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Method for preparation of N-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxy phosphoryl]-L-alanine isopropyl ester

A technology of isopropyl alanine and phenoxyphosphoryl, which is applied in the field of medicinal chemistry, can solve the problems of high equipment requirements, harsh reaction conditions, and low yield, and achieve simple operation, mild conditions, and high yield Effect

Active Publication Date: 2015-07-08
SHANGHAI DESANO CHEM PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In this method, pentafluorophenol dichlorophosphate is first docked with isopropyl alanine hydrochloride at -78°C, and then the resulting product is docked with phenol at -78°C; this method not only has pentafluorophenol dichlorophosphate Fluorophenol ester raw materials are difficult to prepare and purchase, and because the method adopts ultra-low temperature (-78°C) reaction conditions, there are also defects such as harsh reaction conditions, high requirements for equipment, low yield, and unsuitable for industrial production requirements. question

Method used

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  • Method for preparation of N-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxy phosphoryl]-L-alanine isopropyl ester
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  • Method for preparation of N-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxy phosphoryl]-L-alanine isopropyl ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Phenyl dichlorophosphate (50g, 0.24mol) and pentafluorophenol (43.6g, 0.24mol) were added to 150mL of dichloromethane, and triethylamine (79.4g, 0.79mol) was added dropwise; the temperature was raised to reflux, and when stirred to reflux Cool down to room temperature after 7-8 hours, add L-alanine isopropyl ester hydrochloride (40g, 0.24mol), and stir at room temperature for 4-5 hours; Recrystallization with n-hexane and ethyl acetate: first dissolve the residue with an appropriate amount of ethyl acetate, then add n-hexane dropwise at 30-40°C until turbidity appears, then cool down to crystallize; or add the residue first and n-hexane in a mixed solvent with a volume ratio of 1:4, then heated until dissolved, and then cooled to crystallize; the crystals were collected and vacuum-dried to obtain N-[(S)-(2,3,4, 5,6-pentafluorophenoxy)phenoxyphosphoryl]-L-alanine isopropyl ester (compound of formula I) 51.8g, molar yield 48%, HPLC purity 99.1%.

Embodiment 2

[0033] Add phenyl dichlorophosphate (100g, 0.48mol) and pentafluorophenol (96.3g, 0.53mol) into 200mL tetrahydrofuran, add sodium carbonate (101.8g, 0.96mol); heat up to reflux, and reflux for 7 to 8 hours while stirring After cooling down to room temperature, add L-alanine isopropyl hydrochloride (88.3g, 0.53mol), and stir at room temperature for 4 to 5 hours; filter with suction, concentrate the filtrate under reduced pressure, and wash the concentrated residue with n-hexane Recrystallization with ethyl acetate: first dissolve the residue with an appropriate amount of ethyl acetate, then add n-hexane dropwise at 30-40°C until turbidity appears, then lower the temperature to crystallize; or add the residue first by adding ethyl acetate and n-hexane In the mixed solvent formed at a volume ratio of 1:4.5, then heated to dissolve, and then cooled to crystallize; the crystals were collected and vacuum-dried to obtain N-[(S)-(2,3,4,5,6 -Pentafluorophenoxy)phenoxyphosphoryl]-L-alan...

Embodiment 3

[0035] Phenyl dichlorophosphate (50g, 0.24mol) and pentafluorophenol (43.6g, 0.24mol) were added to 150mL of dichloromethane, and 4-dimethylaminopyridine (43.9g, 0.36mol) was added dropwise; the temperature was raised to reflux , when stirred and refluxed for 7 to 8 hours, it was cooled to room temperature, L-alanine isopropyl ester hydrochloride (40g, 0.24mol) was added, and stirred at room temperature for 4 to 5 hours; The concentrated residue is recrystallized with n-hexane and ethyl acetate: first dissolve the residue with an appropriate amount of ethyl acetate, then add n-hexane dropwise at 30-40°C until turbidity appears, and then cool down to crystallize; or add the residue first In a mixed solvent formed by ethyl acetate and n-hexane with a volume ratio of 1:3, then heated to dissolve, and then cooled to crystallize; the crystals were collected and vacuum-dried to obtain N-[(S)-(2, 50.1 g of 3,4,5,6-pentafluorophenoxy)phenoxyphosphoryl]-L-alanine isopropyl ester (compo...

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Abstract

The invention discloses a method for preparation of N-[(S)-(2,3,4,5,6-pentafluorophenyloxy)phenoxy phosphoryl]-L-alanine isopropyl ester; the method comprises the steps: first of all, carrying out a reflux reaction of dichloro phenyl phosphate and pentafluorophenol for 5-15 hours in an organic solvent and under an alkaline condition; followed by, cooling the reaction liquid down to room temperature, adding L-alanine isopropyl ester hydrochloride, and carrying out a stirring reaction for 2-8 hours at room temperature; and then carrying out suction filtration, concentrating the filtrate under reduced pressure, and carrying out recrystallization treatment on the concentrated residue. The method can effectively solve the defect problems that a conventional method has harsh reaction conditions, high requirements on equipment, relatively low yield and the like, prepares the high-purity N-[(S)-(2,3,4,5,6-pentafluorophenyloxy)phenoxy phosphoryl]-L-alanine isopropyl ester with simple operation, mild conditions and relatively high yield, and has an important value on achieving scale production of the compound.

Description

technical field [0001] The invention relates to a method for preparing N-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphoryl]-L-alanine isopropyl ester, which belongs to medicine field of chemical technology. Background technique [0002] Sofosbuvir, also known as PSI-7977 or GS-7977, is an NS5B polymerase inhibitor, a once-daily oral nucleoside analog developed by Gilead Sciences for the treatment of chronic hepatitis C virus (HCV) infection drug inhibitors. In April 2013, Gilead Sciences submitted a new drug application for sofosbuvir to the FDA, and the FDA granted sofosbuvir a new drug priority review qualification in June 2013. [0003] The structure of Sofosbuvir is as follows: [0004] [0005] The synthesis method of sofosbuvir is reported in the international patent application WO2010135569A and the document "JOC.2011, 76(20), 8311-8319", and the specific reaction formula is as follows: [0006] [0007] It can be seen that N-[(S)-(2,3,4,5,6-pentafluoroph...

Claims

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Application Information

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IPC IPC(8): C07F9/24
Inventor 李竟鹏赵楠邓宇
Owner SHANGHAI DESANO CHEM PHARMA
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