Captopril

White or almost white, crystalline powder.

Method 1: A solution of 230g L-proline dissolved in 1L water and 400ml 5mol/L sodium hydroxide, cooled with an ice bath, and under vigorous stirring, add 460ml 5mol/L sodium hydroxide in 5 batches within half an hour And 340ml benzyl chloroformate. After the addition was completed, it was stirred at room temperature for 1 h. After the reaction solution was extracted twice with ether, it was acidified with concentrated hydrochloric acid. The precipitate was filtered and dried to obtain 442g of N-benzylcarbonyl-L-proline, melting point 78-80°C. A solution of 180 g of N-benzylcarbonyl-L-proline dissolved in 300 ml of dichloromethane, 800 ml of liquid isobutylene and 7.2 ml of concentrated sulfuric acid was shaken in a pressure vessel for 72 hours. After depressurization, isobutene was distilled off, and the remaining liquid was washed with 5% sodium carbonate and water, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to obtain 205 g of N-benzylcarbonyl-L-proline tert-butyl ester. 205g N-benzylcarbonyl-L-proline tert-butyl ester is dissolved in 1.2 L of absolute ethanol, under normal pressure with 10% palladium-carbon as a catalyst, hydrogenation hydrogenation until there is only a trace of hydrogen in the escaped hydrogen Carbon dioxide (about 24h). The catalyst was removed by filtration, the filtrate was concentrated at 4.0 kPa, and the residue was vacuum-distilled to obtain tert-butyl L-proline with a boiling point of 50 to 51°C/133 Pa. 5.1 g of L-proline tert-butyl ester was dissolved in 40 ml of dichloromethane, stirred and cooled with an ice bath. 15 ml of DCC (dicyclohexylcarbodiimide) was added, followed immediately by a solution of 4.9 g of 3-acetylmercapto-2-methylpropionic acid dissolved in 5 ml of dichloromethane. After stirring on an ice bath for 15 min, it was stirred at room temperature for 16 h, the precipitate was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate, washed with water until neutral, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The remainder is N-(3-acetylmercapto-2-methylpropionyl)-L-proamino tert-butyl ester, which is purified by column chromatography (silica gel-chloroform) to give 7.9g. To a mixed solution of 55 ml of anisole and 110 ml of trifluoroacetic acid, 7.8 g of N-(3-acetylmercapto-2-methylpropionyl)-L-proline tert-butyl ester was added and left at room temperature for 1 h. The solvent was distilled off under reduced pressure, and the residue was precipitated several times with ether-hexane. The precipitate (6.8 g, racemate) was dissolved in 40 ml of acetonitrile, and 4.5 ml of dicyclohexylamine was added, in which only the (S, S) isomer could form a salt with dicyclohexylamine. Filter out the crystallized salt and boil it in freshly distilled acetonitrile, then cool to room temperature and filter to obtain 3.8g of (S, S)L-proline derivative dicyclohexylamine salt, melting point 187～ 188°C. After recrystallization from propanol, [α]D-67° (C=1.4, ethanol). The salt is suspended in a mixed solution of 5% potassium hydrogen sulfate and ethyl acetate. The separated organic layer was washed with water and concentrated to dryness. The residue was crystallized with ethyl acetate-hexane to obtain optically active (S, S)-N-(3-acetylmercapto-2-D-methylpropionyl) -1-Proline, melting point 83～85℃. 0.85g of the optically active proline derivative obtained above was dissolved in a methanol solution of 5.5 mol/L ammonia and kept at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The residue was dissolved in water and acid-type ion exchange resin (Dowex50 , Analytical grade) chromatography, the developing solution is water. Collect the effluent that is positive for the mercaptan test and dry it in cold ice. The residue was crystallized from acetone-hexane to obtain 0.3 g of captopril, melting point 103-104°C. Method 2: Addition of α-methacrylic acid and thioacetic acid to obtain α-methyl-β-acetylthioacetic acid, and then chlorinated with thionyl chloride to form acid chloride, directly with proline in sodium hydroxide (as Under the action of acid-binding agent), N-(3-acetylmercapto-2-methylpropionyl)-L-proline is obtained, which is a racemate, as in Method 1, salt formation is carried out with dicyclohexylamine After optical resolution, the (S, S) form is obtained, and then the acetyl group is removed by ammonia hydrolysis to obtain captopril. Method 3: 2-Methacrylic acid is dissolved in chloroform, and the theoretical amount of hydrogen bromide is passed through at -10°C under stirring, and the mixture is allowed to stand at 0°C overnight. Concentrate and collect 81.5～84℃/670Pa fractions to obtain 3-bromo-2-methylpropionic acid with a yield of 90.9%～93.1%. To 3-bromo-2-methylpropionic acid, sulfoxide chloride was added dropwise and the temperature was raised to 70°C and stirred. After removing the residual gas, the fractions of 41-43°C/1.2kPa were collected to obtain 3-bromo-2-methylpropionyl chloride in a yield of 89.5%-90.3%. To a solution of 8% sodium hydroxide and L-pyridine at -2°C with stirring, 3-bromo-2-methylpropionyl chloride was added dropwise. After dripping and stirring. Cool, adjust to Ph=1~2 with concentrated hydrochloric acid, extract with ethyl acetate, dry and filter. Dicyclohexylamine was added dropwise with stirring, and then placed in a freezer to cool, filtered with suction, dried, and recrystallized from isopropanol to obtain the dicyclohexylamine salt of compound (I) in a yield of 47.1% to 48.3%. Dissolve it in 10% potassium bisulfate, add ethyl acetate, stir, extract with ethyl acetate, dry, filter, evaporate to dryness, recrystallize with ethyl acetate-n-hexane to obtain optically active compound (I), The yield is 85.5%～88.6%, [α]D20-94°～-95.4°. The compound (I), aqueous sodium hydroxide solution and sodium trithiocarbonate were stirred at 50°C. Cool to room temperature, filter, extract with ethyl acetate, dry, filter, concentrate, recrystallize with ethyl acetate to obtain captopril, yield 65.9%, melting point 104～107°C, [α]D20-127°(C = 2.0, ethanol).

Orally active angiotensin-converting enzyme (ACE) inhibitor

Molecular Weight:217.29
XLogP3:0.3
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:217.07726451
Monoisotopic Mass:217.07726451
Topological Polar Surface Area:58.6
Heavy Atom Count:14
Complexity:244
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes