134523-03-8

Basic information

• Product Name: Atorvastatin calcium
• Synonyms: LIPITOR;ATORVASTATIN CALCIUM SALT;ATORVASTATIN CALCIUM;ATORVASTATIN CA;[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
• CAS NO: 134523-03-8
• Molecular Formula: 2C₃₃H₃₄FN₂O₅*Ca
• Molecular Weight: 1155.36
• EINECS: 200-659-6
• Product Categories: Active Pharmaceutical Ingredients;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Atorvastatin;Aromatics;Chiral Reagents;Pfizer compounds;Pharmaceutical intermediates;Isotope;LIPITOR;Cardiovascular APIs;Antilipemic agent;API
• Mol File: 134523-03-8.mol
• Article Data: 75

Chemical Properties

• Melting Point: 176-178°C
• Boiling Point: 722.2 °C at 760 mmHg
• Flash Point: 390.6 °C
• Appearance: White Crystalline Powder
• Storage Temp.: Store at +4°C
• Solubility: DMSO: ≥10mg/mL
• CAS DataBase Reference: Atorvastatin calcium(CAS DataBase Reference)
• NIST Chemistry Reference: Atorvastatin calcium(134523-03-8)
• EPA Substance Registry System: Atorvastatin calcium(134523-03-8)

Safety Data

• Hazard Codes: Xn,T,F
• Statements: 20/21/22-36/37/38-39/23/24/25-23/24/25-11
• Safety Statements: 26-36-45-36/37-16-7
• WGK Germany: 3
• Hazardous Substances Data: 134523-03-8(Hazardous Substances Data)

Usage

Description

Atorvastatin calcium, also known by its trade name Lipitor, is a statin-class medication primarily used for lowering lipid levels and preventing cardiovascular events. It acts as a selective, competitive HMG-CoA reductase inhibitor, which is an enzyme found in liver tissue that plays a key role in the production of cholesterol in the body. Atorvastatin calcium is a white crystalline powder and is soluble in DMSO and EtOH.

Uses

1. Used in Pharmaceutical Industry:
Atorvastatin calcium is used as an antihyperlipidemic agent for the treatment of dyslipidemia and the prevention of cardiovascular disease. It is specifically indicated for lowering both elevated LDL-cholesterol and triglycerides in patients with hypercholesterolemia.
2. Used in Research and Development:
Atorvastatin Calcium Salt Trihydrate is used as a standard compound in the method development and validation for the simultaneous determination of Atorvastatin calcium and Ezetimibe in tablets using UV spectrophotometric, HPLC, and HPTLC methods.
3. Used in Cholesterol Management:
Atorvastatin calcium is used as a liver-selective, reversible competitive inhibitor of HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis. It has been shown to reduce LDL cholesterol by up to 60% and is about 2-4 times more potent, on a dosage basis, than Simvastatin.
4. Used in Triglyceride Reduction:
In addition to its effects on cholesterol, Atorvastatin calcium is also effective in lowering triglycerides. The mechanism for this effect is not entirely clear, but two proposed theories are: a) the decrease in cholesterol causes a concomitant increase in hepatic LDL-receptor activity, which results in a decrease in triglycerides through an increase in binding of triglycerides to VLDL and LDL, and b) the decreased level of cholesterol impairs VLDL transport of triglycerides.
5. Used in Drug Synthesis:
Atorvastatin calcium can be synthesized by a number of routes, but the most efficient involves the Paal-Knorr reaction of an acetonide protected dihydroxy amino ester and a diaryl phenylacetamide diketone.
6. Used in Economic Impact:
Since its launch in 1996, Lipitor has become the world's best-selling medication, with more than US$125 billion in sales over approximately 14.5 years. As of 2016, in the UK, atorvastatin costs about ￡2 per month, making it an affordable option for patients in need of cholesterol management.

Indication and application

LIPITOR is mainly indicated for the treatment of cardiovascular disease and dyslipidemia due to its effect in lowering the cholesterol in the blood[7-9]. LIPITOR is a prescription medicine that lowers cholesterol in the blood. It lowers the LDL-C["bad” cholesterol] and triglycerides in your blood. It can raise your HDL-C["good" cholesterol] as well[10]. LIPITOR is for adults and children over 10 whose cholesterol does not come down enough with exercise and a low-fat diet alone. LIPITOR can lower the risk for heart attack, stroke, certain types of heart surgery, and chest pain in patients who have heart disease or risk factors for heart disease such as age, smoking, high blood pressure, low HDL-C, or heart disease in the family. LIPITOR can lower the risk for heart attack or stroke in patients with diabetes and risk factors such as eye problems, kidney problems, smoking, or high blood pressure[7-10]. As a drug for the treatment of cardiovascular, LIPITOR is indicated to reduce the risk of myocardial infarction, reduce the risk of stroke and reduce the risk for revascularization procedures and angina[7, 8, 10, 11]. Moreover, for adults patients with type II diabetes[having multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension], it is also highly effective[12, 13]. For adults diagnosed of clinically evident coronary heart disease, LIPITOR can reduce the risk of non-fatalmyocardial infarction, fatal and non-fatal stroke, revascularization procedures as well as hospitalization for CHF and angina. As a drug for the treatment of hyperlipidemia, it is used as an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TGlevels and to increase HDL-C in adult patients with primary hypercholesterolemia or in pediatric patients as well as for the treatment of adult patients with elevated serum TG levels[7, 8, 14].

Mode of action

Atorvastatin takes effect through selectively and competitively inhibiting the hepatic enzyme HMG-CoA reductase, which is responsible for converting HMG-CoA to mevalonate in the cholesterol biosynthesis pathway[15, 16]. This results in a subsequent decrease in hepatic cholesterol levels. Decreased hepatic cholesterol levels stimulates upregulation of hepatic LDL-C receptors which increases hepatic uptake of LDL-C and reduces serum LDL-C concentrations[9. 16].

Adverse reactions

The most serious adverse reactions associated with LIPITOR include Rhabdomyolysis and myopathy as well as liver enzyme abnormality[18]. Common side effects include headache, hoarseness, lower back or side pain, pain or tenderness around the eyes and cheekbones, painful or difficult urination, stuffy or runny nose[8]. Some less common side effects also include abdominal or stomach pain, back pain, belching or excessive gas, constipation, general feeling of discomfort or illness, heartburn, indigestion or stomach discomfort, lack or loss of strength, loss of appetite, nausea, shivering, sweating, trouble sleeping and vomiting[8].

Warning and precaution

Pregnant or lactation women should be disabled from using LIPITOR. Serious drug interactions can occur when certain medicines are used together with atorvastatin. So you should provide those information to your doctor before taking LIPITOR[7, 8, 17]. In rare cases, LIPITOR can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. Call your doctor right away if you have unexplained muscle pain, tenderness, or weakness especially if you also have fever, unusual tiredness, and dark colored urine. Avoid eating foods that are high in fat or cholesterol. LIPITOR will not be as effective in lowering your cholesterol if you do not follow a cholesterol-lowering diet plan[7, 17]. LIPITOR is not approved for use by anyone younger than 10 years old and those patients who are allergic to it, or of liver disease. Moreover, since LIPITOR may pass into breast milk and could harm a nursing baby. Do not breast-feed while you are taking this medicine[7, 17]. Patients who have a history of liver problems, muscle pain or weakness, kidney disease, diabetes. a thyroid disorder; or drink more than 2 alcoholic beverages daily should take with care[7, 17].

Reference

https://www.lipitor.com Kokilambigai, K. S., R. Seetharaman, and K. S. Lakshmi. "Critical Review on the Analytical Techniques for the Determination of the Oldest Statin—Atorvastatin—in Bulk, Pharmaceutical Formulations and Biological Fluids." Critical Reviews in Analytical Chemistry 47.6(2017]:538. Teckchandani, S., et al. "Rhabdomyolysis following co-prescription of Fusidic Acid and Atorvastatin, with review of Statin Antimicrobial Drug Interactions." Scottish Medical Journal 54.3(2009]:50-50. Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, et al.[September 2016]. "Interpretation of the evidence for the efficacy and safety of statin therapy". Lancet. 388: 2532–2561. http://www.crainsnewyork.com/article/20111228/HEALTH_CARE/111229902 Maggon K: Best-selling human medicines 2002-2004. Drug Discov Today. 2005 Jun 1;10(11]:739-42. https://www.webmd.com/drugs/2/drug-3330/lipitor-oral/details https://www.drugs.com/monograph/atorvastatin-calcium.html https://www.drugbank.ca/drugs/DB01076 Jukema, J. W., et al. "LDL-C/HDL-C ratio in subjects with cardiovascular disease and a low HDL-C: results of the RADAR[Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport] study. " Current Medical Research & Opinion 21.11(2005]:1865-1874. Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, Davignon J, Erbel R, Fruchart JC, Tardif JC, Schoenhagen P, Crowe T, Cain V, Wolski K, Goormastic M, Tuzcu EM[April 2006]. "Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial". JAMA.? Chaturvedi, S., Zivin, J., Breazna, A., Amarenco, P., Callahan, A., & Goldstein, L. B., et al.[2009]. Atorvastatin, stroke, transient ischemic attack. Neurology, 72(8], 818-819. Colhoun, H. M., et al. "Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study[CARDS]: multicentre randomised placebo-controlled trial. " Lancet364.9435(2004]:685-696. Milionis, H., et al. "Th-P16:381 Treating to target patients with primary hyperlipidemia: Comparison of the effects of atorvastatin and rosuvastatin[The atoros study]." Current Medical Research & Opinion22.6(2006]:1123-1131. Youssef, S, et al. "The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. " Nature 420.6911(2002]:78-84. Black, D. M., R. G. Bakkerarkema, and J. W. Nawrocki. "An overview of the clinical safety profile of atorvastatin[lipitor], a new HMG-CoA reductase inhibitor. " Archives of Internal Medicine 158.6(1998]:577. https://www.rxlist.com/lipitor-drug.htm#side_effects_interactions

Originator

Parke-Davis (US)

Biological Activity

Potent HMG-CoA reductase inhibitor (IC 50 = 8 nM). Reduces circulating LDL-C by inhibiting cholesterol biosynthesis and inducing expression of LDL receptors. Inhibits smooth muscle cell proliferation in vitro and exhibits antinociceptive effects in the inflammatory hypernociception model.

InChI:InChI=1/2C33H35FN2O5.2Ca.2H/c2*1-21(2)31-30(33(41)35-25-11-7-4-8-12-25)29(22-9-5-3-6-10-22)32(23-13-15-24(34)16-14-23)36(31)18-17-26(37)19-27(38)20-28(39)40;;;;/h2*3-16,21,26-27,37-38H,17-20H2,1-2H3,(H,35,41)(H,39,40);;;;/q;;;+2;;/p-2/t2*26-,27-;;;;/m11..../s1/r2C33H35FN2O5.CaH2.Ca/c2*1-21(2)31-30(33(41)35-25-11-7-4-8-12-25)29(22-9-5-3-6-10-22)32(23-13-15-24(34)16-14-23)36(31)18-17-26(37)19-27(38)20-28(39)40;;/h2*3-16,21,26-27,37-38H,17-20H2,1-2H3,(H,35,41)(H,39,40);1H2;/q;;;+2/p-2/t2*26-,27-;;/m11../s1

Synthetic route

atorvastatin lysine → lipitor (134523-03-8)

Conditions	Yield
With calcium acetate In ethanol; water at 0 - 40℃;	98%
With calcium acetate In water; acetone at 15 - 20℃; for 1h;	88%

tert-butyl (4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate (125971-95-1) → lipitor (134523-03-8)

Conditions	Yield
Stage #1: tert-butyl (4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate With hydrogenchloride; methanol; water at 35℃; for 3h; Stage #2: With calcium hydroxide In methanol; water; toluene at 70℃; for 2h; Stage #3: In methanol; water at 20 - 78℃; for 24.25h;	96%
Stage #1: tert-butyl (4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate With hydrogenchloride; water In methanol at 15 - 30℃; for 12h; Stage #2: With sodium hydroxide In methanol; water at 25 - 30℃; for 6h; pH=12; Stage #3: With hydrogenchloride; calcium acetate Product distribution / selectivity; more than 3 stages;	93.94%
Stage #1: tert-butyl (4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate With hydrogenchloride; water In methanol at 15 - 30℃; for 10 - 12h; Stage #2: With sodium hydroxide In methanol; water at 25 - 30℃; for 4 - 6h; pH=~ 12; Stage #3: With hydrogenchloride; calcium acetate Product distribution / selectivity; more than 3 stages;	86.5%

atorvastatin lactone (125995-03-1) → lipitor (134523-03-8)

Conditions	Yield
Stage #1: atorvastatin lactone With calcium hydroxide In tetrahydrofuran; water at 45 - 50℃; for 2h; Stage #2: In dichloromethane; di-isopropyl ether at 10 - 15℃; for 0.25h; Product distribution / selectivity;	95.1%
Stage #1: atorvastatin lactone With sodium hydroxide In methanol; water at 25 - 50℃; for 2h; Stage #2: With hydrogenchloride In water pH=7.8 - 8.2; Stage #3: With calcium acetate In methanol; water at 25 - 30℃; Product distribution / selectivity;	92.21%
Stage #1: atorvastatin lactone With calcium hydroxide In tetrahydrofuran; water at 45 - 50℃; for 2h; Stage #2: In methanol at 40 - 45℃; Product distribution / selectivity;	91.82%

(3R,5R)-isopropyl 7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate (1035205-25-4) → lipitor (134523-03-8)

Conditions	Yield
Stage #1: (3R,5R)-isopropyl 7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate With sodium hydroxide In methanol; water at 50℃; for 1h; Stage #2: With calcium chloride monohydrate In methanol; water at 20℃; for 1h;	94%
Stage #1: (3R,5R)-isopropyl 7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate With sodium hydroxide In methanol; water at 20℃; for 1h; Stage #2: With calcium chloride In methanol; water at 20℃; for 1h;	90%

atorvastatin sodium (134523-01-6) → lipitor (134523-03-8)

Conditions	Yield
With calcium acetate In water at 20℃; for 2h;	93%
With calcium acetate In methanol; water at 60 - 65℃; for 2h; Industrial scale;	85.4%
With calcium acetate In water at 13 - 63℃;

C33H34FN2O5(1-)*Li(1+) → lipitor (134523-03-8)

Conditions	Yield
With calcium acetate In water at 52℃; for 17h; Reagent/catalyst; Solvent;	92%

(3R,5R)-methyl 7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate (345891-62-5) → lipitor (134523-03-8)

Conditions	Yield
Stage #1: (3R,5R)-methyl 7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate With sodium hydroxide In methanol at 0℃; for 0.5h; Stage #2: With calcium acetate In methanol at 0℃; for 1h;	91%

2C33H32FN2O4(1-)*Ca(2+) → lipitor (134523-03-8)

Conditions	Yield
With calcium hydroxide In water; acetone at 20 - 50℃; Product distribution / selectivity;	90%

2-((4R,6R)-6-(2-(3-(phenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid isopropyl ester (1112262-71-1) → lipitor (134523-03-8)

Conditions	Yield
Stage #1: 2-((4R,6R)-6-(2-(3-(phenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid isopropyl ester With hydrogenchloride In methanol; water at 25℃; for 3h; Stage #2: With sodium hydroxide In methanol; water at 25 - 38℃; Stage #3: With calcium acetate In water at 58℃; for 1h; Product distribution / selectivity;	90%
Stage #1: 2-((4R,6R)-6-(2-(3-(phenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid isopropyl ester With hydrogenchloride In methanol; water at 25 - 37℃; Stage #2: With sodium hydroxide In methanol; water at 25 - 30℃; pH=> 12; Product distribution / selectivity;
Stage #1: 2-((4R,6R)-6-(2-(3-(phenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid isopropyl ester With hydrogenchloride In methanol; water at 25 - 37℃; Stage #2: With sodium hydroxide In methanol; water at 30℃; for 2h; pH=12.2; Stage #3: With calcium acetate In tert-butyl methyl ether; water at 45 - 58℃; pH=8.6 - 8.8; Product distribution / selectivity;
Stage #1: 2-((4R,6R)-6-(2-(3-(phenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid isopropyl ester With hydrogenchloride; methanol; water at 25 - 27℃; for 2h; Stage #2: With sodium hydroxide In methanol; water at 25 - 30℃; for 2h; pH=< 12; Further stages;

[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid potassium (134523-02-7) → lipitor (134523-03-8)

Conditions	Yield
With calcium acetate In water at 20℃; for 2h;	89%

atorvastatin arginine → lipitor (134523-03-8)

Conditions	Yield
With calcium acetate In water; isopropyl alcohol at 15 - 20℃; for 1h;	88%

calcium acetate (62-54-4) + atorvastatin (134523-00-5) → lipitor (134523-03-8)

Conditions	Yield
Stage #1: calcium acetate; atorvastatin In water; acetonitrile at 44℃; for 1.25h; Stage #2: With sodium hydroxide In water at 30 - 70℃; for 9.5h; Product distribution / selectivity;	84.35%

2-((4R,6R)-6-(2-(3-(phenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid 1-methylpropyl ester (1363896-50-7) → lipitor (134523-03-8)

Conditions	Yield
Stage #1: 2-((4R,6R)-6-(2-(3-(phenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid 1-methylpropyl ester With hydrogenchloride; water In methanol at 25 - 30℃; for 3.16667h; Stage #2: With sodium hydroxide In methanol; water at 25 - 38℃; Stage #3: With calcium acetate In water at 48 - 58℃; for 2h;	73%
Stage #1: 2-((4R,6R)-6-(2-(3-(phenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid 1-methylpropyl ester With hydrogenchloride In methanol; water at 25℃; for 3.16667h; Stage #2: With calcium acetate In water at 35 - 58℃; for 5h;	73%

calcium hydroxide + (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]pyrrol-1-yl]ethyl]-2,2-diisopropyl-1,3-dioxa-2-silacyclohexane-4-acetic acid tert-butyl ester (697266-20-9) → lipitor (134523-03-8)

Conditions	Yield
Stage #1: (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]pyrrol-1-yl]ethyl]-2,2-diisopropyl-1,3-dioxa-2-silacyclohexane-4-acetic acid tert-butyl ester With sodium hydroxide In ethanol at 30 - 55℃; for 25h; Stage #2: With hydrogenchloride In ethanol; water at 20℃; pH=2 - 2.5; Stage #3: calcium hydroxide In ethanol; water at 20 - 70℃; for 4h;	56.4%

C49H51FN2O5Si → lipitor (134523-03-8)

Conditions	Yield
With calcium hydroxide In ethanol; water at 70℃; for 5.5h;	26%

(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9) → lipitor (134523-03-8)

Conditions	Yield
Stage #1: (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester With sodium hydroxide In methanol; water at 50℃; for 1h; Stage #2: With calcium acetate In water; ethyl acetate at 50℃; for 1h;
Stage #1: (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester With sodium hydroxide; water In acetonitrile at 40 - 45℃; for 2h; Stage #2: With calcium acetate In water; acetonitrile at 40 - 45℃; for 0.5 - 1h; Stage #3: With sodium hydroxide In water; acetonitrile at 70 - 80℃; for 7 - 9h;
Stage #1: (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester With sodium hydroxide In methanol; water Stage #2: With calcium chloride In water at 55 - 60℃; Product distribution / selectivity;

(6-{2-[2-(4-fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrolidin-1-yl]-ethyl}-2-phenyl-[1,3,2]dioxaborinan-4-yl)-acetic acid ter-butyl ester → lipitor (134523-03-8)

Conditions	Yield
With calcium oxide In methanol; water at 50 - 60℃; for 10h;
With calcium oxide In water; acetonitrile at 50 - 60℃; for 12h;
With calcium oxide In tetrahydrofuran; water at 50 - 60℃; for 8h;

1,1-dimethylethyl (R)-7-<2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-<(phenylamino)carbonyl>-1H-pyrrol-1-yl>-5-hydroxy-3-oxo-1-heptanoate (134394-98-2) → lipitor (134523-03-8)

calcium (3S,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]-3,5-dihydroxyheptanoate → 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid (581772-29-4) + C26H24FNO5 (887196-28-3) + 5'-deshydroxy atorvastatin (887196-27-2) + 3'-deshydroxy atorvastatin (887196-26-1) + 3-oxo atorvastatin (887196-30-7) + C33H35FN2O7 (887470-43-1) + C40H48FN3O8 (887196-24-9) + 2C33H35N2O5(1-)*Ca(2+)*3H2O + O-methyl atorvastatin calcium + lipitor (134523-03-8) + 3-<(4-fluorophenyl)carbonyl>-2-(2-methyl-1-oxopropyl)-N,3-diphenyl-2-oxiranecarboxamide + (3R,5R)-methyl 7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate (345891-62-5)

Conditions	Yield
With water In tetrahydrofuran; cyclohexane at 20 - 70℃; for 4.75h; Product distribution / selectivity; Molecular sieve;

...Expand

[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid; ammonium salt (340266-37-7) → lipitor (134523-03-8)

Conditions	Yield
With calcium acetate In tetrahydrofuran; water for 12h; Product distribution / selectivity;

[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrole-1-heptanoic acid diisopropylamine salt (908852-23-3) → lipitor (134523-03-8)

Conditions	Yield
With calcium acetate In tetrahydrofuran; water for 6h; Product distribution / selectivity;

atorvastatin (134523-00-5) → lipitor (134523-03-8)

Conditions	Yield
With calcium acetate In water for 1h; pH=8;
With calcium acetate In water; butanone
With calcium acetate In methanol; water for 1h;

[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrole-1-heptanoic acid calcium propylene glycol → (S)-1,2-Propanediol (4254-15-3) + (2R)-propane-1,2-diol (4254-14-2) + lipitor (134523-03-8)

Conditions	Yield
at 130 - 140℃; under 1 - 1.5 Torr; Product distribution / selectivity;

calcium acetate (62-54-4) + atorvastatin sodium (134523-01-6) → lipitor (134523-03-8)

Conditions	Yield
In methanol; water at 13 - 63℃; Product distribution / selectivity;

(-)-(4S)-trans-2-(4-fluorophenyl)-5-(1-methylethyl)-N,3-diphenyl-1-<(tetrahydro-4-hydroxy-2-oxo-2H-pyran-6-yl)ethyl>-1H-pyrrole-4-carboxamide (134523-07-2) → lipitor (134523-03-8)

Conditions	Yield
With calcium hydroxide; tetrabutylammomium bromide In methanol; water at 50℃; for 5h;

C39H45FN2O5 → lipitor (134523-03-8)

Conditions	Yield
Stage #1: C39H45FN2O5 With hydrogenchloride; water In methanol at 20 - 26℃; for 6h; Stage #2: With water; sodium hydroxide In methanol at 23 - 40℃; pH=12 - 12.5; Stage #3: With calcium acetate In water at 47 - 50℃;

calcium(II) acetate dihydrate + atorvastatin sodium + aqueous calcium acetate dihydrate → lipitor (134523-03-8)

Conditions	Yield
In water; ethyl acetate
In water; ethyl acetate

C13H25NO4 (1112262-76-6) → lipitor (134523-03-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: Trimethylacetic acid / n-heptane; tetrahydrofuran / Reflux 2.1: hydrogenchloride / water; methanol / 3 h / 25 °C 2.2: 25 - 38 °C 2.3: 1 h / 58 °C View Scheme
Multi-step reaction with 3 steps 1.1: isopropyl alcohol / 25 - 30 °C 2.1: cyclohexane; 1-methyl-pyrrolidin-2-one / 80 - 82 °C 3.1: hydrogenchloride / water; methanol / 3 h / 25 °C 3.2: 25 - 38 °C 3.3: 1 h / 58 °C View Scheme

C2H2O4*C13H25NO4 (1363159-13-0) → lipitor (134523-03-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium pivalate / tert-butyl methyl ether; tetrahydrofuran / 140 h / Reflux 2.1: hydrogenchloride / water; methanol / 3 h / 25 °C 2.2: 25 - 38 °C 2.3: 1 h / 58 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium carbonate / water / 25 °C / pH 10.9 2.1: Trimethylacetic acid / n-heptane; tetrahydrofuran / Reflux 3.1: hydrogenchloride / water; methanol / 3 h / 25 °C 3.2: 25 - 38 °C 3.3: 1 h / 58 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium carbonate / water / 25 °C / pH 10.9 2.1: isopropyl alcohol / 25 - 30 °C 3.1: cyclohexane; 1-methyl-pyrrolidin-2-one / 80 - 82 °C 4.1: hydrogenchloride / water; methanol / 3 h / 25 °C 4.2: 25 - 38 °C 4.3: 1 h / 58 °C View Scheme

pentan-1-ol (71-41-0) + lipitor (134523-03-8) → pentyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate + atorvastatin lactone (125995-03-1)

Conditions	Yield
With sulfuric acid at 0 - 20℃; for 2.58333h;	A 96% B n/a

lipitor (134523-03-8) → (1S,5R)-9-(4-fluorophenyl)-11-isopropyl-10-phenyl-1,2,6,7-tetrahydro-3H,5H-1,5-methanopyrrolo[1,2-e][1,5]oxazonin-3-one

Conditions	Yield
With hydrogenchloride In water for 5h; Reflux;	96%

lipitor (134523-03-8) → (S)-5-(4-fluorophenyl)-2-isopropyl-1-(2-(6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide (442851-50-5)

Conditions	Yield
With toluene-4-sulfonic acid In toluene for 5h; Reagent/catalyst; Reflux;	95%

lipitor (134523-03-8) + butan-1-ol (71-36-3) → butyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate

Conditions	Yield
With sulfuric acid at 0 - 20℃; for 2.5h;	93%

lipitor (134523-03-8) → atorvastatin (134523-00-5)

Conditions	Yield
With hydrogenchloride In tert-butyl methyl ether; water	92%
With hydrogenchloride In water; acetonitrile at 20℃; for 0.25h; pH=2.35 - 7;
With sodium hydrogen sulfate In water; ethyl acetate

methanol (67-56-1) + lipitor (134523-03-8) → (3R,5R)-methyl 7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate (345891-62-5)

Conditions	Yield
With sulfuric acid at 0 - 20℃; for 2.5h;	90%

lipitor (134523-03-8) → atorvastatin lactone (125995-03-1)

Conditions	Yield
Stage #1: lipitor With hydrogenchloride In water; ethyl acetate at 4 - 20℃; Stage #2: In toluene for 2.5h; Reflux; Dean-Stark;	88%
With hydrogenchloride In water at 20℃; for 2h;	55%
Stage #1: lipitor With hydrogenchloride In dichloromethane; water Stage #2: With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; Cooling with ice;	2.78 g

lipitor (134523-03-8) → atorvastatin hemicalcium salt trihydrate

Conditions	Yield
With water In methanol; dichloromethane at 20 - 30℃; for 2h;	85%

lipitor (134523-03-8) → [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemicalcium salt monohydrate

Conditions	Yield
With water In tetrahydrofuran; methanol at 30 - 50℃; for 9h;	80%

ethanol (64-17-5) + lipitor (134523-03-8) → ethyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate (1146977-93-6)

Conditions	Yield
With sulfuric acid at 0 - 20℃; for 2.5h;	77%

C9H6Cl2N4O2 + lipitor (134523-03-8) → C42H40ClFN6O7

Conditions	Yield
With potassium iodide In N,N-dimethyl-formamide for 50h;	76.7%

1-Decanol (112-30-1) + lipitor (134523-03-8) → decyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate

Conditions	Yield
With sulfuric acid at 0 - 20℃; for 2.5h;	75%

lipitor (134523-03-8) + allyl alcohol (107-18-6) → allyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate (915092-85-2)

Conditions	Yield
With sulfuric acid at 0 - 20℃; for 2.5h;	74%

2-methyl-propan-1-ol (78-83-1) + lipitor (134523-03-8) → isobutyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate + atorvastatin lactone (125995-03-1)

Conditions	Yield
With sulfuric acid at 0 - 20℃; for 2.58333h;	A 74% B n/a

octanol (111-87-5) + lipitor (134523-03-8) → octyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate

Conditions	Yield
With sulfuric acid at 0 - 20℃; for 2.5h;	73%

propan-1-ol (71-23-8) + lipitor (134523-03-8) → propyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate + atorvastatin lactone (125995-03-1)

Conditions	Yield
With sulfuric acid at 0 - 20℃; for 2.58333h;	A 70% B n/a

Upstream product

• 134523-01-6 atorvastatin sodium 
• 62-54-4 calcium acetate 
• 134523-00-5 atorvastatin 
• 134395-00-9 (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester 
• 125971-95-1 tert-butyl (4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate 
• 134523-02-7 atorvastatin potassium 
• 125971-93-9 (3R,5R)-tert-butyl-6-cyano-3,5-dihydroxyhexanoate 
• 1331869-19-2 C₂₆H₂₂FNO₃ 
• 125971-96-2 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxopentanoic acid phenylamide 
• 345891-62-5 (3R,5R)-methyl 7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate 

Downstream Products

• 873950-19-7 4-(4-fluoro-phenyl)-2,4-dihydroxy-2-isopropyl-5-phenyl-3,6-dioxa-bicyclo[3.1.0]hexane-1-carboxylic acid phenylamide 
• 873950-18-6 4-[1b-(4-fluoro-phenyl)-6-hydroxy-6-isopropyl-1a-phenyl-6a-phenylcarbamoyl-hexahydro-1,2-dioxa-5a-aza-cyclopropa[a]inden-3-yl]-3-(R)-hydroxy-butyric acid 
• 873950-17-5 4-[6-(4-fluoro-phenyl)-6-hydroxy-1b-isopropyl-6a-phenyl-1a-phenylcarbamoyl-hexahydro-1,2-dioxa-5a-aza-cyclopropa[a]inden-3-yl]-3-(R)-hydroxy-butyric acid 
• 148146-51-4 3-<(4-fluorophenyl)carbonyl>-2-(2-methyl-1-oxopropyl)-N,3-diphenyl-2-oxiranecarboxamide 
• 915092-86-3 benzyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate 
• 1353049-81-6 methyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 
• 581772-29-4 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid 
• 345891-62-5 (3R,5R)-methyl 7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate 
• 1146977-93-6 ethyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate 

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Relevant articles and documents

Asymmetric synthesis of (-)-atorvastatin calcium by tandem catalysis

A seven-step synthesis of (-)-atorvastatin calcium, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase, has been developed. The key transformations of the present synthesis are a tandem olefin cross-metathesis/ hemiacetalization/intramolecular oxa-Michael addition and a subsequent regioselective BaeyerVilliger oxidation for the stereocontrolled construction of the syn-3,5-dihydroxy carboxylic acid substructure.

PROCESS FOR THE CONTINUOUS MANUFACTURE OF STATINS

The present invention relates to process for the continuous manufacture of Statins or salts thereof. The present invention relates to process for the continuous manufacture of Atorvastatin or a salt thereof. The present invention relates to a continuous m

AN IMPROVED AND COMMERCIALLY VIABLE PROCESS FOR PREPARATION OF PYRROLE DERIVATIVES WITH IMPROVED IMPURITY PROFILE & MINIMISATION OF UNIT OPERATIONS.

The present invention relates to improved process for the preparation of a pyrrole derivative as a racemic mixture, an enantiomer, a diastereoisomer, a mixture thereof, a tautomer thereof or a pharmaceutically acceptable salt and hydrates thereof and also intermediates involved therein. Particularly invention is directed to improved processes for the preparation of pyrrole derivatives such as (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(1-methyl-ethyl)-pyrrole-1-yl]-2,2-dimethyl-[1,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV followed by its conversion into [R-(R*, R*]-2-(4-fluorophenyl)- β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1- heptanoic acid particularly calcium salt and its hydrate represented by Formulae I/IA respectively wherein formation of the impurities is either eliminated or minimized in the corresponding intermediaries.