DK142171B - Process for Preparation of 15RS or 15SR Vinyl Derivatives of Prostaglandin Compounds. - Google Patents

Description

\ Ra / (11) PUBLICATION MANUAL 142171 DENMARK (bi) tnt.ci.3 c 07 c 177/00 '(21) Application No 2794/75 (22) Filed on 20 Jun. 1975 (24) Race day 20 Jun. 1975 (44) The application presented and the petition published on 15 · S®P · 1 980

DIRECTORATE OF

PATENT AND TRADEMARKET SYSTEM <30> Pr, ontet ™ it

Jun 21 1974, 7421602, FR

(7D ROUSSEL-UCLAF S.A., 55, Boulevard des Invalides, 75007 Paris, FR.

(72) Inventor: Jean Buendia, 39, Avenue de la Belle Gabrielle, 94130 - No = gent-sur-Marne, ”FR: Michel Vivat, Chemin de 1'Autostrade, 77400 - Team = ny-sur-Marne, FR.

(74) Plenipotentiary in the proceedings:

Patent law firm Magnus Jensens Eftf.

(54) Process for the preparation of 15RS or 15SR vinyl derivatives of prostaglandin interconnects.

The invention relates to a particular process for the preparation of known 15RS or 15SR vinyl derivatives of prostaglandin compounds of the general formula I set forth in the preamble of the claim, and the method of the invention is characterized by the characterizing part of the claim.

As a hydrogenation catalyst, palladium is preferably used on barium sulfate in the presence of a trace of quinoline, but palladium on calcium arbonate in the presence of lead acetate, palladium on coal in the presence of pyridine or Raney nickel can also be used.

Through the process described, the 15-vinyl compounds are obtained in the form of spaced 15SR and 15RS isomers.

142171

It has been found that the 15Sfi isomer (α-OH isomer) is much more active than the 15ES isomer and thus more active than the mixture of 15SR + 15RS listed as 15 "in Danish Patent Application No. 7010/73 .-s

The process described in Danish Patent Application No. 7010/73 is disclosed as follows for the 15-vinyl compounds: 142171 3 A 4) n °° 2E ÅA = / (CH 2 '- (CK

i

HgCsCH-MgBr

A A

Jv ^ '' \ = ^ / (°%) nCi02R /%.y \\/(0H2)n°°2Ii '- \ ^ \ y (^ ^ ° ¾' ^ y \ y (002) mCH3

H ^ KT ^ OH H2C ^ iC OH

Φ 0

sK (^) nCO2R

H2C = HC soh 15Έ X X separation

Jv ^ // (CH2) nCO2K ^ Xs ^, 'Ns - = / <^) nCO2R

\ _C¾} mGH3 '- (CH2 ^ ° ¾ ho "^ ch = ch2 hd vchch2

15 SR 15 RS

In the above formulas, R, m and n have the meaning set forth in the claim and A represents an alkoxy group of 1-4 carbon atoms.

142171 4

However, it has been found that the separation stage of the mixture 15SR + 15ES (= 15 ^) is very delicate. It can only be performed by chromatography using silver nitrate and only in poor yield. The problem is exactly the same when using the synthesis of Danish Patent Application No. 2797/75 »which also leads to a mixture of 15RS + 15SR vinyl compounds,

In contrast, the separation of the compounds of formula 0 Α '' '\ = / (αΗ2) η °° 2Ε V - /

HCT usCH

15 * wherein E, m and n have the meanings specified in the claim, in its two constituents 15SR and 15RS are performed in good yield by chromatography on silica gel eluting with an organic eluent. The ethynyl compounds, 15RS and 15SR, can then be hydrogenated separately to give the corresponding vinyl products in good yield.

Thus, the method of the present application, in comparison with the method of Patent Application No. 7010/73 and Patent Application No. 2795/75, offers the advantage of leading to the desired products by easier synthesis and in obtaining a better yield.

The compounds used as starting products can be prepared as described in Danish Patent Application No. 7010/73.

This process is characterized by treating a compound of formula III

(CB J COOalc1 O '• v. Ν' 2 n, ^ _s 'alcOC “\ II \ (CHJ CH- O' - 2 m 3 (IH)

in Island

wherein, as in the following, m and n are as defined in the claim, and alc and alc1 each represent the same or different alkyl groups of 1-4 carbon atoms, with an acid to give a compound of formula IV

5 U2171 ft ^^ (CH2) nCOO alc1

aic OC

S y ^ y <CH2> mCH3 <ϊνΙ

OH

which is treated with a dlazoalkane having 1-4 carbon atoms to give a compound of formula V

\ y (CH2) nCO ° alc1 alc OC (V) 0 X'—!

OH

wherein A, as in the following, represents an alkoxy group having 1-4 carbon atoms hydrolyzed with a base to give, after acidification, a compound of formula VI

A. (CH.) COOK

X_2 n HOC- (1 (CB2> »®3 (VI) t

OH

which compound YI is heated to effect a decarboxylation at the cyclopentane ring, and if desired, the compound formed is reacted with a diazoalkane of 1-4 carbon atoms to give a mixture of compounds of formulas VII and VII * 6 U2171

A (CH2) nCOOR

ΐτ '-V'V 2'Λ mi,

OH

And

A. Λ (CH „) COOR

x 2 n · \ __ ~. (CH.) JCH, 2 "3 (VII ·)

OH

wherein E., as in the following, represents a hydrogen atom or an alkyl group of 1-4 carbon atoms, which mixture is optionally separated into the two products upon which the mixture or one of its constituents is treated with an oxidizing agent to obtain a mixture of constituents of the formulas THI and VIII1

A ^ (CH_) COOR

y ~ \ ~ V_l ^^ (CH2) mCH3 (vm) o »g

A (CH) COOR

N. / Z U

> -iCli2) Λ {VITI ';

ISLAND

or one of these components, optionally separating an resulting mixture into its two components, then treating the mixture or one of the components with an organomagnesium compound of the formula CHvC-Mg-X

7 denotes a halogen atom to obtain a mixture of constituents down the general formulas IX and IX.

^ (CH2) nCOOR

-L / (CH.) CH, 2 m 3 (IX)

And HO C = CH

A \ <CH2> nC00B

'-L ^ (i «! \ _ XCH2) mCH3 <»'>

HO C ~ CE

or one of these ingredients, optionally separating the resulting mixture into the two ingredients, then treating the mixture or one of its components with an acid to obtain a mixture of ingredients of the general formulas

»WN _ ^ <CH2) n COOR

t “iCH2> mCH3

HO C ^ OH

And

° X ^ "X X (CH2) nCOOR

'CH_ * and 3

OH CR? H

Or to obtain one of these ingredients, separating the mixture into its constituents.

The above-mentioned Danish patent application lists the properties of the compounds obtained by the process according to the present application. These compounds have hypotensive properties, contract ive properties against the smooth muscle, and antibroncho-constrictive properties.

These pharmacological properties make these compounds suitable for use as medicaments, especially in the treatment of hypertension and circulatory disorders as well as in the treatment of respiratory disorders such as asthma.

The wavy lines in the formulas indicate that the substituents attached to the carbon atom may be in one or the other of the possible positions relative to that atom. The corresponding compounds can thus be either pure substances or mixtures, from which one can then separate the components using the usual physical methods such as e.g. chromatography.

The compounds of formula I may be taken in the form of pharmaceutical products containing as active ingredient at least one of the compounds described.

The following examples illustrate the method of the invention.

142171 9

Example 1.

(8RS. 12RS, 15SR) - (5Z.15E) -15-hydroxy-9-oxo-15-vinyl-5.15-Prosta-diacetic acid methyl ester.

108 mg (8RS, 12RS, 15SR) - (5Z, 13E) -15-ethynyl-15-hydroxy-9-oxo-5,13-prostadienic acid methyl ester, 10 ml of ethyl acetate, 20 mg of palladium on barium sulfate (5.25 $) and 0.1 ml of quinoline.

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

Thin layer chromatography on silica gel with benzene and ethyl acetate in the ratio of 9: 1 as eluent: Hf = 0.2.

HMR spectrum (deuterochloroform): Ξ in 15-hydroxyl: 146 Hz H in 15-vinyl: quadrupled 517, 528, 535.5 and 546.5 Hz H2 in 15-vinyl: triplet 451.5, 461.5 and 479 Hz (8RS, 12RS, 15SR) - (5Z, 13E) -15-ethynyl-15-hydroxy-9-oxo-5,13 - prostadienic acid methyl ester used as the starting product in this example is prepared according to the method described in Example 2.

Example 2.

(8RS.12RS.15RS) - (5Z.15E) -15-hydroxy-9-oxo-15-vinyl-5,13-prosta-diene acid methyl ester.

108 g (8RS, 12RS, 15RS) - (5Z, 13E) -15-ethynyl-15-hydroxy-9-oxo-5,13-prostadienic acid methyl ester, 10 ml of ethyl acetate and 20 mg of palladium on barium sulfate (5.25 ^). It is stirred under hydrogen atmosphere at room temperature for 7 minutes. 6.5 ml of hydrogen is absorbed. The catalyst is filtered off, the filtrate is washed with ice-cold 1 N hydrochloric acid and then with water. The magnesium sulfate is dried and the solvent is evaporated in vacuo. The residue obtained is purified by chromatography on silica gel eluting with a mixture of benzene and ethyl acetate in the ratio of 9: 1. 40 mg (8RS, 12RS, 15RS) - (5Z, 13E) -15-hydroxy-9-OXO-15-vinyl-5,13-prostad mono-acid methyl ester is obtained in the form of a pale yellow oil.

10 U2t7 <

Thin layer chromatography on silica gel eluted with a mixture of benzene and ethyl acetate 9: 1, Rf = 0.2.

DMR spectrum (deuterochloroform): H in 15-hydroxyl: 145 Hz H in 15-vinyl: quadrupled 521, 531, 538.5 and 549.5 Hz H2 in 15-vinyl: triplet 453, 563.5 and 481 Hz (8RS , 12RS, 15RS) - (5Z, 13E) -15-ethynyl-15-hydroxy-9-oxo-5,13-prostadienic acid methyl ester used as the starting product in this example is prepared as follows:

Step A: (8RS.12RS, 15SR) - (5Z.13E) -10-carbethoxy-15-hydroxy-9-oxo-5.15-prostadienoic acid ethyl ester.

243 mg (8RS, 12RS, 15SR) - (52.13E) -10-carbethoxy-9-oxo-15-tetrahydropyranyloxy-5,13-prostadienoic acid ethyl ester are introduced into a mixture of 4 ml of an aqueous 2 ° / o solution. of oxalic acid and 4 ml of ethanol. It is heated to 48 ° C for 8 hours and then the ethanol is evaporated under vacuum. The residue is extracted with ether, the ether phase is washed with water and dried over magnesium sulfate. After evaporation of the ether, the obtained oil is chromatographed on silica gel using a mixture of cyclohexane and ethyl acetate in a 1: 1 ratio. There are thus obtained 93 mg (8RS, 12RS, 15SR) - (5Z, 13E) -10-carbethoxy-15-hydroxy-9-oxo-5,13-prostadienic acid ethyl ester in the form of a pale yellow oil.

Step B: (8RS. 12RS, 15SR) - (5Z, 9.13E) -10-oarbethoxy-15-hydroxy.v-9-methoxy-5.9.13-prostatric acid ethyl ester.

550 mg of product prepared according to the previous step is dissolved in 4 ml of methylene chloride. Cool to 0 ° C and add 15 ml of diazomethane solution in methylene chloride at a concentration of 15 g per ml. liter. The room temperature is allowed to react and the reaction is continued for 5 hours. The excess diazomene and methylene chloride are then evaporated in vacuo. There is thus obtained 564 mg (8RS, 12RS, 15 SR) -C (5 Z, 9,13E) -10-carbeth oxy-15-hydroxy-9-methoxy-5,9,13 - prostatric acid ethyl ester in the form of a pale yellow oil.

Step C: (8RS, 12RS, 15SR) - (5Z.9.13E) -10-oreboxy-15-hydroxy-9-methoxyl-prostatric acid.

2.16 g of product from the previous step is dissolved in 21 ml of ethanol. 14.4 ml of 1 H sodium hydroxide solution are added and heated to 70 ° C for 6 hours. 4.8 ml of 1 ΪΓ aqueous sodium hydroxide solution are added and heated to 7 ° C for 10 hours. The ethanol is then evaporated and the residue is taken up in a mixture of water and ether. The separated aqueous phase is sieved with 2 l of hydrochloric acid and then saturated with sodium chloride. Extract with ether, dry the ether phase over magnesium sulfate and evaporate in vacuo. There is thus obtained 1.89 g (8RS, 12RS, 15SR) - (5Z, 9.13E) -10-carboxy-15-hydroxy-9-methoxyprostatric acid in the form of a thick yellow oil.

Step D: (8RS.12RS.15SR) - (5Z.9.13E) -15-Hydroxy-9-methoxy-5.9.15 - Prostatic Acid Methyl Ester and (12RS.15SR) - (5Z.8.15E) - 15-Hydroxy -9-methoxy-5.8.13-prOBtatriensyremethylester.

2.35 g of the diacid from the previous step is introduced into 185 ml of xylene. The mixture is heated to reflux for 8 hours and then the xylene is evaporated under vacuum. The resulting thick oil is dissolved in 10 ml of methylene chloride. The solution is cooled to 0 ° C and 30 ml of diazomethane solution is added in methylene chloride at a concentration of 35 g per ml. liter. After completion of addition, the excess diazomethane and methylene chloride are evaporated in vacuo. A yellow oil is obtained, which is filtered on silica gel in a mixture. benzene and ethyl acetate in the ratio of 8: 2. 1.95 g of oil is obtained, which by R.M.R. spectography is found to be a mixture of (8RS, 12RS, 15 SR) - (5 Z, 9.13E) -15-hydroxy-9-methoxy-5,9,13-pro s tatric acid methyl ester and ( 12RS, 15SR) - (5Z, 8.13E) -15-hydroxy-9-methoxy-5,8,13-prostatic triethyl acid methyl ester in the approximate ratio of 3/5: 2/5.

Step E; (8RS.12RS) - (5Z.9.13E) -9-methoxy-15-oxo-5.9.13-Prostatrienoic acid methyl ester and (12RS) - (5Z + 8.13E) -9-fluethoxy-15-oxo 8.5.13-prostatrlensyremethylester.

180 mg of the mixture obtained in the previous step is introduced into 13 ml of benzene. 580 mg of silver silicate is added and refluxed for 3 hours for 30 minutes. After cooling, filter and wash the filter with benzene. The filtrate is evaporated in vacuo to give 160 mg of oil, which, by 1 L.MR spectrography, turns out to be a mixture of (8RS, 12RS) - (5Z, 9.13E) -9-methoxy-15 9,13-Prostrienoic acid methyl ester and (12RS) - (5Z, 8.13E) -9-methoxy-15-oxo-5,8,13 - Prostrienoic acid methyl ester in the approximate ratio of 4/5: 1/5.

Step F: (8RS. 12RS. 15.fc) - (5Z. 9.13E) -15-Ethylene-15-hydroxy-9-methoxy - 5.9.13-prostatryoic acid methyl ester and (12RS.15) - (5Z .8.13E) - 15-th.v.n.yl-15-h.v.r ox.y-9-methox.v-5.9.13 -procetric acid methyl ester.

520 g of the mixture obtained in the previous step is dissolved in 3 ml of tetrahydrofuran. 3 * 6 ml of 0.5 H solution of ethynylmagnesium bromide in tetrahydrofuran is added. Stir for 1 hour at room temperature, then add 1.4 ml of magnesium derivative solution again and stir again for 1 hour 30 minutes at room temperature.

The reaction mixture is poured into an ice-cold saturated aqueous ammonium chloride solution and extracted with ether. After washing and drying the organic phase, evaporate in vacuo to give an oil which is purified by filtration on silica gel in a mixture of benzene and ethyl acetate at a ratio of 95: 5 * to give 139 mg of a mixture of (8RS, 12RS , 15 (5Z, 9 »13E) -15-Ethynyl-15-hydroxy-9-methoxy-5 * 9,13-pro-statric acid methyl ester. and (12RS, 15 µM5Z, 8.13E) - 15-ethynyl-15-hydroxy-9-methoxy-5,9,13-prostate acid methyl ester.

Step Si f8RS. 12RS. 15SR) -F (5Z, 13E) -15-Ethynyl-15-hydroxy-9-oxo-5.15 - prostadienic acid methyl ester and (8RS.12RS.15RS) - (5Z.15E) - 15e th. vinyl-15-hydroxy-9-oxo-5.15 -procetic acid methyl ester.

139 mg of the mixture obtained in the previous step is dissolved in 5 ml of ethanol. A 5 ml mixture of 0.1 IT aqueous hydrochloric acid and ethanol in a 1: 1 ratio is added. Allow to stand for 45 minutes and then evaporate the ethanol under vacuum. The residue is taken up in ether, the ether phase is washed with brine and then dried over magnesium sulfate. After evaporation of the ether, a yellow oil is obtained, which is chromatographed on silica gel using a mixture of benzene and ethyl acetate in the ratio of 8: 2. Thus, 38 mg (8RS, 12RS, 15RS) - (5Z, 13E) -15-ethynyl-15-hydroxy-9-ozo-5,13-proxy acid acid methyl ester and 24 mg (8RS, 12RS, 15SR) - ( 5Z, 13E) -15-Ethynyl-15-hydroxy-9-oxo-5,13-prostadienic acid methyl ester.