thus obtained is treated in an ethereal solution of diazomethane. After evaporation? the ether gives 14 g of the desired ester. This residue is subjected to column chromatography using 140 g of silica gel, 6.57 g of the desired compound being obtained in the form of an oil. old.

IR spectrum (liquid film) vmax cm "'1:! ()

3480,1740,1200,1140,1120,1030.

NMR spectrum (CDC13) ôppm:

3.67 (3H, singlet),

4.23 (1H, multiplet),

4.80 (1H, multiplet), is

5.50 (2H, multiplet).

(4) la-acetoxy-2a- (6-methoxycarbonyl-2-cis-hexenyl) -3ß- (2-tetrahydropyranyloxymethyl) cyclopentane (XXVI)

In a mixture of 20 ml of pyridine and 10 ml of acetic anhydride, 6.49 g of lcc-hydroxy-2a- (6-methoxycarbonyl-20 2-cis-hexenyl) -3ß- (2-tetrahydropyranyloxymethyl) -cyclopentane is dissolved and the mixture is stirred solution obtained for 2 hours at 40 ° C. After the reaction has ended, the reaction mixture is diluted with 150 ml of water and extracted with a mixture of benzene and ethyl acetate. 25th

The extract is then washed with water and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, leaving 7.26 g of the desired compound in the form of an oil.

IR spectrum (liquid film) vroax cm-1: 1740,1245,1030. 30 NMR spectrum (CDC13) ôppm:

2.03 (3H, singlet),

3.67 (3H, singlet),

4.62 (1H, multiplet),

5.23 (1H, multiplet),

5.42 (2H, multiplet).

(5) la-acetoxy-2a- (6-methoxycarbonyl-2-cis-hexenyl) -3ß-hydroxymethyl-cyclopentane (XXVII)

7.20 g of la-acetoxy-2a- (6-methoxy-40 carbonyl-2-cis-hexenyl) -3ß- (2-tetrahydropyranyloxymethyl) -cyclopentane are dissolved in 150 ml of an aqueous methanol solution containing 10% water, whereupon 1 , 4 g of p-toluenesulfonic acid are added and the mixture is stirred at 40 ° C. for 1 hour. After the reaction is complete, the mixture is diluted with 400 ml of ether and washed with a saturated saline solution to remove the acid. After drying over anhydrous sodium sulfate, the solvent is evaporated off under reduced pressure, leaving 5.79 g of an oily residue. This residue is subjected to column chromatography using 80 g of silica gel, whereby 5.053 g of the desired compound is obtained in the form of an oil.

IR spectrum (liquid film) vmax cm-1: 3500.1740.1380.1250.1170.1025.

NMR spectrum (CDC13) ôppm:

2.03 (3H, singlet),

3.65 (2H, multiplet),

3.68 (3H, singlet),

5.25 (1H, multiplet),

5.45 (2H, multiplet). 60

(6) 1 a-acetoxy-2a- (6-methoxycarbonylhexyl) -3ß-hydroxy-methyl-cyclopentane (XXVIII)

3.0 g of la-acetoxy-2a- (6-methoxycarbonyl-2-cis-hexenyl) -3ß-hydroxymethyl-cyclopen- 65 tan are dissolved in 50 ml of methanol, whereupon the solution obtained is prepared in a conventional manner using 2 0 g of a 5% palladium-on-carbon catalyst hydrogenated in the usual way. After filtering off the

35

50

55

Catalyst, the solvent is evaporated under reduced pressure, 2.8 g of the desired compound in

Takes the form of an oil.

IR spectrum (liquid film) vmax cm-1:

3500.1740.1380.1250.1175.1020.

NMR spectrum (CDC13) ôppm:

2.03 (3H, singlet),

3.63 (2H, multiplet),

3.70 (3H, singlet),

5.28 (1H, multiplet).

(7) la-acetoxy-2a- (6-methoxycarbonylhexyl) -3ß-formyl-cyclopentane (XXIX)

7.36 g of chromic anhydride are introduced into a mixture of 200 ml of anhydrous dichloromethane and 11.7 g of pyridine at 15 ° C. in an argon atmosphere in order to obtain a colloidal oxidant. The solution thus obtained is cooled to 3 to 5 ° C and then mixed with 2.76 g of la-acetoxy-2a- (6-methoxy-carbonylhexyl) -3ß-hydroxymethyl-cyclopentane. Then the mixture is stirred for 20 minutes. When the reaction has ended, the reaction mixture is diluted with 1 liter of ether. The mixture is then washed with a 3% aqueous sodium hydroxide solution, then with a 3% hydrochloric acid solution, then with a 5% aqueous sodium hydrogencarbonate solution and finally with water and then dried over anhydrous sodium sulfate. Then the solvent is evaporated to give 2.56 g of the desired compound in the form of an oil.

(8) 9a-acetoxy-15-oxo-20-isopropylidene-prost-13 (trans) -enoic acid methyl ester (XXX)

0.495 g of 50% oily sodium hydride is washed with dry petroleum ether to remove the oil. The sodium hydride obtained is suspended in 150 ml of anhydrous dimethoxyethane, and 2.7 g of dimethyl 2-oxo-8-methyl-2-nonenylphosphonate are added dropwise to this suspension, while cooling with ice, with stirring in an argon atmosphere. Then the mixture is stirred for 4 hours at room temperature. The solution obtained is then mixed with ice-cooling with 2.50 g of la-acetoxy-2a- (6-methoxycarbonylhe-xyl) -3ß-formyl-cyclopentane and the mixture is stirred for 2 hours. When the reaction has ended, 200 ml of ether are added to the solution obtained. The organic solution is washed with dilute hydrochloric acid and then with water and then dried over anhydrous sodium sulfate. The organic solvent is evaporated under reduced pressure to give 4.58 g of an oily residue which is purified over alumina in a column to give 2.45 g of the desired compound in the form of an oil.

IR spectrum (liquid film) vmax cm-1: 1740, 1700, 1670, 1625, 1370, 1240, 1170, 1020. NMR spectrum (CDC13) ôppm:

2.03 (3H, singlet),

3.64 (3H, singlet),

5.00-5.35 (2H, multiplet),

6.10 (1H, doublet),

6.52 (1H, quartet).

(9) 9a-acetoxy-15-hydroxy-20-isopropylidene prost-13 (trans) -enoic acid methyl ester (XXXi)

2.4 g of 9a-acetoxy-15-oxo-20-isopropylidene-prostate-13 (trans) -enoic acid methyl ester are dissolved in 50 ml of anhydrous methanol, and the solution is cooled to 3 to 5 ° C. and stirred. This solution is then mixed with 210 mg of sodium borohydride and the mixture is stirred at 3 to 5 ° C. for 1 hour. When the reaction is complete, the mixture is diluted with a cold 3% aqueous hydrochloric acid solution and extracted with a mixture of benzene and ethyl acetate. The extract is washed with water and over anhydrous

621 773 28

Dried sodium sulfate. The solvent is then mixed (2) 9a-acetoxy-15-oxo-20-isopropylidene-prost-5 (cis),

evaporated to give 2.5 g of an oily residue. The 13 (trans) -dienoic acid methyl ester (XXXVI)

the residue obtained in this way is charged with 1.95 g of la-acetoxy-2a- (6-methoxycarbonyl-2-cis-hexenyI)

th column, whereby 2.36 g of the desired compound 3ß-formyI-cyclopentane are obtained in the same manner as in the form of an oil. 5 Example G- (8) implemented and treated, wherein 2.53 g of

IR spectrum (liquid film) vmax cm-1: desired compound is obtained as an oil.

3500.1740.1245.1020. IR spectrum (liquid film) vmax cm-1:

Nuclear Magnetic Resonance Spectrum (CDC13) ôppm: 1735.1695.1670.1630.1370.1240.1160.1030.

2.0 (3H, singlet), NMR spectrum (CDC13) ôppm:

3.65 (3H, singlet), ok 2.02 (3H, singlet),

4.07 (1H, multiplet), 3.65 (3H, singlet),

5.0 -5.4 (2H, multiplet), 5.0 -5.5 (3H, multiplet),

5.50 (2H, multiplet). 6.10 (1H, doublet),

(10) 9a-Acetoxy-15- (2-tetrahydropyranyloxy) -20-isopropy-6.72 (1H, quartet).

lidenprost-13 (trans) -enoic acid methyl ester (XXXII) 15 (3) 9a-acetoxy-15-hydroxy-20-isopropylidenprost-5 (cis),

In 5 ml of 2,3-dihydropyran are dissolved 2.3 g of methyl 9a-acetoxy-15-13 (trans) -dienoate (XXXVII) hydroxy-20-isopropylidene-prostate-13 (trans) -enate. 2.58 g9a-acetoxy-15-oxo-20-isopropylidenprost-5 (cis),

10 mg of p-toluenesulfonic acid are then added, and methyl 13 (trans) -dienate is stirred in the same way, and the mixture is stirred for 30 minutes at room temperature. Reacted and treated as in Example G- (9), the reaction being completed, the mixture 200 ml ether 20 2.24 g of the desired compound is obtained as an oil.

added. Then the mixture with three portions of IR spectrum (liquid film) vmax cm-1:

Wash 100 ml of water and over anhydrous sodium sulfate 3500.1740.1370.1240.1160.1020.965.

dried. The solvent is evaporated, leaving 2.8 g NMR spectrum (CDC13) ôppm:

the desired compound in the form of an oil. 2.01 (3H, singlet),

IR spectrum (liquid film) vmax cm-1: 2s 3.67 (3H, singlet),

1740,1375,1240,1200,1020,965. 4.08 (1H, multiplet),

(11) 9a-Hydroxy-15- (2-tetrahydropyranyloxy) -20-isopro- 5.0 -5.6 (5H, multiplet).

pylidenprost-13 (trans) -enoic acid (II)

3.0 g of 9a-acetoxy-15 (2-tetra- (4) 9a-acetoxy-15- (2-tetrahydropyranyloxy) -20-isopropyli-

hydropyranyloxy) -20-isopropylidenprost-13 (trans) -ensäureme-3o denprost-5 (eis), 13 (trans) -dienic acid methyl ester (XXXVIII) thylester, whereupon after the addition of 30 ml of a 5% 2.20 g 9 -Acetoxy-15-hydroxy-20-isopropylidenprost-aqueous sodium hydroxide solution the mixture while 3 5 (cis), 13 (trans) -dienoate are in the same

Stir at 40 ° C for hours. When the reaction is complete, the manner is reacted and treated as in Example G- (10), the mixture being diluted with ice water by adding 2.90 g of the desired compound as an oil.

7% aqueous hydrochloric acid solution neutralized and 35 IR spectrum (liquid film) vraax cm-1:

extracted with ethyl acetate. The organic extract is 1740.1370.1240.1200.1015.970.

Washed water and over anhydrous sodium sulfate (5) 9a-hydroxy-15- (2-tetrahydropyranyloxy) -20-isopropy-

dried. The solvent is reduced under reduced pressure Udenprost-5 (cis), 13 (trans) -dienoic acid (II)

evaporated, 2.6 g of the desired compound being dissolved in 80 ml of methanol, 2.9 l of 9a-acetoxy-15 (2-tetra-

Takes the form of an oil. ^ 40 j1y (jrOpyranyiOxy) -20-isopropylidenprost-5 (cis), 13 (trans) -dien-

IR spectrum (liquid film) vraax cm. acid methyl ester, whereupon after adding 50 ml of a

3420.2750.1710.1200.1110.1020.970. 5% aqueous sodium hydroxide solution, the mixture

NMR spectrum (CDC13) ôppm: stirring at 40 ° C for 3 hours. After completion of the implementation

4.7 (1H, multiplet), the reaction mixture is diluted with 200 ml of ice water, with

5.0-5.5 (3H, multiplet), 45 7% aqueous hydrochloric acid and neutralized with ethyl acetate

6.0 (2H, multiplet. The extract is then washed with water and

dried over anhydrous sodium sulfate. The solvent of Example H is evaporated under reduced pressure, giving 2.51 g

9a-Hydroxy-15- (2-tetrahydropyranyloxy) -20-isopropylidene - of the desired compound in the form of an oil. prost-S (cis), 13 (trans) -dienoic acid (II) 50 IR spectrum (liquid film) vmax cm "" 1:

(1) 7 a-Acetoxy-2a- (6-methoxycarbonyl) -2-cis-hexenyl) -3ß-formyl-cyclopentane (XXXV) 3450.3150.2650.1710.1200.1130.1110.1015.965.

2.0 g la-acetoxy-2a- (6-methoxycarbol-2-cis-hexenyl) -3ß-NMR spectrum (CDC13) ôppm:

hydroxymethyl-cyclopentane are made in the same way as 4.70 (1H, multiplet),

in Example G- (7) implemented and treated, 1.95 g 55 4.95-5.60 (5H, multiplet),

receives the desired compound as an oil. 5.90 (2H, multiplet).

C.

Claims (5)

621773 2. The method according to claim 1, characterized in that one of the following compounds is prepared, namely 9-oxo-lla, 15a- or -15ß-dihydroxy-17ß-methyl-20-isopro-pylidenprost-13 (trans) -enoic acid, 9-oxo-lla, 15a- or -15ß-dihydroxy-17ß-methyl-20-isoprop- pylidenprost-13 (trans) -enoic acid methyl ester, the potassium salt of 9-oxo-lla, 15cx- or -15ß-dihydroxy-17ß- methyl-20-isopropylidene prost-13 (trans) -enoic acid, 9-oxo-lla, 15a- or -15ß-dihydroxy-17ß-methyl-20-isopro-py Iidenprost-5 (eis), 13 (trans) -dienoic acid, 9-oxo-l la, 15a- or -15ß-dihydroxy-17ß-methyl-20-isopro-60 pylidenprost-5 (ice), 13 (trans) -dienoic acid methyl ester, 9-oxo-1 la, 15a- or -15ß-dihydroxy-20-isopropylidene prost-13 (trans) -enoic acid, 9-oxo-lla, 15a- or 15ß-dihydroxy-20-isopropylidene-prost-5 (ice), 13 (trans) -dienoic acid, 65 9-oxo-15a or 15β-hydroxy-20-isopropylidene prost-13 (trans) -enoic acid, Methyl 9-oxo-15a or -15ß-hydroxy-20-isopropylidene-prostate-13 (trans), 2nd PATENT CLAIMS 1. Process for the preparation of new prostatic acid derivatives of the following general formula: 0 wherein the symbol A represents the ethylene group or the cis-vinylene group, each of the symbols R1 and R2, which are the same or different, represent hydrogen atoms or alkyl radicals having 1 to 3 carbon atoms, each of the symbols R3 and R4, which are the same or different are alkyl radicals with 1 to 3 Represent carbon atoms and the symbol R5 means the water, 0 substance atom or the hydroxyl group, or of pharmaceutically acceptable salts thereof, characterized in that a compound of the following formula: oh wherein the symbols A, R1, R2, R3 and R4 have the above meanings, the symbol R5 'represents the hydrogen atom or a group -OR6 and the symbol R6 represents a protective group for the hydroxyl group, oxidized to form a compound to get the following formula: wherein the symbols A, R1, R2, R3, R4, R5 'and R6 have the above meanings, whereupon the protective group (s) are removed from the hydroxyl group or hydroxyl groups of the compound obtained. 3. The method according to claim 1, characterized in that obtained carboxylic acids of formula I, wherein R2 represents a hydrogen atom, in pharmaceutically acceptable salts, in particular in salts of alkali and alkaline earth metals, in ammonium and quaternary ammonium salts and in salts with lower aliphatic , alicyclic, aromatic-aliphatic, heterocyclic or a hydrophilic group containing amines. 3rd 621 773 the potassium salt of 9-oxo-15cc- or -15ß-hydroxy-20-isopro-pylidenprost-13 (trans) -enoic acid, 9-oxo-15a or -15ß-hydroxy-20-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid or 9-Oxo-15a or -15ß-hydroxy-20-isopropylidene-prost-5 (cis), 13 (trans) -dienoic acid methyl ester. 4. The method according to claim 1, characterized in that obtained carboxylic acids of the formula I, in which R 2 is a hydrogen atom, are converted into corresponding methyl esters by esterification with an agent which gives off a methyl radical. 5 5. The method according to claim 1, characterized in that obtained methyl esters of the formula I are converted into corresponding carboxylic acids by saponification.