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Method for preparing monacolin J

A technology for monacolin and lovastatin is applied in the new process field for preparing monacolin J, which can solve the problems of high cost, cumbersome process steps and the like, and achieve the effects of low cost, simple process steps and less environmental harm

Inactive Publication Date: 2012-07-04
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The purpose of the present invention is to provide a new preparation process of monacolin J, to overcome the high cost caused by complex process steps in the prior art and the EHS pressure brought by the use of toxic solvents such as methanol in the production process

Method used

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  • Method for preparing monacolin J
  • Method for preparing monacolin J
  • Method for preparing monacolin J

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Weigh 100 g of Aspergillus terreus obtained by plate and frame filtration after fermentation, add 800 mL of ethanol, stir at 75° C. for 30 min, cool to room temperature, and then filter. The filtrate was concentrated under reduced pressure, and ethanol was recovered. The obtained concentrate contained 8.91 g of lovastatin (lactone type). Dissolve 40g of sodium hydroxide in 200mL of water, dissolve completely and add to the concentrate. The reaction was stirred at 83 °C for 12 h. The conversion rate of lovastatin was 100%. Concentrated hydrochloric acid was added dropwise to 200 mL of the reaction liquid in an ice-water bath to adjust the pH to 3.5, and stirred for 30 min. Subsequently, an equal volume of ethyl ester was added to extract for 3 times, dried by adding anhydrous sodium sulfate, and then concentrated under reduced pressure. 7.17 g of monacolin J in trihydroxy acid form (ring-opening acid form) was obtained with a yield of 96.24%.

Embodiment 2

[0041] Weigh 100 g of Aspergillus terreus obtained by plate and frame filtration after fermentation, add 800 mL of ethanol, stir at 25° C. for 30 min, cool to room temperature and filter. The filtrate was concentrated under reduced pressure, and ethanol was recovered. The obtained concentrate contains 8.54 g of lovastatin (lactone type). Dissolve 60g of sodium hydroxide in 200mL of water, dissolve completely and add to the concentrate. The reaction was stirred at 75 °C for 6 h. The conversion rate of lovastatin was 99.46%. Concentrated hydrochloric acid was added dropwise to 200 mL of the reaction liquid in an ice-water bath to adjust the pH to 4.0, and stirred for 30 min. Subsequently, an equal volume of ethyl ester was added to extract for 3 times, dried by adding anhydrous sodium sulfate, and then concentrated under reduced pressure. 6.83 g of monacolin J in trihydroxy acid form (ring-opening acid form) was obtained with a yield of 95.66%.

Embodiment 3

[0043]Weigh 100 g of Aspergillus terreus obtained by plate and frame filtration after fermentation, add 1200 mL of ethanol, stir at 55° C. for 30 min, cool to room temperature and filter. The filtrate was concentrated under reduced pressure, and ethanol was recovered. The obtained concentrate contained 9.14 g of lovastatin (lactone type). Dissolve 30g of sodium hydroxide in 200mL of water, dissolve completely and add to the concentrate. The reaction was stirred at 80 °C for 37 h. The conversion rate of lovastatin was 98.82%. Concentrated hydrochloric acid was added dropwise to 200 mL of the reaction liquid in an ice-water bath to adjust the pH to 4.0, and stirred for 30 min. Subsequently, an equal volume of ethyl ester was added to extract for 3 times, dried by adding anhydrous sodium sulfate, and then concentrated under reduced pressure. 7.08 g of monacolin J in trihydroxy acid form (ring-opening acid form) was obtained with a yield of 92.59%.

[0044] The NMR data of mo...

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Abstract

The invention discloses a method for preparing monacolin J. A lovastatin production bacterium Aspergillus terreus is used as an initial bacterium to prepare an important precursor monacolin J for synthesizing a cardiovascular drug simvastatin. The yield of the monacolin J is greater than 95%; compared with the monacolin J preparation technique reported at present, the invention does not use methanol or any other toxic solvent, and thus, satisfies the requirements of EHS (Environment, Health and Safety); the lovastatin fermentation mycelium serving as a raw material is treated to directly obtain the monacolin J without extracting the lovastatin pure product, thereby simplifying the technique, lowering the production cost and being applicable to industrial production.

Description

technical field [0001] The invention relates to the field of chemical pharmacy, in particular, the invention relates to a new process for preparing monacolin J. Background technique [0002] Monacolin J is the main precursor for the synthesis of the cardiovascular drug simvastatin. It has two forms of lactone and trihydroxy acid, and the specific structure is: [0003] [0004] I lactone form II trihydroxy acid form [0005] There are two main routes for the synthesis of simvastatin: [0006] One is to directly methylate lovastatin by chemical method to obtain simvastatin; the other is to combine 2,2-dimethylbutyryl to the hydroxyl group at the C8 position of monacolin J by chemical or biological methods to obtain simvastatin statins. [0007] The method reported in U.S. Patent US 2009 / 0191602A1: the acyltransferase expressed by LovD can efficiently and specifically bind 2,2-dimethylbutyryl to the hydroxyl group at the C8 position of monacolin J to obtain simvastatin....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/06
Inventor 孙鹏杨仲毅甘春晖杨勇许海霞白骅
Owner ZHEJIANG HISUN PHARMA CO LTD
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