Synthesis method of key raw material compound C of Elagolix

A synthesis method and compound technology, which is applied in the field of synthesis of Elagolix’s key raw material compound C, can solve the problems of unsuitability for large-scale industrial production, high synthesis cost, and uncommon raw materials, and achieve the goal of reducing synthesis cost, low cost and high efficiency Effect

Inactive Publication Date: 2018-04-20
XIAMEN HALOSYNTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] In the traditional synthesis method of compound C, some of the raw materials used are not basic chemical raw materials. These raw materials are not only uncommon, but also expensive, which makes the synthesis cost of compound C too high and not suitable for large-scale industrial production.

Method used

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  • Synthesis method of key raw material compound C of Elagolix
  • Synthesis method of key raw material compound C of Elagolix
  • Synthesis method of key raw material compound C of Elagolix

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preparation example Construction

[0021] A kind of synthetic method of the key raw material compound C of Elagolix, it comprises the following steps:

[0022] (1) Synthesis of intermediate A: 3-fluoro-trifluorotoluene reacts with organolithium reagents and DMF in the presence of tetramethylethylenediamine (TMEDA) and diisopropanolamine (DIPA) to obtain intermediate A ; Wherein, the structure of intermediate A is:

[0023]

[0024] (2) Synthesis of intermediate B: intermediate A obtained in step (1) is oximated with alkoxyamine hydrochloride or hydroxylamine hydrochloride to obtain intermediate B; wherein, the structure of intermediate B is:

[0025]

[0026] (3) Synthesis of compound C: the intermediate B obtained in step (2) is reduced to obtain compound C; wherein, the structure of compound C is:

[0027]

[0028] Wherein, the concrete operation method of step (1) is:

[0029] Dissolve 3-fluoro-trifluorotoluene, tetramethylethylenediamine, and diisopropanolamine in anhydrous organic solvent A, and...

Embodiment 1

[0041] 1.1 Synthesis of Intermediate A

[0042] In a 5L three-necked flask, add 3-fluoro-trifluorotoluene (492.0g, 3.0mol), TMEDA (383.2g, 3.3mol), DIPA (21.3g, 0.16mol) and anhydrous THF (1.5L), the system Cool down to -70~-78°C, slowly add n-BuLi (211.5g, 3.3mol) solution dropwise at -70~-78°C, react at this temperature for 2-3h; then slowly add DMF (328.7g ,4.5mol), continue to react at this temperature for 1-2h, then slowly rise to room temperature, and use saturated NH 4 Cl solution (500ml) was used to quench the reaction, and ethyl acetate (500ml×3) was used to extract and separate the liquids. The organic layers were combined, and the organic layers were concentrated and dried to obtain 510.1 g of solids with a yield of 88.7%.

[0043] 1 H-NMR (400MHz, DMSO-d6): 12.06 (1H, s), 7.80-7.72 (3H, m).

[0044] 1.2 Synthesis of Intermediate B

[0045] In a 3L three-neck flask, add Intermediate A (192.0g, 1.0mol), ethanol (500ml), NH 2 OH.HCl (82.8g, 1.2mol), NaOH (48g, 1....

Embodiment 2

[0053] 2.1 Synthesis of Intermediate A

[0054] In a 5L three-necked flask, add 3-fluoro-trifluorotoluene (492.0g, 3.0mol), TMEDA (522.5g, 4.5mol), DIPA (42.6g, 0.32mol) and anhydrous THF (2.0L), the system Cool down to -60~-70°C, slowly add n-BuLi (288.4g, 4.5mol) solution dropwise at -60~-70°C, and react at this temperature for 2-3h. Then slowly add DMF (328.7g, 4.5mol), continue the reaction at this temperature for 1-2h, then slowly rise to room temperature, 4 Cl solution (500ml) was used to quench the reaction, and ethyl acetate (500ml×3) was used to extract and separate the layers. The organic layers were combined, and the organic layer was concentrated and dried to obtain 460.6g of solid, with a yield of 80.1%.

[0055] 2.2 Synthesis of Intermediate B

[0056] In a 3L three-neck flask, add intermediate A (192.0g, 1.0mol), methanol (500ml), NH 2 OH.HCl (82.8g, 1.2mol), NaOAc (204.1g, 1.5mol) and H 2 O (300ml), then heated to 70-75°C, reacted at this temperature for 25...

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Abstract

The invention relates to a synthesis method of a key raw material compound C of Elagolix. The synthesis method comprises the following steps: performing reaction of 3-flourine-trifluorotoluene, an organic lithium reagent and DMF in the presence of TMEDA and DIPA to obtain an intermediate A; performing oximation reaction of the intermediate A and alkoxamine hydrochloride or hydroxylamine hydrochloride to obtain an intermediate B; and reducing the intermediate B to obtain a target product compound C. The cheap commercialized basic chemical raw material 3-flourine-trifluorotoluene serving as a starting raw material is subjected to three-step chemical reaction to obtain the target product compound C, the starting raw material which has high cost and is not easily available is avoided, the synthesis cost of the target product compound C is greatly reduced, and the synthesis method has the advantages of being simple in purification, low in cost, high in efficiency, high in yield and suitablefor industrialized mass production.

Description

technical field [0001] The invention relates to a method for synthesizing a key raw material compound C of Elagolix. Background technique [0002] Endometriosis (EMs) refers to a common gynecological disease in women caused by the growth of endometrial cells in abnormal positions. Endometrial cells should grow in the uterine cavity, but because the uterine cavity communicates with the ovary and pelvic cavity through the fallopian tube, endometrial cells can enter the ovary, pelvic cavity and adjacent areas of the uterus for ectopic growth through the fallopian tube. [0003] Endometriosis is a relatively common clinical benign disease in women of reproductive age, with an incidence rate of 10.0% and a clear upward trend. The disease is mainly characterized by dysmenorrhea, pelvic pain and infertility, which seriously affects women reproductive health and quality of life. It is estimated that as many as 176 million women worldwide are affected by endometriosis. [0004] Cu...

Claims

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Application Information

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IPC IPC(8): C07C209/52C07C211/29
Inventor 陈华栋邱炳林钟宝香张锦绣李金林黄志征
Owner XIAMEN HALOSYNTECH CO LTD
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