Preparation method for R-3-aminobutanol

Abstract

The invention relates to a preparation method for R-3-aminobutanol. The preparation method specifically comprises the following steps: (a) reacting R-3-aminobutyric acid with di-tert-butyl carbonate in the presence of a polar solvent so as to form N-Boc-(R)-3-aminobutyric acid; (b) reducing N-Boc-(R)-3-aminobutyric acid in the presence of a reducing agent and Lewis acid so as to form N-Boc-(R)-3-aminobutanol; and (c) subjecting N-Boc-(R)-3-aminobutanol to a Boc removal in the presence of an acid solvent so as to form R-3-aminobutanol. The preparation method of the invention is simple in process, low in cost, friendly to environment, easier for industrial production and worth promotion.

Description

technical field [0001] The invention belongs to the field of chemical synthesis. Specifically, the invention relates to a preparation method of a chiral drug intermediate R-3-aminobutanol. Background technique [0002] Optically active R-3-aminobutanol is a key intermediate of many chiral drugs. Such as J.Org.Chem., 1977, 42:1650, it is reported that it is the key intermediate of the antineoplastic drug 4-methyl cyclophosphamide; Teter.Lett., 1988, 29:231, it is reported that it can be derived into β‐ Lactam, so it is an important intermediate for the synthesis of penem antibiotics; Drugs.Of theFuture 2012,37:697, it is reported that it is also the chiral six of the anti-AIDS drug Dolutegravir (listed in the United States in 2013, trade name Tivicay) Key intermediates of metacyclics. [0003] The synthetic method of this compound was the earliest in 1977, Wojciech J.Stec reported in J.Org.Chem., 1977,42:1650-1652 to obtain (R)-3-aminobutanol by introducing a chiral reagent...

AI Technical Summary

Problems solved by technology

It has two disadvantages: one is that chiral phenylethylamine is more expensive; the other is that solvent recrystallization is required to split a pair of epimers, and in order to achieve a product with optical purity that meets the requirements, repeated crystallization is required. times, leading to a decrease in yield

But the disadvantage is that the temperature of debenzoylation is high, and chiral ligands also have problems such as cost and difficulty in removing metal residues.

[0032] Another patent CN20151044445583 is the same as CN2015104444472, using benzamide instead of acetamide, but still debenzamide first, then esterifying to obtain compound 45, and then reducing it, the yield is 76-77%, because the reduction reaction substrate is Ester, compared with CN104370755, the yield (47-54%) of the acid as the reduction reaction substrate is higher, but its disadvantage is that the yield of the reduction reaction 76-77% still needs to be improved

Wherein the reduction reaction is a two-phase reaction, the reaction temperature is higher (90-120°C), the reaction speed is slow, and the yield is lower (47-54%)

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