A kind of preparation method of (r)-tert-butyldimethylsiloxy-glutaric acid monoester
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A technology of tert-butyldimethylsilyloxy and glutaric acid monoester, which is applied in chemical instruments and methods, compounds of group 4/14 elements of the periodic table, organic chemistry, etc., and can solve problems such as low yields , to achieve the effects of easy-to-obtain raw materials, good chirality of products, and mild reaction conditions
Active Publication Date: 2017-01-18
ZHEJIANG LEPU PHARMA CO LTD
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[0026] WO03097614, JP05032680 use chiral amine for resolution, the yield is low
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example 1
[0073] Preparation of Example 1 Compound IV:
[0074] In the reaction flask, add compound V, ethyl (S)-3-hydroxy-4-bromobutyrate (20.5g), benzyl alcohol (12g), toluene 150ml, YR-LIP (0.1g), heat to 70~ 80°C, 8 hours, TLC monitoring, after the reaction is complete, cool to room temperature, filter, recover the enzyme, and concentrate under reduced pressure to obtain a brown oily substance. The yield of (S)-benzyl 3-hydroxy-4-bromobutyrate (IV) was 96%, and the purity was 97% by GC.
example 2
[0075] The preparation of example 2 compound IV:
[0076] In the above example 1, YR-LIP Novozymes lipase was 4350.2g, and a brown oil was obtained. The yield of (S)-benzyl 3-hydroxy-4-bromobutyrate (IV) was 92%, and the purity was GC93%.
example 3
[0077] Preparation of Example 3 Compound IV:
[0078] In the reaction flask, add compound V, ethyl (S)-3-hydroxyl-4-bromobutyrate (20.5g), p-toluenesulfonic acid (0.3g), toluene, benzyl alcohol (10g), and heat 150ml of toluene to Reflux, react for about 6 hours, cool to normal temperature, wash with baking soda water, wash with brine, concentrate to remove toluene, and obtain oily product (S)-benzyl 3-hydroxy-4-bromobutyrate. The yield is 92%, and the GC purity is 93.5% %.
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Abstract
The invention discloses a rosuvastatin intermediate (R)-tert butyl dimethyl siloxy-glutaric acid monoester preparation method, which belongs to the field of medicine. The method is as follows: compound (S)-4-halogen-3-hydroxy butyric acid ethyl ester is taken as a raw material for ester exchange to obtain other (S)-4-halogen-3-hydroxy butyric ester, (S)-4-halogen-3-tert butyl dimethyl siloxy benzyl butyrate is obtained by protection of the (S)-4-halogen-3-hydroxy butyric ester, and by condensation of the (S)-4-halogen-3-tert butyl dimethyl siloxy benzyl butyrate and chloroformate in the presence of magnesium, tert butyl lithium and n-butyl lithium, (R)-tert butyl dimethyl siloxy-glutaric acid ester benzyl ester is obtained, and the (R)-tert butyl dimethyl siloxy-glutaric acid monoester is obtained by catalytic hydrogenation deprotection. Compared with the original process, the raw material of the process is chiral, natural, needs no resolution and induction and no enzyme hydrolysis to produce the chiral center, so that the product chirality is better. Compared with the original process, enzymes are already-industrialized enzymes, the raw material is easily obtained, reaction conditions are relatively mild, and the process is easy to industrialize. Compared with the original process, the process is shorter and less in three wastes.
Description
technical field [0001] The invention belongs to the field of chemical synthesis, in particular to a method for synthesizing the intermediate (R)-tert-butyldimethylsilyloxy-glutaric acid monoester of the HMG inhibitor rosuvastatin of the hypolipidemic drug. Background technique [0002] Rosuvastatin (also known as rosuvastatin, English name: rosuvastatin). Rosevastatin Calcium was developed by Shionogi (Osaka Shionogi Company) in Japan. In February 1999, Phase I, Phase II, and Phase III clinical trials of the drug were completed in the United States. From its existing clinical verification results and comparison with similar products, high-dose rosuvastatin calcium (80 mg) can reduce LDL up to 65%, which is higher than atorvastatin and simvastatin, rosuvastatin calcium Worthy of being called a "super statin", its lipid-lowering effect is very good, and it is the most powerful lipid-lowering drug on the market so far. In the next few years, rosuvastatin calcium is likely to ...
Claims
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