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EP-4741403-A1 - METHOD FOR PREPARING AND PURIFYING 4-BORONO-L-PHENYLALANINE

EP4741403A1EP 4741403 A1EP4741403 A1EP 4741403A1EP-4741403-A1

Abstract

The present disclosure provides a method for 4-borono-L-phenylalanine preparation and purification including reacting 4-halo-phenylalanine with a Grignard reagent in the presence of an amidine compound or a guanidine compound without using a protecting group for the amino group of the 4-halo-phenylalanine, thereby reducing reaction step and improving yield.

Inventors

  • CHENG, CHIEN
  • Chen, Men-En

Assignees

  • SCI Pharmtech, Inc.

Dates

Publication Date
20260513
Application Date
20251107

Claims (15)

  1. A method for preparing 4-borono-L-phenylalanine comprising: a) reacting 4-halo-phenylalanine with a Grignard reagent in the presence of an organic base to form a reaction mixture; and b) reacting the reaction mixture obtained from step a) with a boronating agent.
  2. The method for preparing 4-borono-L-phenylalanine of claim 1, wherein the halogen of 4-halo-phenylalanin is fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
  3. The method for preparing 4-borono-L-phenylalanine of claim 1, wherein the Grignard reagent is a C 1 -C 15 linear or branched alkylmagnesium halide.
  4. The method for preparing 4-borono-L-phenylalanine of claim 3, wherein the C 1 -C 15 linear or branched alkylmagnesium halide is isopropylmagnesium chloride, sec-butylmagnesium chloride, or trimethylsilylmethylmagnesium chloride.
  5. The method for preparing 4-borono-L-phenylalanine of claim 1, wherein the Grignard reagent is further combined with a metal halide, preferably the metal halide is lithium chloride.
  6. The method for preparing 4-borono-L-phenylalanine of claim 1, wherein the organic base is an amidine compound or a guanidine compound.
  7. The method for preparing 4-borono-L-phenylalanine of claim 6, wherein the amidine compound is represented by formula (I): wherein each ofR 1 to R 4 is independently selected from the group consisting of H, a substituted or unsubstituted C 1 -C 20 alkyl group, and a substituted or unsubstituted C 1 -C 20 cycloalkyl group, or any two of the R 1 to R 4 are not H and are linked to each other to form a substituted or unsubstituted ring, preferably the amidine compound is 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, diminazene, benzamidine, pentamidine, paranyline, or any combination thereof.
  8. The method for preparing 4-borono-L-phenylalanine of claim 6, wherein the guanidine compound is represented by formula (II): wherein each of R 1 to R 5 is independently selected from the group consisting of H, a substituted or unsubstituted C 1 -C 20 alkyl group, and a substituted or unsubstituted C 1 -C 20 cycloalkyl group, or any two of the R 1 to R 5 are not H and are linked to each other to form a substituted or unsubstituted ring, preferably the guanidine compound is 1,1,3,3-tetramethylguanidine, 2-tert-Butyl-1,1,3,3-tetramethylguanidine, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, or any combination thereof.
  9. The method for preparing 4-borono-L-phenylalanine of claim 1, wherein the reaction in the step a) is performed at a temperature ranging from -30°C to 10°C.
  10. The method for preparing 4-borono-L-phenylalanine of claim 1, wherein the reaction in the step a) is performed at a molar equivalent of the Grignard reagent to the 4-halo-phenylalanine is at least 4.0 and a molar equivalent of the organic base to the 4-halo-phenylalanine is at least 1.0.
  11. The method for preparing 4-borono-L-phenylalanine of claim 1, wherein the boronating agent is a boric acid ester or a boric acid amide.
  12. The method for preparing 4-borono-L-phenylalanine of claim 1, wherein the reaction in the step b) is performed at a temperature ranging from -50°C to 10°C.
  13. The method for preparing 4-borono-L-phenylalanine of claim 1, wherein the reaction in the step b) is performed at a molar equivalent of the boronating agent to the 4-halo-phenylalanine is at least 0.9.
  14. The method for preparing 4-borono-L-phenylalanine of claim 1, further comprising c) quenching the reaction of step b) with an acid solution.
  15. A method for purifying 4-borono-L-phenylalanine, comprising purifying the 4-borono-L-phenylalanine obtained from any one of claims 1-14 using a reversed-phase column.

Description

BACKGROUND 1. Technical Field The present disclosure relates to a method for 4-borono-L-phenylalanine preparation and purification. 2. Description of Associated Art 4-Borono-L-phenylalanine is used for Boron Neutron Capture Therapy (BNCT). Many methods for 4-borono-L-phenylalanine preparation are currently known, such as those disclosed in U.S. Patent No. US8765997B2 and U.S. Patent Application Publication No. US2023416280A1. US8765997B2 discloses a reaction between an N-protected 4-iodo-phenylalanine and an n-butyl lithium to form a phenyl carbanion, and then the intermediate compound attacks a boron ester to form a precursor of 4-borono-L-phenylalanine. US2023416280A1 also describes a method where a N-protected 4-iodo-phenylalanine reacts with an isopropylmagnesium chloride-lithium chloride complex (i-PrMgC1.LiCl, also known as a "turbo Grignard reagent") to form a phenyl carbanion. The intermediate compound then attacks a boron ester to form a precursor of 4-borono-L-phenylalanine. It is clear that the current methods for preparing 4-borono-L-phenylalanine in the art involve initiating the reaction with at least one starting material that has protecting group for an amino group. Such protecting group needs to be removed after the initial reaction to produce the target compound 4-borono-L-phenylalanine, thus lengthening reaction time and lowering yield. Further, there is a general need to improve the efficiency or input molar ratio of any reaction method. In the case of the preparation of 4-borono-L-phenylalanine, the reaction efficiency of boronating agents such as aforementioned boron ester is of particular interest as the boronating agents normally are the most expensive ingredient involved in the preparation of 4-borono-L-phenylalanine. For example, US8765997B2 discloses performing the reaction at a molar equivalent of the boronating agent to the N-protected 4-iodo-phenylalanine of over 3, and it is preferable to further decrease the molar ratio. In conclusion, there is an issue needed to be solved urgently in the art to provide a method for 4-borono-L-phenylalanine preparation and purification that reduces reaction steps, improves reaction efficiency and maximizes yield. SUMMARY Given the disadvantages of the prior art described above, the present disclosure provides a method for preparing 4-borono-L-phenylalanine that does not require a starting material having a protecting group, and thus omitting the deprotection process. For the purpose above, the present disclosure provides a method for 4-borono-L-phenylalanine preparation comprises steps of a) reacting 4-halo-phenylalanine with a Grignard reagent in the presence of an organic base to form a reaction mixture; and b) reacting the reaction mixture obtained from step a) with a boronating agent. In one embodiment of the method of the present disclosure, the halogen of 4-halo-phenylalanin is fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). In one embodiment of the method of the present disclosure, the 4-halo-phenylalanin is 4-iodo-phenylalanine. In one embodiment of the method of the present disclosure, the Grignard reagent is a C1-C15 linear or branched alkylmagnesium halide. In one embodiment of the method of the present disclosure, the alkylmagnesium halide is isopropylmagnesium chloride, sec-butylmagnesium chloride, or trimethylsilylmethylmagnesium chloride. In one embodiment of the method of the present disclosure, the Grignard reagent is further combined with a metal halide to form a mixture. In one embodiment of the method of the present disclosure, the metal halide is lithium chloride. In one embodiment of the method of the present disclosure, the mixture of the Grignard reagent and the metal halide is a turbo Grignard reagent. In one embodiment of the method of the present disclosure, the turbo Grignard reagent is an isopropylmagnesium chloride-lithium chloride complex (i-PrMgCl.LiCl). In one embodiment of the method of the present disclosure, the organic base is an amidine compound or a guanidine compound. In one embodiment of the method of the present disclosure, the amidine compound is represented by formula (I): wherein each of R1 to R4 is independently selected from the group consisting of H, a substituted or unsubstituted C1-C20 alkyl group, and a substituted or unsubstituted C1-C20 cycloalkyl group, orany two of the R1 to R4 are not H and are linked to each other to form a substituted or unsubstituted ring. In one embodiment of the method of the present disclosure, the amidine compound is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), diminazene, benzamidine, pentamidine, paranyline, or any combination thereof. In one embodiment of the method of the present disclosure, the guanidine compound is represented by formula (II): wherein each of R1 to R5 is independently selected from the group consisting of H, a substituted or unsubstituted C1-C20 alkyl group, and a substituted or unsubstituted