Fluvastatin Chemical Properties

Melting point:

193.9-196.9 °C

Boiling point:

681.8±55.0 °C(Predicted)

Density 

1.23±0.1 g/cm3(Predicted)

storage temp. 

2-8°C

solubility 

Water 25 mg/ml DMSO 100 mg/ml Ethanol 25 mg/ml

form 

Powder

pka

4.27±0.10(Predicted)

CAS DataBase Reference

93957-54-1(CAS DataBase Reference)

EPA Substance Registry System

6-Heptenoic acid, 7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]- 3,5-dihydroxy-, (3R,5S,6E)-rel- (93957-54-1)

Safety Information

Hazardous Substances Data

93957-54-1(Hazardous Substances Data)

Fluvastatin Usage And Synthesis

Originator

Lipaxan, Italfarmaco spa

Uses

A synthetic HMG-CoA reductase inhibitor

Uses

antineoplastic, aromatase inhibitor

Uses

anti-hyperlipoproteinemic, 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor

Definition

ChEBI: (3R,5S)-fluvastatin is a (6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoic acid diastereoisomer in which the stereocentres beta- and delta- to the carboxy group have R and S configuration, respectively. The drug fluvastatin is an equimolar mixture of this compound and its enantiomer. It is a (6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoic acid and a statin (synthetic). It is a conjugate acid of a (3R,5S)-fluvastatin(1-). It is an enantiomer of a (3S,5R)-fluvastatin.

Manufacturing Process

164 ml (235.1 g, 2.04 moles) of chloroacetyl chloride is added over a 50 min period to a mixture of 400 ml (410 g, 4.22 moles) of fluorobenzene and 300.0 g (2.25 moles) of anhydrous aluminum chloride stirred at 75°C under nitrogen. The reaction mixture is stirred at 80°C under nitrogen for 1 h, cooled to 50°C, 500 ml of fluorobenzene is added, and the reaction mixture is cooled to 0°C and gradually (over a 30 min period) siphoned into 1 L of 6 N hydrochloric acid stirred at 0°C. (The temperature of the aqueous acid is maintained at or below 25°C throughout the addition). The quenched, acidified reaction mixture is stirred for 15 min, and the aqueous phase is separated and extracted with 350 ml of fluorobenzene. The two organicphases are combined and washed twice with 500 ml portions of 3 N hydrochloric acid and once with 500 ml of water. The fluorobenzene is distilled at 30 mm. Hg and 60°C and, upon cooling, the obtained 4-chloroacetyl-1fluorobenzene oily residue solidifies.
562.9 g (4.08 moles) of N-isopropylaniline is rapidly added to a solution of the 4-chloroacetyl-1-fluorobenzene in 500 ml of dimethylformamide stirred at 50°C under nitrogen. The reaction mixture is stirred at 100°C under nitrogen for 10 h and allowed to cool to room temperature overnight. The reaction mixture is heated to 60°C, 2 L of water is added, and the mixture is cooled to 10°C. The obtained solids are collected, washed twice with 500 ml portions of water and dissolved in 550 ml of 95% ethanol at 75°C. The solution is cooled to 0°C, and the obtained solids are collected, washed three times with 100 ml portions of 95% ethanol and vacuum dried at 35°-40°C for 4 h to obtain the 95.3% pure yellow product: N-(4-fluorobenzoylmethyl)-N-(1-methylethyl) aniline (466.0 g, 84.2%, melting point 78° -81°C).
4.5 ml of 1 N sodium hydroxide solution (4.5 mmol) and 2.0 g (4.7 mmol) of N-(4-fluorobenzoylmethyl)-N-(1-methylethyl)aniline are stirred in 150 ml of ethanol at room temperature for 2 h, the solvent is evaporated at reduced pressure, and the residue is dissolved in 50 ml of water. The aqueous solution is gently extracted with diethyl ether, the traces of ether in the aqueous layer are removed at reduced pressure, and the aqueous layer is freeze dried to obtain racemic sodium threo-(+/-)-(E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)1'-(1"-methylethyl )indol-2'-yl]hept-6-enoate (1.8 g (88%)), melting point 194°-197°C.
The crude sodium threo-(+/-)-(E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)-1'(1"-methylethyl )indol-2'-yl]hept-6-enoate is dissolved in water, and the solution is acidified to pH 2 with 2 N hydrochloric acid and extracted with diethyl ether. The diethyl ether extract is washed three times with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated at reduced pressure to obtain the crude solid racemic erythro-(+/)-(E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)-1'-(1"-methylethyl )indol-2'-yl] hept-6-enoic acid (6.9 g).
The racemic erythro-(+/-)-(E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)-1'-(1"methylethyl )indol-2'-yl]hept-6-enoic acid may both be resolved into two optically pure enantiomers, the 3R, 5S and 3S, 5R isomers by chromatography on silica gel column using organic solutions as the eluent.

brand name

Lescol (Novartis).

Therapeutic Function

Antihyperlipidemic

General Description

Fluvastatin, [R*,S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid monosodium salt (Lescol), is very similarto pravastatin. It possesses a heptanoic acid side chain thatis superimposable over the lactone ring found in lovastatinand simvastatin. This side chain is recognized by HMGCoAreductase. Also, much like pravastatin, the CNS sideeffects of this lipid-lowering agent are much lower thanthose of the agents that possess a lactone ring as part of theirarchitectural design.

Clinical Use

HMG CoA reductase inhibitor:
Primary hypercholesterolaemia
Slowing progression of atherosclerosis
Secondary prevention of coronary events after percutaneous coronary intervention

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: rifampicin increases metabolism; increased risk of myopathy with daptomycin; avoid for 7 days after last dose of fusidic acid.
Anticoagulants: anticoagulant effect enhanced.
Antiepileptics: concentration of either or both drugs may be increased with fosphenytoin and phenytoin.
Antifungals: concentration increased by fluconazole - increased risk of myopathy.
Antivirals: possible increased risk of myopathy with ledipasvir - reduce fluvastatin dose; avoid with paritaprevir.
Ciclosporin: concomitant treatment with ciclosporin may lead to risk of muscle toxicity.
Colchicine: isolated cases of myopathy have been reported.
Lipid-lowering drugs: increased risk of myopathy with gemfibrozil, fibrates and nicotinic acid - avoid with gemfibrozil.

Metabolism

Fluvastatin is rapidly and completely absorbed from the gastrointestinal tract and undergoes extensive firstpass metabolism in the liver. Metabolism is mainly by the cytochrome P450 isoenzyme CYP2C9, with only a small amount metabolised by CYP3A4. The major components circulating in the blood are fluvastatin and the pharmacologically inactive N-desisopropyl-propionic acid metabolite. The hydroxylated metabolites have pharmacological activity but do not circulate systemically. About 93% is excreted in the faeces, mainly as metabolites, with only about 6% being excreted in the urine

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