DE2526355A1 - PROCESS FOR THE PREPARATION OF SUBSTITUTED DERIVATIVES OF PROSTANIC ACID AND THE COMPOUNDS OBTAINED THEREOF - Google Patents

Description

Dr. F. Zumstein Sr. ■ Dr. Ξ. Assmann - Dr. R. Koenigsberger Dipl.-Phys. R. Holzbauer - Dipl.-Ing. F .. Klingseisen - Dr. F. Zumstein jun.

PATENT LAWYERS

: COLLECTIVE NO 225341 TELEX 529979 TELEGRAMS: ZUMPAT POST CHECK ACCOUNT:

MUNICH 91139-809. BLZ 7OOIO08O

BANK ACCOUNT: BANKHAUS H. AUFHAUSER

ACCOUNT NO. 397997. BLZ 70030600

BRÄUHAUSSTRASSE A

97 / N

Cas 1644 D

ROUSSEL-UCLAF, Paris / France

Process for the preparation of substituted derivatives

prostanoic acid and the resulting compounds

The invention relates to a new process for the preparation of substituted derivatives of prostanoic acid of the formula I.

(CH ₀ ) COOR i η

(CH-) CH, 2 m 3

wherein

R denotes a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms,

R. an alkyl radical with 2 to 4 carbon atoms and one Double bond means where each double bonded carbon atom carries at least 1 hydrogen atom,

m represents the integer 3, 4 or 5 and η represents the integer 2, 3 or 4,

S093Ö2 / 1001

which is characterized in that with hydrogen in the presence of a catalyst, a compound of the formula II

(CH ₂ J _n COOR

II

reduced, where R, m and η have the above meaning and R _{2 is} an alkyl radical having 2 to 4 carbon atoms which has a triple bond.

R ^ can thus the vinyl, 1-propenyl, 2-propenyl, 1-butenyl, Represent 2-butenyl, 3-butenyl and 1-methyl-2-propenyl radical.

Rp can thus in the starting compounds used the ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and represent 1-methyl-2-propynyl radical.

The invention relates in particular to a process for the preparation of a derivative of prostanoic acid of the formula

COOCH.

which is characterized in that one is in the presence of a catalyst the compound of formula

509882/1001

COOCH.

reduced with hydrogen.

The hydrogenation catalyst used is preferably palladium on barium sulfate in the presence of a trace of quinoline. One can but also palladium on calcium carbonate in the presence of lead acetate, palladium on activated carbon or soot in the presence used by pyridine or Raney nickel.

The starting compounds of the process according to the invention

The connections used can be specified in the DT-PS

(German patent application P 23 64 706.5) described method are produced.

This process is characterized in that with an acid, a compound of the formula III

treated, where m is the integer 3, 4 or 5 and η is the integer 2, 3 or 4 and Alk and Alk .., which are the same or can be different, each denotes an alkyl radical having 1 to 4 carbon atoms to form a compound of the formula IV

509882/1001

Alk:

I OH

to obtain that one with a diazoalkane with 1 to 4 carbon atoms treated to a compound of formula V

(CH ₂ ) _n C00 (CH ₂ ) _m CH ₃

I OH

to obtain, wherein A is an alkoxy radical having 1 to 4 carbon atoms means which are saponified with an alkali base to form a compound of the formula VI after acidification

COOH

HOC

(CH ₉ ) CH δ πι

VI

I I

OH

to obtain, wherein A represents an alkoxy group, which compound VI is subjected to the action of heat, to effect decarboxylation on the cyclopentane core, and, if desired, to the action of a diazoalkane of 1 to 4 carbon atoms is subjected to a mixture of the compounds of the formulas:

509882 / 1G01

and

(CH _n ) COOR
2 η

(CH-) CH

(CH-) COOR

VII

VII ¹

to obtain, wherein A is an alkoxy radical and R is hydrogen or denote an alkyl radical having 1 to 4 carbon atoms, which If desired, mix in each of its components can separate that treating the above mixture or one of its components with an oxidizing agent to a Mixture of compounds of the formulas:

(CH,) COOR
2 η

^(CH 2> _m ^CH 3

VIII

and

(CH-) COOR
2 η

(CH-) CH

2 m

VIII ¹

509882/1001

to obtain, in which A is an alkoxy radical, which mixture one can, if desired, separate into each of its components, that the above mixture or one of its components with an organomagnesium derivative of the formula

R ¹ Mg X

treated, wherein X is halogen and R ^{1 is} in particular an alkyl radical having 2 to 4 carbon atoms and a triple bond, to a mixture of the compounds of the formulas

(CH ₂ J _n COOR

(CH) CH. z m 3

IX.

(CH ₀ ) CH,
2 m 3

IX ¹

HO

to obtain, which can optionally be separated into each of its components, which mixture or which components one then treated with an acid to make a mixture of the general formulas

(CH ₂ J _n COOR

609882/1001

(CH ₂ J _n COOR

OH

to obtain or to obtain one of these compounds, the mixture optionally being separated into each of its components can be.

In the above-mentioned patent application as well as in

DT-PS (patent application P 23 64 706.5),

which corresponds to French patent application 74-00044 filed on January 2, 1974, the properties of the mentioned compounds obtained by the process according to the invention. These compounds are indeed used in medicine hypotensive, smooth muscle contracting and broncho-anti-constricting activities.

These pharmacological properties make this possible To use compounds as medicaments, particularly in the treatment of hypertension and circulatory disorders as well as in the treatment of respiratory diseases such as asthma.

The wavy lines in the formulas indicate that the substituents attached to the so-called carbon atom in the one or other possible position around this atom can be. Thus, the appropriate connections either individual compounds or mixtures, from which each component can be made up using the usual physical Methods such as chromatography can be separated.

The method described above thus allows production of derivatives of prostanoic acid of the formula I, as described in the examples and which are new.

509882/1001

This method makes it possible due to the advantage of easy separation of the components of the mixture of the compounds of formula II used at the beginning of the process with a triple bond, easier to prepare the compounds of formula I in the form of each of their constituents.

The compounds of the formula I can be in the form of pharmaceutical compositions which, as active ingredients, at least contain one of the compounds mentioned.

The following examples illustrate the invention without restricting it.

example 1

Methyl (8RS, 12RS _f 15SR) - (52,13E) -15-hydroxy-9-oxo-15-vinyl-5,13-prostadienoate

Mix 108 mg of methyl (8RS, 12RS, 15SR) - (5Z, 13E) -15-ethinyl-15-hydroxy-9-oxo-5,13-prostadienoate, 10 ecm of ethyl acetate, 20 mg of palladium (5.25 % ) on barium sulfate and 0.1 ecm quinoline.

It is cooled to ⁰ ° C. and stirred in a hydrogen atmosphere for 15 minutes. 6.5 ecm of hydrogen are absorbed. The catalyst is filtered off and the filtrate is washed with an ice-cold 1N hydrochloric acid solution and then with water. The organic solution is dried over magnesium sulfate and the solvent is evaporated to dryness in vacuo. The residue obtained is purified by chromatography on silica, eluting with a mixture of benzene and ethyl acetate (9/1). 60 mg of methyl (8RS, 12RS, 15SR) - (5Z, 13E) -15-hydroxy-9-oxo-15-vinyl-5,13-prostadienoate are obtained in the form of a clear yellow oil.

In thin-layer chromatography on silica [eluent benzene / ethyl acetate (9/1)] the R _f value is 0.2.

509882/1001

NMR spectrum (deuterochloroform)

H of the hydroxyl in the 15-position: 146 Hz; H of vinyl in 15 position: quadruplet at 517, 528, 53 5.5

and 546.5 Hz;

H ₂ of vinyl in 15-position: triplet at 451.5, 461.5 and

479 Hz.

The methyl (8RS, 12RS, 15SR) - (5Z, 13E) ethinyl 15-hydroxy-9-oxo-5,13-prostadienoate used as the starting compound of this example is prepared according to the method described in Example 2.

Example 2

Methyl (8RS, 12RS, 15RS) - (5Z, 13E) -15-hydroxy-9-oxo-15-vinyl-5.13-prostadienoate

Mix 108 mg of methyl (8RS, 12RS, 15RS) - (5Z, 13E) -15-ethinyl-15-hydroxy-9-oxo-5,13-prostadienoate, 10 ecm of ethyl acetate and 20 mg of palladium (5.25 % ) on barium sulfate. The mixture is stirred for 7 minutes at room temperature in a hydrogen atom, with 6.5 ecm of hydrogen being absorbed. The catalyst is filtered off and the filtrate is washed with an ice-cold In — hydrochloric acid solution and then with water. It is dried over magnesium sulphate and the solvent is evaporated off in vacuo. The residue obtained is purified by chromatography on silica using a mixture of benzene and ethyl acetate (9/1) as the eluent. 40 mg of methyl (8RS, 12RS, 15RS) - (5Z, 13E) -15-hydroxy-9-oxo-15-vinyl-5,13-prostadienoate are obtained in the form of a clear yellow oil.

Thin-layer chromatography on silica [eluent benzene / ethyl acetate (9/1)] gives an R _f value of 0.2.

509882/1001

NMR spectrum (deuterochloroform)

H of the hydroxyl in the 15-position: 145 Hz; H of vinyl at 15 position: quadruplet at 521, 531, 538.5

and 549.5 Hz; H _{2 of} the vinyl in 15-position: triplet at 453, 463.5 and 481 Hz,

The methyl (8RS, 12RS, 15RSM5Z, 13E) -15-ethinyl-15-hydroxy-9-oxo-5,13-prostadienoate used as the starting compound of this example is made by the following procedure.

Level A; Ethyl-CSRS ^ lgRS ^ lSSRj-CSZ ^ SEj-lO-carbethoxy-lS-hydroxy-9-oxo-5,13-prostadienoate

243 mg of ethyl- (8RS, 12RS, 15SR) - (5Z, 13E) -10-carbethoxy-9-oxo-15-tetrahydropyranyloxy - 5,13-prostadienoat are in a mixture of 4 ecm of a 2 / oo aqueous oxalic acid solution and 4 ecm of ethanol given. The mixture is heated to 48 ° C. for 8 hours and then the ethanol is evaporated off in vacuo. One extracts remove the residue with ether, wash the ethereal phase with water and dry it over magnesium sulfate. After evaporation of the ether, the oil obtained is chromatographed on silica gel with the aid of a cyclohexane-ethyl acetate mixture (l / l). 93 mg of ethyl (8RS, 12RS, 15SR) - (5Z, 13E) -10-carbethoxy-15-hydroxy-9-oxo-5,13-prostadienoate are obtained in this way in the form of a light yellow oil.

Grade B: Ethyl (8RS, 12RS, 15SR) - (5Z, 9,13E) -10-carbethoxy-15-hydroxy-9-methoxy-5,9,13-prostatrienoate

550 mg of the product prepared in the previous stage are dissolved in 4 ecm of methylene chloride. It is cooled to 0 C. and gives 15 ecm of a methylene chloride solution of diazomethane with 15g / l added. The temperature is allowed to rise to room temperature and the reaction is continued for 5 hours. One vaporizes then the excess diazomethane and methylene chloride in vacuo. 564 mg of ethyl (8RS, 12RS, 15RS) - (5Z, 9, 13E) -10-carbethoxy-15-hydroxy-9-methoxy-5,9,13-prostatrienoate are obtained in this way in the form of a pale yellow oil.

509882/1001

Level C: (8RS, 12RS, 15SR) - (5Z, 9, 13E) -10-carboxy-15-hydroxy-9-methoxyprostatrienoic acid

2.16 g of the product obtained in the previous stage are dissolved in 21 ecm of ethanol. One gives 14.4 ecm of an aqueous, gen In NaOH solution is added and the mixture is heated at 70 ° C. for 6 hours. One gives then 4.8 ecm of an aqueous In-NaOH solution and heated 10 hours at 70 ° C. The ethanol is then evaporated off and the residue is taken in a water-ether mixture on. The separated aqueous phase is treated with a 2N hydrochloric acid acidified and then saturated with sodium chloride. Extract with ether, dry the essential Phase over magnesium sulfate and concentrate it in vacuo. 1.89 g of (8RS, 12RS, 15SR) - (5Z, 9,13E) -10-carboxy-15-hydroxy-9-methoxyprostatrienoic acid are obtained in this way in the form of a thick yellow oil.

Grade D: methyl (8RS, 12RS, 15SR) - (5Z, 9,13E) -15-hydroxy-9-methoxy-5,9,13-prostatrienoate and methyl (12RS, 15SR) - (5Z, 8, 13E) -15-hydroxy-9-methoxy-5,8,13-prostatrienoate

2.35 g of the di-acid prepared in the previous stage will be placed in 185 ecm xylene. The mixture is refluxed for 8 hours after which the xylene is removed in vacuo. The thick oil obtained is dissolved in 10 ecm of methylene chloride. The solution is cooled to 0 ° C. and 30 ecm of a methylene chloride solution are added of diazomethane with a titer of 15 g / l. After the addition is complete, the excess diazomethane and Removed methylene chloride in vacuo. A yellow oil is obtained, which is poured over in a benzene / ethyl acetate mixture (8/2) Silica filtered. 1.95 g of an oil are obtained which, according to the NMR spectrum, is a mixture of methyl- (8RS, 12RS, 15SR) - (5Z, 9.13E) -15-hydroxy-9-methoxy-5,9,13- prostatrienoat and methyl (12RS, 15SR) - (5Z, 8,13E) -15-hydroxy-9-methoxy-5,8,13-prostatrienoate in an approximate ratio of 3/5 to 2/5.

509882/1001

Step E: methyl (8RS, 12RS) - (5Ζ, 9,13Ε) -9-methoxy-15-oxo-5,9,13-prostatrienoate and methyl (12RS) - (5Ζ, 8,13E) -9 methoxy-15-oxo-5,8,13-prostatrienoate

180 mg of the mixture obtained in the previous stage introduced into 13 ecm benzene. 580 mg of silver silicate are added added, after which the mixture is refluxed for 3 1/2 hours. After cooling, it is filtered and the filtrate is washed with benzene. The filtrate is evaporated in vacuo, 160 mg of an oil being obtained, which is determined by NMR spectroscopy as a mixture of methyl (8RS, 12RS) - (5Z, 9,13E) -9-methoxy-15-oxo-5,9,13-prostatrienoate and methyl (12RS) - (5Z, 8,13E) -9-methoxy-15-oxo-5,8,13-prostatrienoate in an approximate ratio of 4/5 to 1/5.

Level F: methyl (8RS, 12RS, 15) - (5Z, 9,13E) -15-ethinyl-15-hydroxy-9-methoxy-5,9,13-prostatrienoate and methyl (12RS, 15) - ( 5Z, 8,13E) -15-ethinyl-15-hydroxy-9-methoxy-5,8,13-prostatrienoate

500 mg of the mixture obtained in the previous stage are dissolved in 3 ecm of tetrahydrofuran. 3.6 ecm of a 0.5N ethynylmagnesium bromide solution are added in tetrahydrofuran added. The mixture is stirred for 1 hour at room temperature and then another 1.4 ecm of the Magnesium solution is added and the mixture is again stirred for 1 1/2 hours at room temperature. The reaction mixture is poured into one containing ammonium chloride saturated, ice-cold aqueous solution and extracted with ether. After washing and drying the organic Phase is evaporated in vacuo, and an oil is obtained, which is obtained by filtration through silica gel in a mixture Benzene and ethyl acetate (95/5) cleans, whereby 139 mg of a mixture of methyl- (8RS, 12RS, 15) - (5Z, 9.13E) -15-ethinyl-15-hydroxy-9-methoxy-5.9, 13-prostatrienoate and methyl- (12RS, 15) - (5Z, 8,13E) -15-ethinyl-15-hydroxy-9-methoxy-5,9,13-prostatrienoate can be obtained.

509882/1001

step G: methyl (8RS, 12RS, 15SR) - (5Z, 13E) -15-ethinyl-15-hydroxy-9-oxo-5,13-prostadienoate and methyl (8RS, 12RS, 15RS) - (5Z, 13E ) -15-ethinyl-15-hydroxy-9-oxo-5,13-prostadienoate

Dissolve 139 mg of the compound obtained in the previous stage mixture in 5 cc of ethanol. 5 ecm of a l / l mixture of aqueous Ο, η-hydrochloric acid solution and ethanol are added. The mixture is left to react for 45 minutes and the ethanol is then removed in vacuo. The residue is taken up in ether, the ethereal phase is washed with salt water and then dried over magnesium sulfate. After evaporation of the ether, a yellow oil is obtained, which is chromatographed on silica gel with the aid of a benzene / ethyl acetate mixture (8/2). This gives 38 mg of methyl (8RS, 12RS, 15RS) - (5Z, 13E) -15-ethinyl-15-hydroxy-9-oxo-5,13-prostadienoate and 24 mg of methyl (8RS, 12RS, 15SR) - (5Z, 13E) -15-ethinyl-15-hydroxy-9-oxo-5,13-prostadienoate.

509882/1001

Claims (7)

Claims 1.) Process for the preparation of substituted derivatives the prostanoic acid of the formula (I) (CH ₂ J _n COOR (CHJ CH, 2 m 3 wherein R is a hydrogen atom or an alkyl radical with 1 to 4 Represents carbon atoms, R _{1 represents} an alkyl radical with 2 to 4 carbon atoms and one double bond, each of the double bonded carbon atoms carrying at least one hydrogen atom, m represents the integer 3, 4 or 5 and η represents the integer 2, 3 or 4, characterized in that a compound of the formula (II) (CH ₂ J _n COOR (CH ₅ ) CH_ δ in 3 (II) where R, m and η are as defined above and R _{2 is} an alkyl radical having 2 to 4 carbon atoms and a triple bond, reduced with hydrogen in the presence of a catalyst. 509882/1001 2. Process according to claim 1 for the preparation of a derivative of prostanoic acid of the formula COOCH. characterized in that a compound of the formula COOCH. C = .CH reduced with hydrogen in the presence of a catalyst. 3. The method according to any one of claims 1 or 2, characterized characterized in that the hydrogenation catalyst consists of palladium on barium sulfate and it is in the presence of a trace of quinoline is used. 4. Methyl (8RS, 12RS, 15SR) - (5Z, 13E) -15-hydroxy-9-oxo-15-vinyl-5,13-prostadienoate. 5. Methyl (8RS, 12RS, 15RS) - (5Z, 13E) -15-hydroxy-9-oxo-15-vinyl-5,13-prostadienoate. 6. Pharmaceutical compositions containing methyl (8RS, 12RS, 15SR) - (5Z, 13E) -15-hydroxy-9-oxo-15-vinyl-5,13-prostadienoate as the active ingredient contain. 7. Pharmaceutical compositions containing methyl- (8RS, 12RS, 15RS) - (5Z, 13E) -15-hydroxy-9-oxo-15-vinyl-5,13- prostadienoat included. 509882/1001