Method for preparing rosuvastatin and pitavastatin 2, 5-diene heptanoate compound

A technology of diene enanthate and pitavastatin, which is applied in the field of preparation of rosustatin and pitavastatin 2,5-diene enanthate compound, which can solve the problems of expanding the application of drugs, complicated process routes, Poor operability and other problems, to achieve the effect of short and easy synthetic route, high product yield and easy operation

Active Publication Date: 2020-05-05
NANTONG CHANGYOO PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The synthetic process route of rosuvastatin, pitavastatin and their analogs in the prior art is complicated, the operability is poor, and the preparation rate is low, these problems limit the expanded application of this type of drug

Method used

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  • Method for preparing rosuvastatin and pitavastatin 2, 5-diene heptanoate compound
  • Method for preparing rosuvastatin and pitavastatin 2, 5-diene heptanoate compound
  • Method for preparing rosuvastatin and pitavastatin 2, 5-diene heptanoate compound

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Preparation of rosuvastatin acid:

[0029]

[0030] In a 1000mL reaction flask, add (4R,6S)-6-[(1E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino ]-5-pyrimidine]vinyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester (45g, 78mmol, 1.0eq) and 400mL tetrahydrofuran, stirred and dissolved, cooled to At 5-10°C, acetic acid (4.7g, 78mmol, 1.0eq) was slowly added dropwise. After dropping, the temperature was raised to 30-35°C for reaction, and the reaction was monitored by TLC. After the reaction was completed, the temperature was lowered to 5-10° C., and 98 mL of 2N lithium hydroxide solution (195 mmol, 2.5 eq) was added dropwise. After dropping, the temperature was raised to 30-35°C for reaction, and the reaction was monitored by TLC. After the reaction was completed, the temperature was lowered to room temperature, and the pH was adjusted to nearly neutral with 1N hydrochloric acid solution. Part of the solvent was distilled off under reduc...

Embodiment 2

[0035] Preparation of rosuvastatin 2,5-diene heptanoate compound:

[0036] 1. Preparation of rosuvastatin 2,5-diene heptanoic acid intermediate:

[0037] In a 500mL reaction flask, add rosuvastatin acid (30g, 63mmol, 1.0eq) and 300mL tetrahydrofuran, stir to dissolve, cool down to 5-10°C, slowly add sulfuric acid (12.3g, 126mmol, 2.0eq) dropwise under nitrogen protection . After dropping, the temperature was raised to room temperature for reaction, and the reaction was monitored by TLC. After the reaction is complete, pour the reaction solution into 600mL ice water, stir, add sodium hydroxide (7.5g, 189mmol, 3.0eq), stir for 10min, react with ether (300mL×1), discard the organic layer, and wash the aqueous layer with 2N Adjust the pH to neutral with sodium hydroxide solution, extract with ethyl acetate (200mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to obtain 24.3g of rosuvasta...

Embodiment 3

[0049] Preparation of pitavastatin 2,5-diene heptanoate compound:

[0050] 1. Preparation of pitavastatin 2,5-diene heptanoic acid intermediate:

[0051] In a 1000mL reaction flask, add pitavastatin acid (45g, 107mmol, 1.0eq) and 400mL tetrahydrofuran, stir to dissolve, cool down to 5-10°C, add potassium tert-butoxide (24g, 214 mmol, 2.0 eq). After dropping, the temperature was raised to room temperature for reaction, and the reaction was monitored by TLC. After the reaction is complete, pour the reaction solution into 600 mL of ice water, stir, react with diethyl ether (300 mL×1), discard the organic layer, adjust the pH of the aqueous layer to neutral with 2N hydrochloric acid solution, and extract with ethyl acetate (200 mL×3) , the organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain 35.3 g of pitavastatin 2,5-diene heptanoic acid intermediate product, with a yield of ...

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Abstract

The invention discloses a method for preparing rosuvastatin and pitavastatin 2, 5-diene heptanoate compound. (4R, 6S)-6-[(1E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methanesulfonyl)amino]-5-pyrimidine] vinyl]-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate and (4R, 6S)-6-[[(1E)-2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl] vinyl]-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate are respectivelytaken as starting materials of rosuvastatin and pitavastatin, deprotection and a hydrolyzation one-step method is adopted to prepare statin acid, then the statin acid is taken as a reaction substratefor dehydration and substitution two-step reaction to prepare the 2, 5-diene heptanoate compound. The preparation and synthesis routes of rosuvastatin and pitavastatin 2, 5-diene heptanoate involved in the invention are short and feasible, the operation is simple and convenient, the product yield is high, and the rosuvastatin and pitavastatin 2, 5-diene heptanoate is more suitable for large-scaleindustrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for preparing rosustatin and pitavastatin 2,5-diene heptanoate compounds. Background technique [0002] Rosuvastatin Calcium is the latest statin drug approved by AstraZeneca in Europe in 2002 for the treatment of primary and familial hypercholesterolemia and mixed dyslipidemia. It was approved for marketing in the United States in August 2003, thus becoming the seventh statin drug to enter the market. Its chemical name is: (3R,5S,6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonamido)-5- Calcium pyrimidine]-3,5-dihydroxy-6-heptenoate. The structure looks like this: [0003] [0004] Pitavastatin Calcium is a third-generation statin lipid-lowering drug jointly developed and produced by Nissan Chemical Industry Co., Ltd. and Kowa Co., Ltd. This product has been launched in Japan in October 2003, and it is used for the treatment of primary hypercholester...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42C07D215/14
CPCC07D239/42C07D215/14
Inventor 李泽标黄虎祁晓庆潘婧邹林
Owner NANTONG CHANGYOO PHARMATECH CO LTD
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