CN109456277B - Preparation method of mirabegron - Google Patents

Preparation method of mirabegron Download PDF

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CN109456277B
CN109456277B CN201811269400.7A CN201811269400A CN109456277B CN 109456277 B CN109456277 B CN 109456277B CN 201811269400 A CN201811269400 A CN 201811269400A CN 109456277 B CN109456277 B CN 109456277B
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mirabegron
amino
nitrophenylethyl
phenylethanol
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CN109456277A (en
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黄欢
黄庆国
李凯
施亚琴
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Anhui Qingyun Medicine Co ltd
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Anhui Qingyun Medicine Co ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D277/00Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38Nitrogen atoms
    • C07D277/40Unsubstituted amino or imino radicals

Abstract

The invention discloses a preparation method of mirabegron, relating to the technical field of medicine preparation and comprising the following steps: performing amide condensation reaction on R-mandelic acid and p-nitroanisole at high temperature to obtain an intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide; reducing amide carbonyl by diisobutyl aluminum hydride to obtain an intermediate (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride; reducing nitro by an ammonium formate-Pd/C reduction system to obtain an intermediate (R) -2- ((4-aminophenylethyl) amino) -1-phenylethanol; finally, the mirabegron is subjected to condensation reaction with aminothiazole acetic acid to obtain the mirabegron. The mirabegron prepared by the method has the advantages of good purity, high yield, few synthesis line steps, mild and controllable conditions, simplicity and convenience in operation, low cost, suitability for industrial production, wide prospect and industrial application value.

Description

Preparation method of mirabegron
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a preparation method of mirabegron.
Background
Mirabegron is developed by astela pharmaceutical company (astella) of japan, and the pharmaceutical company, japan, 1997, 10, 17, applied for the compound patent of mirabegron, protected the preparation method thereof, and currently applied for patent protection in several countries and regions, such as the united states, europe, and china, 2011, 9, 16, mirabegron is marketed in japan, 2012, 6, and approved by the U.S. FDA in the united states. The successful marketing of mirabegron, the first orally effective beta 3 adrenoceptor agonist drug for the treatment of overactive bladder, fills the gap in the treatment of overactive bladder with beta adrenoceptor agonists.
The currently disclosed synthetic routes mainly include the following:
the first synthetic route is as follows: patent WO9920607A1 reports a synthesis method using R-styrene oxide as a starting material, in the method, p-nitrophenylethylamine and R-styrene oxide are subjected to ring opening reaction firstly, secondary amine is protected by a protective agent, palladium-carbon catalytic reduction is performed, and finally mirabegron is obtained through condensation and deprotection.
Figure BDA0001845644690000011
This route is the earliest synthetic route for mirabegron. The route requires multiple steps for column chromatography separation, and has the advantages of long steps, low yield, high cost and difficulty in realizing industrial production.
The second synthetic route is as follows: patent WO2015044965A1 reports a synthesis method of mirabegron, which takes R-mandelic acid as a starting material, and obtains the mirabegron by condensation with p-nitroaniline hydrochloride, reduction of amide carbonyl by a borane-tetrahydrofuran system, catalytic reduction of nitro by palladium-carbon and condensation with aminothiazole acetic acid.
Figure BDA0001845644690000021
The mirabegron is obtained by four-step reaction in the route, which seems to be an industrialized route with a wide prospect, but the reaction uses a condensation reagent with high price, uses borane with high toxicity and high risk, uses the condensation reagent EDCl twice, has high cost, and is difficult to realize industrialized large-scale production.
The third synthetic route is as follows: chinese patent CN103232352A reports a synthetic route using p-aminophenylethanol as a starting material, which is subjected to amino protection, alcohol oxidation, condensation, reduction, deprotection, and finally condensation with aminothiazole acetic acid to obtain mirabegron.
Figure BDA0001845644690000022
The route is a brand new route, but the route uses potassium permanganate with high pollution by oxidation, and the starting raw materials are not easy to obtain, so that the industrial production is difficult to realize.
As can be seen from the above review, the current synthesis of mirabegron has a broad prospect because the synthesis route is too long and the yield is low, or because expensive reagents are used and the cost is high, or because the starting materials which are difficult to obtain are used, so that the industrial production is difficult to realize.
Disclosure of Invention
Based on the technical problems in the background art, the invention provides the preparation method of the mirabegron, the starting raw materials are cheap and easy to obtain, the reaction conditions are controllable, the steps of the synthetic route are few, the cost is low, and the prepared mirabegron is good in purity and high in yield.
The invention provides a preparation method of mirabegron, which comprises the following synthetic route:
Figure BDA0001845644690000031
the method comprises the following steps:
s1, carrying out amide condensation reaction on R-mandelic acid (formula II) and p-nitroacetoamine at high temperature to obtain an intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide (formula III);
s2 reduction of the amide carbonyl of intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide (formula III) by diisobutylaluminum hydride to afford intermediate (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride (formula IV);
s3, reducing the nitro group of the intermediate (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride (formula IV) by an ammonium formate-Pd/C reduction system to obtain an intermediate (R) -2- ((4-aminophenylethyl) amino) -1-phenylethanol (formula V);
s4, and carrying out condensation reaction on the intermediate (R) -2- ((4-aminophenyl ethyl) amino) -1-phenyl ethanol (formula V) and aminothiazoleacetic acid to obtain the mirabegron (formula I).
Preferably, in S1, the molar ratio of R-mandelic acid to p-nitroanisole is 1-2: 1, preferably 1.2: 1; preferably, the reaction temperature of the amide condensation reaction is 140-160 ℃, and the reaction time is 7-10 h.
Preferably, in S1, the solvent for the amide condensation reaction is xylene.
Preferably, in S2, the molar ratio of intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide to diisobutylaluminum hydride is 1: 1-2, preferably 1: 1.2; preferably, the reaction temperature of the amide carbonyl reduction reaction is-78-30 ℃, the reaction time is 1-5h, preferably the reaction temperature is 0-10 ℃, and the reaction time is 2 h.
Preferably, in S2, the solvent for the amide carbonyl reduction reaction is one or more of toluene, dichloromethane, tetrahydrofuran, and diethyl ether, preferably tetrahydrofuran.
Preferably, in S3, the temperature of the nitro reduction reaction is 10-65 ℃, the reaction time is 2-8h, preferably the reaction temperature is 50 ℃, and the reaction time is 6 h.
Preferably, in S4, the molar ratio of the condensation reaction between intermediate (R) -2- ((4-aminophenyl ethyl) amino) -1-phenylethanol and aminothiazoleacetic acid is 1: 1-2; preferably, the reaction time is from 5 to 7h, preferably 6 h.
Preferably, in S4, the condensation reagent for the condensation reaction is 4-dimethylaminopyridine.
The invention also provides the mirabegron prepared by the method.
Has the advantages that: the invention discloses a preparation method of mirabegron, the adopted raw materials are cheap and easy to obtain, the reaction of the starting raw materials of mandelic acid and p-nitroanisole takes dimethylbenzene as a solvent to directly carry out condensation reaction under the condition of high temperature, no condensation reagent is required to be added, and the addition of expensive condensation reagent in the traditional preparation method is avoided; the amide carboxyl reduction reaction adopts a diisobutylaluminum hydride reduction method, the reduction reagent is cheap and easy to obtain, and is relatively environment-friendly, and the reduction reagents with high toxicity and explosive danger such as borane and the like used in the traditional method are avoided; the nitro reduction reaction adopts an ammonium formate method, and compared with the reduction reaction adopting hydrogen, the reduction reaction is safe and controllable; the condensation reaction with aminothiazole acetic acid adopts cheap DMAP for catalytic condensation, and has low cost and high yield. The mirabegron prepared by the method has the advantages of good purity, high yield, few synthesis line steps, mild and controllable conditions, simplicity and convenience in operation, low cost, suitability for industrial production, wide prospect and industrial application value.
Detailed Description
Examples
The invention provides a preparation method of mirabegron, which comprises the following synthetic route:
Figure BDA0001845644690000051
the method comprises the following steps:
s1, carrying out amide condensation reaction on R-mandelic acid (formula II) and p-nitroacetoamine at high temperature to obtain an intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide (formula III);
s2 reduction of the amide carbonyl of intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide (formula III) by diisobutylaluminum hydride to afford intermediate (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride (formula IV);
s3, reducing the nitro group of the intermediate (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride (formula IV) by an ammonium formate-Pd/C reduction system to obtain an intermediate (R) -2- ((4-aminophenylethyl) amino) -1-phenylethanol (formula V);
s4, and carrying out condensation reaction on the intermediate (R) -2- ((4-aminophenyl ethyl) amino) -1-phenyl ethanol (formula V) and aminothiazoleacetic acid to obtain the mirabegron (formula I).
It should be noted that, in the above steps S1-S4, other auxiliary steps for collecting the product, increasing the yield, increasing the purity of the product, removing impurities, etc. may be added, such as common auxiliary means of filtration, washing, extraction, purification, drying, etc.
The technical solution of the present invention will be described in detail below with reference to specific examples.
Example 1
S1, Synthesis of intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide
273g of p-nitroanisole (1.64mol, 1.0eq), (R) -mandelic acid 250g (1.64mol, 1.0eq) and 1500mL of xylene (6V/m of mandelic acid) which participate in the reaction are sequentially added into a 3000mL four-mouth reaction bottle, the temperature is raised to 140 ℃ under the protection of nitrogen for reflux, the reaction is carried out for 7 hours under the heat preservation, sampling and monitoring the reaction by HPLC, completely reacting the p-nitroanisole serving as the raw material, cooling to room temperature under the stirring condition, filtering, dissolving the obtained solid dichloromethane to be clear, washing the clear solution by 500mL of 2 5% diluted hydrochloric acid and 500mL of 2 5% sodium hydroxide respectively, drying an organic phase by anhydrous sodium sulfate, removing dichloromethane under reduced pressure, and drying to obtain the product (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide with about 429g of yield of 87.2% and purity of 99.2%.
S2 synthesis of intermediate (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride
Adding 400g (1.33mol, 1.0eq) of intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide, 800mL of toluene and 800mL of ether into a four-mouth reaction bottle in sequence, cooling to-78 ℃ under the protection of nitrogen, slowly dropwise adding 1330mL (1.33mol, 1.0eq) of 1.0M (toluene solvent) of diisobutylaluminum hydride, controlling the reaction temperature to be not higher than-20 ℃ in the dropwise adding process, preserving the temperature at-78 ℃ for 1 hour after the dropwise adding is finished, monitoring the reaction progress by HPLC until the raw materials are completely reacted, slowly pouring the reaction liquid into 3000mL of 5% diluted hydrochloric acid, and adjusting the pH to about 12 by 10% of sodium hydroxide. Extracting with 2000mL of 3 ethyl acetate, drying with anhydrous sodium sulfate, concentrating to obtain oily substance, dissolving with 400mL of isopropanol, adding 50mL of concentrated hydrochloric acid, crystallizing at 0 deg.C overnight, separating out a large amount of pale yellow solid, filtering the product, and drying to obtain a white solid intermediate (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride 343g, with a yield of 80.3% and a purity of 98.2%.
S3, Synthesis of intermediate (R) -2- ((4-aminophenylethyl) amino) -1-phenylethanol
322g (1.0mol, 1.0eq) of intermediate (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride (R) -involved in the reaction, 2800mL of methanol, 220g (3.5mol, 3.5eq) of ammonium formate, and about 13g (0.04meq) of 4% Pd/C were added in one portion to a 5000mL four-necked flask, and the mixture was heated to 10 ℃ for reaction for 2 hours, followed by monitoring by HPLC for completion of the reaction conversion, filtration, and concentration of the filtrate to dryness. 1500mL of water is added into the concentrated residue, the pH value is adjusted to 10 by 10% sodium hydroxide, a large amount of white solid is separated out, and the product is filtered and dried to obtain 229g of off-white solid intermediate (R) -2- ((4-aminophenethyl) amino) -1-phenylethanol, the yield is 89.5%, and the purity is 98.1%.
S4 synthesis of mirabegron
220g (0.86mol, 1.0eq) of intermediate (R) -2- ((4-aminophenethyl) amino) -1-phenylethanol and 136g (0.86mol, 1.0eq) of aminothiazole acetic acid are added into a reaction kettle, 100mL of concentrated hydrochloric acid and 52g (0.43mol,0.5eq) of DMAP are sequentially added into the reaction kettle under mechanical stirring, the mixture is stirred and reacted for 5 hours at room temperature, the pH value is adjusted to be about 12 by 10 percent of sodium hydroxide, a large amount of solid is separated out, a white-like solid is obtained by filtering, 253g of white solid mirabegron is obtained by recrystallization through 800mL of isopropanol, the yield is 74.4 percent, and the purity is 99.5 percent.
Example 2
S1, Synthesis of intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide
273g of p-nitroanisole (1.64mol, 1.0eq), (R) -mandelic acid 499g (3.28mol, 2.0eq) and 1750mL of xylene (mandelic acid V/m is 3.5) which participate in the reaction are sequentially added into a 3000mL four-mouth reaction bottle, the temperature is raised to 160 ℃ under the protection of nitrogen for reflux, the reaction is carried out for 10 hours under the heat preservation, sampling and monitoring the reaction by HPLC, completely reacting the p-nitroanisole serving as the raw material, cooling to room temperature under the stirring condition, filtering, dissolving the obtained solid dichloromethane to be clear, washing the clear solution by 500mL of 2 5% diluted hydrochloric acid and 500mL of 2 5% sodium hydroxide respectively, drying an organic phase by anhydrous sodium sulfate, removing dichloromethane under reduced pressure, and drying to obtain the product (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide with the yield of about 450.5% and the purity of 99.3%.
S2 synthesis of intermediate (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride
Adding 400g (1.33mol, 1.0eq) of intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide and 1800mL of dichloromethane into a four-mouth reaction bottle in sequence, cooling to 30 ℃ under the protection of nitrogen, slowly dropwise adding 2660mL (2.66mol, 2.0eq) of 1.0M (toluene solvent) diisobutylaluminum hydride, controlling the reaction temperature to be not higher than 30 ℃ in the dropwise adding process, keeping the temperature at 30 ℃ for reaction for 5 hours after the dropwise adding is finished, monitoring the reaction process by HPLC until the reaction of raw materials is completed, slowly pouring the reaction liquid into 3000mL of 5% diluted hydrochloric acid, and adjusting the pH to about 12 by 10% sodium hydroxide. Extracting with 2000mL of 3 ethyl acetate, drying with anhydrous sodium sulfate, concentrating to obtain oily substance, dissolving with 400mL of isopropanol, adding 50mL of concentrated hydrochloric acid, crystallizing at 0 deg.C overnight, separating out a large amount of pale yellow solid, filtering the product, and drying to obtain 386g of white solid intermediate (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride, with yield of 90.4% and purity of 98.0%.
S3, Synthesis of intermediate (R) -2- ((4-aminophenylethyl) amino) -1-phenylethanol
322g (1.0mol, 1.0eq) of intermediate (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride (R) -participating in the reaction, 3000mL of methanol, 378g of ammonium formate (6.0mol,6.0eq), about 19g (0.06meq) of 6% Pd/C were added in one portion to a 5000mL four-necked flask, the reaction was warmed to 65 ℃ for 8 hours, HPLC monitored for complete conversion, filtration, and the filtrate was concentrated to dryness. 1500mL of water is added into the concentrated residue, the pH value is adjusted to 10 by 10% of sodium hydroxide, a large amount of white solid is separated out, and the product is filtered and dried to obtain 240g of off-white solid intermediate (R) -2- ((4-aminophenethyl) amino) -1-phenylethanol, the yield is 93.8%, and the purity is 98.6%.
S4 synthesis of mirabegron
220g (0.86mol, 1.0eq) of intermediate (R) -2- ((4-aminophenethyl) amino) -1-phenylethanol and 272g (1.72mol, 2.0eq) of aminothiazole acetic acid are added into a reaction kettle, 100mL of concentrated hydrochloric acid and 72g (0.60mol,0.7eq) of DMAP are sequentially added into the reaction kettle under mechanical stirring, the mixture is stirred and reacted for 7 hours at room temperature, the pH value is adjusted to be about 12 by 10 percent of sodium hydroxide, a large amount of solid is separated out, a white-like solid is obtained by filtering, 266g of white solid mirabegron is obtained by recrystallization through 800mL of isopropanol, the yield is 78.2 percent, and the purity is 99.2 percent.
Example 3
S1, Synthesis of intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide
273g of p-nitroanisole (1.64mol, 1.0eq), (R) -mandelic acid 375g (2.46mol, 1.5eq) and 1875mL of xylene (mandelic acid V/m is 5) which participate in the reaction are sequentially added into a 3000mL four-mouth reaction bottle, the temperature is raised to 150 ℃ under the protection of nitrogen for reflux, the reaction is carried out for 9 hours under the heat preservation, sampling and monitoring the reaction by HPLC, completely reacting the p-nitroanisole serving as the raw material, cooling to room temperature under the stirring condition, filtering, dissolving the obtained solid dichloromethane to be clear, washing the clear solution by 500mL of 2 5% diluted hydrochloric acid and 500mL of 2 5% sodium hydroxide respectively, drying an organic phase by anhydrous sodium sulfate, removing dichloromethane under reduced pressure, and drying to obtain 454g of the product (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide, wherein the yield is 92.3%, and the purity is 99.2%.
S2 synthesis of intermediate (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride
Adding 400g (1.33mol, 1.0eq) of intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide and 2000mL (2.0mol, 1.5eq) of tetrahydrofuran into a four-mouth reaction bottle in sequence, cooling to 10 ℃ under the protection of nitrogen, slowly dropwise adding 2000mL (2.0mol, 1.5eq) of 1.0M (toluene solvent) of diisobutylaluminum hydride, controlling the reaction temperature to be not higher than 20 ℃ in the dropwise adding process, keeping the temperature at 10 ℃ for reaction for 3 hours after the dropwise adding is finished, monitoring the reaction process by HPLC until the raw materials are completely reacted, slowly pouring the reaction solution into 3000mL of 5% diluted hydrochloric acid, and adjusting the pH to about 12 by 10% sodium hydroxide. Extracting with 2000mL of 3 ethyl acetate, drying with anhydrous sodium sulfate, concentrating to obtain oily substance, dissolving with 400mL of isopropanol, adding 50mL of concentrated hydrochloric acid, crystallizing at 0 deg.C overnight, separating out a large amount of pale yellow solid, filtering the product, and drying to obtain 390g of off-white solid intermediate (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride, with yield of 91.3% and purity of 98.5%.
S3, Synthesis of intermediate (R) -2- ((4-aminophenylethyl) amino) -1-phenylethanol
322g (1.0mol, 1.0eq) of intermediate (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride (R) -participating in the reaction, 3200mL of methanol, 346g (5.5mol,5.5eq) of ammonium formate, and about 16g (0.05meq) of 5% Pd/C were added in one portion to a 5000mL four-necked flask, and the mixture was heated to 40 ℃ for reaction for 5 hours, followed by completion of the reaction monitoring by HPLC, filtration, and concentration of the filtrate to dryness. 1500mL of water is added into the concentrated residue, the pH value is adjusted to 10 by 10% of sodium hydroxide, a large amount of white solid is separated out, and the product is filtered and dried to obtain 240g of off-white solid intermediate (R) -2- ((4-aminophenethyl) amino) -1-phenylethanol, the yield is 93.8%, and the purity is 98.6%.
S4 synthesis of mirabegron
220g (0.86mol, 1.0eq) of intermediate (R) -2- ((4-aminophenethyl) amino) -1-phenylethanol and 204g (1.29mol, 1.5eq) of aminothiazole acetic acid are added into a reaction kettle, 100mL of concentrated hydrochloric acid and 52g (0.43mol,0.5eq) of DMAP are sequentially added into the reaction kettle under mechanical stirring, the mixture is stirred and reacted for 6 hours at room temperature, the pH value is adjusted to be about 12 by 10 percent of sodium hydroxide, a large amount of solid is separated out, a white-like solid is obtained by filtering, 271g of white solid mirabegron is obtained by recrystallization through 800mL of isopropanol, the yield is 79.7 percent, and the purity is 99.0 percent.
Example 4
S1, Synthesis of intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide
273g of p-nitroanisole (1.64mol, 1.0eq), (R) -mandelic acid 300g (1.97mol, 1.2eq) and 1500mL of xylene (mandelic acid V/m is 5) which participate in the reaction are sequentially added into a 3000mL four-mouth reaction bottle, the temperature is raised to 140 ℃ under the protection of nitrogen for reflux, the reaction is carried out for 8 hours under the heat preservation, sampling and monitoring the reaction by HPLC, completely reacting the p-nitroanisole serving as the raw material, cooling to room temperature under the stirring condition, filtering, washing the obtained solid dichloromethane clear solution by using 500mL of 5% diluted hydrochloric acid and 500mL of 2 5% sodium hydroxide respectively, drying an organic phase by using anhydrous sodium sulfate, removing dichloromethane under reduced pressure, and drying to obtain about 453g of the product (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide, wherein the yield is 92.1% and the purity is 99.4%.
S2 synthesis of intermediate (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride
Adding 400g (1.33mol, 1.0eq) of intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide and 2000mL of tetrahydrofuran into a 5000mL four-mouth reaction bottle in sequence, cooling to 0 ℃ under the protection of nitrogen, slowly dropwise adding 1600mL (1.6mol, 1.2eq) of 1.0M (toluene solvent) diisobutylaluminum hydride, controlling the reaction temperature to be not higher than 10 ℃ in the dropwise adding process, keeping the temperature at 0 ℃ for reaction for 2 hours after the dropwise adding is finished, monitoring the reaction process by HPLC until the reaction of raw materials is complete, slowly pouring the reaction liquid into 3000mL of 5% diluted hydrochloric acid, and adjusting the pH to about 12 by 10% sodium hydroxide. Extracting with 2000mL of 3 ethyl acetate, drying with anhydrous sodium sulfate, concentrating to obtain oily substance, dissolving with 400mL of isopropanol, adding 50mL of concentrated hydrochloric acid, crystallizing at 0 deg.C overnight, separating out a large amount of pale yellow solid, filtering, and drying to obtain (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride 389 as white solid intermediate with yield of 91.1% and purity of 98.5%.
S3, Synthesis of intermediate (R) -2- ((4-aminophenylethyl) amino) -1-phenylethanol
322g (1.0mol, 1.0eq) of intermediate (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride (R) -participating in the reaction, 3200mL of methanol, 315g (5.0mol,5.0eq) of ammonium formate, and about 16g (0.05meq) of 5% Pd/C were added in one portion to a 5000mL four-necked flask, the mixture was heated to 50 ℃ for reaction for 6 hours, HPLC (high performance liquid chromatography) was used to monitor the completion of the reaction, the reaction was filtered, and the filtrate was concentrated to dryness. 1500mL of water is added into the concentrated residue, the pH value is adjusted to 10 by 10% of sodium hydroxide, a large amount of white solid is separated out, and the product is filtered and dried to obtain 241g of off-white solid intermediate (R) -2- ((4-aminophenethyl) amino) -1-phenylethanol, the yield is 94.1%, and the purity is 98.6%.
S4 synthesis of mirabegron
In a 5000mL four-mouth reaction bottle, 220g (0.86mol, 1.0eq) of intermediate (R) -2- ((4-aminophenethyl) amino) -1-phenylethanol and 136g (0.86mol, 1.0eq) of aminothiazole acetic acid are added into a reaction kettle, 100mL of concentrated hydrochloric acid and 52g (0.43mol,0.5eq) of DMAP are sequentially added under mechanical stirring, the mixture is stirred and reacted for 6 hours at room temperature, the pH value is adjusted to about 12 by 10 percent of sodium hydroxide, a large amount of solid is separated out, a white-like solid is obtained by filtration, and the white solid is recrystallized by 800mL of isopropanol to obtain 269g of mirabegron, the yield is 79.1 percent, and the purity is 99.6 percent.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.

Claims (7)

1. The preparation method of mirabegron is characterized in that the synthetic route is as follows:
Figure FDA0003497665530000011
the method comprises the following steps:
s1, carrying out amide condensation reaction on R-mandelic acid (formula II) and p-nitroacetoamine at high temperature to obtain an intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide (formula III);
s2 reduction of the amide carbonyl of intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide (formula III) by diisobutylaluminum hydride to afford intermediate (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride (formula IV);
s3, reducing the nitro group of the intermediate (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride (formula IV) by an ammonium formate-Pd/C reduction system to obtain an intermediate (R) -2- ((4-aminophenylethyl) amino) -1-phenylethanol (formula V);
s4, carrying out a condensation reaction on the intermediate (R) -2- ((4-aminophenyl ethyl) amino) -1-phenyl ethanol (formula V) and aminothiazoleacetic acid to obtain mirabegron (formula I);
wherein in S1, the molar ratio of R-mandelic acid to p-nitroanisole is 1-2: 1; the reaction temperature of the amide condensation reaction is 140-160 ℃, and the reaction time is 7-10 h.
2. The method according to claim 1, wherein the solvent for the amide condensation reaction in S1 is xylene.
3. The method according to claim 1, wherein the reaction temperature of the amide carbonyl reduction reaction is-78 to 30 ℃ and the reaction time is 1 to 5 hours.
4. The method according to claim 1, wherein the solvent for the amide carbonyl reduction reaction in S2 is one or more selected from toluene, dichloromethane, tetrahydrofuran, and diethyl ether.
5. The method for preparing mirabegron as claimed in claim 1, wherein in S3, the temperature of nitro reduction reaction is 10-65 ℃ and the reaction time is 2-8 h.
6. The method according to claim 1, wherein the molar ratio of the intermediate (R) -2- ((4-aminophenylethyl) amino) -1-phenylethanol to the aminothiazoleacetic acid in the condensation reaction in S4 is 1: 1-2, and the reaction time is 5-7 h.
7. The method according to claim 1, wherein the condensation reagent used in the condensation reaction in S4 is 4-dimethylaminopyridine.
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CN111440126B (en) * 2020-04-03 2023-11-28 湖南复瑞生物医药技术有限责任公司 Preparation method of mirabegron
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CN112661718B (en) * 2021-01-19 2022-04-19 南京美瑞制药有限公司 Synthesis of mirabegron isomer
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