SE452157B - INTERMEDIATES FOR THE MANUFACTURING OF TRANS- DELTA? 722-PROSTAGLANDIN-E? 711-ANALOGS AND PROCEDURES FOR PRODUCING THESE - Google Patents

Description

The dashed lines 1 of the above formulas and 1 other formulas in the present presentation refer in accordance with generally accepted nomenclature rules that the connected group is behind the general plan of the ring system, ie that the group is in a-configuration. The thicker lines “* §g indicate that the group lies in the general plan of the system, ie that the group is in 1 B configuration, and the wavy line / v ~ 4 / indicates that the group is in 1 a or B configuration.

Such compounds are subclassed according to the position of the double bonds in the side chains connected in the 8- and 12-positions of the alicyclic ring. Thus, PG compounds have a trans-double bond between C13-C14 (transvfigš) and PG2 compounds have a cis-double bond between C-C and a trans-double bond between C15-C14 (cis-ÅÄ5, trans-ÅÄÄÜ). For example, the prostaglandin E1 (PGEI) is characterized by the following structure III. The structure of PGE2 as a member of the PG2 group corresponds to that of formula III with a cis double bond between the carbon atoms in positions 5 and 6. Compounds 1 in which the double bond between the carbon atoms in positions 15 and 14 of members of The PG1 group replaced with ethylene are known as dihydroprostaglandins, eg dihydroprostaglandin E1 (dinydro-PomI).

PGE compounds with a trans-double bond between the carbon atoms in positions 2 and 5 are known as trans-Å2-PGE compounds, and the structure of trans-Å2-PGE1 corresponds to that of formula III with a trans-double bond between the carbon atoms in positions 2 and 5.

When one or more methylene groups are added to or eliminated from the ua chain, i.e. the aliphatic group attached to the 12-position of the alicyclic ring of the prostaglandins, and / or the α-chain, i.e. the aliphatic group connected to 8 position of the alicyclic ring of the prostaglandins, the compounds are known in accordance with the usual rules of organic terminology known as homo-prostaglandins (methylene group added) or nor-prostaglandins (methylene group eliminated), and when more than one ac 452 ac 452 157 methylene group is added or eliminated, the number is indicated by di-, tri- etc before the prefix "homo" or "nor". I.

Prostaglandins are generally known to possess pharmacological properties, in that they, for example, stimulate the smooth muscle, have hypotensive, diuretic, bronchodilator and antilipolytic activity and also inhibit platelet aggregation and gastric juice secretion and are consequently useful in the treatment of hypertension. thrombosis, asthma and intestinal ulcers, in the onset of labor and abortion in pregnant mammals, in the prevention of arteriosclerosis and as diuretics. They are fat-soluble substances, which can be obtained in very small quantities from various tissues of mammals that secrete the prostaglandins in the living body. w PGE, for example, has an inhibitory effect on gastric juice secretion and can consequently be used in the treatment of gastroulcer. They also inhibit the release of free fatty acid induced by epinephrine and as a result they reduce the concentration of free fatty acid in the blood and can consequently be used to prevent arteriosclerosis and hyperlipemia. PGEI inhibits platelet aggregation and also removes thrombus and prevents thrombosis. PGE has a stimulating effect on the smooth muscles and enhances intestinal peristalsis; this effect suggests therapeutic utility on postoperative ileus and as a laxative. PGE can also be used as oxytoxics, as an abortifacient during the first and second trimesters; in the expulsion of the placenta after birth and as oral contraceptives because they regulate the sexual cycle of female mammals. PGE has vasodilator and diuretic effects.

They are useful in improving the condition of patients suffering from cerebral vascular disease because they increase cerebral blood flow, and they are also useful in treating asthmatic conditions in patients due to their bronchodilator effect.

Two methods for introducing a trans (or E) double bond between the carbon atoms at positions 2 and 3 of prostaglandin compounds are known.

A first process is described in British Patent Specification 1,416,410. To form the double bond between the carbon atoms in positions 5 and 6, however, the process requires the use of a phosphorus compound (C 6 H 5) 5 P = CHCH 2 COOH, whose carboxy group (-COOH) is unconjugated. The resulting instability of the phosphorus compound makes it difficult to obtain high yields. In addition, in the series of reactions described for the preparation of the trans-Ä2-prostaglandins, selective hydrogenation is required if a trans-ħ? -PGEI analog is to be obtained. It is necessary to hydrate a double bond between the carbon atoms in positions 5 and 6 while leaving a double bond between the carbon atoms in positions 13 and 14 unaffected. There is a risk of hydrogenation of both double bonds, which leads to a reduced yield of the desired product. Finally, the array is introduced at an early stage in the reaction series leading to the desired trans-ZA2-prostaglandin, so a large amount of expensive substrate required to introduce the desired N-chain is required.

The second process is described in British Pat. Nos. 1,485,240 and 1,540,427. The introduction of the double bond between the carbon atoms in positions 2 and 3 requires the use of selenium or sulfur compounds. Trace amounts of such compounds are harmful to humans, and if the final trans-ZÄ2 prostaglandin products are to be used as medicines, the sulfur or selenium compounds must be removed. Such removal is difficult to perform and requires far-reaching accuracy. In addition, the selenium or sulfur compounds have a very unpleasant odor, which causes difficulties in their production and use.

As a result of research and experimentation, new chemical compounds have now been discovered which are useful as intermediates in improved processes for the preparation of trans-ZÄ? -PGE1- analogs.

The novel chemical compounds of the present invention useful for the preparation of trans-ZA2-prostaglandin-E1 analogs are compounds of the general formula: IV / wherein Y represents 'j: C = O or IIC' (where R4 represents S 452 157 a wet t - basic alkali or a UYÖPOXISKYÖÖSBPUPP which is eliminated under au acet l telïfllselßer and selected from acecyi, kioraeecyi, einer-Y, ri oracetyl, trifluoroacetyl, propionylphenylphenylphenylphenylphenylphenylphenyl. y1 °° h naphthY10Y1), Z represents: c = o or i / ORS ,, C \ H (where R5 represents a hydrogen atom or a tetrahydropyran-2-y1 group), R1 represents a formyl group or a group of the formula -CH2OR (where R is as defined above), R 2 represents a single bond or an alkylene group containing 1-5 carbon atoms, R 3 represents a hydrogen atom, an alkyl or alkoxy group containing 1-8 carbon atoms or a cycloalkyl or cycloalkyloxy group containing 4 -7 carbon atoms unsubstituted or substituted by at least e n alkyl group containing 1 to 8 carbon atoms or represents a phenyl or phenoxy group unsubstituted or substituted by at least one halogen atom, trifluoromethyl group or alkyl group containing 1-Ä carbon atoms, with the proviso that when R 2 represents a single bond, R 3 does not represent an alkoxy, cycloalkyloxy or phenoxy group, THP represents a tetrahydropyran-2-yl group and the double bond between the carbon atoms in positions l1 and 14 is trans, ie E with the proviso that (i) when Z, oRÉ represent: -I: C = 0 or 22C§- (where R54 represents a hydrogen- H _OR atom), Y represents' C§; _ (where now H represents a hydroxy protecting group which is eliminated under basic conditions and has the meaning given above) and R1 represents a group of the formula -CH OBH 2 is eliminated under basic conditions and has the above meaning- (where R represents a hydroxy protecting group as part) and (ii) - when Z represents -_C _, - OR5 / \\\ ~ H (wherein R5 represents a tetrahygropyran-2 -ylgrup p), OR (a) Y represents ::> C:; __ (wherein Ru represents an H hydroxy protecting group which is eliminated under basic conditions and has the previously stated meaning) and B1 represents a group of the formula -CHZOR (wherein R represents a hydroxy protecting group which is eliminated under basic conditions and has the previously stated meaning), ,, ORu f, (Ö) Y PePPëSe fl teraI ':> C ~ \ _- (wherein Ru represents a hydrogen H 1 atom) and R represent a group of the formula -CH ORH (wherein Ru 2 represents a hydrogen atom), or (c) Y represents: j: C = O and R 1 represents a formyl group.

It should be noted that the alkyl and alkylene groups and the alkyl and alkylene units in groups disclosed in the present invention and appended claims may be straight or branched.

The present invention relates to all compounds of the general formula IV in optically active "natural" form or its enantiomeric form or mixtures thereof, in particular the racemic form, consisting of equimolecular mixtures of the optically active "natural" form and its enantiomeric form.

It will be apparent to those skilled in the art that the compounds represented by the general formula IV have at least three asymmetry centers at the C-8, C-11 and C-12 carbon atoms. Additionally, asymmetric centers may occur in branched chain alkyl or alkylene or groups when the symbol Y represents a group I? Cf; H where Ru has the meaning given above, or when the symbol Z re-, OR5 C, \ §} ¿The presence of asymmetry leads to occurrence in a known manner, a group in which R5 has the meaning given above. 10 '15 20 25 ÜO 35 40 452 157 of isomerism. However, the compounds of general formula IV all have such a configuration that the substituent groups attached to the cyclopentane ring carbon atoms 1 in the positions identified as 8 and 12 are trans relative to each other. Thus, all isomers of general formula IV and mixtures thereof having such substituent groups attached to the cyclopentane ring carbon atoms in positions 8 and 12 in the trans configuration are within the scope of general formula IV.

The group -R 2 or R 3 preferably represents, for example, methyl, ethyl, 1-methylethyl, propyl, 1-methylpropyl, 2-methylpropyl, 1-ethylpropyl, butyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1- ethyl butyl, 2-ethylbutyl, pentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylpentyl, 1,2-dimethylpentyl, 1,4-dimethylpentyl, 1-ethylpentyl, 2-ethylpentyl, 1-propylpentyl, 2-probylpentyl, hexyl, 1-methylhexyl, 2-methylhexyl, 1,1-dimethylhexyl, 1-ethylhexyl, 2-ethylhexyl, heptyl, 2-ethylheptyl, nonyl, undecyl, cyclobutyl, 1- propylcyclobutyl, 1-butylcyclobutyl, 1-pentylcyclobutyl, 1-hexylcyclobutyl, 2-methylcyclobutyl, 2-propylcyclobutyl, 3-ethylcyclobutyl, 3-propylcyclobutyl, 2,3,2-triethylcyclopentyl, cycloethyl; cyclopentylethyl, 2-cyclopentylpropyl, 3-cyclopentylpropyl, 2-pentylcyclopentyl, 2,2, -dimethylcyclopentyl, 3-ethylcyclopentyl, 5-propylcyclopentyl, 3-butylcyclopentyl, 3-tert-butylcyclopentyl, ( 3-propyl) cyclopentyl, (2-methyl-5-pr opyl) cyclopentyl, (2-methyl-4-propyl) cyclopentyl, cyclonexyl, cyclohexylmethyl, 1-cyclohexylethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, (1-methyl-2-cyclohexyl) ethyl, 2-cyclohexylpropyl, (1-methyl -1-cyclohexyl) ethyl, 4-cyclohexylbutyl, 3-ethyloyclohexyl, 3-isopropylcyclohexyl, 4-methylcyclohexyl, 4-ethylcyclohexyl, 4-propylcyclohexyl, 4-tert-butylcycloloxyl, 2,6-dimethyl, 2,2-dimethylcyl 2,6-dimethyl-4-propyl) -cyclohexyl, 1-methylcyclohexylmethyl, cycloheptyl, cycloheptylmethyl, 1-cycloheptylethyl, 2-cycloheptylethyl, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylpropyl, 4-phenyl -phenylpentyl, (1-methyl-2-phenyl) ethyl, (1,1-dimethyl-2-phenyl) ethyl, (1-methyl-1-phenyl) -ethyl, 1-phenylpentyl, phenoxymethyl, 2-phenoxyethyl, 3 -phenoxypropyl, M-phenoxybutyl, 5-phenoxypentyl, 3-chlorophenoxymethyl, α-chlorophenox1-methyl, 4-fluorophenoxymethyl, 3-trifluoromethylphenoxymethyl, 2-methylphenoxymethyl, 3-methylphenoxymethyl, 4-methylphenoxymethyl, 4-methylphenoxymethyl, -tert-butylphenoxymethyl, 4-sec-butylphenoxymethyl, p ropoxy-methyl, isopropoxymethyl, butoxymethyl, pentyloxymethyl, hexyloxymethyl, 1-ethoxyethyl, 1-propoxyethyl, 1-isopropoxyethyl, 1-neopentyloxyethyl, 1-pentyloxyethyl, (1-methyl-1-ethoxy-1-ethyl-1-ethyl) -1 (1-methyl-1-propoxy) ethyl, (1-methyl-1-isobutoxy) ethyl, (1-methyl-1-neopentyloxy) ethyl, (1-methyl-1-butoxy) ethyl, (1-methyl-isopentyloxy) ) ethyl, (1-methyl-1-pentyloxy) ethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-butoxyethyl, 2- (1-ethylbutoxy) ethyl, 2-pentyloxyethyl, 1-ethoxypropyl, 1-propoxypropyl, 1- ( 2-methylbutoxy) propyl, 1-pentyloxypropyl, 2-methoxypropyl, 5-methoxypropyl, refethoxypropyl, 3-propoxypropyl, 3-sec-butoxypropyl, 3-isobutoxypropyl, 3-butoxypropyl, (1-methyl-2-methoxy) - ethyl, (1-methyl-2-ethoxy) ethyl, (1-methyl-2-isobutoxy) ethyl, 1-pentyloxybutyl, (1-pentyloxy-2-methyl) propyl, 4-methoxybutyl, 4-ethoxybutyl, 4 -propoxybutyl, (1-methyl-3-methoxy) propyl, (1-methyl-5-propoxy) -propyl, (2-methyl-3-methoxy) propyl, (1,1-dimethyl-2-ethoxy) ethyl, (1,1-dimethyl-2-propoxy) ethyl, (1,1-dimethyl-2-isobutoxy) ethyl, 5-ethoxypentyl , 5-methoxypentyl, 1-pentyloxypentyl, (ethyl-3-propoxy) propyl, cyclobutyloxymethyl, cyclopentyloxymethyl, cyclohexyloxymethyl, cycloheptyloxymethyl, 2-cyclopentyloxyethyl or 2-cyclohexyloxyethyl. 1,1-dimethylpentyl is especially preferred.

The hydroxy protecting groups which are eliminated under basic conditions and represented by H4 according to the present preparation and appended claims are groups which do not affect other parts of the compounds during elimination of the protecting group and can be easily eliminated under mild basic conditions. the protecting group is preferably acetyl.

According to one aspect of the present invention there are prepared the compounds of general formula IV, wherein R 1 represents, OR represents a group -CH 2 OB 4, Y represents Å 3'C '\ H j IC = O, H 4 represents a hydroxy protecting group which is eliminated Hydroxy-, Z represents under basic conditions and has the meaning given above and the other symbols have the meaning given above, ie compounds of the general formula: QR 'cxzoal' a IW 2 3 IVA 15 -R 10 15 20 25 30 35 # 0 _ 452 157 9 (wherein Rua represents a hydroxy protecting group which is eliminated under basic conditions and has the meaning given above and the other symbols have the meaning given above) by Wittig reaction of a compound of the general formula: YR "V cH2oa" ° '/ \\ ~ // ~ \ (Wherein the various symbols have the meaning given above) with a sodium derivative of a dialkylphosphonate having the general formula: (R 60) 2§cH 2c-R 2 -H 3 vi OO (wherein H 6 represents a alkyl group containing 1-4 carbon atoms, preferably methyl or ethyl, and the other symbols have the meaning given above) or with a phosphorus compound of the general formula: (R7) 3P = cHc-R2-H3 VII O (wherein R? represents a phenyl group which is unsubstituted or ß substituted by at least one alkyl group containing 1-Ä carbon atoms, preferably phenyl, or represents an alkyl group containing 1-6 carbon atoms, preferably butyl or hexyl, or represents a cyclohexyl group, and the other symbols have meaning given above). The sodium derivative of the dialkylphosphonate of the general formula VI can be prepared by reacting the dialkylphosphonate and sodium hydride. the wittig reaction is described in "Organic Reactions", vol. 14, chap. 3 (1965), John Wiley & Sons, Inc. (USA). The reaction may be carried out in an inert organic solvent, for example an ether such as diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane, a hydrocarbon such as benzene, toluene, xylene or hexane, a dialkyl sulfoxide such as dimethyl sulfoxide, a dialkylformamide, such as N, N-dimethylformamide, a halogenated hydrocarbon, such as methylene chloride or chloroform, or an alkanol containing 1-kol carbon atoms, such as methanol or ethanol, or a mixture of two or more of them, at a temperature of from -78 ° C to the reaction mixture. reflux temperature.

Dialkylphosphonates of general formula VI and phosphorus compounds of general formula VII are well known and can be readily prepared by methods known per se. The term "methods known per se" as used in the present invention refers to methods which have hitherto been used or described in the chemical literature.

The compounds of the general formula IV, in which B1 represents a group -CH2OR, Y represents 1: '-' OR, Z represents_, oR5 \ 'f' represents:; C. ~ QH _, R represents a hydroxy protecting group which is eliminated under basic conditions and has the previously stated meaning, RS represents a hydrogen atom and the other symbols have the meaning given above, ie compounds with the general formula: on ““ ha eazon I O-THP | The island (wherein the various symbols have the meaning given above) is prepared by reduction of compounds of general formula IVA to convert the 15-oxo group to a 15-hydroxy group.

The reduction for the conversion of the oxo group to a hydroxy group can be carried out using any suitable reducing agent, such as sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, lithium tri-tert-butoxyaluminum hydride, lithium trimethoxyaluminum hydride, sodium cyanoborohydride, sodium cyanoborohydride -butylborohydride, lithium aluminum hydride-quinine complex, (-) - isobornyloxymagnesium iodide in an inert organic solvent, eg an alkanol containing 1-4 carbon atoms, such as methanol, ethanol or isopropanol, or an ether, such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, or a mixture of two or more of these, at a temperature of from -7800 to room temperature. The reduction is preferably carried out using diisobornyloxyaluminum isopropoxide (described in Japanese Patent 54-76552) or a diisobutylphenoxyaluminum (alkyl-substituted or unsubstituted) / described in Japanese Patent 54-154739 and J.org.cnem., 44, 1565 (1979) / a 1fl aum-1,1'-binaphthyl-2,2'-dioxialuminum hydride / described in J.Amer.Chem.Soc. 101, 5843 (1979) /. The product thus obtained is a mixture of isomers in which the 15-hydroxy group is in the c- or B-configuration and the mixture is separated in a conventional manner, for example by thin-layer column or high-speed liquid. chromatography on silica gel to give the desired isomer of the general formula IVB.

The compounds of the general formula IV, ošñri R1 represent a group -CHQORÄ, Y represents ,, C:; b, Z represents- H \, .oR5 represents, R represents a hydroxy protecting group which C. wH .J is eliminated under basic conditions and has the meaning previously indicated, R5 represents a tetrahydropyran-2-yl group, and the other symbols have the meaning given above, ie compounds of the general formula: see 'I _ Ivc W' I 0-TH? | O-THP (wherein the various symbols are as defined above) is prepared by etherifying the 15-hydroxy group of a compound of general formula IVB with 2,3-dihydropyran in an inert organic solvent, for example methylene chloride or tetrahydrofuran, in presence of an acid catalyst, eg p-toluenesulfonic acid, sulfuric acid, trifluoroborane etherate or phosphorus oxychloride, at or below room temperature.

The compounds of the general formula IV, ošâri R1 represent a group -CHQORÄ, Y represents: 1C ;; ” , Z repre- \ _C _, »OR 'centers a tetrahydropyran-2-yl group and the other symbols center R represent a hydrogen atom, H5 repre- has the meaning given above, i.e. compounds of the general formula: IVD 10 15 20 25 50 35 nd 12 452 157 (wherein the various symbols have the meaning given above) is prepared by saponifying compounds of the general formula IÜC for the conversion of the groups O hydrox into hydroxy groups. The saponification can be carried out using an aqueous solution of an alkali metal, for example sodium or potassium or lithium, hydroxide, carbonate or bicarbonate, or of an alkaline earth metal hydroxide or carbonate (for example of calcium or barium ) in the absence or presence of a water-soluble solvent, for example an ether, such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, or an alkanol containing 1-4 carbon atoms, such as methanol or ethanol, at a temperature of from -10 ° C to the reflux temperature of the reaction mixture, preferably at a temperature of from room temperature to 5000, or by using an anhydrous solution of an alkali metal hydroxide or carbonate (eg of sodium, potassium or lithium) in an anhydrous alkanol containing 1-4 carbon atoms , for example absolute methanol or ethanol, at a temperature of from -10 ° C to the refluxing temperature of the reaction mixture, preferably at a temperature of from room temperature to 50 ° C.

The compounds of the general formula IV, wherein R1 represents a formyl group, Y represents:> C = O, Z represents OR \\ _, / Csi fl the other symbols have the meaning given above, i.e. compounds where R5 represents a tetrahydropyran-2 -yl group and having the general formula: O / IVVCPIO 2 3 -R IVB I (Ia-mr § 0-THP (wherein the various symbols have the meaning given above) is prepared from compounds of the general formula IVD by oxidation to convert 9- the hydroxy group to a 9-oxo group and simultaneously to convert the hydroxymethyl group to a formyl group.

The oxidation is carried out by methods known per se for converting a hydroxy group into an oxo group, for example the method described in (1) Tetsuji Kameya, "Synthetic Organic Chemistry III, Organic Synthesis 1", pages 176-206 (1976) , Nankodo 10 15 20 25 ÉO 35 40 13 452 157 (Japan), or in (2) "Compendium of Organic Synthetic Methods", vol. 1 (1971), 2 (1974) and 5 (1977), section 48, John Wiley & Sons, Inc. (USA) The oxidation is preferably carried out under mild and neutral conditions, for example with dimethylsulfide-N-chlorosuccinimide complexes, thioanisole-N-chlorosuccinimide complexes, dimethylsulfide chlorine complexes or thioanisole chlorocomplex / fi from J.A. Chem.Soc., 94, 7586 (1972) /, dicyclohexylcarbodiimide-dimethylsulfoxide complex / cf. J.Amer.Chem.Soo., 87, 5661 (1965) /, pyridinium chlorochromate (C5H5NHCrO3Cl) / cf. Tetrahedron Letters, 2647 (1975) /, sulfur-trioxide-pyridine complex / cf. J.Amer.Chem.Soc., 89, 5505 (1967) /, chromyl chloride / Cf. Jmmernchennsoc., 97, 5929 (1975) /, chromium trioxia-pyridine complex (eg Collins reagent) or Jones reagent.

The oxidation using dimethylsulfide-N-chlorosuccinimide complexes, thioanisole-N-chlorosuccinimide complexes, dimethylsulfide chlorine complexes or thioanisole chlorine complexes can be carried out by reaction in a halogenated hydrocarbon such as chloroform, methylene chloride or carbon tetrachloride} or carbon tetrachloride}. 0 ° to 0 ° C and then treatment with triethylamine. The oxidation using the dicyclohexylcarbodiimide-dimethylsulfoxide complex is normally carried out by reacting in excess dimethylsulfoxide in the presence of an acid, eg phosphoric acid, phosphoric acid, cyanoacetic acid, pyridinephosphoric acid salt or trifluoroacetic acid. The oxidation using pyridinium chlorochromate can be carried out by reaction in a halogenated hydrocarbon such as chloroform, methylene chloride or carbon tetrachloride in the presence of sodium acetate, normally at room temperature. The oxidation using the sulfur trioxide-pyridine complex is normally carried out by reaction in dimethyl sulfoxide in the presence of triethylamine at room temperature. The oxidation using chromyl chloride is normally carried out by reacting in a halogenated hydrocarbon such as chloroform, methylene chloride or carbon tetrachloride in the presence of tert-butanol and pyridine at a temperature of from -BOOC to the reflux temperature of the reaction mixture. The oxidation using the chromium trioxide-pyridine complex can be carried out by reaction in a halogenated hydrocarbon, such as chloroform, methylene chloride or carbon tetrachloride, at a temperature of from 0 ° C to room temperature, preferably at 0 ° C. The oxidation using Jones reagent is normally carried out with acetone and dilute sulfuric acid at a temperature of from 0 ° C to room temperature.

The compounds of general formula V can be prepared by the series of reactions schematically set forth below under Scheme A, wherein H8 represents a benzyl group or a hydroxy protecting group which is more easily eliminated than a tetrahydropyran-2-yl group under acidic conditions. , the double bond is E or Z or a mixture thereof, i.e. EZ, and the other symbols have the meaning given above. (1-methoxy-1-methyl) ethyl; The 1-methoxycyclohexyl, 1-methoxy-1-phenoxyethyl, 1-ethoxyethyl, tetrahydrofuran-2-yl and trimethylsilyl groups are suitable hydroxy protecting groups which are more easily removed than the tetrahydropyran-2-yl group. 15 452 157 Scheme A OH - I lx '\ 8 [a], Q / Qclïcrß CHZOH OR' R 'Å o-mv -' VIII b] X XI 10 15 20 25 50 35 40 452 157 16 With reference to methods A can the conversion / a / is carried out using a ylide of a phosphonium compound of the general formula: (D f I * I 7 0 Q _, (R) 5PCH 2 CH 2 CH 2 OH X XII (wherein X represents a halogen atom and R 7 has the meaning given above) by means of the above-mentioned conversion of compounds of general formula V to those of general formula IVA.

The ylide of a phosphonium compound of the general formula XII can be prepared by reacting a phosphonium compound of the general formula XII with a suitable base, for example butyllithium, or a lithium compound of the general formula: H9 \\ NLi 101 / XIII R (wherein R9 and B10, which may be the same or different, each represents an alkyl group containing 1-6 carbon atoms, or a cycloalkyl group containing 3-6 carbon atoms), for example lithium diisopropylamide, in an inert organic solvent, at a temperature from -7800 to room temperature, for example a solvent previously described as suitable for the Wittig reaction of a compound of general formula V.

Phosphonium compounds of general formula XII are well known or can be readily prepared by methods known per se.

The conversion / b / can be carried out, for example, when Raa represents an acyl group using an acyl chloride R4aCl, wherein Rua has the meaning given above, or an acid anhydride (R4a) 2O, wherein Ra has the same meaning, in an inert organic solution. agents, eg methylene chloride or pyridine, in the presence of a tertiary amine, eg pyridine or triethylamine, at a temperature below room temperature, preferably at a temperature below 0 ° C.

In the conversion / o /, when R8 represents a benzyl group, compounds of general formula XI can be prepared by reduction of compounds of general formula X to simultaneously convert the vinylene and benzyloxy groups to ethylene and ethylene, respectively. hydroxy groups.

The reduction can conveniently be carried out under a hydrogen atmosphere in the presence of a hydrogenation catalyst, eg palladium on carbon. 10 15 20 25 30 35 40 1; Palladium black, platinum dioxide or Raney nickel, in an inert organic solvent, for example an alkanol containing 1-Å carbon atoms, such as methanol or ethanol, or ethyl acetate or a mixture of two or more of them, at a temperature of from room temperature to the reflux temperature of the reaction mixture at normal or elevated pressure, for example at a hydrogen pressure from the atmosphere-you now 15 leg / amg.

When R is other than a benzyl group, compounds of the general formula X may be converted into compounds of the general formula: R 4a 'b' '\ cn = cn / \ c1-12on4 ° OH XIV I am (wherein the various symbols have above) by mild hydrolysis under acidic conditions so as to avoid the risk of elimination of the tetrahydropyran-2-yl group, followed by hydrogenation of the obtained compound of general formula XIV in the manner previously mentioned for the conversion of compounds of the general formula X, wherein H8 represents a benzyl group, to those of the general formula XI for converting the vinylene group of formula XIV to an ethylene group.

The mild hydrolysis under acidic conditions can be effected (1) with an aqueous solution of an organic acid, for example acetic acid, propionic acid, oxalic acid or p-toluenesulfonic acid, or an inorganic acid, for example hydrochloric acid, sulfuric acid, or phosphoric acid , preferably in the presence of a water-miscible organic solvent, for example an alkanol containing 1-4 carbon atoms, such as methanol or ethanol, preferably methanol, or an ether, such as 1,2-dimethoxyethane, dioxane or tetrahydrofuran, preferably tetrahydrofuran, or below room temperature, preferably at 0 ° C or (2) with an anhydrous solution of an organic acid, such as p-toluenesulfonic acid or trifluoroacetic acid in an anhydrous alkanol containing 1-4 carbon atoms, such as absolute methanol or ethanol, at or below 0 ° C.

The conversion / H / 'can be carried out in the manner previously indicated for the conversion of compounds of general formula IVD to those of general formula IVE. 4bZ 157 18 The starting material of general formula VIII, wherein R 8 represents a benzyl group, is a known compound described in J.Org.Chem., 37, 2921 (1972). The starting materials of general formula VIII, wherein R is other than a benzyl group, are prepared as described in Japanese Patent 53-149954.

The compounds of the general formula IV, in which R1 represents a formyl group, Y represents; IC = 0, Z represents \ l / OR 5 _ ,, C fl ~ _, RH the other symbols have the meaning given above, i.e. compounds with represent a tetrahydropyran -2-yl group and the general formula IVE, to compounds of the general formula: 0 3 cooall ^ \\ v, / ^ \\ v // §§ï {ß 'XV az-R3 I.

I I I 0-TH? o_THæ (wherein R 11 represents an alkyl group containing 1-4 carbon atoms, the double bonds between the carbon atoms in positions 2 and 3 and positions 13 and 14 are trans (ie E), and the other symbols have the meaning given above) by a Wittig reaction with a phos precursor of the general formula: (R7) 3P = cHcooR111 xvl (wherein R 1 and R 1 are as defined above) in a manner previously mentioned for the conversion of compounds of the general formula V to those of the general formula IVA.

Phosphorus compounds of the general formula XVI are well known or can be easily prepared by methods known per se. Compounds of the general formula XV are converted into trans-ZÄ2-prostaglandin E1 analogues of the general formula: XVII 10 15 20 25 30 55 40 m 452 157 (wherein the various symbols have the meaning given above) by hydrolysis under acidic conditions for converting the tetrahydropyran-2-yloxy groups to hydroxy groups.

The hydrolysis for the conversion of the tetrahydropyran-2-yloxy groups to hydroxy groups under acidic conditions is well known.

The hydrolysis can be carried out, for example, with (1) an aqueous solution of an organic acid, such as acetic acid, propionic acid, oxalic acid, p-toluenesulfonic acid, or of an inorganic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, preferably in the presence of an inert organic solvent such as is miscible with water, for example a lower alkanol, such as methanol or ethanol, preferably methanol, or an ether, such as 1,2-dimethoxyethane, dioxane, tetrahydrofuran, preferably tetrahydrofuran, at a temperature of from room temperature to 75 ° C, or (2) an anhydrous solution of an organic acid, such as p-toluenesulfonic acid or trifluoroacetic acid in a lower alkanol, such as methanol or ethanol, at a temperature of from 0 to 45 ° C, or (3) an anhydrous solution of p- toluenesulfonic acid-pyridine complex or trifluoroacetic acid-pyridine complex in a lower alkanol, such as methanol or ethanol at a temperature of from 10 to 6000.

The mild hydrolysis under acidic conditions can be advantageously carried out with a mixture of dilute hydrochloric acid and tetrahydrofuran, a mixture of dilute hydrochloric acid and methanol, a mixture of acetic acid, water and tetrahydrofuran, a mixture of phosphoric acid, water and tetrahydrofuran, a mixture of p-toluenesulfonic acid and methanol, a mixture of p-toluenesulfonic acid-pyridine complex and methanol or a mixture of trifluoroacetic acid-pyridine complex and methanol.

The trans-ZA2-prostaglandin-E1 analogs of the general formula XVII thus obtained are useful in human or veterinary medicine, as described in British Pat. Nos. 1,416,410, 1,485,240 and 1,540,427. They possess the valuable pharmacological properties which are typical of prostaglandins in a selective manner including especially hypotensive activity, inhibitory activity on platelet aggregation, inhibitory activity on gastric acid secretion and gastroulcer and bronchodilator activity and are useful in the treatment of hypertension, in the treatment of disorders of the peripheral circulation, in the treatment and prevention of cerebral thrombosis and myocardial infarction, in the treatment of gastroulcer and in the treatment of asthma. 10 15 20 25 30 35 NO 452,15? The trans-L 1 -prostaglandin-E1 analog of the general formula XVII, wherein the group -R 2 -R 3 represents a 1,1-dimethylphenyl group and H 11 represents a methyl group, i.e. (2E, 13E) - (11a, 15R) 9-Oxo-11,15-dihydroxy-16,16-dimethylprosta-2,3-diene acid methyl ester, described in British Patent 1,540,427, is useful in terminating pregnancy and initiating labor in pregnant mammals and in control of oestrus, as a contraceptive and for menstrual regulation in female mammals.

Thus, it appears that the novel compounds of the present invention of the general formula IV, i.e. compounds of the general formula IVA, IVB, IVC, IVD and IVE are useful and important intermediates for the preparation of therapeutically useful trans-Ål2-prostaglandin -El analogues.

In addition, the new compounds of the general formula V, IX, X, XI and XIV, i.e. compounds of the general formula:? R12 '' l \\ * x - / (\\\ cH¿oRl2 .i 13 - 6- THP / wherein X represents an ethylene or vinylene group, Big represents a hydrogen atom or a hydroxy protecting group, which is eliminated XVIII - under basic conditions and selected from acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl, phenophenyl), benzophyl; , B13 hydroxymethyl group (-CHEOH), or a group -CHEORB, wherein RB has a fi mmyl group, a meaning given above, and the other symbols have the meaning given above, with the proviso that a formyl group, X represents an ethylene group and R1 a hydroxy protecting group, which is eliminated under basic conditions and has the previously stated meaning, (ii) when R 10 represents- (i) when B13 represents 2 PGPTGSGII- represents a hydroxymethyl group, E12 represents a hydroxy protecting group, which is eliminated under basic conditions and has previously 13, and (iii) when R represents a group -CH 2 OR 8, X represents a vinylene group / also useful and essential intermediates for the preparation of trans-Ä 2 -prestaglandin-E 1 analogues. When X represents a vinylene group, the double bond may be E, Z or a mixture thereof.

The use of the compounds of the general formulas IV and XVIII enables the synthesis of trans-α-2 prostaglandin-E1 analogues by methods described above, in which certain disadvantages of the previously mentioned two known methods are avoided. The use of phosphonium compounds of the general formula XII makes it possible to avoid the need to use the unstable phosphorus compound required in the process described in British Patent 1,416,410 (the compounds of the formula XII have the group -CHQOH instead of the unconjugated carboxy group and is therefore more stable, leading to higher yields); selective hydrogenation which entails a risk of reduced yield of the desired product is not required; and the watch chain is introduced at a relatively late stage in the process. In addition, the use of selenium or sulfur compounds is not required and the necessary thorough purification steps to remove traces of such compounds in the final prostaglandin products are not necessary.

The following examples illustrate the present invention.

In the examples, "TLC", "IR" and "NMR" represent "thin layer chromatography", infrared absorption spectrum "and" magnetic nuclear resonance spectrum "respectively. When the solvent ratios are given in the chromatographic separations, the ratios are based on the volume, and the solvents in parentheses show use. Except where otherwise stated, infrared spectra have been recorded by the liquid film method and magnetic nuclear resonance spectra are given in deuterochloroform solution (CDCl3).

Example 1 (EZ) -2d- (5-hydroxypent-2-enyl) -3β- (1-methoxy-1-methyl) ethoxymethyl-4α- (tetrahydropyran-2-yloxy) cyclopentan-1a-cl Under nitrogen atmosphere was added 29, 1 ml of a 1.5M solution of butyllithium in hexane to a suspension of 8.748 g of 3-hydroxypropyltriphenylphosphonium bromide in 70 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 10 minutes. to form a ylide solution. To the thus obtained ylide solution was added a solution of 3 g of 2-oxa-6-syn- (1-methoxy-1-methyl) ethoxymethyl-7-anti- (tetrahydropyran-2-yloxy) -cis-bicyclo / B, 5 .0 / octan-3-ol (prepared as described in ref, ex. 2 of Japanese Patent 53-149954) in 10 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 1 hour and then at 4000 for 30 minutes. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, and the mixture was washed with water and a saturated aqueous solution of sodium chloride, dried, extracted with ethyl acetate. over magnesium sulfate and concentrated under reduced pressure to give the title compound in crude form having the following physical characteristics. The crude product was used in the next step without purification. 10 15 20 25 EG 35 40 452 157 ”TIC (ethyl acetate cyclohexane) = 2: 1): Rf = 0.23. (a) Using the above procedure but substituting 2-oxa-6-syn- (1-methoxy-1-methyl) ethoxymethyl-7-ant1- (tetrahydropyran-2-yloxy) -cis-bicyclo [3, 3,0-bctan-3-μl against 2-oxa-6-syn-benzyloxymethyl-7-anti- (tetrahydropyran-2-yloxy) -cis-bicyclo [3.3.0] bctan-3-ol / prepared as described in J. Org. Chem., 37, 2921 (1972) / obtained (EZ) -2a- (5-hydroxypent-2-enyl) -3β-benzyloxymethyl-4a- (tetrahydropyran-2-yloxy) cyclopentane 1a-ol with the following physical characteristics: TIC (ethyl acetate-cyclohean = 2: 1): Example gel 2 (EZ) -la-acetoxy-2a- (5-acetoxypent-2-ene 1) -3β- (1-methoxy-1 -methyl) -ethoxymethyl-4a- (tetrahydropyran-2-yloxy cyclopentane The crude product, prepared as described in Example 1, was stirred overnight with 14 ml of acetic anhydride and 35 ml of pyridine at room temperature.The reaction mixture was diluted with ethyl acetate, washed with hydrochloric acid, 5N hydrochloric acid , water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to give the title crude compound. with the following physical characteristics. steps without purification.

TIG (ethyl acetate cyclohexane = 2: 1) Rf = 0.79. (a) According to the procedure described above but during exchange of the crude product from ex. l used as starting material against the crude product according to ex. In (a) the following compound was prepared. The product was purified by column chromatography on silica gel using a mixture of ethyl acetate and cyclohexane (1: 2) as eluent to give 73% yield based on the starting material from e.g. 1 (a): (EZ) -1α-acetoxy-2α- (5-acetoxypent-2-enyl) -3B-benzyloxylmethyl-Ed- (tetrahydropyran-2-yloxy) cyclopentane: TIG (cyclohexane ethyl acetate = 2: 1): Rf = 0.82 Inn) = 1740, 1243, 1ø21 etc.

NMB (CCl 3 solution): δ = 7.12 (5H, m), m), 4.61 (1H, m), 4.56 (2H, s), 4.20-3.20 (EH, m ), 2.00 (GH, s).

Example 2 (EZ) -1α-acetoxy-2α4 (5-acetoxypent-2-enyl) -3β-hydroxymethyl-4α-tetrahydropyran-2-yloxy) cyclopentane Rf = 0.25.

The crude product was used in the next 5.40 (2H, M), 5.97 (2H, t), 5.00 (1H, 3.40 (2H, d). The crude product, prepared as described in Example 2, was stirred with 40 The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure to a mixture of tetrahydrofuran and 15 ml of 1N hydrochloric acid at 0 DEG C. for 30 minutes. The residue was purified by column chromatography on silica gel using diethyl ether as eluent to give 2.30 g of the title compound having the following physical characteristics: TIG (ethyl acetate-cyclohexane = 2: 1): Rf = 0.42 IR = \ 7 = 3460, 1737, 1243, 1023 cm -1 mm / cm 3 (cciu-1 solution) = 6 = 5.35 (an, m), (1H, N), 3:95 (2H = t), Example 4 1a-acetoxy -2a- (5-acetoxypentyl) -3B-hydroxymethyl-4a- (tetrahydropyran-2-yloxy) cyclopentane Under a hydrogen atmosphere, a mixture of 10.402 g of the pentenyl compound prepared according to Example 3 was stirred. 120 ml of methanol and the reaction mixture were filtered and the filtrate was concentrated under reduced pressure to give 10.264 g of the title compound having the following physical characteristics: TIC (ethyl acetate: benzene = 2: 1, using a silica gel -Rf = 0 4.47 (1H, N), 4.55 4: 20 "5: 16 m) .v (6H: 5) 100 mg of platinum dioxide at room temperature for 5 hours. plate pretreated with silver nitrate): In: ȉ = 3469, 1740, 1247, 1020 cm'l.

NM (cola solution) = δ = 4.96 (1n, m), 4.52 (1n, m), 4.20-3.15 (5H, m), L, 97 (6H, s).

Example §. 1a-acetoxy-2α- (5-acetoxypentyl) -3B-formyl-4u- (tetrahydropyran-2-yloxy) cyclopentane To a suspension of 5.79 g of N-chlorosuccinimide in 300 ml of toluene was added 3.94 ml of dimethyl sulfide at 0 ° The mixture was stirred at this temperature for 40 minutes. To the resulting solution was added a solution of 1.1 g of the hydroxymethyl compound prepared as described in e.g. 4 in 20 ml of toluene at -20 ° C. The mixture was stirred at the same temperature for 1 hour and then stirred with 12.1 ml of crystalline amine at -20 ° C for 30 minutes. neutralized with 0.1N hydrochloric acid, diluted with diethyl ether, washed with 0.1N hydrochloric acid, a saturated aqueous solution of sodium 3,93 (2H, 3), the reaction mixture of hydrogen carbonate, water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on. Silica gel using a mixture of ethyl acetate and cyclohexane (1: 1) as eluent to give 10.327 g of the title compound having the following physical characteristics: TIG (ethyl acetate-benzene = 2: 1): Rf = 0.74 iR = 0 = 17ßo, 1377, 1247, 1025 cm -1.

NMB = δ = 9.65 (1H, t), 5.50-4.35 (1H, m), Exemgel 6a-aethoxy-2a- (5-acetoxypentyl) -3B-hydroxymethyl-4d- (tetrahydropyran -2-yloxy) cyclopentane Under a hydrogen atmosphere, a mixture of 4.74 g of the benzyloxymethyl compound prepared as described in ex. 2 (a), 100 ml of ethanol and 20 g of Raney nickel (w-7) under reflux for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 3.48 g of the title compound having the same physical characteristics as the product, e.g. 4.

Example 1 (E) -1d-acetoxy-2α- (5-acetoxypentyl) -5β- (3-oxa-4,4-dimethyloct-1-enyl) -4d- (tetrahydropyran-2-yloxy) cyclopentane Under a nitrogen atmosphere a solution of 11,54 g of dimethyl 2-oxo-5,3-dimethylheptylphosphonate in 50 ml of tetrahydrofuran dropwise to a suspension of 1.317 g of sodium hydride (63.5% content) in 250 ml of tetrahydrofuran at room temperature, and the mixture is stirred at room temperature for 30 min. To the solution thus obtained was added a solution of 10.937 g of the formyl compound prepared as described in e.g. In 100 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 2.5 hours.

The reaction mixture was acidified with acetic acid, filtered and the filtrate was concentrated under reduced pressure. 3f: 8'3: 1 111): The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (}: 1) as eluent to give 12.3 g of the title compound having the following physical characteristics: TIG (cyclohexane ethyl acetate = 1: 1): Rf = 0, 0 IR = v = 1740, 1695, 1625, 1246, 1025 cm -1.

NMR: δ = 7.10-6.30 (2H, m), 5.40-5.00 (1H, m), (1H-fl713): 4:35 "3.vlo (SH: m) - Exemgel 8 (E) -la-acetoxy-2a- (5-acetoxypentyl) -} B- (3R-hydroxy-4,4-dimethyl-oct-1-enyl) -4a- (tetrahydropyran-2-yloxy) cyclopentane Under nitrogen atmosphere 100 ml of a 25% (w / v) 4.80-4.35 solution of diisobutylaluminum hydride in toluene was added to a solution of & g8 g 2,6-di-tertiary butyl-4-methylphenol in 660 ml of toluene at 0 DEG-5 DEG C. and the mixture was stirred at the same temperature for 1 hour. To the solution was added a solution of 8.64 g of the 3-oxo compound prepared as described in 1 Example 7 1 60 ml of toluene at -78 ° C, and the mixture was stirred at -30 to -2000 for 5 hours, the reaction mixture was stirred with 80 ml of water at 4006 for 30 minutes, filtered and the filtrate was concentrated under reduced pressure. was purified by column chromatography on silica gel using a mixture of methylene chloride and ethyl acetate (4: 1) as eluent to give 7.5 g of the title compound. d the following physical characteristics: TIG (benzenesethyl acetate = 3: 1): Rf = 0.30, (38-isomer, Rf = 0.59) IR = v = 3740, 1738, 1372, 1243, 1017 cm -1.

NMB (CCl 3 solution): δ = 5.42 (2H, m), 4.96 (1H, m), 4.46 (1H, m), 3.90 (2H, t), 4.10-3.15 (HH, m), 1.97 (an, S), 1.93 (3H, S).

Example Gel 2 (E) -1α-acetoxy-2α- (5-acetoxypentyl) -3β- / BR- (tetrahydropyran-2-yloxy) -4,4-dimethyloct-1-enyl / β4a- (tetrahydropyran-2-yloxy) - cyclopentane A mixture of 7.5 g of the BR-hydroxy compound prepared as described in ex. 8.3 ml of 2,3-dihydropyran, 25 mg of p-toluenesulfonic acid and 80 ml of methylene chloride were stirred at room temperature for 15 minutes. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate.

The extract was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to give 8.88 g of the title compound having the following physical characteristics: TIG (cyclohexane ethyl acetate = 2: 1): Rf = 0.57.

Example 10 (E) -2a- (5-hydroxypentyl) -β- (R- (tetrahydropyran-2-yloxy) -4,4-dimethyloct-1-enyl] -4a- (tetrahydropyran-2-yloxy) cyclopentane -la-ol A mixture of 8.88 g of the acetoxy compound prepared as described in ex. 9, 4.05 g of potassium carbonate and 80 ml of methanol are stirred at 50 DEG C. for 1.5 hours. with ethyl acetate, washed with a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate and concentrated. The reaction mixture was diluted under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and cyclohexane (2: 1) as eluent to give 7.2 g of the title compound having the following physical characteristics: TIC (ethyl acetate: cyclohexane, = 2: 1): Rf = 0.27 1R = \) = 3400, 1137, 1026, 978 cm -1.

NM: δ = 5.60-5.25 (2H, m), 4.60 (2H, m), 4.50-3.20 (9H, m).

Example 11 (E) -2a- (4-formylbutoxy) -3β- [3n- (tenranyaropyranphenioxy) -4,4-dimethyloct-1-enyl] -2- (tetrahydropyran-2-yloxy) cyclopentan-1-one A solution of 0.335 ml of chromyl chloride in 2 ml of carbon tetrachloride was added dropwise to a solution of 0.786 ml of tert-butanol and 1.01 ml of pyridine in 13 ml of methylene chloride at -78 °. To the solution was added a solution of 902 mg of the cyclopentan-1a-ol compound prepared as described in ex. 10 ml of methylene chloride at room temperature, and the mixture was stirred at room temperature for 2 hours and then at 54 ° C for 40 minutes. The reaction mixture was stirred with 0.5 ml of dimethyl sulfide at room temperature for 10 minutes. 60 ml of diethyl ether and 20 ml of water were added and the mixture was filtered through a pad of infusion soil. The ether layer of the filtrate was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (3: 1) as eluent to give 675 mg of the title compound having the following physical characteristics: TIG (cyclohexane ethyl acetate = 2: 1): Ef = 0 44 IR: L1 = 1745, 1730, 1130, 1078, 1037, 1023 cm -1 Nmm (cc14-1solution): δ = 9.50 (1H, t), 5.70-5.30 (2H, m) , 4.71-1 +, 42 (zman), 451-107 (6H, m) - Exemgel 12 (2E, 15E) - (11a, 15R) -9-oxo-11,15-bis (tetrahydropyran-2- yloxy) - 16,16-aminoeniprosta-2,13-diene acid methyl ester Under a nitrogen atmosphere, a mixture of 184 mg of cyclopentan-1-one prepared as described in ex. 11.32 mg of methoxycarbonylmethylivine triphenylphosphorane and 2 ml of chloroform at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (5: 1) as eluent to give 192 mg of the title compound having the following physical characteristics: TIG (benzene: ethyl acetate = 2: 1): Rf = 0.74 In = v = 1745, 1726, 1654, 1196, 1128, 1950 cm-1. 10 NMR: δ = 6.90 (1H, dt), 5.70 (1H, d), 5.80-5.40 (2H, m), 4.60 (2H, m) . - Rubr. compound was also prepared by the procedure described above in exchange for the methoxycarbonylmethylidentrifhenylphosphorane for a phosphorane compound (R 7) 3 P = CHCOOCH 3, wherein R 7 is as defined in the table below, and while modifying the reaction temperature, reaction time and solvent.

R7 Éââšššâ fi â; Reaïï ° ° ns' Solvent Yield -c4H9 -eo: 111 o ° c 2 sim: one cyclohexyl r.t.X 15 hours chloroform 94.1% -C6Hl3 r.t.x 1.5 hours tetrahydrofuran 98% xr.t. means room temperature.

Example gel lay (2E, 13E) - (11a, 15R) -9-oxo-11,15-dihydroxy-16,16-dimethylprosta-2,13-dienoic acid methyl ester To a solution of 732 mg of (2E, 13E) - ( 11α, 15R) -9-oxo-11,15-bis (tetrahydropyran-2-yloxy) -16,16-dimethylprosta-2,1} -dienoic acid methyl ester (which can be prepared as described in Example 12) in 1, 9 ml of tetrahydrofuran was added 19 ml of a 65% (v / v) aqueous solution of acetic acid, and the solution was stirred at 55-60 ° C for 1 hour. The reaction mixture was then extracted with ethyl acetate, and the extract was washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to give 119 mg of the title compound having the following physical characteristics: TIC (developer solvent: chloroform: tetrahydrofuran acetic acid) = 10: 2: 1): Rf = 0.51.

IH: »J = 5400, 2940, 2850, 1750, 1730, 1660, 1440, 1280 em '.

NMR = δ = 7.10-6.75 (1H, m), 5.95-5.40 (§H, m), 5.71 (3H, S), 4.20-3.60 (an, m), 2.75 (ln, aa), 1.00-0.75 (9H, m).

Example Gel IU (2E, 13E) - (11u, 15s) -9-oxo-11,15-bis (tetrahyaropyran-2-yloxy) -17,20-dimethylprosta-2,3-diene acid methyl ester. Under an atmosphere of nitrogen, a mixture of 506 mg of (E) -2a- (U-formylbutyl) -3B-t} S- (tetrahydropyran-2-yloxy) -5-methyl-non-1-enyl] -Hu was stirred. - (tetrahydropyran-2-yloxy) cyclopentan-1-one, 666 mg of methoxycarbonylmethylidenephrenylphosphorane and 5 ml of chloroform at room temperature for 3 hours, after which the mixture was concentrated under reduced pressure. the residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (3: 1) as eluent to give 53H mg of the title compound having the following physical characteristics: TLC (cyclohexane : ethyl acetate = 2: 1): Rf = 0.08; In: u = 17n7, 1725, 165u, 1195, 1126 cm-1; NMR: δ = 6.92 (1H, dt), 5.72 (1H, d), 5.82-5.52 (2H, m), 14.82-1z, 52 (zu, mf, 3.72 (311, s), 1.03-o, 70 (GH, m).

The starting material, (E) -2a- (4-formylbutyl) -3β- [§S- (tetrahydropyran-2-yloxy) -5-methylnon-1-enyl] -4a- (tetrahydropyran-2-yloxy) - cyclopentan-1-one, was prepared by the procedure described in Examples 7 to 11, replacing the dimethyl 2-oxo-3,3-dimethylheptylphosphonate with a dimethyl-2-oxo-U-methyloctylphosphonate, with the following physical characteristics: TLC (cyclohexane: ethyl acetate = 2: 1): Rf = 0.1, 3; 1a = \> = 17h7, 1730, 1130, 1075 cm'1; NMR: δ = 9.52 (1H, t), 5.75-5.32 (2H, m), δ, 82-δ, 52 (2H, m), δ, 30-3.20 (6H, m ), 1.02-0.70 (§H, m),

Claims (10)

A compound of the general formula: 10 'Iv 1 was 1 2 E 1 zR -R 30 O-THP_v> Ä, .OR 4 wherein Y represents:; C = 0 or ÉFC' (where Ru represents H a hydrogen atom or a hydroxy protecting group which is eliminated under basic conditions and selected from acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl, benzoyl, p-phenylbenzoyl and naphthyloyl), Z represents 2> C = O or \\\ _, - 'ORS N 5. /// CH (where R represents a hydrogen atom or a tetrahydropyran-2-yl group), B1 represents a formyl group or a group of the formula -CHEOBÄ (where Ru has the meaning given above), R represents a simple bond or an alkylene group containing 1-5 carbon atoms, R 3 represents a hydrogen atom, an alkyl or alkoxy group containing 1-8 carbon atoms or a cycloalkyl or cycloalkyloxy group containing 4-7 carbon atoms unsubstituted or substituted by at least one alkyl group containing 1-8 carbon atoms or represents a phenyl- or phenoxy group unsubstituted or substituted by at least one halogen atom, trifluoromethyl group or alkyl group containing 1-Ä carbon atoms, with the proviso that when R 2 represents a monobin moiety, R 3 does not represent an alkoxy, cycloalkyloxy or phenoxy group, THP represents a tetrahydropyran-2-yl group and the double bond between the carbon atoms in positions 13 and Ia is trans, i.e. E, with the proviso that (i) when Z represents fI = C = 0 or r, -oR5 \\\ ø (where H5 C, / "/ \" \: HH terat \\ * C "" OR which is eliminated under basic conditions and has the above-mentioned condition) and H1 R represents a hydroxy protecting group which eliminated under ba- represents a hydrogen atom), Y represents- (where Ru represents a hydroxy protecting group represents a group of the formula -CHZOR (where 452 157 conditions and has the meaning given above) and (ii) when 5, OR p Z represents: :: I CZ: ~ _! (wherein R 5 represents a tetra-H hydropyran-2-yl group), __OR 4 (a) Y represents ::: 3C 1;:;. H (wherein Ru represents a hydroxy protecting group which is eliminated under basic conditions and has the previously stated meaning) and B 1 represents a group of the formula -CH 2 OR (wherein R "represents a hydroxy protecting group which is eliminated under basic conditions and has the previously indicated meaning), RH - -O '-". H (b) Y represents _ \\ * '(wherein R represents a / ÉH u hydrogen atom) and B1 represents a group of the formula -CHQOR (wherein Ru represents a hydrogen atom), or (c) Y represents 2: = C = O and R 1 represents a formyl group. A compound according to claim 1, wherein the group -R 2 -R 3 represents the 1,1-dimethylpentyl group. A compound according to claim 1 or 2, wherein the hydroxy protecting group ß represented by R is acetyl. HRS. A compound according to any one of claims 1-3, wherein R 1 represents a group -CH 2 OR, Y represents R 14; /, C 2 - _ ~ I 1, Z represents ::: C = O, R represents a hydroxy protecting group, which is eliminated under basic conditions and has the previously stated meaning and the other symbols have the meaning given in claim 1. A compound according to any one of claims 1-3, wherein R 1 represents a group -CH 29 R, Y represents 5> C 1 {: R, Z represents> C 11, R represents a hydroxy protecting group which is eliminated under basic conditions and has in claim 1 stated meaning, R5 represents a hydrogen atom and the other symbols have the meaning given in claim 1. A compound according to any one of claims 1-3, wherein E 1 represents a group -CH 2 OR, Y represents, -OR _ 5 \ _ \ x / on G1: Z t R t //, H, represents _, H, represents a hydroxy protecting group which is eliminated under basic conditions and has the meaning given in claim 1, R 5 represents a tetrahydropyran-2-yl group and the other symbols have given in claim 1 meaning. A compound according to any one of claims 1-3, wherein R1 represents a group -CHQOR, Y represents 45, OR, ZR, Z represents: II C "H, Ru represents is a hydrogen atom, RS represents a tetrahydropyran-2-yl group and the other symbols have the meaning given in claim 1. A compound according to claim 1 or 2, wherein R 1 represents a formyl group, Y represents E 1 = C = O, Z represents ::: C __, - OR 5 R 5 * \ __ H 'and the other symbols have the meaning given in claim 1. 9. (E) -la-acetoxy-2α- (5-acetoxypentyl) -38- (3-oxo-H, β-dimethyloct-1-enyl) -Ha- (tetrahydropyran-2-yloxy) cyclopentane, (E ) -la-acetoxy-2u- (5-acetoxypentyl) -3B- (3R-hydroxy- represents a tetrahydropyran-2-yl group -H, U-dimethyloct-1-enyl) -uu- (tetrahydropyran-2-yloxy) cyclopentane , se (E) -la-acetoxy-2a- (5-acetoxypentyl) -3β- fl} R- (tetrahydropyran-2-yloxy) -H, β-dimethyloct-1-enyl] -α- (tetrahydropyran- -2-yloxy) cyclopentane, (E) -zu- (5-nydroxypentyl) -ss- [3R- (tetranyaropyran-2-yloxy) -4, H-dimethyloct-1-enyl] -ha- (tetrahydropyran-2 -yloxy) -cyclopentan-1a-ol "and (E) -za- (H-rormylbutyl) -ze- [3R- (tecrahyaropyran-2-yloxy) -U, U-dimethyloct-1-enyl] -Ha- (tetrahydropyran-2-yloxy) -cyclopentan-1-one. Process for the preparation of a compound of the general formula IV according to Claim 1, in which the various symbols have the meaning given in claim 1, characterized in that a compound of the general formula is reacted: 452,157 wherein Raa represents a hydroxy protecting group which is eliminated under basic conditions and has the meaning given in claim 1 and THP represents a tetrahydropyran-2-yl group) with a sodium derivative of a dialkylphosphonate of the general formula: (R60) 2§cH2c-R2-R5 vI O (Wherein R 6 represents an alkyl group containing 1-4 carbon atoms and R 2 and H 3 have the meaning given in claim 1) or with a phosphorus precursor of the general formula: (n 7) 31> = cr 1c-n 2 -n 3 VII O (wherein H 7 represents a phenyl group which is unsubstituted or substituted by at least one alkyl group containing 1-4 carbon atoms or represents an alkyl group containing 1-6 carbon atoms or represents a cyclohexyl group, and R 2 and H 3 have the meaning given in claim 1) to formation of a compound of the general formula:. galla I f \ / \ / ° “2 °“ 4 ° 2 3 IVA | (where R 4a and THP have the meaning given above and the other symbols have the meaning given in claim 1) followed if it is desired by one or more of the following steps in turn: (a) reduction of the compound with the general formula IVA for the conversion of the 15-oxo group to a 15-hydroxy group, (b) etherification of the product from step (a) with 2,3-dihydropyran in an inert organic solvent in the presence of an acidic catastrophe. ._u. ___... mmlzzrxnrrr f * '| _- wav-v- ß- 452 157 š 33 lysator at or below room temperature for conversion of the 15-hydroxy group to a 15-tetrahydropyran-2-yloxy group, (c) saponifying the product from step (b) for the conversion of the groups OR4a to hydroxy groups, and (d) oxidation of the product from step (c) for the conversion of a hydroxymethyl group and a new hydroxyl group 19 position to formyl and oxo group.