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Preparation method of mirabegron intermediate

A technology of intermediates and compounds, which is applied in the field of preparation of Mirabegron intermediates, can solve problems such as unfavorable industrial production, high price, and not being environmentally friendly

Active Publication Date: 2021-04-30
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the prior art, using chemical synthesis method to prepare Mirabegron has problems such as difficult sources of raw materials, high prices, difficult product purification, and unfavorable industrial production.
As in the synthetic method of CN108658797A, expensive and highly toxic chiral inducer (R)-2-methyl-CBS-oxazole borane and borane-tetrahydrofuran are used, and tetrahydrofuran is expensive as a solvent and not environmentally friendly
Another example is in the synthetic method of CN104876890A, the target compound is obtained by the method of L-tartaric acid resolution, the yield is about 30% in the specific examples, the theoretical yield is no more than 50%, and the yield is relatively low

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] The preparation of embodiment 1 compound 2-1

[0041]

[0042] At room temperature, add 20mg of compound 1-1 and 16.85mg of D-glucose into 3ml of 0.2M phosphate buffered saline with pH=6.7, add 10mg of ketoreductase ET-027, 5mg of coenzyme II, and 5mg of glucose dehydrogenase, at 20°C Magnetic stirring at -30°C, adding saturated sodium carbonate aqueous solution dropwise to control pH = 6-8, liquid phase detection after 18 hours showed that the remaining raw materials were 0.24%, the purity of compound 2-1 was 95.80%, and the isomer impurity (S)-2 of the compound -(4-nitrophenethylamino)-1-phenylethanol was 0.19%, and the optical purity of compound 2-1 was 99.81%; 5ml of ethyl acetate was added to the system, extracted and separated, and concentrated to obtain compound 2-1 : White solid 16mg, yield 89.6%, detection:

[0043] 1H NMR (400MHz, DMSO) δ9.31 (d, J = 170.0Hz, 2H), 8.20 (d, J = 8.3Hz, 2H), 7.57 (d, J = 8.6Hz, 2H), 7.46-7.35 ( m, 4H), 7.34-7.26(m, 1H), 6.25...

Embodiment 2

[0044] The preparation of embodiment 2 compound 2-2

[0045]

[0046] At room temperature, add 20mg compound 1-2, 13.21mg D-glucose to 400ul pH=6.7 0.2M phosphate buffered saline, add 5mg ketoreductase ET-027, 5mg coenzyme Ⅱ, 5mg glucose dehydrogenase, at 20℃ Stir magnetically at -30°C, add sodium carbonate aqueous solution dropwise to control pH = 6-8, after 18 hours, there is no raw material remaining in the liquid phase test, the purity of the target product is 92.45%, the isomer impurity of compound 2-2 (S)-2- The content of (4-aminophenethylamino)-1-phenylethanol is 0.15%, and the optical purity of compound 2-2 is 99.85%. Add 2ml of ethyl acetate to the system, extract and separate, and concentrate to obtain compound 2-2: white Solid 14mg, yield 89.4%, detection:

[0047] 1H-NMR (400MHz, DMSO): δ: 2.87-2.90 (2H, m); 2.97-3.16 (4H, m); 5.06-5.09 (3H, m); 6.22 (1H); 6.55-6.57 (2H, d , J=7.7Hz); 6.88-6.91 (2H, d, J=7.7Hz); 7.29-7.42 (5H, m); 9.22 (1H, br).

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Abstract

The invention relates to a preparation method of a mirabegron intermediate, and belongs to the field of medicinal chemistry. The preparation method comprises that a compound 1 or a salt thereof undergoes a reduction reaction under the action of ketoreductase, coenzyme, glucose dehydrogenase, glucose and a buffer solution to produce a compound 2 or a salt thereof. The preparation method disclosed by the invention is a biological conversion method, and the method is mild in condition, high in conversion rate, high in chiral purity, high in yield and less in three wastes; and the method can be used for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of a mirabegron intermediate. Background technique [0002] Mirabegron (compound shown in formula 1), chemical name is (R)-2-(2-amino-1,3-thiazol-4-yl)-4'-[2-[2-(2-hydroxyl -2-Phenylethyl) amino] ethyl] phenylacetamide, which was developed by Japan Astellas Corporation, first listed in Japan in September 2011, and approved by the US FDA in June 2012 for the treatment of adult overactive bladder . [0003] [0004] In the prior art, the preparation of mirabegron by chemical synthesis method has problems such as difficult sources of raw materials, high price, difficult product purification, and unfavorable industrialized production. For example, in the synthetic method of CN108658797A, expensive and highly toxic chiral inducers (R)-2-methyl-CBS-oxazole borane and borane-tetrahydrofuran are used, and tetrahydrofuran is expensive as a solvent and is not en...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P13/00
CPCC12P13/008C12P13/001Y02P20/55
Inventor 王仲清丰亚辉何方梁锡裕杨虎罗忠华黄芳芳
Owner SUNSHINE LAKE PHARM CO LTD
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