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Preparation method of simvastatin ammonium salt

A simvastatin ammonium salt and substrate technology, applied in the field of medicine, can solve the problems of high production cost, large amount of solvent usage, poor stability, etc., and achieve the effects of increased production efficiency, reduced production cost, and simple synthesis process

Active Publication Date: 2014-04-16
ENZYMEWORKS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The existing problems are: 1: The raw material cost of the acyl donor is high; 2: The acyl donor has poor stability in the reaction system, and it is easy to hydrolyze to produce 3-mercaptopropionic acid, which is difficult to recycle, resulting in high cost of the acyl donor; 3: Hydrolysis produces 3-mercaptopropionic acid. The 3-mercaptopropionic acid impurity is easy to remain in simvastatin and degrade the simvastatin product, which affects the quality of the product; 4: The amount of solvent used is large, the production cost is high, and the market competitiveness of the product is limited

Method used

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  • Preparation method of simvastatin ammonium salt
  • Preparation method of simvastatin ammonium salt
  • Preparation method of simvastatin ammonium salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] In a 50 mL three-necked flask, add 3 g of monacolin J acid (8.86 mmol, 1 eq), 30 mL of deionized water, and then add 1.81 g of ammonia (25% concentration by mass, 26.6 mmol, 3 eq). Adjust pH with 6M concentrated hydrochloric acid=8.6~8.9. Add 9.5mL recombinant acyltransferase enzyme solution, add 2,2-dimethylbutanoic acid-2-mercaptoethoxyacetate (2.9g, 13.3mmol, 1.5eq), 6M concentrated hydrochloric acid to adjust pH=8.6~ 8.9. The reaction process was monitored by HPLC, the reaction was 48 hours, and the conversion rate was 98.2%.

[0053] The reaction solution was centrifuged to obtain a solid. The solid was added to 20 mL of acetone for 4 hours to be slurried. The solid was dried under vacuum (40 degrees Celsius) to obtain a white crystalline product weighing 3.32 g, purity 97.9%, content 97.1%, yield 80.3 %.

Embodiment 2

[0055] In a 50 mL three-necked flask, add 3 g of monacolin J acid (8.86 mmol, 1 eq), 30 mL of deionized water, and then add 1.81 g of ammonia (25% concentration by mass, 26.6 mmol, 3 eq). 6M concentrated hydrochloric acid adjusts pH=8.6~8.9. Add activated carbon (100~200 mesh), add 3.17mL recombinant acyltransferase enzyme solution, add 2,2-dimethylbutyric acid-2-mercaptoethoxyacetate (2.9g, 13.3mmol, 1.5eq) , 6M concentrated hydrochloric acid adjust pH=8.6~8.9. The reaction process was monitored by HPLC, the reaction was 24 hours, and the conversion rate was 99.1%.

[0056] The reaction solution was centrifuged to obtain a solid. Add the solid to 15 mL of methanol, dissolve it at 40-50°C and then filter. The filtrate is concentrated to obtain a solid. After drying under vacuum (40°C), the white crystalline product weighs 3.45 g and has a purity of 98.5%. The content is 98.2%, and the yield is 82.0%.

Embodiment 3

[0058] In a 50 mL three-necked flask, add 3 g of monacolin J acid (8.86 mmol, 1 eq), 30 mL of deionized water, and then add 1.81 g of ammonia (25% concentration by mass, 26.6 mmol, 3 eq). Adjust pH with 6M concentrated hydrochloric acid=9.5~9.8. Add activated carbon (100~200 mesh), add 3.17mL recombinant acyltransferase enzyme solution, add 2,2-dimethylbutyric acid-2-mercaptoethoxyacetate (2.9g, 13.3mmol, 1.5eq) , 6M concentrated hydrochloric acid adjusts pH=9.5~9.8. The reaction process was monitored by HPLC. After 24 hours of reaction, the conversion rate was 99.3%.

[0059] The reaction solution was centrifuged to obtain a solid. The solid was added to 15 mL of methanol, dissolved at 40-50°C and then filtered. The filtrate was concentrated to obtain a solid, which was dried under vacuum (40°C) to obtain a white crystalline product weighing 3.63 grams with a purity of 99.5%. The content is 98.6%, and the yield is 89.1%.

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Abstract

The invention relates to a preparation method of a simvastatin ammonium salt. A substrate monacolin J acid, 2,2-dimethylbutyric acid-2-sulfhydrylethoxyacetate and ammonia water react under the pH value of 8.5-10 under the action of recombinant acyltransferase to generate the simvastatin ammonium salt, wherein the mass ratio of the monacolin J acid to the 2,2-dimethylbutyric acid-2-sulfhydrylethoxyacetate is 1:(0.6-1). The 2,2-dimethylbutyric acid-2-sulfhydrylethoxyacetate, which has the advantages of low addition amount and cheap synthesis raw material and is easy to synthesize, is used as an acyl donor for synthesizing the simvastatin side chain, so the method obviously lowers the production cost and has important use value.

Description

Technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a preparation method of simvastatin ammonium salt. Background technique [0002] Simvastatin, the trade name is Zocor, the English name is Simvastatin, and the chemical name is 2,2-dimethylbutyrate 1,2,3,7,8,8α-hexahydro-3,7- Dimethyl-8-[2-[tetrahydro-4-hydroxy-6-oxy-2H-pyran-2]ethyl]-1-naphthalene [0003] (2,2-dimethyl-Butanoic acid1,2,3,7,8,8α-hexahydro-3,7-dimethyl-8-[2- [0004] (Tetrahydro-4-hydroxy-6-oxo-2-H-pyran-2-yl)ethyl]-1-naphthol ester). The molecular formula is C 25 H 38 O 5 , The molecular weight is 418.57, and the structural formula is [0005] [0006] Simvastatin ammonium salt, the English name is Simvastatin ammonium salt, and the chemical name is (3R,5R)-7-[(1S,2S,6R,8S,8aR)-8-(2,2-dimethylbutanoyloxy) (Base)-1,2,6,7,8,8a-hexahydro-2,6-dimethyl-1-naphthyl]-3,5-dihydroxyheptanoate; [0007] ((3R,5R)-7-[(1S,2S,6R,8S,8aR)-8-(2,2-dimethylbutyryloxy)-1,2,6,7,8...

Claims

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Application Information

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IPC IPC(8): C12P17/06
Inventor 李斌邓阳生陶军华
Owner ENZYMEWORKS
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