Method for synthesizing ADA

Abstract

The invention relates to a compound synthesized in the medicine field, and particularly relates to a rosuvastatin intermediate. The method for synthesizing ADA comprises the following five steps: 1, reacting S-4-chloro-3-hydroxy butyronitrile with hexamethyl-disilazane to generate an intermediate I; 2, reacting the prepared intermediate I, a reducing agent and methanesulfonic acid with tert-butyl bromoacetate to prepare an intermediate II; 3, preparing an intermediate III from the prepared intermediate II by enzyme selective reduction; 4, reacting the prepared intermediate III with acetone acetal to prepare an intermediate IV; and 5, reacting the prepared intermediate IV and tetrabutylammonium bromide with sodium acetate to prepare the target intermediate ADA. According to the method, operation for preparing ADA is more convenient; and the method has high safety coefficient and low cost, and is very suitable for industrial production.

Description

technical field [0001] The present invention relates to a compound synthesized and used in the field of pharmaceutical chemicals, specifically the intermediate (4R-cis)-6-[(acetyloxy)methyl]-2,2-bis of rosuvastatin (Rosuvastatin) The synthetic method of methyl-1,3-dioxane-4-acetic acid tert-butyl ester (hereinafter referred to as ADA). Background technique [0002] ADA is an important intermediate of Rosuvastatin; moreover, ADA can be easily converted into (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane -4-tert-butyl acetate (CAS number: 124752-23-4, referred to as ADA-6), the structural formula of ADA-6 is as follows, this intermediate is also an important fragment for the synthesis of a series of statins, such as atorvastatin (Atorvastatin), Cerivastatin (Cerivastatin), Fluvastatin (Fluvastatin), Pitavastatin (pitavastatin), etc., have very broad application prospects. [0003] [0004] Rosuvastatin is a statin drug approved by AstraZeneca in Europe in 2002, and was apprai...

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Problems solved by technology

[0009] 2. Patent EP1282719B1 (WO01 / 85975) reported a synthetic method, which obtained (3R,5S)-3 through asymmetric reduction of S-5,6-dihydroxy-3-oxohexanoic acid tert-butyl ester, tert-Butyl 5,6-trihydroxyhexanoate, one of which is the asymmetric hydrogenation using a chiral catalyst, di-μ-chlorobis[(p-isopropyltoluene)ruthenium chloride ( II)] and (1S, 2S)-(+)-N-(4-toluenesulfonyl)-1,2-diphenylethylenediamine, but the de% value is only 70%, and the catalyst is relatively expensive and difficult to use At the same time, the literature also reported enzyme-catalyzed chiral reduction, although de% can be increased to 99%

[0011] 3. Patent EP1317440B reports a synthetic method, oxidizing 6-chloro-2,4,6-trideoxy-D-erythro-hexose under the action of bromine and sodium bicarbonate to obtain (4R, 6S )-4-hydroxyl-6-chloromethyl-tetrahydropyran-2-one, and then generate a dioxane structure with 2,2-dimethoxypropane, and then alkali hydrolyze the ester group, Boc2O into tert-butyl ester, ADA is obtained by substituting acetate for 6-chloro. This route uses highly toxic bromine, and the starting product 6-chloro-2,4,6-trideoxy-D-erythro-hexose has no stable supply source on the market , difficult to obtain; while the yield of the first step reaction is low, only 67%

[0015] 5. Tetrahedron Letters, 34, 1993, 513-516 reported a synthetic method in which tert-butyl acetoacetate was linked to a chiral ligand, and then the 3-carbonyl group was reduced to a hydroxyl group, and then diethylmethoxy Under the action of borane / sodium borohydride, the 5-carbonyl group is reduced to a hydroxyl group, and the chiral ligand is removed to obtain ADA-6; this method uses a large number of highly flammable reagents, such as butyllithium, sodium hydride, DIBAL- H, diethylmethoxyborane, etc., have great potential safety hazards

[0017] 6. The patent US7205418 reports a synthetic method to convert tert-butyl S-3,4-epoxybutyrate into ADA. The method has relatively long steps and at least six steps to complete, and the overall yield is low , and the route needs to separate the cis and trans isomers of tert-butyl 2-[6-iodomethyl-2-oxo-1,3-dioxan-4-yl]acetate by column chromatography, not Conducive to industrial production;

[0019] 7. Organic Letters, 2002, 4, 619-621. Reported a method to convert 2-[6-chloromethyl-2-oxo-1,3-dioxan-4-yl] tert-butyl acetate The cis and trans isomers are separated by selective hydrolysis, but the product also needs to be purified by column chromatography, so it is not suitable for industrial production

[0027] 11. Patent CN105399770 reports a synthetic method, through the induction of chiral catalyst, sodium acetylene is used to selectively attack epichlorohydrin to obtain chiral products, but this method uses highly toxic sodium cyanide, and Chiral catalysts are expensive and difficult to industrialize

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