CN103387500A - Preparation methods for mirabegron and intermediate thereof - Google Patents
Preparation methods for mirabegron and intermediate thereof Download PDFInfo
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- CN103387500A CN103387500A CN2013101701339A CN201310170133A CN103387500A CN 103387500 A CN103387500 A CN 103387500A CN 2013101701339 A CN2013101701339 A CN 2013101701339A CN 201310170133 A CN201310170133 A CN 201310170133A CN 103387500 A CN103387500 A CN 103387500A
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Abstract
The invention discloses a preparation method for mirabegron. The preparation method comprises the following steps: 1, reducing a compound I in an alcoholic solvent in a hydrogen environment under the catalysis of palladium-carbon so as to obtain a compound II; and 2, mixing the compound II obtained in step 1 with 2-amino-4-thiazole acetic acid in water in an environment with a pH value of 1 to 7 under the action of a condensing agent and carrying out acylation so as to obtain mirabegron, wherein reaction temperature is 10 to 30 DEG C. The invention further discloses a preparation method for an intermediate II of mirabegron, and the preparation method comprises the step of reducing the compound I in the alcoholic solvent in the hydrogen environment under the catalysis of palladium-carbon so as to obtain the compound II. The preparation methods provided by the invention have the advantages of easiness, low cost, mild reaction conditions and suitability for industrial production.
Description
Technical field
The present invention relates to technical field of medicine synthesis, be specifically related to (R)-2-(2-aminothiazole-4-yl)-4 '-[2-[(2-hydroxyl-2 styroyl) amino] ethyl] preparation method of ethanoyl aniline (Mirabegron) and intermediate thereof.
Background technology
Overactive bladder (Overactive Bladder, OAB) is a kind of syndrome take symptoms of urgency as feature,, often with frequent micturition and enuresis nocturna symptom, can accompany or without urge incontinence; Do not include the symptom due to acute urinary tract infection or other forms of bladder urethra local patholoic change.This disease sickness rate in worldwide is higher, and larger on patient's life impact, more and more is subject to the attention of Chinese scholars.Estimate that at present the whole world has 5,000 ten thousand～100,000,000 populations to suffer from OAB.
Mirabegron (Mirabegron) is the suprarenin β by the exploitation of Japanese Astellas company
3Receptor stimulant, be used for the treatment of OAB, and this product has side effect still less and alleviates the uroschesis effect than anticholinergic agents, and at present in Europe, many countries such as Japan and the U.S. are in and register front or three phase clinical stages.
The synthetic method of Mirabegron (Mirabegron) has bibliographical information: high must prettyly going waits (CN100406011C) report take (R)-MA as raw material, obtain acid amides with the condensation of p-nitrophenyl ethamine,, through borane reduction, with 2-amino-4-thiazolyl acetic acid condensation, form again.This route, with borine tetrahydrofuran (THF) reducing amide, carry out under anhydrous and nitrogen protection, complicated operation, and cost is higher, is not suitable for large-scale industrial production.
Summary of the invention
Technical problem to be solved by this invention is, have complicated operation in the method for preparing Mirabegron now in order to overcome, cost is higher, severe reaction conditions, be not suitable for the defect of large-scale industrial production, and the preparation method of a kind of Mirabegron and intermediate thereof is provided.Preparation method of the present invention is easy and simple to handle, and cost is lower, and reaction conditions is gentle, is suitable for suitability for industrialized production.
The invention provides a kind of preparation method of Mirabegron intermediate II, it comprises the following steps: in alcoholic solvent, under the catalysis of palladium carbon, under hydrogen environment, Compound I is carried out reduction reaction, obtains Compound I I, gets final product;
Wherein, described alcoholic solvent can be alcohol, particular methanol and/or the ethanol as solvent of this area routine.The consumption of described alcoholic solvent can be does not affect normally getting final product of reaction, with the volume mass ratio of Compound I, is preferably 1～100ml/g Compound I, more preferably 5～10ml/g Compound I.Described palladium carbon can be the palladium carbon as the hydrogenation catalytic reaction catalyst of this area routine, preferred 10% palladium carbon, and percentage ratio is massfraction.Preferred 0.5MPa～the 10MPa of the pressure of described hydrogen environment, more preferably 0.9MPa～1.5MPa.Described palladium carbon quality used can be palladium carbon quality used in the hydrogenation catalyzed reaction of this area routine, is preferably 0～100% of Compound I quality, and more preferably 1%～10% of the Compound I quality, most preferably be 5% of Compound I quality.The temperature of described reduction reaction can be the conventional temperature of conventional this type of reaction in this area, preferred 15 ℃～30 ℃.The process of described reduction reaction can be monitored by TLC or HPLC, when the Compound I of generally using disappears as the terminal of reaction.In order further to obtain pure Compound I I, also can comprise last handling process after described reduction reaction, described last handling process can be the last handling process of this area routine, preferably includes the following step: system is filtered, and filtrate is concentrated, dry getting final product.
The present invention also provides a kind of preparation method of Mirabegron, and it comprises the following steps:
1. in alcoholic solvent, under the catalysis of palladium carbon, under hydrogen environment, Compound I is carried out reduction reaction, obtain Compound I I, get final product;
2. in water under the environment of pH=1～7, under the effect of condensing agent, the Compound I I that 1. step is obtained mixes with 2-amino-4-thiazolyl acetic acid, carries out acylation reaction, obtains Mirabegron and gets final product, and temperature of reaction is 10 ℃～30 ℃;
Mirabegron
Step 1. in, described alcoholic solvent can be this area routine as alcohol, particular methanol and/or the ethanol of solvent.The consumption of described alcoholic solvent can be does not affect normally getting final product of reaction, with the volume mass ratio of Compound I, is preferably 1～100ml/g Compound I, more preferably 5～10ml/g Compound I.Described palladium carbon can be the palladium carbon as the hydrogenation catalytic reaction catalyst of this area routine, preferred 10% palladium carbon, and percentage ratio is massfraction.Preferred 0.5MPa～the 10MPa of the pressure of described hydrogen environment, more preferably 0.9MPa～1.5MPa.Described palladium carbon quality used can be palladium carbon quality used in the hydrogenation catalyzed reaction of this area routine, is preferably 0～100% of Compound I quality, and more preferably 1%～10% of the Compound I quality, most preferably be 5% of Compound I quality.The temperature of described reduction reaction can be the conventional temperature of conventional this type of reaction in this area, preferred 15 ℃～30 ℃.The process of described reduction reaction can be monitored by TLC or HPLC, when the Compound I of generally using disappears as the terminal of reaction.In order further to obtain pure Compound I I, step 1. after, also can comprise last handling process, described last handling process can be the last handling process of this area routine, preferably includes the following step: system is filtered, and filtrate is concentrated, dry getting final product.
Step 2. described acylation reaction preferably includes the following step: Compound I I, 2-amino-4-thiazolyl acetic acid and water are mixed, drip acid to pH=1～7 under 10 ℃～30 ℃, then add condensing agent, carry out acylation reaction, obtain Mirabegron and get final product.Described condensing agent can be the condensing agent of this area routine, preferred 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC hydrochloride) and/or N, N'-dicyclohexylcarbodiimide (DCC).Described pH value preferably is controlled at pH=4～6, more preferably is controlled at pH=5.Described pH value can regulate and control by acid.Described acid can be mineral acid and/or organic acid.The preferred hydrochloric acid of described mineral acid and/or sulfuric acid.Described organic acid can be the organic acid of this area routine.Preferred 2:1～the 1:5 of mol ratio of described Compound I I and 2-amino-4-thiazolyl acetic acid, more preferably 1:1～1:5.The volume mass of described water and Compound I I is than preferred 1～100ml/g Compound I I, more preferably 5～20ml/g Compound I I.Preferred 15 ℃～30 ℃ of the temperature of reaction of described acylation reaction.The process of described acylation reaction can be monitored by TLC or HPLC, when the Compound I I of generally using disappears as the terminal of reaction.Step 2. after, can also be further purified and obtain the compound Mirabegron through last handling process, described last handling process can be the last handling process of this area routine.Described last handling process preferably includes following steps: with alkali, system is transferred to pH=10, filter, filter residue is drained, dry getting final product.Described alkali can be this area alkali commonly used, can be organic bases or mineral alkali.The preferred sodium hydroxide of described mineral alkali.Described sodium hydroxide preferably adds with the form of the aqueous solution.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, but arbitrary combination obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material be commercially available obtaining all.
Positive progressive effect of the present invention is: preparation method's reaction conditions of the present invention is gentle, and is simple to operate, is very beneficial for suitability for industrialized production.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, according to ordinary method and condition, or select according to catalogue.
Embodiment 1(R)-2-{N-benzyl-[2-(4-nitrophenyl) ethyl] amino }-preparation of 1-phenylethyl alcohol [I]
(R)-Styryl oxide (2.31g, 19.2mmol) and N-benzyl-4-oil of mirbane ethamine (3.28g, 12.8mmol) in the 12ml Virahol, back flow reaction 20h.Remove solvent under reduced pressure, normal hexane/isopropyl ether recrystallization, dry yellow solid I 3.61g, the yield 75% of obtaining.
1H-NMR(CDCl
3)δ:1.28(1H,s)2.69～2.98(6H,m)，3.57(1H,d,J=13.2Hz)，3.95(1H,d,J=13.2Hz)，4.67～4.69(1H,m)，7.21～7.36(12H,m)，8.10～8.12(2H,m)。
Embodiment 2(R)-2-[(4-amino-benzene ethyl) amino]-preparation of 1-phenylethyl alcohol [II]
Chemical compounds I (3.0g, 8.0mmol), 10%Pd/C(0.15g) and methyl alcohol (25ml) in hydrogenation reaction cauldron, be filled with 1MPa hydrogen, room temperature (10 ℃～30 ℃) reaction 30h, filter, and filtrate is concentrated, the dry II (1.03g, yield 100%, HPLC purity 99.8%) that obtains.
Embodiment 3(R)-2-[(4-amino-benzene ethyl) amino]-preparation of 1-phenylethyl alcohol [II]
Chemical compounds I (3.0g, 8.0mmol), 10%Pd/C(0.03g) and methyl alcohol (25ml) in hydrogenation reaction cauldron, be filled with 10MPa hydrogen, room temperature (10 ℃～30 ℃) reaction 30h, filter, filtrate is concentrated, dry II (1.03g, yield 100%).
Embodiment 4(R)-2-[(4-amino-benzene ethyl) amino]-preparation of 1-phenylethyl alcohol [II]
Chemical compounds I (3.0g, 8.0mmol), 10%Pd/C(0.3g) and methyl alcohol (25ml) in hydrogenation reaction cauldron, be filled with 1.5MPa hydrogen, room temperature (10 ℃～30 ℃) reaction 30h, filter, filtrate is concentrated, dry II (1.03g, yield 100%).
Embodiment 5(R)-2-[(4-amino-benzene ethyl) amino]-preparation of 1-phenylethyl alcohol [II]
Chemical compounds I (3.0g, 8.0mmol), 10%Pd/C(0.2g) and methyl alcohol (25ml) in hydrogenation reaction cauldron, be filled with 0.5MPa hydrogen, room temperature (10 ℃～30 ℃) reaction 30h, filter, filtrate is concentrated, dry II (1.03g, yield 100%).
The preparation of embodiment 6 Mirabegrons
Compound ii (0.5g, 2.0mmol) and 2-amino-4-thiazolyl acetic acid (0.32g, 2.0mmol) in water (10ml), under stirring at room, drip concentrated hydrochloric acid to pH=5, then add EDC hydrochloride (0.42g), room temperature (10 ℃～30 ℃) stirring reaction 1h.Transfer pH=10 with the 2M aqueous sodium hydroxide solution, filter, filter residue is drained, the dry white solid 0.76g(yield 96% that obtains), purity 99.5%(HPLC);
1H-NMR (DMSO-d
6) δ: 1.89 (1H, s), 2.50～2.62 (4H, m), 2.63～2.78 (2H, m), 3.45 (2H, s), 4.59 (1H, m), (5.21 1H, m), 6.29 (1H, s), 6.82 (2H, s), 7.01 (2H, d, J=8.5Hz), 7.12～7.22 (1H, m), 7.27～7.33 (4H, m), 7.47 (2H, d, J=8.5Hz), 9.90 (1H, s).m/z397(M+H)
+。
The preparation of embodiment 7 Mirabegrons
Compound ii (0.5g, 2.0mmol) and 2-amino-4-thiazolyl acetic acid (1.6g, 10mmol) in water (20ml), under stirring at room, drip concentrated hydrochloric acid to pH=1, then add DCC(1.0g), room temperature (10 ℃～30 ℃) (PLSCONFM.If incorrect please the modification.) stirring reaction 1h.Transfer pH=10 with the 2M aqueous sodium hydroxide solution, filter, filter residue is drained, the dry white solid 0.72g that obtains.
The preparation of embodiment 8 Mirabegrons
Compound ii (0.5g, 2.0mmol) and 2-amino-4-thiazolyl acetic acid (0.64g, 4mmol) in water (5ml), under stirring at room, drip concentrated hydrochloric acid to pH=7, then add EDC hydrochloride (0.42g), room temperature (10 ℃～30 ℃) stirring reaction 1h.Transfer pH=10 with the 2M aqueous sodium hydroxide solution, filter, filter residue is drained, the dry white solid 0.74g that obtains.
The preparation of embodiment 9 Mirabegrons
Compound ii (1.0g, 4.0mmol) and 2-amino-4-thiazolyl acetic acid (0.32g, 2mmol) in water (5ml), under stirring at room, drip concentrated hydrochloric acid to pH=7, then add EDC hydrochloride (0.42g), room temperature (10 ℃～30 ℃) stirring reaction 1h.Transfer pH=10 with the 2M aqueous sodium hydroxide solution, filter, filter residue is drained, the dry white solid 0.70g that obtains.
Claims (14)
1. the preparation method of a Mirabegron intermediate II, is characterized in that comprising the following steps: in alcoholic solvent, under the catalysis of palladium carbon, under hydrogen environment, Compound I carried out reduction reaction, obtains Compound I I, gets final product;
2. the preparation method of Mirabegron intermediate II as claimed in claim 1, is characterized in that, described alcoholic solvent is methyl alcohol and/or ethanol.
3. the preparation method of Mirabegron intermediate II as claimed in claim 1, is characterized in that, the pressure of described hydrogen environment is 0.5MPa～10MPa.
4. the preparation method of Mirabegron intermediate II as claimed in claim 3, is characterized in that, the pressure of described hydrogen environment is 0.9MPa～1.5MPa.
5. the preparation method of Mirabegron intermediate II as claimed in claim 1, is characterized in that, described palladium carbon quality used is 1%～10% of Compound I quality.
6. the preparation method of Mirabegron intermediate II as claimed in claim 1, is characterized in that, the temperature of described reduction reaction is 15 ℃～30 ℃.
7. the preparation method of a Mirabegron, is characterized in that comprising the following steps:
1. in alcoholic solvent, under the catalysis of palladium carbon, under hydrogen environment, Compound I is carried out reduction reaction, obtain Compound I I, get final product;
Step 1. in, the method for described reduction reaction and each condition are all as described in claim 1～6 any one;
2. in water under the environment of pH=1～7, under the effect of condensing agent, the Compound I I that 1. step is obtained mixes with 2-amino-4-thiazolyl acetic acid, carries out acylation reaction, obtains Mirabegron and gets final product, and temperature of reaction is 10 ℃～30 ℃;
Mirabegron
8. the preparation method of Mirabegron as claimed in claim 7, is characterized in that,
Step 2. described acylation reaction comprises the following steps: Compound I I, 2-amino-4-thiazolyl acetic acid and water are mixed, and drips acid to pH=1～7 under 10 ℃～30 ℃, then adds condensing agent, carries out acylation reaction, obtains Mirabegron and gets final product.
9. the preparation method of Mirabegron as claimed in claim 7 or 8, is characterized in that, step 2. in, described condensing agent is 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and/or N, the N'-dicyclohexylcarbodiimide.
10. the preparation method of Mirabegron as claimed in claim 7 or 8, is characterized in that, step 2. in, described pH value is controlled at pH=4～6.
11. the preparation method of Mirabegron, is characterized in that as claimed in claim 7 or 8, step 2. in, described pH value regulates and controls by acid; Described acid is mineral acid and/or organic acid; Described mineral acid is hydrochloric acid and/or sulfuric acid.
12. the preparation method of Mirabegron, is characterized in that as claimed in claim 7 or 8, the mol ratio of described Compound I I and 2-amino-4-thiazolyl acetic acid is 2:1～1:5.
13. the preparation method of Mirabegron, is characterized in that as claimed in claim 7 or 8, described water is 1～100ml/g Compound I I with the volume mass ratio of Compound I I.
14. the preparation method of Mirabegron, is characterized in that as claimed in claim 7 or 8, the temperature of described acylation reaction is 15 ℃～30 ℃.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103641792A (en) * | 2013-12-27 | 2014-03-19 | 上海医药工业研究院 | Mirabegron related substance or salt thereof, and preparation method and use thereof |
| CN104016877A (en) * | 2014-06-13 | 2014-09-03 | 南京海融医药科技有限公司 | Acetylaniline compounds and application thereof in preparation of mirabegron |
| WO2016024284A2 (en) | 2014-08-07 | 2016-02-18 | Wanbury Ltd. | A process for the preparation of mirabegron and its intermediates |
| WO2017137784A1 (en) * | 2016-02-10 | 2017-08-17 | Egis Gyógyszergyár Zrt. | Method for the production of morphologically homogenous mirabegron and mirabegron monohydrochloride |
| US9815771B2 (en) | 2014-08-06 | 2017-11-14 | Interquim, S.A. | Method for the synthesis of mirabegron and its derivatives |
| EP3335700A1 (en) | 2016-12-13 | 2018-06-20 | Stada Arzneimittel Ag | Solid pharmaceutical oral dosage form comprising an extended release of the active ingredient comprising mirabegron |
| CN111440126A (en) * | 2020-04-03 | 2020-07-24 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of mirabegron |
| CN113816864A (en) * | 2020-06-18 | 2021-12-21 | 南京正大天晴制药有限公司 | Preparation method of (R) -2-hydroxy-N- [2- (4-aminophenyl) ethyl ] -2-phenylethylamine |
| CN113880720A (en) * | 2021-11-12 | 2022-01-04 | 山东百诺医药股份有限公司 | Preparation method of mirabegron key intermediate |
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Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015096604A1 (en) * | 2013-12-27 | 2015-07-02 | 国药集团国瑞药业有限公司 | Mirabegron-related substance or salt thereof, and preparation method and use thereof |
| CN103641792A (en) * | 2013-12-27 | 2014-03-19 | 上海医药工业研究院 | Mirabegron related substance or salt thereof, and preparation method and use thereof |
| CN104016877A (en) * | 2014-06-13 | 2014-09-03 | 南京海融医药科技有限公司 | Acetylaniline compounds and application thereof in preparation of mirabegron |
| CN104016877B (en) * | 2014-06-13 | 2017-02-15 | 南京海融制药有限公司 | Acetylaniline compounds and application thereof in preparation of mirabegron |
| US9815771B2 (en) | 2014-08-06 | 2017-11-14 | Interquim, S.A. | Method for the synthesis of mirabegron and its derivatives |
| WO2016024284A2 (en) | 2014-08-07 | 2016-02-18 | Wanbury Ltd. | A process for the preparation of mirabegron and its intermediates |
| WO2017137784A1 (en) * | 2016-02-10 | 2017-08-17 | Egis Gyógyszergyár Zrt. | Method for the production of morphologically homogenous mirabegron and mirabegron monohydrochloride |
| EP3335700A1 (en) | 2016-12-13 | 2018-06-20 | Stada Arzneimittel Ag | Solid pharmaceutical oral dosage form comprising an extended release of the active ingredient comprising mirabegron |
| WO2018108939A2 (en) | 2016-12-13 | 2018-06-21 | Stada Arzneimittel Ag | Solid oral pharmaceutical dosage form with extended active principle release comprising mirabegron |
| CN111440126A (en) * | 2020-04-03 | 2020-07-24 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of mirabegron |
| 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 |
| CN113816864A (en) * | 2020-06-18 | 2021-12-21 | 南京正大天晴制药有限公司 | Preparation method of (R) -2-hydroxy-N- [2- (4-aminophenyl) ethyl ] -2-phenylethylamine |
| CN113816864B (en) * | 2020-06-18 | 2024-03-29 | 南京正大天晴制药有限公司 | Preparation method of (R) -2-hydroxy-N- [2- (4-aminophenyl) ethyl ] -2-phenethylamine |
| CN113880720A (en) * | 2021-11-12 | 2022-01-04 | 山东百诺医药股份有限公司 | Preparation method of mirabegron key intermediate |
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Application publication date: 20131113 |