METHOD FOR PREPARING L-BPA

• US 20180155368A1
• Filed: 02/01/2018
• Published: 06/07/2018
• 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
• Granted Patent: US 10,323,046 B2
• Time in Patent Office: 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-methylaminoethyl)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-methylaminoethyl)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;

2. The method according to claim 1, wherein the R¹ group of N-protected (S)-4-halophenylalanine of Formula I is iodide or bromide, 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, the Grignard reagent includes alkylmagnesium chloride, alkylmagnesium bromide, arylmagnesium chloride or arylmagnesium bromide.

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-methylaminoethyl)ether to obtain a reaction mixture comprises reacting N-protected (S)-4-halophenylalanine of Formula I, a boronating agent, Grignard reagent and bis(2-methylaminoethyl)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-boronophenylalanine;

adding a first extractive solvent so as to obtain N-protected (S)-4-boronophenylalanine.

8. The method according to claim 2, wherein 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 trialkyl 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 a second 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 a second 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 a third organic solvent into a reaction vessel;

adjusting the pH value to 6.15-6.25 so as to obtain L-BPA.

11. The method according to claim 1, wherein the Grignard reagent is tert-butylmagnesium chloride (t-BuMgCl).

12. 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 reaction mixture comprises N-protected (S)-4-boronophenylalanine of Formula II and the R² group represents a protecting group;

13. The method according to claim 12, wherein the R¹ group of N-protected (S)-4-halophenylalanine of Formula I is iodide or bromide, 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, the Grignard reagent includes alkylmagnesium chloride, alkylmagnesium bromide, arylmagnesium chloride or arylmagnesium bromide.

14. The method according to claim 12, 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.

15. The method according to claim 12, 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.

16. The method according to claim 12, wherein the Grignard reagent is tert-butylmagnesium chloride (t-BuMgCl).

17. 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-methylaminoethyl)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;

18. The method according to claim 17, wherein the Grignard reagent is tert-butylmagnesium chloride (t-BuMgCl).

19. The method according to claim 17, wherein the step of reacting N-protected (S)-4-halophenylalanine of Formula I, a boronating agent, Grignard reagent and bis(2-methylaminoethyl)ether to obtain a reaction mixture comprises reacting N-protected (S)-4-halophenylalanine of Formula I, a boronating agent, Grignard reagent and bis(2-methylaminoethyl)ether at a temperature ranging from 0°

C. to 60°

C. to obtain the reaction mixture.

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