PRODUCTS

ATORVASTATIN CALCIUM

CAS Number:134523-03-8
Molecule Formula:C66H68Ca2F2N4O10
Molecular Weight:1195.42

Atorvastatin Calcium Anhydrous is an anhydrous calcium salt form of atorvastin, a synthetic lipid-lowering agent.

-Propreties-
Molecular Weight: 1155.3
Hydrogen Bond Donor Count: 6
Hydrogen Bond Acceptor Count: 12
Rotatable Bond Count: 22
Exact Mass: 1154.4529416
Monoisotopic Mass: 1154.4529416
Topological Polar Surface Area: 229 Å²
Heavy Atom Count: 83
Formal Charge: 0
Complexity: 817
Isotope Atom Count: 0
Defined Atom Stereocenter Count: 4
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 0
Undefined Bond Stereocenter Count: 0
Covalently-Bonded Unit Count: 3
Compound Is Canonicalized: Yes

-Manufacturing Process-
285 ml 2.2 M n-butyl lithium in hexane was added dropwise to 92 ml diisopropylamine at -50-60°C under nitrogen.
The well stirred solutions warmed to about -20°C, then it was cannulated into a suspension of 99 g of S(+)-2-acetoxy-1,1,2-triphenylethanol in 500 ml absolute tetrahydrophuran (THF) at -70°C and the reaction mixture was allowed to warm to -10°C for 2 hours.
A suspension of MgBr2 was made from 564 ml (0.63 mol) of bromine and 15.3 g of magnesium (0.63 mol) in 500 ml THF cooled to -78°C.
The enolate solution was cannulated into this suspension within 30 min and was stirred for 60 min at -78°C.

150 g 5-(4-fluorophenyl)-2-(1-methylethyl)-1-(3- oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide in 800 ml absolute THF was added dropwise over 30 min, stirred 90 min at -78°C, then was added 200 ml acetic acid, this is removed to a cool bath, 500 ml of H2O was added and the mixture concentrate in vacuo at 40-50°C.
After adding of 500 ml of 1:1 EtOAc/heptane the mixture was filtered.
The filtrate was washed extensively with 0.5 N HCl, then several times with H2O and finally EtOAc/heptane (3:1) and cooled with dry ice to -20°C.

The light brown crystalline product was dried in vacuum oven at 40°C.
The yield was 194 g. 112 g of the same product was produced by evaporation of mother liquor after recrystallization and chromatographic purification on a silicagel.
162 g of this substance was suspended in methanol/THF (5:3) and was stirred with 11.7 g of sodium methoxide until everything was dissolved and kept in the freezer overnight.
Later it was quenched with AcOH concentrated in vacuo, was added to 500 ml H2O and extracted twice with EtOAc (300 ml).
The combined extracts was washed with saturated NaHCO3 brine and dried over anhydrous MgSO4, purified on silica-gel and gave 86.1 g of white crystals m.p. 125-126°C, αD 20=4.23° (1.17 M, CH3OH).
81 g of the last product in 500 ml absolute THF was added as quickly as possible to the mixture of 77 ml THF at diisopropylamine, 200 ml 2.2 M of nbutyl lithium and 62 ml of t-butylacetate in 200 ml THF -40-42°C under nitrogen.

Stirring was continued for 4 hours at -70°C. The reaction mixture was concentrated in vacuo, the residue was taken up in EtOAc, washed with water, then saturated NH4Cl, NaHCO3 (saturated), dried over anhydrous MgSO4, filtred and the solvent evaporated.
The organic phase was dried and concentrated in vacuo to yield 73 g crude product, that was dissolved in 500 ml absolute THF, 120 ml triehtylborane and 0.7 g t-butylcarboxylic acid, 70 ml methanol and 4.5 g sodium borohydride was added.

The mixture was stirred at -78°C under a dry atmosphere for 6 hours, poured slowly into 4:1:1 mixture of ice/30%H2O2/H2O and stirred overnight.
CHCl3 (400 ml) was added and organic layer washed extensively with H2O until no peroxide could be found, was dried over MgSO4, filtered and was treated by chromatography on silica gel to yield 51 g.
The product was dissolved in THF/methanol and saponificated with NaOH and, concentrated to remove organic solvents at room temperature, added 100 ml H2O, and extracted with Et2O twice.

Organic layer was thoroughly dried and it was left at room temperature for the next 10 days, then concentrated.
Chromatography on silica gel yielded 13.2 g racemate of lactone - trans-(+/- )-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-di-diphenyl-1-[2-(tetrahydro-4- hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.
This racemate was divided by chiral synthesis which was made analogously the method in US Pat. No. 4,581,893.
Then each isomer was saponificated with NaOH and purificated by HPLC.
The calcium salt corresponding acid was prepared by reaction with 1 eq. of CaCl2·2H2O in water.

-Uses-
The primary uses of atorvastatin is for the treatment of dyslipidemia and the prevention of cardiovascular disease.

A selective, competitive HMG-CoA reductase inhibitor.
The only drug in its class specfically indicated for lowering both elevated LDL-cholesterol and triglycerides in patients with hypercholesterolemia.

A selective, competitive HMG-CoA reductase inhibitor.
Atorvastatin is the only drug in its class specfically indicated for lowering both elevated LDL-cholesterol and triglycerides in patients with hypercholesterolemia.

-Synonyms-
ATORVASTATIN CA
ATORVASTATIN CALCIUM
ATORVASTATIN CALCIUM SALT
LIPITOR
[r-(r*, r*)]-7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-(phenylaminocarbonyl)-1h-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid calcium salt
1h-pyrrole-1-heptanoicacid,beta,delta-dihydroxy-2-(4-fluorophenyl)-5-(1-methy
calciumsalt(2:1),(r-(r*,r*))-lethyl)-3-phenyl-4-((phenylamino)carbonyl)
ci-981
delta-dihydroxy-2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-((phenylamino)carbonyl)-betcalci1h-pyrrole-1-heptanoicaci
pd134298-38a
ATORVASTATINCALCUIM
Atrovastatin calcium
(3R ,5R )-7-[2-(4-Fluorophenyl)-5-Isopropyl-3-Phenyl-4-(Pheynylcarbamoyl) Pyrrol-1-yl]-3 ,5-Dihydroheptanoic Acid, calcium salt (2:1) Trihydrate
3R ,5R )-7-[2-(4-Fluorophenyl)-5-Isopropyl-3-Phenyl-4-(Pheynylcarbamoyl) Pyrrol-1-yl]-3 ,5 ydroheptanoic Acid, calcium salt (2:1) Trihydrate
Atorvastatin Calclum
ATORVASTATIN CALCIUM MM(CRM STANDARD)
ATORVASTATINE CADIUM
Atorvastatinecalcium
(bR,dR)-2-(4-Fluorophenyl)-b,d-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic Acid
3S,5S-Atorvastatin