Method for preparing t-butyl (3R, 5S)-3,5,6-trihydroxy-hexanoate

A technology of tert-butyl hexanoate and ethyl benzyloxybutyrate, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of low production rate and low production rate, and achieve the effect of reducing production costs

Active Publication Date: 2007-12-12
SHANGHAI QINGSONG PHARMA
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Problems solved by technology

Several protecting groups were selected, and finally it was found that when the protecting group was tetrahydropyran, the reaction effect was the best, and the main condi

Method used

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  • Method for preparing t-butyl (3R, 5S)-3,5,6-trihydroxy-hexanoate
  • Method for preparing t-butyl (3R, 5S)-3,5,6-trihydroxy-hexanoate
  • Method for preparing t-butyl (3R, 5S)-3,5,6-trihydroxy-hexanoate

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Embodiment Construction

[0024] The first step of preparation of ethyl benzyloxyacetoacetate (II)

[0025] 7.35g (55%-60%) of sodium hydride (168-184mmol) was suspended in 100ml of toluene, cooled in an ice bath, and 16.2g of benzyl alcohol (15.5ml, 150mmol) was slowly dropped into it within 30 minutes. After stirring at room temperature for 2 hours, a white slurry formed. After cooling in an ice bath, 12.5 g of ethyl chloroacetoacetate (76 mmol) was dropped into it, and the reaction was carried out overnight at room temperature for 19 hours. Add 75.5ml of 2N citric acid, separate the layers, extract the aqueous phase with toluene twice, combine the organic phases, dry, rotary evaporate, and wash the residue with (2×10ml) heptane. The residue was distilled under reduced pressure to obtain 15 g of ethyl benzyloxyacetoacetate (II), with a yield of 84%.

[0026] The second step (3S) - preparation of ethyl 3-hydroxy-4-benzyloxybutyrate (III)

[0027] Catalyst preparation: 36mg (R)-(+)-BINAP, 14mg dipol...

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Abstract

The invention relates to a method for preparing (3R, 5S) - 3, 5, 6- trihydroxy- butylacetic acic tertbutyl ester, belonging to medical intermediate preparation technique. It comprises following steps: taking ethyl chloroacetate as raw material, oxides it with benzyl, catalyzing and hydrogenizing with RuCl2[(R)-BINAP] and getting(3S)- 3- hydroxy- 4- benzyloxy butyl acetate, employing methoxy benzyl to protect hydroxy, carryingout condensation reaction with Claisen ester to increase carbon chain, catalyzing and hydrogenizing the carbonyl at No. 3 carbon with RuCl2[(R)-BINAP] and getting (3R, 5S)- 5- p-methoxy benzyloxy- 6- benzyloxy- 3- hydroxy- butylacetic acic tertbutyl ester; removing p-methoxy benzyloxy with ammonium cerous nitrate, protecting with acetone, removing benzyl and getting (3R, 5S)- 6- hydroxy- 3, 5- 0- isopropylidene- 3, 5- dihydroxy butylacetic acic tertbutyl ester. The total productivity is 39.5%, d, e value is 99%. The cost is low and it is easy to industrialization.

Description

technical field [0001] The invention relates to a preparation method of (3R,5S)-3,5,6-trihydroxy-tert-butyl hexanoate, belonging to the technical field of preparation of pharmaceutical intermediates. Background technique [0002] Statins are the fastest-growing category of cardiovascular drugs, and they dominate the blood lipid regulating drug market. (3R,5S)-3,5,6-trihydroxy-hexanoic acid tert-butyl ester contains two chiral centers, and its structural characteristics are as follows: [0003] [0004] R 1 It is hydrogen or benzyl, R2 is ethyl or tert-butyl, R is a protecting group of hydrogen or alcohol, or a protecting group of 1,3-diol, and it is an important intermediate for preparing statin blood lipid-lowering drugs. [0005] US Patent No. 5,399,722 provides a method for preparing (3R,5S)-3,5,6-trihydroxy-hexanoic acid tert-butyl ester. This method does not use a protecting group, and first uses ethyl chloroacetoacetate as a starting material, benzyl oxidation, a...

Claims

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Application Information

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IPC IPC(8): C07D319/06C07C69/757
Inventor 杨琍苹王文金张磊顾君琳
Owner SHANGHAI QINGSONG PHARMA
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