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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, which is applied in the field of preparation of chiral pharmaceutical intermediates, can solve the problems of high industrialization cost, many reaction by-products, long process routes, etc., and achieve easy industrial production and reduce by-products. The effect of simple reaction and synthesis process conditions

Active Publication Date: 2012-03-28
湖北楚维药业有限公司 +1
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  • Summary
  • 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, 5S)-7-amino-3,5-O-isopropylidene-3,5-dihydroxyheptanoic acid tert-butyl ester using (S)-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
Comparison scheme
Effect test

Embodiment 1

[0032] 1. Add 73.2g of nitromethane and 92.5g of S-propylene oxide into the reaction flask, feed 1.0g of boron trifluoride gas, stir and react at 20°C for 5 hours, detect with gas chromatography, when S-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 It was confirmed by H-NMR and MS to be 1-chloro-4-nitro-(S)-2-butanol with a yield of 90.1% and a content of 98.0%.

[0033]2. Add 153g of 1-chloro-4nitro-(S)-2-butanol prepared in step (1), 200ml of 95% ethanol and 500ml of water in the reaction flask, and start to add 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-(S)-2-butanol is detected by gas c...

Embodiment 2

[0040] 1. Add 73.2g of nitromethane and 92.5g of S-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 S-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 It was confirmed by H-NMR and MS to be 1-chloro-4-nitro-(S)-2-butanol with a yield of 88.0% and a content of 98.4%.

[0041] 2. Add 153g of 1-chloro-4nitro-(S)-2-butanol prepared in step (1), 200ml of 95% ethanol and 500ml of water in the reaction flask, heat up to 50°C, and start to add 30% cyanide 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 the reaction of 1-chl...

Embodiment 3

[0048] 1. Add 73.2g nitromethane and 92.5g S-epoxypropylene into the reaction flask, feed 2.5g hydrogen chloride, stir and react at 50°C for 8 hours, detect with gas chromatography, when the S-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 It was confirmed by H-NMR and MS to be 1-chloro-4-nitro-(S)-2-butanol with a yield of 92.3% and a content of 98.7%.

[0049] 2. Add 153g of 1-chloro-4nitro-(S)-2-butanol prepared in step (1), 200ml of 95% ethanol and 500ml of water in the reaction flask, heat up to 50°C, and start to add 30% cyanide 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 reaction was stopped when the 1-chloro-4ni...

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Abstract

The invention discloses a preparation method of an atorvastatin intermediate (3R, 5R)-7-amino-3,5-O-isopropylidene-3,5-dyhydroxyl heptylic acid tert-butyl acetate. The method comprises the following steps of: reacting (R)-epichlorohydrin and nitromethane to generate 1-chlorine-4-nitryl-(R)-2-butanol, and reacting with sodium cyanide to obtain (R)-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, 5R)-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 an atorvastatin intermediate (3R, 5S)-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 of 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 binding of HMG-CoA reductase to the substrate. At the same time, statins can also reduce low-density lipoprotein and triglyceride and increase high-density l...

Claims

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Application Information

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Patent Type & Authority Applications(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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