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Cholyglycine polyethylene glycol derivative and preparation method of cholyglycine polyethylene glycol derivative

A technology of polyethylene glycol and polyethylene glycol carbamate, which is applied in the field of glycolic acid polyethylene glycol derivatives and their preparation fields, and can solve the problem of preparation methods for derivatives that do not see the coupling of glycolic acid and PEG, etc. problem, to achieve the effect of improving water solubility, high yield, and improving action efficiency

Active Publication Date: 2017-12-22
湖南华腾制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the prior art, there is no derivate coupled with glycocholic acid and PEG or its preparation method

Method used

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  • Cholyglycine polyethylene glycol derivative and preparation method of cholyglycine polyethylene glycol derivative
  • Cholyglycine polyethylene glycol derivative and preparation method of cholyglycine polyethylene glycol derivative
  • Cholyglycine polyethylene glycol derivative and preparation method of cholyglycine polyethylene glycol derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] (1) Add 20g of tert-butyl amino-terminated polyethylene glycol carbamate to 100ml of saturated sodium bicarbonate, weigh 13.8g of N-methoxycarbonylmaleimide, and slowly add The above solution, and stirred for 2h. TLC showed that the reaction was complete, and ethyl acetate was extracted 3 times. The ethyl acetate phase was dried with anhydrous sodium sulfate, spin-dried, and column purified to obtain 22 g of the product, yield: 90%. The NMR data are as follows: 1 HNMR (400MHz, CDCl 3 ): δ: 6.726 (s, 2H); 5.501 (s, 1H); 3.652-3.635 (m, 6H); 3.130 (t, J=4.8Hz, 2H); 1.412 (s, 9H).

[0041] (2) Dissolve 22g of the product in step (1) in 250ml of dichloromethane, add 30ml of trifluoroacetic acid, and react at 20°C for 5h. TLC showed that the reaction was complete, spin-dried, and purified on a silica gel column to obtain 13 g of product with a yield of 91%. The NMR data are as follows: 1 HNMR (400MHz, CDCl 3 ): δ: 8.721 (s, 1H); 6.701 (s, 2H); 5.530 (s, 1H); 3.650~3.6...

Embodiment 2

[0044] (1) Add 20g of tert-butyl amino-terminated polyethylene glycol carbamate to 100ml of saturated sodium bicarbonate, weigh 13.8g of N-methoxycarbonylmaleimide, and slowly add The above solution, and stirred for 1h. TLC showed that the reaction was complete, and extracted 3 times with ethyl acetate. The ethyl acetate phase was dried with anhydrous sodium sulfate, spin-dried, and column purified to obtain 20.7 g of the product, yield: 85%. The NMR data are as follows: 1 HNMR (400MHz, CDCl 3 ): δ: 6.726 (s, 2H); 5.501 (s, 1H); 3.652~3.635 (m, 6H); 3.130 (t, J=4.8Hz, 2H); 1.412 (s, 9H).

[0045] (2) Dissolve 20.7g of the product in step (1) in 250ml of dichloromethane, add 30ml of trifluoroacetic acid, and react at 20°C for 5h. TLC showed that the reaction was complete, spin-dried, and purified on a silica gel column to obtain 13 g of product with a yield of 93%. The NMR data are as follows: 1 HNMR (400MHz, CDCl 3 ): δ: 8.712 (s, 1H); 6.711 (s, 2H); 5.520 (s, 1H); 3.65...

Embodiment 3

[0048] (1) Add 20g of tert-butyl amino-terminated polyethylene glycol carbamate to 100ml of saturated sodium bicarbonate, weigh 13.8g of N-methoxycarbonylmaleimide, and slowly add The above solution, and stirred for 3h. TLC showed that the reaction was complete, and extracted 3 times with ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate, spin-dried, and column purified to obtain 19.8 g of the product, yield: 81%. The NMR data are as follows: 1 HNMR (400MHz, CDCl 3 ): δ: 6.726 (s, 2H); 5.501 (s, 1H); 3.652~3.635 (m, 6H); 3.130 (t, J=4.8Hz, 2H); 1.412 (s, 9H).

[0049] (2) Dissolve 19.8g of the product in step (1) in 250ml of dichloromethane, add 30ml of trifluoroacetic acid, and react at 20°C for 5h. TLC showed that the reaction was complete, spin-dried, and purified on a silica gel column to obtain 11.7 g of product with a yield of 91%. The NMR data are as follows: 1 HNMR (400MHz, CDCl 3 ): δ: 8.721 (s, 1H); 6.706 (s, 2H); 5.532 (s, 1H); 3....

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Abstract

The invention relates to a cholyglycine polyethylene glycol derivative and a preparation method of the cholyglycine polyethylene glycol derivative. The method mainly comprises the following steps: 1), enabling amine-terminated polyethylene glycol tert-Butyl carbamate and N-methoxy carbonyl maleimide to react under the action of an alkali to obtain an amino tert-butyl formate polyethylene glycol maleimide intermediate, wherein the molar ratio of amine-terminated polyethylene glycol tert-Butyl carbamate to N-methoxy carbonyl maleimide is (1.1-1.3):1; 2) removing tert-Butyl formate in the amino tert-butyl formate polyethylene glycol maleimide intermediate to obtain an amine-terminated polyethylene glycol maleimide intermediate; 3) enabling cholyglycine and the amine-terminated polyethylene glycol maleimide intermediate to react under the action of a condensing agent and the alkali to obtain cholyglycine polyethylene glycol maleimide. The technological process of the preparation method is short, the reaction operation is simple and convenient, the side reaction is few, the cost is low, the selectivity of the reaction is high, and the yield of the preparation method is higher.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a glycocholic acid polyethylene glycol derivative and a preparation method thereof. Background technique [0002] Serum cholyglycine (CG) is one of the conjugated bile acids formed by the combination of bile acid and glycine. In hepatocytes, cholesterol is transformed into primary bile acids through an extremely complex enzymatic reaction. Among them are cholic acid (CA) and chenodeoxycholic acid (CD-CA). There are three hydroxyl groups (C3, C7 and C12) on the steroid core of cholic acid, and the hydroxyl group at the end of the side chain is combined with glycine through a peptide bond, with a molecular weight of 462U. Bile acid is synthesized by liver cells, discharged into the gallbladder through the capillaries and bile ducts, and enters the duodenum with bile to help digest food. 95% of the bile acid is reabsorbed in the terminal ileum, returns to the liver through...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J43/00C08G65/333A61K47/28
CPCA61K47/28C07J43/003C08G65/33396
Inventor 邓泽平成佳张安林李虎
Owner 湖南华腾制药有限公司