Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

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
View PDF4 Cites 5 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 aminoalkylation and substitution reaction, and finally acid deprotection to obtain the elagolix intermediate. As shown in the following steps, the key starting materials of this route are expensive and difficult to obtain, resulting in high process costs. Not suitable for industrial production, low application value

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Method for efficiently synthesizing elagolix intermediate
  • Method for efficiently synthesizing elagolix intermediate
  • Method for efficiently synthesizing elagolix intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044]

[0045] Aminoalkylation reaction: at room temperature, put 12.6g of 6-methyluracil, 63g of D-Boc phenylglycinyl mesylate and 32g of 2,6-lutidine into the reaction flask, then add 126mL of N,N - Dimethylformamide, raise the temperature to 55°C, start the heat preservation reaction for 24h, cool down to room temperature, add 100mL isopropyl acetate and 100mL water, stir and separate layers, add 50mL water to the organic layer, wash 3 times, and dry with anhydrous sodium sulfate , filtered, and the filtrate was concentrated to dryness to obtain 30 g of intermediate III, with a weight yield of 86.9% and a HPLC purity of 98%.

[0046] Halogenation reaction: The reaction bottle is protected by nitrogen, add 11.5g of the above intermediate III, 10.8g of iodine chloride and 115mL of methanol at room temperature, heat up to 50°C, keep the temperature for 30h, cool down to room temperature, filter, and rinse the solid with a small amount of methanol. After drying, 15 g of int...

Embodiment 2

[0051] Aminoalkylation reaction: the same operation as in Example 1, except that 32 g of 2,6-lutidine was added instead of 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, but the halogenation reagent was changed to 10.7g bromine and 10.2g acetic acid, the weight yield was 120%, and the HPLC purity was 95%.

[0053] Coupling reaction: with the operation of embodiment 1, the consumption of palladium acetate is changed from 0.04g to 0.02g, and the consumption of 2-fluoro-3-methoxyphenylboronic acid is changed from 4.3g to 8g, and the reaction weight yield is 95%, HPLC purity 97%.

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

...

Embodiment 3

[0057] Aminoalkylation reaction: the operation was the same as in Example 1, except that 32 g of 2,6-lutidine was added instead of 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 10.8g iodine chloride to 20.2g iodine chloride, the reaction weight yield was 113%, and the HPLC purity was 94%.

[0059] Coupling reaction: with the operation of embodiment 1, the consumption of palladium acetate is changed from 0.04g to 0.01g, and the consumption of 2-fluoro-3-methoxyphenylboronic acid is changed from 4.3g to 3.2g, and the reaction weight is obtained Yield 92%, HPLC purity 95%.

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
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
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com