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A kind of preparation method of elagolime key intermediate

A technology for elagolime and intermediates, which is applied in the field of preparation of key intermediates of elagolime, can solve the problems of being unsuitable for large-scale industrial production and harsh reaction conditions, and achieves mild reaction conditions suitable for large-scale production in workshops , post-processing simple effects

Active Publication Date: 2021-01-29
AURISCO PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As shown in the following synthetic route, this route uses highly toxic substances such as bromine and 1,4-dioxane, and the reaction conditions are relatively harsh, which is not suitable for large-scale industrial production

Method used

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  • A kind of preparation method of elagolime key intermediate
  • A kind of preparation method of elagolime key intermediate
  • A kind of preparation method of elagolime key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Amination reaction: under ice bath, add 23.7g Boc-D-phenylglycinol, 15.5g phthalimide, 28.8g triphenylphosphine, 20.9g diethyl azodicarboxylate and 500mL tetrahydrofuran In the reaction bottle, stir for 15 minutes, rise to room temperature and react for 6 hours, concentrate to remove tetrahydrofuran, add 50 mL of ethanol and 250 mL of hydrazine hydrate to continue the reflux reaction for 2 hours, add dichloromethane to extract, concentrate to remove the organic layer, and obtain 23.5 g of intermediate II , 98.5% purity, 99% weight yield.

[0040] Amidation reaction: under ice bath, add 21.2g of compound II, 36.4g of triethylamine and 200mL of acetonitrile into the reaction flask, slowly add 44.1g of n-propyl chloroformate dropwise, after completion of the dropwise reaction, keep the reaction for 3.5h and complete the reaction. The reaction solution was poured into 2L of ice water for solidification, suction filtered, and dried to obtain 28.6g of intermediate IV with a p...

Embodiment 2

[0046] Amination reaction: same as in Example 1, except adding 500mL tetrahydrofuran to 250mL DMF, and changing 250mL hydrazine hydrate to 400mL ammonia water to finally obtain 22.5g of intermediate II with a purity of 97.5% and a weight yield of 95%.

[0047] Amidation reaction: the same operation as in Example 1, changing the dropwise addition of 44.1 g of n-propyl chloroformate to 44.1 g of ethyl chloroformate to obtain 25 g of intermediate IV with a purity of 98.6% and a weight yield of 106.1%.

[0048] Arylation coupling reaction: the same operation as in Example 1, changing the addition of 4 g of copper acetate to 2 g of cuprous chloride to obtain 24.2 g of intermediate VII with a purity of 97.2% and a weight yield of 75%.

[0049] Ring closure reaction: the same operation as in Example 1, except that the addition of 22.8g p-toluenesulfonic acid was changed to 28.5g p-toluenesulfonic acid, and finally 35.2g intermediate VIII was obtained, with a purity of 98.1% and a weig...

Embodiment 3

[0053] Amination reaction: with the operation of Example 1, the difference is that the addition of 20.9g diethyl azodicarboxylate is changed to 19.5g diethyl azodicarboxylate, the reaction time is extended to 7 hours, and the reflux reaction is continued for 4 hours , to obtain 21.8g of intermediate II with a purity of 97.9% and a weight yield of 92%.

[0054] Amidation reaction: with the operation of Example 1, change the dropwise addition of 44.1g n-propyl chloroformate to 44.1g methyl chloroformate, and keep warm for 3 hours to obtain 24.5g intermediate IV with a purity of 98.5% and a weight yield 115.6%.

[0055] Arylation coupling reaction: The operation was the same as in Example 1, except that 4 g of copper acetate was added instead of 3 g of copper oxide, and the temperature was raised to 55° C. for 9 hours to obtain 25.1 g of intermediate VII with a purity of 98.2% and a weight yield of 78%.

[0056] Ring closure reaction: the same operation as in Example 1, changing...

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Abstract

The present invention relates to the field of pharmacy, in particular to a method for preparing a key intermediate of elagolix, which uses simple and easy-to-obtain Boc-D-phenylglycinol as a starting material, including amination, amidation and arylation The six-step reaction of coupling, cyclization, benzylamine substitution and deprotection, the starting materials of this synthetic route are simple and easy to obtain, the reaction conditions are relatively mild, the post-treatment is simple, the use of noble metal catalysts is avoided, the cost of process synthesis is greatly reduced, and the obtained intermediate The purity and yield of the body are also high, which is very suitable for large-scale production in the workshop.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a preparation method of a key intermediate of elagolil. Background technique [0002] As an oral preparation, Orilissa is jointly developed by AbbVie and Neurocrine Biosciences Inc (NBIX). Its active ingredient is elagolix, which is a non-peptide gonadotropin-releasing hormone GnRH receptor antagonist. GnRH receptor, inhibits endogenous GnRH signaling. After the administration of Elagolix, it can lead to a dose-dependent inhibition of luteinizing hormone and follicle-stimulating hormone, which eventually leads to a decrease in the levels of ovarian sex hormones estradiol and progesterone in the blood circulation, reducing dysmenorrhea or non-menstrual pelvic cavity in patients with endometriosis pain. [0003] In the patent WO2009062087, 1-[2-fluoro-6-(trifluoromethyl)benzyl]urea is used as the starting material, which is cyclized with tert-butyl acetoacetate to obtain a uracil intermed...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/54
CPCC07D239/54
Inventor 车峰峰蒋涛王爱民许陈柯
Owner AURISCO PHARMACEUTICAL CO LTD
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