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EP-4737440-A1 - METHOD FOR PREPARING FMOC-TRP(BOC)-OH

EP4737440A1EP 4737440 A1EP4737440 A1EP 4737440A1EP-4737440-A1

Abstract

The present application provides a method for preparing Fmoc-Trp(Boc)-OH, comprising steps of: reacting tryptophan with N-(9-fluorenylmethoxycarbonyloxy)succinimide in the presence of a base to obtain an intermediate compound as represented by formula (3), reacting the intermediate compound as represented by formula (3) with benzyl halide in the presence of a base to obtain an intermediate compound as represented by formula (4); reacting the intermediate compound as represented by formula (4) with di-tert-butyl dicarbonate in the presence of a catalyst to obtain an intermediate compound as represented by formula (6), deprotecting the intermediate compound as represented by formula (6) to obtain Fmoc-Trp(Boc)-OH. The method provided in the present application uses a four-step reaction to synthesize Fmoc-Trp(Boc)-OH, avoiding a step of introducing Fmoc on H-Trp(Boc)-OH. The method simplifies the process, features simple operations and mild reaction conditions, and reduces the difficulty of industrial production. Furthermore, the method does not involve expensive raw materials, which is beneficial for controlling production costs, and the product can be obtained with a high purity and a high yield.

Inventors

  • FANG, XIAOLONG
  • DENG, Jianlong
  • LIANG, Hongguo
  • LIU, RUNYU
  • LIN, Shiyu
  • FENG, Xubin
  • LI, Jiaxun

Assignees

  • Sichuan Shifang Sangao Biochemical Industrial Co., Ltd.

Dates

Publication Date
20260506
Application Date
20251015

Claims (10)

  1. A method for preparing Fmoc-Trp(Boc)-OH, comprising steps of: a) reacting tryptophan with N-(9-fluorenylmethoxycarbonyloxy)succinimide in the presence of a base to obtain an intermediate compound as represented by formula (3); b) reacting the intermediate compound as represented by formula (3) with benzyl halide in the presence of a base to obtain an intermediate compound as represented by formula (4); c) reacting the intermediate compound as represented by formula (4) with di-tert-butyl dicarbonate in the presence of a catalyst to obtain an intermediate compound as represented by formula (6); and d) deprotecting the intermediate compound as represented by formula (6) to obtain Fmoc-Trp(Boc)-OH.
  2. The method according to claim 1, wherein in step a), the base is an inorganic base; and tryptophan, N-(9-fluorenylmethoxycarbonyloxy)succinimide, and the base have a mole ratio of 1:(0.8 to 1.3):(1 to 2.5).
  3. The method according to claim 2, wherein in step a), the reaction is performed at 25°C to 35°C for 2 h to 6 h; and the reaction is performed in a medium, and the medium is water and an organic solvent, wherein the organic solvent is selected from the group consisting of ethyl acetate, acetone, and tetrahydrofuran.
  4. The method according to claim 1, wherein in step b), the base is an inorganic base; and the intermediate compound as represented by formula (3), benzyl halide, and the base have a mole ratio of 1:(1 to 1.5):(1.1 to 2.0).
  5. The method according to claim 4, wherein in step b), the base is selected from the group consisting of sodium carbonate and potassium carbonate.
  6. The method according to claim 4, wherein in step b), the reaction is performed at 60°C to 80°C for 2 h to 4 h; and the reaction is performed in a medium, and the medium is an organic solvent, wherein the organic solvent is selected from the group consisting of acetonitrile and ethyl acetate.
  7. The method according to claim 1, wherein in step c), the catalyst is 4-dimethylaminopyridine; and the intermediate compound as represented by formula (4), the catalyst, and di-tert-butyl dicarbonate have a mole ratio of 1:(0.040 to 0.045):(1 to 2).
  8. The method according to claim 7, wherein in step c), the reaction is performed at 10°C to 35°C for 0.5 h to 2 h; and the reaction is performed in a medium, and the medium is an organic solvent, wherein the organic solvent is selected from the group consisting of dichloromethane, acetonitrile, ethyl acetate, and tetrahydrofuran.
  9. The method according to claim 1, wherein step d) specifically comprises: reacting the intermediate compound as represented by formula (6) with hydrogen in the presence of a catalyst to obtain Fmoc-Trp(Boc)-OH.
  10. The method according to claim 9, wherein in step d), the catalyst is selected from the group consisting of Pd/C, raney nickel, and Pd/BaSO 4 ; the intermediate compound as represented by formula (6) and the catalyst have a mass ratio of 1:(0.01 to 0.1); and the reaction is performed at 20°C to 30°C for 16 h to 20 h.

Description

FIELD The present disclosure relates to the field of pharmaceutical synthesis technology, and more specifically relates to a method for preparing Fmoc-Trp(Boc)-OH. BACKGROUND Fmoc-Trp(Boc)-OH is a common intermediate in the synthesis of peptides such as semaglutide, tirzepatide, and the like. The full chemical name of Fmoc-Trp(Boc)-OH is N-alpha-(9-fluorenylmethoxycarbonyl)-N-in-tert-butoxycarbonyl-L-tryptophan, with a molecular formula of C31H30N2O6, a CAS number of 143824-78-6, and a structural formula of: In the synthetic routes of Fmoc-Trp(Boc)-OH disclosed in the prior art, an intermediate H-Trp(Boc)-OH is always obtained first, then Fmoc is introduced to obtain Fmoc-Trp(Boc)-OH. However, H-Trp(Boc)-OH is unstable during the step of introducing Fmoc, resulting in production of Fmoc-Trp-OH as an impurity, which is almost impossible to be removed from Fmoc-Trp(Boc)-OH, thereby influencing the yield and purity of Fmoc-Trp(Boc)-OH. For example, CN202110672717 has disclosed two routes for synthesizing Fmoc-Trp(Boc)-OH. The first route is: The second route is: CN202211006819 has also disclosed a synthesis route as follows: The aforementioned synthesis routes have a relatively low yield and purity, as well as a complex process. SUMMARY In view of the foregoing, the present disclosure provides a method for preparing Fmoc-Trp(Boc)-OH. The method provided in the present disclosure features a simple process, a mild reaction condition, and Fmoc-Trp(Boc)-OH can be obtained with a high purity and a high yield. The present disclosure provides a method for preparing Fmoc-Trp(Boc)-OH, comprising steps of: a) reacting tryptophan with N-(9-fluorenylmethoxycarbonyloxy)succinimide in the presence of a base to obtain an intermediate compound as represented by formula (3); b) reacting the intermediate compound as represented by formula (3) with benzyl halide in the presence of a base to obtain an intermediate compound as represented by formula (4); c) reacting the intermediate compound as represented by formula (4) with di-tert-butyl dicarbonate in the presence of a catalyst to obtain an intermediate compound as represented by formula (6); and d) deprotecting the intermediate compound as represented by formula (6) to obtain Fmoc-Trp(Boc)-OH. In some specific embodiments, in step a), the base is an inorganic base; and tryptophan, N-(9-fluorenylmethoxycarbonyloxy)succinimide, and the base have a mole ratio of 1:(0.8 to 1.3):(1 to 2.5). In some specific embodiments, in step a), the reaction is performed at 25°C to 35°C for 2 h to 6 h; and the reaction is performed in a medium, and the medium is water and an organic solvent, wherein the organic solvent is selected from the group consisting of ethyl acetate, acetone, and tetrahydrofuran. In some specific embodiments, in step b), the base is an inorganic base; and the intermediate compound as represented by formula (3), benzyl halide, and the base have a mole ratio of 1:(1 to 1.5):(1.1 to 2.0). In some specific embodiments, in step b), the base is selected from the group consisting of sodium carbonate and potassium carbonate. In some specific embodiments, in step b), the reaction is performed at 60°C to 80°C for 2 h to 4 h; and the reaction is performed in a medium, and the medium is an organic solvent, wherein the organic solvent is selected from the group consisting of acetonitrile and ethyl acetate. In some specific embodiments, in step c), the catalyst is 4-dimethylaminopyridine; and the intermediate compound as represented by formula (4), the catalyst, and di-tert-butyl dicarbonate have a mole ratio of 1:(0.040 to 0.045):(1 to 2). In some specific embodiments, in step c), the reaction is performed at 10°C to 35°C for 0.5 h to 2 h; and the reaction is performed in a medium, and the medium is an organic solvent, wherein the organic solvent is selected from the group consisting of dichloromethane, acetonitrile, ethyl acetate, and tetrahydrofuran. In some specific embodiments, step d) specifically comprises: reacting the intermediate compound as represented by formula (6) with hydrogen in the presence of a catalyst to obtain Fmoc-Trp(Boc)-OH. In some specific embodiments, in step d), the catalyst is selected from the group consisting of Pd/C, raney nickel, and Pd/BaSO4; the intermediate compound as represented by formula (6) and the catalyst have a mass ratio of 1:(0.01 to 0.1); andthe reaction is performed at 20°C to 30°C for 16 h to 20 h. The present disclosure provides a method for preparing Fmoc-Trp(Boc)-OH, comprising steps of: a) reacting tryptophan with N-(9-fluorenylmethoxycarbonyloxy)succinimide in the presence of a base to obtain an intermediate compound as represented by formula (3); b) reacting the intermediate compound as represented by formula (3) with benzyl halide in the presence of a base to obtain an intermediate compound as represented by formula (4); c) reacting the intermediate compound as represented by formula (4) with di-tert-butyl dicarbonate in the prese