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Elagolix synthesis method

A synthetic method, the technology of elagoli, is applied in the field of medicine and chemical industry, and can solve the problem of high cost of raw materials

Active Publication Date: 2018-09-28
HANGZHOU CHEMINSPIRE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this route greatly simplifies the reaction steps, the starting materials and intermediates are relatively special, and the cost of raw materials is high. It is still necessary to find a method with simple process route, high yield, low cost, and suitable for industrial production. Ragoli

Method used

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043]

[0044] Add 5-bromo-6-methylpyrimidine-2,4(1H,3H)-dione 1 (20.50g, 100mmol) and 2-(bromomethyl)-1-fluoro-3-trifluoromethane into a three-necked flask Benzene 2 (25.70g, 100mmol) and N,N-dimethylformamide (103mL), stirred and dissolved, then added potassium carbonate (27.64g, 200mmol), stirred evenly and heated to 75-85°C to react overnight. After the reaction was completed, water (205 mL) was added, and a large amount of solid was precipitated, which was filtered and dried to obtain compound 3 (30.88 g, 81%).

[0045] Potassium carbonate can be replaced by sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine or diisopropylethylamine, and the solvent N,N-dimethylformamide can be replaced by N,N-dimethylformamide Acetamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, xylene or chlorobenzene instead.

Embodiment 2

[0047]

[0048]Add compound formula 3 (38.11g, 100mmol) and tetrahydrofuran (190mL) into the three-necked flask, stir and dissolve, cool in an ice-salt bath to 0-5°C, add iron triacetylacetonate (1.77g, 5mmol), tetramethylethylenediamine (2.32g, 20mmol), switch the nitrogen gas 3 times under vacuum, add Grignard reagent 4 (200mmol, 190mL) tetrahydrofuran solution dropwise, and then raise the temperature to 40-45°C for 6-8 hours after the dropping. After the reaction was completed, dilute hydrochloric acid (2mol / L, 381mL) was added to quench the reaction, the precipitated solid was slurried, filtered and dried to obtain compound 5 (32.83g, 77%).

[0049] Here, iron triacetylacetonate can be replaced by ferric chloride or ferric bromide; tetramethylethylenediamine can be omitted, and can also be replaced by anhydrous lithium chloride or anhydrous lithium bromide.

Embodiment 3

[0051]

[0052] Add compound formula 6a (20.50g, 100mmol), 7a (15.62g, 120mmol) and dimethyl sulfoxide (102mL) in the three-necked flask, add cuprous iodide (1.90g, 10mmol) after stirring and dissolving, L-proline Acid (1.15g, 10mmol), potassium carbonate (27.64g, 200mmol), nitrogen was switched 3 times under vacuum, and the temperature was raised to 45-50°C for 6-8 hours. After the reaction was completed, ammonium chloride solution (204 mL) was added to quench the reaction, ethyl acetate (102 mL) was added to extract three times, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove part of the solvent, and added The product 8a (21.66g, 74%) was obtained after beating with petroleum ether, filtering, collecting and drying the solid.

[0053] Here cuprous iodide can be replaced by cuprous bromide or cuprous chloride; L-proline can be omitted, and can also be replaced by TMEDA or...

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Abstract

The invention provides an elagolix synthesis method. The elagolix synthesis method comprises enabling a compound 5 and a compound 10 to participate in a condensation reaction to finish N-alkylation reaction to obtain a compound 11, and then implementing alkaline hydrolysis to obtain elagolix 12. The invention further discloses two synthesis methods of the compound 5: the method I comprises enabling a 5-bromine-6-methylpyrimidine-2,4(1H,3H)-diketone compound 1 and a 2-(brooethyl)-1-fluorin-3-(trifluoromethyl) benzene compound 2 to have a condensation reaction to obtain an intermediate 3, and then having a coupling reaction; the method II comprises enabling 1-halide-3-fluorin-2-anisole and acetoacetate 7 to have a coupling reaction to obtain a compound 8, and then having a condensation cyclization reaction with a compound 9; the improvements greatly shorten the route steps, the route efficiency is improved, the use of a noble metal catalyst is avoided, and the process cost is greatly lowered. The operation of the route is simple, the total yield is high, the purity of an obtained product is also relatively high, and the method is suitable for the enlarged production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a chemical synthesis method of an intermediate and a raw material drug of a novel oral GnRH antagonist elagolix. Background technique [0002] Elagolix is ​​an oral GnRH antagonist jointly developed by Abbvie and its partner Neurocrine Biosciences. It inhibits the pituitary gonadotropin-releasing hormone receptor and ultimately reduces the level of circulating gonadotropin. Currently, AbbVie is investigating elagolix for the treatment of some diseases mediated by sex hormones, such as uterine fibroids and endometriosis. So far, there have been more than 40 clinical trials of elagolix, involving a total of more than 3,000 patients. In addition, phase III clinical trials of elagolix in the treatment of uterine fibroids are also underway, which has great market prospects. [0003] Elagoli chemical name: 4-[[(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/54
CPCC07D239/54
Inventor 郑旭春张一平付晨晨
Owner HANGZHOU CHEMINSPIRE TECH CO LTD
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