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Preparation method of elagolix impurities

A technology for elagolime and impurities, which is applied in the field of preparation of elagolime impurities, and can solve the problems of no literature reports on the preparation method

Inactive Publication Date: 2019-02-01
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are no literature reports on compound III, compound IV and their preparation methods at home and abroad; there are reports on the physical and chemical properties of compound II, but there are no literature reports on their preparation methods

Method used

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  • Preparation method of elagolix impurities
  • Preparation method of elagolix impurities
  • Preparation method of elagolix impurities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1: (R)-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-3- Preparation of [2-(2-oxopyrrolidin-1-yl)-2-phenylethyl]pyrimidine-2,4(1H,3H)-dione (II)

[0030] Add 0.5 g of compound I, 0.16 g of triethylamine, and 10 mL of dichloromethane into the reaction flask, stir at room temperature for 1 hour, add 0.16 g of N,N'-carbonyldiimidazole, stir at room temperature for 24 hours, concentrate the reaction solution under reduced pressure, and leave The product was subjected to silica gel column chromatography to obtain 0.31 g of a white solid with a yield of 64.8%.

[0031] Its structural identification data are as follows: 1 H NMR (300MHz, Chloroform-d) δ7.57(t, J=6.2Hz, 1H), 7.49-7.25(m, 8H), 7.14(tt, J=7.8, 1.5Hz, 1H), 7.01(td, J=8.1, 1.6Hz, 1H), 6.93-6.72(m, 1H), 6.00-5.72(m, 2H), 5.27(dd, J=17.3, 6.8Hz, 1H), 4.97(td, J=12.3, 4.8Hz, 1H), 4.23(dt, J=13.0, 3.9Hz, 1H), 3.92(d, J=1.8Hz, 3H), 3.74-3.57(m, 1H), 2.85(q, J=8.0Hz, 1H), 2.34 (he...

Embodiment 2

[0032] Example 2: (R)-4,4'-[[2-[5-(2-fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoromethyl)benzyl Base]-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl]azadiyl]-dibutyric acid ethyl ester Preparation of (III)

[0033] Add 0.1g of compound IX, 1mL of N,N-dimethylformamide, 0.14g of ethyl 4-bromobutyrate and 0.1g of N,N-diisopropylethylamine into the reaction flask, stir, heat to 52°C, and react for 24 hours, cooled to room temperature, added 10mL water and 10mL isopropyl acetate, stirred for 10 minutes, separated, the aqueous layer was extracted with 10mL isopropyl acetate, separated, combined organic layers, and washed with 10mL saturated saline and 10mL water respectively , liquid separation, the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 52 mg of light yellow oil with a yield of 36.6%.

[0034] Its structural identification...

Embodiment 3

[0035] Example 3: Preparation of 2,2'-difluoro-3,3'-dimethoxy-1,1'-biphenyl (IV)

[0036] Add 12g of compound VI, 9.53g of 2-fluoro-3-methoxyphenylboronic acid, 4.48g of sodium hydroxide, 3.24g of tetraphenylphosphine palladium and 200mL of acetone into the reaction flask, under nitrogen protection, heat to reflux, after 5 hours , add 3.32g of acetic acid, continue to reflux for 1 hour, cool to normal temperature, filter, the filtrate is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography to obtain 0.34g of white solid.

[0037] Its structural identification data are as follows: 1 H NMR (300 MHz, Chloroform-d) δ 7.21-7.12 (m, 2H), 7.09-6.94 (m, 4H), 3.97 (s, 6H). ESI-MS(m / z): 251.1[M+H] + .

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Abstract

The invention relates to a synthetic method of three elagolix impurities which is important to the synthesis of high-quality elagolix. The invention mainly focuses on the study on a preparation methodof (R)-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-3-[2-(2-oxopyrrolidine-1-yl)-2-phenylethyl]pyrimidin-2,4(1H,3H)-dione (II), diethyl (R)-4,4'-[[2-[5-(2-fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoromethyl)benzyl]-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl]azadiyl]-dibutyrate (III), and 2,2'-difluoro-3,3'-dimethyoxy-1,1'-biphenyl (IV). A synthesis route is shown in the description.

Description

technical field [0001] The present invention relates to the preparation method of elagolime impurity. Background technique [0002] Elagolix (Elagolix, I), chemical name: (R)-4-[[2-[5-(2-fluoro-3-methoxyphenyl)-3-[2-fluoro-6-( Trifluoromethyl)benzyl]-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl]amino]butanoic acid, Is an oral gonadotropin-releasing hormone receptor antagonist, by inhibiting the pituitary gonadotropin-releasing hormone receptor, ultimately reducing the level of gonadal hormones in the blood circulation. This product is jointly developed by AbbVie and Neurocrine Biosciences. AbbVie submitted the NDA for the drug in September 2017, obtained the FDA priority review qualification more than a month later, and was approved by the FDA on July 23, 2018. The trade name is Orilissa, which is used to treat the Pain caused by endometriosis, and became the first new oral drug for this indication in more than 10 years. [0003] [0004] The main s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/06C07D239/54
CPCC07D239/54C07D401/06
Inventor 常月赏胡孔泉郑琳日陈国华
Owner CHINA PHARM UNIV
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