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

A technology of phenoxydichlorophosphate and phosphorylamino is applied in the field of preparation of -2-[--phenoxy-phosphorylamino] isopropyl propionate, and can solve the problems of high price, low yield, high Complex preparation process and other problems, to achieve the effects of improved chemical purity and optical purity, high purity and yield, and simple process technology

Active Publication Date: 2014-12-24
BEIJING THTD PHARMA TECH JOINT CO LTD
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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 gener

Method used

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

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Embodiment 1

[0026] Such as Figure 1 to Figure 3 Shown: a kind of (s)-2-[(s)-(4-nitro-phenoxy)-phenoxy-phosphorylamino] preparation method of isopropyl propionate of the embodiment of the present invention, comprising The following steps:

[0027] 1. Dissolve 21.1g of phenoxy dichlorophosphate in 210mL of dichloromethane, cool down to -40°C, prepare solution A, and set aside;

[0028] 2. Separately take 15.3 g of p-nitrophenol; 11.1 g of triethylamine and dissolve it in 105 mL of dichloromethane to prepare solution B. Keep the temperature <-40°C, slowly add solution B to solution A dropwise, keep stirring at this temperature for about 1 hour, and monitor the completion of the reaction by HPLC (high performance liquid chromatography analysis);

[0029] 3. Another 16.8 g of L-alanine isopropyl ester hydrochloride was dissolved in 105 mL of dichloromethane, and the temperature was lowered to 0°C to prepare solution C. Keeping at <0°C, the reaction solution was added dropwise to solution C...

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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...

Claims

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Application Information

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IPC IPC(8): C07F9/24
Inventor 王红平王汉超
Owner BEIJING THTD PHARMA TECH JOINT CO LTD
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