CN103896872A - Method for synthesizing mirabegron - Google Patents
Method for synthesizing mirabegron Download PDFInfo
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- CN103896872A CN103896872A CN201410177823.1A CN201410177823A CN103896872A CN 103896872 A CN103896872 A CN 103896872A CN 201410177823 A CN201410177823 A CN 201410177823A CN 103896872 A CN103896872 A CN 103896872A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic 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
- C07D277/32—Heterocyclic 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
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
Abstract
The invention discloses a method for synthesizing mirabegron, relates to a method for preparing mirabegron, and aims at solving the problems that the existing method for synthesizing the mirabegron is not friendly to environment, more in reaction steps, low in yield, and complicated in post-treatment, and cannot be amplified to produce. The method disclosed by the invention comprises the following steps: 1, carrying out ring-opening reaction by taking p-nitrophenylethylamine and (R)-phenylethylene oxide as initial raw materials; 2, carrying out reduction reaction; 3 carrying out condensation reaction. The method disclosed by the invention is cheap and available in selected raw materials, high in yield, low in cost, friendly to environment and applicable to industrial amplifying production. The method is applied to synthesis of the mirabegron.
Description
Technical field
The present invention relates to the preparation method of Mirabegron, belong to chemicals synthesis technical field.
Background technology
Mirabegron (Mirabegron) by the beta 3 adrenoreceptor agonists of Japanese Astellas pharmaceuticals research and development in order to treat overactive bladder, and go on the market and sell in Japan on September 16th, 2011, be used for the treatment of grownup's overactive bladder (OAB) on June 28th, 2012 through U.S. food Drug Administration (FDA) approval.
Mirabegron: C
21h
24n
4o
2s, chinesization formal name used at school is called: (R)-2-(2-amino-1,3-thiazoles-4-yl)-4'-[2-[(2-hydroxyl-2-styroyl) amino] ethyl] phenylacetamide.
The preparation method of Mirabegron mainly contains following two kinds:
Method one (Maruyama T, Suzuki T, Onda K, et al.Amide derivatives or salts thereof:U.S., 6346532[P] .2002-2-12.) synthetic route is as follows:
This synthetic route is mainly taking p-nitrophenyl ethylamine hydrochloride (1) as raw material, obtain (R)-2-[(4-oil of mirbane ethyl with the condensation of (R)-Styrene oxide 98min.) amino]-1-styroyl-1-alcohol (2), compound (2) obtains the tertiary butyl (R)-(2-hydroxyl-2-styroyl) (4-oil of mirbane ethyl) t-butyl carbamate (3) through amido protecting, compound (3) obtains the tertiary butyl (R)-(4-amino phenol ethyl) (2-hydroxyl-2-styroyl) t-butyl carbamate (4) through nitroreduction, compound (4) obtains the tertiary butyl (R)-(4-(2-(thiazolamine-4-yl) kharophen) styroyl) (2-hydroxyl-2-styroyl) t-butyl carbamate (5) with 2-(thiazolamine-4-yl) acetic acid condensation, compound (5) Deprotection obtains Mirabegron, this route second step has been used BOC acid anhydrides, use the aftertreatment of BOC acid anhydrides to need column chromatography, aftertreatment more complicated, productive rate is lower, some more expensive chemical reagent have been used simultaneously, being not suitable for industrialization amplifies, need to further carry out process optimization, improve reaction yield.
Method two (Kawazoe S, Sakamoto K, Awamura Y, et al.Alpha-form or beta-form crystal of acetanilide derivative:EP, 1440969[P] .2002-10-29.) synthetic route is as follows:
This route is taking p-nitrophenyl ethamine (1) as raw material, react to obtain (R)-2-hydroxy-n-(4-oil of mirbane ethyl)-2-phenyl-acetamides (2) with (R)-amygdalic acid, compound (2) reducing carbonyl obtains (R)-2-(4-oil of mirbane ethyl) amino)-1-phenyl second-1-alcohol (3), compound (3) through nitroreduction obtain (R)-2-((4-amino-benzene ethyl) amino)-1-phenyl second-1-alcohol (4), compound (4) obtains Mirabegron with 2-(thiazolamine-4-yl) acetic acid condensation.This route exists that reactions steps is many, yield is low, aftertreatment is complicated, can not amplify the problem of production.
Summary of the invention
To the object of the invention is that existing Mirabegron synthetic method environment is unfriendly, reactions steps is many, yield is low, aftertreatment is complicated in order solving, can not to amplify the problem of production, the synthetic method of Mirabegron is provided.
The synthetic method of Mirabegron of the present invention, realizes by following steps:
One, by oil of mirbane ethamine and (R)-Styrene oxide 98min. be 1:(1.0～1.5 according to mol ratio) ratio join in solvent, at 60 DEG C～70 DEG C, carry out ring-opening reaction, after question response completes, carry out recrystallization with recrystallization solvent again, obtain (R)-2-((4-oil of mirbane ethyl) amino)-1-styroyl-1-alcohol;
Two, (R)-2-(4-oil of mirbane ethyl) amino step 1 being obtained)-1-styroyl-1-alcohol adds in solvent, be (0.01～0.05) according to the mol ratio of catalyzer and (R)-2-((4-oil of mirbane ethyl) amino)-1-styroyl-1-alcohol again: 1 ratio adds catalyzer, under room temperature, hydrogen atmosphere condition, carry out reduction reaction, after completing, question response by pressure reducing and steaming solvent, obtains (R)-2-((4-aminophenyl) amino)-1-styroyl-1-alcohol; Wherein said solvent is methyl alcohol, dehydrated alcohol or Virahol, and described catalyzer is Pd/C, raney Ni or Lithium Aluminium Hydride;
Three, (R)-2-((4-aminophenyl) amino)-1-styroyl-1-alcohol step 2 being obtained and 2-(thiazolamine-4-yl) acetic acid are (1～1.5) according to mol ratio: 1 ratio adds in solvent, then be (1～1.5) according to the mol ratio of condensing agent and 2-(thiazolamine-4-yl) acetic acid: 1 ratio adds condensing agent to carry out condensation reaction, after completing, question response first extracts, clean, after dry, carry out recrystallization with recrystallization solvent again, obtain Mirabegron.
Synthetic route of the present invention is as follows:
Beneficial effect of the present invention:
1, to react step number few in the present invention, and do not use BOC acid anhydrides, avoid column chromatography,, after ring-opening reaction, need not purify and be directly used in lower step condensation reaction by the reduction of palladium carbon catalytic hydrogenation with oil of mirbane ethamine and (R)-Styrene oxide 98min. raw material, make Mirabegron, greatly shorten reactions steps, convenient post-treatment, has improved yield, uses kind and the usage quantity of solvent while having reduced industrialization.
2, the medicine and the reagent that in the present invention, use is cheap, be easy to get, and yield is high, cost is low, environmental friendliness, is therefore applicable to industrial amplification production.
3, finished product makes by recrystallization purifying, and product purity is high.
Brief description of the drawings
Fig. 1 is the HRMS figure of the synthetic Mirabegron of embodiment mono-;
Fig. 2 is the synthetic Mirabegron of embodiment mono-
1h-NMR figure;
Fig. 3 is the synthetic Mirabegron of embodiment mono-
13c-NMR figure.
Embodiment
Embodiment one: the synthetic method of present embodiment Mirabegron, carry out according to the following steps:
One, by oil of mirbane ethamine and (R)-Styrene oxide 98min. be 1:(1.0～1.5 according to mol ratio) ratio join in solvent, at 60 DEG C～70 DEG C, carry out ring-opening reaction, after question response completes, carry out recrystallization with recrystallization solvent again, obtain (R)-2-((4-oil of mirbane ethyl) amino)-1-styroyl-1-alcohol;
Two, (R)-2-(4-oil of mirbane ethyl) amino step 1 being obtained)-1-styroyl-1-alcohol adds in solvent, be (0.01～0.05) according to the mol ratio of catalyzer and (R)-2-((4-oil of mirbane ethyl) amino)-1-styroyl-1-alcohol again: 1 ratio adds catalyzer, under room temperature, hydrogen atmosphere condition, carry out reduction reaction, after completing, question response by pressure reducing and steaming solvent, obtains (R)-2-((4-aminophenyl) amino)-1-styroyl-1-alcohol; Wherein said solvent is methyl alcohol, dehydrated alcohol or Virahol, and described catalyzer is Pd/C, raney Ni or Lithium Aluminium Hydride;
Three, (R)-2-((4-aminophenyl) amino)-1-styroyl-1-alcohol step 2 being obtained and 2-(thiazolamine-4-yl) acetic acid are (1～1.5) according to mol ratio: 1 ratio adds in solvent, then be (1～1.5) according to the mol ratio of condensing agent and 2-(thiazolamine-4-yl) acetic acid: 1 ratio adds condensing agent to carry out condensation reaction, after completing, question response first extracts, clean, after dry, carry out recrystallization with recrystallization solvent again, obtain Mirabegron.
The beneficial effect of present embodiment:
The medicine and the reagent that in present embodiment, use is cheap, be easy to get, and yield is high, cost is low, environmental friendliness, is therefore applicable to industrial amplification production.
Present embodiment finished product makes by recrystallization purifying, and product purity is high.
Embodiment two: present embodiment is different from embodiment one: the solvent described in step 1 is Virahol, ethyl acetate, methylene dichloride, tetrahydrofuran (THF) or acetonitrile.Other is identical with embodiment one.
Embodiment three: present embodiment is different from embodiment one or two: carry out ring-opening reaction described in step 1 at 60 DEG C～65 DEG C.Other is identical with embodiment one or two.
Embodiment four: present embodiment is different from one of embodiment one to three: the recrystallization solvent described in step 1 is: the mixed solution of normal heptane and toluene, the mixed solution of normal heptane and ethyl acetate, the mixed solution of normal hexane and toluene, the mixed solution of normal hexane and ethyl acetate, the mixed solution of the mixed solution of sherwood oil and toluene or sherwood oil and ethyl acetate, wherein the volume ratio of normal heptane and toluene is (5～10): 1, the volume ratio of normal heptane and ethyl acetate is (5～10): 1, the volume ratio of normal hexane and toluene is (5～10): 1, the volume ratio of normal hexane and ethyl acetate is (5～10): 1, the volume ratio of sherwood oil and toluene is (5～10): 1, the volume ratio of sherwood oil and ethyl acetate is (5～10): 1.Other is identical with one of embodiment one to three.
Embodiment five: present embodiment is different from one of embodiment one to four: the ratio by oil of mirbane ethamine and (R)-Styrene oxide 98min. is 1:1.5 according to mol ratio described in step 1 joins in solvent.Other is identical with one of embodiment one to four.
Embodiment six: present embodiment is different from one of embodiment one to five: the ratio that is 0.01:1 according to catalyzer and (R)-2-((4-oil of mirbane ethyl) amino) mol ratio of-1-styroyl-1-alcohol again described in step 2 adds catalyzer.Other is identical with one of embodiment one to five.
Embodiment seven: present embodiment is different from one of embodiment one to six: the solvent described in step 3 is DMF, methylene dichloride, chloroform, acetonitrile or tetrahydrofuran (THF).Other is identical with one of embodiment one to six.
Embodiment eight: present embodiment is different from one of embodiment one to seven: the ratio that ((4-aminophenyl) the amino)-1-styroyl-1-alcohol of (the R)-2-that step 2 is obtained described in step 3 and 2-(thiazolamine-4-yl) acetic acid are 1.5:1 according to mol ratio adds in solvent.Other is identical with one of embodiment one to seven.
Embodiment nine: present embodiment is different from one of embodiment one to eight: the condensing agent described in step 3 is DCC, EDCI or TBTU.Other is identical with one of embodiment one to eight.
Embodiment ten: present embodiment is different from one of embodiment one to nine: the recrystallization solvent described in step 3 is that first alcohol and water is by volume for 10:(3～5) the methanol solution that mixes of ratio or dehydrated alcohol and water be 10:(3～5 by volume) the ethanolic soln that mixes of ratio.Other is identical with one of embodiment one to nine.
Embodiment 11: present embodiment is different from one of embodiment one to ten: the solvent described in step 1 is preferably acetonitrile.Other is identical with one of embodiment one to ten.
Embodiment 12: present embodiment is different from one of embodiment one to 11: the recrystallization solvent described in step 1 is preferably the mixed solution of normal heptane and toluene, and wherein the volume ratio of normal heptane and toluene is preferably (5～8): 1.Other is identical with one of embodiment one to 11.
Embodiment 13: present embodiment is different from one of embodiment one to 12: the recrystallization solvent described in step 1 is preferably the mixed solution of normal heptane and toluene, and wherein the volume ratio of normal heptane and toluene is preferably 8:1.Other is identical with one of embodiment one to 12.
Embodiment 14: present embodiment is different from one of embodiment one to 13: the solvent described in step 2 is preferably methyl alcohol.Other is identical with one of embodiment one to 13.
Embodiment 15: present embodiment is different from one of embodiment one to 14: the catalyzer described in step 2 is Pd/C.Other is identical with one of embodiment one to 14.
Embodiment 16: present embodiment is different from one of embodiment one to 15: the solvent described in step 3 is preferably DMF.Other is identical with one of embodiment one to 15.
Embodiment 17: present embodiment is different from one of embodiment one to 16: the condensing agent described in step 3 is preferably EDCI.Other is identical with one of embodiment one to 16.
Embodiment 18: present embodiment is different from one of embodiment one to 17: the recrystallization solvent described in step 3 is preferably first alcohol and water by volume for 10:(3～5) the methanol solution that mixes of ratio.Other is identical with one of embodiment one to 17.
Following examples are used for illustrating the present invention, but are not used for limiting the scope of the invention.
Embodiment mono-:
The synthetic method of the present embodiment Mirabegron, carry out according to the following steps:
One, (R)-2-(4-oil of mirbane ethyl) amino)-1-styroyl-1-alcohol synthetic:
Reaction formula:
In the four-hole bottle of 250mL, add p-nitrophenyl ethamine 20.0g (0.12mol), 120mL acetonitrile, then drip (R)-Styrene oxide 98min. 17.3g (0.144mol), drip and finish, under magnetic agitation, be warming up to 60 DEG C, insulation reaction 12h, TLC tracks to and reacts completely.
Aftertreatment: after completion of the reaction, cooling, pressure reducing and steaming solvent acetonitrile, in residual solution, add 30mL normal hexane, stirring and crystallizing, filters, then the mixed solution recrystallization with normal heptane and toluene by the crude product obtaining, wherein the volume ratio of normal heptane and toluene is 8:1, is dried and obtains 24.22g beige solid, and yield is 70.5%.
Two, (R)-2-((4-aminophenyl) amino)-1-styroyl-1-alcohol is synthetic:
Reaction formula:
In the four-hole bottle of 250mL, add 105mL methyl alcohol, (R)-2-(4-oil of mirbane ethyl) amino)-1-styroyl-1-alcohol 15.0g (0.05mol), 5% the Pd/C of 0.15g, under room temperature, passing into nitrogen catches up with the air in four-hole bottle to the greatest extent, pass into again hydrogen, stirring reaction under room temperature normal pressure, TLC tracks to and reacts completely.
Aftertreatment: after completion of the reaction, filtered and recycled Pd/C is in order to recycling next time, and pressure reducing and steaming solvent methanol, obtains colourless liquid (R)-2-((4-aminophenyl) amino)-1-styroyl-1-alcohol 11.67g, yield is 91.2%, is directly used in the next step.
Three, Mirabegron is synthetic:
Reaction formula:
In the there-necked flask of 250mL, add 2-(thiazolamine-4-yl) acetic acid 8.71g (0.043mol), N, dinethylformamide 100mL, and then add HOBT7.56g (0.052mol), add (R)-2-((4-aminophenyl) amino)-1-phenyl second-1-alcohol 10g (0.039mol), add triethylamine 6.52g (0.065mol), add EDCI10.73g (0.052mol) in batches, under magnetic agitation, room temperature reaction 4h, TLC tracks to and reacts completely.
Aftertreatment: after completion of the reaction, reaction solution is added to 500mL saturated aqueous common salt, then use the dichloromethane extraction of 200mL at every turn, extract 3 times, organic phase is each washing of the saturated aqueous sodium carbonate with 100mL then, wash 3 times, wash with the distillation of 100mL more at every turn, wash 3 times, organic phase anhydrous sodium sulfate drying, concentrating under reduced pressure steaming vibrating dichloromethane obtains white solid Mirabegron crude product, crude product methanol solution recrystallization, wherein in methanol solution, the volume ratio of first alcohol and water is 10:3, and recrystallization obtains 12.68g, and yield is 82.0%.
The Mirabegron synthetic to the present embodiment detects:
m.p.138～140℃(137～139℃)
[α]
20-18°～-22°(CH
3OH)
Chemical purity HPLC:99.90%
Optical purity: 97.33ee%
Embodiment bis-:
The synthetic method of the present embodiment Mirabegron, carry out according to the following steps:
One, (R)-2-(4-oil of mirbane ethyl) amino)-1-styroyl-1-alcohol synthetic:
Reaction formula:
In the four-hole bottle of 500mL, add p-nitrophenyl ethamine 40.0g (0.24mol), 220mL Virahol, drip (R)-Styrene oxide 98min. 34.6g (0.288mol), drip and finish, under magnetic agitation, be warming up to 65 DEG C, insulation reaction 12h, TLC tracks to and reacts completely.
Aftertreatment: after completion of the reaction, cooling, decompression evaporates solvent Virahol, in steamed backward concentrated solution, add 30mL normal hexane, stirring and crystallizing, filters, then the mixed solution recrystallization with normal heptane and toluene by the crude product obtaining, wherein the volume ratio of normal heptane and toluene is 10:1, is dried and obtains 48.46g beige solid, and yield is 70.6%.
Two, (R)-2-((4-aminophenyl) amino)-1-styroyl-1-alcohol is synthetic:
Reaction formula:
In the four-hole bottle of 500mL, add 180mL ethanol, (R)-2-(4-oil of mirbane ethyl) amino)-1-styroyl-1-alcohol 30.0g (0.1mol), 5% the Pd/C of 0.3g, under room temperature, passing into nitrogen catches up with the air in four-hole bottle to the greatest extent, pass into again hydrogen, stirring reaction under room temperature normal pressure, TLC tracks to and reacts completely.
Aftertreatment: after completion of the reaction, filtered and recycled Pd/C is in order to recycling next time, and pressure reducing and steaming etoh solvent, obtains colourless liquid (R)-2-((4-aminophenyl) amino)-1-styroyl-1-alcohol 23.35g, yield is 91.2%, is directly used in the next step.
Three, Mirabegron is synthetic:
Reaction formula:
In the there-necked flask of 500mL, add 2-(thiazolamine-4-yl) acetic acid 17.42g (0.086mol), N, dinethylformamide 180mL, and then add HOBT15.12g (0.104mol), add (R)-2-((4-aminophenyl) amino)-1-phenyl second-1-alcohol 20g (0.078mol), add triethylamine 13.04g (0.13mol), add EDCI21.46g (0.104mol) in batches, under magnetic agitation, room temperature reaction 5h, TLC tracks to and reacts completely.
Aftertreatment: after completion of the reaction, reaction solution is poured in 900mL saturated aqueous common salt and washed, then use the dichloromethane extraction of 400mL at every turn, extract 3 times, organic phase is each washing of the saturated aqueous sodium carbonate with 200mL then, wash 3 times, wash with the distilled water of 200mL more at every turn, wash 3 times, organic phase anhydrous sodium sulfate drying, concentrating under reduced pressure evaporates methylene dichloride and obtains white solid Mirabegron crude product, crude product methanol solution recrystallization, wherein in methanol solution, the volume ratio of first alcohol and water is 10:4, and recrystallization obtains 25.08g, and yield is 81.0%.
The synthetic Mirabegron of the present embodiment is detected and Structural Identification:
m.p.138～140℃(137～139℃)
[α]
20-18°～-22°(CH
3OH)
Chemical purity HPLC:99.96%
Optical purity: 97.55ee%
HRMS(ESI-MS,m/z)calcd:for?C
21H
25N
4O
2S[M+H]
+397.16.Found:397.16.
1H?NMR(400MHz,DMSO)δ10.00(s,1H),7.50(d,J＝8.5Hz,2H),7.30(dd,J＝9.5,5.1Hz,4H),7.23(dd,J＝6.0,2.7Hz,1H),7.12(d,J＝8.5Hz,2H),6.90(s,2H),6.30(s,1H),5.24(s,1H),4.60(s,1H),3.45(s,2H),2.74(dd,J＝9.8,3.5Hz,2H),2.64(m,4H).
13C?NMR(101MHz,DMSO)δ168.69(s),168.26(s),146.35(s),145.03(s),137.66(s),135.51(s),129.24(s),128.38(s),127.22(s),126.33(s),119.46(s),103.03(s),71.88(s),57.94(s),51.20(s),40.40(s),40.20(s),39.99(s),39.78(s),39.57(s),35.77(s).
The present invention is taking p-nitrophenyl ethamine and (R)-Styrene oxide 98min. as starting raw material, obtain final product Mirabegron through open loop, reduction and condensation reaction, the selected raw material of the present invention is cheap and easy to get, yield is high (yield is about 52.7%～55%), cost low (cost has approximately reduced by 30%), environmental friendliness, is applicable to industry's enlarging production.
Finally, it is also to be noted that above what enumerate is only specific embodiments of the invention.Obviously, the invention is not restricted to above embodiment, can also have many distortion.All distortion that those of ordinary skill in the art can directly derive or associate from content disclosed by the invention, all should think protection scope of the present invention.
Claims (10)
1. the synthetic method of Mirabegron, is characterized in that it comprises the following steps:
One, by oil of mirbane ethamine and (R)-Styrene oxide 98min. be 1:(1.0～1.5 according to mol ratio) ratio join in solvent, at 60 DEG C～70 DEG C, carry out ring-opening reaction, after question response completes, carry out recrystallization with recrystallization solvent again, obtain (R)-2-((4-oil of mirbane ethyl) amino)-1-styroyl-1-alcohol;
Two, (R)-2-(4-oil of mirbane ethyl) amino step 1 being obtained)-1-styroyl-1-alcohol adds in solvent, be (0.01～0.05) according to the mol ratio of catalyzer and (R)-2-((4-oil of mirbane ethyl) amino)-1-styroyl-1-alcohol again: 1 ratio adds catalyzer, under room temperature, hydrogen atmosphere condition, carry out reduction reaction, after completing, question response by pressure reducing and steaming solvent, obtains (R)-2-((4-aminophenyl) amino)-1-styroyl-1-alcohol; Wherein said solvent is methyl alcohol, dehydrated alcohol or Virahol etc., and described catalyzer is Pd/C, raney Ni or Lithium Aluminium Hydride;
Three, (R)-2-((4-aminophenyl) amino)-1-styroyl-1-alcohol step 2 being obtained and 2-(thiazolamine-4-yl) acetic acid are (1～1.5) according to mol ratio: 1 ratio adds in solvent, then be (1～1.5) according to the mol ratio of condensing agent and 2-(thiazolamine-4-yl) acetic acid: 1 ratio adds condensing agent to carry out condensation reaction, after completing, question response first extracts, clean, after dry, carry out recrystallization with solvent again, obtain Mirabegron.
2. the synthetic method of Mirabegron according to claim 1, is characterized in that the solvent described in step 1 is Virahol, ethyl acetate, methylene dichloride, tetrahydrofuran (THF) or acetonitrile.
3. the synthetic method of Mirabegron according to claim 1, is characterized in that at 60 DEG C～65 DEG C, carrying out ring-opening reaction described in step 1.
4. the synthetic method of Mirabegron according to claim 1, it is characterized in that the recrystallization solvent described in step 1 is: the mixed solution of normal heptane and toluene, the mixed solution of normal heptane and ethyl acetate, the mixed solution of normal hexane and toluene, the mixed solution of normal hexane and ethyl acetate, the mixed solution of the mixed solution of sherwood oil and toluene or sherwood oil and ethyl acetate, wherein the volume ratio of normal heptane and toluene is (5～10): 1, the volume ratio of normal heptane and ethyl acetate is (5～10): 1, the volume ratio of normal hexane and toluene is (5～10): 1, the volume ratio of normal hexane and ethyl acetate is (5～10): 1, the volume ratio of sherwood oil and toluene is (5～10): 1, the volume ratio of sherwood oil and ethyl acetate is (5～10): 1.
5. the synthetic method of Mirabegron according to claim 1, is characterized in that the ratio that is 1:1.5 according to mol ratio by oil of mirbane ethamine and (R)-Styrene oxide 98min. described in step 1 joins in solvent.
6. the synthetic method of Mirabegron according to claim 1, is characterized in that the ratio that is 0.01:1 according to catalyzer and (R)-2-((4-oil of mirbane ethyl) amino) mol ratio of-1-styroyl-1-alcohol again described in step 2 adds catalyzer.
7. the synthetic method of Mirabegron according to claim 1, is characterized in that the solvent described in step 3 is DMF, methylene dichloride, chloroform, acetonitrile or tetrahydrofuran (THF).
8. the synthetic method of Mirabegron according to claim 1, is characterized in that the ratio that ((4-aminophenyl) the amino)-1-styroyl-1-alcohol of (the R)-2-that step 2 is obtained described in step 3 and 2-(thiazolamine-4-yl) acetic acid are 1.5:1 according to mol ratio adds in solvent.
9. the synthetic method of Mirabegron according to claim 1, is characterized in that the condensing agent described in step 3 is DCC, EDCI or TBTU.
10. the synthetic method of Mirabegron according to claim 1, is characterized in that the recrystallization solvent described in step 3 is that first alcohol and water is by volume for 10:(3～5) the methanol solution that mixes of ratio or dehydrated alcohol and water be 10:(3～5 by volume) the ethanolic soln that mixes of ratio.
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| CN104230840A (en) * | 2014-09-05 | 2014-12-24 | 安徽联创药物化学有限公司 | Synthesis method of mirabegron |
| CN105111165A (en) * | 2015-09-14 | 2015-12-02 | 河南师范大学 | Merariveron preparation method |
| CN105198830A (en) * | 2015-09-14 | 2015-12-30 | 河南师范大学 | Mirabegron preparation method |
| 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 |
| CN109651290A (en) * | 2018-10-31 | 2019-04-19 | 安徽省庆云医药股份有限公司 | A kind of preparation method of Mirabegron |
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| CN104230840A (en) * | 2014-09-05 | 2014-12-24 | 安徽联创药物化学有限公司 | Synthesis method of mirabegron |
| CN105111165A (en) * | 2015-09-14 | 2015-12-02 | 河南师范大学 | Merariveron preparation method |
| CN105198830A (en) * | 2015-09-14 | 2015-12-30 | 河南师范大学 | Mirabegron preparation method |
| 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 |
| CN109651290B (en) * | 2018-10-31 | 2022-04-01 | 安徽省庆云医药股份有限公司 | Preparation method of mirabegron |
| CN109651290A (en) * | 2018-10-31 | 2019-04-19 | 安徽省庆云医药股份有限公司 | A kind of preparation method of Mirabegron |
| CN109912665A (en) * | 2019-04-28 | 2019-06-21 | 梯尔希（南京）药物研发有限公司 | A kind of synthetic method of Mirabegron metabolin |
| CN112745276B (en) * | 2019-10-31 | 2023-10-03 | 四川国为制药有限公司 | Crystallization method of milbegron |
| CN112745276A (en) * | 2019-10-31 | 2021-05-04 | 四川国为制药有限公司 | Crystallization method of mirabegron |
| CN111072589A (en) * | 2019-12-25 | 2020-04-28 | 北京振东光明药物研究院有限公司 | Recrystallization method and preparation method of 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 |
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