PROCESS FOR THE PREPARATION AND PURIFICATION OF MISOPROSTOL

Abstract

Preparation of the compounds of general formula I, among them misoprostol where R represents a straight- or branched-chain C.sub.1-4 alkyl group by cuprate coupling of the vinyl cuprate of general formula II prepared by reacting the vinyl stannane of general formula III with copper halide CuX and alkyllithium R.sup.1Li wherein: R.sup.2 stands for H or an alcohol-protecting group which may contain silicium atom, as for instance trimethylsilyl-, triethylsilyl-, tert.-butyldimethylsilyl- group, or a cyclic or open-chain alkyl group containing oxygen atom, as for instance tetrahydropyranyl-, methoxymethyl- or ethoxymethyl- group; X means I, Br, CN, SCN, OSO.sub.2 CF.sub.3 group, R.sup.1 represents C.sub.1-6 alkyl group, n>2, if R.sup.2 is not hydrogen atom, n>3, if R.sup.2 is hydrogen atom, and the protected enone of the general formula IV 30 22 IV where R.sup.3 represents THP- or trialkylsilyl-group and the meaning of R is as defined above takes part in the cuprate reaction 5 in a manner that a.) the excess of the alkyllithium, which is applied as compared to the Cu(I) iodide in the case of R.sup.2H in 2-2.4 molar ratio, in the case of R.sup.2=H in 3-3.4 molar ratio, is decomposed before the coupling reaction of II and IV, b.) the protecting groups of the resulting compound of the general formula V 15 V where the meanings of R, R.sup.2 and R.sup.3 are as defined above are removed, the obtained compound of the general formula I is purified by chromatography.

##STR00001##

Claims

1-18. (canceled)

19. A process of preparing compounds of general formula I, ##STR00031## where R represents straight- or branched-chain C1-4 alkyl group, which comprises cuprate coupling of a vinyl cuprate of general formula II ##STR00032## wherein R2 stands for H or an alcohol-protecting group, optionally containing silicon atom or a cyclic or open-chain alkyl group containing oxygen atom; and R1 represents C1-6 alkyl group; with a protected enone of general formula IV ##STR00033## where R3 represents THP- or trialkylsilyl group and R is as defined above to produce a compound of general formula (V) ##STR00034## where the meanings of R, R2 and R3 are as defined above, removing the protecting groups of the compound of general formula (V) and purifying the compound of general formula (I) by chromatography; wherein the compound of general formula (II) is prepared by reacting a vinyl stannane of general formula III with copper halide CuX and alkyllithium R1Li ##STR00035## where X means iodo atom, bromo atom, CN, SCN, OSO2CF3 group, n>2, if R2 is other than hydrogen atom, and n>3, if R2 is hydrogen atom; and wherein an excess of the alkyllithium, which is in an amount compared to the Cu(I) iodide in the case where R2H in 2-2.4 molar ratio, in the case where R2=H in 3-3.4 molar ratio, is decomposed before the coupling reaction of the compounds of the general formula II and IV.

20. The process of claim 19, wherein the decomposition of the excess alkyllithium is carried out with ketone, ester or trialkylsilyl halogenide compounds.

21. The process of claim 20, wherein the decomposition of the excess alkyllithium is carried out with acetone or ethyl acetate.

22. The process of claim 19, wherein the purification of the compound of general formula (I) comprises purification chromatography and filtration chromatography.

23. The process of claim 22, wherein the purification chromatography removes the technological impurities originating from reagents or side reactions, including related isomeric impurities, and the filtration chromatography removes the contaminations of solvents used as eluent in the purification chromatography.

24. The process of claim 22, wherein the purification is carried out on silica gel column by gravity column chromatography.

25. The process of claim 24, wherein the chromatography on silica gel uses a multicomponent stepwise gradient mixture as eluent.

26. The process of claim 25, wherein the multicomponent mixture contains 0.01-0.1% acid.

27. The process of claim 26, wherein the acid is acetic acid or formic acid.

28. The process of claim 26, wherein eluents of the silica gel chromatography contain 0.05% of formic acid.

29. The process according to any of claims 22, wherein the purification chromatography uses (a) spherical silica gel having average particle size of 79 m; or (b) irregular silica gel having a size of 0.063-0.200 mm silica gel, then the united main fraction is concentrated and, with adding an apolar solvent, passed through an activated carbon bed.

30. The process of claim 29, where a multicomponent stepwise gradient mixture containing diisopropyl ether, C1-6 alcohol and 0.05% of formic acid and optionally acetone and/or methyl ethyl ketone is used as eluent.

31. The process of claim 29, where the multicomponent stepwise gradient mixture is in point (a): diisopropyl ether:acetone:methanol solvent mixture containing 0.05% formic acid, or in point (b): diisopropyl ether:isopropanol solvent mixture containing 0.05% formic acid.

32. The process according to point (b) of claim 29, wherein hexane:acetone solvent mixtures are used on the activated carbon bed.

33. The process of claim 22, wherein the filtration chromatography is performed with irregular silica gel column having a size of 0.063-0.200 mm and stepwise gradient mixtures of dichloromethane:acetone and methyl tert.-butyl ether:acetone solvents, containing 0.05% formic acid is used as eluent.

34. The process according to any of claims 30, wherein the fractions from the chromatography, which contain 0.05% of acid, are optionally washed to neutral pH.

35. The process of claim 19, wherein the alcohol-protecting group containing silicon atom in the definition of R.sup.2 comprises a trimethylsilyl group, a triethylsilyl group or a tert-butyldimethylsilyl group.

36. The process of claim 19, wherein the cyclic or open-chain alkyl group containing oxygen atom in the definition of R.sup.2 comprises a tetrahydropyranyl group, a methoxymethyl group or an ethoxymethyl group.

Description

EXAMPLES

Example 1

()-5-oxo-3-[(trimethylsilyl)oxy]-1-cyclopenten-1-heptanoic Acid Methyl Ester

[0116] ##STR00026##

[0117] 1955 g of 3-hydroxy-5-oxo-1-cyclopenten-1-heptanoic acid methyl ester (HO-enone) is dissolved in tetrahydrofuran (20 kg) under inert atmosphere. To the solution 1.7 L of triethylamine and then 1.14 L of trimethylsilyl chloride are added. After reaching the desired conversion the excess of the trimethylsilyl chloride is decomposed with methanol, the reaction mixture is filtered, the precipitate is washed with tetrahydrofuran, to the liquid filtrate triethylamine is added and the mixture is concentrated with evaporation.

[0118] The silylated product (TMS-enone) is transferred into the next step without further purification.

Example 2

()-(11,13E)-16-methyl-9-oxo-11,16-bis[(trimethylsilyl)oxy]-13-en-prostanoic Acid Methyl Ester

Preparation of the Cuprate Reagent

[0119] ##STR00027##

Decomposition of the Methyllithium Excess

[0120] ##STR00028##

Coupling (Conjugated Addition)

[0121] ##STR00029##

Preparation of the Cuprate Reagent

[0122] 8.4kg of tributyl[1(E)-4-methyl-4-[trimethylsilyl)oxy]1-octen-1-yl]-stannane (vinyl stannane) is dissolved in tetrahydrofuran in an inert atmosphere. To the solution 2.72 kg of copper(I)iodide is added. The reaction mixture is agitated at room temperature for 30 minutes, then cooled to ()35 C. and methyllithium solution equivalent to 34.5 mol of methyllithium is added and the reaction mixture is agitated at ()20-()25 C. If the conversion after 30 minutes of stirring is not sufficient, a further amount of methyllithium solution equivalent to 0.7 mol of methyllithium is added and stirring at ()20-()25 C. is continued for another 30 minutes.

Coupling (Conjugated Addition)

[0123] The reaction mixture is cooled to ()60 C. and in order to decompose the methyllithium excess, acetone is added. At ()55 C. the tetrahydrofuran solution of the TMS-enone derivative is added to the reaction mixture. After 30-40 minutes of agitation the reaction mixture is decomposed by adding it to ammonium chlorideammonium hydroxyde solution (77 kg of water, 9.2 g of ammonium hydroxide solution, 25.3 kg of ammonium chloride).

[0124] The decomposed reaction mixture is extracted with methyl tert.-butyl ether, the organic phase is washed with sodium hydrogen sulfate in sodium chloride solution, and then with saturated sodium chloride solution, then dried over sodium sulfate.

[0125] The evaporated reaction mixture is transferred into the next reaction step without further purification.

Example 3

Misoprostol

()-(11,13E)-11,16-dihydroxy-16-methyl-9-oxo-13-en-prostanoic Acid Methyl Ester

[0126] ##STR00030##

[0127] The TMS-misoprostol (8.11 mol) prepared in the coupling reaction according to Example 2. is dissolved in methanol (17 kg) at room temperature, 205g of pyridinium tosylate is added to it and the mixture is agitated until the desired conversion is reached. The mixture is then let onto sodium chloride solution. The product is extracted with methyl tert.-butyl ether, the united organic phase is washed with sodium chloride solution, dried over sodium sulfate, filtered and the filtrate solution is evaporated.

Example 4

Misoprostol

[0128] The crude misoprostol concentrate (8.11 mol) prepared according to Example 3. is dissolved in diisopropyl ether and purified by chromatography on a column made of 100 kg of silica gel (Kieselgel Si 60 (0.063-0.200 mm)) using as eluent stepwise gradient mixtures of diisopropyl ether:acetone:methanol and 0.05% formic acid, wherein

[0129] diisopropyl ether:acetone:methanol=100:5:2, 100:10:2, 100:0.5:5, 100:0.5:7.5.

[0130] The united main fraction is concentrated. To the diisopropyl ether solution of the main fraction hexane is added until it undergoes opaque, then it is filtered through a 1.6 kg active carbon bed using hexane:acetone=5:1 and hexane:acetone=1:1 solvent mixtures. The filtrate containing the product is concentrated, during concentration the solvent is changed to toluene.

[0131] The pre-purified misoprostol concentrate is purified by chromatography using a column of 20 kg of silica gel (Kieselgel Si 60 (0.063-0.200 mm) and eluent mixtures made of dichloromethane:acetone=10:1, 0.05% formic acid, dichloromethane:acetone=7:1, 0.05% formic acid, methyl tert.-butyl ether:acetone=2:1, 0.05% formic acid.

[0132] The aim of the filtration chromatography is to remove the contaminations arising from the solvents used during the purification, therefore to this chromatography distilled solvents are used.

[0133] The main fraction of the chromatography is neutralized with sodium hydrogen carbonate solution, washed to neutral with water, dried over sodium sulfate which contains active carbon, filtered, evaporated and made solvent-free.

[0134] Yield: 1.65 kg, 53% (calculated on HO-enone), colorless oil.

Example 5

Misoprostol

[0135] The crude misoprostol concentrate (1.3 mol) prepared from 1.3 mol of enone according to Example 3., is dissolved in methyl tert.-butyl ether and purified by chromatography using a column made of 22.5 kg of silica gel (YMC S75) and eluent mixtures made of diisopropyl ether:isopropanol=15:1, 0.05% formic acid and diisopropyl ether:isopropanol=10:1, 0.05% formic acid.

[0136] The united main fraction is washed with sodium hydrogen carbonate solution and then with sodium chloride solution, the neutralized solution is evaporated. The concentrate obtained after evaporation is dissolved in dichloromethane and purified by chromatography using silica gel column (Kieselgel Si 60 (0.063-0.200 mm) and eluent mixtures made of dichloromethane:acetone=10:1, 0.05% formic acid, dichloromethane:acetone=7:1, 0.05% formic acid and methyl tert.-butyl ether:acetone=2:1, 0.05% formic acid.

[0137] To the filtration chromatography distilled solvents are used.

[0138] The united main fraction is washed to neutral with sodium hydrogen carbonate solution and then with water, dried over sodium sulfate which contains active carbon, filtered and evaporated to solvent-free.

[0139] Yield: 275 g, 55% (calculated to HO-enone), colorless oil.