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Preparation method of gonadotropin-releasing hormone antagonist intermediate and antagonist sodium

A gonadotropin and hormone-releasing technology, applied in the direction of organic chemistry, can solve the problems of waste water in acid and alkali, unfavorable environmental protection, etc., and achieve the effects of safe raw materials, easy separation and purification, high product purity and yield

Active Publication Date: 2021-02-09
LIVZON NEW NORTH RIVER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After the reaction is completed, acid is generally used to remove BOC protection. Although the effect of this deprotection operation is good, the reaction will produce a large amount of waste water in acid and alkali, which is not conducive to environmental protection.

Method used

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  • Preparation method of gonadotropin-releasing hormone antagonist intermediate and antagonist sodium
  • Preparation method of gonadotropin-releasing hormone antagonist intermediate and antagonist sodium
  • Preparation method of gonadotropin-releasing hormone antagonist intermediate and antagonist sodium

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preparation example Construction

[0068]In some examples of the preparation of intermediates, the active zinc is zinc elemental, Rieke zinc, or an organozinc compound obtained by a metal displacement reaction between zinc and a zinc-free metal organic reagent. The zinc element can be in various shapes such as powder, flakes, or granules.

[0069]In the preparation examples of some intermediates, the zinc element is activated by acid; preferably, the acid is selected from at least one of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, organic carboxylic acid, organic sulfonic acid, and organic sulfinic acid Further, the acid is selected from at least one of organic carboxylic acid, organic sulfonic acid, and organic sulfinic acid; further, the molar ratio of the acid to the zinc element is (0.04-0.05): 1, wherein, Acid with H+meter. If the activated acid is not enough, the zinc powder will be difficult to activate completely, which will affect the progress of the reaction; if the activated acid is too mu...

Embodiment 1

[0098]Preparation of compound 4 from compound 1-1

Embodiment 11

[0100]

[0101]1) In a 250mL three-necked flask, add 20mL of N,N-dimethylformamide, 300 mesh zinc powder (1.7g, 25.70mmoL) at room temperature, replace with nitrogen three times, and add methanesulfonic acid (0.1g, 1.17mmoL) dropwise. Raise the temperature to 60-70℃, keep for 0.5h, and lower the temperature to 10-20℃. A solution of compound 1-1 (10.0 g, 23.36 mmoL) in N,N-dimethylformamide (20 mL) was added dropwise. After the addition is complete, keep it at 20-30°C for 1 hour to obtain the intermediate compound 2-1, and lower the temperature to 10±5°C for later use;

[0102]2) Add 20mL of N,N-dimethylformamide at room temperature, add compound 3-1 (6.5g, 25.70mmoL), tris(dibenzylideneacetone)dipalladium (0.42g, 0.46mmoL), tris(ortho Phenylphenyl) phosphorus (0.28g, 0.93mmoL), replaced with nitrogen three times, and heated to 50-60°C. Add the N,N-dimethylformamide solution of compound 2-1 in the three-neck flask dropwise, after the dropwise addition, keep it at 50-60℃ for 1h;

[0103]3) Add...

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Abstract

The invention discloses a preparation method of a gonadotropin-releasing hormone antagonist intermediate and antagonist sodium. An organic zinc reagent is obtained by reacting compound 1 with active zinc in an aprotonated solvent, and then performing Negishi coupling reaction to obtain the target intermediate body, and then synthesized to obtain gonadotropin-releasing hormone antagonist sodium. The invention has mild reaction conditions, simple operation, less side reactions, and reduces the production quality risk of preparing GnRHR medicine. The intermediate compound can be prepared directly in a "one-pot method", the intermediate is easy to separate and purify, the operation is simple and reproducible, and the product purity and yield are higher than the prior art. At the same time, the raw materials of the present invention are safe and low in cost, and are environmentally friendly, which is beneficial to cost control and environmental protection.

Description

Technical field[0001]The invention relates to the field of synthesis of medical molecules, in particular to a method for preparing a gonadotropin releasing hormone antagonist intermediate and sodium gonadotropin releasing hormone antagonist.Background technique[0002]Endometriosis is a common gynecological disease in women formed by planting endometrial cells in an abnormal position. It is an estrogen-related disease. Globally, as many as 176 million women are affected by endometriosis, and the age of onset is mostly 30 to 49 years old. The incidence of women in childbearing period is 6% to 10%, accounting for 70% to 80% of infertility patients. At present, the cause is not clear, and there is no medicine that can cure endometriosis. The current treatment methods for this disease are mainly oral contraceptives, progestins, androgen derivatives, gonadotropin releasing hormone agonists, mifepristone, gonadotropin releasing hormone (GnRHR) antagonists, aromatase inhibitors , Immunothera...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/54
CPCC07D239/54
Inventor 王标彭木荣黄丽霞冯绮晴周国飞李成波
Owner LIVZON NEW NORTH RIVER PHARMA
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