Method for efficiently synthesizing elagolix intermediate

A technology for elagolime and intermediates, which is applied in the field of high-efficiency synthesis of elagolime intermediates, and can solve problems such as expensive starting materials, high process costs, and inapplicability to industrial production.

Active Publication Date: 2019-09-06
AURISCO PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] In the patent US8765948B2, 2-(2-fluoro-3-methoxyphenyl)-ethyl glyoxylate is used as raw material, reduced by sodium borohydride, brominated by methanesulfonyl chloride and tetraethylammonium bromide, and then processed by zinc Powder catalysis and substitution reaction, followed by aminoalkylati

Method used

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  • Method for efficiently synthesizing elagolix intermediate
  • Method for efficiently synthesizing elagolix intermediate
  • Method for efficiently synthesizing elagolix intermediate

Examples

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Comparison scheme
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Example Embodiment

[0043] Example 1:

[0044]

[0045] Amino alkylation reaction: At room temperature, put 12.6g 6-methyluracil, 63g D-Boc phenylglycinol mesylate and 32g 2,6-lutidine into the reaction flask, and then add 126mL N,N -Dimethylformamide, warm up to 55°C, start the incubation reaction for 24h, and cool down to room temperature, add 100mL of isopropyl acetate and 100mL of water, stir to separate the layers, wash the organic layer with 50mL of water for 3 times and then dry with anhydrous sodium sulfate , Filter, and concentrate the filtrate to dryness to obtain 30 g of Intermediate III, with a weight yield of 86.9% and an HPLC purity of 98%.

[0046] Halogenation reaction: The reaction flask is protected by nitrogen. Add 11.5g of the above intermediate III, 10.8g of iodine chloride and 115mL methanol at room temperature, warm up to 50℃, keep the reaction for 30h, cool to room temperature, filter, and rinse the solid with a small amount of methanol. After drying, 15 g of Intermediate IV w...

Example Embodiment

[0050] Example 2:

[0051] Ammonia alkylation reaction: the same operation as in Example 1, changing the addition of 32 g of 2,6-lutidine to 30.4 g of triethylamine, the reaction weight yield was 82%, and the HPLC purity was 96%.

[0052] Halogenation reaction: the same operation as in Example 1, changing the halogenating reagent to 10.7g bromine and 10.2g acetic acid, the weight yield is 120%, and the HPLC purity is 95%.

[0053] Coupling reaction: the same operation as in Example 1, changing the amount of palladium acetate from 0.04g to 0.02g, and the amount of 2-fluoro-3-methoxyphenylboronic acid from 4.3g to 8g. The reaction weight yield is 95%. HPLC purity is 97%.

[0054] Benzyl halide substitution reaction: the same operation as in Example 1, the addition of 4.4 g potassium carbonate was changed to 3.5 g sodium carbonate, and 35 mL of tetrahydrofuran was changed to 35 mL of acetonitrile. The reaction weight yield was 123% and the HPLC purity was 96%.

[0055] Deprotection reacti...

Example Embodiment

[0056] Example 3:

[0057] Ammonia alkylation reaction: the same operation as in Example 1, the addition of 32 g of 2,6-lutidine was changed to 30 g of pyridine, the reaction weight yield was 84%, and the HPLC purity was 94%.

[0058] Halogenation reaction: the same operation as in Example 1, changing the addition of 10.8 g of iodine chloride to 20.2 g of iodine chloride, the reaction weight yield was 113%, and the HPLC purity was 94%.

[0059] Coupling reaction: the same operation as in Example 1, the dosage of palladium acetate was changed from 0.04g to 0.01g, and the dosage of 2-fluoro-3-methoxyphenylboronic acid was changed from 4.3g to 3.2g, the reaction weight was recovered The rate is 92%, and the HPLC purity is 95%.

[0060] Benzyl halide substitution reaction: the same operation as in Example 1, the addition of 4.4g potassium carbonate was changed to 2.5g cesium carbonate, and 35mL tetrahydrofuran was added instead of 35mL 1,4-dioxane. The reaction weight yield was 120%. HPL...

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Abstract

The invention relates to the field of pharmacy, in particular to a method for efficiently synthesizing an elagolix intermediate. The method takes 6-methyluracil as a starting material, and comprises five reactions of aminoalkylation, halogenation, coupling, benzyl halide substitution and deprotection. The synthetic method has the advantages that the starting material is cheap and easy to obtain, areaction reagent is friendly to the environment, the reaction steps are simple, the aftertreatment is convenient, the overall yield is higher, and the method is especially suitable for industrial mass production and has larger application value.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a method for efficiently synthesizing an elagolix intermediate. Background technique [0002] Elagolix is ​​an orally active non-peptide gonadotropin-releasing hormone receptor antagonist (GnRH-a) developed by AbbVie in collaboration with Neurocrine Biosciences Inc (NBIX) for the treatment of endometriosis. Compared with the GnRH-a preparations already on the market, which are all injections, as an oral GnRH-a, it has greater advantages in terms of ease of use and patient acceptance. In addition, antagonists have theoretically more advantages than agonists. Better safety, faster onset, shorter medication time, and great potential for future clinical application. [0003] Patent CN1819829A uses 2-fluoro-6-(trifluoromethyl)benzonitrile as the starting material, first undergoes borane reduction, then condenses with urea, then cyclizes with diketene, and then undergoes bromination and aminoa...

Claims

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Application Information

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IPC IPC(8): C07D239/54
CPCC07D239/54
Inventor 车峰峰蒋涛王爱民金明亮洪卿褚潇攀叶张熠
Owner AURISCO PHARMACEUTICAL CO LTD
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