Method for preparing L-BPA

• US 10,323,046 B2
• Filed: 02/01/2018
• Issued: 06/18/2019
• Est. Priority Date: 08/14/2015
• Status: Active Grant

• Current Assignee: Neuboron Medtech, Ltd.
• Original Assignee: Neuboron Medtech, Ltd.
• Inventors: Li, Shihong, He, Jing, Liu, Yuanhao, Wang, Zheng
• Primary Examiner(s): Valenrod, Yevgeny
• Assistant Examiner(s): Doletski, Blaine G
• Application Number:
  US15/886,221
• Publication Number:
  US 20180155368A1
• Time in Patent Office: 502 Days
• CPC Class Codes: C07B 41/08 of carboxyl groups or salts, halides or anhydrides thereof
• CPC Class Codes: C07B 47/00 Formation or introduction of functional groups not provided for in groups C07B39/00 - C07B45/00
• CPC Class Codes: C07B 63/00 Purification; Separation separation of optically-active compounds C07B57/00; Stabilisation; Use of additives
• CPC Class Codes: C07F 3/02 Magnesium compounds
• CPC Class Codes: C07F 5/02 Boron compounds
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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 R² group represents a protecting group;

• isolating the N-protected (S)-4-boronophenylalanine from the reaction mixture; and
• deprotecting the R² group of the N-protected (S)-4-boronophenylalanine to obtain L-BPA, wherein the L-BPA has a structure of Formula III.

Claims

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 R¹ 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 R² group represents a protecting group;

2. The method according to claim 1, wherein the R² 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 R² group of the N-protected (S)-4-boronophenylalanine to obtain L-BPA comprises deprotecting the R² 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 ¹⁰B purity not less than 95%, the N-protected (S)-4-boronophenylalanine is N-protected (S)-4-(¹⁰B)boronophenylalanine of Formula IV and the L-BPA is L-¹⁰BPA of Formula V

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

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 R² 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 R¹ 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 R² group represents a protecting group;

12. The method according to claim 11, wherein the R² 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 ¹⁰B purity not less than 95%, the N-protected (S)-4-boronophenylalanine is N-protected (S)-4-(¹⁰B)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 R² group represents a protecting group;

16. The method according to claim 15, 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.

17. The method according to claim 15, wherein the R¹ group of N-protected (S)-4-halophenylalanine of Formula I is iodide.