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Synthesis of mirabegron intermediate (R)-2-(4-nitrophenethylamino)-1-phenylethanol hydrochloride

A technology of nitrophenethylamino and phenylethanol, which is applied in the field of drug synthesis, can solve the problems of many condensation by-products, cumbersome post-processing steps, and high price, and achieve the benefits of large-scale industrial production and the feasibility of industrial operation Great effect of reducing production cost

Inactive Publication Date: 2018-10-16
ANHUI DEXINJIA BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] This route only needs four-step reactions to obtain Mirabegron, and the yield of each step is relatively high. It seems to be a practical and simple route, but in the first step condensation reaction method A, the more expensive 1 -Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) and N-hydroxybenzotriazole (HOBt) and condensation by-products are many, post-treatment needs to be washed with water, acid Washing, alkali washing, hydrochloric acid washing, recrystallization with toluene, high toxicity, cumbersome post-processing steps and easy to produce a large amount of three wastes
In method B, the condensation yield is low and the product purity is not high. The chemical purity of intermediate (I) reported in WO2015044965A1 is 98.65%, and the post-treatment is cumbersome
Expensive 1,3-dimethylimidazolinone (DMI) is used in the second step of amide reduction, and the recovery of DMI is difficult, resulting in high production costs

Method used

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  • Synthesis of mirabegron intermediate (R)-2-(4-nitrophenethylamino)-1-phenylethanol hydrochloride
  • Synthesis of mirabegron intermediate (R)-2-(4-nitrophenethylamino)-1-phenylethanol hydrochloride
  • Synthesis of mirabegron intermediate (R)-2-(4-nitrophenethylamino)-1-phenylethanol hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Preparation of Intermediate I: Add 20g of α-bromoacetophenone, 16.6g of 4-nitrophenethylamine, 48.9g of cesium carbonate, and 150mL of acetonitrile into a 250mL three-neck flask, react at 70°C for 5h, cool to room temperature, filter, and vacuum Concentrate the solvent to obtain an oil, add 50mL of petroleum ether to crystallize for 12h, filter, wash with 20mL of petroleum ether, and dry to obtain 20.7g of white solid, Intermediate I, with a yield of 73% and a purity of 99.31%.

[0034] Preparation of intermediate II hydrochloride: nitrogen protection, -5 ° C, BH 3 -THF (1M, 70mL) was added dropwise to CBS (1M, 3.6mL,) for 30 minutes, and stirred for 60 minutes after the addition, and intermediate I (10g) was dissolved in THF (50mL), - Add dropwise to the reaction system at 5°C for 60 minutes. After the dropwise addition, keep warm for 2 hours and control the liquid phase. The remaining raw materials are less than 1%. Add methanol (10mL) to quench, concentrate the solve...

Embodiment 2

[0037]Preparation of Intermediate I: Add 10g of α-bromoacetophenone, 8.3g of 4-nitrophenethylamine, 41g of potassium carbonate, and 75mL of 1,4-dioxane into a 250mL three-neck flask, react at 90°C for 4h, and cool After reaching room temperature, filter, concentrate the solvent in vacuo to obtain an oil, add 25mL of petroleum ether to crystallize for 12h, filter, wash with 10mL of petroleum ether, and dry to obtain 9.6g of white solid, Intermediate I, with a yield of 68% and a purity of 99.40%.

[0038] Preparation of intermediate II hydrochloride: nitrogen protection, -5 ° C, BH 3 -DMS (1M, 70mL) was added dropwise to CBS (1M, 3.6mL,) for 30 minutes, and stirred for 60 minutes after the addition, Intermediate I (10g) was dissolved in THF (50mL), 0 ℃ was added dropwise to the reaction system, the dropping time was 60 minutes, the dropwise addition was completed and the reaction was incubated for 2 hours, the liquid phase was controlled in the middle, and the remaining raw mate...

Embodiment 3

[0040] Preparation of Intermediate I: Add 20g of α-bromoacetophenone, 18g of 4-nitrophenylethylamine, 41g of potassium carbonate, and 150mL of DMF into a 250mL three-neck flask, react at 60°C for 6h, cool to room temperature, filter, and concentrate the solvent in vacuo The oil was obtained, crystallized by adding 50mL of petroleum ether for 12h, filtered, washed with 20mL of petroleum ether, and dried to obtain 20g of white solid, Intermediate I, with a yield of 70.4% and a purity of 99.40%.

[0041] Preparation of intermediate II hydrochloride: nitrogen protection, -10°C, BH 3 -THF (1M, 70mL) was added dropwise to CBS (1M, 3.6mL,) for 30 minutes, and stirred for 60 minutes after the addition, and intermediate I (10g) was dissolved in THF (50mL), - Add it dropwise to the reaction system at 10°C for 60 minutes. After the dropwise addition, keep it warm for 2 hours and control the liquid phase. The remaining raw materials are less than 1%. Add methanol (10mL) to quench, concent...

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Abstract

The invention discloses synthesis of a mirabegron intermediate (R)-2-(4-nitrophenethylamino)-1-phenylethanol hydrochloride. The synthesis comprises the following steps: firstly, enabling alpha-bromoacetophenone and 4-nitro-phenethylamine to react in a solvent in the presence of alkali to generate an intermediate I; then carrying out reduction reaction on the intermediate I under the action of a chiral inducing agent and a reducing agent to generate an intermediate II; enabling the intermediate II to react with concentrated hydrochloric acid in a solvent to generate a target product. Accordingto the synthesis method disclosed by the invention, EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), HOBt (Hydroxybenzotriazole) and DMI (1,3-dimethyl-2-imidazolidinone) which have a relatively high price, and hypertoxic R-styrene oxide can be avoided; the synthesis method has the advantages of easiness for obtaining raw materials, low cost, simplicity in operation and few impurities and is suitable for industrial production.

Description

technical field [0001] The invention relates to the synthesis of mirabegron intermediate (R)-2-(4-nitrophenethylamino)-1-phenylethanol hydrochloride, belonging to the field of drug synthesis. Background technique [0002] Mirabegron is an aryl ethanolamine receptor agonist and was approved for marketing by the US Food and Drug Administration (FDA) in June 2012. Mirabegron was developed by Japan's Astellas Pharmaceutical Company (Astellas), and Yamanouchi Pharmaceutical Co., Ltd. (later merged into Astellas Pharmaceutical Company) applied for the compound of Mirabegron in Japan on October 17, 1997 Patent, the molecular mass of Mirabegron is 396.5, and the molecular formula is C 21 h 24 N 4 o 2 S, CAS number: 223673-61-8, its Chinese chemical name is: (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-benzene Base ethyl) amino] ethyl] acetate anilide, the chemical structural formula is as follows: [0003] [0004] Patents WO9920607A1, WO2015044965A1, CN103896872A, and U...

Claims

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Application Information

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IPC IPC(8): C07C221/00C07C225/16C07C213/00C07C215/30
CPCC07B2200/07C07C213/00C07C221/00C07C225/16C07C215/30
Inventor 张启龙许坤郑庚修王红磊齐书耀
Owner ANHUI DEXINJIA BIOPHARM
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