Preparation method of elagolix intermediate

A technology of elagolix and intermediates, which is applied in the field of drug preparation, can solve problems such as the purification of aryl coupling intermediates, and achieve the effects of reducing the cost of process preparation, not easy to inactivate, and simple operation

Active Publication Date: 2021-03-23
NANJING CHEMPION BIOTECHNOLOGY CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0019] This route has improved the process of multiple steps on the basis of compound patents, but it still cannot solve the problem of purification of aryl coupling intermediates. The residue of metal palladium has brought certain problems to the quality control of raw materials and process stability. challenge

Method used

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  • Preparation method of elagolix intermediate

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Experimental program
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Effect test

Embodiment 1

[0032] In a 5L three-necked reaction flask, add compound II, 500.0g, compound III, 238.2g, potassium carbonate 484g, and 2-methyl-N1, N3-di-o-tolylbenzene-1,3-diamine 35.3g , stirred and heated to 100°C and refluxed for 10 hours. Thin-layer chromatography showed that the conversion of the raw materials was complete, and the aqueous solution of acetic acid was added dropwise to the reaction solution. Compound I 478g, yield: 95.98%.

Embodiment 2

[0034] In a 2L three-necked reaction flask, sequentially add compound II, 100.00g, compound III, 47.64g, cesium carbonate 228.31g, 2-methyl-N1,N3-di-o-tolylbenzene-1,3-diamine 7.06g , stirred and heated to 60°C and refluxed for 6 hours. Thin-layer chromatography showed that the conversion of the raw materials was complete, and the aqueous solution of acetic acid was added dropwise to the reaction solution. Compound I 90.6g, yield: 91%.

[0035] Catalyst 2-methyl-N1, the synthetic route of N3-di-o-tolylbenzene-1,3-diamine is as follows:

[0036]

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Abstract

The invention discloses a preparation method of an elagolix intermediate. The preparation method comprises the following steps: in the presence of a catalyst and alkali, heating a compound II and a compound III to 50-100 DEG C in an organic solvent, and carrying out a reflux coupling reaction to obtain a compound I. According to the preparation method of the elagolix intermediate, 2-methyl-N1,N3-di-o-tolylphenyl-1,3-diamine is adopted as a coupling catalyst, so metal residues of a traditional coupling metal catalyst are effectively avoided, the quality of the intermediate is improved, reactionconditions are mild, operation is simple, the catalyst is stable and is not easy to inactivate, anaerobic harsh reaction conditions are not needed, and process preparation cost is greatly reduced.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a preparation method of an elagolix intermediate. Background technique [0002] Elagolix sodium (structural formula V) is an orally administered non-peptide small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist that inhibits endogenous GnRH signaling by binding competitively to the GnRH receptor in the pituitary gland conduction. Administration will produce dose-dependent inhibition of luteinizing hormone and follicle-stimulating hormone, and reduce the plasma concentration of ovarian sex hormones, estradiol and progesterone. In July 2018, the drug received FDA approval for the treatment of women with moderate to severe endometriosis pain. It is worth mentioning that elagolix sodium is the first oral therapy approved by the FDA for this indication in ten years; [0003] . [0004] At present, the main synthetic route of elagolix s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/54
CPCC07D239/54
Inventor 陈剑余长泉嵇晓勇
Owner NANJING CHEMPION BIOTECHNOLOGY CO LTD
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