CN-122010783-A - Synthesis method of N-Fmoc-N- (2-fluoroethyl) glycine

Abstract

The application relates to a synthesis method of N-Fmoc-N- (2-fluoroethyl) glycine, which comprises the following synthesis routes: S1, adding 2-fluoroethylamine hydrochloride and tert-butyl bromoacetate into an organic solvent, adding a base catalyst to carry out SN2 nucleophilic substitution reaction, carrying out post-treatment to obtain a compound 1, S2, adding the compound 1 into the organic solvent, adding the base catalyst, then adding Fmoc-OSu to carry out Fmoc-protected nucleophilic acyl substitution reaction, carrying out post-treatment to obtain a compound 2, S3, adding the compound 2 into the organic solvent, adding a deprotection reagent to carry out deprotection reaction, and carrying out post-treatment to obtain the N-Fmoc-N- (2-fluoroethyl) glycine. The application has the effect of improving the synthesis efficiency of N-Fmoc-N- (2-fluoroethyl) glycine, and meets the requirements of high purity and high yield of polypeptide inhibitor research and development and amplified production.

Inventors

• XU HONGYAN
• WANG PENGTAO

Assignees

• 康化（上海）新药研发有限公司

Dates

Publication Date

20260512

Application Date

20260130

Claims (10)

1. 1. A synthesis method of N-Fmoc-N- (2-fluoroethyl) glycine is characterized by comprising the following synthesis routes: ; The method comprises the following steps: S1, adding 2-fluoroethylamine hydrochloride and tert-butyl bromoacetate into an organic solvent, adding a base catalyst to carry out SN2 nucleophilic substitution reaction, and carrying out aftertreatment to obtain a compound 1; S2, adding the compound 1 into an organic solvent, adding a base catalyst, adding Fmoc-OSu to perform Fmoc-protected nucleophilic acyl substitution reaction, and performing post-treatment to obtain a compound 2; s3, adding the compound 2 into an organic solvent, adding a deprotection reagent for deprotection reaction, and performing post-treatment to obtain the N-Fmoc-N- (2-fluoroethyl) glycine.
2. 2. The method for synthesizing N-Fmoc-N- (2-fluoroethyl) glycine according to claim 1, wherein said base catalyst in step S1 is selected from one or more of DIPEA, DMAP, DBU, TEA.
3. 3. The method for synthesizing N-Fmoc-N- (2-fluoroethyl) glycine according to claim 2, wherein the base catalyst in step S1 comprises DBU and TEA.
4. 4. The method for synthesizing N-Fmoc-N- (2-fluoroethyl) glycine according to claim 1, wherein the base catalyst in step S2 is one or both selected from DIPEA and DMAP.
5. 5. The method for synthesizing N-Fmoc-N- (2-fluoroethyl) glycine according to claim 4, wherein said base catalyst in step S2 comprises DIPEA and DMAP.
6. 6. The method for synthesizing N-Fmoc-N- (2-fluoroethyl) glycine according to claim 5, wherein said DIPEA and DMAP are present in a molar ratio of 1 (0.05-0.1).
7. 7. The method for synthesizing N-Fmoc-N- (2-fluoroethyl) glycine according to claim 1, wherein the organic solvent in step S3 comprises dichloromethane and trifluoroethanol.
8. 8. The method for synthesizing N-Fmoc-N- (2-fluoroethyl) glycine according to claim 1, wherein said deprotection reagent in step S3 is selected from one or more of TFA, acetic acid, TFAA.
9. 9. The method for synthesizing N-Fmoc-N- (2-fluoroethyl) glycine according to claim 8, wherein the deprotection reagent in step S3 comprises TFA, acetic acid and TFAA.
10. 10. The method for synthesizing N-Fmoc-N- (2-fluoroethyl) glycine according to claim 1, wherein said step S3 further comprises magnesium sulfate.

Description

Synthesis method of N-Fmoc-N- (2-fluoroethyl) glycine Technical Field The application relates to the technical field of organic synthesis, in particular to a synthesis method of N-Fmoc-N- (2-fluoroethyl) glycine. Background N-Fmoc-N- (2-fluoroethyl) glycine is taken as an important amino acid derivative of N-substituted glycine, has Fmoc protecting groups and fluoroethyl modifying groups in the molecular structure, has key application value (US 2024/158446) in the field of polypeptide synthesis, particularly in the research and development of RAS protein polypeptide inhibitors and other medicaments, and along with the promotion of the research and development of related medicaments, the market demand for the compound with high purity and mass production is increasingly vigorous. In order to meet the application requirements of the method in the synthesis of medicines, the development of efficient, mild and amplified synthesis technology becomes an important research point in the field, and targeted technical innovation and optimization are needed. At present, the conventional synthesis of N-substituted glycine mainly uses glycine derivatives, amine compounds and halogenated esters as starting materials, an N-substituted structure is constructed through nucleophilic substitution reaction, and then the preparation of a target product is completed through the steps of modification of a protecting group, deprotection and the like. The core logic of such methods is to utilize the nucleophilic activity of amine groups and the electrophilic activity of haloesters to build carbon-nitrogen bonds while regulating the reaction selectivity through protecting groups (e.g., fmoc). Aiming at N-Fmoc-N- (2-fluoroethyl) glycine, no special synthesis report exists due to the specificity of fluoroethyl in the structure (electronegativity of fluorine atoms affects amine nucleophilicity) and the suitability requirement of Fmoc protecting groups, and the related research needs to explore the matched raw material combination and reaction path based on the synthesis principle of similar compounds. However, the preparation of N-Fmoc-N- (2-fluoroethyl) glycine by using the conventional synthesis thought of N-substituted glycine has remarkable challenges, namely on one hand, the difficulty in regulating and controlling the reactivity of fluoroethyl-substituted amine raw materials is high, side reactions (such as polysubstituted and fluorine atoms are easy to fall off), and on the other hand, the conventional method has the problems of expensive raw materials, harsh reaction conditions (such as high temperature and high pressure), complex purification steps and the like, and is difficult to adapt to the requirement of large-scale production. In addition, the selective introduction of Fmoc protecting groups and the directional deprotection of tert-butyl ester groups require precise control of reaction conditions, and a conventional single reagent system is difficult to achieve both reaction efficiency and product purity, so that the large-scale preparation of the compound is further limited, and therefore, development of a synthesis method which is low in raw material cost, mild in condition, simple in purification and suitable for amplification is needed. Disclosure of Invention In order to improve the synthesis efficiency of preparing N-Fmoc-N- (2-fluoroethyl) glycine, the application provides a synthesis method of N-Fmoc-N- (2-fluoroethyl) glycine. The application provides a synthesis method of N-Fmoc-N- (2-fluoroethyl) glycine, which adopts the following technical scheme: a synthesis method of N-Fmoc-N- (2-fluoroethyl) glycine comprises the following synthesis routes: ; The method comprises the following steps: S1, adding 2-fluoroethylamine hydrochloride and tert-butyl bromoacetate into an organic solvent, adding a base catalyst to carry out SN2 nucleophilic substitution reaction, and carrying out aftertreatment to obtain a compound 1; S2, adding the compound 1 and Fmoc-OSu into an organic solvent, adding a base catalyst to perform Fmoc-protected nucleophilic acyl substitution reaction, and performing post-treatment to obtain a compound 2; s3, adding the compound 2 into an organic solvent, adding a deprotection reagent for deprotection reaction, and performing post-treatment to obtain the N-Fmoc-N- (2-fluoroethyl) glycine. The inventor can efficiently and selectively synthesize the target compound according to the structural characteristics of N-Fmoc-N- (2-fluoroethyl) glycine through three directional synthesis routes of SN2 nucleophilic substitution, fmoc protection nucleophilic acyl substitution and deprotection, which are obtained through a large number of experiments. Specifically, the nucleophilic property of the amino group of 2-fluoroethylamine hydrochloride and the alpha-methylene electrophilicity of tert-butyl bromoacetate are utilized in the first step, a carbon-nitrogen bond is constructed through an SN2 mechanism, a com