Method for preparing L-BPA

Patent metadata

Field	Value
Publication number	US-10323046-B2
Application number	US-201815886221-A
Country	US
Kind code	B2
Filing date	Feb 1, 2018
Priority date	Aug 14, 2015
Publication date	Jun 18, 2019
Grant date	Jun 18, 2019

Abstract

Provided is a method for preparing L-BPA, which includes steps of:
reacting N-protected (S)-4-halophenylalanine of Formula I, a boronating agent, Grignard reagent and bis(2-dimethylaminoethyl)ether to obtain a reaction mixture, wherein the reaction mixture comprises N-protected (S)-4-boronophenylalanine of Formula II and the R 2 group represents a protecting group;

isolating the N-protected (S)-4-boronophenylalanine from the reaction mixture; and
deprotecting the R 2 group of the N-protected (S)-4-boronophenylalanine to obtain L-BPA, wherein the L-BPA has a structure of Formula III.

First claim

What is claimed is:

1. A method for preparing L-BPA comprises steps of:
reacting N-protected (S)-4-halophenylalanine of Formula I, a boronating agent, Grignard reagent and bis(2-dimethylaminoethyl)ether to obtain a reaction mixture, wherein the R 1 group of N-protected (S)-4-halophenylalanine of Formula I is iodide or bromide, the Grignard reagent is tert-butylmagnesium chloride (t-BuMgCl), the reaction mixture comprises N-protected (S)-4-boronophenylalanine of Formula II and the R 2 group represents a protecting group;

isolating the N-protected (S)-4-boronophenylalanine from the reaction mixture; and
deprotecting the R 2 group of the N-protected (S)-4-boronophenylalanine to obtain L-BPA, wherein the L-BPA has a structure of Formula III.

2. The method according to claim 1 , wherein the R 2 group of N-protected (S)-4-halophenylalanine of Formula I and N-protected (S)-4-boronophenylalanine of Formula II is selected from the group consisting of: tert-butoxycarbonyl (t-Boc) group, trityl (Trt) group, 3,5-dimethoxyphenylisopropoxycarbonyl (Ddz) group, 2-(4-Biphenyl)isopropoxycarbonyl (Bpoc) group, and 2-nitrophenylsulfenyl (Nps) group, the boronating agent is trialkyl borate.

3. The method according to claim 1 , wherein the step of reacting N-protected (S)-4-halophenylalanine of Formula I, a boronating agent, Grignard reagent and bis(2-dimethylaminoethyl)ether to obtain a reaction mixture comprises reacting N-protected (S)-4-halophenylalanine of Formula I, a boronating agent, Grignard reagent and bis(2-dimethylaminoethyl)ether at a temperature ranging from 0° C. to 60° C. to obtain the reaction mixture.

4. The method according to claim 1 , wherein the step of deprotecting the R 2 group of the N-protected (S)-4-boronophenylalanine to obtain L-BPA comprises deprotecting the R 2 group of the N-protected (S)-4-boronophenylalanine at a temperature ranging from 30° C. to 60° C. to obtain L-BPA.

5. The method according to claim 1 , wherein the boronating agent has a 10 B purity not less than 95%, the N-protected (S)-4-boronophenylalanine is N-protected (S)-4-( 10 B)boronophenylalanine of Formula IV and the L-BPA is L- 10 BPA of Formula V

6. The method according to claim 1 , wherein the method for preparing L-BPA further comprises a step of:

protecting the amine terminal of (S)-4-halophenylatermilanine of Formula VI to obtain N-protected (S)-4-halophenylalanine of Formula I.

7. The method according to claim 6 , wherein the step of protecting the amine terminal of (S)-4-halophenylalanine of Formula VI to obtain N-protected (S)-4-halophenylalanine of Formula I comprises:
adding the (S)-4-halophenylalanine, 1,4-dioxane, water, sodium hydroxide and di-t-butyl dicarbonate into reaction vessel to perform the reaction;
adjusting the pH value to less than 2 to crystallize the N-protected (S)-4-boronophenyl alanine;
adding a first extractive solvent so as to obtain N-protected (S)-4-boronophenylalanine.

8. The method according to claim 2 , wherein trialkyl borate is tributyl borate, the method of preparing L-BPA further comprises a step of reacting the boronic acid with sulfuric acid and butan-1-ol in a first organic solvent, to prepare the tributyl borate.

9. The method according to claim 1 , wherein the step of isolating the N-protected (S)-4-boronophenylalanine from the reaction mixture comprises:
adding an organic solvent and acid solution into the reaction mixture, adjusting pH value to less than 5, and extractive, to obtain organic phase;
adding alkaline solution to said organic phase, adjusting the pH value to 7.1-14;
adding an extractive solvent so as to obtain the N-protected (S)-4-boronophenylalanine.

10. The method according to claim 1 , wherein the step of deprotecting the R 2 group of the N-protected (S)-4-boronophenylalanine to obtain L-BPA comprises:
adding the N-protected (S)-4-borono-L-phenylalanine, water, acid solution and an organic solvent into a reaction vessel;
adjusting the pH value to 6.15-6.25 so as to obtain L-BPA.

11. A method for preparing L-BPA comprises steps of:
reacting N-protected (S)-4-halophenylalanine of Formula I, a boronating agent and Grignard reagent to obtain a reaction mixture, wherein the R 1 group of N-protected (S)-4-halophenylalanine of Formula I is iodide or bromide, the Grignard reagent is tert-butylmagnesium chloride (t-BuMgCl), the reaction mixture comprises N-protected (S)-4-boronophenylalanine of Formula II and the R 2 group represents a protecting group;

isolating the N-protected (S)-4-boronophenylalanine from the reaction mixture; and
deprotecting the R 2 group of the N-protected (S)-4-boronophenylalanine to obtain L-BPA, wherein the L-BPA has a structure of Formula III.

12. The method according to claim 11 , wherein the R 2 group of N-protected (S)-4-halophenylalanine of Formula I and N-protected (S)-4-boronophenylalanine of Formula II is selected from the group consisting of: tert-butoxycarbonyl (t-Boc) group, trityl (Trt) group, 3,5-dimethoxyphenylisopropoxycarbonyl (Ddz) group, 2-(4-Biphenyl)isopropoxycarbonyl (Bpoc) group, and 2-nitrophenylsulfenyl (Nps) group, the boronating agent is trialkyl borate.

13. The method according to claim 11 , wherein the step of reacting N-protected (S)-4-halophenylalanine of Formula I, a boronating agent and Grignard reagent to obtain a reaction mixture comprises reacting N-protected (S)-4-halophenylalanine of Formula I, a boronating agent and Grignard reagent at a temperature ranging from 0° C. to 30° C. to obtain the reaction mixture.

14. The method according to claim 11 , wherein the boronating agent has a 10 B purity not less than 95%, the N-protected (S)-4-boronophenylalanine is N-protected (S)-4-( 10 B)boronophenylalanine of Formula IV and the L-BPA is L-′° BPA of Formula V

15. A method for preparing L-BPA comprises steps of:
reacting N-protected (S)-4-halophenylalanine of Formula I, a boronating agent, Grignard reagent and bis(2-dimethylaminoethyl)ether to obtain a reaction mixture, wherein the Grignard reagent is tert-butylmagnesium chloride (t-BuMgCl), the reaction mixture comprises N-protected (S)-4-boronophenylalanine of Formula II and the R 2 group represents a protecting group;

isolating the N-protected (S)-4-boronophenylalanine from the reaction mixture; and
deprotecting the R 2 group of the N-protected (S)-4-boronophenylalanine to obtain L-BPA, wherein the L-BPA has a structure of Formula III;
wherein the R 1 group of N-protected (S)-4-halophenylalanine of Formula I is iodide or bromide, the R 2 group of N-protected (S)-4-halophenylalanine of Formula I and N-protected (S)-4-boronophenylalanine of Formula II is selected from the group consisting of: tert-butoxycarbonyl (t-Boc) group, trityl (Trt) group, 3,5-dimethoxyphenylisopropoxycarbonyl (Ddz) group, 2-(4-Biphenyl)isopropoxycarbonyl (Bpoc) group, and 2-nitrophenylsulfenyl (Nps) group, the boronating agent is trialkyl borate.

16. The method according to claim

Assignees

• Neuboron Medtech Ltd

Inventors

• Li Shihong
• He Jing
• Liu Yuanhao
• Wang Zheng

Classifications

• C07B41/08 Primary

  of carboxyl groups or salts, halides or anhydrides thereof · CPC title

• C07F5/02 Primary

  Boron compounds · CPC title

• C07F3/02

  Magnesium compounds · CPC title

• C07B63/00

  Purification; Separation (separation of optically-active compounds C07B57/00); Stabilisation; Use of additives · CPC title

• C07B47/00

  Formation or introduction of functional groups not provided for in groups C07B39/00 - C07B45/00 · CPC title