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Preparation method of N-Fmoc-N '-Boc-alpha-methyl-L-lysine

A n-fmoc-n, -boc- technology, applied in the field of synthetic chemistry, can solve the problems of poor chiral purity of products, and achieve the effect of safety and reliability, simple process conditions and high purity

Pending Publication Date: 2022-04-05
上海药坦药物研究开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The present invention provides a new synthetic route and preparation method for the defect of poor chiral purity of the product existing in the existing preparation method of N-Fmoc-N'-Boc-α-methyl-L-lysine

Method used

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  • Preparation method of N-Fmoc-N '-Boc-alpha-methyl-L-lysine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] (1) Synthesis of compound 4

[0045] Under nitrogen protection, 100 g of compound 3 (ie: tert-butylbenzyl carbamate), 448 g of 1,4-diiodobutane were added into 1000 mL of anhydrous tetrahydrofuran, stirred and cooled to 0°C. Control the temperature below 0°C, add 58 g of 60% sodium hydrogen solution in batches, stir for 1 hour after the addition is complete, then warm to room temperature, stir for 6 hours, liquid chromatography detects that the remaining 0.2% of the mass of the raw material compound 3 is 0.2%.

[0046] Control the temperature below 5°C, add the reaction suspension liquid dropwise into 1000mL citric acid aqueous solution with a mass concentration of 15%, add dropwise for 2h, then add 500mL ethyl acetate, stir and separate the layers, wash the organic phase with 500mL water, and concentrate to dry. Use an oil pump to distill under reduced pressure at 150°C and 0.09Mpa to recover 1,4-diiodobutane. The obtained crude concentrate is a product containing co...

Embodiment 2

[0057] (1) Synthesis of compound 4

[0058] Under the protection of helium, 50g of tert-butylbenzyl carbamate and 187g of 1,4-diiodobutane were added into 750mL of anhydrous tetrahydrofuran, stirred and cooled to -10°C. Control the temperature below -10°C, add 24 g of 60% sodium hydrogen solution in batches, stir for 0.5 hours after the addition is complete, then warm up to room temperature, stir for 18 hours, liquid chromatography detects that the remaining 0.5% of the mass of the raw material compound 3 is 0.5%.

[0059] Control the temperature below 10°C, add the reaction suspension liquid dropwise into 500mL citric acid aqueous solution with a mass concentration of 15%, dropwise for 15min, then add 350mL 2-methyltetrahydrofuran, stir and separate the layers, and wash the organic phase with 500mL water, Concentrate to dryness. Use an oil pump to distill under reduced pressure at 120°C and 0.09Mpa to recover 1,4-diiodobutane. The obtained crude concentrate is a product con...

Embodiment 3

[0068] (1) Synthesis of compound 4

[0069] Under nitrogen protection, 50 g of tert-butylbenzyl carbamate and 261 g of 1,4-diiodobutane were added into 1000 mL of anhydrous tetrahydrofuran, stirred and cooled to 5°C. Control the temperature below 5°C, add 34g of 60% sodium hydrogen solution in batches, stir for 0.5 hours after the addition is complete, then warm to room temperature, stir for 5 hours, liquid chromatography detects that the remaining 1.5% of the mass of the raw material compound 3 is 1.5%.

[0070] Control the temperature below 10°C, add the reaction suspension dropwise to 750mL of water for 60min, then add 450mL of methyl tert-butyl ether, stir and separate layers, wash the organic phase with 500mL of water, and concentrate to dryness. Use an oil pump to distill under reduced pressure at 150°C and 0.09Mpa to recover 1,4-diiodobutane. The obtained crude concentrate is a product containing compound 4, and the crude concentrate can be directly used in the next re...

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Abstract

The invention belongs to the field of medical chemistry, and particularly relates to a preparation method of N-Fmoc-N '-Boc-alpha-methyl-L-lysine (hereinafter referred to as a compound 1). Aiming at the defects of tedious steps, high byproduct content, low yield and poor production safety in the existing preparation method of N-Fmoc-N '-Boc-alpha-methyl-L-lysine, the invention provides a new synthesis route and preparation method: 1, 4-diiodobutane is used as a starting material and is subjected to nucleophilic substitution with a compound 3 to generate a compound 4; the method comprises the following steps: reacting a compound 1 with a compound 2 to generate a compound 5 under the action of KHMDS, removing chiral prothetic groups and protecting groups through hydrogenation reduction, and protecting with Fmoc to obtain a compound 1, and the total yield is 52.6%. According to the route, N-Fmoc-N '-Boc-alpha-methyl-L-lysine is obtained through four-step convergent synthesis, and the production period is greatly shortened. The method has the advantages of simple production process steps, high yield, few byproducts, high process safety, good stability and environmental protection.

Description

technical field [0001] The invention belongs to the field of synthetic chemistry, and specifically relates to a preparation method of N-Fmoc-N'-Boc-α-methyl-L-lysine. Background technique [0002] Unnatural optically pure amino acids play a vital role in the synthesis of bioactive peptides and the synthesis of novel amino acids. They can also be used to increase the stability of polypeptides against enzymatic degradation. [0003] Among them, Cα-alkylated amino acids are less prone to racemization under basic or acidic conditions due to the lack of lossable or enolized α-hydrogens. At the same time, it also restricts the rotation of N-Cα(φ) and Cα-C(o)(ψ) bonds of amino acids in the peptide sequence, stabilizing the conformation of the peptide backbone. [0004] N-Fmoc-N'-Boc-α-methyl-L-lysine is one of the most widely used and very valuable compounds. [0005] The document "Novel synthesis of various orthogonally protected Cα-methyllysine analogues and biological evaluat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/04C07C271/22C07C269/06C07C271/14C07D265/32
Inventor 刘学军陈晓冬洪辉意曲海深张士磊魏林
Owner 上海药坦药物研究开发有限公司
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