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A kind of preparation method of dexloglutamine

A technology of dexloglutamine and glutamic acid, which is applied in the field of medicine, can solve the problems of cumbersome post-processing and low total yield, and achieve the effect of simple operation and high yield

Active Publication Date: 2021-02-26
LANZHOU INST OF ANIMAL SCI & VETERINARY PHARMA OF CAAS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] 1. The total yield of the reaction is extremely low, and D-glutamic acid is used as a raw material to synthesize dexloglutamine 1, and the total yield is about 10%.
[0013] 2. During the synthesis of 1, since intermediate 4 has an unprotected carboxyl group, it reacts with the raw material 3,4-dichlorobenzoyl chloride to form an ester. After the reaction, it needs to be purified with dicyclohexylamine to form a salt, and then acidified to form The target product 1 makes this post-treatment not only cumbersome, but also yields only 63.8%

Method used

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  • A kind of preparation method of dexloglutamine
  • A kind of preparation method of dexloglutamine
  • A kind of preparation method of dexloglutamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1. Preparation of N-Boc-D-glutamic acid-5-benzyl ester (compound 6)

[0042] Add 4.84g (0.02mol, 98%) of D-glutamic acid 5-benzyl ester (compound 5), 60mL of tetrahydrofuran and 20mL of N,N-dimethylformamide mixed solution in a 250mL flask, 8.1g of Triethylamine and 6.55 g of di-tert-butyl dicarbonate. After heating to 60°C for 4 hours, evaporate tetrahydrofuran and N,N-dimethylformamide to dryness under reduced pressure, and dissolve the obtained oil in 100 mL of 0.25 M KHSO 4 The solution was acidified to pH 2.0-3.0 and stirred for 15 min. Extract with ethyl acetate (30 mL) 4 times. After drying, the solvent was evaporated under reduced pressure, and the obtained oily liquid was directly used in the next reaction with a yield of 91%. IR(KBr):3421,2977,2930,1718,1508,1457,1393,1368,1251,1165,1054,750,698cm -1 ; 1 H NMR (400MHz, CDCl 3 )δ7.23(d,J=4.6Hz,5H),5.00(s,2H),4.19(s,1H),4.12(s,1H),2.38(d,J=7.0Hz,3H),2.16- 2.09(m,3H),1.32(s,10H). 13 C NMR (101MHz,...

Embodiment 2

[0043] Example 2. Preparation of Compound 7

[0044] Add 6.9g of N-Boc-D-glutamic acid-5-benzyl ester (compound 6) into a 100mL bottle, dissolve it in 50mL of tetrahydrofuran, stir and cool to -10°C, add 2.02g of N-methylmethanol 2.73 g of isobutyl chloroformate was added dropwise while vigorously stirring (completely added within 10 min). After stirring the reaction at -10°C for 20 minutes, add 3.25 g of N-(3-methoxypropyl)-pentylamine in three batches The temperature was reacted for 5h. The filtrate was evaporated to dryness under reduced pressure, and the obtained residue was added to 60 mL of ethyl acetate, and extracted successively with 0.5M hydrochloric acid (2×30 mL), 1M sodium bicarbonate (2×20 mL) and saturated NaCl (2×20 mL). Anhydrous Na 2 SO 4 After drying, the solvent was evaporated to dryness, and 50 mL of 2.4 M HCl ethyl acetate solution was added to the obtained viscous light yellow liquid, and reacted at room temperature for 1 h. After the reaction, 20 ...

Embodiment 3

[0045] Example 3. Preparation of compound 8

[0046] 7.56g of compound 7 was placed in a 250mL flask, and 40mL of 0.5M Na 2 CO 3 and 20 mL of tetrahydrofuran. After dissolving, 20 mL of THF solution containing 3.89 g of 3,4-dichlorobenzoyl chloride was added dropwise at 0-5°C (dropped over 30 min), and the reaction was continued at this temperature for 1 h. After the reaction, tetrahydrofuran was evaporated to dryness, and the obtained aqueous phase was diluted with 60 mL of dichloromethane, filtered to remove insoluble impurities, and the filtrate was separated into two phases. The organic phase was sequentially washed with 20 mL of 1M NaHCO 3 , 1M hydrochloric acid and saturated NaCl aqueous solution were extracted twice respectively, and the solvent was evaporated to dryness to obtain 9.71 g of light yellow oily liquid (ie compound 8), with a yield of 89%. IR(KBr):3422,2960,2931,2873,1735,1711,1642,1610,1497,1455,1387,1366,1250,1172,1118,1050,778,750,698cm -1 ; 1 H NM...

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Abstract

The invention discloses a preparation method of dexchloroglutamine, which comprises: mixing N-tert-butoxycarbonyl-D-glutamic acid-5-benzyl ester and N-(3-methoxypropyl)-pentylamine After acylation by the acid anhydride method, the tert-butoxycarbonyl group is removed, and then reacted with 3,4-dichlorobenzoyl chloride to generate the final debenzylation, that is, to obtain dexchloroglutamine. Compared with the prior art, the method of the invention has simpler operation and higher yield.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation method of dexloglutamine. Background technique [0002] Cholecystokinin (CCK) is an important peptide hormone widely present in the gastrointestinal tract, mainly regulating gallbladder contraction and pancreatic enzyme secretion. The biological effect of CCK is controlled by type I cholecystokinin (cholecystokinin type-1, CCK 1 ) and type II cholecystokinin (cholecystokinin type-2, CCK 2 ) Two receptor subtypes are mediated by binding to target organs. where CCK 1 Regulate gastrointestinal function, CCK 2 It is mainly found in the central nervous system. Dexloxiglumide (Dexloxiglumide, molecular structure shown in formula 1) is a potent and selective CCK 1 Receptor antagonists, mainly used in the treatment of constipation-predominant irritable bowel syndrome, is the most advanced CCK in clinical gastroenterology research 1 receptor antagonists. [0003] ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C237/08C07C231/12C07C231/14C07C269/06C07C271/22
CPCC07C231/12C07C231/14C07C269/06C07C271/22C07C237/08
Inventor 尚若锋衣云鹏刘宇郝宝成杨珍梁剑平
Owner LANZHOU INST OF ANIMAL SCI & VETERINARY PHARMA OF CAAS
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