CN105481705A - Preparation and application of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethyl alcohol - Google Patents
Preparation and application of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethyl alcohol Download PDFInfo
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- CN105481705A CN105481705A CN201410439865.8A CN201410439865A CN105481705A CN 105481705 A CN105481705 A CN 105481705A CN 201410439865 A CN201410439865 A CN 201410439865A CN 105481705 A CN105481705 A CN 105481705A
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- TUAHDMSPHZSMQN-UHFFFAOYSA-N Nc1ccc(CCNCC(c2ccccc2)O)cc1 Chemical compound Nc1ccc(CCNCC(c2ccccc2)O)cc1 TUAHDMSPHZSMQN-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention provides an intermediate, (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethyl alcohol, of mirabegron, and a synthetic method and application of the intermediate, and belongs to the technical field of pharmaceutical synthesis. The structural formula of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethyl alcohol is shown in the description. A synthetic step comprises: reducing (R)-2-[[2-(4-nitrophenyl)ethyl]amino]-1-phenylethyl alcohol monohydrochloride (I) into (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethyl alcohol (II) in the presence of an alcohol solvent through taking Pd/C as a catalyst and using a phase-transfer reagent. The synthetic method is mild in reaction condition and simple to operate. What's more, an organic compound instead of hydrogen is taken as a hydrogen donor during reaction, thereby overcoming technique, equipment, and safety problems due to usage of hydrogen. The synthetic method is extremely beneficial for industrial production.
Description
Technical field
The present invention relates to technical field of medicine synthesis, be specifically related to the preparation method of (R)-2-[[2-(4-aminophenyl) ethyl] is amino]-1-phenylethyl alcohol (Mirabegron intermediate).
Background technology
The syndrome of overactive bladder (OveractiveBladder, OAB) to be a kind of with symptoms of urgency be feature, often with frequent micturition and nocturia, can to accompany or without urge incontinence; Do not include acute urinary tract infection or the symptom caused by other forms of wing skin urethra local patholoic change.This disease sickness rate in worldwide is higher, and comparatively large on the life impact of patient, is more and more subject to the attention of Chinese scholars.The current estimation whole world has 5,000 ten thousand to 1 hundred million populations to suffer from OAB.
The synthetic method of Mirabegron (Mirabegron) has bibliographical information: high must prettyly going waits (CN100406011C) report with (R)-amygdalic acid for raw material, acid amides is obtained with the condensation of p-nitrophenyl ethylamine hydrochloride, again through borane reduction and hydrogen reducing, last and thiazolamine-4-acetic acid condensation forms.This route uses hydrogen to be reductive agent, has special requirement to the equipment of reaction, and complicated operation, be not suitable for large-scale industrial production.
(R)-2-[[2-(4-aminophenyl) ethyl] is amino]-1-phenylethyl alcohol and salt thereof are all the important intermediate of Mirabegron.
Summary of the invention
First object of the present invention is, the technical problem that solve.Namely using hydrogen to overcome existing preparation in the method for Mirabegron, reacting higher to the requirement of equipment, there is potential safety hazard, being not suitable for the defect of large-scale industrial production.And the invention provides a kind of preparation method of Mirabegron intermediate, preparation method is easy and simple to handle, and cost is lower, and avoids using hydrogen to eliminate potential safety hazard in production, is suitable for suitability for industrialized production.
Second object of the present invention is, provides a kind of Mirabegron intermediate, and this intermediate is (R)-2-[[2-(4-aminophenyl) ethyl] is amino]-1-phenylethyl alcohol.Concrete structure formula is as follows:
The invention provides a kind of preparation method of Mirabegron intermediate, it comprises the following steps: in alcoholic solvent, under the catalysis of palladium carbon, under ammonium formiate environment, Compound I is carried out reduction reaction, obtains Compound II per:
Wherein, described alcoholic solvent can be the alcohol being used as solvent of this area routine, and particular methanol or ethanol, be more preferably methyl alcohol.The consumption of described alcoholic solvent is do not affect normally carrying out of reaction, and be preferably 1 ~ 100: 1 (ml/g) with the volume mass ratio of Compound I, preferred ratio is 5 ~ 10: 1 (ml/g).
Described metal catalyst is the hydrogenation catalyst of this area routine, preferably 5% ~ 10% palladium carbon or Raney's nickel, more preferably 10% palladium carbon (percentage ratio is massfraction).The quality that 10% described palladium carbon is used, preferably with the mass ratio 0.01 ~ 1: 1 of Compound I, preferred ratio is 0.05 ~ 0.15: 1, and most preferred ratio is 0.1: 1.
Described organic compound is the phase-transfer-catalyzed reactions reagent of this area routine, preferable formic acid ammonium, ammonium acetate etc., more preferably ammonium formiate.The molar weight that described ammonium formiate is used, be preferably 1 ~ 20: 1 with the mol ratio of Compound I, preferred ratio is 5: 1.
The temperature of described reduction reaction can be the ordinary temperature of this area this type of reaction conventional, preferably 30 DEG C ~ 70 DEG C, is more preferably 60 DEG C ~ 70 DEG C.
The process of described reduction reaction is monitored by TLC or HPLC, as the terminal of reaction when generally disappearing using Compound I.In order to obtain pure Compound II per further, 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 filtered, and filtrate concentrates, dry.
Positive progressive effect of the present invention is: preparation method's reaction conditions of the present invention is gentle, simple to operate, the more important thing is with organic compound replacement hydrogen as the hydrogen donor in reaction, can avoid using hydrogen and the problems of aspect such as the technology, equipment and the safety that cause, be very beneficial for suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of (R)-2-[[2-(4-aminophenyl) ethyl] is amino]-1-phenylethyl alcohol
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of Mirabegron
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, conventionally and condition, or selects according to catalogue.
Embodiment 1:(R) preparation of-2-[[2-(4-nitrophenyl) ethyl] amino]-1-phenylethyl alcohol monohydrochloride (I)
(R)-amygdalic acid (15.0g, 0.0986mol) and p-nitrophenyl ethylamine hydrochloride (20.0g, 0.0986mol) are in 75mlN, in dinethylformamide, drip triethylamine under stirring, finally add HOBT and EDC again, 30 DEG C of reaction 6h.TLC monitors (GF
254thin layer plate, developping agent: ethyl acetate: methyl alcohol=5: 1, if hangover, can add 3 triethylamines) disappear to p-nitrophenyl ethylamine hydrochloride phosphor dot.Add water and extraction into ethyl acetate, concentrating under reduced pressure removing ethyl acetate, obtains yellow solid (III) 23.08g, yield: 80.03%.
1H-NMR(d-DMSO)：δ(ppm)＝2.86～2.90(2H，t)，3.33～3.47(2H，m)，4.87～4.88(1H，d)，6.11～6.12(1H，d)，7.26～7.34(5H，m)，7.37～7.40(2H，d)，8.04～8.07(3H，m)
Compound III (20g, 0.0666mol), in 60ml1,3-dimethyl-2-imidazolinone and tetrahydrofuran (THF), is added dropwise to 133.2ml1mol/L borane and closes tetrahydrofuran solution, 70 DEG C of back flow reaction 4h.TLC monitors (GF
254thin layer plate, developping agent: ethyl acetate) disappear to compound III phosphor dot.Drip methyl alcohol and concentrated hydrochloric acid, after wet chemical washing, with water and extraction into ethyl acetate.Concentrating under reduced pressure removing ethyl acetate, Virahol, concentrated hydrochloric acid recrystallization, obtain faint yellow solid (I): 17.73g, yield 82.35%.1H-NMR(d-DMSO)：δ(ppm)＝3.00～3.08(1H，m)；5.00～5.05(1H，m)；6.23(1H，d，J＝4.0Hz)；7.29～7.35(1H，m)；7.36～7.43(4H，m)；7.57(2H，d，J＝8.4Hz)；8.21(2H，d，J＝8.4Hz)；9.12(2H，br)
Embodiment 2:(R) preparation of-2-[[2-(4-aminophenyl) ethyl] amino]-1-phenylethyl alcohol (II)
Compound I (15g, 0.0465mol), in 150ml methyl alcohol, adds ammonium formiate (14.6g, 0.2325mol) under stirring, 1.5g10% palladium carbon, stirs and is warming up to 65 DEG C, backflow 5h.TLC monitors (GF
254thin layer plate, developping agent: ethyl acetate: methyl alcohol=5: 1) disappear to Compound I phosphor dot.Concentrating under reduced pressure removing methyl alcohol, water and extraction into ethyl acetate.Concentrating under reduced pressure removing ethyl acetate, obtains off-white color solid (II): 10.91g, yield 91.71%.1H-NMR(d-DMSO)：δ(ppm)：2.87～2.90(2H，m)；2.97～3.16(4H，m)；5.06～5.09(3H，m)；6.22(1H)；6.55～6.57(2H，d，J＝7.7Hz)；6.88～6.91(2H，d，J＝7.7Hz)；7.29～7.42(5H，m)；9.22(1H，br)
Embodiment 3: the application of Compound II per: the preparation of Mirabegron
Compound II per (10.0g, 0.0391mol) and thiazolamine-4-acetic acid (6.2g, 0.0391mol) stir in 100ml dilute hydrochloric acid, add EDC (8.2g, 0.0430mol), and 30 DEG C are stirred 5h.TLC monitors (GF
254thin layer plate, developping agent: ethyl acetate: methyl alcohol=5: 1) disappear to Compound II per phosphor dot.Be added dropwise to sodium hydroxide solution, filtration under diminished pressure, 50 DEG C of forced air dryings, obtain off-white color solid (Mirabegron): 13.66g, yield: 88.31%.1H-NMR(d-DMSO)：δ(ppm)＝δ1.60(1H，s)；2.59～2.66(4H，m)；2.68～2.80(2H，m)；3.45(2H，s)；4.59(1H，br)；5.21(1H，br)；6.30(1H，s)；6.89(2H，s)；7.11(2H，d，J＝8.5Hz)；7.19～7.23(1H，m)；7.27～7.33(4H，m)；7.49(2H，d，J＝8.5Hz)；9.99(1H，s)。
Claims (11)
1. the preparation method of (R)-2-[[2-(4-aminophenyl) ethyl] is amino]-1-phenylethyl alcohol, it is characterized in that comprising the following steps: at conventional temperatures, in alcoholic solvent, under metal catalyst exists, by the catalytic hydrogenation that organic compound replaces gaseous hydrogen to carry out as the hydrogen donor in reaction, Compound I is carried out reduction reaction, obtains Compound II per:
2. the preparation method of (R)-2-as claimed in claim 1 [[2-(4-aminophenyl) ethyl] is amino]-1-phenylethyl alcohol, it is characterized in that, described alcoholic solvent is methyl alcohol or ethanol.
3. the preparation method of (R)-2-as claimed in claim 1 [[2-(4-aminophenyl) ethyl] is amino]-1-phenylethyl alcohol, it is characterized in that, described organic compound is ammonium formiate or ammonium acetate.
4. the preparation method of (R)-2-as claimed in claim 1 [[2-(4-aminophenyl) ethyl] is amino]-1-phenylethyl alcohol, it is characterized in that, described metal catalyst is 5% ~ 10% palladium carbon or Raney's nickel.
5. the preparation method of (R)-2-as claimed in claim 1 [[2-(4-aminophenyl) ethyl] is amino]-1-phenylethyl alcohol, it is characterized in that, the temperature of described reduction reaction is 30 DEG C ~ 70 DEG C.
6. the preparation method of (R)-2-as claimed in claim 2 [[2-(4-aminophenyl) ethyl] is amino]-1-phenylethyl alcohol, it is characterized in that, described alcoholic solvent is preferably methyl alcohol.
7. the preparation method of (R)-2-as claimed in claim 3 [[2-(4-aminophenyl) ethyl] is amino]-1-phenylethyl alcohol, it is characterized in that, described organic compound is preferably ammonium formiate.
8. the preparation method of (R)-2-as claimed in claim 4 [[2-(4-aminophenyl) ethyl] is amino]-1-phenylethyl alcohol, it is characterized in that, described metal catalyst is preferably 10% palladium carbon.
9. the preparation method of (R)-2-as claimed in claim 6 [[2-(4-aminophenyl) ethyl] is amino]-1-phenylethyl alcohol, it is characterized in that, described methyl alcohol and Compound I ratio are 1 ~ 100: 1 (ml/g).
10. the preparation method of (R)-2-as claimed in claim 7 [[2-(4-aminophenyl) ethyl] is amino]-1-phenylethyl alcohol, it is characterized in that, described ammonium formiate and the mol ratio of Compound I are 1 ~ 20: 1.
The preparation method of 11. (R)-2-as claimed in claim 8 [[2-(4-aminophenyl) ethyl] is amino]-1-phenylethyl alcohol, it is characterized in that, 10% described palladium carbon and the mass ratio of Compound I are 1% ~ 20%: 1.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106278909A (en) * | 2016-08-12 | 2017-01-04 | 浙江华海药业股份有限公司 | A kind of post-processing approach of Mirabegron intermediate |
| CN109456277A (en) * | 2018-10-29 | 2019-03-12 | 安徽省庆云医药股份有限公司 | A kind of 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 |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106278909A (en) * | 2016-08-12 | 2017-01-04 | 浙江华海药业股份有限公司 | A kind of post-processing approach of Mirabegron intermediate |
| WO2018028679A1 (en) * | 2016-08-12 | 2018-02-15 | 浙江华海药业股份有限公司 | Post-processing method for mirabegron intermediate |
| CN106278909B (en) * | 2016-08-12 | 2022-07-15 | 浙江华海药业股份有限公司 | Post-treatment method of mirabegron intermediate |
| CN109456277A (en) * | 2018-10-29 | 2019-03-12 | 安徽省庆云医药股份有限公司 | A kind of preparation method of Mirabegron |
| CN109456277B (en) * | 2018-10-29 | 2022-04-22 | 安徽省庆云医药股份有限公司 | 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 |
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