Preparation method of mirabegron and intermediate thereof

A mirabegron, inert gas technology, applied in the field of drug synthesis, can solve the problems of production efficiency restriction, unfavorable production cost, time cost, large amount of auxiliary materials, etc., to ensure product quality and safety, enhance market competitiveness, economical obvious effect

Pending Publication Date: 2022-05-27
SHANGHAI VIWIT PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] CN 1575287A In the preparation method of Mirabegron intermediate ((R)-2-(4-nitrophenylethyl)amino)-1-phenylethanol hydrochloride), when borane tetrahydrofuran is used as reducing agent , in order to reduce the occurrence of side reactions and ensure product purity, 1,3 - The amount of dimethylimidazolinone (DMI) needs to reach 23L (the density at 25°C is 1.056g / mL, about 212.77mol), that is, the molar amount of 1,3-dimethylimidazolinone is (R)- 8.5 times the molar amount of 2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide, there are problems of large amount of auxiliary materials and high cost, and also increases the inconvenience of subsequent operations, resulting in processing time Substantial increase: the second addition of concentrated hydrochloric acid crystallization requires overnight stirring, which severely restricts the production efficiency of this method, which is not conducive to reducing the production cost and time cost of unit products, and affects its industrial application

Method used

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  • Preparation method of mirabegron and intermediate thereof
  • Preparation method of mirabegron and intermediate thereof
  • Preparation method of mirabegron and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0113] 1. Preparation of compound 3

[0114]

[0115] Include the following steps:

[0116] ①, in 240kg N,N-dimethylformamide, add 26.02kg (about 171mol) D-mandelic acid (compound 1), 31.5kg (about 155.45mol) 4-nitrophenethylamine hydrochloride (compound 2), 23.12kg (about 171mol) 1-hydroxybenzotriazole, and 35.28kg (about 171mol) N, N-dicyclohexylcarbodiimide, 18.84kg (about 186mol) triethylamine, the temperature of reaction is at 20~25 ℃, stirring and reacting for 5h, after high performance liquid chromatography (HPLC) detects that the reaction is basically complete (the remaining amount of compound 2 is less than or equal to 2%), a reaction solution is obtained;

[0117] 2., in above-mentioned reaction solution, add 360kg ethyl acetate and 604.8kg purified water, stir, pad diatomaceous earth filter afterwards, stand, separatory, get organic phase, the water phase of lower floor is with ethyl acetate (285kg, 171kg) Extract twice, combine the organic phases, add 32.82kg ...

Embodiment 2～4

[0151] In step i of the preparation method of compound 4, the amount of 1,3-dimethylimidazolidinone (DMI) was changed to 0mol, 200mol, and 600mol respectively, that is: in terms of compound 3 (mol), 1,3-dimethylimidazolidinone (DMI) The consumption of diimidazolidinone (DMI) is respectively 0 equivalent, 2.5 equivalent, 7.5 equivalent, other process conditions remain unchanged (identical to embodiment 1), prepare compound 4, its yield and HPLC purity, impurity content are shown in Table 3 .

[0152]

[0153] Table 3, the effect of 1,3-dimethylimidazolidinone (DMI) dosage on the preparation of compound 4

[0154] Example 2 Example 3 Example 1 Example 4 DMI dosage / equivalent 0 2.5 5 7.5 yield 83.0％ 86.6％ 88.7％ 89.2％ HPLC purity 96.7％ 99.61％ 99.6％ 99.44％ Impurities (337008) 3.1％ ND ND ND

[0155] ND means not detected, which means its content is below the detection limit.

Embodiment 5～6

[0157] In step i of the preparation method of compound 4, the dosage of borane dimethyl sulfide was changed to 168 mol and 200 mol, respectively, that is, in terms of compound 3 (mol), the dosage of borane dimethyl sulfide was respectively 2.1 equivalent and 2.5 equivalent. , other process conditions remain unchanged (same as Example 1), compound 4 is prepared, and its yield, HPLC purity and impurity content are shown in Table 4.

[0158] Table 4, the effect of borane dimethyl sulfide dosage on the preparation of compound 4

[0159] Example 5 Example 1 Example 6 Borane dimethyl sulfide amount / equivalent 2.1 2.3 2.5 yield 86.0％ 88.7％ 88.5％ HPLC purity 99.76％ 99.6％ 99.73％ Impurities (337008) ND ND ND

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Abstract

The invention discloses a preparation method of mirabegron and an intermediate thereof. According to the preparation method, on one hand, the relative dosage of auxiliary materials can be reduced, the cost expenditure of the auxiliary materials can be effectively reduced, and on the other hand, generation and / or residues of dehydroxylation impurities can be reduced, so that the content of the dehydroxylation impurities in the product can be kept in a very low level range; the product quality and safety of the mirabegron intermediate and / or the raw material medicine can be better guaranteed.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and in particular relates to a preparation method of mirabegron and an intermediate thereof. Background technique [0002] Overactive Bladder (OAB) is a syndrome characterized by urinary urgency symptoms, often accompanied by frequent urination, urinary incontinence, etc. . [0003] Mirabegron, CAS No.: 223673-61-8, with the following structural formula, is a selective β3-adrenergic receptor agonist, mainly used for the treatment of urinary urgency, frequency and incontinence caused by overactive bladder Equivalent. It was first listed in Japan in 2011, and later in the United States, the European Union and other countries or regions. It has been widely praised by patients due to its advantages of good therapeutic effect and small side effects. [0004] [0005] At present, a mainstream route for synthesizing mirabegron is: taking 4-nitrophenethylamine or its salt and D-mandelic acid...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/02C07C235/34C07C213/02C07C215/30C07C213/08C07D277/40
CPCC07C231/02C07C213/02C07C213/08C07D277/40C07B2200/13C07B2200/07C07C235/34C07C215/30
Inventor 魏彦君孔猛刘希望徐青景邢艳平
Owner SHANGHAI VIWIT PHARMA CO LTD
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