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A method for synthesizing pitavastatin tert-butyl ester
Active Publication Date: 2022-05-17
CHUZHOU QINGYUN PHARM CO LTD
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[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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[0053] Under nitrogen protection, 160g (1.5mol, 3.0eq) of sodiumcarbonate, (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: petroleumether: 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 potassiumcarbonate, (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: petroleumether: 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
This invention discloses a method for synthesizing pitavastatin tert-butyl ester, comprising the following steps: (4R-Cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester reacts with substance A under the action of a first base catalyst to obtain substance B; then, it is oxidized by an oxidant to obtain substance C; then, it reacts with 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carboxaldehyde under the action of a second base catalyst to obtain substance D; finally, it is deprotected by acid to obtain pitavastatin tert-butyl ester. The reaction conditions of this invention are mild and controllable, the reaction conditions for the synthesis of Jurlique olefins do not require ultra-low temperature reactions, the operation is convenient and simple, the stereoselectivity is good, the yield is high, and the synthesized pitavastatin tert-butyl ester is completely free of cis isomers and has high 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] PitavastatinCalcium 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 bloodcholesterol 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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