NL8000428A - INTERMEDIATES FOR THE PREPARATION OF PROSTAGLANDINE ANALOGS, METHODS FOR PREPARING THEM AND THEIR USE IN THE PREPARATION OF PROSTAGLANDINE ANALOGS. - Google Patents

Description

i i Ν.Ο. 28,659 -1-

Intermediates for the preparation of prostaglandin analogs, methods of their preparation and their use in the preparation of prostaglandin analogs.

The present invention relates to new chemical compounds suitable as intermediates for the preparation of trans-Δ-prostaglandin E. analogs, to methods of their preparation and to their use in the preparation of trans-Δ · -5 prostaglandin E1 analogues.

Prostaglandins are derivatives of prostanoic acid, which has the formula 1.

Different types of prostaglandins are known, the types depending inter alia on the structure and the substituents on the alicyclic ring. For example, the alicyclic ring of prostaglandin E (PGE) has the structure of formula 2. The dashed lines in the preceding formulas and in other subsequent formulas indicate, in accordance with generally accepted nomenclature rules, that the attached group is behind the general plane of the ring system 15, i.e. the group is in the α configuration, the thickened lines indicate that the group is in the general plane of the system, i.e. the group is in the β configuration and the wavy line A / W indicates that the group is in the a or β configuration.

Such compounds are classified according to the position of the double bond (s) in the side chain (s) linked to the 8 and 12 positions of the alicyclic ring. Therefore, PG compounds have a trans-double bond between G13'CH (trans-Δ) and PG compounds have a cis-double bond between and a trans- double bond between trans- Δ). For example, prostaglandin E ^ (PGE ^) is characterized by the structure of formula 3. s *

The structure of PGE ^, as a member of the PG2 group, corresponds to that of formula 3 with a cis-double bond between the carbon atoms in positions 5 and 6. Compounds, wherein the double bond between the carbon atoms at positions 13 and 1½ of members of the PG1 group is replaced by ethylene are known as dihydro-prostaglandins, for example, dihydro-prostaglandin E1 (dihydro-PGE1).

35 PGE compounds with a trans-double bond between the carbon atoms in positions 2 and 3 are known as trans-Δ-PGE compounds 800 0 4 26 2 -2 and the structure of trans-Δ - PGE ^ corresponds to that of formula 3 with a trans-double bond between the carbon atoms in positions 2 and 3 *

In addition, when one or more methylene groups are added to, or removed from, the γ1 chain, ie, the aliphatic group, are bound at the 12-position of the alicyclic ring of the prostaglandins, and / or the α chain, i.e. the aliphatic group bound at the 8-position of the alicyclic ring of the prostaglandins, the compounds known, according to the usual rules of organic nomenclature, as homo-prostaglandins ( methylene group added) or nor-prostaglandins (methylene group removed), and, if more than one methylene group is added or removed, this number is indicated by di-, tri-, etc. for the prefix “homo” or “nor”, 15 prostaglandins are well known to possess pharmacological properties, for example, stimulate smooth muscle, have hypotensive, diuretic, bronchodilating and anti-lipolytic activities, and also inhibit platelet aggregation and gastric acid secretion. g and are consequently useful in the treatment of hypertension, thrombosis, asthma and gastrointestinal tracts, induction of labor and abortion in pregnant female mammals, in the prevention of arteriosclerosis and as diuretics. They are fat-soluble products, available in very small amounts from various animal tissues, which secrete the prostaglandins into the living body.

For example, the PGEs have an inhibitory effect on gastric acid secretion and can therefore be used to treat stomach ulcers. 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 blood and are therefore useful in the prevention of arteriosclerosis and hyperlipemia. PGE ^ inhibits platelet aggregation and also removes the thrombus and prevents thrombosis. PGEs have a stimulating effect on the smooth muscles and increase intestinal peristalsis; these actions indicate therapeutic utility in post-operative ileus and as purgatives, PGEs can also be used as oxytocics, as abortive agents in the first and second trimesters; in the expulsion of the placenta and as oral contraceptives, because they regulate the sexual cycle of female mammals. PGEs have ^ • 0 vasodilating and diuretic activities. They are suitable for the improvement of patients suffering from cerebral vascular diseases because they increase cerebral blood flow and are also useful in the treatment of asthmatic conditions in patients due to their bronchodilating activity.

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

A first method is described in British Patent Specification 1,416,410. However, to form the double bond between the carbon-10 atoms in positions 5 and 5, the method requires the use of a phosphorane compound (CgH ^ ^ PsCHCi ^ COOH, of which the carboxyl group (-C00H) is not conjugated. the phosphorane compound makes it difficult to obtain high yields.

Furthermore, in the described series of reactions to prepare the trans-2 Δ-prostaglandins, a selective hydrogenation is necessary, if 2 is to obtain a trans-Δ-PGE-analog. It is necessary to hydrogenate a double bond between carbon atoms in positions 5 and 6, while a double bond between carbon atoms in positions 13 and 14 remains unaffected. There is a risk of hydrogenation of both double bonds, which leads to a decrease in the yield of desired product. Finally, the µ chain is introduced at an early stage in the series of reactions, leading to the desired trans-Δ prostaglandin, so that a large amount of required expensive substrate is required to introduce any desired β chain.

The second method is described in British Pat. Nos. 1,483,240 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. Spore amounts of such compounds are harmful to humans and if the final 2 trans-Δ-prostaglandin products are to be used as medicaments, the sulfur or selenium compounds must be removed.

Such removal is difficult and requires considerable care. In addition, the selenium or sulfur compounds have a very unpleasant odor, which presents difficulties in their preparation and application.

As a result of research and experimentation, new chemical compounds have been found which are useful as intermediates 2 in improved methods of preparing trans-Δ-PGE analogs.

The novel chemical compounds of the present invention, ftnn ok 2 -4- suitable for the preparation of trans-Δ-prostaglandin E 1 analogs, are the compounds of the general formula 4, wherein if .OR 4 Y 'pCsO or (wherein B a hydrogen atom or a hydroxy

^ ^> H

that protecting group, which is eliminated under basic conditions, represents 5), Z q ^ 5 (where R ^ is a hydrogen atom or ^ C = 0 or ^

Xh 1 represents a tetrahydropyran-2-yl group), R a formyl group or a

Ij.

group of the formula -CH 2 OR (wherein R has the aforementioned definition), R a single bond or an alkylene group of 1 to 5 carbon atoms, R a hydrogen atom, an alkyl or alkoxy group of 10 1 to 8 carbon atoms, or a cycloalkyl or cycloalkyloxy group of 4-7 carbon atoms, unsubstituted or substituted with at least one alkyl group of 1-8 carbon atoms or a phenyl or phenoxy group, unsubstituted or substituted with at least one halogen atom, trifluoromethyl group or alkyl group of 1-4 cabbage 2

15 represent material atoms with the proviso that when R represents a single bond, R 4 does not represent an alkoxy, cycloalkoxy, or phenoxy group, THP represents a tetrahydropyran-2-yl group, and the double bond between the carbon at positions 13 and 14 trans, i.e. E, with the proviso that (i) when Z

^ '' ° b5 5 represents 20 ^ 3C = 0 or ^ TC ^, (wherein R "7 is a hydrogen atom),

4 H

^ -'0B if Y (wherein R represents a hydroxy protecting group, which is removed under alkaline conditions) and 1 4 4 R represents a group of the formula -Ci ^ OR (wherein R represents a hydroxy protecting group, which is under alkaline conditions Ί 25 is removed), and (ii), when Y represents, R represents a for myl group.

It should be noted that alkyl and alkylene groups and alkyl and alkylene moieties of the groups referred to can be straight or branched.

The present invention relates to all compounds of the general formula 4 in the optically active "natural" form or its enantiomeric form, or mixtures thereof, more particularly the racemic form, consisting of equimolar mixtures of the optically active "natural" "form and its enantiomeric form.

As will be apparent to those skilled in the art, the compounds in the general formula k have presented at least three centers of chirality at the carbon atoms in the 8-, 11- and 12-position.

Still other centers of chirality may exist in branched alkyl

or alkylene groups, or when the symbol Y represents a group, -OR

if ^ 5, where R represents the above meanings ^ N * -

5 H

or when the symbol Z represents a group X0R, where R has the aforementioned meanings. The presence of chirality, as is well known, leads to the existence of isomerism. However, all compounds of the general formula have such a configuration that the substituent groups bonded to the cyclopentane ring carbon atoms at the positions identified as 8 and 12 are trans relative to each other. Accordingly, all isomers of the general formula if, and mixtures thereof, containing these substituent groups bonded to the cyclopentane ring carbon atoms at positions 8 and 12 in the trans configuration should be understood to fall within the scope of the general formula if.

2 3

Preferably, the group -R -R represents, for example, methyl, ethyl, 1-methyl-ethyl, propyl, 1-methylpropyl, 2-methylpropyl, 1-ethylpropyl, butyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-20 ethylbutyl , 2-ethylbutyl, pentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, if-methylpentyl, 1,1-dimethylpentyl, 1,2-dimethylpentyl, 1, if-dimethylpentyl, 1-ethylpentyl, 2-ethylpentyl, 1 -propylpentyl, 2-propylpentyl, hexyl, 1-methylhexyl, 2-methylhexyl, 1,1-dimethylhexyl, 1-ethylhexyl, 2-ethylhexyl, heptyl, 2-ethylheptyl, nonyl, undecyl, 25 cyclobutyl, 1-propylcyclobutyl butylcyclobutyl, 1-pentylcyclobutyl, 1-hexylcyclobutyl, 2-methylcyclobutyl, 2-propylcyclobutyl, 3-ethylcyclobutyl, 3-propylcyclobutyl, 2,3-triethyl cyclobutyl, cyclopentyl, cyclopentylmethyl, 1-cyclopentylethyl, 2 - cyclopentylpropyl, 3-cyclopentylpropyl, 2-pentylcyclopentyl, 2,2-30 dimethylcyclopentyl, 3-ethylcyclopentyl, 3-propylcyclopentyl, 3-butylcyclopentyl, 3-tert-butylcyclopentyl, (1-methyl 1-3-propyl) cyclopentyl, (2-methyl-3-propyl) cyclopentyl, (2-methyl-if-propyl) cyclopentyl, cyclohexyl, cyclohexylmethyl, 1-cyclohexylethyl, 2-cyclohexylethyl, 3- cyclohexylpropyl, (1-methyl-2-cyclohexyl) ethyl-2-cyclo-35 hexylpropyl, (1-methyl-1-cyclohexyl) ethyl, if-cyclohexylbutyl ,, 3-ethylcyclohexyl, 3-isopropylcyclohexyl, if-methylcyclohexyl, if- ethyl-cyclohexyl, if-propylcyclohexyl, if-tert-butylcyclohexyl, 2,6-dimethyl-cyclohexyl, 2,2-dimethylcyclohexyl, (2,6-dimethyl-if-propyl) cyclo-hexyl, 1-methylcyclohexylmethyl, cycloheptyl, cycloheptylmethyl , 1-

diwi fU 9P

-6- cycloheptylethyl, 2-cycloheptylethyl, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, * f-phenylbutyl, 5-phenylpentyl, (1-methyl-2-phenyl) ethyl, (1,1- dimethyl-2-phenyl) ethyl, (1-methyl-1-phenyl) ethyl, 1-phenylpentyl, phenoxymethyl, 2-phenoxyethyl, 3-phenoxypropyl, 1-phenoxy-5-butyl, 3-phenoxypentyl, 3-chlorophenoxymethyl, Jf- chlorphenoxymethyl, 4-fluorophenoxymethyl, 3-trifluoromethylphenoxymethyl, 2-methylphenoxy-methyl, 3-methylphenoxymethyl, ^ f-methylphenoxymethyl, 4-ethylphenoxy-methyl, ^ -tert.butylphenoxymethyl, ^ f-sec.butylphenoxymethyl, propoxy-methyl, isopropoxymethyl butoxymethyl, pentyloxymethyl, hexyloxy-10 methyl, 1-ethoxyethyl, 1-propoxyethyl, 1-isopropoxyethyl, 1-neopen-tyloxyethyl, 1-pentyloxyethyl, (1-methyl-1-ethoxy) ethyl, (1-methyl-1-propoxy ) ethyl, (1-methyl-1-isobutoxy) ethyl, (1-methyl-1-neopentyl-oxy) ethyl, (1-methyl-1-butoxy) ethyl, (1-methyl-1-isopentyloxy) ethyl, ( 1-methyl-1-pentyloxy) ethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-butoxy-15 ethyl, 2- (1-ethylbutoxy) ethyl, 2-pentyl oxyethyl, 1-ethoxypropyl, 1-propoxypropyl, 1- (2-methylbutoxy) propyl, 1-pentyloxypropyl, 2-methoxy-propyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 3-sec-butoxypropyl, 3 -isobutoxypropyl, 3-butoxypropyl, (1-methyl-2-methoxy) -ethyl, (1-methyl-2-ethoxy) ethyl, (1-methyl-2-isobutoxy) ethyl, 1-20 pentyloxybutyl, (1-pentyloxy -2-methyl) propyl, ^ -methoxybutyl, * f -ethoxybutyl, 4-propoxybutyl, (1-methyl-3-methoxy) propyl, (1-methyl-3-propoxy) propyl, (2-methyl-3-methoxy ) propyl, (1,1-dimethyl-2-ethoxy) -ethyl, (1,1-diraethyl-2-propoxy) ethyl, (1,1-dimethyl-2-isobutoxy) -ethyl, 5-methoxypentyl, 5- ethoxypentyl, 1-pentyloxypentyl, (1-ethyl-3-propoxy) propyl, cyclobutyloxymethyl, cyclopentyloxymethyl, cyclohexyloxymethyl, cycloheptyloxymethyl, 2-cyclopentyloxyethyl or 2-cyclohexyloxyethyl. 1,1-Dimethylpentyl is particularly preferred.

The hydroxy protecting groups which are eliminated under alkaline conditions represented by R are groups which do not affect other parts of the compounds during the deprotection of the protecting group and which are easily removed under weak alkaline conditions. Preferably, the hydroxy protecting group is, for example, an acyl group such as acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl, benzoyl, p-phenylbenzoyl or naphthyloyl; acetyl is particularly preferred.

According to a feature of the present invention, the compounds of the general formula b, wherein R is a group -CH_0R,

JfO Y ^ 0 '^ Ε, Z ^ C = 0, R represent a hydroxy protecting group which is eliminated under 80 0 0 4 28 „alkaline conditions and the other symbols have the meanings indicated above, ie, compounds of the general formula 4A (wherein fi represents a hydroxy protecting group which is eliminated under alkaline conditions and the other symbols have the aforementioned meanings) prepared according to the Wittig reaction of a compound of the general formula 5i in which the various symbols have the aforementioned meanings, with a sodium derivative of a dialkylphosphonate of the general formula 6, wherein B 1 represents an alkyl group of 1 to 4 carbon atoms, preferably methyl or ethyl, and the other symbols have the aforementioned meanings, or having 7 a phosphorane compound of the general formula 7 wherein B represents a phenyl group unsubstituted or substituted with at least one alkyl group a group of 1 to 4 carbon atoms, preferably phenyl, 15 or an alkyl group of 1 to 6 carbon atoms, preferably represents butyl or hexyl or represents a cyclohexyl group and the other symbols have the above meanings. The sodium derivative of the dialkyl phosphonate of the general formula 6 can be prepared by reacting the dialkyl phosphonate with sodium hydride.

The Wittig reaction is described in "Organic Beactions," Part 14, Chapter 3 (1965) John Wiley & Sons, Ine. (USA). The reaction can 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 dialkyl formamide such as NN-dimethylformamide, a halogenated hydrocarbon such as dichloromethane or chloroform or an alkanol of 1-4 carbon atoms such as methanol or ethanol, or a mixture of two or more thereof, at a temperature of -78 ° C to a reflux temperature of the mixture takes place.

Dialkyl phosphonates of the general formula 6 and phosphoran compounds of the general formula 7 are known or can be readily prepared by methods known per se. The term "methods known per se" as used herein refers to the methods which have been used heretofore or have been described in chemical literature.

The compounds of the general formula IV, wherein B is a group 4 5 4 4 O 4 R 4 O 4 -CH-OB, Y, Z ^ C ', B a hydroxy protecting group,

> H> H

5 which is eliminated under alkaline conditions, R represents a hydrogen fln η ni? R -8 substance atom and the other symbols have the aforementioned meanings, i.e. compounds of the general formula 4b, wherein the different symbols have the aforementioned meanings are prepared by reduction of compounds of the general formula 4A, wherein the 15-oxo group is converted into 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 boron hydride, zinc borohydride, lithium tri-tert-butoxyaluminum hydride, lithium trimethoxyaluminum hydride, sodium cyanoborohydride, tri-butyl borohydride, lithium aluminum hydride-quinine complex, (-) - isobornyloxymagnesium iodide in an inert organic solvent, for example an alkanol with 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 thereof, at a temperature of from -8 ° C to ambient temperature. Preferably, the reduction is performed using diisobornyloxyaluminum isopropoxide (described in Japanese Patent 54- 76552) or a diisobutyl (alkyl-substituted or unsubstituted) phenoxyaluminum (described in Japanese Patent 54-154739 and J. Org. Chem. 44, (1979) 1363) or a lithium 1,1'-binaphthyl-2,2'-dioxyaluminum hydride (described in J. Araer. Chem. Soc., 101, (1979) 5843). The product thus obtained is a mixture of isomers in which the 15-hydroxy group is in the α or β configuration and the mixture is separated by conventional methods, for example, by thin layer column chromatography or high speed liquid chromatography on silica gel to give the desired isomer of general formula 4B.

The compounds of the general formula 4, in which R is a group 4 5 4 ^ -'0R ^ ^ 0R 4 -CH-0R, Y ^ 0 ", Z, R a hydroxy protecting group

^> H

5 removed under alkaline conditions, R represent a tetrahydropyran-2-yl group and the other symbols have the aforementioned meanings, i.e. compounds of the general formula 4C, in which the different symbols have the aforementioned meanings, are prepared by etherification of the 15-hydroxyl group of a compound of the general formula 4B with 2,3-dihydro-pyran in an inert organic solvent, for example dichloromethane or tetrahydrofuran, in the presence of an acidic catalyst 800 0 4 28 * Λ - 9-tor, for example p-toluenesulfonic acid, sulfuric acid, trifluoroborane etherate or phosphorus oxychloride at or below ambient temperature,

The compounds of the general formula 4, wherein R is a group b -, '0sk - -'0r5 b 5 -CH-OR, Y C-, ZC', R a hydrogen atom, R a te- 'Nh 5 trahydropyran-2- yl group and the other symbols have the aforementioned meanings, i.e. compounds of the general formula 4D, in which the different symbols have the aforementioned meanings, are prepared by saponification of compounds of the general formula 4C around the groups OR to convert hydroxyl-10 groups. The saponification can be carried out by using an aqueous solution of an alkali metal, for example sodium, potassium or lithium hydroxide, carbonate or hydrogen carbonate, or of an alkaline earth metal, for example calcium or barium hydroxide or carbonate in the presence or presence Of a water-miscible 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 -10 ° C to the temperature at which the reflux reaction mixture, preferably at ambient temperature up to 50 ° C or by using an anhydrous solution of an alkali metal, e.g., sodium, potassium or lithium hydroxide or carbonate in an anhydrous alkanol containing 1-4 carbon atoms, for example absolute methanol or ethanol, at a temperature of -10 ° C to the temperature at which the reaction mixture is boils fluently, preferably at an ambient temperature of up to 50 ° C.

The compounds of the general formula 4, wherein R represents a formyl-R-R5 group, Y ^ C = O, wherein R ^ is a tetrahydropyran-2-yl group, and the other symbols are the aforementioned -50 have knowledge, i.e. compounds of the general formula 4e, in which the various symbols have the aforementioned meanings, are prepared from compounds of the general formula 4D by oxidation to convert the 9-hydroxyl group to a 9-oxo group and at the same time converting the hydroxymethyl group to a formyl-55 group.

The oxidation is carried out according to methods known per se for the conversion of a hydroxy group to an oxo group, for example according to methods described in (1) Tetsuji Kameya, "Synthetic Organic Chemistry III, Organic Synthesis 1n, pp. 176-206 (1976), Nankodo (Japan), or in (2) "Compendium of Organic Synthetic Methods", Part 1 (1971) »2 (197 * 0 and 3 (1977), Section 48, John Wiley & Sons, Inc. (USA) Preferably, the oxidation is carried out under cautious and neutral conditions, for example with dimethyl sulfide N-chlorosuccinimide complex, thioanisole N-chlorosuccinimide complex, dimethyl sulfide chlorine complex or thioanisole chlorine complex [see J. Amer. Chem. Soc., 94, (1972) 7586], dicyclohexylcarbodiimide-dimethylsulfoxide complex [see J. Amer. Chem. Soc., 87, (1965) 5661], 10 pyridinium chlorochromate (CH2 NHCrO ^ Cl) [see Tetrahedron Letters, 2647 (1975)], sulfur trioxide-pyridine complex [see J. Amer. Chem. Soc. 89, (1967) 5505], chromyl chloride [see J. Am there. Chem. Soc., 97 (1975), 5929], chromium trioxide pyridine complex (e.g., Collins 'reagent) or Jones' reagent.

13 The oxidation using dimethylsulfide-N-chlorosuccinimide complex, thioanisole-N-chlorosuccinimide complex, dimethylsulfide-chlorine complex or thioanisole-chlorine complex are carried out by conversion to a halogenated hydrocarbon such as chloroform, dichloromethane, or carbon tetrachloride. 20 ° C, followed by treatment with triethylamine. The oxidation using the dicyclohexylcarbodiimide dimethyl sulfoxide complex is usually carried out by conversion to excess dimethyl sulfoxide in the presence of an acid, for example, phosphoric acid, phosphorous acid, cyanoacetic acid, pyridine phosphoric acid salt or trifluoroacetic acid as a catalyst. The oxidation using pyridinium chlorochromate can be carried out by conversion to a halogenated hydrocarbon such as chloroform, dichloromethane or carbon tetrachloride in the presence of sodium acetate, usually at ambient temperature. The oxidation using the sulfur trioxide-pyridine complex is usually carried out by conversion to dimethyl sulfoxide in the presence of triethylamine at ambient temperature. Oxidation using chromyl chloride is usually carried out by conversion to a halogenated hydrocarbon such as chloroform, dichloromethane or carbon tetrachloride in the presence of tert, butanol and pyridine at a temperature of -30 ° C to the temperature at which the reaction mixture is refluxed. The oxidation using the chromium trioxide-pyridine complex can be carried out by conversion into a halogenated hydrocarbon such as chloroform, dichloromethane or carbon-40 tetrachloride at a temperature of 0 ° C to ambient temperature, preferably 80 0 0 4 28 -11- 0 ° C. The oxidation using Jones reagent is usually carried out with acetone and dilute sulfuric acid at a temperature from 0 ° C to ambient temperature.

Compounds of general formula 5 can be prepared by the series of reactions schematically represented in the figure, in which g represents a benzyl group or a hydroxy protecting group, which is more easily removed than a tetrahydropyran-2-yl group under acidic conditions, the double bond E or Z, or a mixture thereof, ie EZ and the other symbols have the meanings mentioned above. The (1-methoxy-1-methyl) ethyl, 1-methoxycyclohexyl, 1-methoxy-1-phenylethyl, 1-ethoxyethyl, tetrahydrofuran-2-yl and trimethylsilyl groups are suitable hydroxy protecting agents.

Ltetrahyd.ropyran-2 groups, which are more easily removed than d <T1yl group.

Referring to the figure, the conversion [a] can be carried out using an ylide of a phosphonium compound of 7 of the general formula 12, wherein X represents a halogen atom and R has the aforementioned meanings, by methods mentioned above for the conversion of compounds of general formula 5 to those of general formula 4A.

The ylide of a phosphonium compound of the general formula 12 can be prepared by reacting a phosphonium compound of the general formula 12 with a suitable base, for example, butyl lithium, or a lithium compound of the general formula 13, wherein 9 10 R and R, which may be the same or different, each represents an alkyl-25 group with 1-6 carbon atoms or a cycloalkyl group with 3-6 carbon atoms, for example lithium diisopropylamide, in an inert organic solvent, at a temperature of -7B ° C to ambient temperature, for example, a solvent, previously described as suitable for the Wittig reaction of a compound of general formula 5.

Phosphonium compounds of the general formula 12 are known or can be readily prepared by methods known per se.

For example, the conversion [b] can be carried out when 4a 35 H represents an acyl group, using an acyl chloride R Cl, where R has the aforementioned meaning, or an acid A * cl anhydride (R) ^ 0, where R is the has the aforementioned meaning, in an inert organic solvent, for example dichloromethane or pyridine, in the presence of a tertiary amine, for example py-40 ridin or triethylamine, at a temperature below ambient temperature, preferably at a temperature below 0 ° C.

g

In the reaction [c], when E represents a benzyl group, compounds of the general formula 11 can be prepared by reducing compounds of the general formula 10 to simultaneously convert the vinylene and benzyloxy groups to ethylene and hy- droxyl groups, respectively.

The reduction can suitably be carried out under a hydrogen atmosphere in the presence of a hydrogenation catalyst, for example palachum on carbon, palladium black, platinum oxide or 10 Eaney nickel, in an inert organic solvent, for example an alkanol with 1 to 4 carbon atoms such as methanol or ethanol, or ethyl acetate, or a mixture of two or more thereof, at a temperature from ambient temperature to the temperature at which the reaction mixture is refluxed at normal or elevated pressure, for example, at a hydrogen pressure of atmospheric pressure up to 1500 kPa.

g

When R ° is other than a benzyl group, compounds of the general formula 10 can be converted into compounds of the general formula 14, in which the various symbols have the aforementioned meanings, by careful hydrolysis under acid conditions, avoiding the risk of elimination of the tetrahydropyran-2-yl group, followed by hydrogenation of the obtained compound of general formula 14 by methods as mentioned above for the conversion of compounds of general g of formula 10, in which κ represents a benzyl group, to compounds 25 of the general formula 11, for converting the vinylene group in formula 14 to an ethylene group,

Gentle hydrolysis under acidic conditions can be performed (1) with an aqueous solution of an organic acid, for example acetic acid, propionic acid, oxalic acid or p-toluene-50 sulfonic acid, or an inorganic acid, for example hydrogen chloride, sulfuric acid or phosphoric acid, advantageously in the presence of a water-miscible organic solvent, for example an alkanol with 1-4 carbon atoms such as methanol or ethanol, preferably methanol, or an ether such as 1,2-dimethoxyethane, dioxane or tetrahydrofuran, preferably tetrahydrofuran, at or below ambient 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 of 1-4 carbon atoms such as absolute methanol or ethanol, at or below 0 ° C.

The conversion [d] can be carried out by means such as mentioned above for the conversion of compounds of the general formula * fD to compounds of the general formula * + E.

g

The starting product of the general formula 8, in which B represents a benzyl group, is a known compound described in J, 5 Org. Chem., 37, 2921 (1972). The starting compounds of the general formula 8, wherein R 0 is other than a benzyl group, are prepared as described in Japanese Patent 53-1,995.

According to a further feature of the present invention, Ί compounds of the general formula ^ f, wherein R represents a formyl group, 10 Yi ^ C = O, Z ^ C '', Ir represent a tetrahydropyran-2-yl group and the other symbols the above listed meanings, ie compounds of the general formula "E", converted to compounds of the general formula "15" in which B represents an alkyl group having 1 - k carbon atoms, have the double bonds between the carbon atoms in the positions 2 and 3 and positions 13 and Ik are trans (i.e. E) and the other symbols have the aforementioned meanings, according to the Wittig reaction with a phosphorane compound 11 of the general formula 16, wherein W and R are the have the aforementioned meanings, by methods such as those previously reported for the conversion of compounds of general formula 5 to compounds of general formula kA.

Phosphoran compounds of the general formula 16 are known or can be readily prepared by methods known per se.

Compounds of general formula 15 are converted into trans-Δ-prostaglandin E analogs of general formula 17 in which the various symbols have the above meanings, by hydrolysis under acidic conditions to convert the tetrahydropyran-2-yloxy groups to hydroxyl groups. put.

The hydrolysis for the conversion of the tetrahydropyran-2-yloxy groups to hydroxyl groups under the acidic conditions is 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 hydrogen chloride, sulfuric acid, phosphoric acid, advantageously in the presence of an inert organic solvent, which is miscible with water, for example an alkanol with a small number of carbon atoms such as methanol or ethanol, preferably methanol, or an ether such as 1,2-diraethoxyethane, dioxane, tetrahydrofuran, and preferably 0 0 4 28 -14 tetrahydrofuran , at a temperature of from ambient temperature to 75 ° C, or (2) an anhydrous solution of an organic acid such as p-toluenesulfonic acid or trifluoroacetic acid in an alkanol with a small number of carbon atoms, such as methanol or ethanol, at a temperature of 0 - 45 ° C, or (3) an anhydrous solution of p-toluenesulfonic acid pyridine complex or trifluoroacetic acid pyridine complex in an alkanol with a small number of carbon atoms such as methanol or ethanol, at a temperature of 10 - 60 ° C. Advantageously, the cautious hydrolysis under acidic conditions can be 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-Δprostaglandin E1 analogs of the general formula 17 thus obtained are useful in human and animal drugs as described in British Pat. Nos. 1,416,410, 1,483,240 and 1,540,427. They possess the valuable pharmacological properties characteristic of prostaglandins in a selective manner, especially including hypotensive activity, platelet aggregation inhibiting activity, gastric secretion and gastric ulcer inhibiting activity, and source-chodilating activity. the treatment of hypertension, for the treatment of diseases of the peripheral circulation, in the prevention and treatment of cerebral thrombosis and myocardial infarction, for the treatment of stomach ulcers and for the treatment of asthma. The trans-Δ-prostaglandin E. analogous to the 2 3 'general formula 17, wherein the group -S -H represents a 1,1-dimethylpentyl-11 group and E represents a methyl group, i.e. (2E.13E) - (11a .15R) -9-oxo-11,15-dihydroxy-1,6,16-dimethylprosta-2,13-dienoic acid methyl ester described in British Patent No. 1,540,427 is suitable for termination of pregnancy and inducing labor in pregnant female mammals and in the regulation of oestrone, contraception and menstrual regulation in female mammals.

It will therefore be appreciated that the new compounds of the present invention of the general formula 4, i.e. the compounds of the general formulas 4A, 4B, 4C, 4D and 4E, are suitable and important intermediates for the preparation of 80 0 0 428 t * -15-2 therapeutically suitable trans-Δ-prostaglandin analogues.

Furthermore, the new compounds of the general formulas 5i 9, 10, 11 and 1 * t, ie compounds of the general formula 12 18 [wherein X is an ethylene or vinylene group, R a hydrogen atom or a hydroxy protecting group, which under alkaline conditions, R is a formyl group, a hydroxymethyl group 8 (-CH 2 OH) or a -CH 2 OR group, where R has the above meanings, and the other symbols represent the aforementioned 13

have the meanings, provided that (i) when R

12 represents a formyl group, X represents an ethylene group and R represents a hydroxy protecting group, which is removed under alkaline conditions, (ii) when R represents a hydroxymethyl group 12, R represents a hydroxy protecting group, which is under alkaline 13 conditions is removed, and (iii) when R represents a group -CHgORO, X represents a vinylene group] also represents suitable and important intermediates for the preparation of trans-2 Δ-prostaglandin E 1 analogs. When X represents a vinylene group, the double bond can be E, Z or a mixture thereof.

The use of the compounds of the general formulas b and 20 allows the synthesis of trans-Δ-prostaglandin E 1 analogs by the methods described above, which avoid certain drawbacks of the two known methods mentioned above. Use of the phosphonium compounds of general formula 12 avoids the need to use the unstable phosphorane compound required in the method described in British Patent Specification 1.bl6.b10 (the compounds of formula 12 have the group -CH 2 OH in place of the unconjugated carboxyl group and are therefore more stable, leading to higher yields); selective hydrogenation, which carries the risk of a reduced yield of the desired product, is not required; and the Cu chain is introduced at a relatively late stage in the process. Furthermore, the use of selenium or sulfur compounds and the necessary careful purification steps to remove traces of such compounds in the final prostaglandin products are not required. The following examples illustrate the present invention.

In the examples, "DLC", "TIE" and "NMR" represent "thin layer chromatography", "infrared absorption spectrum" and "nuclear magnetic resonance spectrum", respectively. When solvent ratios are specified for chromatographic separations, the ratios are volume ratios: leave the solvents in brackets

O Λ Λ A A OQ

-16- see the applied developmental solvents. Unless otherwise specified, infrared spectra are recorded by the liquid film method and nuclear magnetic resonance spectra are recorded in deuterochloroform (CDCl 2) solution.

5 Example I.

(EZ) -2a- (5-hydroxypent-2-enyl) -33- (1-methoxy-1-methyl) -ethoxymethyl- * fa- (tetrahydropyran-2-yloxy) cyclopentan-1ol.

Under a nitrogen atmosphere, 29.1 ml of a 1.3 molar solution of butyl lithium in hexane was added to a suspension of 8.7 ^ 8 g of 3-hydroxypropyltriphenylphosphonium bromide in 70 ml of tetrahydrofuran and the mixture was stirred at ambient temperature for 10 minutes, to obtain a ylide solution. A solution of 3 g of 2-oxa-6-syn- (1-methoxy-1-methyl) ethoxymethyl-7-anti- (tetrahydropyran-15-2-yloxy) -cis-bicyclo was added to the ylide solution thus obtained [ 3.3.ojoctan-3-ol (prepared as described in Reference Example 2 of Japanese Patent 53-1 ^ 995 * 0 in 10 ml of tetrahydrofuran and the mixture was stirred at ambient temperature for one hour and then at 40 ° C for 30 minutes. reaction mixture was poured into a saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate The extract was washed with water and a saturated aqueous sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to the crude desired compound having the following physical properties was obtained The crude product was used in the next step without purification.

TLC (ethyl acetate: cyclohexane = 2: 1): fif = 0.23.

(a) Using the method described above, however replacing 2-oxa-6-syn- (1-methoxy-1-methyl) ethoxymethyl-7-anti- (tetrahydropyran-2-yloxy) -cis-bicyclo [3.3 .0] octan-3-ol by 2-30 oxa-6-syn-benzyloxymethyl-7-anti- (tetrahydropyran-2-yloxy) -cis-bi-cyclo [3.3.0] octan-3-ol [prepared as described in J. Org. Chem., 37, (1972) 2921], (EZ) -2a- (5-hydroxypent-2-yl) -33-benzyloxymethyl-4a- (tetrahydropyran-2-yloxy) cyclopentan-1a-ol was obtained with the following physical property: 35 TLC (ethyl acetate: cyclohexane = 2: 1): Ef = 0.25.

Example II.

(EZ) -1a-acetoxy-2a- (5-acetoxypent-2-enyl) -33- (1-methoxy-1-methyl) -ethoxymethyl- * fa- (tetrahydropyran-2-yloxy) cyclopentane.

The crude product, prepared as described in Example 1.10, was stirred overnight with 14 ml of acetic anhydride and 33 ml of pyridine at ambient temperature. The reaction mixture was diluted with ethyl acetate, washed with 0.5 N hydrochloric acid, water and a saturated aqueous sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to give the crude desired compound having the following physical property . The crude product was used in the next step without purification.

TLC (ethyl acetate: cyclohexane = 2: 1): Rf = 0.79.

(a) According to the above-described method, but replacing the crude product of Example 1, used as a starting product, by the crude product of Example 1 (a), the following compound was prepared. The product was purified by silica gel koi chromatography using a mixture of ethyl acetate and cyclohexane (1: 2) as an eluent to yield 73% based on the starting product of Example 1 (a): (EZ) -1a-acetoxy-2a- (5-acetoxypent-2-enyl) -33-benzyloxymethyl-4a- (tetrahydropyran-2-yloxy) cyclopentane: TLC (cyclohexane: ethyl acetate = 2: 1): Rf = 0, 82; IR: ^ = 17 ^ 0.1243, 1021 cm-1; NMR (CCl ^ solution): ξ = 7.12 (5H, m), 5.40 (2H, m), 5.00 (1H, m ), 4.61 (1H, m), 4.36 (2H, s), 3.97 (2H, t), 3.40 (2H, d), 4.20-3.20 (3H, m) 2.00 (6H, s).

Example III.

(EZ) -1a-acetoxy-2a- (5-acetoxypent-2-enyl) -33-hydroxymethyl-4a- (tetrahydropyran-2-yloxy) cyclopentane.

The crude product, prepared as described in Example II, was stirred with 40 ml of tetrahydrofuran and 15 ml of 1N hydrochloric acid at 0 ° C for 30 minutes. The reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, washed with water and a saturated aqueous sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using diethyl ether as an eluent to yield 2.30 g of the desired compound having the following physical properties: TLC (ethyl acetate: cyclohexane = 2: 1): Rf = 0.42; IR: ^ = 3460, 1737, 1243, 1023cm -1; NMR (CCl ^ solution): & = 5.35 (2H, m), 4.97 (1H, m), 4.56 (1H, m) .40 3.95 (2H, t), 4.20-3.16 (5H, m), 1.97 (6h, s).

ρη η n k -18-

Example IV.

1a-Acetoxy-2a- (5-acetoxypentyl) -3P-hydroxymethyl-4a- (tetrahydropyran-2-yloxy) cyclopentane.

Under a hydrogen atmosphere, a mixture of 10.402 g of the pentenyl compound was prepared as described in Example III, 120 ml of methanol and 100 ml of platinum dioxide were stirred at ambient temperature for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 10.264 g of the desired compound having the following physical properties: TLC (ethyl acetate: benzene = 2: 1) using a silica gel plate, which was silver nitrate is pretreated): Rf = 0.47; IR: V = 3460, 1740, 1247, 1020 cm-1; NMR (CC14 solution): & = 4.96 (1H, m), 4.52 (1H, m), 3.93 (2H, t), 4.20-3.15 (5H, m), 1.97 (6H, s).

Example V.

1a-Acetoxy-2a- (5-acetoxypentyl) -33-formyl-4a- (tetrahydropyran-2-yloxy) cyclopentane.

To a suspension of 5.79 g of N-chlorosuccinimide in 300 ml to-20 luene, 3.94 ml of dimethyl sulfide at 0 ° C were added and the mixture was stirred at that temperature for 40 minutes. To the resulting solution, a solution of 11.1 g of the hydroxymethyl compound prepared as described in Example IV in 20 ml of toluene at -20 ° C was added. The mixture was stirred at the same temperature for one hour and then stirred with 12.1 ml of triethylamine at -20 ° C for 30 minutes. The reaction mixture was neutralized with 0.1 N hydrochloric acid, diluted with diethyl ether, washed with 0.1N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure . The residue was purified by silica gel column chromatography using a mixture of ethyl acetate and cyclohexane (1: 1) as an eluent to give 10.327 g of the desired compound having the following physical properties: 35 TLC (ethyl acetate: benzene = 2) : 1): Bf = 0.74; IR: 1740, 1377, 1247, 1025 cm-1; NMR: S = 9.65 (1H, t), 5.30-4.85 (1H, m), 4.8-3.1 (6h, m ).

Example VI.

1a-Acetoxy-2a- (5-acetoxypentyl) -33-hydroxymethyl-4a- (tetrahydropy-40 ran-2-yloxy) cyclopentane.

80 0 0 428 * »-19-

Under a hydrogen atmosphere, a mixture of 4.74 g of the benzyloxymethyl compound, prepared as described in Example 11 (a), 100 ml of ethanol and 20 g of Raney nickel (W-7) was refluxed for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 3.48 g of the desired compound having the same physical properties as the product of Example IV.

Example VII.

(E) -1a-Acetoxy-2a- (5-acetoxypentyl) -3P- (3-QXQ-4,4-dimethyloct-1-10 enyl) -4a- (tetrahydropyran-2-yloxy) cyclopentane.

Under a nitrogen atmosphere, a solution of 11.154 g of dimethyl 2-oxo-3,3-dimethylheptylphosphonate in 50 ml of tetrahydrofuran was added dropwise to a suspension of 1.317 g of sodium hydride (content 63.5%) in 250 ml of tetrahydrofuran at ambient temperature and the mixture was stirred at ambient temperature for 30 minutes. To the solution thus obtained, a solution of 10.997 g of the formyl compound, prepared as described in Example V, in 100 ml of tetrahydrofuran was added and the mixture was stirred at ambient temperature for 2.5 hours. The reaction mixture was acidified with acetic acid, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using a mixture of cyclohexane and ethyl acetate (3i1) as an eluent to yield 12.3g of the desired compound with the following physical properties: TLC (cyclohexane: ethyl acetate) = 1: 1): Rf = 0.70; IR: V = 1740, 1695, 1625, 1246, 1025 cm-1; NMR: 6 = 7.10-6.30 (2H, m), 5.40-5.00 (1H, m), 4.80 -4.35 (1H, m), 4.35-3.10 (5H, m).

Example VIII.

(E) -1a-Acetoxy-2a- (5-acetoxypentyl) -33- (3R-hydroxy-4,4-dimethyloct-1-enyl) -4a- (tetrahydropyran-2-yloxy) cyclopentane.

Under a nitrogen atmosphere, 100 ml of a 25 w / v solution of diisobutyl aluminum hydride in toluene was added dropwise to a solution of 1.8 g of 2,6-di-tert-butyl-4-methyl-phenol in 660 ml of toluene at 0 - 5 ° C and the mixture was stirred at the same temperature for one hour. To the solution was added a solution of 8.64 g of the 3-oxo compound, prepared as described in Example VII, in 60 ml of toluene at -78 ° G and the mixture was heated at -30 ° C to -20 ° for 40 hours for 3 hours. C stirred. The reaction mixture was stirred with 80 ml of water at 40 ° C for 30 minutes at 40 ° C, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and ethyl acetate (4: 1) as an eluent-5 part to yield 7.5 g of the desired compound having the following physical properties: TLC (benzene: ethyl acetate) = 3il): Rf = 0.30, (3S isomer, Rf = 0.39) IR: 0 = 3740, 1738, 1372, 1243, 1017cm-1; NMR (CCl 3 solution): = = 5.42 (2H, m), 4.96 (1H, m), 4.46 (1H, m), 3.90 (2H, t), 4.10- 3.15 (4h, m), 1.97 (3H, s), 1.93 (3H, s).

Example IX.

(E) -1a-Acetoxy-2a- (5-acetoxypentyl) -3P-r 3R- (tetrahydropyran-2-yloxy) - 4,4-dimethyloct-1-enyl -4a (tetrahydropyran-2-yloxy) cyclopentane.

A mixture of 7> 5 g of the 3R-hydroxy compound, prepared as described in Example VIII, 3 ml of 2,3-dihydropyran, 25 mg of p-toluenesulfonic acid and 80 ml of dichloromethane was stirred at ambient temperature for 15 minutes. The reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to give 8.88 g of the desired compound having the following physical properties: TLC (cyclohexane : ethyl acetate = 2: 1): Rf = 0.57.

25 Example X.

(E) -2a- (5-Hydroxypentyl) -3P- [3R- (tetrahydropyran-2-yloxy) -4,4-dimethyloct-1-enyl] -4a- (tetrahydropyran-2-yloxy) -cyclopentan-1a- ol.

A mixture of 8.88 g of the acetoxy compound prepared as described in Example IX, 4.05 g of potassium carbonate and 80 ml of methanol was stirred at 50 ° C for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous ammonium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using a mixture of ethyl 35 acetate and cyclohexane (2: 1) as an eluent to yield 7.2 g of the desired compound having the following physical properties: TLC (ethyl acetate '). cyclohexane = 2: 1): Rf = 0.27; IR: 1) = 3400, 1137, 1026, 978 cm -1 · 40 NMR: δ = 5.60-5.23 (2H, m), 4.60 (2H, m), 4.30-3.20 (9H, m).

80 0 0 4 28

* V

-21-

Example XI.

(Ξ) -2α- (4-Formylbutyl) —33 — Γ 3R- (too trahydropyran-2-yloxy) -4,4-dimethyloct-1-enyl] -4a- (tetrahydropyran-2-yloxy) cyclopentan -1-on.

A solution of 0.335 nil chromyl chloride in 2 ml carbon tetrachloride was added dropwise to a solution of 0.786 ml tert-butanol and 1.01 ml pyridine in 13 ml dichloromethane at -78 ° C. To the solution was added a solution of 902 mg of the cyclopentan-1a-ol compound, prepared as described in Example X, in 5 ml of dichloromethane at ambient temperature and the mixture was stirred at ambient temperature for 2 hours and then at 40 ° C for 40 minutes. The reaction mixture was stirred with 0.5 ml of dimethyl sulfide at ambient temperature for 10 minutes; 60 ml of diethyl ether and 20 ml of water were added and the mixture was filtered through a layer of infusion earth. The ether layer of the filtrate was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using a mixture of cyclohexane and ethyl acetate (3s1) as an eluent to yield 675mg of the desired compound having the following physical properties: TLC (cyclohexane: ethyl acetate = 2) : 1): Hf = 0.44; IB: V = 1745, 1730, 1130, 1078, 1037, 1023 cm-1; MS (CC1k solution): £ = 9.50 (1H, t), 5.70-5.30 (2H, m), 4.71-4.42 (2H, m), 4.31-3, 07 (6h, m).

Example XII.

(2E.13E) - (11a.155) -9-oxo-11.15-bis- (tetrahydropyran-2-yloxy) -1,16-dimethylprosta-2,13-dienoic acid methyl ester.

Under a nitrogen atmosphere, a mixture of 184 mg of the cyclopentan-1-one prepared as described in Example XI, 231 mg of methoxycarbonylmethylidene triphenylphosphoran and 2 ml of chloroform was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using a mixture of cyclohexane and ethyl acetate (3: 1) as an eluent to yield 192 mg of the desired compound having the following physical properties: TLC (benzene: ethyl acetate = 2: 1): Rf = 0.74; IE: 1) = 1745, 1726, 1654, 1196, 1128, 1030 cm -1; NMR: <$ = 6.90 (1H, dt), 5.70 (1H, d), 5.80-5.40 (2H, m), 4.60 (2H, m).

The desired compound was also prepared by the method described above 800 0 4 28 -22-, replacing the methoxycarbonylmethylidene-triphenylphosphoran with a phosphorane compound (5) -, P = CHCCOCH ,, 7 * ^ ^ where R 'is as is indicated in the following table and under change of the reaction temperature, the reaction time and solvent.

I 7 I | 5 R Reaction- Reaction- Solvent Yield temperature time -C ^ Hg -20 to 0 ° C 2 hours toluene 100% cyclohexyl o.t. * 15 hours of chloroform 94.1% -C ^ iL, o.t. * 1.5 hours tetrahydrofuran 98% o 15 __! ______ 10 * o.t. = ambient temperature.

Example XIII.

(2E-13E) - (11a.15R) -9-oxo-11 * 15-dihydroxy-16,16-dimethylprosta-2,13-dienoic acid methyl ester.

To a solution of 732 mg (2E.15E) - (11a.15B) -9-oxo-11.15-15 bis-C tetrahydropyran-2-yloxy) - 16.16-dimethylprosta-2.13-dienoic acid methyl ester (which can be prepared as described in Example XII) in 1.9 ml of tetrahydrofuran, 19 ml of a 65% aqueous acetic acid solution was added and the solution was stirred at 55-60 ° C for one hour. The reaction mixture was then extracted with ethyl 20 acetate and the extract was washed with water and an aqueous sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to give 119 mg of the desired compound having the following physical properties: TLC (developing solvent, chloroform: tetrahydrofuran: acetic acid = 10: 2: 1): Rf = 0.51; IR:)) = 3400, 2940, 2850, 1750, 1730, 1660, 1440, 1280 cm -1; NMR: S '= 7.10-6.73 (1H, m), 5.95-5.40 (3H, m), 3.71 (3H, s), 4.20-3.60 (2H, m), 2.75 (1E, dd), 1.00-0.75 (9H, m).

80 0 0 4 28

Claims (19)

1. Compounds of general formula 4, wherein I ^ C = 0 or ^, '° * kb C' (wherein B represents a hydrogen atom or a hydroxy protecting group, which is removed under alkaline conditions), Z ^ TC = 0 or (where & represents a hydrogen atom or a \ tetrahydropyran-2-yl group), B represents a formyl group or an ij. Ij. group of the formula -CH? OB (wherein E has the above-mentioned meanings), B a single bond or an alkylene group with 1 to 5 copper atoms and E 1 a hydrogen atom, an alkyl or alkoxy-10 group with 1 8 carbon atoms, or a cycloalkyl or cycloalkyloxy group of b - 7 carbon atoms, unsubstituted or substituted with at least one alkyl group of 1 to 8 carbon atoms, or a phenyl or phenoxy group, unsubstituted or substituted with at least one halogen, trifluoromethyl group or alkyl group having 1 to 15 carbon atoms, with the proviso that when B 3 represents a single bond, B 1 represents no alkoxy, cycloalkyloxy or phenoxy group, THP represents a tetrahydropyran-2-yl group and the double bond between the carbon atoms at positions 13 and Ik is trans, with the proviso that (i) when Z ^ -C = 0 or 2 °, χΟΕ5 (where EJ represents a hydrogen atom), Y represents (where B represents the hydroxy protective gro ep represents Ί, which is removed under alkaline conditions) and E 1). li represents a group of the formula -C ^ OB (wherein B represents a hydroxy protecting group, which is removed under alkaline conditions) and (ii) when Y ^ represents -C = 0, B represents a formyl group * Compounds according to claim 1, characterized in that the group -B -B represents the 1,1-dimethylpentyl group. Compounds according to claim 1 or 2, characterized in that the hydroxy protecting group represented by the symbol B represents acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl, benzoyl, p-phenylbenzoyl or naphthyloyl. 35 b. Compounds according to claims 1-3, characterized in that the hydroxy protecting group represented by R is acetyl. Compounds according to claims 1-4, characterized in that R 1 is a group -CHpOR, Y ^ C ', Z.0 = 0, R is a hy - 5 represent a hydroxy protecting group which is removed under alkaline conditions and the other symbols have the meanings set out in claim 1. 6. Compounds according to claims 1-4, characterized in that R 1 is a group -CELOR, Y, R is a 2> H '2 - C 1 -H 10 hydroxy protecting group, which is alkaline conditions and R 1 represents a hydrogen atom, and the other symbols have the meanings set forth in claim 1. 7. Compounds according to claims 1-4, characterized by "-0R, OR. that R represents a group -CH-OR, Y, Z, R a hydroxy protecting group which is removed under alkaline conditions and R represents a tetrahydropyran-2-yl group and the other symbols have the meanings set out in claim 1. 8. Compounds according to claims 1-4, characterized in that r "'is a group -CH_OR, Y, Z_4 2. Nh 7 SH 'E represents a hydrogen atom and R 1 represents a tetrahydropyran-2-yl group and the other symbols have the meanings set out in claim 1, 9. Compounds according to claim 1 or 2, characterized in that R represents a formyl group, Y 2 O = 0, Z and R represent a tetrahydropyran-2-yl group and the other symbols represent the -25 clusion 1 have the meanings stated. 10. (E) -1a-Acetoxy-2a- (5-acetoxypentyl) -3p- (3-oxo-4,4-dimethyl-oct-1-enyl) -4a- (tetrahydropyran-2-yloxy) cyclopentane. 11. (E) -1a-Acetoxy-2a- (5-acetoxypentyl) -3p- (3R-hydroxy-4,4-dimethyloct-1-enyl) -4a- (tetrahydropyran-2-yloxy) cyclopentane. 12. (E) -1a-Acetoxy-2a- (5-acetoxypentyl) -3p- [3H- (tetrahydropyran-2-yloxy) -4,4-dimethyloct-1-enyl] -4a- (tetrahydropyran-2- yloxy) cyclopentane. - 13. (E) -2α- (5-Hydroxypentyl) -3β- [32- (tetrahydropyran-2-yloxy) - 4,4-dimethyloct-1-enyl] -4a- (tetrahydropyran-2-yloxy) cyclopentan-1a- ol. 800 0 4 28 -25- 14. (E) -2a- (4-Formylbutyl) -3p- [3R- (tetrahydropyran-2-yloxy) -4,4-dimethyloct-1-enyl] -4a- (tetrahydropyran- 2-yloxy) cyclopentan-1-one. # Process for the preparation of pentane compounds, characterized in that compounds of the general formula (5), in which the symbols have the meanings stated in claim 1, are prepared in a manner known per se. 16. Process for the preparation of pentane compounds, characterized in that compounds of the general formula 4, in which the symbols have the meanings stated in claim 1, are prepared by preparing a compound of the general formula 5, wherein R reacts a hydroxy protecting group, which is removed under alkaline conditions and THP represents a tetrahydropyran-2-yl group, with a sodium derivative of a dialkylphosphonate of the general formula 6, wherein an alkyl group having 1-4 carbon atoms and R and R 2 have the meanings set forth in claim 1, or with a phosphorane compound of the general formula 7l wherein R represents a phenyl group unsubstituted or substituted with at least one alkyl group of 1-4 carbon atoms, or an alkyl group of 1 -6 carbon atoms or a cyclohexyl group 20 and R 1 and R 2 have the meanings set out in claim 1 for obtaining a compound of the general fo Formula 4A, 3. wherein R and THP have the above meanings and the other symbols have the meanings set out in claim 1, optionally followed by one or more of the following steps: (a) reduction of the compound of the general formula 4A for converting the 15-oxo group to a 15-hydroxyl group, (b) etherifying the product of step (a) with 2,3-dihydropyran in an inert organic solvent in the presence of an acidic catalyst at or below ambient temperature every 15 -hydroxyl group 30 to convert to a 15-tetrahydropyran-2-yloxy group, (c) saponification of the product of step (b) to convert the 4a groups CR to hydroxyl groups and (d) oxidation of the product of step ( c) for converting a hydroxymethyl group and a 9-position hydroxyl group to formyl and oxo groups, respectively. Process according to claim 16, characterized in that the reaction of the compound of formula 5 with the dialkylphosphonate of the general formula 6 or with the phosphorane of the general formula 7 is carried out in an inert organic solvent at a temperature of - 8 ° C to the temperature at which the reaction mixture is refluxed. 18. Process according to claim 16, characterized in that the reduction according to step (a) is carried out using diisobornyloxyaluminum isopropoxide, a diisobutyl (alkyl-substituted or unsubstituted) phenoxyaluminum or a lithium 1,1'-binaphthyl-2.2 '. -dioxyaluminum hydride. 19. Process according to claim 16, characterized in that step (c) is carried out using an aqueous solution of an alkali metal hydroxide, carbonate or hydrogen carbonate or of an alkaline earth metal hydroxide or carbonate in the absence or presence of a water-miscible solvent at a temperature of -10 ° C to the temperature at which the reaction mixture is refluxed or using an anhydrous solution of an alkali metal hydroxide or carbonate 15 in an anhydrous alkanol containing 1-4 carbon atoms, at a temperature of -10 ° C to the temperature at which the reaction mixture is refluxed. 20. Process according to claim 16, characterized in that step (d) is carried out under cautious and neutral conditions. 21. Process for the conversion of a compound of the general formula 4, wherein R represents a formyl group, Y ^> C = O, Z ^ OR and 5> cr * ~ Br a tetrahydropyran-2-yl group and the ^ other symbols have the meanings given in claim 1, 11 to a compound of the general formula 15 wherein R represents an alkyl group having 1-4 carbon atoms, the double bonds between the carbon atoms in positions 2 and 3 and positions 13 and 14 are trans, and the other symbols have the meanings set forth in claim 1, characterized in that the compound of the general formula 4 is reacted with a phosphorane compound of η the general formula 16, wherein R 'is the in claim 16 has 11 meanings and R has the above meanings, optionally followed by hydrolysis of the compound of general formula 15 to convert the 11- and 15-tetrahydropyran-2-yloxy groups to hydroxy groups to obtain a connection with d e 11 general formula 17. wherein R has the meanings mentioned above and the other symbols have the meanings stated in claim 1. The process according to claim 21, characterized in that the reaction of the compound of the general formula with the phosphorane compound of the general formula 16 is carried out in an inert organic solvent at a temperature of -78 ° C to the temperature at which the reaction mixture is refluxed. 23. Process according to claim 21, characterized in that the hydrolysis of the compound of the general formula 15 is 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. 2k, Compounds of the general formula 18, wherein X is an ethylene or vinylene group. R is a hydrogen atom or a hydroxy protecting group, which is removed under alkaline conditions, R is a formyl group, a hydroxymethyl group or a group of 8 -CH2 OR, wherein R ° represents a benzyl group or a hydroxy protecting group, which is more easily removed under acidic conditions than a tetrahydrofuran-2-yl group, THP has the meanings set forth in claim 1 and the configuration of the vinylene group is E or Z or a mixture thereof, provided that 13 (i) when R is a formyl group, X represents an ethylene group-12 and R represents a hydroxy protecting group, which is removed under alkaline conditions, (ii) when R represents a hydroxy-methyl group, R represents a hydroxy protecting group, which is alkaline conditions are removed and (iii) 1 "3 8 when R 1 represents a -CH 2 OR group, X represents a vinylene group. 25. (EZ) -2a- (5-Hydroxypent-2-eny1) -3β- (1-me th oxy-1-methyl) ethoxymethyl-Jfa-tetrahydropyran-2-yloxy) cyclopentan-1a-ol. 26. (EZ) -1a-Acetoxy-2a- (5-acetoxypent-2-enyl) -3P- (1-methoxy-1-methyl) ethoxymethyl-4a- (tetrahydropyran-2-yloxy) cyclopentane. 27. (EZ) -1a-Acetoxy-2a- (5-acetoxypent-2-enyl) -3P-hydroxymethyl-35 ^ a- (tetrahydropyran-2-yloxy) cyclopentane. 28. 1a-Acetoxy-2a- (5-acetoxypentyl) -33-hydroxymethyl-4a- (tetrahydropyran-2-yloxy) cyclopentane. 29. 1a-Acetoxy-2a- (5-acetoxypentyl) -3P-formyl-α- (tetrahydropyran-2-yloxy) cyclopentane. ^ 0 30. (EZ) -2a- (5-Hydroxypent-2-enyl) -30-benzyloxymethyl- ^ a- (tetra-28-hydropyran-2-yloxy) cyclopentan-1a-ol. 31. (EZ) -1a-Acetoxy-2a- (5-acetoxypent-2-enyl) -3p-benzyloxy-methyl-4a- (tetrahydropyran-2-yloxy) cyclopentane. 32, Process for preparing pentane compounds, characterized in that compounds of formula 18, in which the symbols have the meanings stated in claim 2k, are prepared in a manner known per se. 33. Process for the preparation of pentane compounds, characterized in that compounds of the general formula (I) 18, in which the symbols have the meanings stated in claim 2k, are prepared by preparing a compound of the general formula (O), wherein R ° represents a benzyl group or a hydroxy protecting group, which is more easily removed than a tetrahydropyran-2-yl group under acidic conditions and THP has the meanings set out in claim 1, converts with a ylide of a phosphonium compound of the general formula 12, wherein X is a represents halogen and n R 'has the meanings set forth in claim 16, to obtain a compound of the general formula 9, wherein R4 has the meanings listed above and THP has the meanings listed in claim 1, optionally followed successively by one or more of the following steps: (a) conversion of the hydroxyl groups in the compound of formula 9 to groups OE, wherein S has the meanings set forth in claim 16, (b) reduction of the product of step (a) for the conversion of the g vinylene group to an ethylene group and, when R represents a henzyl group 0, the benzyloxymethyl group to hydroxymethyl or, when R otherwise than is benzyl, cautious hydrolysis of the product of step (a) under acidic conditions avoiding the risk of elimination of the tetrahydropyran-2-yl group for the conversion of the group -CO2 OR0 to hydroxymethyl followed by reduction of the hydrolysis product for the conversion of the vinylene group to an ethylene group and (c) oxidation of the product of step (b) for the conversion of the hydroxymethyl group to a formyl group. ****** 800 0 4 28 1, 2.0 OH ^ A 0 VW ^ ^ ~ ^^^^> Ns'z-R2-R3 OH fa O-THP j4a OR ^ a - & - OR ^ a ! A - .CH, ORia ry - ^^ A * \ -l 2 3 \ ~ \ ^^ · 2- ^ S & * ^ \ 15A * "RIDE | Ay o-THP i O-THP Ij 6th 4c 4 ί OR ^ a - OH 1 ΛηΖ | Β ί O-THP! O-THP j O-THP O-THP 4th o 80 0 0 4 28 ά'ΤΗΡ <L *