A method for preparing rosustatin and pitavastatin 2,6-diene enanthate compound

A technology of diene enanthate and pitavastatin, which is applied in the field of preparation of rosustatin and pitavastatin 2,6-diene enanthate compound, can solve the problem of expanding the application of limited drugs, complex process routes, Low preparation yield and other problems, to achieve the effect of short and easy synthetic route, high product yield and easy operation

Active Publication Date: 2022-04-12
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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  • A method for preparing rosustatin and pitavastatin 2,6-diene enanthate compound
  • A method for preparing rosustatin and pitavastatin 2,6-diene enanthate compound
  • A method for preparing rosustatin and pitavastatin 2,6-diene enanthate 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 2,6-diene heptanoate compound:

[0036] 1. Preparation of rosuvastatin 2,6-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 600 mL of ice water, stir, add sodium hydroxide (7.5 g, 189 mmol, 3.0 eq), stir for 10 min, react with diethyl ether (300 mL×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 2...

Embodiment 3

[0049] Preparation of pitavastatin 2,6-diene heptanoate compound:

[0050] 1. Preparation of pitavastatin 2,6-diene heptanoic acid intermediate:

[0051] In a 1000mL reaction flask, add pitavastatin acid (45g, 107mmol, 1.0eq) and 400mL tetrahydrofuran, stir to dissolve, cool to 5-10°C, add potassium tert-butoxide (24g, 214mmol, 2.0eq ). After dropping, the temperature was raised to room temperature for reaction, and the reaction was monitored by TLC. After the reaction was completed, the reaction solution was poured into 600 mL of ice water, stirred, reacted with diethyl ether (300 mL×1), the organic layer was discarded, the pH of the aqueous layer was adjusted to neutral with 2N hydrochloric acid solution, and extracted 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 2,6-diene heptanoic acid intermediate prod...

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Abstract

The invention discloses a method for preparing rosustatin and pitavastatin 2,6-diene enanthate compound, which comprises (4R,6S)-6-[(1E)-2-[4-(4- Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)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 was used as the starting material of rosuvastatin and pitavastatin respectively, and statinic acid was prepared by deprotection and hydrolysis in one step; As the reaction substrate, the 2,6-diene heptanoate compound was prepared through two steps of dehydration and substitution. The preparation and synthesis routes of rosuvastatin and pitavastatin 2,6-diene heptanoate involved in the present invention are short and easy to operate, easy to operate, high in product yield, and more suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for preparing rosustatin and pitavastatin 2,6-diene enanthate 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 hypercholestero...

Claims

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Application Information

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Patent Type & Authority Patents(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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