PROCESS FOR THE PREPARATION OF CARBOPROST AND ITS TROMETHAMINE SALT

Abstract

The subject of the invention is a novel process for the preparation of Carboprost tromethamine salt where alkylation the enone of the general formula (II) is carried out in the presence of a chiral auxiliary in aprotic solvent with a Grignard reagent. The methyl ester epimers of formula (VII) are separated by gravity silicagel chromatography and the salt formation is carried out by using solid tromethamine base.

##STR00001##

Claims

1. Process for the preparation of Carboprost of formula I ##STR00030## and its tromethamine salt of formula Ia ##STR00031## by selective alkylation of the enone of the general formula II, ##STR00032## where R stands for hydrogen atom or protecting group, by reduction of the resulting enol of the general formula III ##STR00033## where the meaning of R is as defined above, by removal of the R protecting group of the resulting lactol of the general formula IV, ##STR00034## by reacting the lactol epimers of formula V in Wittig reaction ##STR00035## to obtain the Carboprost epimers of formula VI, ##STR00036## by transforming the Carboprost epimers into their methyl ester, by chromatographic separation of the methyl ester epimers of formula VII ##STR00037## by hydrolysis of the epimer of formula VIII ##STR00038## and if desired by formation of the tromethamine salt, comprising that the selective alkylation is carried out in the presence of chiral auxiliary, in aprotic organic solvent, with Grignard reagent, chromatography is carried out by gravity silica gel chromatography, the tromethamine salt is formed by using solid tromethamine base.

2. Process as defined in claim 1, comprising that as Grignard reagent methylmagnesium chloride or methylmagnesium bromide, preferably methylmagnesium bromide is applied.

3. Process as defined in claim 2, comprising that methylmagnesium bromide is applied in 3-4 molar equivalent, preferably 3.5 molar equivalent amount.

4. Process as defined in claim 1, comprising that as chiral auxiliary a complex-forming chiral auxiliary material is used.

5. Process as defined in claim 4, comprising that as complex-forming chiral auxiliary material (S)-Taddol is applied.

6. Process as defined in claim 5, comprising that (S)-Taddol is used in 1 molar equivalent amount.

7. Process as defined in claim 1, comprising that as R protecting group ether-, silyl ether-, benzyl-, substituted benzyl-, or acyl-groups are applied.

8. Process as defined in claim 7, comprising that as R protecting group -p-phenylbenzoyl group is applied.

9. Process as defined in claim 1, comprising that as aprotic organic solvent ethers, as diethyl ether, methyl tertiary-butyl ether, diisopropyl ether, tetrahydrofuran, methyltetrahydrofuran, dimethoxyethane; aromatic hydrocarbons, as benzene, toluene, xylene; halogenated solvents, as dichloromethane, or the mixture of these solvents are applied.

10. Process as defined in claim 9, comprising that as solvent, toluene is applied.

11. Process as defined in claim 1, comprising that methylation is carried out at ()-80-()-20 C., preferably at ()-50 C.

12. Process as defined in claim 1, comprising that the eluent used for the gravity silica gel chromatography contains a base.

13. Process as defined in claim 12, comprising that as base, an organic base or ammonia, preferably triethylamine is applied.

14. Process as defined in claim 13, comprising that the amount of the triethylamine is 0.1%.

15. Process as defined in claim 12, comprising that as eluent dichloromethane: triethylamine or dichloromethane: acetone: triethylamine mixture is applied.

16. Process as defined in claim 1, comprising that during the gravity silica gel chromatography a slightly basic silica gel is applied.

17. Process as defined in claim 16, comprising that as eluent acetone-dichloromethane gradient mixtures are applied.

18. Process as defined in claim 1, comprising that salt formation is carried out in water-free polar organic solvent.

19. Process as defined in claim 18, comprising that as polar organic solvent alcohols and/or ketones, preferably isopropyl alcohol and/or acetone are applied.

20. Process as defined in claim 13, comprising that as eluent dichloromethane: triethylamine or dichloromethane: acetone: triethylamine mixture is applied.

Description

EXAMPLES

1.a [1,1-Bisphenyl]-4-carboxylic acid, (3aR,4R,5R,6aS)-hexahydro-2-oxo-4-[(1E)-3-hydroxy-3-methyl-1-octen-1-yl]-2H-cyclopenta[b]furan-5-yl ester

[0145] ##STR00023##

[0146] 4.66 kg of (S)-Taddol was added to 25.4 L distilled toluene under nitrogen atmosphere. The almost homogenous solution was cooled and 25 L of 1.4 M methylmagnesium bromide solution was added at ()-50 C. After 30 minutes of agitation the solution of 4.46 kg of [1,1-bisphenyl]-4-carboxylic acid (3aR,4R,5R,6aS)-hexahydro-2-oxo-4-[(1E)-3-oxo-l-octen-1-yl]-2H-cyclopenta[b]furan-5-yl ester in distilled toluene was added at ()-50 C. After completion of the reaction the mixture was poured onto the mixture of 1 M hydrochloric acid and toluene and thoroughly agitated. The phases were separated, the aqueous phase was extracted with toluene. The organic phase was washed with 1 M sodium hydrogen carbonate solution and with saturated salt solution. The organic phase was evaporated.

[0147] The dry residue was dissolved in methanol at 50 C. and then cooled to 0 C. The precipitated (S)-Taddol was removed by filtration.

[0148] The filtrate was evaporated, the residue was dissolved in toluene and the remains of (S)-Taddol were removed by filter chromatography on silica gel column using hexane:ethyl acetate and ethyl acetate eluents.

[0149] The main fraction of the chromatography containing the product was evaporated.

[0150] Yield: 4.40 kg (95%).

[0151] Recovery of (S)-Taddol

[0152] 4.6 kg of (S)-Taddol re-gained by crystallisation and by chromatographic separation was dissolved in acetone at 50 C. and crystallized at 0 C. after the addition of hexane. The crystals were collected by filtration, washed and dried.

[0153] Yield: 4.3 kg (93.5%), purity by HPLC: 99.96%.

1.b [1,1-Bisphenyl]-4-carboxylic acid, (3aR,4R,5R,6aS)-hexahydro-2-hydroxy-4-[(1E)-3-hydroxy-3-methyl-1-octen-1-yl]-2H-cyclopenta[b]furan-5-yl ester

[0154] ##STR00024##

[0155] 9.7 kg of [1,1-Bisphenyl]-4-carboxylic acid, (3aR,4R,5R,6aS)-hexahydro-2-oxo-4-[(1E)-3-hydroxy-3-methyl-1-octen-1-yl]-2H-cyclopenta[b]furan-5-yl ester was dissolved in 62 kg of water-free tetrahydrofuran under nitrogen atmosphere. At ()-75 C. the toluene solution of 9.8 kg of diisobutylaluminum hydride was added. At the end of the reduction the reaction mixture was transferred by suction onto 2M sodium hydrogen sulphate solution, the phases were thoroughly mixed and separated after sedimentation. The aqueous phase was extracted with toluene, the united organic phase was washed with 1 M sodium hydrogen carbonate solution and with saturated salt solution. The organic phase was evaporated.

[0156] Yield: 9.74 kg (99.96%).

1c. 2H-Cyclopenta[b]furan-2,5-diol, hexahydro-4-(3-hydroxy-3-methyl-1-octen-1-yl)

[0157] ##STR00025##

[0158] 10.3 kg of [1,1-Bisphenyl]-4-carboxylic acid, (3aR,4R,5R,6aS)-hexahydro-2-hydroxy-4-[(1E)-3-hydroxy-3-methyl-1-octen-1-yl]-2H-cyclopenta[b]furan-5-yl ester was dissolved in 46 L of methanol, 1.5 kg of potassium carbonate was added and reacted at 40 C. After completion of the reaction the mixture was cooled to 0 C. and neutralised with diluted phosphoric acid. The precipitated crystals were filtered off, washed with methanol:water mixture and the filtrate was concentrated. To the concentrate water and sodium chloride were added. The product was extracted with ethyl acetate, the united organic phase was decolorized with active charcoal, the charcoal was filtered off and the filtrate was evaporated.

[0159] Yield: 6.1 kg (97%).

1d. Carboprost Crude

(5Z,9a,11a,13E)-15-methyl-9,11,15-trihydroxy-prosta-5,13-diene-1-carboxylic acid, crude (R,S)

[0160] ##STR00026##

[0161] 20 kg of carboxybutyltriphenylphosphonium bromide (CBFBr) was added into 133 L of water-free tetrahydrofuran in an inert atmosphere, cooled to 0 C., and in several portions 17 kg of potassium tert-butylate was added to the mixture. The orange-coloured suspension was cooled to ()-5-()-10 C. and the solution of 5.9 kg of 2H-cyclopenta[b]furan-2,5-diol, hexahydro-4-(3-hydroxy-3-methyl-1-octen-1-yl) in water-free tetrahydrofuran was added. After completion of the reaction water was added to the reaction mixture and with 2 M sodium hydrogen sulphate solution the pH was set to 10-11. The reaction mixture was concentrated and cooled to 20 C. The precipitated crystals were filtered off, washed with 1 M sodium hydrogen carbonate solution and with water. The filtrate was extracted with dichloromethane. The pH of the aqueous phase was set to neutral with 2 M sodium hydrogen sulphate solution, then after the addition of ethyl acetate, acidified to pH=2. The precipitated crystals were filtered off, washed with ethyl acetate. The phases of the filtrate were separated. The aqueous phase was extracted with ethyl acetate. The united organic phase was washed with saturated salt solution, dried over sodium sulphate and concentrated. The concentrate was cooled to 20 C. and crystallized by addition of diisopropyl ether. The crystals were filtered off and washed with diisopropyl ether:acetone mixture. The filtrate was evaporated.

[0162] Yield: 7.1 kg, (93%).

1e1. Carboprost Methyl Ester

(5Z,9a,11a,13E,15S)-15-methyl-9,11,15-trihydroxy-prosta-5,13-diene-1-carboxylic acid methyl ester

[0163] ##STR00027##

[0164] 7.7 kg of crude Carboprost (R,S) was dissolved in 28 L of distilled acetone, 9 kg of potassium carbonate and 9.1 kg of methyl iodide were added to the solution and the reaction mixture was agitated at 50 C. At the end of the reaction the mixture was transferred by suction onto the mixture of methyl tert-butyl ether and 1 M sodium hydrogen sulphate solution. Following agitation and sedimentation, the phases were separated and the aqueous phase was extracted with methyl tert-butyl ether. The united organic phase was washed with 1 M sodium hydrogen carbonate solution and with saturated salt solution, dried over sodium sulphate and evaporated. Crude product: 8 kg (100%).

[0165] Based on the above, the yield of the crude Carboprost methyl ester calculated for the PG-enone is 86%.

[0166] At the beginning of the evaporation 70 ml of triethylamine was added to the solution. The concentrate was purified by chromatography on silica gel column using methyl tert-butyl ether:triethylamine (0.1%), then methyl tert-butyl etheracetone:triethylamine=20:1:0.1% eluent mixtures. The main fraction containing the Carboprost methyl ester epimers (R,S) was evaporated. The epimers were separated on silica gel column, using dichloromethane:triethylamine (0.1%) and dichloromethane:acetone:triethylamine=2:1:0.1% eluent mixtures, by repeated chromatography. Between the two chromatographic cycles the silica gel column was regenerated with acetone:triethylamine (0.1%) and then with dichloromethane:triethylamine (0.1%) eluent mixtures.

[0167] The main fraction was evaporated.

[0168] Yield: for Carboprost methyl ester (VII) 2.35 kg (42%) (taking into account that the crude Carboprost methyl ester contains the epimers in 70:30 ratio).

1e2. Alternative Method for the Purification

[0169] Crude Carboprost methyl ester was dissolved in dichloromethane and purified by chromatography on Chromatorex MB70-40/75 silica gel column using dichloromethane-acetone=4:1, 2:1 gradient mixtures and then acetone eluents. The fractions containing Carboprost methyl ester were investigated by HPLC, the fractions of adequate quality were evaporated.

[0170] Yield: 2.97 kg (57.5%).

1f. Carboprost

(5Z,9a,11a,13E)-15-methyl-9,11,15-trihydroxy-prosta-5,13-diene-1-carboxylic acid)

[0171] ##STR00028##

[0172] 550 g of Carboprost methyl ester was dissolved in 5 L of distilled methanol and 5 L of 2N sodium hydroxide solution was added. After completion of the hydrolysis, water was added to the reaction mixture and the solution was concentrated. To the concentrated reaction mixture water and methyl tert-butyl ether were added, thoroughly mixed, then the phases were separated. To the aqueous phase sodium chloride and methyl tert-butyl ether were added and the pH was set to 4 with 2M sodium hydrogen sulphate solution. The phases were separated, the aqueous phase was extracted with a methyl tert-butyl ether, the organic phase was washed with saturated salt solution, dried over sodium sulphate and evaporated.

[0173] Yield: 519 g, (98%).

1g. Carboprost Tromethamine

Salt of (5Z,9a,11a,13E)-15-methyl-9,11,15-trihydroxy-prosta-5,13-diene-1-carboxylic acid formed with 2-amino-2-(hydroxymethyl)-1,3-propanediol

[0174] ##STR00029##

[0175] 509 g of Carboprost was dissolved in 2.7 L of filtered, distilled isopropanol, then 170.8 g of tromethamine was added and the reaction mixture was agitated at room temperature for approx. 1 hour. The solution was filtered and concentrated. To the concentrate isopropanol (filtered, distilled) and acetone (filtered, distilled) were added. The reaction mixture was agitated at 20 C. while crystals precipitated. To the crystal suspension filtered, distilled ethyl acetate, then filtered, distilled hexane were added and agitation was continued for another hour. The crystals were filtered off, washed with hexane:acetone:ethyl acetate mixture and dried.

[0176] Yield: 593 g, (86%).

1h. Recrystallization of Carboprost Tromethamine

[0177] 500 g of Carboprost tromethamine salt was dissolved in filtered, distilled isopropanol. To the obtained solution filtered, distilled acetone was added dropwise at 20 C. After the majority of the crystals precipitated, ethyl acetate (filtered, distilled) then hexane (filtered, distilled) were added and the crystal suspension was further agitated. After approx. 1 hour of agitation the crystals were filtered off, washed with hexane:acetone:ethyl acetate mixture and dried.

[0178] Yield: 480 g, 96%.