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KR-20260062871-A - METHOD FOR PREPARING FMOC-TRP(BOC)-OH

KR20260062871AKR 20260062871 AKR20260062871 AKR 20260062871AKR-20260062871-A

Abstract

The present invention provides a method for preparing Fmoc-Trp(Boc)-OH, comprising the steps of: reacting tryptophan with N-(9-fluorenylmethoxycarbonyloxy)succinimide in the presence of a base to obtain an intermediate compound represented by Formula 3; reacting the intermediate compound represented by Formula 3 with a benzyl halide in the presence of a base to obtain an intermediate compound represented by Formula 4; reacting the intermediate compound represented by Formula 4 with di-tert-butyl dicarbonate in the presence of a catalyst to obtain an intermediate compound represented by Formula 6; and deprotecting the intermediate compound represented by Formula 6 to obtain Fmoc-Trp(Boc)-OH. The method provided in the present invention synthesizes Fmoc-Trp(Boc)-OH using a four-step reaction and avoids the step of introducing Fmoc into H-Trp(Boc)-OH. The method of the present invention simplifies the process and features simple operation and mild reaction conditions, thereby reducing the difficulties of industrial production. Furthermore, since the method does not involve expensive raw materials, it is advantageous for controlling manufacturing costs and enables the production of products with high purity and high yield.

Inventors

  • 팡, 시아오롱
  • 덩, 지안롱
  • 량, 홍구오
  • 리우, 런위
  • 린, 시위
  • 펑, 수빈
  • 리, 지아선

Assignees

  • 쓰촨 스팡 상가오 바이오케미컬 인더스트리얼 씨오., 엘티디.

Dates

Publication Date
20260507
Application Date
20251028
Priority Date
20241029

Claims (10)

  1. A method for preparing Fmoc-Trp(Boc)-OH comprising the following steps: a) a step of reacting tryptophan with N-(9-fluorenylmethoxycarbonyloxy)succinimide in the presence of a base to obtain an intermediate compound represented by the following chemical formula 3; [Chemical Formula 3] b) a step of reacting the intermediate compound represented by Chemical Formula 3 above with a benzyl halide in the presence of a base to obtain an intermediate compound represented by Chemical Formula 4 below; [Chemical Formula 4] c) a step of reacting the intermediate compound represented by Chemical Formula 4 above with di-tert-butyl dicarbonate in the presence of a catalyst to obtain an intermediate compound represented by Chemical Formula 6 below; and [Chemical Formula 6] d) A step of deprotecting the intermediate compound represented by the above chemical formula 6 to obtain Fmoc-Trp(Boc)-OH.
  2. In paragraph 1, in step a), the base is an inorganic base; A method in which the molar ratio of tryptophan, N-(9-fluorenylmethoxycarbonyloxy)succinimide, and base is 1:(0.8 to 1.3):(1 to 2.5).
  3. In paragraph 2, in step a), the reaction is carried out at 25°C to 35°C for 2 to 6 hours, and A method in which the reaction is carried out in a medium, the medium is water and an organic solvent, and the organic solvent is selected from the group consisting of ethyl acetate, acetone, and tetrahydrofuran.
  4. In paragraph 1, in step b), the base is an inorganic base; A method in which the molar ratio of the intermediate compound represented by Chemical Formula 3, the benzyl halide, and the base is 1:(1 to 1.5):(1.1 to 2.0).
  5. In paragraph 4, in step b), the base is selected from the group consisting of sodium carbonate and potassium carbonate.
  6. In paragraph 4, in step b), the reaction is carried out at 60°C to 80°C for 2 to 4 hours, and A method in which the reaction is carried out in a medium, the medium is an organic solvent, and the organic solvent is selected from the group consisting of acetonitrile and ethyl acetate.
  7. In claim 1, in step c), the catalyst is 4-dimethylaminopyridine, and A method in which the molar ratio of the intermediate compound represented by Chemical Formula 4, the catalyst, and the di-tert-butyl dicarbonate is 1:(0.040 to 0.045):(1 to 2).
  8. In claim 7, in step c), the reaction is carried out at 10°C to 35°C for 0.5 hours to 2 hours, and A method in which the reaction is carried out in a medium, the medium is an organic solvent, and the organic solvent is selected from the group consisting of dichloromethane, acetonitrile, ethyl acetate, and tetrahydrofuran.
  9. In paragraph 1, step d) is, A method specifically comprising the step of reacting an intermediate compound represented by Chemical Formula 6 with hydrogen in the presence of a catalyst to obtain Fmoc-Trp(Boc)-OH.
  10. In claim 9, at step d), the catalyst is selected from the group consisting of Pd/C, Raney nickel, and Pd/ BaSO4 ; The mass ratio of the intermediate compound represented by Chemical Formula 6 and the catalyst is 1:(0.01 to 0.1); A method in which the reaction is carried out at 20°C to 30°C for 16 to 20 hours.

Description

Method for Preparing FMOC-TRP(BOC)-OH The present invention relates to the field of pharmaceutical synthesis technology, and more specifically, to a method for producing Fmoc-Trp(Boc)-OH. Fmoc-Trp(Boc)-OH is a common intermediate in the synthesis of peptides such as semaglutide and tirzepatide. The full chemical name of Fmoc-Trp(Boc)-OH is N-alpha-(9-fluorenylmethoxycarbonyl)-N-phosphorus-tert- butoxycarbonyl - L - tryptophan , the molecular formula is C₃H₃O₆N₂O₆ , the CAS number is 143824-78-6, and the structural formula is as follows: . In conventionally disclosed synthesis pathways for Fmoc-Trp(Boc)-OH, the intermediate H-Trp(Boc)-OH is always obtained first, followed by the introduction of Fmoc to obtain Fmoc-Trp(Boc)-OH. However, H-Trp(Boc)-OH is unstable during the Fmoc introduction step, resulting in the formation of Fmoc-Trp-OH as an impurity. Since this impurity is nearly impossible to remove from Fmoc-Trp(Boc)-OH, it affects the yield and purity of the product. For example, CN202110672717 describes two pathways for synthesizing Fmoc-Trp(Boc)-OH. The first path is as follows: . The second path is as follows: . CN202211006819 also described the following synthesis route: . The aforementioned synthesis route involves not only a complex process but also relatively low yield and purity. Figure 1 is an HPLC chromatogram of the intermediate Fmoc-Trp-OH prepared in Example 1. Figure 2 is an HPLC chromatogram of the intermediate Fmoc-Trp-OBZl prepared in Example 1. Figure 3 is an HPLC chromatogram of the intermediate Fmoc-Trp(Boc)-OBZl prepared in Example 1. Figure 4 is an HPLC chromatogram of the intermediate Fmoc-Trp(Boc)-OH prepared in Example 1. Figure 5 is the infrared spectrum of the intermediate Fmoc-Trp(Boc)-OH prepared in Example 1. Figure 6 is an HPLC chromatogram of the intermediate Fmoc-Trp-OH prepared in Example 2. Figure 7 is an HPLC chromatogram of the intermediate Fmoc-Trp-OBZl prepared in Example 2. Figure 8 is an HPLC chromatogram of the intermediate Fmoc-Trp(Boc)-OBZl prepared in Example 2. Figure 9 is an HPLC chromatogram of Fmoc-Trp(Boc)-OH prepared in Example 2. Figure 10 is the infrared spectrum of Fmoc-Trp(Boc)-OH prepared in Example 2. Figure 11 is the nuclear magnetic resonance spectrum of Fmoc-Trp(Boc)-OH prepared in Example 2. Unless otherwise understood from the context and usage, the expression “one or more” should be understood to include, individually, each object cited after the expression as well as various different combinations of two or more of the cited objects. The expression “and/or” combined with three or more cited objects should be understood to have the same meaning unless otherwise understood from the context. The use of the terms "containing," "having," or "containing," including grammatical synonyms, should generally be understood as open-ended and non-restrictive unless otherwise specifically stated or understood from the context, and, for example, does not exclude other unmentioned elements or steps. It should be understood that, as long as the present disclosure is kept operable, the order of steps or the order in which specific operations are performed is not important. Additionally, two or more steps or operations may be performed simultaneously. All exemplary expressions used herein, such as “e.g.” or “comprising,” are merely intended to clarify the content of the disclosure and are not intended to limit the scope of the disclosure unless claimed. Nothing in the language of this specification should be construed as indicating that any unclaimed element is essential to carrying out the disclosure. Furthermore, numerical ranges and parameters used to define the present disclosure are approximations, and relevant figures in specific embodiments are presented as accurately as possible in this specification. However, any figures include standard deviations inherently and inevitably arising from individual test methods. Accordingly, unless specifically stated otherwise, all ranges, quantities, figures, and percentages used in the present invention should be understood as modified by "approximately." In this specification, "approximately" generally means that the actual value is within ±10%, ±5%, ±1%, or ±0.5% of a specific figure or range. The present invention provides a method for producing Fmoc-Trp(Boc)-OH, comprising the following steps: a) a step of reacting tryptophan with N-(9-fluorenylmethoxycarbonyloxy)succinimide in the presence of a base to obtain an intermediate compound represented by the following chemical formula 3; [Chemical Formula 3] b) a step of reacting the intermediate compound represented by Chemical Formula 3 above with a benzyl halide in the presence of a base to obtain an intermediate compound represented by Chemical Formula 4 below; [Chemical Formula 4] c) a step of reacting the intermediate compound represented by Chemical Formula 4 above with di-tert-butyl dicarbonate in the presence of a catalyst to obtain an intermediate compound