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CN-121991108-A - Method for preparing and purifying 4-dihydroxyboryl-L-phenylalanine

CN121991108ACN 121991108 ACN121991108 ACN 121991108ACN-121991108-A

Abstract

The present disclosure provides a method for preparing and purifying 4-dihydroxyboryl-L-phenylalanine comprising 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 4-halo-phenylalanine, thereby reducing the reaction steps and improving the reaction efficiency.

Inventors

  • CHENG JIAN
  • Chen Menen

Assignees

  • 旭富制药科技股份有限公司

Dates

Publication Date
20260508
Application Date
20251106
Priority Date
20241108

Claims (18)

  1. 1. A method for preparing 4-dihydroxyboryl-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 resulting from step a) with a boration agent.
  2. 2. The method for producing 4-dihydroxyboryl-L-phenylalanine according to claim 1, wherein the halogen of 4-halo-phenylalanine is fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  3. 3. The process for preparing 4-dihydroxyboryl-L-phenylalanine according to claim 1, wherein the grignard reagent is a C 1 -C 15 linear or branched alkyl magnesium halide.
  4. 4. The process for preparing 4-dihydroxyboryl-L-phenylalanine according to claim 3, wherein said C 1 -C 15 linear or branched alkyl magnesium halide is isopropyl magnesium chloride, sec-butyl magnesium chloride or trimethylsilylmethyl magnesium chloride.
  5. 5. The method for preparing 4-dihydroxyboryl-L-phenylalanine according to claim 1, wherein the grignard reagent is further combined with a metal halide.
  6. 6. The method for preparing 4-dihydroxyboryl-L-phenylalanine according to claim 5, wherein said metal halide is lithium chloride.
  7. 7. The method for producing 4-dihydroxyboryl-L-phenylalanine according to claim 1, wherein the organic base is an amidine compound or a guanidine compound.
  8. 8. The method for producing 4-dihydroxyboryl-L-phenylalanine according to claim 7, wherein said amidine compound is represented by formula (I): (I), Wherein each of R 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 R 1 to R 4 are not H and are linked to each other to form a substituted or unsubstituted ring.
  9. 9. The method for preparing 4-dihydroxyboryl-L-phenylalanine according to claim 8, wherein the amidine compound is1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene, diamidinazine, benzamidine, pentamidine, ranitidine, or any combination thereof.
  10. 10. The method for producing 4-dihydroxyboryl-L-phenylalanine according to claim 7, wherein said guanidine compound is represented by formula (II): (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 R 1 to R 5 are not H and are linked to each other to form a substituted or unsubstituted ring.
  11. 11. The method for preparing 4-dihydroxyboryl-L-phenylalanine according to claim 10, wherein the guanidine compound is 1, 3-tetramethylguanidine, 2-tert-butyl-1, 3-tetramethylguanidine, 7-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene, or any combination thereof.
  12. 12. The process for preparing 4-dihydroxyboryl-L-phenylalanine according to claim 1, wherein the reaction in step a) is performed at a temperature in the range of-30 ℃ to 10 ℃.
  13. 13. The process for preparing 4-dihydroxyboryl-L-phenylalanine according to claim 1, wherein the reaction in step a) is performed with a molar equivalent of the grignard reagent to the 4-halo-phenylalanine of at least 4.0 and a molar equivalent of the organic base to the 4-halo-phenylalanine of at least 1.0.
  14. 14. The method for producing 4-dihydroxyboryl-L-phenylalanine according to claim 1, wherein the borating agent is a borate ester or a boric acid amide.
  15. 15. The process for preparing 4-dihydroxyboryl-L-phenylalanine according to claim 1, wherein the reaction in step b) is performed at a temperature in the range of-50 ℃ to 10 ℃.
  16. 16. The process for preparing 4-dihydroxyboryl-L-phenylalanine according to claim 1, wherein the reaction in step b) is performed with a molar equivalent of the borating agent to the 4-halo-phenylalanine of at least 0.9.
  17. 17. The method for producing 4-dihydroxyboryl-L-phenylalanine according to claim 1, further comprising: c) Quenching the reaction of step b) with an acid solution.
  18. 18. A method for purifying 4-dihydroxyboryl-L-phenylalanine comprising purifying 4-dihydroxyboryl-L-phenylalanine obtained from any one of claims 1 to 17 using a reverse phase column.

Description

Method for preparing and purifying 4-dihydroxyboryl-L-phenylalanine Technical Field The present disclosure relates to a method for the preparation and purification of 4-dihydroxyboryl-L-phenylalanine. Background 4-Dihydroxyboryl-L-phenylalanine is used in Boron Neutron Capture Therapy (BNCT). Various methods for the preparation of 4-dihydroxyboryl-L-phenylalanine are currently known, such as those disclosed in U.S. Pat. No. 4,930,26B 2 and U.S. patent application publication No. 5,262A 1. US8765997B2 discloses a reaction between N-protected 4-iodo-phenylalanine and N-butyllithium to form phenyl carbanion, and then allowing the intermediate compound to attack the boron ester to form a precursor of 4-dihydroxyboryl-L-phenylalanine. US2023416280A1 also describes a process in which N-protected 4-iodo-phenylalanine is reacted with an isopropyl magnesium chloride-lithium chloride complex (i-prmgcl. Licl, also known as "turbo grignard reagent") to form phenyl carbanions. The intermediate compound then attacks the borate ester to form a precursor of 4-dihydroxyboryl-L-phenylalanine. Obviously, the current methods in the art for preparing 4-dihydroxyboryl-L-phenylalanine use at least one starting material with a protecting group for the amino group to initiate the reaction. This protecting group needs to be removed after the initial reaction to produce 4-dihydroxyboryl-L-phenylalanine, the target compound, thus lengthening the reaction time and decreasing the yield. Furthermore, it is common for any reaction development method to increase the reaction efficiency or molar ratio. In the case of the preparation of 4-dihydroxyboryl-L-phenylalanine, the reaction efficiency of a borating agent such as the aforementioned boron esters is of particular concern, since the borating agent is normally the most expensive component involved in the preparation of 4-dihydroxyboryl-L-phenylalanine. For example, US8765997B2 discloses that the reaction is carried out with a molar equivalent of the borating agent to the N-protected 4-iodo-phenylalanine exceeding 3, so that it is preferable to further reduce the molar ratio. In summary, a key problem to be solved in the art is to provide a method for the preparation and purification of 4-dihydroxyboryl-L-phenylalanine which reduces the reaction steps, increases the reaction efficiency and maximizes the yield. Disclosure of Invention In view of the above-described shortcomings of the prior art, the present disclosure provides a process for preparing 4-dihydroxyboryl-L-phenylalanine that does not require starting materials with protecting groups and thus omits the deprotection process. For the above purpose, the present disclosure provides a process for the preparation of 4-dihydroxyboryl-L-phenylalanine comprising the 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 resulting from step a) with a boration agent. In one embodiment of the disclosed method, the halogen of 4-halo-phenylalanine is fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). In one embodiment of the methods of the present disclosure, the 4-halo-phenylalanine is 4-iodo-phenylalanine. In one embodiment of the disclosed method, the grignard reagent is a C 1-C15 linear or branched alkyl magnesium halide. In one embodiment of the disclosed process, the alkyl magnesium halide is isopropyl magnesium chloride, sec-butyl magnesium chloride or trimethylsilyl methyl magnesium chloride. In one embodiment of the disclosed method, the grignard reagent is further combined with a metal halide to form a mixture. In one embodiment of the disclosed method, the metal halide is lithium chloride. In one embodiment of the disclosed method, the mixture of grignard reagent and metal halide is a turbo grignard reagent. In one embodiment of the disclosed method, the turbo grignard reagent is an isopropyl magnesium chloride-lithium chloride complex (i-prmgcl. Licl). In one embodiment of the methods of the present disclosure, the organic base is an amidine compound or a guanidine compound. In one embodiment of the disclosed method, the amidine compound is represented by formula (I): (I), Wherein each of R 1 to R 4 is independently selected from the group consisting of H, a substituted or unsubstituted C 1-C20 alkyl group, and a substituted or unsubstituted C 1-C20 cycloalkyl group, or Any two of R 1 to R 4 are not H and are linked to each other to form a substituted or unsubstituted ring. In one embodiment of the disclosed method, the amidine compound is 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN), diamidinazine (diminazene), benzamidine, pentanamidine, ryatolin (paranyline), or any combination thereof. In one embodiment of the methods of the present disclosure, the guanidine compound is represented by formula (II): (II), Wherein each of R 1 to R 5 is independently selected from the grou