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Process for producing simvastatin

A technology for simvastatin and its derivatives, applied in the field of preparation of simvastatin, can solve the problems of unreachable total yield, insufficient reaction selectivity, low yield and productivity, etc.

Inactive Publication Date: 2001-04-04
KANEKA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Above-mentioned method (1) requires high temperature and long-time hydrolysis reaction, so yield and productivity are all lower
Moreover, selective silylation and subsequent steps were not sufficiently selective to achieve the desired overall yield

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Embodiment 1 The method for preparing diol lactone (compound of formula (3))

[0058] To a solution of 300 mL of KOH (7.92 g) in tert-butanol was added 8.09 g (20 mmol) of lovastatin and the mixture was stirred at room temperature under argon for 30 minutes. Then, the temperature was raised, and the mixture was refluxed for 4 hours with stirring. The reaction mixture was concentrated under reduced pressure, added with water, acidified with phosphoric acid (pH=3.5), and extracted with ethyl acetate. The extract was concentrated under reduced pressure to obtain a brown oil. The brown oil was dissolved in 200 ml of isopropyl acetate, and after adding 65 μl (1 mmol) of methanesulfonic acid, it was concentrated to about 1 / 5 volume under reduced pressure. The residue was washed with saturated aqueous sodium bicarbonate solution, cooled to -20°C and stirred. The resulting slurry was filtered and dried under vacuum to yield white crystals. This product was identified as the...

Embodiment 2

[0059] Example 2 Preparation of 2,2-dimethyl-6(R)-(2-(8(S)-hydroxyl-2(S),6(R)-dimethyl-1,2,6,7, 8,8a(R)-hexahydronaphthyl-1(S) ethyl)-(R)-(methoxycarbonyl)methyl-1,3-dioxane (compound of formula (4)) method

[0060] To a solution of diol lactone (1.62 g, 5 mmol) in 25 ml of dichloromethane was added 3.69 ml (30 mmol) of 2,2-dimethoxypropane and 48 mg (0.25 mol) p-toluenesulfonic acid, and the mixture was stirred at room temperature under argon for 1 hour. The reaction mixture was neutralized with pyridine, concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography to obtain a clear oil. This product was identified as the title compound.

[0061] NMR (CDCl 3 , 400MHz) δ: 0.89(d, 3H), 1.1-1.9(m, 16H), 1.2(d, 3H), 2.2-2.6(m, 5H), 3 .65(s, 3H), 3.85(m, 1H), 4.2(m, 1H), 4.3(m, 1H), 5.5(bt, 1H), 5.78(dd, 1H), 6.0(d, 1H)

Embodiment 3

[0062] Example 3 Preparation of 2,2-dimethyl-6(R)-(2-(8(S)-(2,2-dimethylbutyryloxy)-2(S),6(R)- Dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S))ethyl)-4(R)-(methoxycarbonyl)methyl-1,3 - method of dioxane (compound of formula (5))

[0063] 2,2-Dimethyl-6(R)-(2-(8(S)-hydroxy-2(S),6(R)-dimethyl -1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S))ethyl)-4(R)-(methoxycarbonyl)methyl-1,3-diox In alkane (1.96 g, 5 mmol) solution, add 122 mg (1 mmol) of 4-dimethylaminopyridine and 2.69 g (20 mmol) of 2,2-dimethylbutyryl chloride, in The mixture was stirred at 100°C for 6 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added. The organic layer was washed with 10% aqueous citric acid, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a clear oil. This product was identified as the title compound.

[0064] NMR (CDCl 3 , 400MHz) δ: 0.88(t, 3H), 0.89(d, 3H), 1.08(d, 3H), 1.11(s, 3H), 1.12(s,...

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PUM

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Abstract

A convenient, efficient and industrially favorable process for producing simvastatin which is useful as an HMG-coA reductase inhibitor. This process comprises deacylating lovastatin by treating with an inorganic base and a secondary or tertiary alcohol to thereby form diol lactone, and then selectively protecting, acylating, deblocking and lactonizing the diol lactone by using a ketal or acetal protective group to thereby give simvastatin.

Description

technical field [0001] The present invention relates to the method for preparing simvastatin (simvastatin), said method comprises using inorganic base and secondary alcohol or tertiary alcohol to deacylate lovastatin to prepare diol lactone, and make it to ketal or acetal continuously Protecting group selective protection, acylation and deprotection - lactonization. Simvastatin is known as a compound useful as an inhibitor of HMG-CoA reductase. Background of the invention [0002] Known method for preparing simvastatin has: (1) comprises hydrolysis lovastatin with lithium hydroxide, and lactonization makes diol lactone, uses the method for TBDS selective silylation, acylation and desilylation ( USP 4444784), (2) method for direct methylation of lovastatin potassium salt (USP 4582915), and (3) method for direct methylation of lovastatin monoalkylamide (USP 4820850). [0003] The above method (1) requires a high temperature and a long time for the hydrolysis reaction, so the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/30C07D319/06
CPCC07D319/06C07D309/30Y02P20/55
Inventor 田冈直明井上健二
Owner KANEKA CORP
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