CH644360A5 - INTERMEDIATES FOR THE PREPARATION OF TRANS-PROSTAGLANDIN ANALOGS HAVING A DOUBLE LINK BETWEEN CARBON ATOMS 13 AND 14 AND 2 AND 3. - Google Patents

Description

The present invention relates to novel chemical compounds useful as intermediates for the preparation of analogs of A2trans-prostaglandin Ei, to methods for their preparation and to their use in the preparation of analogs of A: trans-prostaglandin Ei.

Prostaglandins are derivatives of prosta-noic acid, which has the following formula:

(I)

COOH

20

Different types of prostaglandins are known, depending, among other things, on the structure of the alicyclic ring and the substituents that it carries. For example, the alicyclic ring of Prostaglandin E (PGE) has the structure:

0

OH

In the formulas above and in the other formulas of the present text, the dotted lines indicate, in accordance with the rules generally accepted in nomenclature, that the attached grouping stands behind the general plan of the ring system, it that is, the grouping is in configuration a, the thickened lines indicate that the grouping stands in front of the general plane of the system, i.e. this grouping is in configuration ß, and the line in zig- zag indicates that the grouping is in configuration aouß.

These compounds are divided into subdivisions according to the position of the double bond (s) in the side chain (s) attached to positions 8 and 12 of the alicyclic ring. Thus, the PGi compounds have a double bond between the carbon atoms of positions 13 and 14 (Al3trans) and the PGi compounds have a double bond eis between the carbon atoms of positions 5 and 6 and a double bond between the atoms carbon of positions 13 and 14 (A5cis, Al3trans). For example, Prostaglandin Ei (PGEi) is characterized by the following structure:

0

COOH

i

OH

OH

(III)

The structure of PGE :, as a member of the PG2 group, corresponds to that of formula (III) with a double bond eis between the carbon atoms of positions 5 and 6. Compounds in which the double bond between atoms carbon of positions 13 and 14 of the members of the PGi group is replaced by an ethylene link are known under the name of dihydroprostaglandins, for example dihydroprostaglan-dine Ei (dihydro-PGEi).

The PGE compounds with a trans double bond between the carbon atoms in positions 2 and 3 are known by the name of A2trans-PGE compounds and the structure of the A2trans-PGEi corresponds to that of formula (III) 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 co chain, that is to say the aliphatic group attached to position 12 of the alicyclic ring of prostaglandins, and / or of the chain a, that is to say the aliphatic group attached to position 8 of the alicyclic ring of the prostaglandins, the compounds, according to the usual rules of organic nomenclature, are called homo-prostaglandins (methylene group added) or norprosta- glandins (methylene group removed), and when more than one methylene group is added or removed, the number is s

î »

15

20

25

30

35

40

45

50

55

60

65

5

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indicated by di-, tri-, etc, before the prefix "homo" or

"Nor".

Prostaglandins are generally known to have pharmacological properties; for example, they stimulate smooth muscle, have a hypotensive, diuretic, bronchodilator and antilipolytic action and also inhibit the aggregation of blood platelets and the secretion of gastric acid; therefore, they are useful for the treatment of hypertension, thrombosis, asthma and gastrointestinal ulcers, for induction of labor and abortion in pregnant female mammals, for prevention of arteriosclerosis and as a diuretic agent. These are liposoluble substances which can be obtained in very small quantities from various animal tissues which secrete prostaglandins in the living organism.

For example, PGEs have an inhibitory action on the secretion of gastric acid and can therefore be used for the treatment of gastric ulcers. They also inhibit the release of fatty acids caused by epinephrine and, therefore, they reduce the concentration of free fatty acids in the blood and are therefore useful for the prevention of arteriosclerosis and hyperlipemia. PGEi inhibits the aggregation of blood platelets and also eliminates the thrombus and prevents thrombosis. PGEs have a stimulating action on smooth muscle and increase intestinal peristalsis; these actions indicate their therapeutic usefulness on the postoperative ileus and as purgatives. In addition, PGEs can be used as oxytocics, as first and second trimester abortives, in the delivery of the placenta after work, and as oral contraceptives because they regulate the sexual cycle of female mammals. PGEs have vasodilatory and diuretic actions. These PGEs are useful for improving the condition of patients with cerebrovascular disorders because they increase cerebral blood flow, and are also useful for the treatment of asthmatic states in patients due to their bronchodilator action.

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

A first method is described in British Patent No. 1,416,410 to Latitulain, published on December 3, 1975. However, to form the double bond between the carbon atoms of positions 5 and 6, this method requires the use of a compound phosphorane (CöHs) 3P = CHCH2COOH in which the carboxy group (-COOH) is unconjugated. The instability resulting from the phosphorane compound makes it difficult to obtain high yields. Furthermore, in the reaction series described for preparing the A2trans-prostaglandins, selective hydrogenation is necessary if an analogue of the A2trans-PGEi is to be obtained. It is necessary to hydrogenate a double bond between the carbon atoms of positions 5 and 6 while leaving unaltered a double bond between the carbon atoms of positions 13 and 14. There is a risk of hydrogenation of the two double bonds, leading to a reduction in the yield of the desired product. Finally, the co chain is introduced at an early stage into the reaction series leading to the desired A2trans-prostaglandin, so that a large amount of the expensive substrate required to introduce any desired co chain is required.

The second method is described in British Patents Nos. 1,483,240 and 1,540,427 to Titulan, published on August 17, 1977 and February 14, 1979, respectively. The introduction of the double bond between the carbon atoms in positions 2 and 3 requires the use of selenium or sulfur compounds. Traces of such compounds are harmful to humans and if the final A2transprostaglandinic products are to be used as drugs, the sulfur or selenium compounds must be eliminated. Such removal is difficult and requires considerable care. In addition, the sulfur and selenium compounds have a very unpleasant odor, which causes difficulties in their preparation and use.

Novel chemical compounds have now been discovered which are useful as intermediates in improved processes for the preparation of A2trans-PGEi analogs.

The new chemical compounds of the present invention, useful for the preparation of analogs of A2trans-prostaglandin Ei, are the compounds of general formula:

(IV)

20

2 "3 Z-R -R

O-THP in which Y represents

(where R4 represents a hydrogen atom or a protecting group for hydroxy group, eliminable in basic medium), Z represents

-OR5

.C = O or

35

H

(where R5 represents a hydrogen atom or a tetrahydropyranyl-2 group), R1 represents a formyl group or a group of formula -CH2OR4 (where R4 is as defined above), R2 represents a single bond or an alkylene group containing from 1 to 5 carbon atoms, R3 represents a hydrogen atom, an alkyl or alkoxy group containing from 1 to 8 carbon atoms, or a cycloalkyl or cycloalkyloxy group containing from 4 to 7 carbon atoms, unsubstituted or substituted by at least one alkyl group containing from 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 from 1 to 4 carbon atoms , with this restriction that when R2 represents a single bond R3 does not represent an alkoxy, cycloalkoxyloxy or phenoxy group, THP represents a tetrahydropyranyl-2 group, and the double bond between the carbon atoms of positions 13 and 14 is trans, i.e. E, with these restrictions that: 1) 55 when Z represents

■ C = O or

;vs

-OR5

'H

60

(where R5 represents a hydrogen atom), Y represents

VS'

65

-OR4 rH *

(where R4 represents a protective group of hydroxy group, eliminable in basic medium) and R1 represents a group

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of formula -CH2OR4 (where R4 represents a protective group of hydroxy group, eliminable in basic medium), and 2 °) when Y represents

R 'represents a formyl group.

It should be understood that the alkyl and alkylene groups and the alkyl and alkyl radicals of the groups mentioned in the present text may be straight or branched chain.

The present invention relates to all the compounds of general formula (IV) in their optically active "natural" form or in their enantiomeric form, or their mixtures, more particularly the recemic form consisting of equimolecular mixtures of the optically active "natural" form and of its enantiomeric form.

As can be seen, the compounds represented in the general formula (IV) have at least three chiral centers, with carbon atoms numbered 8, 11 and 12. Other chiral centers can also appear in the alkyl or branched chain alkylene groups , or when the symbol Y represents a group

OR4

-, _ ✓ * "

R4 being as defined above, or when the symbol Z represents a group

\ OR5 \ H

R5 being as defined above. The presence of chira-lity leads, as we know, to the existence of isomerism. However, the compounds of general formula (IV) all have a configuration such that the substituent groups attached to the carbon atoms of the cyclopentane ring in the positions listed 8 and 12 are trans relative to each other. Consequently, all the isomers of general formula (IV), and their mixtures, which have these substituent groups attached to the carbon atoms of the cyclopentane ring in position 8 and 12 in the trans configuration must be considered to be included by the formula general (IV).

Preferably, the group -R2-R3 represents, for example, a methyl, ethyl, 1-methyl ethyl, propyl, 1-methyl propyl, 2-methyl propyl, 1-ethyl propyl, butyl, 1-methyl butyl, methyl group. -2 butyl, methyl-3 butyl, ethyl-1 butyl, ethyl-2 butyl, pentyl, methyl-1 pentyl, methyl-2 pentyl, methyl-3 pentyl, methyl-4 pentyl, dimé-thyl-1,1 pentyl, 1,2-dimethyl pentyl, 1,4-dimethyl pentyl, 1-ethyl pentyl, 2-ethyl pentyl, 1-propyl pentyl, 2-propyl pentyl, hexyl, 1-methyl hexyl, 2-methyl hexyl, 1-dimethyl, 1 hexyl, 1-ethyl hexyl, 2-ethyl hexyl, heptyl, 2-ethyl heptyl, nonyl, undecyl, cyclobutyl, 1-propyl cyclobutyl, 1-butyl cyclobutyl, 1-pentyl cyclobutyl, 1-hexyl cyclobutyl, 2-methyl cyclobutyl , 2-propyl cyclobutyl, 3-ethyl cyclobutyl, 3-propyl cyclobutyl, tri-2,3,4-ethyl cyclobutyl, cyclopentyl, cyclopentylmethyl, 1-cyclopentyl ethyl, 2-cyclopentyl ethyl, 2-cyclopentyl propyl, cyclo-pentyl-3 propyl, 2-pentyl cyclopentyl, 2,2-dimethyl cyclopenty le, 3-ethyl cyclopentyl, 3-propyl cyclopentyl, 3-butyl cyclopentyl, tert.-3-butyl cyclopentyl, 1-methyl-3-propyl cyclopentyl, 2-methyl-3-propyl cyclopentyl, 2-methyl-4-propyl cyclopentyl, cyclohexyl , cyclohexylmethyl,

cyclohexyl-1 ethyl, cyclohexyl-2 ethyl, cyclohexyl-3 propyl, methyl-1 cyclohexyl-2 ethyl, cyclohexyl-2 propyl, methyl-1 cyclohexyl-1 ethyl, cyclohexyl-4 butyl, 3-ethyl cyclohexyl, isopropyl-3 cyclohex , 4-methyl cyclohexyl, 4-ethyl cyclohexyl, 4-propyl cyclohexyl, tert.-butyl-4 cyclohexyl, dimethyl-2,6 cyclohexyl, dimethyl-2,2 cyclohexyl, dimethyl-2,6 propyl-4 cyclohexyl, methyl- 1 cyclohexylmethyl, cycloheptyl, cycloheptylmethyl, cycloheptyl-1 ethyl, 2-cycloheptyl ethyl, phenyl, benzyl, 1-phenyl ethyl, 2-phenyl ethyl, 3-phenyl propyl, 4-phenyl butyl, 5-phenyl, 1-methyl phenyl -2 ethyl, 1,1-dimethyl-2-phenyl ethyl, 1-methyl-1-phenyl-ethyl, 1-phenyl-pentyl, phenoxymethyl, 2-phenoxy-ethyl, 3-phenoxy-propyl, 4-phenyl-butyl, 5-phenoxy-pentyl , 3-chloro-phenoxymethyl, 4-chloro-phenoxymethyl, 4-fluoro-phenoxymethyl, 3-fluormethyl-3-phenoxymethyl, 2-methylphenoxymethyl, 3-methylphenoxymethyl, 4-methylphenoxymethyl,

4-ethylphenoxymethyl, 4-tert-butylphenoxymethyl, sec.-butyl-4 phenoxymethyl, propoxymethyl, isopropoxy-methyl, butoxymethyl, pentyloxymethyl, hexyloxymethyl-methyl, 1-ethoxy-ethyl, 1-propoxy-ethyl, isopropoxy-1-ethyl, neopentyloxy -1 ethyl, pentyloxy-1 ethyl, methyl-1 ethoxy-1 ethyl, methyl-1 propoxy-1 ethyl, methyl-1 isobu-toxy-1 ethyl, methyl-1 neopentyloxy-1 ethyl, methyl-1 butoxy-1 ethyl , 1-methyl-isopentyloxy-ethyl, 1-methyl-1-pentyloxy-ethyl, 2-ethoxy-ethyl, 2-propoxy-ethyl, 2-butoxy-ethyl, (1-ethyl butoxy) -2 ethyl, 2-pentyloxy-ethyl, 1-ethoxy propyl, propoxy-1 propyl (2-methyl-butoxy) -l propyl, pentyloxy-1 propyl, methoxy-2 propyl, methoxy-3 propyl, ethoxy-3 propyl, propoxy-3 propyl, sec.-butoxy-3 propyl, isobutoxy -3 propyl, butoxy-3 propyl, methyl-1 methoxy-2 ethyl, methyl-1 ethoxy-2 ethyl, methyl-1 isobutoxy-2 ethyl, pentyloxy-1 butyl, pentyloxy-1 methyl-2 propyl, methoxy-4 butyl , 4-ethoxy butyl, 4-pro-poxy butyl, 1-methyl-3-methoxy pyle, methyl-1 pro-poxy-3 propyl, methyl-2 methoxy-3 propyl, dimethyl-1,1 ethoxy-2 ethyl, dimethyl-1,1 propoxy-2 ethyl, dimethyl-1,1 isobutoxy-2 ethyl, 5-methoxy-pentyl, 5-ethoxy-pentyl, 1-pentyloxy-pentyl, 1-ethyl-3-propoxy-propyl, cyclobuty-loxymethyl, cyclopentyloxymethyl, cyclohexyloxymethyl, cycloheptyloxymethyl, 2-cyclopentyloxy-ethyl or cyelo-hexyloxy-2-ethyl. Particularly preferred is dimethyl * 1,1-pentyl.

The hydroxy protecting groups, eliminable in basic medium, represented by R4, as used in the present text, are groups which have no influence on the other parts of the compounds during the elimination of the group. protective, and which are easily eliminated in a weak basic medium. Preferably, the hydroxy protecting group is, for example, an acyl group such as an acetyl, chloro-ketyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl, benzoyl, p-phenylbenzoyl or naphthyloyl group; particularly preferred is the acetyl group.

According to a characteristic of the present invention, the compounds of general formula (IV) in which R1 represents a group -CH2OR4, Y represents

, OR4.

C C 5 Z represents ^ C = O,

R4 represents a hydroxy protective group, eliminable in basic medium, and the other symbols are as defined above, that is to say the compounds of general formula:

6

5

10

15

20

25

30

35

40

45

50

55

60

65

7

644360

CH ^ OR

The dialkyl phosphonates of general formula (VI) and the phosphorane compounds of general formula (VII) are well known, or can be readily prepared by methods known per se. By the term "methods known per se" as used in the present text is meant methods previously used or described in the chemical literature (IVA).

The compounds of general formula (IV) in which R1 represents a group -CH2OR4, Y represents

10

(in which R4a represents a protective hydroxy group, eliminable in basic medium, and the other symbols are as defined above), are prepared by the Wittig reaction of a compound of general formula:

CHgOR

VS

-OR4

'H

Z represents C -

.OR5

'H

R4 represents a hydroxy protecting group, eliminable in basic medium, R5 represents a hydrogen atom, and the other symbols are as defined above, that is to say the compounds of general formula:

0-THP

(in which the various symbols are as defined above) with a sodium derivative of a dialkyl phosphonate of general formula:

CHgOR

4a

(IVB)

b-THP

OH

30

(R "0) 2PCH2C-R2-R; I

o o

(VI)

35

(in which R6 represents an alkyl group containing from 1 to 4 carbon atoms, preferably a methyl or ethyl group, and the other symbols are as defined above) or with a phosphorane compound of general formula:

40

(R> P = CHC-R2-R3

O

(VII)

(in which R7 represents an unsubstituted phenyl group 45 or substituted by at least one alkyl group containing from 1 to 4 carbon atoms, preferably a phenyl group, or represents an alkyl group containing from 1 to 6 carbon atoms, preferably a butyl or hexyl group, or else represents a cyclohexyl group, and the other symbols are as defined above). The sodium derivative of the dialkyl phosphonate of general formula (VI) can be prepared by reaction of the dialkoyl phosphonate and sodium hydride.

The Wittig reaction is described in "Organic Reactions", volume 14, chapter 3 (1965), John Wiley & Sons, Inc. (U.S.A.). This 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 dialkoylsulfoxide such as dimethyl sulfoxide, a dialkoylformamide such as N, N-dimethylformamide, a halogenated hydrocarbon such as methylene chloride or chloroform, or an alkanol containing from 1 to 4 carbon atoms, such as methanol or ethanol, or a mixture of two or more of these bodies, at a temperature ranging from -78 ° C to the reflux temperature of the reaction mixture.

50

55

60

(in which the various symbols are as defined above), are prepared by reduction of the compounds of general formula (IVA) to transform the oxo-15 group into a hydroxy-15 group.

The reduction transforming the oxo group into a hydroxy group can be carried out using any suitable reducing agent, such as sodium, potassium, lithium, zinc borohydride, lithium-tri-tert.-butoxyalumi-nium hydride, lithium-trimethoxyaluminum hydride, sodium cyano-borohydride, tri-sec.-potassium butylborohydride, complex of lithium aluminum hydride and quinine, iodide of (-) - isobornyloxy-megnesium, within an inert organic solvent, for example an alkanol containing from 1 to 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 bodies, at a temperature ranging from -78 ° C to ambient temperature. Preferably, the reduction is carried out using diisobornyloxyaluminium isopropoxide (described in the Japanese patent application published before examination No. 54-76552 of the holder), or a diisobutylphenoxyaluminium (in which the phenyl ring is unsubstituted or alkyl substituted) ) [described in Japanese patent application published before examination No. 54-154739 of the proprietor and in J. Org. Chem., 44.1363 (1979)], or a lithium hydride and binaphthyl-1,1 'dioxy-2,2' aluminum [described in J. Amer. Chem. Soc., 101, 5843 (1979)]. The product thus obtained is a mixture of isomers in which the hydroxy-15 group is in the α or β configuration; this mixture is separated by traditional means, for example by thin layer, column or high performance liquid chromatography, on silica gel, to obtain the desired isomer of general formula (IVB).

The compounds of general formula (IV) in which R1 represents a group -CH2OR4, Y represents

65

.-OR4 'H

.OR5

C "L, Z represents C

^> H

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8

R4 represents a hydroxy protecting group, eliminable in basic medium, R5 represents a tetrahydropyra-nyle-2 group and the other symbols are as defined previously, that is to say the compounds of general formula:

absolute ethanol, at a temperature ranging from - 10 ° C to the reflux temperature of the reaction mixture and, preferably, at a temperature ranging from room temperature to 50 ° C.

The compounds of general formula (IV) in which R1 represents a formyl group, Y represents ch2or

4a

C = O, Z represents C

10

.OR5

H

(Ivc) where R5 represents a tetrahydropyranyl-2 group, and the other symbols are as defined above, that is to say the compounds of general formula:

O-THP

15

O-THP

(in which the various symbols are as defined above), are prepared by etherification of the hydroxy-15 group of a compound of general formula (IVB) using 2,3-dihydro pyran in an organic solvent inert, for example methylene chloride or tetrahy-drofuran, in the presence of an acid catalyst, for example p-toluenesulfonic acid, sulfuric acid, trifluoroborane etherate or phosphorus oxychloride, to the room temperature or below.

The compounds of general formula (IV) in which R1 represents a group -CH2OR4, Y represents

20

25

, .OR4

CC, Z represents' H

-OR5

^ ^ H

R4 represents a hydrogen atom, R5 represents a tetrahydropyranyl-2 group, and the other symbols are as defined above, that is to say the compounds of general formula:

35

CHjgOH

(IVD)

o-thp o-thp

45

50

(in which the various symbols are as defined above), are prepared by saponification of the compounds of general formula (IVC) to transform the OR4a groups into hydroxy groups. The saponification can be carried out using an aqueous solution of an alkali metal hydroxide, carbonate or bicarbonate, for example sodium, potassium or lithium, or a hydroxide or of an alkaline earth metal carbonate, for example of calcium or barium, in the absence or in the presence of a water-miscible solvent, for example an ether such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, or an alkanol 60 containing from 1 to 4 carbon atoms, such as methanol or ethanol, at a temperature ranging from −10 ° C. to the reflux temperature of the reaction mixture and, from preferably at a temperature ranging from room temperature to 50 ° C., or else using an anhydrous solution of an alkali metal hydroxide or carbonate, for example sodium, potassium or lithium , in an anhydrous alkanol containing from 1 to 4 carbon atoms, for example methanol or cho

(IVE)

0-thp

(in which the various symbols are as defined above), are prepared from the compounds of general formula (IVD) by oxidation to transform the hydroxy-9 group into an oxo-9 group and simultaneously transform the hydroxymethyl group to the formyl group.

This oxidation is carried out by methods known per se for the transformation of a hydroxy group into an oxo group, for example by the methods described in (1) Tetsuji Kameya, "Synthetic Organic Chemistry III, Organic Syn-thesis 1", pp. 176-206 (1976), Nankodo (Japan), or in (2) "Compendium of Organic Synthetic Methods", volume 1 (1971), 2 (1974) and 3 (1977), Section 48, John Wiley & Sons, Inc (USA). Preferably, the oxidation is carried out under moderate conditions and in a neutral medium, for example using the dimethyl sulfide-N-chlorosuccinimide complex, the thioanisole-N-chlorosuccinimide complex, the dimethyl sulfide-chlorine complex or thioanisole-chlorine complex [cf. J. Amer. Chem. Soc., 94.756 (1972)], of the dicyclohexylcarbodiimide-dimethylsulfoxide complex [cf. J. Amer. Chem. Soc., 87, 5661 (1965)], pyridium chlorochromate (CsHsNHCrOsCl) [cf. Tetrahedron Letters, 2647 (1975)], of the sulfur trioxide-pyridine complex [cf. J. Amer. Chem. Soc., 89.5505 (1967)], of chromyl chloride [cf. J. Amer. Chem. Soc., 97.5929 (1975)], chromium trioxide-pyridine complex (for example the Collins reagent) or the Jones reagent.

The oxidation using the dimethyl sulfide-N-chlorosuccinimide complex, the thioanisole-N-chlorosuccinimide complex, the dimethyl sulfide-chlorine complex or the thioanisole-chlorine complex can be carried out by reaction within a halogenated hydrocarbon such as chloroform, methylene chloride or carbon tetra-chloride, or toluene, from -30 ° to 0 ° C, then treatment with triethylamine. The oxidation using the dicyclohexylcarbodiimide-dimethylsulfoxide complex is normally carried out by reaction in an excess of dime-thylsulfoxide in the presence of an acid, for example phosphoric acid, phosphorous acid, cyanoacetic acid, pyridine salt of phosphoric acid or trifluoro-roacetic acid as catalyst. Oxidation using pyridinium chlorochromate can be carried out by reac

9

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tion 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 within dimethyl sulfoxide in the presence of tri-ethylamine, at room temperature. Oxidation using chromyl chloride is normally carried out by reaction in a halogenated hydrocarbon such as chloroform, methylene chloride or carbon tetrachloride in the presence of tert.-butanol and pyridine, at a temperature ranging from -30 ° C to the reflux temperature of the reaction mixture. The oxidation using the chromium trioxide-pyridine complex can be carried out by reaction within a halogenated hydrocarbon such as chloroform, methylene chloride or carbon tetrachloride, at a temperature ranging from 0 °. C at room temperature and preferably at 0 ° C. The oxidation using the Jones reagent is normally carried out with acetone and dilute sulfuric acid, at a temperature ranging from 0 ° C. to ambient temperature.

The compounds of general formula (V) can be prepared by the series of reactions shown below in Scheme A, in which R8 represents a benzyl group or a hydroxy protecting group which is more easily removed than a tetrahydropyranyl group -2 in an acid medium, the double bond is E or Z or a mixture of the two, that is to say EZ, and the other symbols are as defined above.

The methoxy-1 methyl-1 ethyl, 1-methoxy-cyclohexyl, 1-methoxy-1-phenyl-ethyl, 1-ethoxy-ethyl, 2-tetrahy-drofuranyl-2 and trimethylsilyl groups are suitable hydroxy protecting groups which are more easily removed than tetrahydropyranyl-2 group.

Diagram A

ch2oh ch2or

4a o-thp o-thp

(x)

gold

4a o-thp ch2or

4a

(xi)

(V)

644,360

10

Referring to Scheme A, transformation [a] can be performed using a ylide of a phosphonium compound of general formula:

(R7): PCH2CH2CH2OH.X

(XII)

(in which X represents a halogen atom and R7 is as defined above) by the means indicated above for the transformation of the compounds of general formula (V) into compounds of general formula (IVA).

The ylide of a phosphonium compound of general formula (XII) can be prepared by reacting such a phosphonium compound with an appropriate base, for example butyllithium, or a lithium compound of general formula:

15

R?

R10-

"NLi

(XIII)

(in which R9 and R10, which may be identical or different, each represent an alkyl group containing from 1 to 6 carbon atoms, or a cycloalkyl group containing from 3 to 6 carbon atoms), for example lithic diisopropylamide, within an inert organic solvent, for example a solvent described above as suitable for the Wittig reaction of a compound of general formula (V), at a temperature ranging from -78 ° C to room temperature.

The phosphonium compounds of general formula (XII)

are well known or can be easily prepared by methods known per se.

Transformation [b] can be carried out, for example when R4- 'represents an acyl group, using an acyl chloride R4aCl, or an anhydride (R4a) 20, R4a being as defined above, within a solvent inert organic, for example methylene chloride or pyridine, in the presence of a tertiary amine, for example pyridine or triethylamine, at a temperature below room temperature and, preferably, below 0 ° C.

In transformation [c], when R8 represents a benzyl group, the compounds of general formula (XI) can be prepared by reduction of the compounds of general formula (X) to simultaneously transform the vinylene and ben-zyloxy groups, respectively into ethylene and hydroxy.

This reduction can be carried out suitably under a hydrogen atmosphere, in the presence of a hydrogenation catalyst, for example palladium on black, palladium black, platinum dioxide or Raney nickel, within a inert organic solvent, for example an alkanol containing from 1 to 4 carbon atoms, such as methanol or ethanol, or ethyl acetate, or a mixture of one or more of these bodies, to a temperature ranging from room temperature to the reflux temperature of the reaction mixture, under ordinary pressure or higher, for example under hydrogen pressure ranging from atmospheric pressure to 15 kg / cm 2.

When Rs is other than a benzyl group, the compounds of general formula (X) can be transformed into compounds of general formula:

CH ^ OR

4a

20

25

30

35

(in which the various symbols are as defined above) by moderate hydrolysis in an acid medium, under conditions avoiding the risk of elimination of the tetrahy-dropyranyl-2 group, then hydrogenation of the compound of general formula (XIV) obtained, by means indicated above for the transformation of the compounds of general formula (X) in which R8 represents a benzyl group into compounds of general formula (XI), in order to transform the vinylene group of formula (XIV) into an ethylene group.

Moderate hydrolysis can be carried out in an acid medium: (1) using an aqueous solution of an organic acid, for example acetic, propionic, oxalic or p-toluè-nesulfonic acid, or a mineral acid, for example hydrochloric, sulfuric or phosphoric acid, advantageously in the presence of an organic solvent miscible with water, for example an alkanol containing from 1 to 4 carbon atoms, such as methanol or ethanol, preferably methanol, or an ether such as 1,2-dimethoxyethane, dioxane or tetrahydrofuran, preferably tetrahydrofuran, at room temperature or below and preferably at 0 ° C, or (2) using an anhydrous solution of an organic acid such as p-toluenesulfonic or trifluoroacetic acid within an anhydrous alkanol containing from 1 to 4 carbon atoms, such as methanol or absolute ethanol, at 0 ° C or below.

The transformation [d] can be carried out by the means indicated above for the transformation of the compounds of general formula (IVD) into compounds of general formula (IVE).

The starting material of general formula (VIII) in which R8 represents a benzyl group is a known compound described in J. Org. Chem., 37.2921 (1972). The starting materials of general formula (VIII) in which R8 is other than a benzyl group are prepared as described in the Japanese patent application published before examination No. 53-149954 of the applicant.

According to another characteristic of the present invention, the compounds of general formula (IV) are transformed in which R1 represents a formyl group, Y represents

40

~ C = O, Z represents -C

OR5

H

45 R5 represents a tetrahydropyranyl-2 group, and the other symbols are as defined above, that is to say the compounds of general formula (IVE), into compounds of general formula:

he

COOR

(XV)

O-THP

O-THP

O-THP

(XIV)

65 [in which R11 represents an alkyl group containing from 1 to 4 carbon atoms, the double bonds between the carbon atoms of positions 2 and 3 and of positions 13 and 14 are trans (that is to say E) and the other symbols are such as

11

644,360

defined above] by Wittig reaction with a phosphorane compound of general formula:

(R7) .ÎP = CHCOOR "(XVI)

(in which R7 and R11 are as defined above) by the means indicated above for the transformation of the compounds of general formula (V) into compounds of general formula (IVA).

The phosphorane compounds of general formula (XVI)

are well known or can be easily prepared by methods known per se.

The compounds of general formula (XV) are transformed into analogues of A2trans-prostagandandine Ei of general formula:

O

COOR

R -R '

(XVII)

OH

i i

OH

(in which the various symbols are as defined above) by hydrolysis in an acid medium to transform the tetrahydropyranyl-2 oxy groups into hydroxy groups.

Hydrolysis in an acid medium to transform the tetrahydropyranyl-2 oxy groups into hydroxy groups is well known. We can execute it, for example:

(1) using an aqueous solution of an organic acid such as acetic, propionic, oxalic or p-toluenesulfonic acid or a mineral acid such as hydrochloric, sulfuric or phosphoric acid, advantageously in the presence of an inert organic solvent 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 ranging from room temperature to 75 ° C, or

(2) using 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 ranging from 0 ° at 45 ° C, or

(3) using an anhydrous solution of p-toluè-nesulfonic-pyridine acid complex or of trifluoroacetic-tick-pyridine acid complex in a lower alkanol such as methanol or ethanol, at a temperature of 10 to 60 ° C. Advantageously, this moderate hydrolysis can be carried out in an acid medium using 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-toluenesulphonic acid-pyridine complex and methanol or a mixture of trifluoroacetic acid complex -pyridine and methanol.

The analogs of A2-trans-prostaglandin Ei of general formula (XVII) thus obtained are useful in human or veterinary medicine as described in the British patents n 1 416410, 1 483 240 and 1 540 427 of the holder. They have the interesting pharmacological properties typical of prostaglandins, selectively, comprising in particular the hypotensive action, the action of inhibiting the aggregation of blood platelets, the action of inhibiting the secretion of gastric acid and gastric ulceration and bronchodilator action; they are useful for the treatment of hypertension, for the treatment of peripheral circulation disorders, for the prevention and treatment of cerebral thrombosis and myocardial infarction, for the treatment of gastric ulceration and for asthma treatment. The analogue of A2trans-prostaglandin Ei of general formula (XVII) in the formula of which the group -R2-R3 represents a 1,1-dimethyl pentyl group and R11 represents a methyl group, that is to say the ester methyl-9,15-dihydroxy-acid 11,16 dimethyl-16,16 prosta-diene-2,13 oïque- (2E, 13E) - (l Ia, 15R), which is described and claimed in British patent no 1 540 427, is useful for the termination of pregnancy and the induction of labor in pregnant female mammals and for the control of oestrus, contraception and menstrual regulation in female mammals.

It will therefore be understood that the new compounds of the present invention having the general formula (V), that is to say the compounds of general formulas (IVA), (IVB), (IVC), (IVD) and (IVE ), are useful and important intermediates for the preparation of therapeutically useful analogs of α2trans-prostaglandin Ei.

In addition, the new compounds of general formulas (V), (IX), (X), (XI) and (XIV), that is to say the compounds of general formula:

i

R '

\

O-THP

[in which Z represents an ethylene or vinylene group, R12 represents a hydrogen atom or a protective group of hydroxy group, eliminable in basic medium, R13 represents a formyl group, a hydroxymethyl group (-CH2OH) or a group -CH2OR8, in which R8 is as defined above, and the other symbols are as defined above, with these restrictions that: 1 °) when Rn represents a formyl group, X represents an ethylene group and R12 represents a protective group of hydroxy group, eliminable in basic medium, 2 °) when R13 represents a hydroxymethyl group, R12 represents a protective group of hydroxy group, eliminable in basic medium, and 3 °) when R13 represents a group -CH2OR8, X represents a vinylene group], are also useful and important intermediates for the preparation of analogs of À2trans-prostaglandin Ei. When X represents a vinylene group, the double bond can be E, Z or a mixture of the two.

The use of the compounds of general formulas (IV) and (XVIII) allows the synthesis of analogs of la2trans-prosta-glandin Ei by the methods described above, which avoid certain disadvantages of the two known methods mentioned above. The use of phosphonium compounds of general formula (XII) avoids the obligation to use the unstable phosphorane compound necessary in the method described in British Patent No. 1,416,410 [the compounds of formula (XII) have the group -CH2OH instead of the unconjugated car-boxy group and are therefore more stable,

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leading to higher yields]; selective hydrogenation, which carries the risk of reducing the yield of the desired product, is not necessary; and the chain co is introduced at a relatively late stage of the method. In addition, there is no need to use selenium or sulfur compounds and to carry out the necessary careful purification steps to remove traces of these compounds in the final prostaglandinic products.

The following examples illustrate the present invention. In these examples, "CCM", "IR", "NMR" and "CCGS" mean respectively "Thin layer chromatography", "Infrared absorption spectrum", "Nuclear magnetic resonance spectrum" and "Gel column chromatography of silica ". When relative proportions of solvents are indicated in the chromatographic and other treatments, the quantities are expressed in volumes; the solvents in parentheses are the development solvents used. Unless otherwise indicated, the infrared spectra are established by the liquid film method and the nuclear magnetic resonance spectra are established in solution in deuterochloroform (CDCh).

Example 1

(Hydro xy-5 pentene-2 yl) -2a (1-methoxy-1 methyl-1 ethoxy) -methyl-3p (tetrahydropyranyl-2 oxy) -4a cyclopen-tanol-la (EZ)

Under a nitrogen atmosphere, 29.1 ml of a 1.5 M solution of butyllithium in hexane is added to a suspension of 8.748 g of 3-hydroxypropyltriphenylphosphonium bromide in 70 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 10 minutes to obtain a solution of ylide. To the solution of ylide thus obtained is added a solution of 3 g of oxa-2 (1-methoxy-1 methyl-1 ethoxy) -methyl-6 syn- (tetrahydropyranyl-2 oxy) -7 anti-bicyclo [3.3.0 ] cis-octanol-3 (prepared as described in reference example 2 of the Japanese patent application published before examination no. 53-149954 beyond the application) in 10 ml of tetrahydrofuran, and the mixture is stirred at room temperature for one hour, then at 40 ° C for 30 minutes. The reaction mixture is poured into a saturated aqueous ammonium chloride solution and the mixture is extracted with ethyl acetate. The extract is washed with water and with a saturated aqueous solution of chloride. sodium, dried over magnesium sulfate and concentrated under reduced pressure, giving the crude desired compound having the following physical characteristic. This crude product is used in the next step without purification.

TLC (ethyl acetate-cyclohexane = 2/1); Rf = 0.23.

(a) Using the method described above but starting from 2-oxa-benzyloxymethyl-6 syn- (tetrahydropyranyl-2 oxy) -7 antibicyclo [3.3.0] cis-octanol-3 [prepared as described in J Org. Chem., 37.2921 (1972)], we prepare:

(5-hydroxy-pentene-2 yl) -2a benzyloxymethyl-3p (tetrahydropyranyl-2 oxy) -4a cyclopentanol-la- (EZ) having the following physical characteristic:

TLC (ethyl acetate-cyclohexane = 2/1): Rf = 0.25.

Example 2

Acetoxy-la (acetoxy-5 pentene-2 yl) -2a (methoxy-1 methyl-1 ethoxy) -methyl-3P (tetrahydropyranyl-2 oxy) -4a cyclopentane- (EZ)

The crude product prepared as described in Example 1 is stirred overnight with 14 ml of acetic anhydride and 33 ml of pyridine, at room temperature. The reaction mixture is diluted with ethyl acetate, washed with 0.5 N hydrochloric acid, with water and with a saturated aqueous solution of sodium chloride, dried over sulfate. magnesium and concentrated under reduced pressure, which gives the crude desired compound having the following physical characteristic. This crude product is used in the next step without purification.

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

(a) Using the method described above but from the crude product of Example 1 (a), the following compound is prepared. This product is purified by CCGS using as eluent a mixture (1/2) of ethyl acetate and cyclohexane, which gives, with a yield of 73% base on the starting material of Example 1 (a ):

acetoxy-la (acetoxy-5 pentene-2 yl) -2a benzyloxymé-thyl-3ß (tetrahydropyranyl-2-oxy) -4a cyclopentane- (EZ).

TLC (cyclohexane-ethyl acetate = 2/1): Rf = 0.82; IR: v = 1740,1243,1021 cm "1;

NMR (solution in CCU): 8 = 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 3

Acetoxy-la (5-acetene-pentene-2 yl) -2a hydroxymethyl-3p (tetrahydropyranyl-2 oxy) -4a cyclopentane- (EZ)

The crude product prepared as described in Example 2 is stirred with 40 ml of tetrahydrofuran and 15 ml of IN hydrochloric acid at 0 ° C. for 30 minutes. The reaction mixture is neutralized with a saturated aqueous sodium bicarbonate solution, washed with water and with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by CCGS using diethyl ether as eluent, which gives 2.30 g of the desired compound having the following physical characteristics:

TLC (ethyl acetate-cyclohexane = 2/1): Rf = 0.42; IR: v = 3460,1737,1243,1023 cm "1;

NMR (solution in CCU): 8 = 5.35 (2H, m), 4.97 (1H, m), 4.56 (1H, m), 3.95 (2H, t), 4.20- 3.16 (5H, m), 1.97 (6H, s).

Example 4

Acetoxy-1a (5-acetoxy-pentyl) -2a hydroxymethyl-3P (tetrahydropyranyl-2 oxy) -4a cyclopentane

Under a hydrogen atmosphere, a mixture of 10.402 g of the pentenyl compound prepared as described in Example 3, 120 ml of methanol and 100 mg of platinum dioxide is stirred at ambient temperature for 3 hours. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure, which gives 10.264 g of the desired compound having the following physical characteristics:

TLC (ethyl acetate-benzene = 2/1, using a silica gel plate pretreated with silver nitrate): RF = 0.47;

IR: v = 3460, 1740, 1247, 1020 cm "1;

NMR (solution in CCU): ô = 4.96 (1 H, m), 4.52 (1 H, m),

3.93 (2H, t), 4.20-3.15 (5H, m), 1.97 (6H, s).

Example 5

Acetoxy-1a (5-acetoxy-pentyl) -2a formyl-3ß (tetrahydro-pyranyl-2 oxy) -4a cyclopentane

To a suspension of 5.79 g of N-chlorosuccinimide in 300 ml of toluene, 3.94 ml of dimethyl sulfide is added, at 0 ° C., and the mixture is stirred at this temperature for 40

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644360

minutes. To the solution obtained is added a solution of 11.1 g of the hydroxymethyl compound prepared as described in Example 4 in 20 ml of toluene, at -20 ° C. The mixture is stirred at the same temperature for one hour, then stirred with 12.1 ml of triethylamine, at -20 ° C, for 30 minutes. The reaction mixture is neutralized with 0.1N hydrochloric acid, diluted with diethyl ether, washed with 0.1N hydrochloric acid, with a saturated aqueous solution of sodium bicarbonate, with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by CCGS using as eluent a mixture (1/1) of ethyl acetate and cyclohexane, which gives 10.327 g of the desired compound having the following physical characteristics:

TLC (ethyl acetate-benzene = 2/1): Rf = 0.74;

IR: v = 1740, 1377,1247,1025 cm- ';

NMR: S = 9.65 (1H, t), 5.30-4.85 (1H, m), 4.8-3.1 (6H, m).

Example 6

Acetoxy-la (5-acetoxy-pentyl) -2a hydroxymethyl-3p (tetrahydropyranyl-2 oxy) -4a cyclopentane

Under a hydrogen atmosphere, the mixture is refluxed for 2 hours for a mixture of 4.74 g of the benzyloxymethyl compound prepared as described in Example 2 (a?), 100 ml of ethanol and 20 g of Raney nickel ( W-7). The reaction mixture is filtered and the filtrate is concentrated under reduced pressure, which gives 3.48 g of the desired compound having the same physical characteristics as the product of Example 4.

Example 7

Acetoxy-la (acetoxy-5 pentyl) -2a (oxo-3-dimethyl-4,4 octene-1 yl) -3ß (tetrahydropyranyl-2 oxy) -4a cyclopen-tane- (E)

Under a nitrogen atmosphere, a solution of 11.154 g of 2-dimethyl-3,3-oxo-dimethyl heptylphosphate in 50 ml of tetrahydrofuran is added dropwise to a suspension of 1.317 g of sodium hydride (purity 63.5 %) in 250 ml of tetrahydrofuran, at room temperature, and the mixture is stirred at room temperature for 30 minutes. To the mixture thus obtained is added a solution of 10.987 g of the formyl compound prepared as described in Example 5 in 100 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 2 1/2 hours. The reaction mixture is acidified with acetic acid, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by CCGS using as eluent a mixture (3/1) of cyclohexane and ethyl acetate, which gives 12.3 g of the desired compound having the following physical characteristics:

TLC (cyclohexane-ethyl acetate = 1/1): Rf = 0.70; IR: v = 1740,1695,1625,1246, 1025 cm- ';

NMR: S = 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 8

Acetoxy-la (acetoxy-5 pentyl) -2a (hydroxy-3R-dimethyl-4,4 octene-1 yl) -3ß (tetrahydropyranyl-2 oxy) -4a cyclo-pentane- (E)

Under a nitrogen atmosphere, 100 ml of a 25% (w / v) solution of diisobutylaluminum hydride in toluene are added dropwise to a solution of 1.8 g of di-tert. 2,6-butyl-4-methylphenol in 660 ml of toluene, at 0 ° -5 ° C, and the mixture is stirred at the same temperature for one hour. To the mixture is added a solution of 8.64 g of the oxo-3 compound prepared as described in Example 7 in 60 ml of toluene, at -78 ° C, and the mixture is stirred between -30 and -20 ° C for 3 hours. The reaction mixture is stirred with 80 ml of water at 40 ° C for 30 minutes, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by CCGS using as eluent a mixture (4/1) of methylene chloride and ethyl acetate, which gives 7.5 g of the sought compound having the following physical characteristics:

TLC (benzene-ethyl acetate = 3/1): Rf = 0.30 (3S isomer, Rf = 0.39);

IR: v = 3740, 1738,1372,1243, 1017 cm "';

NMR (solution in CCU): 8 = 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 9

Acetoxy-la (acetoxy-5-pentyl) -2a [(tetrahydropyranyl-2 oxy) -3R dimethyl-4,4 octene-1 yl] -3ß (tetrahydropyranyl-2 oxy) -4a cyclopentane- (E)

A mixture of 7.5 g of the hydroxy-3R compound prepared as described in Example 8, 3 ml of 2,3-dihydro-pyran, 25 mg of p-toluenesulfonic acid is stirred at room temperature for 15 minutes. and 80 ml of methylene chloride. The reaction mixture is neutralized with a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The extract is washed with water and with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure, which gives 8.88 g of the desired compound having the characteristic following physics:

TLC (cyclohexane-ethyl acetate = 2/1): Rf = 0.57.

Example 10

(5-hydroxy-pentyl) -2 [(tetrahydropyranyl-2 oxy) -3R dimethyl-4,4 octene-1 yl] -3ß (tetrahydropyranyl-2 oxy) -4a cyclo-pentanol-la- (E)

A mixture of 8.88 g of the acetoxy compound prepared as described in Example 9, 4.05 g of potassium carbonate and 80 ml of methanol is stirred at 50 ° C. for 1 hour 1/2 The reaction mixture is diluted with ethyl acetate, washed with a saturated aqueous ammonium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by CCGS using as eluent a mixture (2/1) of ethyl acetate and cyclohexane, which gives 7.2 g of the desired compound having the following physical characteristics:

TLC (ethyl acetate-cyclohexane = 2/1): Rf = 0.27;

IR: v = 3400,1137,1026,978 cm "';

NMR: 8 = 5.60-5.23 (2H, m), 4.60 (2H, m), 4.30-3.20 (9H,

m).

Example 11

(4-Formyl butyl) -2a [(tetrahydropyranyl-2 oxy) -3R dimethyl-4,4 octene-1 yl] -3ß (tetrahydropyranyl-2 oxy) -4a cyclo-pentanone-1- (E)

A solution of 0.335 ml of chromyl chloride in 2 ml of carbon tetrachloride is added dropwise to a solution of 0.786 ml of tert.-butanol and 1.01 ml of pyridine in 13 ml of methylene chloride, to - 78 ° C. To the mixture is added a solution of 902 mg of the cyclopen-tanol-1 compound prepared as described in Example 10 in 5 ml of methylene chloride, at room temperature, and the mixture is stirred at room temperature for 2 hours. , then at 34 ° C for 40 minutes. The reaction mixture is stirred

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tional with 0.5 ml of dimethyl sulfide, at room temperature for 10 minutes; 60 ml of diethyl ether and 20 ml of water are added and the mixture is filtered through a bed of diatomaceous earth. The ethereal layer of the filtrate is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by CCGS using as eluent a mixture (3/1) of cyclohexane and ethyl acetate, which gives 675 mg of the desired compound having the following physical characteristics:

TLC (cyclohexane-ethyl acetate = 2/1): Rf = 0.44; IR: v = 1745, 1730, 1130, 1078, 1037, 1023 cm "1; NMR (solution in CCU): S = 9.50 (1 H, t), 5.70-5.30 (2H, 'm ), 4.71 -4.42 (2H, m), 4.31 -3.07 (6H, m).

(R7) 3P = CHCOOCH3 in which R7 is as indicated in the table below, and by modifying the reaction temperature, the reaction time and the solvent as necessary.

R7 solvent time temperature reaction reaction yield

-C4H9 —20 at 0 ° C 2 hours toluene 100% cyclohexyl t.a. 15 hours chloroform 94.1%

—CsHi3 t.a. 1 hour 1/2 tetrahydro- 98%

furanne t.a. means room temperature.

15

Example 12

Oxo-9 bis (tetrahydropyranyl-2 oxy) -l 1,15 1,16-dimethyl-16,16prostadiene-2,13 oic- (2E, 13E) - (l ia, 15R)

Under a nitrogen atmosphere, a mixture of 184 mg of cyclo-pentanone-1 prepared as described in Example 11, 231 mg of methoxycarbonylmethylidenetriphenylphosphorane and 2 ml of chloroform is stirred at ambient temperature for 2 hours. then it is concentrated under reduced pressure. The residue is purified by CCGS using as eluent a mixture (3/1) of cyclohexane and ethyl acetate, which gives 192 mg of the sought compound having the following physical characteristics:

TLC (benzene-ethyl acetate = 2/1): Rf = 0.74;

IR: v = 1745, 1726,1654,1196,1128,1030 cm "';

NMR: 5 = 6.90 (1H, dt), 5.70 (1H, d), 5.80-5.40 (2H, m), 4.60

(2H, m).

The compound sought is also prepared by the method described above, replacing the methoxycarbonylmethyli-dénetriphenylphosphorane. By a phosphorane compound

Example 13

Methyl ester of oxo-9 dihydroxy-11,15 dimé-20 thyl-16,16 prostadiene-2,13 oïque- (2E, 13E) - (1 la, 15R)

To a solution of 732 mg of methyl ester of oxo-9 bis acid (tetrahydropyranyl-2 oxy) -11.15 dimethyl-16.16 prostadiene-2.13 oic- (2E, 13E) - (1 la, 15R) (which can be prepared as described in Example 12) in 1.9 ml of tetrahydrofuran, 19 ml of an aqueous solution of acetic acid at 65% (by volume) are added and the solution is stirred. 55-60 ° C for one hour. The reaction mixture is then extracted with ethyl acetate and the extract is washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under pressure reduced, which gives 119 mg of the sought compound having the following physical characteristics:

TLC (development solvent: chloroform-tetrahydro-35 furan-acetic acid = 10/2/1): Rf = 0.51;

IR: v = 3400, 2940.2850, 1750, 1730, 1660, 1440, 1280 cm "1; NMR: 8 = 7.10-6.75 (1 H, m), 5.95-5.40 (3H , m), 3.71 (3H, s), 4.20-3.60 (2H, m), 2.75 (1H, dd), 1.00-0.75 (9H, m).

B

Claims (15)

644360 CLAIMS 1. Compounds of general formula: (IV) 2 3 z-r -r O-THP in which Y represents X = O or VS OR4 9 H where R4 represents a hydrogen atom, or else a protective group for a hydroxy group, eliminable in basic medium, Z represents the symbol R4, is an acetyl, chloroacetyl, dichlo-roacetyl, trichloroacetyl, trifluoroacetyl, propionyl, ben-zoyl group, p-phenylbenzoyl or naphthyloyl. 3. As compounds according to claim 1, acé-s toxy-la (acetoxy-5 pentyl) -2cc (oxo-3 dimethyl-4,4octene-1 yl) -3ß (tetrahydropyranyl-2 oxy) -4a cyclopentane- (E), acé-toxy-la (acetoxy-5 pentyl) -2a (hydroxy-3R-dimethyl-4,4 octene-1 yl) -3ß (tetrahydropyranyl-2 oxy) -4a cyclopen-tane- ( E), acetoxy-la (5-acetoxy-pentyl) -2a [(tetrahydropy-2-ranyl-2 oxy) -3R dimethyl-4,4 octene-1 yl] -3ß (tetrahydropyranyl-2 oxy) -4a cyclopentane- (E), (5-hydroxy pentyl) -2a [(tetrahydropyranyl-2 oxy) -3R 4,4-dimethyl octene-1 yl] -3ß (tetrahydropyranyl-2 oxy) -4a cyclopentanol-la- (E) , (4-formyl-butyl) -2a [(tetrahydropyranyl-2 oxy) -3R dimé-15 thyl-4,4 octene-1 yl] -3ß (tetrahydropyranyl-2 oxy) -4a cyclo-pentanone-1- (E ). 4. Process for the preparation of a compound of general formula (IV) according to claim 1, in which R1 represents a group -ch2or4, Y represents -C = O or rc; OR5 h where R5 represents a hydrogen atom or a tetrahy-dropyranyl-2 group, R1 represents a formyl group or a group of formula -ch2or4, where R4 is as defined above, R2 represents a single bond or an alkylene group containing 1 to 5 carbon atoms, R3 represents a hydrogen atom, an alkyl or alkoxy group containing from 1 to 8 carbon atoms, or a cycloalkyl or cycloalkyloyloxy group containing from 4 to 7 carbon atoms, unsubstituted or substituted by at least one alkyl group containing from 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 from 1 to 4 carbon atoms , with this restriction that when R2 represents a single bond R3 does not represent an alkoxy, cycloalkyloxy or phenoxy group, THP represents a tetrahydropyranyl-2 group, and the double bond between the carbon atoms of positions 13 and 14 is tr years, with these restrictions that: 1 °) when Z represents OR5 : c = o or Nh where R5 represents a hydrogen atom, Y represents OR4 ^ ^ S. ' ^ Nh where R4 represents a protective group of hydroxy group, eliminable in basic medium and R1 represents a group of formula -ch2or4, where R4 represents a protective group of hydroxy group, eliminable in basic medium, and 2 °) when Y represents "> C = 0, R1 represents a formyl group. 2. Compounds according to claim 1, in the formula of which the hydroxy protecting group, represented by OR4 Z represents C = O, 25 R4 represents a protective hydroxy group, eliminable in basic medium, and the other symbols are as defined above, characterized in that a compound of general formula is reacted: 1 CHgOR 4a (v) othp in which R4a represents a protective group for hydroxy group, eliminable in basic medium, and THP is as defined in claim 1, with a sodium derivative of a dialkyl phosphonate having the general formula: (R60) 2PCH2C-R2-R3 (vi) O o 50 in which R6 represents an alkyl group containing from 1 to 4 carbon atoms and R2 and R3 are as defined in claim 1, or with a phosphorane compound of general formula: 55 (R7> P = CHC-R2-R3 O (VII) In which R7 represents a phenyl group which is unsubstituted or substituted by at least one alkyl group containing from 1 to 4 carbon atoms, or represents an alkyl group containing from 1 to 6 carbon atoms, or represents a cyclohexyl group, and R2 and R3 are as defined in claim 1. 5. Method according to claim 4, characterized in that the reaction of the compound of general formula (V) with the dialkyl phosphonate of general formula (VI) or with the 3 644360 phosphorane of general formula (VII) is carried out in an inert organic solvent, at a temperature ranging from -78 ° C to the reflux temperature of the reaction mixture. 6. Process for the preparation of a compound of general formula (IV) according to claim 1, in which R1 represents a group -ch2or4, Y represents \ ^, OR4 ^ -OH C, Z represents C, ^ / H R4 represents a hydroxy protecting group, eliminable in basic medium, and the other symbols are as defined above, characterized in that a compound of general formula (IV) is prepared in which the symbols are as defined in claim 4, by the process according to claim 4 and in that the compound obtained is reduced in order to convert its oxo-15 group into a hydroxy-15 group. 7. Method according to claim 6, characterized in that the reduction is carried out using diisobor-nyloxyaluminium isopropoxide, a diisobutylphenoxyaluminium in which the phenyl ring is unsubstituted or alkylsubstituted, or a lithium hydride and binaphthyl-1,1 'dioxy-2,2' aluminum. 8. A method of preparing a compound of general formula (IV) according to claim 1 wherein R1 represents a group -CH: OR4, Y represents , OR4 H , Z represents OR5 'H R4 represents a hydroxy protecting group, eliminable in basic medium, R5 represents a tetrahydropyra-nyle-2 group, and the other symbols are as defined above, characterized in that, by the process according to claim 6, a compound of general formula (IV) in which the symbols are as defined in claim 6 and in that the product obtained is etherified using 2,3-dihydro-pyran in an inert organic solvent, in the presence of an acid catalyst, at room temperature or below. 9. A method of preparing a compound of general formula (IV) according to claim 1 wherein R 'represents a group -CH: OH, Y represents x ^ OH \ ^ OR5 C ', Z represents C H H of the reaction mixture. 11. A process for the preparation of a compound of general formula (IV) according to claim 1 in which R1 represents a formyl group, Y represents a group 'OR5 ~ C = O, Z represents C % H R5 represents a tetrahydropyranyl-2 group, and the other symbols are as defined above, characterized in that, by the method according to claim 9, a compound of general formula (IV) is prepared in which the symbols are as defined in claim 9 and in that the product obtained is oxidized. 12. Method according to claim 11, characterized in that the oxidation step is carried out under moderate conditions and in neutral medium. 13. Process for the transformation of a compound of general formula (IV) according to claim 1 and in the formula of which R1 represents a formyl group, Y represents \ \ / '- OR5 = O, Z represents .C 25 ^ H R5 represents a tetrahydropyranyl-2 group, and the other symbols are as defined in claim 1, in a compound of general formula: COOR he (XV) Rf represents a tetrahydropyranyl-2 group, and the other symbols are as defined above, characterized in that, by the method according to claim 8, a compound of general formula (IV) is prepared in which the symbols are as defined in claim 8 and in that the product obtained is saponified in order to transform the OR4 groups into OH groups. 10. Method according to claim 9, characterized in that the saponification step is carried out using an aqueous solution of an alkali metal hydroxide, carbonate or bicarbonate, or an alkali metal hydroxide or carbonate -terreous, in the absence or presence of a water-miscible solvent, at a temperature ranging from -10 ° C. to the reflux temperature of the reaction mixture, or using an anhydrous solution d '' an alkali metal hydroxide or carbonate in an anhydrous alkanol containing from 1 to 4 carbon atoms, at a temperature ranging from - 10 ° C to the reflux temperature O-THP in which R "represents an alkyl group containing from 1 to 4 carbon atoms, the double bonds between the atoms 45 of carbon of positions 2 and 3, and of positions 13 and 14, are trans, and the other symbols are as defined in claim 1, characterized in that this compound of general formula (IV) is reacted with a phosphorane compound of general formula: 50 (R7) 3P = CHCOOR "(XVI) wherein R7 is as defined in claim 4 and R "is as defined above. 55 14. Process according to claim 13, characterized in that the reaction of the compound of general formula (IV) and of the phosphorane of general formula (XVI) is carried out in an inert organic solvent, at a temperature ranging from —78 ° C at the reflux temperature of the reaction mixture. 15. Process for the transformation of a compound of general formula (IV) according to claim 1 and in the formula of which R1 represents a formyl group, Y represents 65 C = O, Z represents -OR5 'H R5 represents a tetrahydropyranyl-2 group, and the others 644360 4 symbols are as defined in claim 1, in a compound of general formula: O COOK ' IT-ROH in which R1 represents an alkyl group containing from 1 to 4 carbon atoms, the double bonds between the carbon atoms of positions 2 and 3, and of positions 13 and 14, are trans, and the other symbols are as defined in claim 1, characterized in that a compound of general formula (XV) is prepared by the process according to claim 13, then the compound of general formula (XV) is hydrolyzed to transform the groups (tetrahydropyranyl-2 oxy) - 11 and -15 in hydroxy groups. 16. The method of claim 15, characterized in that the hydrolysis of the compound of general formula (XV) is carried out using a mixture of dilute hydrochloric acid and detetrahydrofuran, 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, d '' a mixture of p-toluenesulfonic acid-pyridine complex and methanol, or a mixture of trifluoroacetic acid-pyridine complex and methanol. 17. Method according to one of claims 15 and 16, characterized in that the methyl ester of 9-oxo-dihydroxy-11,15 dimethyl-16,16 prostadiene-2,13 oic acid is prepared ( 2E, 13E) - (l lct, 15R).