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A kind of preparation method of tatirelin and its intermediate

A tatirelin and intermediate technology, applied in the field of medicinal chemistry, can solve the problems of high production equipment requirements, harsh reaction conditions, low yield, etc., to overcome the low utilization rate of raw materials, strong operability and controllability, The effect of high methylation selectivity

Active Publication Date: 2018-01-23
重庆莱美隆宇药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] In order to fill up the gaps in the prior art, the present invention aims to provide a new method for preparing tatirelin, adopting the new technical scheme of the present invention to prepare tatirelin can overcome the prior art method to prepare tatirelin raw materials Defects or difficulties such as low utilization rate, cumbersome operation, long preparation steps, harsh reaction conditions, high production equipment requirements, low yield, high cost, etc.

Method used

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  • A kind of preparation method of tatirelin and its intermediate
  • A kind of preparation method of tatirelin and its intermediate
  • A kind of preparation method of tatirelin and its intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0048] (1) preparation formula N-2 compound is L-aspartic acid-4-carboxamide:

[0049] Mix the compound of formula N-1, that is, L-aspartic acid-4-methyl ester, with 10% methylamine-methanol solution at a mass ratio of 1:5, in a closed container at 25°C, The reaction occurred under the condition of 0psi, and the reaction time was 12 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure to obtain a light yellow semi-solid product, that is, L-aspartic acid-4-carboxamide, which was directly used for next step reaction;

[0050] (2) preparation formula N-3 compound is L-aspartic acid benzyl ester-4-formamide:

[0051] The compound of formula N-2, that is, L-aspartic acid-4-formamide and sodium hydroxide solution is salified, and the mol ratio of L-aspartic acid-4-formamide and sodium hydroxide is 1:1, and then Add dichloromethane, add tributylmethylammonium chloride and benzyl bromide to react at -5°C, the molar ratio ...

Embodiment 2

[0059] (1) preparation formula N-2 compound is L-aspartic acid-4-carboxamide:

[0060] Mix the compound of formula N-1, that is, the hydrochloride salt of L-aspartic acid-4-methyl ester, with the methylamine methanol solution with a mass concentration of 40% at a mass ratio of 1:20, in a closed container at 100 ° C, 50 psi The reaction occurred under the following conditions, and the reaction time was 2 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure to obtain a light yellow semi-solid product, that is, L-aspartic acid-4-carboxamide, which was directly used in the next step without purification. one step reaction;

[0061] (2) preparation formula N-3 compound is L-aspartic acid benzyl ester-4-formamide:

[0062] The compound of formula N-2, that is, L-aspartic acid-4-formamide and sodium hydroxide solution is salified, and the mol ratio of L-aspartic acid-4-formamide and sodium hydroxide is 1:1.5, and then Ad...

Embodiment 3

[0070] (1) prepare the compound of formula N-2, namely L-aspartic acid-4-carboxamide:

[0071] The compound of formula N-1, that is, L-aspartic acid-4-methyl ester, is mixed with a methylamine methanol solution with a mass concentration of 40% in a mass ratio of 1:8, and the reaction occurs in a closed container at 45 ° C and 25 psi. , the reaction time is 6 hours, after the reaction is completed, it is lowered to room temperature and concentrated under reduced pressure to obtain a light yellow semi-solid product, namely L-aspartic acid-4-carboxamide, which is directly used in the next reaction without purification;

[0072] (2) prepare the compound of formula N-3, namely L-aspartic acid benzyl ester-4-carboxamide:

[0073] The compound of formula N-2, namely L-aspartic acid-4-carboxamide and sodium hydroxide solution are salified, and the molar ratio of L-aspartic acid-4-carboxamide and sodium hydroxide is 1:1.2, and then Add ethyl acetate, add tetrabutylammonium chloride an...

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Abstract

The invention discloses a preparing method for taltirelin and a midbody of taltirelin. The preparing method comprises the steps that L-aspartic acid-4-methyl ester or other hydrochloride serves as raw materials, a compound A-5 is obtained through ammonolysis, carboxyl protection and cyclization, the compound A-5 and a compound B are simultaneously subjected to deprotection through a one-pot reaction under the acid condition, and 1-methyl-L-4,5-dihydro orotic acid (a compound A) and a compound C are obtained. The compound A and the compound C can be used for a next-step condensation reaction through separation or without separation, and taltirelin shown in the formula I is prepared through the condensation reaction. According to the technical scheme, the prepared compound A and compound C or taltirelin has the advantages that the utilization rate of the raw materials is high, operation changes gradually, the preparation steps are few, the reaction condition is mild, the requirement for production equipment is low, the yield is high, and cost is low.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new preparation method of the drug tatirelin and its intermediate for improving the ataxia of spinocerebellar degeneration patients. . Background technique [0002] Spinocerebellar ataxias (spinocerebellar ataxias, SCAs), formerly known as autosomal dominant ataxias, are a group of chronic degenerative diseases of the central nervous system with the main clinical manifestations of ataxia and dysmetria. Since the disease is genetic, there is no effective treatment so far. The only approved drug for ataxia is TRH. However, clinical studies have shown that due to the rapid metabolic degradation of TRH in the body, the half-life is only 4-5 minutes, and the action time is too short. Therefore, people modify or change the molecular structure of TRH to enhance its biological activity and prolong the half-life. There are nearly a hundred kinds of TRH derivatives. Among them, tati...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/22C07D403/06C07D403/14
CPCC07D239/22C07D403/06C07D403/14
Inventor 黄文峰李胜伟黄胜陈进许辉川
Owner 重庆莱美隆宇药业有限公司
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