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Preparation method of atorvastatin intermediate (3R, 5S)-7-amino-3,5-O-isopropylidene-3,5-dyhydroxyl heptylic acid tert-butyl acetate

A technology of tert-butyl hydroxyheptanoate and atorvastatin is applied in the field of preparation of chiral drug intermediates, can solve the problems of many reaction by-products, high industrialization cost, low synthesis efficiency, etc., achieves easy industrialized production and reduces side effects Effects of reaction, improved yield and product purity

Active Publication Date: 2013-11-06
湖北楚维药业有限公司 +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] The present invention aims at the defects in the prior art of intermediate (R)-(-)-4-cyano-3-hydroxybutyrate ethyl ester with low synthetic efficiency, long process route, many reaction by-products and high industrialization cost, etc., and provides a Method for preparing atorvastatin intermediate (3R,5R)-7-amino-3,5-O-isopropylidene-3,5-dihydroxyheptanoic acid tert-butyl ester by using (R)-epichlorohydrin as raw material

Method used

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  • Preparation method of atorvastatin intermediate (3R, 5S)-7-amino-3,5-O-isopropylidene-3,5-dyhydroxyl heptylic acid tert-butyl acetate
  • Preparation method of atorvastatin intermediate (3R, 5S)-7-amino-3,5-O-isopropylidene-3,5-dyhydroxyl heptylic acid tert-butyl acetate
  • Preparation method of atorvastatin intermediate (3R, 5S)-7-amino-3,5-O-isopropylidene-3,5-dyhydroxyl heptylic acid tert-butyl acetate

Examples

Experimental program
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Effect test

Embodiment 1

[0032] 1. Add 73.2g nitromethane and 92.5g R-propylene oxide into the reaction flask, feed 1.0g boron trifluoride gas, stir and react at 20°C for 5 hours, detect with gas chromatography, when R-epoxy After the complete conversion of chloropropane, the unreacted nitromethane was removed under reduced pressure to obtain 137.7 g of light yellow oily liquid. 1 H-NMR and MS confirm that it is 1-chloro-4-nitro-(R)-2-butanol, the yield is 90.1%, and the content is 98.0%.

[0033]2. Add 153g of 1-chloro-4-nitro-(R)-2-butanol prepared in step (1), 200ml of 95% ethanol and 500ml of water into the reaction flask, and start adding 30% sodium cyanide dropwise at 0°C The solution is 196g, the reaction is exothermic, the dropwise addition temperature is controlled at 15±5°C, and the dropwise addition is completed in 8 hours. After the dropwise addition, react at a temperature of 15±5°C, and stop the reaction when the reaction of 1-chloro-4nitro-(R)-2-butanol is detected by gas chromatograph...

Embodiment 2

[0040] 1. Add 73.2g of nitromethane and 92.5g of R-epoxypropylene into the reaction flask, pass through 2.5g of hydrogen chloride, stir and react at 0°C for 8 hours, detect with gas chromatography, when the R-epoxychlorohydrin is completely converted Rear unreacted nitromethane was removed under reduced pressure to obtain 134.6 g of light yellow oily liquid, and the product structure was verified by 1 H-NMR and MS confirm that it is 1-chloro-4-nitro-(R)-2-butanol, the yield is 88.0%, and the content is 98.4%.

[0041] 2. Add 153g of 1-chloro-4nitro-(R)-2-butanol prepared in step (1), 200ml of 95% ethanol and 500ml of water into the reaction flask, raise the temperature to 50°C, and start adding 30% cyanide dropwise 196g of sodium chloride solution, the reaction is exothermic, the dropwise addition temperature is controlled at 50±5°C, and the dropwise addition is completed in 2 hours. After the dropwise addition, control the temperature at 50±5°C, and stop the reaction when t...

Embodiment 3

[0048] 1. Add 73.2g of nitromethane and 92.5g of R-epoxypropane into the reaction flask, pass through 2.5g of hydrogen chloride, stir and react at 50°C for 8 hours, detect with gas chromatography, when the R-epoxychlorohydrin is completely converted Rear unreacted nitromethane was removed under reduced pressure to obtain 141.0 g of light yellow oily liquid, and the product structure was verified by 1 H-NMR and MS confirmed that it was 1-chloro-4-nitro-(R)-2-butanol, the yield was 92.3%, and the content was 98.7%.

[0049] 2. Add 153g of 1-chloro-4nitro-(R)-2-butanol prepared in step (1), 200ml of 95% ethanol and 500ml of water into the reaction flask, raise the temperature to 50°C, and start adding 30% cyanide dropwise 196g of sodium chloride solution, the reaction is exothermic, the dropwise addition temperature is controlled at 55±5°C, and the dropwise addition is completed in 2 hours. After the dropwise addition, the temperature was raised to 80°C for reaction, and the rea...

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Abstract

The invention discloses a preparation method of an atorvastatin intermediate (3R, 5S)-7-amino-3,5-O-isopropylidene-3,5-dyhydroxyl heptylic acid tert-butyl acetate. The method comprises the following steps of: reacting (S)-epichlorohydrin and nitromethane to generate 1-chlorine-4-nitryl-(S)-2-butanol, and reacting with sodium cyanide to obtain (S)-3-hydroxyl-5-nitryl-valeronitrile; dropwise adding the product into a tert-butyl bromoacetate zinc reagent to generate 7-nitryl-5-hydroxyl-3-carbonyl-heptylic acid tert-butyl acetate; reacting with sodium borohydride to generate 7-nitryl-3,5-dyhydroxyl-heptylic acid tert-butyl acetate; reacting with 2,2-dimethoxypropane, acetone and methanesulfonic acid to obtain 7-nitryl-3,5-O-isopropylidene-3,5-dyhydroxyl-heptylic acid tert-butyl acetate; and obtaining (3R, 5S)-7-amino-3,5-O-isopropylidene-3,5-dyhydroxyl heptylic acid tert-butyl acetate by hydrogen reduction. The yield of the product is 80-86%, and the purity of the product is greater than or equal to 99.0%.

Description

technical field [0001] The invention relates to a preparation method of a chiral drug intermediate, in particular to atorvastatin intermediate (3R,5R)-7-amino-3,5-O-isopropylidene-3,5-dihydroxyheptanoic acid tertiary The preparation method of butyl ester belongs to the field of medicine and chemical industry. Background technique [0002] Statins are currently the world's best-selling lipid-regulating drugs, and are a class of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors. Studies at the molecular level of cardiovascular diseases have shown that HMG-CoA reductase is the rate-limiting enzyme for cholesterol biosynthesis, and factors that affect the synthesis or functional expression of this enzyme can effectively inhibit cholesterol synthesis. Statins inhibit the synthesis of cholesterol by inhibiting the combination of HMG-CoA reductase and substrate. At the same time, statins can also reduce low-density lipoprotein and triglyceride and increase high-density lip...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D319/06
Inventor 熊绪杰熊进军何年兵
Owner 湖北楚维药业有限公司
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