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88889-14-9

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  • L-Proline,4-cyclohexyl-1-[2-[(R)-[(1S)-2-methyl-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetyl]-,sodium salt (1:1), (4S)- 88889-14-9

    Cas No: 88889-14-9

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88889-14-9 Usage

Hypotensive drug

Fosinopril sodium is a unique novel angiotensin converting enzyme inhibitor containing phosphono,it is a sodium of fosinopril , belonging to lowering blood pressure drugs in the cardiovascular system drugs , it is originally and successfully developed by the US Bristol-Myers Squibb company , the trade name is Monopril, it was first listed in the UK in 1991, followed by a number of countries including the United States and European countries,it is used for the treatment of hypertension ,and for treatment of heart failure in combination with a diuretic. Fosinopril is a prodrug, after oral absorption,it is hydrolyzed in the gastrointestinal tract and liver to become a diacids complex complex, fosinopril sodium which has pharmacological activity and to play its role. It can competitively bind with ACE active ligand zinc ion , blocking angiotensin Ⅰ becoming into angiotensin Ⅱ, so that the blood vessels are dilate, aldosterone secretion is decreased, and blood pressure is decreased. Its ACE inhibition strength is similar to enalapril. Hypertension patients are treated with fosinopril ,the drug plays its role one hour after administration ,after 2 to 6 hours .it is up to maximum antihypertensive effect, it can hold effect for 24 hours, 1 times/day administration. Fosinopril can reduce peripheral vascular resistance, so that systemic vascular resistance is decreased, the cardiovascular output, left ventricular ejection fraction and left ventricular filling increase, thereby cardiac function is improved . The product also allows renal blood flow, glomerular filtration, plasma volume maintained or improved, renal vascular resistance is decreased, it does not affect cerebral blood flow. Oral bioavailability 36%, the concentration of blood Fosinoprilat reaches the peak 3 hours after the administration, t1/2 is 11.5 hours, and for hypertension associated with reduced renal function patients, when they take the drug, there is compensatory increase in hepatic metabolism, and when hypertension associated reduced liver function, renal function increases the elimination of the drug, due to the elimination of this compensatory mechanism, fosinopril treatment for high blood pressure,when it comes to that liver and kidney function is reduced, it is generally not necessary to adjust the dosage. First treatment of hypertension with the drug is an oral dose of 10mg/times, 1 time/day, general therapeutic dose range is 20~40mg/d. It can"in a lasting time and stably decrease blood pressure to protect heart and kidney , the dual elimination of kidney and liver is safer" because fosinopril sodium-does not have free thiol group, clinically, skin rashes and other allergic reactions caused by mercapto are less generated,it is the based medication for hypertension combined crown heart disease and chronic heart failure patients, it is also the preferred treatment of hypertension and diabetes patients , it is suitable for all strong indications of high blood pressure. Especially for the elderly and patients with liver and kidney dysfunction, the use of the product is more safe and convenient. The above information is edited by the lookchem of Tian Ye.

Description

Fosinopril sodium, an ester prodrug of fosinoprilat, is the first of a new generation of phosphinic acid ACE inhibitors indicated for the once-daily treatment of hypertension. Unlike captopril and lisinopril, it is reportedly effective in increasing the left ventricular peak filling rates and peak ejection rates in hypertensive patients at rest. Another advantage is that fosinopril sodium is metabolized equally by renal and hepatic routes, thereby avoiding the requirement to modify dosage in patients with renal insufficiency.

Uses

Different sources of media describe the Uses of 88889-14-9 differently. You can refer to the following data:
1. A phosphinic acid containing angiotensin converting enzyme (ACE) inhibitor. Antihypertensive.
2. A labelled phosphinic acid containing angiotensin converting enzyme (ACE) inhibitor.
3. Fosinopril sodium is the ester prodrug of an angiotensin-converting enzyme (ACE) inhibitor, used for the treatment of hypertension and some types of chronic heart failure.

Definition

ChEBI: The sodium salt of fosinopril. It is used for the treatment of hypertension and heart failure. A pro-drug, its phosphinate ester group is hydrolysed in vivo to give the corresponding phosphininc acid, fosinoprilat, which is the active metaboli e.

Manufacturing Process

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.

Brand name

Monopril (Bristol-Myers Squibb);Staril.

Therapeutic Function

Antihypertensive

General Description

Fosinopril sodium, (4S)-4-cyclohexyl-1-[[[(RS)-1-hydroxy-2-methylpropoxy](4-phenylbutyl)phosphinyl]acetyl]-L-proline sodium salt (Monopril),is a phosphorus-containing ACE inhibitor. It is inactive butserves as a prodrug, being completely hydrolyzed by intestinaland liver enzymes to the active diacid fosinoprilat.

Clinical Use

Angiotensin-converting enzyme inhibitor: Hypertension Heart failure

Drug interactions

Potentially hazardous interactions with other drugs Anaesthetics: enhanced hypotensive effect. Analgesics: antagonism of hypotensive effect and increased risk of renal impairment with NSAIDs; hyperkalaemia with ketorolac and other NSAIDs. Antihypertensives: increased risk of hyperkalaemia, hypotension and renal failure with ARBs and aliskiren. Bee venom extract: possible severe anaphylactoid reactions when used together. Ciclosporin: increased risk of hyperkalaemia and nephrotoxicity. Cytotoxics: increased risk of angioedema with everolimus. Diuretics: enhanced hypotensive effect; hyperkalaemia with potassium-sparing diuretics. ESAs: increased risk of hyperkalaemia; antagonism of hypotensive effect. Gold: flushing and hypotension with sodium aurothiomalate. Lithium: reduced excretion, possibility of enhanced lithium toxicity. Potassium salts: increased risk of hyperkalaemia. Tacrolimus: increased risk of hyperkalaemia and nephrotoxicity.

Metabolism

Fosinopril acts as a prodrug of the diacid fosinoprilat, its active metabolite. Fosinopril is rapidly and completely hydrolysed to fosinoprilat in both gastrointestinal mucosa and liver. Fosinoprilat is excreted both in urine and in the faeces via the bile.

references

[1] shionoiri h, naruse m, minamisawa k, ueda s, himeno h, hiroto s, takasaki i. fosinopril. clinical pharmacokinetics and clinical potential. clin pharmacokinet. 1997 jun;32(6):460-80.

Check Digit Verification of cas no

The CAS Registry Mumber 88889-14-9 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 8,8,8,8 and 9 respectively; the second part has 2 digits, 1 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 88889-14:
(7*8)+(6*8)+(5*8)+(4*8)+(3*9)+(2*1)+(1*4)=209
209 % 10 = 9
So 88889-14-9 is a valid CAS Registry Number.
InChI:InChI=1/C30H46NO7P.Na/c1-4-28(33)37-30(22(2)3)38-39(36,18-12-11-15-23-13-7-5-8-14-23)21-27(32)31-20-25(19-26(31)29(34)35)24-16-9-6-10-17-24;/h5,7-8,13-14,22,24-26,30H,4,6,9-12,15-21H2,1-3H3,(H,34,35);/q;+1/p-1/t25-,26+,30+,39-;/m1./s1

88889-14-9 Well-known Company Product Price

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  • Sigma-Aldrich

  • (Y0001227)  Fosinopril sodium  European Pharmacopoeia (EP) Reference Standard

  • 88889-14-9

  • Y0001227

  • 1,880.19CNY

  • Detail
  • Sigma

  • (F1308)  Fosinopril sodium  ≥98% (HPLC), powder

  • 88889-14-9

  • F1308-5MG

  • 1,062.36CNY

  • Detail
  • Sigma

  • (F1308)  Fosinopril sodium  ≥98% (HPLC), powder

  • 88889-14-9

  • F1308-25MG

  • 4,288.05CNY

  • Detail

88889-14-9SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 18, 2017

Revision Date: Aug 18, 2017

1.Identification

1.1 GHS Product identifier

Product name fosinopril sodium

1.2 Other means of identification

Product number -
Other names Fosinopril sodium

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

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