Supercharge Your Innovation With Domain-Expert AI Agents!

Synthesis of mirabegron intermediate (R)-2-hydroxy-N-(4-nitrophenyl ethyl)-2-phenylacetamide

A technology of nitrophenethyl and nitrophenethylamine, which is applied in the field of synthesis of Mirabegron intermediate -2-hydroxy-N--2-phenylacetamide, can solve the problem of high price condensation by-products, The post-processing steps are cumbersome, the product purity is not high, etc., and the industrial operation is feasible, the post-processing is simple, and the yield is high.

Active Publication Date: 2018-11-02
ANHUI DEXINJIA BIOPHARM
View PDF2 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] This route is the main method of synthesizing Mirabegron intermediate (II) at present, and R-mandelic acid can obtain intermediate (II) through one-step reaction, but in the first step condensation reaction method A, used the more expensive 1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and N-hydroxybenzotriazole (HOBt) have many condensation by-products, and the post-treatment needs to be washed with water, Pickling, 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

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Synthesis of mirabegron intermediate (R)-2-hydroxy-N-(4-nitrophenyl ethyl)-2-phenylacetamide
  • Synthesis of mirabegron intermediate (R)-2-hydroxy-N-(4-nitrophenyl ethyl)-2-phenylacetamide
  • Synthesis of mirabegron intermediate (R)-2-hydroxy-N-(4-nitrophenyl ethyl)-2-phenylacetamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Preparation of Intermediate I: Under mechanical stirring, add 15.2g R-mandelic acid, 22.2g triethylamine, 32.5g triphosgene and 150mL acetonitrile into a 250mL three-neck flask, react at 25°C for 6h, complete the reaction in TLC, and cool to room temperature , filtered, the solvent was concentrated in vacuo, 150mL ethyl acetate and 150mL water were added to the residue, stirred for half an hour, the layers were left to stand, the organic phase was dried, and concentrated to give 17.7g of a white solid, namely intermediate I, with a yield of 99%. 1 H NMR (400MHz, CDCl 3 )d 6.02(s, 1H), 7.40-7.46(m, 5H).

[0028] Preparation of the target product: Dissolve 8.9g of intermediate I in 90mL of acetone, add 9.1g of 4-nitrophenylethylamine, react at 56°C for 3 hours, the reaction in TLC is completed, and the solvent is concentrated in vacuo at room temperature, and 30mL of Dissolve methanol at 50°C, cool down and crystallize for 12 hours, filter, wash with 15mL of methanol, an...

Embodiment 2

[0030] Preparation of Intermediate I: Add 30g of R-mandelic acid, 60g of potassium carbonate, 65g of triphosgene and 300mL of DMF into a 500mL three-neck flask under mechanical stirring, and react at 30°C for 5h. After the reaction is completed in TLC, cool to room temperature, filter, and vacuum Concentrate the solvent, add 300mL ethyl acetate and 300mL water to the residue, stir for half an hour, let stand to separate layers, dry the organic phase, and concentrate to obtain 35.5g of white solid, Intermediate I, with a yield of 99%.

[0031] Preparation of the target product: Dissolve 18g of intermediate I in 150mL THF, add 18.2g of 4-nitrophenylethylamine, react at 40°C for 3 hours, the reaction is completed in TLC, and the solvent is concentrated in vacuo at room temperature, and 60mL of methanol is added Dissolve at 50°C, cool down and crystallize for 12 hours, filter, wash with 30mL of methanol, and dry to obtain 13.7g of white solid, namely Mirabegron intermediate (R)-2-h...

Embodiment 3

[0033] Preparation of Intermediate I: Add 30g of R-mandelic acid, 26g of DMAP, 65g of triphosgene and 300mL of acetonitrile into a 500mL three-neck flask under mechanical stirring, react at 15°C for 8h, the reaction is controlled by TLC, cool to room temperature, filter, and concentrate in vacuo Solvent, add 300mL ethyl acetate and 300mL water to the residue, stir for half an hour, let stand to separate layers, dry the organic phase, and concentrate to obtain 35.5g of white solid, namely intermediate I, with a yield of 99%.

[0034] Preparation of the target product: Dissolve 18g of intermediate I in 150mL of acetonitrile, add 18.2g of 4-nitrophenylethylamine, react at 70°C for 3 hours, the reaction is completed in TLC, and the solvent is concentrated in vacuo at room temperature, and 60mL of methanol is added Dissolve at 50°C, cool down and crystallize for 12 hours, filter, wash with 30mL of methanol, and dry to obtain 13.4g of white solid, which is the Labegron intermediate (...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses synthesis of mirabegron intermediate (R)-2-hydroxy-N-(4-nitrophenyl ethyl)-2-phenylacetamide. The synthesis method comprises the following steps: performing esterification reaction on R-mandelic acid and triphosgene in a solvent under the existence of alkali to generate a lactide intermediate I; and performing acylation reaction on the intermediate I and 4-nitrophenylethylamine in a solvent to obtain a target product. The synthesis method avoids use of EDCI and HOBt with high price, has the advantages of easily available raw materials, low cost, simplicity in operationand few impurities, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to the synthesis of a mirabegron intermediate (R)-2-hydroxyl-N-(4-nitrophenethyl)-2-phenylacetamide, which belongs 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 chemical structural formula of Mirabegron is as follows: [0003] [0004] Patents (EP1440969, EP1559427, WO2015044965A1) relate to a method for synthesizing Mirabegron intermediate (R)-2-hydroxyl-N-(4-nitrophenethyl)-2-phenylacetamide, using R- The raw material of mandelic acid is reacted with 4-nitrophenethylamine hydrochloride to obtain (R)-2-hydroxyl-N-(4-nitrop...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/02C07C235/34
CPCC07C231/02C07D317/34C07C235/34
Inventor 张启龙许坤郑庚修王红磊齐书耀
Owner ANHUI DEXINJIA BIOPHARM
Features
  • R&D
  • Intellectual Property
  • Life Sciences
  • Materials
  • Tech Scout
Why Patsnap Eureka
  • Unparalleled Data Quality
  • Higher Quality Content
  • 60% Fewer Hallucinations
Social media
Patsnap Eureka Blog
Learn More

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2025 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com