Search

KR-20260062870-A - METHOD FOR PREPARING FMOC-LYS(IVDDE)-OH

KR20260062870AKR 20260062870 AKR20260062870 AKR 20260062870AKR-20260062870-A

Abstract

The present invention provides a method for preparing Fmoc-Lys(Ivdde)-OH, comprising the steps of: reacting dimedone with isovaleric acid in the presence of a condensing agent to obtain an intermediate compound; subsequently reacting the intermediate compound with N-alpha-tert-butoxycarbonyl-L-lysine in the presence of an organic base to obtain an intermediate; subsequently reacting the intermediate with an acid to obtain another intermediate; and finally, reacting the other 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 invention is a method for synthesizing Fmoc-Lys(Ivdde)-OH using dimedone as a starting material through a four-step reaction including two condensation reactions: a Boc deprotection reaction and a Fmoc protection reaction. This method simplifies the process and features simple operation and mild reaction conditions, thereby reducing the difficulties of industrial production. Furthermore, since this method does not involve expensive raw materials, it is advantageous for controlling manufacturing costs and yields products of high purity and high yield.

Inventors

  • 량, 홍구오
  • 팡, 시아오롱
  • 리, 치
  • 완, 신
  • 양, 지안
  • 티안, 밍청
  • 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-Lys(Ivdde)-OH comprising the following steps: a) a step of reacting dimedone with isovaleric acid in the presence of a condensing agent to obtain an intermediate compound Ivdde-OH represented by the following chemical formula 3; [Chemical Formula 3] b) a step of reacting the intermediate compound Ivdde-OH represented by Chemical Formula 3 above with N-alpha-tert-butoxycarbonyl-L-lysine in the presence of an organic base to obtain the intermediate Boc-Lys(Ivdde)-OH represented by Chemical Formula 5 below; [Chemical Formula 5] c) a step of reacting the intermediate Boc-Lys(Ivdde)-OH represented by the above chemical formula 5 with an acid to obtain the intermediate Lys(Ivdde)-OH represented by the following chemical formula 6; and [Chemical Formula 6] d) a step of reacting the intermediate Lys(Ivdde)-OH represented by Chemical Formula 6 above with N-(9-fluorenylmethoxycarbonyloxy)succinimide in the presence of an inorganic base to obtain Fmoc-Lys(Ivdde)-OH represented by Chemical Formula 8 below; [Chemical Formula 8] .
  2. In claim 1, in step a), the condensing agent is selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide, and mixtures thereof; A method in which the molar ratio of dimedone, isovaleric acid, and condensing agent is 1:(0.8 to 1.3):(1 to 1.5).
  3. In paragraph 2, in step a), the reaction is carried out in a medium selected from the group consisting of dichloromethane, acetone, and tetrahydrofuran; A method in which the reaction is carried out at room temperature for 12 to 16 hours.
  4. In claim 1, in step b), the organic base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine and mixtures thereof; A method in which the molar ratio of N-alpha-tert-butoxycarbonyl-L-lysine, Ivdde-OH, and organic base is 1:(1 to 1.5):(1.1 to 2.0).
  5. In paragraph 4, in step b), the reaction is carried out in a medium selected from the group consisting of acetonitrile, methanol, and ethanol; A method in which the reaction is carried out at 65°C to 75°C for 12 to 14 hours.
  6. In paragraph 1, in step c), the acid is hydrochloric acid; A method in which the molar ratio of Boc-Lys(Ivdde)-OH to acid is 1:(5 to 8).
  7. In claim 6, in step c), the reaction is carried out at room temperature for 6 to 8 hours.
  8. A 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 mixtures thereof.
  9. In claim 8, the method wherein, in step d), the molar ratio of Lys(Ivdde)-OH, N-(9-fluorenylmethoxycarbonyloxy)succinimide, and the inorganic base is 1:(0.7 to 1.0):(1.2 to 1.5).
  10. In claim 8, at step d), the reaction is carried out in a medium selected from the group consisting of ethyl acetate, acetone, and tetrahydrofuran; A method in which the reaction is carried out at 25°C to 30°C for 3 to 4 hours.

Description

Method for Preparing FMOC-LYS(IVDDE)-OH The present invention relates to the field of pharmaceutical synthesis technology, and more specifically, to a method for preparing Fmoc-Lys(Ivdde)-OH. Fmoc-Lys(Ivdde)-OH is a common intermediate in the synthesis of peptides such as semaglutide and tirzepatide. 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 , its molecular formula is C₃₄H₄₂N₂O₆ , its CAS number is 204777-78-6 , and its structural formula is as follows: . Prior art (Reference: Chhabra, Siri Ram et al., Tetrahedron Letters (1998), 39(12), 1603-1606) describes 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 hours, followed by post-treatment to obtain Fmoc-Lys(Ivdde)-OH. The reaction process is as follows: However, in the above reaction process, trifluoroacetic acid is highly corrosive, and since the reaction proceeds at high temperatures for a long time, it poses a high safety risk and is not suitable for large-scale production. FIG. 1 is an HPLC chromatogram of Fmoc-Lys(Ivdde)-OH prepared in Example 2 provided in the present invention; FIG. 2 is the infrared spectrum of Fmoc-Lys(Ivdde)-OH prepared in Example 2 provided in the present invention; Figure 3 is the nuclear magnetic resonance spectrum of Fmoc-Lys(Ivdde)-OH prepared in Example 2 provided in the present invention. The technical means of the present invention is described clearly and completely with reference to some embodiments of the present invention. It should be understood that the described embodiments are only some, not all, of the possible embodiments of the present disclosure. Based on the embodiments of the present disclosure, all other embodiments obtained by a person skilled in the art without applying the inventive effort shall fall within the scope of protection of the present invention. In the disclosure of the present invention, terms such as “center,” “longitudinal,” “transverse,” “length,” “width,” “thickness,” “top,” “bottom,” “front,” “rear,” “left,” “right,” “vertical,” “horizontal,” “top,” “bottom,” “inner,” “outer,” “clockwise,” and “counterclockwise” are to be understood as referring to directional or positional relationships as depicted in the accompanying drawings. These terms are used merely for convenience and to simplify the description of the present disclosure and are not intended to indicate or imply that the referenced device or element must have a specific orientation or be configured and operated in a specific orientation. Accordingly, these terms should not be interpreted as limiting the present invention. Furthermore, terms such as "first" and "second" are used for descriptive purposes only and should not be interpreted as indicating or implying relative importance, nor should they be interpreted as implicitly indicating the number of specified technical features. Accordingly, a feature defined by "first" or "second" may explicitly or implicitly include one or more of the aforementioned features. In the disclosure of the present invention, the meaning of "plural" is two or more unless specifically otherwise defined. Moreover, the terms "mounting," "connection," and "coupling" should be understood in a broad sense. For example, a connection may be a fixed connection, a detachable connection, or an integrated connection; a mechanical connection or an electrical connection; a direct connection or an indirect connection through an intermediate medium; or an internal communication between two elements. A person skilled in the art to which the present invention pertains will understand the specific meaning of the above terms in the present invention according to the specific context. The present invention provides a method for preparing Fmoc-Lys(Ivdde)-OH, comprising the following steps: a) a step of reacting dimedone with isovaleric acid in the presence of a condensing agent to obtain an intermediate compound Ivdde-OH represented by the following chemical formula 3; [Chemical Formula 3] b) a step of reacting the intermediate compound Ivdde-OH represented by Chemical Formula 3 above with N-alpha-tert-butoxycarbonyl-L-lysine in the presence of an organic base to obtain the intermediate Boc-Lys(Ivdde)-OH represented by Chemical Formula 5 below; [Chemical Formula 5] c) a step of reacting the intermediate Boc-Lys(Ivdde)-OH represented by the above chemical formula 5 with an acid to obtain the intermediate Lys(Ivdde)-OH represented by the following chemical formula 6; and [Chemical Formula 6] d) a step of reacting the intermediate Lys(Ivdde)-OH represented by Chemical Formula 6 above with N-(9-fluorenylmethoxycarbonyloxy)succinimide in the presence of an inorganic base to obtain Fmoc-Lys(Ivdde)-OH represented by Chemical Formula 8 below; [Chemical Formula 8] . The method provided in the present invention is a method for