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Preparation method of mirabegron key intermediate

A key and integrated technology, which is applied in the field of preparation of key intermediates of Mirabegron, can solve problems such as production safety risks not being effectively resolved, affecting the quality of Mirabegron finished products, and strong dependence on equipment, etc., to achieve easy scale The effects of high performance amplification, less impurities, high product purity and yield

Inactive Publication Date: 2022-01-04
SHANDONG BESTCOMM PHARMA CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Chinese patent CN108947853A adopts the problem of high-pressure equipment in order to solve the Mirabegron intermediate formula (III) compound palladium-carbon hydrogenation pressurization catalytic reaction, adopts the method for preparing this intermediate by adopting the low-pressure palladium-carbon hydrogenation of microchannel reactor, although this method avoids High-pressure equipment is used, but precious metal catalysts and flammable and explosive hydrogen are still required. In addition, the reaction requires a separately customized microchannel reactor reaction equipment. The high production cost and production safety risks have not been effectively resolved.
Using ammonium formate and other hydrogen sources for reduction will produce impurities such as formylation. The product has low purity and is difficult to purify. Participating in subsequent reactions will affect the quality of Mirabegron finished products, and multiple refinements are required; additional large-scale production is dependent on equipment Strong nature, difficult to scale up production

Method used

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  • Preparation method of mirabegron key intermediate
  • Preparation method of mirabegron key intermediate
  • Preparation method of mirabegron key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Embodiment 1: preparation of formula (V) compound

[0039]

[0040] Add 200 g of compound of formula (VII) and 286 g of compound of formula (VI) into 1.6 kg of N,N-dimethylformamide, and add 132 g of triethylamine, 178 g of 1-hydroxybenzotriazole and 264 g of EDCI at room temperature. Stir the reaction at room temperature for 1 h, add 1.6 kg of purified water, stir and crystallize for 2 h, filter, and dry to obtain 371 g of the compound of formula (V), with a yield of 93.7%.

Embodiment 2

[0041] Embodiment 2: preparation of formula (IV) compound

[0042]

[0043] Add 300 g of the compound of formula (V) into 1.5 kg of tetrahydrofuran, and slowly add 675 g of 2 mol / L borane dimethyl sulfide complex. After the addition, the temperature was raised to reflux for 3 hours, and the reaction ended. Cool down to room temperature and add 120 g of methanol and 200 g of hydrochloric acid. The temperature was raised to 60°C and stirred for 1 hour. The solvent was evaporated under reduced pressure, 1.2 kg of methanol was added after concentration, stirred for 2 hours, suction filtered, and air-dried at 50±5°C to obtain 300 g of the compound of formula (IV), with a yield of 93.2%.

Embodiment 3

[0044] Embodiment 3: preparation of formula (III) compound

[0045]

[0046] Add 200g of the compound of formula (IV) into 1600g of methanol, add 16.8g of ferric chloride hexahydrate, and 60.0g of activated carbon; keep stirring for 30 minutes, slowly add 234g of hydrazine hydrate, dropwise, heat up to reflux and keep warm for 5h, and the reaction is complete , lower the temperature to 25±5°C, and obtain the filtrate by suction filtration; add the filtrate to the reaction flask, slowly add 3.0kg of purified water, and gradually solids precipitate; keep warm at 10±5°C for crystallization for 2 hours, suction filter, and dry to obtain formula (III) Compound 151g; Yield 94.9%. Such as figure 1 , shown in table 1, impurity formula (VIII) compound, impurity formula (IX) compound and impurity formula (X) compound all do not detect.

[0047] The formula (III) compound chromatographic peak result that table 1 embodiment 3 prepares

[0048] keep time area %area ...

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Abstract

The invention provides a preparation method of a mirabegron key intermediate, namely, a compound as shown in a formula (III). The method is simple, convenient and safe to operate, free of harsh reaction conditions, high in reaction purity and yield and low in process cost which is about 40% of that of a process using a metal catalyst such as palladium carbon, is suitable for large-scale production and conforms to the green chemistry principle. A finished product of mirabegron continues to be prepared by using the intermediate compound as shown in the formula (III) prepared by the method so as to meet the existing requirements.

Description

1. Technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of a mirabegron key intermediate. 2. Background technology [0002] Mirabegron (Mirabegron) tablet was developed by Japan Astellas (Astellas) pharmaceutical company, began clinical trials in Japan in 2005, and was first approved in Japan on July 1, 2011 (trade name: Betanis, 25mg, 50mg), and subsequently launched in Japan on September 16. On June 28, 2012, Mirabegron was approved by the US FDA for the treatment of overactive bladder in adults (trade name: Myrbetriq, 25mg, 50mg). In December 2012 and March 2013, it was approved for marketing in the European Union (trade name: Betmiga) and Canada (trade name: Myrbetriq). [0003] The chemical name of mirabegron (compound of formula (I)) is: 2-(2-amino-1,3-thiazol-4-yl)-N-[4-[2-[[(2R)-2- Hydroxy-2-phenylethyl]amino]ethyl]phenyl]acetamide, molecular formula C 21 h 24 N 4 o 2 S, t...

Claims

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Application Information

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IPC IPC(8): C07C213/00C07C215/30C07D277/40
CPCC07C213/00C07D277/40C07C215/30
Inventor 凌浩解加福高冈李红宾蔡西武毕爱莲
Owner SHANDONG BESTCOMM PHARMA CO LTD
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