Fluvastatin sodium salt

Iupac Name：sodium;(E,3R,5S)-7-[3-(4-fluorophenyl)-1-propan-2-ylindol-2-yl]-3,5-dihydroxyhept-6-enoate

Molecular Weight：433.45

Modify Date.: 2022-12-10 11:27

Introduction: Fluvastatin sodium is the fourth HMG-CoA reductase inhibitor to reach the marketas a dietary adjunct for lowing total and low-density lipoprotein (LDL) cholesterol.Fluvastatin sodium is the first totally synthetic inhibitor of its class and has morepotent effects on reducing serum total and LDL cholesterol and serum triglyceridelevels than compactin or lovastatin. Moreover, fluvastatin exhibits a unique set ofpharmacological properties including a biopharmaceutical profile most consistentwith hepatoselectivity. It has been reported to be well tolerated and to exhibit asafety profile superior to other agents of its class. The main mechanism by whichHMG-CoA reductase inhibitors lower plasma cholesterol has been suggested to beup-regulation of hepatocellular LDL-receptor expression and enhancement ofreceptor-mediated clearance and catabolism of LDL cholesterol. View more+

Request For Quotation

1. Names and Identifiers

1.1 Name: Fluvastatin sodium salt
1.2 Synonyms: (+/-)-(3R',5S',6E)-7-[3-(4-FLUOROPHENYL)-1-ISOPROPYLINDOL-2-YL]-3,5-DIHYDROXY-6-HEPTENOATE, SODIUM (3R,5S,6E)-7-[3-(4-fluorophényl)-1-(1-méthyléthyl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-énoate de sodium (r*,s*-(e))-monosodiumsal(+-)-2-yl) 3,5-dihydro-7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1h-indol-6-heptenoicaci 5-dihydro-7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1h-indol-2-yl)-monosodiumsalt,(r*,s*-(e))-(6-heptenoicaci 6-heptenoic acid, 7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-, monosodium salt, (3R,5S,6E)- 6-Heptenoic acid, 7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-, sodium salt, (3R,5S,6E)- (1:1) fluindostatin Fluvastatin (sodium) FLUVASTATIN NA FLUVASTATIN SODIUM Fluvastatinsodium Lipaxan MFCD00929076 Natrium-(3R,5S,6E)-7-[3-(4-fluorphenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoat sodium (3r,5s,6e)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1h-indol-2-yl]-3,5-dihydroxy-6-heptenoate sodium (3R,5S,6E)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoate sodium (3R,5S,6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoate Sodium (3R,5S,6E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoate Sodium (3R,5S,6E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoate XU 62-320

1.3 CAS No.: 93957-55-2

1.4 CID: 23663976

1.5 EINECS(EC#): 1308068-626-2

1.6 Molecular Formula: C24H25FNNaO4 (isomer)

1.7 Inchi: InChI=1/C24H26FNO4.Na/c1-15(2)26-21-6-4-3-5-20(21)24(16-7-9-17(25)10-8-16)22(26)12-11-18(27)13-19(28)14-23(29)30;/h3-12,15,18-19,27-28H,13-14H2,1-2H3,(H,29,30);/q;+1/p-1/b12-11+;/t18-,19-;/s2

1.8 InChkey: ZGGHKIMDNBDHJB-ZADPHQEYNA-M

1.9 Canonical Smiles: [Na+].CC(C)N1C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C2=C1C=CC=C2)C1=CC=C(F)C=C1

1.10 Isomers Smiles: CC(C)N1C2=CC=CC=C2C(=C1/C=C/[C@H](C[C@H](CC(=O)[O-])O)O)C3=CC=C(C=C3)F.[Na+]

2. Properties

2.1 Melting point: 194-197°C

2.1 Boiling point: 681.8 °C at 760 mmHg

2.1 Flash Point: 366.1 °C

2.1 Precise Quality: 433.16700

2.1 PSA: 85.52000

2.1 logP: 3.29340

2.1 Solubility: H2O: ≥9mg/mL

2.2 Appearance: white to tan

2.3 Storage: Desiccate at -20°C

2.4 Color/Form: white to tan

2.5 Water Solubility: H2O: ≥9mg/mL

2.6 StorageTemp: 2-8°C

3. Use and Manufacturing

3.1 Usage: HMG-CoA reductase inhibitors.

4. Safety and Handling

4.1 RIDADR: NONH for all modes of transport

4.1 WGK Germany: 3

4.1 RTECS: MJ9675050

4.1 Safety: Contraindications:
1)Hypersensitivity to drug
2)Active hepatic disease
3)Severe renal impairment
4)Pregnancy or breastfeeding
?

4.2 Specification: Yellow Powder
usageEng:A synthetic HMG-CoA reductase inhibitor. Antilipemic

4.3 Toxicity

CHEMICAL IDENTIFICATION

RTECS NUMBER :: MJ9675100

CHEMICAL NAME :: 6-Heptenoic acid, 3,5-dihydro-7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1 H-indol-2-yl)-, monosodium salt, (R*,S*-(E))-, (+-)-

CAS REGISTRY NUMBER :: 93957-55-2

LAST UPDATED :: 199612

DATA ITEMS CITED :: 3

MOLECULAR FORMULA :: C24-H26-F-N-O4.Na

MOLECULAR WEIGHT :: 434.50

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 2912 mg/kg/26W-I

TOXIC EFFECTS :: Blood - changes in serum composition (e.g. TP, bilirubin, cholesterol) Biochemical - Metabolism (Intermediary) - lipids including transport

REFERENCE :: FAATDF Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1981- Volume(issue)/page/year: 29,48,1996

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 5824 mg/kg/2Y-I

TOXIC EFFECTS :: Blood - changes in serum composition (e.g. TP, bilirubin, cholesterol) Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - transaminases

REFERENCE :: FAATDF Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1981- Volume(issue)/page/year: 29,48,1996 ** REPRODUCTIVE DATA **

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 396 mg/kg

SEX/DURATION :: female 7-17 day(s) after conception

TOXIC EFFECTS :: Reproductive - Effects on Embryo or Fetus - extra-embryonic structures (e.g., placenta, umbilical cord) Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus)

REFERENCE :: KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 29,853,1995

View all

5. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

Acute toxicity - Oral, Category 4

Skin irritation, Category 2

Skin sensitization, Category 1

Eye irritation, Category 2

Specific target organ toxicity \u2013 repeated exposure, Category 1

Hazardous to the aquatic environment, long-term (Chronic) - Category Chronic 3

2.2 GHS label elements, including precautionary statements

Pictogram(s)
Signal word	Danger
Hazard statement(s)	H302 Harmful if swallowed H315 Causes skin irritation H317 May cause an allergic skin reaction H319 Causes serious eye irritation H372 Causes damage to organs through prolonged or repeated exposure H412 Harmful to aquatic life with long lasting effects
Precautionary statement(s)
Prevention	P264 Wash ... thoroughly after handling. P270 Do not eat, drink or smoke when using this product. P280 Wear protective gloves/protective clothing/eye protection/face protection. P261 Avoid breathing dust/fume/gas/mist/vapours/spray. P272 Contaminated work clothing should not be allowed out of the workplace. P260 Do not breathe dust/fume/gas/mist/vapours/spray. P273 Avoid release to the environment.
Response	P301+P312 IF SWALLOWED: Call a POISON CENTER/doctor/\u2026if you feel unwell. P330 Rinse mouth. P302+P352 IF ON SKIN: Wash with plenty of water/... P321 Specific treatment (see ... on this label). P332+P313 If skin irritation occurs: Get medical advice/attention. P362+P364 Take off contaminated clothing and wash it before reuse. P333+P313 If skin irritation or rash occurs: Get medical advice/attention. P305+P351+P338 IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. P337+P313 If eye irritation persists: Get medical advice/attention. P314 Get medical advice/attention if you feel unwell.
Storage	none
Disposal	P501 Dispose of contents/container to ...

2.3 Other hazards which do not result in classification

none

View all

6. NMR Spectrum

Predict 1H proton NMR

7. Other Information

7.0 Merck: 14,4218

7.1 Target: Value

7.2 HMG-CoA reductase (Cell-free assay): 8 nM

7.3 Commonly used cholesterol-lowering drugs: Fluvastatin sodium salt is commonly used as a cholesterol-lowering drug, cholesterol-lowering effect is very good, the trade name of the commercially available products is Lescol,which is produced by Novartis. Fluvastatin sodium salt is a fully synthetic cholesterol-lowering drug, it belongs to methylglutaryl coenzyme A (HMC-CoA) reductase inhibitors, the main function is performed in the liver ,it can transform HMG-CoA into 3-methyl-3,5-dihydroxy acid, it can inhibit the synthesis of endogenous cholesterol ,and reduce cholesterol content in liver cells, it can stimulate the synthesis of low density lipoprotein (LDL) receptors,and enhance the uptake of LDL particles, reduce the plasma total cholesterol concentration.it can significantly reduce total cholesterol, LDL cholesterol, triglycerides, and increase high-density lipoprotein cholesterol.

7.4 Chemical Properties: Melting point 194~197 ℃.

7.5 Uses: HMG-CoA reductase inhibitors.

7.6 production method: 1. After condensation of (chloroacetyl) fluorobenzeneand N-isopropyl aniline , the compound (I) is obtained. Then in acetonitrile, under the presence of phosphorus oxychloride, react with N, N-dimethylamino acrolein , the compound (Ⅱ) is obtained. Compound (Ⅱ) in the role of a strong base, after condensation with methyl acetoacetate , and then splitting ,the compound (Ⅲ) is produced. At-77 ~-74 ℃, the compound (Ⅲ) is added dropwise into a mixture of boron sodium borohydride , methanol, tetrahydrofuran and diethyl methoxy ,stir 30min; cyclic boronic ester obtained in ethyl acetate is treated with 30% hydrogen peroxide; then it is hydrolyzed to obtain fluvastatin sodium.
2. the compound (Ⅳ)is obtained by catalytic hydrogenation of Phloroglucinol . React it With tert-butyldiphenylsilyl chloride to produce the compound (V), and then oxidize it to generate (Ⅵ). After oxidation of chloroperbenzoic acid to obtain (Ⅶ), (Ⅷ) is produced through ring-opening . And then it is oxidized to (IX) . (Ⅺ) is obtained through condensation of (Ⅸ) and intermediate x , after deprotection and hydrolysis, obtain fluvastatin sodium. Intermediate (X) can be made through starting from the compound (I), via formylation, reduction, chlorination, and then reacting with triphenylphosphine .

7.7 Description: Fluvastatin sodium is the fourth HMG-CoA reductase inhibitor to reach the market as a dietary adjunct for lowing total and low-density lipoprotein (LDL) cholesterol. Fluvastatin sodium is the first totally synthetic inhibitor of its class and has more potent effects on reducing serum total and LDL cholesterol and serum triglyceride levels than compactin or lovastatin. Moreover, fluvastatin exhibits a unique set of pharmacological properties including a biopharmaceutical profile most consistent with hepatoselectivity. It has been reported to be well tolerated and to exhibit a safety profile superior to other agents of its class. The main mechanism by which HMG-CoA reductase inhibitors lower plasma cholesterol has been suggested to be up-regulation of hepatocellular LDL-receptor expression and enhancement of receptor-mediated clearance and catabolism of LDL cholesterol.

7.8 Chemical Properties: Yellow Powder

7.9 Originator: Sandoz (Switzerland)

7.10 Uses: A synthetic HMG-CoA reductase inhibitor. Antilipemic

7.11 Uses: Anti- hyperlipoproteinemic;'HMG CoA reductase inhibitor

7.12 Uses: Fluvastatin-d6 Sodium Salt is the labeled analogue of Fluvastatin Sodium Salt (F601250), a synthetic HMG-CoA reductase inhibitor. Antilipemic.

7.13 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.

7.14 Brand name: Lescol (Novartis).

7.15 Therapeutic Function: Antihyperlipidemic

7.16 General Description: Fluvastatin sodium is a lipid-lowering drug that belongs to the group of compounds known as statins. It acts by inhibiting the enzyme HMG-CoA reductase that plays a key role in the cholesterol production. It is generally used to reduce plasma cholesterol levels and prevent cardiovascular disease.
Pharmaceutical secondary standards for application in quality control, provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards.

7.17 Biological Activity: Orally active, potent and competitive HMG-CoA reductase inhibitor (IC 50 = 40 -100 nM at human liver microsomes). Inhibits vascular smooth muscle proliferation in vitro (IC 50 = 70 nM) and exhibits antihypercholesterolemic and antioxidant activity in vivo .

7.18 Biochem/physiol Actions: Fluvastatin is a competitive inhibitor of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonic acid, the rate-limiting step in cholesterol biosynthesis. Fluvastatin is antilipemic and is used to reduce plasma cholesterol levels and prevent cardiovascular disease.

7.19 References: 1) Dansette?et al. (2000),?HMG-CoA reductase activity in human liver microsomes: comparative inhibition by statins; Exp. Toxicol. Pathol.,?52?145 2) Turner?et al.?(2007),?Comparison of the efficacies of five different statins on inhibition of human saphenous vein smooth muscle cell proliferation and invasion: J. Cardiovasc. Pharmacol.,?50?458 3) McFarland?et al.?(2017),?Statins Reduce Lipopolysaccharide-Induced Cytokine and Inflammatory Mediator Release in an In Vitro Model of Microglial-like Cells; Mediators Inflamm.,?2582745 4) Yang?et al.?(2017),?Fluvastatin Prevents Lung Adenocarcinoma Bone Metastasis by Triggering Autophagy; EBioMedicine,?19?49 5)Higashi?et al.?(2016),?Statin attenuates cell proliferative ability via TAZ (WWTR1) in hepatocellular carcinoma; Med. Oncol.,?33?123

7.20 Livertox Summary: Fluvastatin is a commonly used cholesterol lowering agent (statin) that is associated with mild, asymptomatic and self-limited serum aminotransferase elevations during therapy and rarely with clinically apparent acute liver injury.

7.21 Drug Classes: Antilipemic Agents

7.22 Mesh Entry Terms: 7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl)-3,5-dihydroxy-6-heptenoate

7.23 Use Classification: Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

8. Computational chemical data

Molecular Weight: 433.45g/mol
Molecular Formula: C₂₄H₂₅FNNaO₄
Compound Is Canonicalized: True
XLogP3-AA: null
Exact Mass: 433.16653072
Monoisotopic Mass: 433.16653072
Complexity: 596
Rotatable Bond Count: 8
Hydrogen Bond Donor Count: 2
Hydrogen Bond Acceptor Count: 5
Topological Polar Surface Area: 85.5
Heavy Atom Count: 31
Defined Atom Stereocenter Count: 2
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 1
Undefined Bond Stereocenter Count: 0
Isotope Atom Count: 0
Covalently-Bonded Unit Count: 2
CACTVS Substructure Key Fingerprint: AAADceB6OSAAAAAAAAAAAAAAAAAAAWAAAAAwYAAAAAAAAFgB9AAAHwAACAAADDzhng4yyPMMEgCoAyTyTACCgCAhAiAI2CE4ZJgINPbAkZGEcAhloADI2AeY7MROgAAAAAACAAAAAAAAAAQAAAAAAAAAAA==