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Preparation method of double-protected lysine containing boc side chain amino protection

A lysine, double protection technology, applied in the field of synthesis of double protected lysine (Fmoc-Lys-OH), can solve the problems of high price and high raw material cost, reduce costs, solve safety and environmental protection problems, solve The effect of high cost of raw materials

Active Publication Date: 2017-09-29
GENCHEM & GENPHARM CHANGZHOU CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The process of the present invention will avoid the generation of irritating and toxic gases when sodium sulfide is decoppered, and solve the problem of safety and environmental protection; at the same time, it will solve the problem of high raw material cost caused by the high price of 8-hydroxyquinoline

Method used

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  • Preparation method of double-protected lysine containing boc side chain amino protection

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1, the synthesis process of double-protected lysine (Fmoc-Lys(Boc)-OH) containing Boc side chain amino protection. refer to figure 1 .

[0045] ⑴. Disperse 146 grams of lysine in 300 ml of tetrahydrofuran; ⑵. Add 57 grams of sodium methoxide while stirring in an ice bath; ⑶. Naturally warm to room temperature and stir for 1 hour. ⑷. Add 203 grams of 50% boron trifluoride tetrahydrofuran solution; ⑸. Slowly heat up to 50 degrees; ⑹. Stir for 5 hours until the system is clear. ⑺. Add 262 grams of di-tert-butyl dicarbonate in tetrahydrofuran; ⑻. Control the pH of liquid caustic soda to about 8 until the reaction is complete. ⑼. Add 20 ml of liquid caustic soda; ⑽. Stir in ice bath for half an hour. ⑾. Tetrahydrofuran was recovered under reduced pressure, and a large amount of white solids were precipitated; ⑿. The wet intermediate H-Lys(Boc)-OH was obtained by centrifugation.

Embodiment 2

[0047] .Add 800 grams of water and 800 grams of ethyl acetate to the wet product of H-Lys(Boc)-OH obtained in Example 1, stir well and adjust the pH to 9 with liquid caustic soda. .Add about 350 grams of Fmoc-osu in batches until the reaction is complete, and use liquid caustic soda to control the pH to 9-10 during the reaction. .After the reaction, adjust the pH to 3 with industrial hydrochloric acid; . Separate the ethyl acetate layer, and wash the ethyl acetate layer with saturated brine; .Dried over anhydrous sodium sulfate, filtered with suction, and precipitated; . Add 4.3KG of tertiary methyl ether and beat for 2 hours, filter with suction, and dry the solid to obtain 202 grams. HPLC analysis product content is greater than 99.5%. . Suction filtration, and the solid was air-dried to obtain a product content greater than 99.5% according to HPLC analysis.

Embodiment 3

[0048] Embodiment 3 is basically the same as Embodiment 1 and 2, but has the following changes:

[0049] In step (1), the weight-volume ratio of lysine and THF is: 1:5;

[0050] In step (2), the mol ratio of lysine and sodium methylate is: 1:0.8;

[0051] In step (4), the mol ratio of lysine and boron trifluoride is: 1:0.9;

[0052] In step (7), the mol ratio of lysine and di-tert-butyl dicarbonate is: 1:0.9;

[0053] In step ⑼, the weight ratio of lysine to 30% liquid caustic soda is: 4:1; described liquid caustic soda adopts sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

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Abstract

A preparation method of double-protection lysine with Boc side-chain amino protection is characterized by comprising the following steps: alpha-amino and carboxyl of lysine are protected with boron trifluoride as a complexing agent; Boc anhydride is added to perform selective protection on epsilon-amino; a boron complex is removed with alkali liquor; alpha-amino is protected by Fmoc-OSU (9-fluorenylmethyl N-succinimidyl carbonate), and the required product is obtained. With the adoption of the preparation method, irritable and toxic gas produced during decoppering of sodium sulfide in a traditional process is avoided, and the problems about safety and environmental protection are solved; the problem of high raw material cost caused by high price of 8-hydroxyquinoline is also solved, and the cost can be reduced by 15% by comparison with the traditional process.

Description

technical field [0001] The invention relates to the field of synthesis of polypeptide derivatives, in particular to a synthesis process of double-protected lysine (Fmoc-Lys(Boc)-OH) containing Boc side chain amino protection. Background technique [0002] Lysine, one of the most common amino acids, contains an amino group in the side chain and is therefore a basic amino acid. Side chain amino groups have strong reactivity, so they need to be protected during peptide synthesis. Fmoc-L-Lys(Boc)-OH is a commonly used double-protected lysine, and the side chain amino protecting group is commonly used Boc. [0003] The traditional preparation process of this product is to use Cu +2 Or 9-BBN is used as a complexing reagent to protect the lysine alpha-amino group and carboxyl group, then add Boc anhydride to selectively protect the epsilon-amino group, and finally use sodium sulfide or 8-hydroxyquinoline and other copper removal reagents to remove copper or The 9-BBN is removed ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C271/22C07C269/04
CPCC07C269/04C07C269/06C07F5/02C07C271/22
Inventor 王玉琴詹玉进张璞
Owner GENCHEM & GENPHARM CHANGZHOU CO LTD
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