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Relugolix intermediate and preparation method thereof

A volume and time technology, which is applied in the field of relugoli intermediates and their preparation, can solve the problems of unsuitability for industrial production, excessive heavy metal elements, and low product purity, and achieves heavy metal residues up to standard, high total yield, and high purity. Effect

Active Publication Date: 2021-10-29
上海新礼泰药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The technical problem to be solved by the present invention is to overcome the harsh reaction conditions, low yield, low purity of the prepared product, excessive heavy metal elements, high equipment requirements, and unsuitability for industrialization in the preparation method of Relugoli in the prior art. Defects such as production provide a completely different Relugoli intermediate and preparation method thereof from the prior art

Method used

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  • Relugolix intermediate and preparation method thereof
  • Relugolix intermediate and preparation method thereof
  • Relugolix intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0148] The synthesis of embodiment 1 compound B

[0149]

[0150] Compound A (80.0g) is added methanol (640mL) in a nitrogen atmosphere, 10%Pd-C (8.0g, described percentage refers to the percentage that the quality of palladium accounts for the total mass of palladium carbon) is added thereto, and the The mixture was stirred under hydrogen balloon pressure at 25±5°C for 4-6 hours. Activated carbon and catalyst were filtered off and washed with methanol (160 mL). Concentrate under reduced pressure at 45±5° C. until the weight is constant to obtain compound B as a yellow-brown oil with a yield of 99.0% and a purity of 98.0% by HPLC.

Embodiment 2

[0151] The synthesis of embodiment 2 compound C

[0152]

[0153]Acetonitrile (30 mL) and 1,1'-carbonyldiimidazole or (CDI, 5.01 g, 1.7 eq) were added to the reactor, and the mixture was stirred. Under stirring, triethylamine (1.56 g, 0.85 eq) was added thereto, and cooled to an internal temperature of 10±5°C. Methoxylamine hydrochloride (2.90 g, 1.91 eq) was added thereto in portions with stirring at a lower internal temperature of 30°C, and the container used for the reagent was washed with acetonitrile (5 mL). The mixture was stirred at an internal temperature of 25±5° C., and after it was confirmed that the mixture was dissolved, the solution was further stirred for 10 minutes or more. Then, Compound B (10.00 g) was added thereto under stirring, and the container used for the reagent was washed with acetonitrile (5 mL). The reaction mixture was heated to an internal temperature of 50±5°C, and stirred at the same temperature for 2-3 hours, cooled to an internal tempera...

Embodiment 3

[0154] The synthesis of embodiment 3 compound D

[0155]

[0156] Compound C (10.0 g) was dissolved in ethanol (100 mL), 2N NaOH (45.7 ml, 5.0 eq) was added thereto, and stirred at an external temperature of 60° C. for about 6 hours. Concentrate the reaction solution until ethanol is basically removed, cool down to 20±5°C, and slowly adjust the pH to about neutral with 1N HCl (5.0eq). And stirred at room temperature for more than 2 hours, filtered to obtain a yellow solid, rinsed with water (20ml). The wet product was baked in an air blast oven at 50°C for 2 hours, then heated up to 60°C and baked overnight to obtain 7.7 g of off-white solid, compound D, with a yield of 81%.

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PUM

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Abstract

The invention discloses a Relugolix intermediate and a preparation method thereof. The invention provides a preparation method of a compound D. The preparation method comprises the following steps of: by taking an organic solvent and / or water as a solvent, carrying out hydrolysis reaction on a compound C under the action of alkali to obtain the compound D. The preparation method disclosed by the invention is simple and safe to operate, simple in post-treatment step, environment-friendly and high in total yield, and the Relugolix product prepared from the intermediate disclosed by the invention is high in purity, low in heavy metal element content, capable of reaching the standard of raw material medicines, low in production cost and suitable for industrial production.

Description

technical field [0001] The invention relates to a relugoli intermediate and a preparation method thereof. Background technique [0002] Relugolix is ​​a small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist jointly developed by Myovant and Takeda. Launched in Japan in 2018, it is used to treat bleeding and pain caused by uterine fibroids. Relugolix rapidly lowers estrogen and progesterone levels in women when taken by mouth once daily. Takeda Pharmaceutical compared the safety and effectiveness of Relugolix and leuprorelin (leuprorelin) in the treatment of uterine fibrosis with menorrhagia through a series of clinical phase III studies conducted in Japan, and the above two drugs in the treatment of uterine fibrosis The safety and effectiveness of pain symptoms related to uterine fibroids finally confirmed the safety and efficacy of relugolix for uterine fibroids. In addition, Takeda Pharmaceutical conducted a phase II clinical study of relugolix on endo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/38C07D409/12C07D495/04
CPCC07D495/04C07D409/12C07D333/38Y02P20/55
Inventor 汪仙阳赖中柳刘广振唐超王婷婷应述欢
Owner 上海新礼泰药业有限公司
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