Preparation method of elagolix sodium and intermediate thereof

A technology for elagolix sodium and intermediates, which is applied in the field of pharmaceutical synthesis and preparation, can solve the problems of unfavorable large-scale industrial production, complicated post-treatment of environmental pollution, and difficulty in impurity removal and purification, and achieves easy scale-up, low cost, and strong The effect of cost competitiveness

Inactive Publication Date: 2021-03-09
CHENGDA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] The synthetic routes of the prior art all have the disadvantages as follows: the steps are longer, expensive reagents and catalysts need to be used, and the environmental pollution is more complicated than the post-treatment, especially if the steps are longer, it will make it difficult to remove impurities and purify, and the obtained The product has poor purity and low yield, which is not conducive to large-scale industrial production

Method used

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  • Preparation method of elagolix sodium and intermediate thereof
  • Preparation method of elagolix sodium and intermediate thereof
  • Preparation method of elagolix sodium and intermediate thereof

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preparation example Construction

[0041] A preparation method of elagolix sodium and intermediates thereof, comprising the following preparation steps:

[0042] (1) Substitution reaction: Dissolve D-phenylglycinol 1 in tetrahydrofuran, add ethyl 4-bromobutyrate under stirring, and stir the reaction. If there is no raw material point detected by TLC, the reaction is stopped, and the reaction solution is layered with brine. The organic phase was concentrated and stripped with tetrahydrofuran to obtain the reaction solution of compound 2

[0043] The reaction formula is:

[0044]

[0045] (2) Condensation reaction: add NMP and compound 3 in compound 2, stir reaction, HPLC detects purity: compound 1≤0.5% (wavelength 210nm), stop reaction, drop to room temperature, add IPAC and water washing in reaction liquid, separate Organic phase, the organic phase has passed through H 3 PO 4 ,IPAC,K 2 CO3 Extraction, and finally through concentration, the concentrated product is stripped with EtOH to obtain the EtOH rea...

Embodiment 1

[0061] Step (1) compound 1 and ethyl 4-bromobutyrate react to generate compound 2

[0062] The synthetic route equation is as follows:

[0063]

[0064] In a reaction vessel, the compound 1 (1g, 1eq) was dissolved in tetrahydrofuran (4ml, 4V), and ethyl 4-bromobutyrate (1.5g, 1.05eq) was added thereto, and the reaction was stirred at 50°C for 3h; After the reaction, the reaction solution was washed with saturated brine, and the organic phase was concentrated and entrained with tetrahydrofuran twice. 1.65 g of compound 1 was obtained with a yield of 90%.

[0065] The NMR data of compound 3 are as follows:

[0066] 1H-NMR (400MHz, Chloroform-d) δ10.63(s, 1H), 4.90(t, J=1.1Hz, 1H), 2.34(d, J=1.0Hz, 3H).

[0067] Step (2) compound 2 and compound 3 react to generate compound 4

[0068]

[0069] In the reaction vessel, the compound 2 (1g, 1eq) was dissolved in NMP (2ml, 1X), and compound 2 (1.3g, 0.6eq) was added thereto, and the reaction was stirred at 50°C for 20h; after...

Embodiment 2

[0080] Step (1) In a reaction vessel, the compound 1 (1g, 1eq) was dissolved in 2ml of dichloromethane (2ml, 2X), and ethyl 4-bromobutyrate (1.35g, 0.95eq) was added thereto. The reaction was stirred at 20° C. for 3 h; after the reaction, the reaction solution was washed with saturated brine, and the organic phase was concentrated and entrained with tetrahydrofuran twice. Finally, 10.77 g of compound was obtained with a yield of 42%.

[0081] Step (2) In a reaction vessel, dissolve Compound 2 (1g, 1eq) in dichloromethane (10ml, 10X), add Compound 2 (1.5g, 0.7eq) to it, and stir the reaction at 40°C for 20h ; After the reaction, the reaction solution was concentrated and washed with ethyl acetate and water, and the organic phase was separated; the organic phase was successively passed through 10% H 3 PO 4 , ethyl acetate, 20% K 2 CO 3 After extraction and concentration, the concentrated product was stripped with EtOH to obtain a relatively pure EtOH reaction solution of com...

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Abstract

The invention relates to a preparation method of elagolix sodium and an intermediate thereof, and relates to the technical field of medicine synthesis and preparation. The preparation method comprisesthe following synthesis steps: (1) synthesizing a compound 2 by taking D-phenyl glycinol 1 and ethyl 4-bromobutyrate as raw materials through a substitution reaction; (2) reacting with a compound 3 to generate a compound 4; and (3) salifying to obtain a target product 5, namely elagolix sodium. The preparation method disclosed by the invention has the characteristics of suitability for industrialproduction, lower cost, high purity of the prepared product and high yield.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis and preparation, in particular to a preparation method of elagolix sodium and an intermediate thereof. Background technique [0002] Elagolix is ​​an oral GnRH antagonist that treats endometriosis by inhibiting the pituitary gland-promoting gonadal-releasing hormone receptors, and ultimately reducing gonadal hormone levels in the bloodstream for the treatment of endometriosis Pain caused by endometriosis (EMS). [0003] Compound 2, the chemical name of this compound is (S)-3-((2-hydroxy-1-phenylethyl) amino) ethyl propionate, and its structural formula is as follows: [0004] [0005] Compound 5 (elagolix sodium), the chemical name of this compound is 4-[[(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro -6-(Trifluoromethyl)phenyl]methyl]-3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-1-phenylethyl ] amino] sodium butyrate, the structural formula is as follows: [0006] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/54C07C227/08C07C229/16
CPCC07C227/08C07D239/54C07C229/16
Inventor 冯宇许宏项鑫黄宗玺钱伟
Owner CHENGDA PHARM CO LTD
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