Relugolix synthesis method

A purification method and compound technology, applied in the direction of organic chemistry, etc., can solve the problems of harsh reaction conditions and high equipment requirements, and achieve the effect of less side reactions, high purity and product purification.

Active Publication Date: 2019-09-03
四川伊诺达博医药科技有限公司
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

However, this method adopts the method of coupling first and then closing the ring, the reaction conditions are harsh, and the reaction needs to be carried out under heating and pressurized conditions, and the requirements for equipment are relatively high.

Method used

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Experimental program
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Embodiment 1

[0059] The synthesis of embodiment 1 Relugoli

[0060] According to the following synthetic route, the compound Relugoli was prepared:

[0061]

[0062]

[0063] Synthesis of step 1, ethyl 2-amino-4-methyl-5-(4-nitrophenyl)-3-thiophenecarboxylate (compound 1):

[0064] 4-Nitropropiophenone (30g, 0.17mol), ethyl cyanoacetate (19.2g, 0.17mol) and ethanol (200ml) were added to the reaction flask, stirred and dissolved, then triethylamine (17.2g, 0.17mol ) and sulfur powder (5.4g, 0.17mol), heated to 50°C for 6h, and the reaction was complete by TLC monitoring. Concentrate to remove ethanol, add 300ml of ethyl acetate to the residue, extract with 100ml of saturated brine, and concentrate the organic phase to obtain a crude product. Then crystallize and purify with ethyl acetate / n-hexane (200ml / 200ml), filter, and dry to obtain ethyl 2-amino-4-methyl-5-(4-nitrophenyl)-3-thiophenecarboxylate (compound 1) 35.4g, yield 69%.

[0065] Synthesis of step 2, 2-amino-4-methyl-5-(4...

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Abstract

The present invention provides a method for preparing a relugolix intermediate compound 8. The method comprises: (a) carrying out a reaction on a compound 2 and N,N'-carbonyldiimidazole to obtain a compound 3; (b) carrying out a reaction on the compound 3 and 2,6-difluorobenzyl chloride to obtain a compound 4; (c) carrying out a reaction on the compound 4 and 3-amino-6-methoxypyridazine to obtaina compound 5; (d) carrying out a reaction on the compound 5 and N,N'-carbonyldiimidazole to obtain a compound 6; (e) carrying out a reaction on the compound 6, N-bromosuccinimide and azobisisobutyronitrile to obtain a compound 7; and (f) carrying out a reaction on the compound 7 and dimethylamine hydrochloride to obtain a compound 8. The invention further provides a relugolix preparation method, which comprises: (g) carrying out a reaction on the compound 8 obtained by the method and hydrogen under a catalyst to obtain a compound 9; and (h) carrying out a reaction on the compound 9, N,N'-carbonyldiimidazole and methoxy amine hydrochloride to obtain relugolix. According to the present invention, the method adopts the route sequentially comprising loop closing and coupling, such that the method has characteristics of simple operation, less side-reaction, mild reaction condition, high yield, high product purity and easy product purification, and is suitable for commercial scale production.

Description

technical field [0001] The present invention relates to the field of drug synthesis, in particular to a method for synthesizing relugoli. Background technique [0002] The secretion of anterior pituitary hormones is feedback-controlled by peripheral hormones secreted from various hormone target organs and by secretory-regulatory hormones from the hypothalamus. Currently, nine hormones belonging to the above have been discovered, for example, thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone [GnRH, sometimes referred to as LH-RH (luteinizing hormone-releasing hormone)]. The secretion of these hormones is related to their corresponding receptors. Therefore, finding antagonists or agonists that can specifically and selectively act on the receptors can realize the secretion of specific anterior pituitary hormones. [0003] Relugolix, CAS No. 737789-87-6, chemical name N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl) -3-(6-methoxy-3-pyridazinyl)-2,4-d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
CPCC07D495/04
Inventor 万华斯涛周平吴夏徐国燕岳利剑
Owner 四川伊诺达博医药科技有限公司
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