Mirabegron related substance or salt thereof, and preparation method and use thereof

A related substance, mirabegron technology, applied in carboxylate preparation, organic chemistry, etc., can solve problems such as ineffective identification and quality control, and generation of impurities

Active Publication Date: 2014-03-19
CHINA NAT MEDICINES GUORUI PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem to be solved by the present invention is to overcome the existing mirabegron synthesis producing impurities, technical problems

Method used

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  • Mirabegron related substance or salt thereof, and preparation method and use thereof
  • Mirabegron related substance or salt thereof, and preparation method and use thereof
  • Mirabegron related substance or salt thereof, and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] The preparation of embodiment 1N-(4-nitrophenylethyl)-2-phenylacetamide (compound shown in formula 4)

[0056] The compound shown in formula 2 (10.0g, 0.073mol) and the compound shown in formula 3 (14.88g, 0.073mol) were added to DMF (50mL), followed by triethylamine (7.43g, 0.073mol) , 1-Hydroxybenzotriazole (9.93g, 0.073mol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (14.78g, 0.077mol) Added to the above reaction solution, stirred at room temperature for 18h. Add water and dichloromethane to extract. The organic layer was dried, filtered, and concentrated under reduced pressure. Recrystallization from toluene gave a white solid (17.33g, 82.99%).

[0057] mp130.2~131.0℃.

[0058] ESI-MS(m / z):285[M+H] + ,307[M+Na] + .

[0059] 1 H NMR (400MHz, DMSO-d 6 )δ:2.84~2.88(t,2H,NO 2 PhCH 2 ),3.29(s,2H,COCH 2 ), 3.34~3.39(m, 2H, NCH2), 7.19~7.28(m, 5H, Ph-H), 7.42~7.44(d, 2H, nitrobenzene meta H), 8.04(s, 1H, heavy water exchange Signal disap...

Embodiment 2

[0060] The preparation of embodiment 2N-(4-nitrophenylethyl)-2-phenethylamine hydrochloride (the hydrochloride of the compound shown in formula 5)

[0061] Add the compound shown in Formula 4 (5.0g, 17.59mmol), anhydrous THF (15mL), 1,3-dimethyl-2-imidazolidinone (15ml) into a three-necked flask, protect it with nitrogen, and cool to Add 1M BH dropwise after -20℃ 3 -THF solution (38.69mL, 38.69mmol), after dropping, stirred at 65°C for 5h. The reaction solution was cooled to -15°C, and methanol (2.5 mL) and concentrated hydrochloric acid (3.3 mL) were added dropwise. After dropping, stir at 65°C for 1 h, concentrate under reduced pressure, add 20% potassium carbonate solution (50 mL) to the residue, extract with ethyl acetate (3×25 mL), wash the organic layer with saturated brine, dry, filter, and concentrate under reduced pressure . The residue was dissolved in isopropanol (50 mL), crystallized with concentrated hydrochloric acid (1.45 mL), filtered, the filter cake was wa...

Embodiment 34

[0064] Preparation of Example 34-[2-(phenylethylamino)ethyl]aniline hydrochloride (the hydrochloride of the compound shown in formula 6)

[0065] Add the compound shown in Formula 5 (3.5g, 11.41mmol), 10%Pd / C (0.35g) into methanol, pass in hydrogen, stir for 12h, filter the reaction solution, concentrate the filtrate under reduced pressure, and wash the residue with methanol (10mL ) was dissolved, crystallized by adding isopropyl ether (70mL) dropwise, filtered, the filter cake was washed with isopropyl ether, and dried in vacuo to obtain a white solid (2.9g, 91.83%).

[0066] mp186°C (decomposition). ESI-MS(m / z):241[M+H] + .

[0067] 1 H NMR (400MHz, DMSO-d 6 )δ:2.80~3.16(m,8H,4CH 2 ),4.99(br s,2H,NH 2), 6.53~6.55(d, 2H, aniline ortho-H), 6.90~6.92(d, 2H, aniline meta-position H), 7.24~7.36(m, 5H, Ph-H), 9.22(br s, 2H, NH 2 ＋ Cl － ).

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PUM

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Abstract

The invention discloses a mirabegron related substance as shown in a formula I or a salt thereof, and a preparation method and a use thereof. The preparation method of the mirabegron related substance or the hydrochloride thereof disclosed by the invention comprises the following step: in a solvent, carrying out a condensation reaction as shown in specification between a compound as shown in a formula 6 and a compound as shown in a formula 7 or an active ester thereof under the action of a condensating agent to obtain the mirabegron related substance as shown in the formula I; or in the solvent, carrying out the condensation reaction between the hydrochloride of the compound as shown in the formula 6 and the compound as shown in the formula 7 or the active ester thereof under the action of the condensating agent to obtain the hydrochloride of the mirabegron related substance as shown in the formula I. The mirabegron related substance disclosed by the invention is capable of effectively identifying impurities generated in the synthesis of the mirabegron so as to control the medicine quality of the mirabegron.

Description

technical field [0001] The invention relates to a mirabegron-related substance or a salt thereof, a preparation method and application thereof. Background technique [0002] Mirabegron, chemical name (R)-2-(2-aminothiazol-4-yl)-N-(4-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} Phenyl)acetamide, molecular formula C 21 h 24 N 4 o 2 S, molecular weight 396.51, CAS registration number 223673-61-8, is a new orally effective selective β-β drug developed by Japan Astellas Pharmaceutical Co., Ltd. 3 Adrenergic receptor agonist, which was first launched in Japan in 2011, was approved by FDA in June 2012 for the treatment of overactive bladder (OAB) in adults. Its structure is as follows: [0003] [0004] Patent WO2003037881 reports that the synthesis method of mirabegron is as follows: D-mandelic acid and p-nitrophenethylamine are used as starting materials to obtain the compound shown in formula 9 through amide condensation, and then the compound shown in formula 9 is obtained...

Claims

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Application Information

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IPC IPC(8): C07D277/40C07C51/41C07C57/15C07C59/255C07C55/10
CPCC07D277/40
Inventor 张福利章磊焦慧荣谭支敏徐兰霞徐建国裘鹏程
Owner CHINA NAT MEDICINES GUORUI PHARMA
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