CH622247A5 - Process for the preparation of prostaglandin A2 and of certain of its derivatives - Google Patents

Description

622,247

2

1. Process for the preparation of products of general formula:

(I)

co2r in which R represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, Ri represents a hydrogen atom or a methyl radical, X represents an oxygen atom or a methylene radical and R2 represents a alkyl radical having from 1 to 4 carbon atoms, characterized in that a product of general formula is treated, in the presence of a strong base:

formula in which A, R, Ri, R2 and X have the preceding meaning, product of formula III which is heated to obtain the product of formula I desired.

2. Method according to claim 1 for preparing the product of formula:

0

(I ')

characterized in that the product of formula is treated:

0

I H. I

OH

35

in which R, Ri, R2 and X have the above meaning, by a product of formula A — SO — Hai, in which A represents a methyl, phenyl or paratolyl radical and Hai represents a halogen atom, to obtain a product of formula:

(II ') C02H

40 with paratoluenesulfinyl chloride in the presence of a strong base to obtain the product of formula:

product which is heated to obtain the product of the desired formula.

The subject of the present invention is a new process for the preparation of prostaglandin A2 and certain of its derivatives, corresponding to the general formula:

in which R represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, Ri represents a hydrogen atom or a methyl radical, X represents an oxygen atom or a methylene radical and R2 represents a alkyl radical having from 1 to 4 carbon atoms. This process is characterized in that, in the presence of a strong base, a product of general formula 60 is treated:

0

(II)

3

622,247

in which R, Rl5 R2 and X have the above meaning, by a product of formula A - SO - Hai, in which A represents a methyl, phenyl or paratolyl radical and Hai represents a halogen atom, to obtain a product of formula :

0 5

(III)

, C02R

(I ')

02h

-R,

formula in which A, R, Rj, R2 and X have the above meaning, product of formula III which is heated to obtain the desired product of formula I.

The values which the substituents R and R2 may represent are preferably chosen from methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl or tert.-butyl radicals.

The Hai substituent can represent in particular a chlorine, bromine or iodine atom.

The invention more particularly relates to a process for preparing the product of formula:

characterized in that the product of formula is treated:

with paratoluenesulfinyl chloride in the presence of a strong base to obtain the product of formula:

(III ')

OH

product which is heated to obtain the product of the desired formula.

The strong base, in the presence of which the products of formula II or II 'are transformed into products of formula III or III' respectively, is preferably a mixture of diisopropylamine and butyllithium.

However, butyllithium can be used alone or with another amino base such as diethylamine.

Methyllithium or phenyllithium can also be used alone or with diethylamine or diisopropylamine.

Sodium hydride can also be used in dimethyl sulfoxide.

The transformation by heating of products of formula III or III 'into products of formula I or is carried out advantageously in an organic solvent at a temperature preferably between 70 and 140 ° C. The solvent which is used preferably toluene, but other organic solvents such as benzene or xylene can also be used.

The products of formula II, which are not known, can be prepared according to the process described in French patent application No. 2251323.

The products of formula I, obtained according to the process of the present invention and in which R 1 represents a methyl group and X an oxygen atom, are described as medicaments in French patent application No. 2279390. They demonstrate properties in pharmacology spasmogenic, bronchodilator and hypotensive.

0

alc02C '

The products obtained according to the process of the present invention and in which Rx represents a hydrogen atom and X an oxygen atom are used as intermediates in Belgian patent 40 No. 807047 to obtain products having properties in pharmacology among others antihypertensives and bronchodilators.

The products of formula I in which Rx represents a hydrogen atom and X represents a methylene radical are described in 45 Dutch patent application No. 7301094.

These products have properties similar to those of other prostaglandins; they can also be used as intermediates.

The other products of formula I are mentioned in Japanese publication J5 No. 0088.054.

The process of the invention makes it possible in particular to obtain prostaglandin A2 under conditions more satisfactory than those which the prior art makes it possible to achieve.

55 Indeed:

a) In French patent No. 2104916, a process for the synthesis of prostaglandin A2 of formula I 'has been described.

This synthesis is carried out in eight stages from the products of formula:

^ (CH2) nC02alci

(B)

622 TAI

formula in which ale represents a lower alkyl radical and alci an alkyl radical, n is an integer equal to 2.3 or 4 and m is an integer equal to 3.4 or 5.

In addition, this synthesis includes a step requiring separation of the two isomers of formulas:

'CH.

(CH.

(CH,

CH-;

•OH.

(CH9V -COpH

and obtained during the hot treatment of the product of formula:

OCH

^ CH2) n-C02H

^ (CH „) -CH.,

b) In French patent No. 2085654, a three-stage synthesis of dihydroprostaglandin A2 has been described from the products of formula B.

However, the present invention describes a synthesis of prostaglandin A2 in two stages from dihydroprostaglandin A2. This synthesis is therefore shorter than that described in patent No. 2104916. In addition, it is easier to implement, because it makes it possible to avoid separation of isomers. Finally, the synthesis which is the subject of the present invention makes it possible to obtain prostaglandin A2 with an overall yield, from product B, which is higher.

On another level, the present process also has two important advantages over that described in "J.A.C.S.", 98.6 (1976) p. 83, a process which consists in preparing prostaglandin A2 from a derivative of dihydroprostaglandin A2 by using phenyleelenyl chloride.

Indeed, the synthesis described in "J.A.C.S." is carried out in four stages, while that of the present invention comprises only two. In addition, the synthesis described in "J.A.C.S." uses a toxic reagent, while the reagent used in this synthesis is not.

The following example illustrates the invention.

Example:

Acid (8RS, 12SR, 15SR) (5Z, 13E) 9-oxo 15-hydroxyprosta-triene 5,10,13 oic

Stage A: Acid (8RS, 12SR, 15SR) (5Z, 13E) 9-oxo 10-parato-luenesulfinyl 15-hydroxyprostadiene 5.13 oic 363 mg of diisopropylamine in 5 cm3 of glyme are introduced under inert gas. Cooled to -78 ° C and slowly introduced 2.8 cm3 of butyllithium grading 1.3N. The mixture is allowed to return to 0 ° C. and after 15 minutes at this temperature, it is again cooled to -78 ° C. and slowly added 336 mg of the acid (8RS, 12SR, 15SR) (5Z, 13E) 9- 5.13 oic 15-hydroxyprostadiene oxo in solution in 5 cm3 of glyme, then 210 mg of paratoluenesulfinyl chloride.

The mixture is left for 1 hour at -78 ° C., poured into a saturated solution of sodium phosphate, extracted with ethyl acetate, dried and evaporated to dryness under reduced pressure. A yellow oil is obtained.

Stage B: Acid (8RS, 12SR, 15SR) (5Z, 13E) 9-oxo 15-hydroxy-prostatriene 5,10,13 oic

The oil obtained in the previous stage is dissolved in 5 cm3 of toluene and is heated for 30 min at reflux. The oil obtained is evaporated to dryness and the oil obtained is chromatographed on silica gel using a benzene / ethyl acetate / acetic acid mixture (60/40/1).

109 mg of expected product are obtained [Rf = 0.5 (chloroform / methanol / acetic acid: 95/5/5)] and 145 mg of starting product is recovered.

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