Efficient synthesis method of mirabegron

A synthetic method and high-efficiency technology, applied in organic chemistry and other fields, can solve the problems of high equipment requirements and expensive equipment, and achieve the effects of cheap raw materials, reduced reaction costs, and high yields

Inactive Publication Date: 2016-11-09
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The raw material (R)-styrene oxide that this route is used is very expensive, and use hydrogenation reduction nitrile group under the effect ...

Method used

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  • Efficient synthesis method of mirabegron
  • Efficient synthesis method of mirabegron
  • Efficient synthesis method of mirabegron

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030]

[0031] In a 500mL reaction flask, dissolve 32g of p-aminophenylacetonitrile (0.2mol) in 200mL of methanol, then add 3.2g of palladium-calcium catalyst, slowly add 32g of hydrazine hydrate dropwise under nitrogen protection, and react at 40°C for 12h after the addition , TLC monitoring the reaction of the raw materials is complete, filter the reaction solution, rotary evaporation to remove the solvent methanol, add a certain amount of dichloromethane, wash with water three times, the organic phase is spin-dried to obtain 30g of p-aminophenethylamine. 1 H NMR (400MHz, DMSO-d 6 )δ6.98(dt,J 1 =8.4Hz,J 2 =2.0Hz,2H,Ar-H),6.63(dt,J 1 =8.4Hz,J 2 =2.0Hz,2H,Ar-H),3.57(brs,2H,NH 2 -H),2.89(t,J=6.8Hz,2H,CH 2 -H),2.63(t,J=6.8Hz,2H,CH 2 -H),1.15(bra,2H,NH 2 -H).

Embodiment 2

[0033]

[0034]In a 500mL reaction flask, add 20g (R)-1-phenyl-1,2-ethanediol (0.145mol) and 25g piperidine (0.29mol) into 200mL dichloromethane, and slowly Add 100 mL of dichloromethane solution dissolved with 18 g of methanesulfonyl chloride (0.16 mol), rise to room temperature and react for 1 h after the dropwise addition, TLC monitors that the raw materials have reacted completely, add a certain amount of water to wash, separate the organic phase, and wash the water phase with two Extracted with methyl chloride, the combined organic phases were spin-dried to obtain 21 g of (R)-1-phenyl-1-hydroxy-2-methanesulfonate-ethane. 1 H NMR (400MHz, CDCl 3 ): δ7.77(d,J=8.2Hz,2H,Ar-H),7.36-7.27(m,3H,Ar-H),4.97(dd,J 1 =8.6Hz,J 2 =3.3Hz,1H,CH-H),4.15(dd,J 1 =10.3Hz,J 2 =3.3Hz,1H,CH 2 -H),4.05(dd,J 1 =10.3Hz,J 2 =8.6Hz,1H,CH 2 -H),2.45(s,3H,CH 3 -H).

Embodiment 3

[0036]

[0037] In a reaction flask equipped with a water separator, add 32.5 g (0.25 mol) of ethyl acetoacetate into 300 mL of cyclohexane, then add 20 g (0.275 mol) of pyrrolidine and 0.5 g of p-toluenesulfonic acid monohydrate ( 2.63mmol), warming up to reflux and removing water, cooling to room temperature after reacting for 5h, filtering the reaction solution, steaming out cyclohexane and pyrrolidine in the filtrate, adding the resulting distilled product to 500mL of anhydrous pyridine, and then Add 16g (0.5mol) of elemental sulfur, set the reaction temperature at 0°C, slowly add 50mL of pyridine solution with 21g (0.5mol) of cyanamide dissolved in it dropwise, after the dropwise addition, slowly raise the temperature to 90°C for 60 minutes, and monitor the reaction of raw materials by TLC Completely, cooling to room temperature has a large amount of solid to separate out, suction filtration reaction liquid, filter cake is dried after washing with ether (200mL * 3), obt...

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Abstract

The invention discloses an efficient synthesis method of mirabergron. The method comprises the specific steps that nitrophenylacetonitrile is subjected to a nitroreduction and nitrile group reduction reaction in hydrazine hydrate under the catalysis effect of a catalyst of palladium on carbon hydrogenation to obtain ethylamine; (R)-1-phenyl-1,2-ethanediol and methylsulfonyl chloride react under the catalysis effect of a basic catalyst of piperidine or triethylamine to obtain (R)-1-phenyl-1-hydroxy-2-mesyl-ethane; the (R)-1-phenyl-1-hydroxy-2-mesyl-ethane and the ethylamine react under the catalysis effect of a basic catalyst of potassium carbonate or triethylamine to obtain (R)-2-((4-amino phenyl ethyl amine)-1-phenethyl alcohol; the (R)-2-((4-amino phenyl ethyl amine)-1-phenethyl alcohol and 2-aminothiazole-4-ethyl acetate are subjected to a condensation reaction under the effect of potassium methoxide to obtain mirabergron. The method is simple and easy to implement, the raw materials are cheap and easy to obtain, the reaction efficiency is high, and the repeatability is good.

Description

technical field [0001] The invention belongs to the technical field of synthesis of chemical drugs, and in particular relates to an efficient synthesis method of mirabegron. Background technique [0002] Mirabegron (Myrbetriq, Mirabegron) is a drug approved by the U.S. Food and Drug Administration (FDA) on June 28, 2012 for the treatment of overactive bladder (OAB) with symptoms of urge incontinence, urgency, and frequency. . [0003] The English name of Mirabellon: 2-Amino-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethy]amino]ethyl]pheny]-4-thiazoleacetamide, the chemical structure is: [0004] [0005] In the prior art, the synthetic method for Mirabegron mainly contains the following several: [0006] As European invention patent (EP1440969) relates to the synthetic method of Mirabegron, the synthetic route of this synthetic method is as follows: [0007] [0008] However, the above synthetic method uses expensive borane-tetrahydrofuran solution and 1,3-dimethyl-2-imidazol...

Claims

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Application Information

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IPC IPC(8): C07D277/40
CPCC07D277/40
Inventor 毛龙飞张淑婷郝秉慧李伟徐桂清姜玉钦马春华丁清杰周勇刘冰
Owner HENAN NORMAL UNIV
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