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Synthetic method of pitavastatin tert-butyl ester

A technology of pitavastatin tert-butyl ester and a synthesis method, which is applied in the field of synthesis of pitavastatin tert-butyl ester, can solve the problems of unsuitability for industrial production, incomplete oxidation of intermediates, poor stereoselectivity, etc., and achieves small steric hindrance. , the reaction conditions are mild and controllable, and the stereoselectivity is good.

Active Publication Date: 2020-11-03
ANHUI QINGYUN PHARMA & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In summary, the current synthetic method of pitavastatin tert-butyl ester mainly has poor stereoselectivity, harsh reaction conditions, incomplete oxidation of intermediates, multiple column chromatography is required, low yield, and is not suitable for industrialization Production

Method used

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  • Synthetic method of pitavastatin tert-butyl ester
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  • Synthetic method of pitavastatin tert-butyl ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Embodiment 1 (R is a methyl group)

[0053] Under nitrogen protection, 160g (1.5mol, 3.0eq) of sodium carbonate, (4R-Cis)-6-chloromethyl-2,2-dimethyl-1,3- Dioxolane-4-acetic acid tert-butyl ester 139.5g (0.5mol, 1.0eq), 1,4-dioxane 700g, 2-mercapto 5-methyl 1,3,4-thiadiazole 79g (0.6 mol, 1.2eq) to start stirring, slowly raise the temperature to 80°C, stir and react for 6h, take a sample for TLC (developing solvent: petroleum ether: ethyl acetate = 1:1v / v) to detect the complete conversion of raw materials, then concentrate under reduced pressure to remove the solvent 1 , 4-dioxane, add 500mL of water, 500mL of ethyl acetate, continue to stir for 15 minutes, then stand for layering, separate the organic phase, extract the water phase with 500mL of ethyl acetate x 2, and combine the organic phases. Concentrate to brown-black oily substance B

[0054] 195g (with a small amount of solvent), the purity is 93.7%. Not purified, directly used in the next oxidation reaction;...

Embodiment 2

[0059] Embodiment 2 (R is phenyl)

[0060] Under nitrogen protection, 207g (1.5mol, 3.0eq) of potassium carbonate, (4R-Cis)-6-chloromethyl-2,2-dimethyl-1,3- Dioxolane-4-acetic acid tert-butyl ester 139.5g (0.5mol, 1.0eq), N,N-dimethylformamide 700g, 2-mercapto 5-phenyl 1,3,4-thiadiazole 116g ( 0.6mol, 1.2eq), start stirring, slowly raise the temperature to 80°C, stir and react for 6 hours, take a sample for TLC (developing solvent: petroleum ether: ethyl acetate = 1:1v / v) to detect the complete conversion of raw materials, then concentrate under reduced pressure to remove the solvent N,N-Dimethylformamide, add 500mL of water, 500mL of ethyl acetate, continue to stir for 15 minutes, then stand for layering, separate the organic phase, extract the water phase with 500mL of ethyl acetate*2, and combine the organic phases. Concentration gave 225 g of substance B (with a small amount of solvent) in a brownish-black oily substance with a purity of 94.7%. Not purified, directly use...

Embodiment 3

[0065] The substituent R of substance A is cyclopropyl, and other conditions and charging ratio are the same as in Example 1.

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Abstract

The invention discloses a synthesis method of pitavastatin tert-butyl ester, which comprises the following steps: carrying out a reaction on (4R-Cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxolane-4-tert-butyl acetate with a substance A under the action of a first base catalyst to obtain a substance B; oxidizing the substance B with an oxidizing agent to obtain a substance C; carrying out a reaction with 2-Cyclopropyl-4-(4-fluorophenyl)-quinoline-3-formaldehyde under the action of a second base catalyst to obtain a substance D; and finally, performing acid deprotection to obtain the pitavastatin tert-butyl ester. The method has the advantages of mild and controllable reaction conditions, wherein the reaction conditions of Julia olefination are free of requirement of ultralow-temperature reaction, so that the synthesis method has advantages of convenience and simplicity in operation, good stereoselectivity and high yield, and the synthesized pitavastatin tert-butyl ester is completely free of cis-isomer and high in purity.

Description

[0001] field of invention [0002] The invention belongs to the field of chemical synthesis, and in particular relates to a synthetic method of pitavastatin tert-butyl ester. Background technique [0003] Pitavastatin Calcium is the first fully synthetic HMG-CoA reductase inhibitor jointly developed by Nissan Chemical and Kowa Co., Ltd., which belongs to statin drugs. It mainly reduces the liver's ability to produce cholesterol by inhibiting a liver enzyme called HMG-CoA reductase, thereby improving elevated blood cholesterol levels. 6-[[(1E)-2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-vinyl]-2,2-dimethyl-1,3-dioxahexa Tert-butyl cyclo-4-acetate is referred to as pitavastatin tert-butyl ester, which is the key intermediate of pitavastatin calcium. In the existing synthetic routes of pitavastatin calcium, most of them need to synthesize this intermediate. [0004] The synthetic route of pitavastatin tert-butyl ester mainly contains following several at present: [0005] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/14
CPCC07D215/14B01J31/0212B01J31/121B01J31/0274B01J23/28B01J23/30B01J27/232B01J27/24B01J31/122B01J31/128B01J2531/11B01J2531/12
Inventor 黄欢李凯黄庆云詹福明黄庆国
Owner ANHUI QINGYUN PHARMA & CHEM
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