98048-97-6

Fosinopril Sodium,Bristol-Myers Squibb

mydriatic,

ChEBI: A phosphinate ester-containing N-acyl derivative of (4S)-cyclohexyl-L-proline. It is used for the treatment of hypertension and heart failure. A pro-drug, it is hydrolysed in vivo to the corresponding phosphin nc acid, fosinoprilat, which is the active metabolite.

To a solution of 4-phenylbutyl phosphinic acid (2.0 g, 0.01 mole) in chloroform (40 ml) was added triethylamine (3.2 ml, 0.022 mole) and the mixture was cooled in an ice bath to 0°C. Trimethylsilyl chloride (2.8 ml, 0.022 mole) was added to the above solution dropwise, followed by benzyl bromoacetate (1.6 ml, 0.011 mole). The ice bath was removed and the mixture stirred at room temperature for 5 hours and poured into 10% aqueous HCl (30 ml) and crushed ice (20 g). After shaking the mixture in a separatory funnel, the chloroform layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvents removed in vacuum. The resulting crude thick oil (3.5 g) was dissolved in 30 ml ether, hexane was added dropwise to get a turbid solution and the mixture was left at room temperature overnight to complete the crystallization. It was cooled in the freezer for 2 hours, filtered and the solid was washed very thoroughly with hexane (50 ml), ether (50 ml) and again hexane (50 ml), ether (50 ml) in that order. The solid was vacuum dried to get 2.48 g (71%) of [hydroxy-(4-phenylbutyl)-phosphinyl]acetic acid, phenylmethyl ester, m.p. 68-70°C. TLC (Silica gel, CH2Cl2:MeOH:HOAc (20:1:1)) shows a single spot.
A solution of 50 g (0.14 mole) of [hydroxy-(4-phenylbutyl)-phosphinyl]acetic acid, phenylmethyl ester in 300 ml of dry CHCl3 was treated with 28.6 g (0.28 mole) of Et3N, 35.6 g (0.21 mole) of 1-chloroisobutyl propionate, 12.0 g (0.035 mole) of (n-Bu)4NHSO4 and 5.3 g (0.035 mole) of NaI. The above mixture was stirred and heated to mild reflux for 20 hours, then cooled and the solvent evaporated in vacuo. The oil residue was dissolved in 150 ml of ether and washed with 150 ml of water. The aqueous wash was extracted with 150 ml of ether. The combined ether solutions were washed with 5% NaHCO3, 10% NaHSO3 and brine. After drying (MgSO4) the ether was evaporated in vacuo to give 57.0 g (83%) of crude [[2-methyl-1-(1-oxopropoxy)propoxy](4- phenylbutyl)phosphinyl]acetic acid, phenyl methyl ester as an oil product. A solution of 57.0 g (0.12 mole) of [[2-methyl-1-(1-oxopropoxy)propoxy](4- phenylbutyl)phosphinyl]acetic acid, phenyl methyl ester in 300 ml of ethyl acetate was treated with 3.0 g of 10% Pd/C and hydrogenated on the Parr apparatus (45 psi) for 4 hours. The mixture was filtered through Hyflo and the solution was extracted with 5% NaHCO3. The aqueous extracts were washed with ether, cooled to 5°C and treated with 36 ml of HOAc. The product was extracted into ethyl acetate, dried (MgSO4) and the solvent was evaporated in vacuo. The residue was dissolved in 300 ml of toluene and the solvent was evaporated in vacuo to remove last traces of acetic acid. The oil residue became semi-solid on standing at room temperature. The yield of the product of debenzoylation - 2-[carboxymethyl)-(4-phenylbutyl)-phosphinoyloxy]-2- methylpropionic acid ethyl ester (racemic mixtures) was 39.8 g (72%).
A suspension of 10.0 g (0.026 mole) of [[2-methyl-1-(1-oxopropoxy)propoxy] (4-phenylbutyl)phosphinyl]acetic acid in 50 ml of isopropyl ether was stirred vigorously for 15 min, then kept at 5°C for 20 hours. The colorless product was filtered, washed with a small amount of cold isopropyl ether to give 5.0 g of [[2-methyl-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetic acid (A/B isomer, racemic mixture) , m.p. 87-89°C. The filtrate was evaporated in vacuo and retained for isolation of isomer C/D. A solution of the above material in 110 ml of hot isopropyl ether was filtered through a hot glass funnel (glass wool). The cooled solution gave 4.6 g (92%) of desired product, m.p. 90-92°C.
To a vigorously stirred suspension of 980 g (3.33 mol) of l-cinchonidine in 6 L of ethyl acetate maintained at 45°C was gradually added 1275.5 g (3.33 mol) of A/B isomer mixture and stirring then continued for an additional 2.5 hours while the resulting suspension of salt was gradually heated to 70°C when complete solution was obtained. After filtration (Hyflo) from a small amount of insoluble material, the solution was seeded and cooled. The crystalline product which separated was then filtered, washed with 1200 ml of 1:1 ethyl acetate/isopropyl ether, and dried in vacuo to give 1897.2 g of cinchonidine salt enriched in the B-isomer, m.p. 106-109°C, [α]D = -59.3° (c = 1, methanol). This material was combined with 136.8 g of similarly prepared material (from 0.412 mol of A/B isomer) and the total quantity (2014 g) recrystallized from 10.18 L of boiling ethyl acetate to afford after filtration, washing with 1500 ml of the same solvent mixture used before, and drying in vacuo 1162 g (92%) of [[2-methyl-1-(1-oxopropoxy)propoxy](4-phenylbutyl) phosphinyl]acetic acid (Resolution; isomer B), cinchonidine salt (1:1), m.p. 120-122°C (dec.), [α]D= -45° (c = 1, methanol), [α]365 = -185.5° (c = 1, methanol). A sample (10 g) was recrystallized twice from acetonitirle and three times from ethyl acetate additionally to give salt of m.p. 125-126°C (dec.), [α]D= -42.2°.
A slurry of methyl-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetic acid (B-isomer), dried in vacuo at room temperature for 72 hours, (230.4 g, 0.6 moles) and hydroxybenzotriazole hydrate, dried, in vacuo at 80°C for 24 hours, (101.1 g, 0.66 mole) dichloromethane (sieved dried) (6 L) was chilled in an ice/acetone bath and treated with N,N-dicyclohexylcarbodiimide (136 g, 0.66 mole). The mixture was warmed to room temperature and stirred for 3 hours. The mixture was then chilled in ice/acetone and treated with (trans)-4- cyclohexyl-L-proline, hydrochloride (154.2 g, 0.66 mole) followed by diisopropylethylamine (170.7 g, 1.32 mole). The reaction mixture was stirred at room temperature for 18 hours. The mixture was then chilled, treated with water (1 L) and concentrated in vacuo to remove dichloromethane. The residue was diluted with ether (3600 ml) and water (3600 ml) and filtered. The filtrate was brought to pH = 1.8 with 10% hydrochloric acid. The ether layer was separated and the aqueous layer washed with ethyl acetate (3 x 2 L). The combined organic layers were washed with 5% KHSO4 (3 x 1 L), water (3 x 1 L) and brine (1 L), dried over magnesium sulfate and concentrated in vacuo to yield 398.9 g of crude [R,1S,4S]-4-Cyclohexyl-1-[[[2-methyl-1-(1- oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetyl]-L-proline, monosodium salt (isomer B). The crude product was dissolved in acetone (4393 ml), treated with a solution of 2-ethyl hexanoic acid, sodium salt (117.3 g) in acetone (1468 ml), then stirred at room temperature overnight. The resultant precipitate was collected by filtration, washed with acetone (3 x 400 ml) and hexane (1 L) then dried in vacuo. Yield 277 g, m.p. 195-196°C, [α]D= -5.1° (MeOH, c = 2), HI = 99.8%. Isomer "A" was not detectable.

Monopril (Bristol-Myers Squibb).

Antihypertensive