Search

EP-4737434-A2 - METHOD FOR PREPARING FMOC-LYS(IVDDE)-OH

EP4737434A2EP 4737434 A2EP4737434 A2EP 4737434A2EP-4737434-A2

Abstract

The present disclosure provides a method for preparing Fmoc-Lys(Ivdde)-OH, comprising steps of: reacting dimedone with isovaleric acid in the presence of a condensing agent to obtain an intermediate compound; then reacting the intermediate compound with N-alpha-tert-butoxycarbonyl-L-Lysine in the presence of an organic base to obtain an intermediate; then reacting the intermediate with an acid to obtain another intermediate; and finally reacting the another intermediate with N-(9-fluorenylmethoxycarbonyloxy)succinimide in the presence of an inorganic base to obtain Fmoc-Lys(Ivdde)-OH. The method provided by the present disclosure uses dimedone as a starting material to synthesize Fmoc-Lys(Ivdde)-OH via a four-step reaction comprising two condensation reactions, a Boc deprotection reaction, and an Fmoc protection reaction. 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 a product is obtained with a high purity and a high yield.

Inventors

  • LIANG, Hongguo
  • FANG, XIAOLONG
  • LI, QI
  • WAN, XIN
  • YANG, JIAN
  • TIAN, Mingcheng
  • 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-Lys(Ivdde)-OH, comprising steps of: a) reacting dimedone with isovaleric acid in the presence of a condensing agent to obtain an intermediate compound Ivdde-OH as represented by formula (3); b) reacting the intermediate compound Ivdde-OH as represented by formula (3) with N-alpha-tert-butoxycarbonyl-L-Lysine in the presence of an organic base to obtain an intermediate Boc-Lys(Ivdde)-OH as represented by formula (5); c) reacting the intermediate Boc-Lys(Ivdde)-OH as represented by formula (5) with an acid to obtain an intermediate Lys(Ivdde)-OH as represented by formula (6); d) reacting the intermediate Lys(Ivdde)-OH as represented by formula (6) with N-(9-fluorenylmethoxycarbonyloxy)succinimide in the presence of an inorganic base to obtain Fmoc-Lys(Ivdde)-OH as represented by formula (8);
  2. The method according to claim 1, wherein in step a), the condensing agent is selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide and a mixture thereof; the dimedone, the isovaleric acid, and the condensing agent have a mole ratio of 1:(0.8 to 1.3):(1 to 1.5).
  3. The method according to claim 2, wherein in step a), the reaction is performed in a medium selected from the group consisting of dichloromethane, acetone, and tetrahydrofuran; the reaction is performed at room temperature for 12 h to 16 h.
  4. The method according to claim 1, wherein in step b), the organic base is selected from the group consisting of triethylamine, N, N-diisopropylethylamine and a mixture thereof; N-alpha-tert-butoxycarbonyl-L-Lysine, Ivdde-OH and the organic 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 reaction is performed in a medium selected from the group consisting of acetonitrile, methanol, and ethanol; the reaction is performed at 65°C to 75°C for 12 h to 14 h.
  6. The method according to claim 1, wherein in step c), the acid is hydrochloric acid; Boc-Lys(Ivdde)-OH and the acid have a mole ratio of 1:(5 to 8).
  7. The method according to claim 6, wherein in step c), the reaction is performed at room temperature for 6 h to 8 h.
  8. The method according to claim 1, wherein in step d), the inorganic base is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate and a mixture thereof.
  9. The method according to claim 8, wherein in step d), Lys(lvdde)-OH, N-(9-fluorenylmethoxycarbonyloxy)succinimide, and the inorganic base have a mole ratio of 1:(0.7 to 1.0):(1.2 to 1.5).
  10. The method according to claim 8, wherein in step d), the reaction is performed in a medium selected from the group consisting of ethyl acetate, acetone, and tetrahydrofuran; the reaction is performed at 25°C to 30°C for 3 h to 4 h.

Description

FIELD The present disclosure relates to the field of pharmaceutical synthesis technology, and more specifically relates to a method for preparing Fmoc-Lys(Ivdde)-OH. BACKGROUND Fmoc-Lys(Ivdde)-OH is a common intermediate in the synthesis of peptides such as semaglutide, tirzepatide, and the like. The full chemical name of Fmoc-Lys(Ivdde)-OH is N-(9-fluorenylmethoxycarbonyl)-N'-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]-L-lysine, with a molecular formula of C34H42N2O6, a CAS number of 204777-78-6, and a structural formula of: The prior art (By Chhabra, Siri Ram; et al. Tetrahedron Letters (1998), 39(12), 1603-1606) discloses a method for preparing Fmoc-Lys(Ivdde)-OH. This method involves reacting Fmoc-Lys, Ivdde-OH and trifluoroacetic acid in ethanol under reflux for 60 h, followed by a post-process to obtain Fmoc-Lys(Ivdde)-OH. The reaction process is as follows: However, in the above reaction process, trifluoroacetic acid has strong corrosiveness, and the reaction is carried out at high temperature for a long time, resulting in high safety risks and poor suitability for large-scale production. SUMMARY In view of the foregoing, the purpose of the present disclosure is to provide a method for preparing Fmoc-Lys(Ivdde)-OH. The method provided in the present disclosure features a simple process, a mild reaction condition, a low cost, and an implementability of industrial production. The present disclosure provides a method for preparing Fmoc-Lys(Ivdde)-OH, comprising steps of: a) reacting dimedone with isovaleric acid in the presence of a condensing agent to obtain an intermediate compound Ivdde-OH as represented by formula (3); b) reacting the intermediate compound Ivdde-OH as represented by formula (3) with N-alpha-tert-butoxycarbonyl-L-Lysine in the presence of an organic base to obtain an intermediate Boc-Lys(Ivdde)-OH as represented by formula (5); c) reacting the intermediate Boc-Lys(Ivdde)-OH as represented by formula (5) with an acid to obtain an intermediate Lys(Ivdde)-OH as represented by formula (6); d) reacting the intermediate Lys(Ivdde)-OH as represented by formula (6) with N-(9-fluorenylmethoxycarbonyloxy)succinimide in the presence of an inorganic base to obtain Fmoc-Lys(Ivdde)-OH as represented by formula (8); In some specific embodiments, in step a), the condensing agent is selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide and a mixture thereof; dimedone, isovaleric acid, and the condensing agent have a mole ratio of 1:(0.8 to 1.3):(1 to 1.5). In some specific embodiments, in step a), the reaction is performed in a medium selected from the group consisting of dichloromethane, acetone, and tetrahydrofuran; the reaction is performed at room temperature for 12 h to 16 h. In some specific embodiments, in step b), the organic base is selected from the group consisting of triethylamine, N, N-diisopropylethylamine and a mixture thereof; N-alpha-tert-butoxycarbonyl-L-Lysine, Ivdde-OH and the organic base have a mole ratio of 1:(1 to 1.5):(1.1 to 2.0). In some specific embodiments, in step b), the reaction is performed in a medium selected from the group consisting of acetonitrile, methanol, and ethanol; the reaction is performed at 65°C to 75°C for 12 h to 14 h. In some specific embodiments, in step c), the acid is hydrochloric acid; Boc-Lys(Ivdde)-OH and the acid have a mole ratio of 1:(5 to 8). In some specific embodiments, in step c), the reaction is performed at room temperature for 6 h to 8 h. In some specific embodiments, in step d), the inorganic base is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate and a mixture thereof. In some specific embodiments, in step d), Lys(Ivdde)-OH, N-(9-fluorenylmethoxycarbonyloxy)succinimide, and the inorganic base have a mole ratio of 1:(0.7 to 1.0):(1.2 to 1.5). In some specific embodiments, in step d), the reaction is performed in a medium selected from the group consisting of ethyl acetate, acetone, and tetrahydrofuran; the reaction is performed at 25°C to 30°C for 3 h to 4 h. The present disclosure provides a method for preparing Fmoc-Lys(Ivdde)-OH, comprising steps of: a) reacting dimedone with isovaleric acid in the presence of a condensing agent to obtain an intermediate compound Ivdde-OH as represented by formula (3); b) reacting the intermediate compound Ivdde-OH as represented by formula (3) with N-alpha-tert-butoxycarbonyl-L-Lysine in the presence of an organic base to obtain an intermediate Boc-Lys(Ivdde)-OH as represented by formula (5); c) reacting the intermediate Boc-Lys(Ivdde)-OH as represented by formula (5) with an acid to obtain an intermediate Lys(Ivdde)-OH as represented by formula (6); d) reacting the intermediate Lys(Ivdde)-OH as represented by formula (6) with N-(9-fluorenylmethoxycarbonyloxy)succinimide in the presence of an inorganic base to obtain Fmoc-Lys(Ivdde)-OH as represented by formula (8). T