Preparation method of (s)-2-[(s)-(4-nitro-phenoxy)-phenoxy-phosphoryl amino] isopropyl propionate

Abstract

The invention relates to a preparation method of (s)-2-[(s)-(4-nitro-phenoxy)-phenoxy-phosphoryl amino] isopropyl propionate. The (s)-2-[(s)-(4-nitro-phenoxy)-phenoxy-phosphoryl amino] isopropyl propionate, which is excellent in chemical purity and optical purity, is prepared by the following steps: preparing a compound as shown in a formula (III) from phenoxy dichlorophosphite as shown in a formula (I) and nitrophenol as shown in a formula (II), preparing a compound as shown in formula (V) from the compound as shown in the formula (III) and L-alanine isopropyl ester hydrochloride, and implementing solvent recrystallization on the compound as shown in the formula (V). The preparation method disclosed by the invention has the beneficial effects that the method for preparing the (s)-2-[(s)-(4-nitro-phenoxy)-phenoxy-phosphoryl amino] isopropyl propionate is simple in technological process and convenient to operate, and meanwhile the method is high in both purity and yield and is applicable to mass production.

Description

technical field [0001] The invention relates to a preparation method of isopropyl (s)-2-[(s)-(4-nitro-phenoxy)-phenoxy-phosphorylamino]propionate. Background technique [0002] Isopropyl (s)-2-[(s)-(4-nitro-phenoxy)-phenoxy-phosphorylamino]propionate is a key intermediate for the synthesis of sofosbuvir, a drug for the treatment of hepatitis C virus. Sofosbuvir (sofosbuvir) is a once-daily oral nucleoside analog polymerase inhibitor, which was approved by the FDA and the European Union in December 2013 and January 2014, respectively, and is the first to be approved for hepatitis C An all-oral regimen of drugs that eliminates the need for the traditional anti-HCV injectable drug interferon (Peg-IFN) when used in the treatment of genotype-specific chronic hepatitis C. The industry agrees that the drug Sofosbuvir is the most important drug approved by the FDA in 2013. Analysts predict that Gilead's hepatitis C business with Sofosbuvir as the mainstay will have sales of US$2.2...

AI Technical Summary

Problems solved by technology

[0004] Existing preparation (s)-2-[(s)-(4-nitro-phenoxy group)-phenoxy group-phosphoryl amino] the method for isopropyl propionate mainly contains following several, as figure 2 Shown: In route a, L-alanine isopropyl hydrochloride is used as the starting material to synthesize compound 5 with phenoxy dichlorophosphate. A large number of by-products are easily generated during the reaction, and the properties of this compound are extremely It is unstable and cannot be effectively purified, and subsequently generates compound 1a with p-nitrophenol or phenol. Since compound 1a needs to be subjected to chiral separation to obtain compound 1, the impurities generated during the preparation of compound 5 are subject to chiral separation. Bring great difficulty, if only use the method for solvent recrystallization to purify, the optical purity of the obtained compound 1 is far from meeting the requirement of next step reaction, so it is necessary to obtain better optical purity by chiral column chromatography Compound 1, the whole preparation process is complicated and the yield is low, and the chiral column chromatography separation method cannot realize industrial production; the p-nitrophenoxy dichlorophosphate used in route b is currently difficult to purchase in large quantities on the market get, more expensive

Images