Method for preparing 4-(hydroxymethylphosphinyl)-2-oxobutanoic acid

Patent metadata

Field	Value
Publication number	US-2025084110-A1
Application number	US-202318562309-A
Country	US
Kind code	A1
Filing date	Mar 6, 2023
Priority date	Sep 8, 2022
Publication date	Mar 13, 2025
Grant date	—

Abstract

A method for preparing 4-(hydroxymethylphosphinyl)-2-oxobutanoic acid, comprising the following steps: a) mixing 3-chloropropionyl chloride, a first solvent, trimethylsilyl cyanide and cyanide salt, performing a substitution reaction to obtain a material solution containing 4-chloro-2-oxobutyronitrile, then performing distillation under reduced pressure, and performing separation to obtain 4-chloro-2-oxobutyronitrile intermediate; b) subjecting the 4-chloro-2-oxobutyronitrile intermediate obtained in step a) and methyl phosphonite diester to Arbuzov reaction in a second solvent in the presence of cuprous iodide to obtain a material solution of (3-cyano-3-oxopropyl) methyl phosphinate, and performing purification to obtain crude (3-cyano-3-oxopropyl) methyl phosphinate; c) mixing the obtained crude (3-cyano-3-oxopropyl)methyl phosphinate with hydrochloric acid, performing hydrolysis reaction, and then performing purification treatment to obtain 4-(hydroxymethylphosphinyl)-2-oxobutanoic acid. This preparation method can prepare 4-(hydroxymethylphosphinyl)-2-oxobutanoic acid with high yield, and the reaction conditions are mild, the operation is simple, the production cost is low, and it is easy to realize industrialization.

First claim

1 . A method for preparing 4-(hydroxymethylphosphinyl)-2-oxobutanoic acid, comprising the following steps:
a) mixing 3-chloropropionyl chloride, a first solvent, trimethylsilyl cyanide and cyanide salt, performing a substitution reaction to obtain a material solution containing 4-chloro-2-oxobutyronitrile, then performing distillation under reduced pressure, and performing separation to obtain 4-chloro-2-oxobutyronitrile intermediate; b) subjecting the 4-chloro-2-oxobutyronitrile intermediate obtained in step a) and methyl phosphonite diester to Arbuzov reaction in a second solvent in the presence of cuprous iodide to obtain a material solution of (3-cyano-3-oxopropyl)methyl phosphinate, and performing purification to obtain crude (3-cyano-3-oxopropyl)methyl phosphinate; c) mixing the crude (3-cyano-3-oxopropyl)methyl phosphinate obtained in step b) with hydrochloric acid, performing hydrolysis reaction, and then performing purification treatment to obtain 4-(hydroxymethylphosphinyl)-2-oxobutanoic acid.

2 . The method according to claim 1 , wherein in step a), the first solvent is selected from the group consisting of acetonitrile, toluene, 2-methyltetrahydrofuran, phenylacetonitrile and a combination thereof;
the cyanide salt is selected from the group consisting of sodium cyanide, potassium cyanide, cuprous cyanide and a combination thereof; the trimethylsilyl cyanide, cyanide salt and 3-chloropropionyl chloride are in a molar ratio of (0.005-0.2):(0.8-3):1.

3 . The method according to claim 1 , wherein in step a), the substitution reaction is performed at a temperature of 0° C.-150° C. for 0.5 h-48 h.

4 . The method according to claim 1 , wherein in step b), the methyl phosphonite diester is selected from the group consisting of dimethyl methylphosphonite, diethyl methylphosphonite, dipropyl methylphosphonite, dibutyl methylphosphonite, and a combination thereof;
the methylphosphonite diester and the 4-chloro-2-oxobutyronitrile intermediate are in a molar ratio of (0.8-10):1.

5 . The method according to claim 1 , wherein in step b), the cuprous iodide and 4-chloro-2-oxobutyronitrile intermediate are in a molar ratio of (0.005-0.2):1.

6 . The method according to claim 1 , wherein in step b), the second solvent is selected from the group consisting of 1,2-dichloroethane, 2-methyltetrahydrofuran, benzene, toluene, xylene and a combination thereof;
the second solvent and the 4-chloro-2-oxobutyronitrile intermediate are in a mass ratio of (1-10):1.

7 . The method according to claim 1 , wherein in step b), the Arbuzov reaction is conducted at a temperature of 50° C.-150° C. for 1 h to 24 h.

8 . The method according to claim 1 , wherein in step c), the hydrochloric acid has a mass concentration of 20%-36%;
the hydrochloric acid and the 4-chloro-2-oxobutyronitrile intermediate in step b) are in a molar ratio of (1-15):1.

9 . The method according to claim 1 , wherein in step c), the hydrolysis reaction is conducted at a temperature of 50° C.-130° C. for 1 h-24 h.

10 . The method according to claim 1 , wherein in step c), the process of the purification treatment is specifically conducted by:
removing acid water from the product obtained by the hydrolysis reaction under reduced pressure to obtain a mixture containing 4-(hydroxymethylphosphinyl)-2-oxobutanoic acid and inorganic salts, then adding acetone for dissolution, performing filtration to remove insoluble salts, concentrating the filtrate under reduced pressure to half of the volume, and adding methyl isobutyl ketone for crystallization to obtain the product 4-(hydroxymethylphosphinyl)-2-oxobutanoic acid.

Assignees

• Zhejiang Wynca Chemical Industry Group Co Ltd
• Univ Zhejiang

Inventors

• Zhou Shuguang
• Yang Lirong
• Qin Long
• Zhou Haisheng
• Yu Shenluan
• Wu Jianping
• Wang Linlin
• Zhan Bo
• Wang Ping

Classifications

• C07F9/301 Primary

  Acyclic saturated acids which can have further substituents on alkyl · CPC title

• C07F9/32

  Esters thereof · CPC title

• C07C253/14

  by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups · CPC title

• C07C255/17

  containing cyano groups and doubly-bound oxygen atoms bound to the same acyclic carbon skeleton · CPC title

• C07F9/30

  Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids {; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]} · CPC title