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Preparation method of atorvastatin calcium

A technology of atorvastatin calcium and intermediates, applied in the field of drug synthesis, can solve the problems of high environmental toxicity, increase and synthesis cost, expensive dosage, etc., and achieve the effect of good operation safety performance, low cost, and low reagent price

Inactive Publication Date: 2015-05-27
BAODING LONGRUI PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method requires the use of expensive chiral catalysts with a large amount, which increases the cost of synthesis and uses liquid bromine as an oxidant, which is highly toxic to the environment.

Method used

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  • Preparation method of atorvastatin calcium
  • Preparation method of atorvastatin calcium
  • Preparation method of atorvastatin calcium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] (1) Synthesis of intermediate (1)

[0031] Under the protection of nitrogen, 418 g (1 mol) of 5-methyl-2-phenyl-1-(4-fluorophenyl)-3-(phenylcarbamoyl)-1,4-hexanedione, 2-( 140g (1.2mol) of 2-aminoethyl)-1,3-dioxolane was added to 1000mL of tetrahydrofuran, the equivalent of pivalic acid was added dropwise, heated to reflux for 8h, the solvent was evaporated under reduced pressure, and the solid obtained was acetone -Ethyl acetate (1:1) was recrystallized to obtain 359 g of intermediate (1), with a yield of 72%. Characterization data:

[0032] m.p: 159-160°C. 1 H NMR(CDCl 3 , 400MHz) δ: 1.54 (d, 6H, J = 7Hz), 1.91 (m, 2H), 3.60 (sep, 1H, J = 7Hz), 3.7-4.1 (m, 6H), 4.74 (t, 1H, J = 4.3 Hz), 7.0-7.3 (m, 15H); LC-MS (m / z): 394 (M+1).

[0033] (2) Synthesis of intermediate (2)

[0034] Intermediate (1) 300g (0.6mol) was added to 1000mL methanol, 50mL 37% concentrated hydrochloric acid was added dropwise, stirred at room temperature for 3h, 0~5℃ was added dropwise 20% NaOH solutio...

Embodiment 2

[0046] (1) Synthesis of intermediate (1)

[0047] Under the protection of nitrogen, 418 g (1 mol) of 5-methyl-2-phenyl-1-(4-fluorophenyl)-3-(phenylcarbamoyl)-1,4-hexanedione, 2-( 140g (1.2mol) of 2-aminoethyl)-1,3-dioxolane was added to 1000mL of methyl tert-butyl ether, the equivalent of acetic acid was added dropwise, heated to reflux for 8h, and the solvent was evaporated under reduced pressure. The solid was recrystallized with acetone-ethyl acetate (1:1) to obtain intermediate (1) with a yield of 70%.

[0048] (2) Synthesis of intermediate (2)

[0049] Intermediate (1) 300g (0.6mol) was added to 1000mL methanol, 50mL 37% concentrated hydrochloric acid was added dropwise, stirred at room temperature for 3h, 0~5℃ was added dropwise 20% NaOH solution to adjust pH 6~7, 1000mL of formazan was added with stirring Butyl tert-butyl ether, let stand overnight, a large amount of solid precipitated, filtered, washed, and dried under vacuum to obtain intermediate (2) (3-[2-(4-fluorophenyl...

Embodiment 3

[0060] (1) Synthesis of intermediate (1)

[0061] Under the protection of nitrogen, 418 g (1 mol) of 5-methyl-2-phenyl-1-(4-fluorophenyl)-3-(phenylcarbamoyl)-1,4-hexanedione, 2-( 140g (1.2mol) of 2-aminoethyl)-1,3-dioxolane was added to 1000mL of dioxane, and the equivalent of formic acid (or propionic acid, butyric acid) was added dropwise, heated to reflux for 8h, and reduced pressure The solvent was evaporated, and the obtained solid was recrystallized with acetone-ethyl acetate (1:1) to obtain intermediate (1) with a yield of 73%.

[0062] (2) Synthesis of intermediate (2)

[0063] Intermediate (1) 300g (0.6mol) was added to 1000mL methanol, 50mL 37% concentrated hydrochloric acid was added dropwise, stirred at room temperature for 3h, 0~5℃ was added dropwise 20% NaOH solution to adjust pH 6~7, 1000mL of formazan was added with stirring Butyl tert-butyl ether, let stand overnight, a large amount of solid precipitated, filtered, washed, and dried under vacuum to obtain intermedi...

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Abstract

The invention relates to a preparation method of atorvastatin calcium. The method comprises the steps that 5-methyl--2-benzene-1-(4-fluorophenyl)-3-(phenyl amine formyl)-1,4-hexanedione as a starting material, and subjected to cyclization, hydrolysis, aldol condensation, asymmetric hydrogenation, resolution and salifying reaction, and atorvastatin calcium is obtained. The method is short in synthetic route, rich in raw material source, easy and simple to operate and mild in reaction condition and has a good industrialization prospect.

Description

Technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of atorvastatin calcium, a blood lipid-lowering drug. Background technique [0002] The chemical name of atorvastatin calcium is (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(aniline formyl)-pyrrole-1 -Yl]-3,5-dihydroxyheptanoate calcium salt (2:1), the trade name is Lipitor, and the structural formula is as follows: [0003] [0004] There are two sources of cholesterol in plasma, endogenous and exogenous. Exogenous cholesterol is mainly derived from food, so the intake of cholesterol can be controlled by adjusting the diet; endogenous cholesterol is obtained in the liver through 26-step reactions with acetic acid as the starting material, among which 3-hydroxy-3-methylpentan Diacyl-CoA (HMG-CoA) reductase is the rate-limiting enzyme in the synthesis process. Atorvastatin can selectively and competitively inhibit HMG-CoA reductase, so it can effectively in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/34
Inventor 张月忠赵俊女张志媛
Owner BAODING LONGRUI PHARMA TECH
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