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10 g (36.7 mmol) of (S) -2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid was dissolved in 80 mL of N, N- dimethylformamide. After purging with nitrogen, 6.3 g (157 mmol) of 60% sodium hydride was slowly added over 1 hour 30 minutes at room temperature. After stirring for 1 hour, a solution of 9.56 g (51.3 mmol) of 4,6-dimethyl-2- (methylsulfonyl) pyrimidine in N, N-dimethylformamide (20 mL) was slowly added dropwise over 1 hour at room temperature , And the mixture was stirred for 15 hours. After cooling to 0 C, 10 mL of methanol was slowly added dropwise over 20 minutes, then 100 mL of cold water was added. After adding 75 mL of 10% hydrochloric acid, it was extracted twice with 100 mL of ethyl acetate. The organic layer was extracted 3 times with 1 N sodium hydroxide 50 mL. Further, 60 mL of 10% hydrochloric acid was slowly added to the aqueous layer, and the mixture was stirred for 1 hour. Precipitated crystals were collected by filtration and washed twice with 25 mL of water. The obtained crystals were dried under reduced pressure at 60 C. for 5 hours to obtain 13.1 g of ambrisentan (yield 95%, optical purity 98.6%).
75%
(S) -2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (40 g) was dissolved in DMF (200 ml), and then 3.6 g of lithium hydride (LiH) was slowly added thereto. The temperature of the reaction mixture was raised to 60 to 70 C , stirred for 1 hour, and then 30 g of 4,6-dimethyl-2- (methylsulfonyl) pyrimidine was added slowly. The mixture was stirred at an isothermal temperature for 5 hours, and when the reaction is finished, then cooled to room temperature. 360 ml of water was added and stirred for 30 minutes, and 200 ml of 3N HCl aqueous solution was slowly added to crystallize. The resulting crystals were collected by filtration, washed and vacuum dried to obtain 50 g of ambrisentan,(S) -2- (4,6-dimethylpyrimidin-2-yloxy) -3-methoxy-3,3-diphenylpropionic acid (Yield: 90%) (chemical purity = 97.28%, ee = 100%). 50 g of an ambrisentan containing impurities was suspended in 400 ml of an acetonitrile: water = 7: 3 mixed solution, and the temperature was raised to 50 to 55 C to dissolve completely. 5 g of activated carbon was added and stirred at an isothermal temperature for 1 hour. The activated carbon was removed by filtration and washed with a mixed solution of acetonitrile: water = 7: 3. The filtrate was heated to 50-55 C to completely dissolve the solid. The resulting solid was filtered, washed and vacuum-dried to obtain 37.5 g (yield: 75%) of a white solid (chemical purity = 100%, ee = 100%).
Example-19: Preparation of ambrisentan compound of formula-la:(S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (20 grams in 20 ml of THF),, was added to a mixture of sodium hydroxide (8.5 grams) and tetrahydrofuran (110 ml) and stirred for 20 minutes at 25-35C. 456-dimethyl-2-(methylsulphonyl)pyrimidine , (19 grams) was added to the reaction mixture and heated to 40-450C then stirred for 24 hours. The reaction mixture was cooled to 25-350C and quenched with water then washed with cyclohexane. The reaction mixture was acidified with hydrochloric acid and then extracted into ethyl acetate. The combined ethyl acetate layer was washed with sodium chloride solution and then distilled off completely under reduced pressure. The reaction mixture was cooled to 25-35C, cyclohexane (100 ml) was added to it and then heated to 60-65C. The reaction mixture was cooled to 25-3O0C and stirred for 45 minutes. The solid obtained was filtered, washed with cyclohexane and then dried to get the title compound. Yield: 19 grams; S.O.R: + 144.87 (C = 0.5 in MeOH)
Into a 1L round bottomed flask a mixture of DMF(400ml) and S-2-Hydroxy-3-mehoxy- 3,3-diphenyl propionic acid(50g) were, charged and stirred for 30 minutes. sodium hydride(18.9g) was added slowly for lhour and reaction mass was maintained at room temperature for one hours. 2-(methylsulfonyl)-4,6-dimethyl pyrimidine(47.8g) was dissolved in DMF( 100ml) and added to the reaction mass at room temperature during 45-60 minutes and reaction mass was maintained overnight under stirring. After reaction completion methanol(50ml)l was added slowly to the reaction mass during 30 minutes. Reaction mass was quenched into DM water (5L) and acidified with diluted hydrochloric acid(600ml). Aqueous layer was extracted with ethyl acetate(2x500ml) and combined ethyl acetate layer was extracted with IN sodium hydroxide solution. Sodium hydroxide layer was separated and acidified with IN hydrochloride solution . Reaction mass was maintained under stirring for 2hours . The product of the formula-I was filtered and washed with purified water. It was dried in oven at 60-65CDry weight : 60gPurity by HPLC : related : 99.5%Chiral : 99.5%
Preparation of Ambrisentan Compound of Formula-1a (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (20 grams in 20 ml of THF) was added to a mixture of sodium hydroxide (8.5 grams) and tetrahydrofuran (110 ml) and stirred for 20 minutes at 25-35 C. 4,6-dimethyl-2-(methylsulphonyl)pyrimidine (19 grams) was added to the reaction mixture and heated to 40-45 C. then stirred for 24 hours. The reaction mixture was cooled to 25-35 C. and quenched with water then washed with cyclohexane. The reaction mixture was acidified with hydrochloric acid and then extracted into ethyl acetate. The combined ethyl acetate layer was washed with sodium chloride solution and then distilled off completely under reduced pressure. The reaction mixture was cooled to 25-35 C., cyclohexane (100 ml) was added to it and then heated to 60-65 C. The reaction mixture was cooled to 25-30 C. and stirred for 45 minutes. The solid obtained was filtered, washed with cyclohexane and then dried to get the title compound.Yield: 19 grams;S.O.R: +144.87 (C=0.5 in MeOH)
Lithium amide (30.4 g; 1.32 mol) was suspended in N,N dimethylformamide (200 ml). A solution of (2S)-2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid (120.0 g; 0.44 mol) in N,N-dimethylformamide (750 ml) was added dropwise at 20 C within 45 minutes, and the mixture was stirred for additional 10 minutes. A solution of 4,6-dimethyl-2 (methyl sulfonyl)pyrimidine (90.3 g; 0.48 mol) in N,N dimethylformamide (500 ml) was added dropwise within 20 minutes, and the mixture was stirred for 17 hours. Water (3000 ml) and 2M citric acid (800 ml) were added to the reaction mixture. The product was extracted three times with dichloromethane (2000 ml). The combined organic phases were dried over sodium sulfate and the solvent was evaporated under reduced pressure. The oily yellow residue was crystallized from a mixture of isopropanol (800 ml) and water (2000 ml). The formed crystals were filtered off, washed with water and dried (98.5 g), mp 156-158 C.
60 g
Into a 1 L round bottomed flask a mixture of DMF (400 ml) and S-2-Hydroxy-3-mehoxy-3,3-diphenyl propionic acid (50 g) were, charged and stirred for 30 minutes. sodium hydride (18.9 g) was added slowly for 1 hour and reaction mass was maintained at room temperature for one hours. <strong>[35144-22-0]2-(methylsulfonyl)-4,6-dimethylpyrimidine</strong> (47.8 g) was dissolved in DMF (100 ml) and added to the reaction mass at room temperature during 45-60 minutes and reaction mass was maintained overnight under stirring. After reaction completion methanol (50 ml)1 was added slowly to the reaction mass during 30 minutes. Reaction mass was quenched into DM water (5 L) and acidified with diluted hydrochloric acid (600 ml). Aqueous layer was extracted with ethyl acetate (2×500 ml) and combined ethyl acetate layer was extracted with 1N sodium hydroxide solution. Sodium hydroxide layer was separated and acidified with 1N hydrochloride solution. Reaction mass was maintained under stirring for 2 hours. The product of the formula-I was filtered and washed with purified water. It was dried in oven at 60-65 C. Dry weight: 60 g Purity by HPLC: related: 99.5% Dry weight: 60 g Purity by HPLC: related: 99.5% Chiral: 99.5%
With sodium methylate; dimethyl sulfate; In water; N,N-dimethyl-formamide;
EXAMPLE 9 Preparation of (S)-methyl-2-hydroxy-3-methoxy-3,3-diphenylpropionate (compound IV from compound VIII; R'=methyl) Stirred (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (compound VIII; 79 gms/0.290 moles) in dimethyl formamide (790 ml) under nitrogen and cooled to 5 C. Sodium methoxide (17.3 gms/0.320 moles) was added followed by slow addition of dimethyl sulfate (54.81 gms/0.44 moles) under nitrogen. The reaction mass was further stirred for 3 hours at 25-28 C. and quenched in DI water (2.4 lit). The reaction mass was extracted with ethyl acetate (3*790.0 ml), washed with water and distilled completely under vacuum below 50 C. to obtain 79 gms of the title compound (IV). Efficiency: 95.11%
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