Carboprost tromethamine
- Product NameCarboprost tromethamine
- CAS58551-69-2
- MFC25H47NO8
- MW489.65
- EINECS200-000-0
- MOL File58551-69-2.mol
Chemical Properties
| Melting point | >85°C (dec.) |
| storage temp. | Hygroscopic, -20°C Freezer, Under inert atmosphere |
| solubility | Soluble in water. |
| color | White to Pale Beige |
| Stability | Hygroscopic |
| InChIKey | UMMADZJLZAPZAW-XOWPVRJPSA-N |
Usage And Synthesis
ChEBI: The tromethamine salt of carboprost. It is used as an abortifacient agent that is effective in both the first and second trimesters of pregnancy.
(+)-2β4β-Dihydroxy-3α-iodo-5α-(methoxymetyl)cyclopentane-1β-acetic acid γ-
lactone 4-benzoate:
To a stirred solution at 20°C of 75 g of (+)-2β,4β-dihydroxy-3α-iodo-5α - (methoxymetyl)cyclopentane-1β-acetic acid γ-lactone (M.P. 101-102°C, [α]D = -50° (c 0.98, CHCl3) in 135 ml of dry pyridine was added 30.4 ml of benzoyl chloride. After 30 min, 250 ml of toluene was added and the resulting solution evaporated to dryness under reduced pressure. The residue was dissolved in 1000 ml of ethyl acetate. The organic solution was washed with 200 ml 20% of aqueous sulfuric acid and 200 ml of brine. The aqueous solution was washed with 200 ml of ethyl acetate. The ethyl acetate solution was dried and evaporated under reduced pressure to give 95 g of oil which crystallized. The crude product was recrystallized to give 90 g of the white solid, M.P. 84-86°C, [α]D = +5° (c 1.03, CHCl3).
(-)-3α,5α-Dihydroxy-2β-(methoxymethyl)cyclopentane-1-α-acetic acid γ- lactone 3-benzoate:
To a solution of 4.2 g of lithium aluminum hydride in 420 ml of ether under a nitrogen atmosphere and cooled in a ice bath was added dropwise a solution of 99 g of tributyltin chloride in 210 ml of ether. The cooling bath was removed and stirring continued at ambient temperature for 1.5 hours. To the cooled solution was added 260 ml of water. The organic layer was washed with water and dried. This solution was added slowly at 15°C to a solution of (+)-2β,4β-dihydroxy-3α-iodo-5α-(methoxymethyl)cyclopentane-1β-acetic acid γ-lactone 4-benzoate in 240 ml of benzene. Then the solution was evaporated and the product was stirred with water. Yield of (-)-3α,5α-dihydroxy-2β- (hydroxymethyl)cyclopentane-1α-acetic acid γ-lactone 3-benzoate 93%.
(-)-3α,5α-Dihydroxy-2β-(methoxymethyl)cyclopentane-1α-acetic acid γ-lactone 3-benzoate:
To a solution of 20 g of (-)-3α,5α-dihydroxy-2β-(hydroxymethyl)cyclopentane- 1α-acetic acid γ-lactone 3-benzoate in 320 ml of methylene chloride under nitrogen atmosphere and cooled in an ice bath was added dropwise 24.8 ml of boron trifluoride in 320 ml of methylene chloride. After 1 hour to the solution was added 78 g of sodium carbonate in 200 ml of water and then 66 g of solid sodium chloride. The aqueous phase was extracted with ethyl acetate. Yield of (-)-3α,5α-dihydroxy-2β-(methoxymethyl)cyclopentane-1α-acetic acid γ-lactone 3-benzoate 95%, M.P. 116-118°C.
(-)-3α,5α-Dihydroxy-2β-(3-oxo-trans-1-octenyl)cyclopentane-1α-acetic acid γ- lactone 3-benzoate:
To a mixture of 1.75 g of sodium hydride and 2509 ml of tetrahydrofuran at 5°C was added 8.0 g of (2-oxoheptyl)phosphonate. After 2.5 hours a thick white precipitate formed (ilide mixture). To a stirred mixture of 11 g of anhydrous cromium trioxide and 150 ml of methylene chloride under nitrogene atmosphere and cooled in an ice bath was added 17 g of anhydrous pyridine. The mixture was stirred for 15 min at 0°C for 2 hours at room temperature, then at 0°C again. A solution of 5.0 g of (-)-3α,5α-dihydroxy-2β- (methoxymethyl)cyclopentane-1α-acetic acid γ-lactone 3-benzoate in 150 ml methylene chloride was added to at 0°C to a to the cold Collins oxidant solution. The resulting black mixture was stirred 5 min. After addition of 100 ml of benzene, the mixture was filtered through Celite, washing with benzene. The filtrate was concentrated to 50 ml under reduced pressure and then diluted with 100 ml of benzene. This solution was added to the cold ilide mixture. The resulting dark mixture was stirred for 1.5 hours at room temperature. After dropwise addition of 3 ml of acetic acid the mixture was concentrated to dryness. The residue was dissolved in 400 ml of ethyl acetate. The solution was washed with water and then with brine. Organic phase was dried and evaporated to give dark oil. This oil was purified on silica gel, yield of (-)-3α,5α-dihydroxy-2β-(3-oxo-trans-1-octenyl)cyclopentane-1α-acetic acid γ-lactone 3-benzoate 48%, M.P. 63-63.8°C, [α]D = -113° (c 1.18, CHCl3).
(-)-3α,5α-Dihydroxy-2β-[(3RS)-3-hydroxy-3-methyl-trans-octenyl] cyclopentane-1α-acetic acid γ-lactone 3-benzoate:
To a solution of 0.20 g of (-)-3α,5α-dihydroxy-2β-(3-oxo-trans-1-octenyl) cyclopentane-1α-acetic acid γ-lactone 3-benzoate in 15 ml of tetrahydrofuran at -78°C under nitrogen was added dropwise 3 ml etheral solution 3 M methylmagnesium bromide. The solution became heterogeneous after 2 hours, to the mixture was added 10 ml of saturated aqueous ammonium chloride and then ether and water. Organic extract was washed with brine, dried over sodium sulfate, and evaporated to give 0.21 g of (-)-3α,5α- dihydroxy-2β-[(3RS)-3-hydroxy-3-methyl-trans-octenyl]cyclopentane-1α-acetic acid γ-lactone 3-benzoate as a colorless oil; [α]D = -80° (c 1.0, CHCl3).
(-)-3α,5α-Dihydroxy-2β-[3-(RS)-3-hydroxy-3-methyl-trans-octenyl] cyclopentane-1α-acetaldehyde γ-lactol 3-benzoate:
To a solution of 0.50 g of (-)-3α,5α-dihydroxy-2β-[(3RS)-3-hydroxy-3-methyl-trans-octenyl]cyclopentane-1α-acetic acid γ-lactone 3-benzoate in 15 ml of tetrahydrofuran at -78°C under nitrogen was added 10 ml of 10% diisobutylaluminum hydride in toluene. After a gas evolution was ceased, the reaction was quenched by addition of 10 ml of saturated aqueous ammonium chloride. The resulting mixture was stirred at room temperature, filtered through Celite, and extracted with ethyl acetate. Extract was evaporated to give 0.48 g of (-)-3α,5α-dihydroxy-2β-[3-(RS)-3-hydroxy-3-methyl-trans-octenyl]cyclopentane-1-α-acetaldehyde γ-lactol 3-benzoate as an oil.
(15R)- and (15S)-15-methyl-PGF2α methyl esthers:
A mixture of 0.23 g sodium hydride (50% dispersion in mineral oil) and 10 ml of dimethyl sulfoxide stirred under nitrogene at 70-75°C. After 1 hours, gas evolution had ceased. After 0.5 hour, the mixture was cooled to room temperature. To the mixture was added 1.06 g 4- carboxybutyltriphenylphosphonium bromide and the resulting dark red solution stirred 0.5 hour. To this solution was added a solution of 0.48 g of (-)-3α,5α-dihydroxy-2β-[3-(RS)-3-hydroxy-3-methyl-trans-octenyl] cyclopentane-1α-acetaldehyde γ-lactol 3-benzoate in 15 ml of dimethyl sulfoxide. The resulting dark orange mixture was stirred at room temperature for 12 hours. Another 1.2 mmol of freshly prepared ilide in 3.6 ml of solution (prepared as above) was added. After 24 hours, the reaction was quenched by addition to 15 ml of 2 M sodium bisulfate (diluted with ice water) and 25 ml of ether. The organic extract was washed with 5 ml of 1 N sodium hydroxide, and twice with water. The aqueous washings were combined (pH ￡ 11) and acidified with sodium bisulfate to pH about 1 in the presence of ether. The aqueous phase was extracted with ether. The extract was evaporated to give 0.45 g of dark oily solid. The crude product was dissolved in a mixture of methylene chloride, ether and methanol and treated with excess etheral diazomethane. Evaporation gave 0.40 g of dark oil. The crude product was chromatographed on 10 g of silica gel. Fraction 9-12 contained a mixture of epimers (15R)- and (15S)-15-methyl-PGF2α-methyl esthers, yield 160 mg (35%) as an oil. The structure of product was confirmed by 1H-NMR spectrum. (15S)-15-methyl-PGF2α methyl esthers:
1 g of the mixture of epimers was chromatographed on 100 g (eluent acetone-methylene chloride). It was obtained 150 mg of pure (15S)-15- methyl-PGF2α methyl esthers; M.P. 55-56°C, [α]D = +24° (c 0.81, ethanol).
Carboprost tromethamine:
The drug was prepared by mixing of (15S)-15-methyl-PGF2α methyl esthers with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1).
To a stirred solution at 20°C of 75 g of (+)-2β,4β-dihydroxy-3α-iodo-5α - (methoxymetyl)cyclopentane-1β-acetic acid γ-lactone (M.P. 101-102°C, [α]D = -50° (c 0.98, CHCl3) in 135 ml of dry pyridine was added 30.4 ml of benzoyl chloride. After 30 min, 250 ml of toluene was added and the resulting solution evaporated to dryness under reduced pressure. The residue was dissolved in 1000 ml of ethyl acetate. The organic solution was washed with 200 ml 20% of aqueous sulfuric acid and 200 ml of brine. The aqueous solution was washed with 200 ml of ethyl acetate. The ethyl acetate solution was dried and evaporated under reduced pressure to give 95 g of oil which crystallized. The crude product was recrystallized to give 90 g of the white solid, M.P. 84-86°C, [α]D = +5° (c 1.03, CHCl3).
(-)-3α,5α-Dihydroxy-2β-(methoxymethyl)cyclopentane-1-α-acetic acid γ- lactone 3-benzoate:
To a solution of 4.2 g of lithium aluminum hydride in 420 ml of ether under a nitrogen atmosphere and cooled in a ice bath was added dropwise a solution of 99 g of tributyltin chloride in 210 ml of ether. The cooling bath was removed and stirring continued at ambient temperature for 1.5 hours. To the cooled solution was added 260 ml of water. The organic layer was washed with water and dried. This solution was added slowly at 15°C to a solution of (+)-2β,4β-dihydroxy-3α-iodo-5α-(methoxymethyl)cyclopentane-1β-acetic acid γ-lactone 4-benzoate in 240 ml of benzene. Then the solution was evaporated and the product was stirred with water. Yield of (-)-3α,5α-dihydroxy-2β- (hydroxymethyl)cyclopentane-1α-acetic acid γ-lactone 3-benzoate 93%.
(-)-3α,5α-Dihydroxy-2β-(methoxymethyl)cyclopentane-1α-acetic acid γ-lactone 3-benzoate:
To a solution of 20 g of (-)-3α,5α-dihydroxy-2β-(hydroxymethyl)cyclopentane- 1α-acetic acid γ-lactone 3-benzoate in 320 ml of methylene chloride under nitrogen atmosphere and cooled in an ice bath was added dropwise 24.8 ml of boron trifluoride in 320 ml of methylene chloride. After 1 hour to the solution was added 78 g of sodium carbonate in 200 ml of water and then 66 g of solid sodium chloride. The aqueous phase was extracted with ethyl acetate. Yield of (-)-3α,5α-dihydroxy-2β-(methoxymethyl)cyclopentane-1α-acetic acid γ-lactone 3-benzoate 95%, M.P. 116-118°C.
(-)-3α,5α-Dihydroxy-2β-(3-oxo-trans-1-octenyl)cyclopentane-1α-acetic acid γ- lactone 3-benzoate:
To a mixture of 1.75 g of sodium hydride and 2509 ml of tetrahydrofuran at 5°C was added 8.0 g of (2-oxoheptyl)phosphonate. After 2.5 hours a thick white precipitate formed (ilide mixture). To a stirred mixture of 11 g of anhydrous cromium trioxide and 150 ml of methylene chloride under nitrogene atmosphere and cooled in an ice bath was added 17 g of anhydrous pyridine. The mixture was stirred for 15 min at 0°C for 2 hours at room temperature, then at 0°C again. A solution of 5.0 g of (-)-3α,5α-dihydroxy-2β- (methoxymethyl)cyclopentane-1α-acetic acid γ-lactone 3-benzoate in 150 ml methylene chloride was added to at 0°C to a to the cold Collins oxidant solution. The resulting black mixture was stirred 5 min. After addition of 100 ml of benzene, the mixture was filtered through Celite, washing with benzene. The filtrate was concentrated to 50 ml under reduced pressure and then diluted with 100 ml of benzene. This solution was added to the cold ilide mixture. The resulting dark mixture was stirred for 1.5 hours at room temperature. After dropwise addition of 3 ml of acetic acid the mixture was concentrated to dryness. The residue was dissolved in 400 ml of ethyl acetate. The solution was washed with water and then with brine. Organic phase was dried and evaporated to give dark oil. This oil was purified on silica gel, yield of (-)-3α,5α-dihydroxy-2β-(3-oxo-trans-1-octenyl)cyclopentane-1α-acetic acid γ-lactone 3-benzoate 48%, M.P. 63-63.8°C, [α]D = -113° (c 1.18, CHCl3).
(-)-3α,5α-Dihydroxy-2β-[(3RS)-3-hydroxy-3-methyl-trans-octenyl] cyclopentane-1α-acetic acid γ-lactone 3-benzoate:
To a solution of 0.20 g of (-)-3α,5α-dihydroxy-2β-(3-oxo-trans-1-octenyl) cyclopentane-1α-acetic acid γ-lactone 3-benzoate in 15 ml of tetrahydrofuran at -78°C under nitrogen was added dropwise 3 ml etheral solution 3 M methylmagnesium bromide. The solution became heterogeneous after 2 hours, to the mixture was added 10 ml of saturated aqueous ammonium chloride and then ether and water. Organic extract was washed with brine, dried over sodium sulfate, and evaporated to give 0.21 g of (-)-3α,5α- dihydroxy-2β-[(3RS)-3-hydroxy-3-methyl-trans-octenyl]cyclopentane-1α-acetic acid γ-lactone 3-benzoate as a colorless oil; [α]D = -80° (c 1.0, CHCl3).
(-)-3α,5α-Dihydroxy-2β-[3-(RS)-3-hydroxy-3-methyl-trans-octenyl] cyclopentane-1α-acetaldehyde γ-lactol 3-benzoate:
To a solution of 0.50 g of (-)-3α,5α-dihydroxy-2β-[(3RS)-3-hydroxy-3-methyl-trans-octenyl]cyclopentane-1α-acetic acid γ-lactone 3-benzoate in 15 ml of tetrahydrofuran at -78°C under nitrogen was added 10 ml of 10% diisobutylaluminum hydride in toluene. After a gas evolution was ceased, the reaction was quenched by addition of 10 ml of saturated aqueous ammonium chloride. The resulting mixture was stirred at room temperature, filtered through Celite, and extracted with ethyl acetate. Extract was evaporated to give 0.48 g of (-)-3α,5α-dihydroxy-2β-[3-(RS)-3-hydroxy-3-methyl-trans-octenyl]cyclopentane-1-α-acetaldehyde γ-lactol 3-benzoate as an oil.
(15R)- and (15S)-15-methyl-PGF2α methyl esthers:
A mixture of 0.23 g sodium hydride (50% dispersion in mineral oil) and 10 ml of dimethyl sulfoxide stirred under nitrogene at 70-75°C. After 1 hours, gas evolution had ceased. After 0.5 hour, the mixture was cooled to room temperature. To the mixture was added 1.06 g 4- carboxybutyltriphenylphosphonium bromide and the resulting dark red solution stirred 0.5 hour. To this solution was added a solution of 0.48 g of (-)-3α,5α-dihydroxy-2β-[3-(RS)-3-hydroxy-3-methyl-trans-octenyl] cyclopentane-1α-acetaldehyde γ-lactol 3-benzoate in 15 ml of dimethyl sulfoxide. The resulting dark orange mixture was stirred at room temperature for 12 hours. Another 1.2 mmol of freshly prepared ilide in 3.6 ml of solution (prepared as above) was added. After 24 hours, the reaction was quenched by addition to 15 ml of 2 M sodium bisulfate (diluted with ice water) and 25 ml of ether. The organic extract was washed with 5 ml of 1 N sodium hydroxide, and twice with water. The aqueous washings were combined (pH ￡ 11) and acidified with sodium bisulfate to pH about 1 in the presence of ether. The aqueous phase was extracted with ether. The extract was evaporated to give 0.45 g of dark oily solid. The crude product was dissolved in a mixture of methylene chloride, ether and methanol and treated with excess etheral diazomethane. Evaporation gave 0.40 g of dark oil. The crude product was chromatographed on 10 g of silica gel. Fraction 9-12 contained a mixture of epimers (15R)- and (15S)-15-methyl-PGF2α-methyl esthers, yield 160 mg (35%) as an oil. The structure of product was confirmed by 1H-NMR spectrum. (15S)-15-methyl-PGF2α methyl esthers:
1 g of the mixture of epimers was chromatographed on 100 g (eluent acetone-methylene chloride). It was obtained 150 mg of pure (15S)-15- methyl-PGF2α methyl esthers; M.P. 55-56°C, [α]D = +24° (c 0.81, ethanol).
Carboprost tromethamine:
The drug was prepared by mixing of (15S)-15-methyl-PGF2α methyl esthers with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1).
Carboprost tromethamine,15-(S)-methyl-PGF2α (Hemabate), is a prostaglandin derivativethat has been modified to prevent metabolic oxidation ofthe 15-position alcohol function. This derivative may be administeredin a hospital setting only in a dose of 250 μg bydeep intramuscular injection to induce abortion or to amelioratesevere postpartum hemorrhage.
Preparation Products And Raw materials
Raw materials
- Benzoyl chlorideTris(hydroxymethyl)aminomethaneSodium hydroxideLithium Aluminum Hydride1,3-Propanediol, 2-(2,2-diethoxyethyl)-,monoacetate,(R)-Sodium bisulfateDiazomethaneMethylmagnesium BromideDiisobutylaluminium hydrideBoron trifluoride(4-Carboxybutyl)triphenylphosphonium bromideSodium hydrideTributyltin chloride1,3-Propanediol
Carboprost tromethamine manufacturers
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