CN106083758B - A kind of high-efficiency synthesis method of Mirabegron - Google Patents
A kind of high-efficiency synthesis method of Mirabegron Download PDFInfo
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- CN106083758B CN106083758B CN201610462336.9A CN201610462336A CN106083758B CN 106083758 B CN106083758 B CN 106083758B CN 201610462336 A CN201610462336 A CN 201610462336A CN 106083758 B CN106083758 B CN 106083758B
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- 0 *c1ccc(CC#N)cc1 Chemical compound *c1ccc(CC#N)cc1 0.000 description 3
- RESNCUIUTUVMDJ-UHFFFAOYSA-N Nc1ccc(CCNCC2(CC2)c2ccccc2)cc1 Chemical compound Nc1ccc(CCNCC2(CC2)c2ccccc2)cc1 RESNCUIUTUVMDJ-UHFFFAOYSA-N 0.000 description 1
- DYCLHZPOADTVKK-UHFFFAOYSA-N Nc1nc(CC(O)=O)c[s]1 Chemical compound Nc1nc(CC(O)=O)c[s]1 DYCLHZPOADTVKK-UHFFFAOYSA-N 0.000 description 1
- PWMWNFMRSKOCEY-QMMMGPOBSA-N OC[C@@H](c1ccccc1)O Chemical compound OC[C@@H](c1ccccc1)O PWMWNFMRSKOCEY-QMMMGPOBSA-N 0.000 description 1
Classifications
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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 kind of high-efficiency synthesis method of Mirabegron, the specific steps are：Para orientation nitration obtains p-aminophenyl ethamine in hydrazine hydrate under the catalytic action of palladium calcium carbonate catalyst by nitro reduction and itrile group reduction reaction；(R) 1 hydroxyl of (R) 1 phenyl, 2 mesyl ethane is obtained by the reaction with mesyl chloride in 1 phenyl, 1,2 ethylene glycol under the catalytic action of basic catalyst piperidines or triethylamine；(R) (R) 2 ((4 aminophenethyl amino) 1 benzyl carbinol is obtained by the reaction with p-aminophenyl ethamine in 1 phenyl, 1 hydroxyl, 2 mesyl ethane under the catalytic action of basic catalyst potassium carbonate or triethylamine；(R) 2 (condensation reaction under the action of potassium methoxide of (4 aminophenethyl amino) 1 benzyl carbinol and 2 aminothiazole, 4 ethyl acetate obtains Mirabegron.Operation is simple, raw material is cheap and easy to get, reaction efficiency is higher and reproducible by the present invention.
Description
Technical field
The invention belongs to the synthesis technical fields of chemicals, and in particular to a kind of high-efficiency synthesis method of Mirabegron.
Background technology
Mirabegron (Myrbetriq, Mirabegron) is Food and Drug Adminstration of the US (FDA) June 28 in 2012
Day ratify and for treat mix urge incontinence, urgent urination, frequency symptoms overactive bladder (OAB) drug.
The English name of Mirabegron：2-Amino-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethy]amino]
Ethyl] pheny] -4-thiazoleacetamide, chemical constitution is：
The synthetic method of Mirabegron is mainly the following in the prior art：
As Europatent (EP1440969) is related to the synthetic method of Mirabegron, the synthetic route of the synthetic method
It is as follows：
However, above-mentioned synthetic method uses expensive monoborane-tetrahydrofuran solution and 1,3- dimethyl -2- imidazoles
Quinoline ketone, monoborane-tetrahydrofuran solution foul smelling meet water reaction acutely and release inflammable gas, can form explosion to wet sensitive sense
Property peroxide, and have stimulation to eyes, respiratory system and skin, 1,3- diformazan all unfavorable to operating personnel and ecological environment
Base -2- imidazolones, which are not easily recycled, to be applied mechanically, and is caused raw material and post processing cost to increase, is unfavorable for industrialized production.
Chinese patent (CN 105198830A) report with (R) -1- phenyl -1,2- ethylene glycol be starting material, elder generation and sulphur
Chloride compounds mesyl chloride or paratoluensulfonyl chloride obtain (R)-under the catalytic action of basic catalyst piperidines or triethylamine
1- phenyl -1,2- hydroxy-sulfonic acids ester compounds；Again with p-nitrophenyl ethamine basic catalyst potassium carbonate or triethylamine catalysis
(R) -2- ((4- nitrophenethyls) amino) -1- benzyl carbinols are obtained under effect；It is obtained again through reduced iron powder catalysis nitro reduction amino
To compound (R) -2- ((4- aminophenethyls) amino) -1- benzyl carbinols；Finally with thiazolamine -4- acetic acid in coupling reagent
Under the action of obtain Mirabegron.The route that the route uses is simple, but reduced iron powder is used to carry out nitro reduction, reduced iron
The dosage of powder is very big, and solid waste processing is difficult that can cause serious pollution problem, indirectly improve and be produced into
This.
The route of Chinese patent (CN 105111165A) report includes the following steps：A, amido protecting, p-aminophenyl acetonitrile
Protection is reacted with di-tert-butyl dicarbonate to obtain to Boc aminopheny-lacetonitriles bit amino；B, itrile group restores, to Boc aminobenzene second
Nitrile hydrogenating reduction itrile group under the action of reducing catalyst Raney's nickel or palladium carbon is obtained to Boc amino phenyl ethylamines；C, condensation reaction,
(R)-styrene oxide and (R) -2- ((4-Boc aminophenethyls) amino) -1- benzene second is obtained by the reaction to Boc amino phenyl ethylamines
Alcohol；D, it is deprotected, (R) -2- ((4-Boc aminophenethyls) amino) -1- benzyl carbinols slough Boc groups under trifluoroacetic acid effect
Obtain (R) -2- ((4- aminophenethyls) amino) -1- benzyl carbinols；E, amine ester condensation, (R) -2- ((4- aminophenethyls) ammonia
Base) -1- benzyl carbinols and thiazolamine -4- acetic acid is condensed to yield target product Mirabegron under the action of coupling reagent.It should
Raw material used in route (R)-styrene oxide is very expensive, and under the action of use reducing catalyst Raney's nickel or palladium carbon
Hydrogenating reduction itrile group obtains needing to use autoclave to Boc amino phenyl ethylamines, high to equipment requirement condition.
Invention content
The technical problem to be solved by the present invention is to provide it is a kind of operation is simple, raw material is cheap and easy to get, reaction efficiency compared with
The high-efficiency synthesis method of high and reproducible Mirabegron.
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of high-efficiency synthesis method of Mirabegron,
It is characterized in that the specific steps are：
Step (1), para orientation nitration is under the catalytic action of palladium calcium carbonate catalyst, in hydrazine hydrate also by nitro
Former and itrile group reduction reaction obtains p-aminophenyl ethamine；
The catalysis of step (2), (R) -1- phenyl -1,2- ethylene glycol and mesyl chloride in basic catalyst piperidines or triethylamine
(R) -1- phenyl -1- hydroxyls -2- mesyls-ethane is obtained by the reaction under effect；
Step (3), (R) -1- phenyl -1- hydroxyls -2- mesyls-ethane is with p-aminophenyl ethamine in basic catalyst carbon
(R) -2- ((4- aminophenethyls amino) -1- benzyl carbinols are obtained by the reaction under the catalytic action of sour potassium or triethylamine；
Step (4), after ethyl acetoacetate is heated to reflux in hexamethylene, pyrrolidines and p-methyl benzenesulfonic acid except water process,
Hexamethylene and pyrrolidines is evaporated off, anhydrous pyridine and elemental sulfur is added, cyanamide is added under the conditions of 0 DEG C, 90 are warming up to after dripping
DEG C thiazolamine -4- ethyl acetate is obtained by the reaction；
Step (5), ((4- aminophenethyls amino) -1- benzyl carbinols are with thiazolamine -4- ethyl acetate in first by (R) -2-
Condensation reaction obtains Mirabegron under the action of potassium alcoholate.
Further preferably, the specific building-up process of step (1) is：32g p-aminophenyl acetonitriles are dissolved in the reaction vessel
In 200mL methanol, add 3.2g palladium calcium carbonate catalysts, under the conditions of nitrogen protection, be added dropwise 32g hydrazine hydrates, after adding in
40 DEG C of reaction 12h, TLC monitors raw material, and the reaction was complete, and filtering reacting liquid, revolving removes solvent methanol, adds dichloromethane, uses
Three times, organic phase is spin-dried for obtaining p-aminophenyl ethamine water washing.
Further preferably, the specific building-up process of step (2) is：In the reaction vessel by 20g (R) -1- phenyl -1,2- second
Glycol and 25g piperidines are added in 200mL dichloromethane, and it is molten dissolved with the dichloromethane of 18g mesyl chlorides that 100mL is added at 0 DEG C
Liquid is warmed to room temperature reaction 1h after dripping, TLC monitors raw material, and the reaction was complete, and organic phase is separated after water washing is added, and water phase is with two
Chloromethanes extracts, and merges organic phase and is spin-dried for obtaining (R) -1- phenyl -1- hydroxyl -2- methylsulphurs acidic group-ethane.
Further preferably, the specific building-up process of step (3) is：In the reaction vessel by 20g p-aminophenyls ethamine, 32g
(R) -1- phenyl -1- hydroxyl -2- methylsulphurs acidic group-ethane and 44g basic catalyst triethylamines are added in 300mL toluene, heating
To 100 DEG C of reaction 15h, through TLC monitoring raw material, the reaction was complete, and reaction solution is cooled to -5 DEG C, has a large amount of solids to be precipitated, and filters solid
It is used in combination cold toluene solution to wash, (R) -2- ((4- aminophenethyls amino) -1- benzyl carbinols is obtained after filter cake drying.
Further preferably, the specific building-up process of step (4) is：By 32.5g second in the reaction vessel equipped with water knockout drum
Ethyl acetoacetic acid ethyl ester is added in 300mL hexamethylenes, adds 20g pyrrolidines and 0.5g mono- is hydrated p-methyl benzenesulfonic acid, heat up back
It flows and removes water, for reaction 5h postcoolings to room temperature, filtering reacting liquid steams the hexamethylene and pyrrolidines in filtrate, obtained
Product after distillation is added in 500mL anhydrous pyridines, adds 16g elemental sulfurs, and reaction temperature is set as 0 DEG C, and 50mL is added dropwise
Dissolved with the pyridine solution of 21g cyanamides, 90 DEG C of reaction 60min are warming up to after dripping, TLC monitors raw material, and the reaction was complete, is cooled to
Room temperature has a large amount of solids to be precipitated, and filters reaction solution, and filter cake dries after being washed with ether and obtains flaxen product 2- amino thiophenes
Azoles -4- ethyl acetate.
Further preferably, the specific building-up process of step (5) is：In the reaction vessel by 20g (R) -2- ((4- aminobenzenes
Ethylamino) -1- benzyl carbinols, 16g thiazolamine -4- ethyl acetate and 14g potassium methoxides be added to 300mL N, N- dimethyl
In formamide, 10h is reacted at room temperature, TLC monitors raw material, and the reaction was complete, and 600mL saturated common salt aqueous solutions are added into reaction solution and wash
Reaction solution is washed, then reaction solution is extracted three times with the dichloromethane of 300mL, merges organic phase, then water washing is distilled with 200mL, has
Machine is mutually spin-dried for obtaining product Mirabegron.
The synthetic route of the Mirabegron of the present invention is as follows：
The present invention has the advantages that compared with prior art：1, since calcium carbonate has very relatively rich hole knot
Structure, surface area possessed by unit mass is very big, therefore uses palladium calcium carbonate as catalyst, can be same under hydrazine hydrate effect
When reduction nitro and itrile group, than using palladium calcium to simplify reaction route；2, use (R) -1- phenyl -1,2- ethylene glycol as raw material
Reaction cost is directly reduced than use (R)-styrene oxide；3, thiazolamine -4- acetic acid second is synthesized using novel method
Ester, not only raw material is cheap but also yield is very high；4, coupling reagent is replaced using potassium methoxide, operation is simple, raw material is inexpensively easy
, reaction efficiency it is higher and reproducible.
Specific implementation mode
The above of the present invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on the above of the present invention belong to this hair
Bright range.
Embodiment 1
In 500mL reaction bulbs, 32g p-aminophenyls acetonitrile (0.2mol) is dissolved in 200mL methanol, 3.2g palladiums are added
32g hydrazine hydrates are slowly added dropwise in calcium catalyst under the conditions of nitrogen protection, react 12h in 40 DEG C after adding, it is anti-that TLC monitors raw material
Should be complete, filtering reacting liquid, revolving removes solvent methanol, and a certain amount of dichloromethane is being added, is being washed with water three times, organic phase
It is spin-dried for obtaining p-aminophenyl ethamine 30g.1H NMR(400MHz,DMSO-d6)δ6.98(dt,J1=8.4Hz, J2=2.0Hz, 2H,
Ar-H),6.63(dt,J1=8.4Hz, J2=2.0Hz, 2H, Ar-H), 3.57 (brs, 2H, NH2- H), 2.89 (t, J=6.8Hz,
2H,CH2- H), 2.63 (t, J=6.8Hz, 2H, CH2-H),1.15(bra,2H,NH2-H)。
Embodiment 2
In 500mL reaction bulbs, by 20g (R) -1- phenyl -1,2- ethylene glycol (0.145mol) and 25g piperidines
(0.29mol) is added in 200mL dichloromethane, and 100mL is slowly added under the conditions of 0 DEG C dissolved with 18g mesyl chlorides
The dichloromethane solution of (0.16mol) is warmed to room temperature reaction 1h after dripping, TLC monitors raw material, and the reaction was complete, is added a certain amount of
Water washing after separate organic phase, water phase is extracted with dichloromethane, merge organic phase be spin-dried for obtaining (R) -1- phenyl -1- hydroxyls -
2- methylsulphurs acidic group-ethane 21g.1H NMR(400MHz,CDCl3):δ 7.77 (d, J=8.2Hz, 2H, Ar-H), 7.36-7.27 (m,
3H,Ar-H),4.97(dd,J1=8.6Hz, J2=3.3Hz, 1H, CH-H), 4.15 (dd, J1=10.3Hz, J2=3.3Hz, 1H,
CH2-H),4.05(dd,J1=10.3Hz, J2=8.6Hz, 1H, CH2-H),2.45(s,3H,CH3-H)。
Embodiment 3
In the reaction bulb equipped with water knockout drum, ethyl acetoacetate 32.5g (0.25mol) is added in hexamethylene 300mL,
The hydration p-methyl benzenesulfonic acid 0.5g of pyrrolidines 20g (0.275mol) and one (2.63mmol) are added, temperature rising reflux simultaneously removes water, instead
Answer 5h postcoolings to room temperature, filtering reacting liquid steams the hexamethylene and pyrrolidines in filtrate, the product after obtained distillation
It is added in 500mL anhydrous pyridines, adds 16g (0.5mol) elemental sulfur, reaction temperature is set as 0 DEG C, 50mL is slowly added dropwise
Dissolved with the pyridine solution of 21g (0.5mol) cyanamide, it is to slowly warm up to 90 DEG C of reactions 60min, TLC after dripping and monitors raw material reaction
Completely, a large amount of solids have been cooled to room temperature to be precipitated, have filtered reaction solution, filter cake is dried after being washed with ether (200mL × 3), obtained
The flaxen product thiazolamine -4- ethyl acetate of 45g, yield 97%.1HNMR(400MHz,CDCl3)δ：6.32(s,
1H), 5.27 (s, 2H), 4.17 (q, J=7.1Hz, 2H), 3.54 (S, 2H), 1.26 (t, J=7.1Hz, 3H).
Embodiment 4
In 500mL reaction bulbs, by 20g p-aminophenyls ethamine (0.147mol), 32g (R) -1- phenyl -1- hydroxyl -2- first
Sulfonic group-ethane (0.147mol) and 44g basic catalysts triethylamine (0.441mol) are added in 300mL toluene, are heated to
100 DEG C of reaction 15h, through TLC monitoring raw material, the reaction was complete, and reaction solution is cooled to -5 DEG C, gradually has a large amount of solids to be precipitated, and filters solid
Body is used in combination a certain amount of cold toluene to wash, and (R) -2- ((4- aminophenethyls amino) -1- benzyl carbinols 45g are obtained after filter cake drying.1H NMR(400MHz,DMSO-d6):δ 7.33-7.20 (m, 5H, Ar-H), 6.84 (d, J=12.0Hz, 2H, Ar-H), 6.48
(d, J=8.0Hz, 2H, Ar-H), 5.26 (s, 1H, OH-H), 4.83 (s, 2H, NH2- H), 4.60 (t, 1H, J=8.0Hz, CH-
H),2.73-2.58(m,4H,C2H4- H), 2.52 (d, J=8.0Hz, 2H, CH2-H)。
Embodiment 5
In 1000mL reaction bulbs, by 20g (R) -2- ((4- aminophenethyls amino) -1- benzyl carbinols (0.078mol),
16g thiazolamine -4- ethyl acetate (0.086mol) and 14g potassium methoxides (0.2mol) are added to 300mL N, N- dimethyl
In formamide, 10h is reacted at room temperature, TLC monitors raw material, and the reaction was complete, and 600mL saturated common salt aqueous solutions are added into reaction solution and wash
Reaction solution is washed, then reaction solution is extracted three times with the dichloromethane of 300mL, merges organic phase, then water washing one is distilled with 200mL
Secondary, organic phase is spin-dried for obtaining product Mirabegron 26g.1H NMR(400MHz,DMSO-d6):δ 7.50 (d, J=8.0Hz, 2H,
), Ar-H 7.29 (t, J=8.0Hz, 4H, Ar-H), 7.21 (t, J=8.0Hz, 1H, Ar-H), 7.11 (d, J=12.0Hz, 2H,
Ar-H),6.93(s,2H,NH2-H),6.30(s,1H,CH-H),5.26(s,1H,OH-H),4.60(s,1H,CH-H),3.45
(s,2H,CH2-H),2.75-2.71(m,2H,CH2- H), 2.65 (d, J=4.0Hz, 4H, C2H4-H)。
Embodiment above describes the basic principles and main features and advantage of the present invention, and the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe the originals of the present invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (6)
1. a kind of high-efficiency synthesis method of Mirabegron, it is characterised in that the specific steps are：
Step（1）, para orientation nitration under the catalytic action of palladium calcium carbonate catalyst, in hydrazine hydrate by nitro reduction and
Itrile group reduction reaction obtains p-aminophenyl ethamine；
Step（2）, the catalytic action of (R) -1- phenyl -1,2- ethylene glycol and mesyl chloride in basic catalyst piperidines or triethylamine
Under (R) -1- phenyl -1- hydroxyls -2- mesyls-ethane is obtained by the reaction；
Step（3）, (R) -1- phenyl -1- hydroxyls -2- mesyls-ethane is with p-aminophenyl ethamine in basic catalyst potassium carbonate
Or (R) -2- (4- aminophenethyls amino) -1- benzyl carbinols are obtained by the reaction under the catalytic action of triethylamine；
Step（4）, after ethyl acetoacetate is heated to reflux in hexamethylene, pyrrolidines and p-methyl benzenesulfonic acid except water process, it is evaporated off
Hexamethylene and pyrrolidines are added anhydrous pyridine and elemental sulfur, cyanamide are added under the conditions of 0 DEG C, and 90 DEG C are warming up to after dripping instead
It should obtain thiazolamine -4- ethyl acetate；
Step（5）, (R) -2- (4- aminophenethyls amino) -1- benzyl carbinols are with thiazolamine -4- ethyl acetate in potassium methoxide
Under the action of condensation reaction obtain Mirabegron.
2. the high-efficiency synthesis method of Mirabegron according to claim 1, it is characterised in that step（1）Specific synthesized
Cheng Wei：32g p-aminophenyl acetonitriles are dissolved in 200mL methanol in the reaction vessel, add 3.2g palladium calcium carbonate catalysts,
Under the conditions of nitrogen protection, 32g hydrazine hydrates are added dropwise, react 12h after adding in 40 DEG C, TLC monitors raw material, and the reaction was complete, filtering reaction
Liquid, revolving remove solvent methanol, add dichloromethane, be washed with water three times, organic phase is spin-dried for obtaining p-aminophenyl ethamine.
3. the high-efficiency synthesis method of Mirabegron according to claim 1, it is characterised in that step（2）Specific synthesis
Process is：20g (R) -1- phenyl -1,2- ethylene glycol and 25g piperidines are added in 200mL dichloromethane in the reaction vessel,
Dichloromethane solutions of the 100mL dissolved with 18g mesyl chlorides is added at 0 DEG C, it is former that reaction 1h, TLC monitoring is warmed to room temperature after dripping
The reaction was complete for material, and organic phase is separated after water washing is added, and water phase is extracted with dichloromethane, merges organic phase and is spin-dried for obtaining (R) -1-
Phenyl -1- hydroxyl -2- methylsulphurs acidic group-ethane.
4. the high-efficiency synthesis method of Mirabegron according to claim 1, it is characterised in that step（3）Specific synthesis
Process is：In the reaction vessel by 20g p-aminophenyls ethamine, 32g (R) -1- phenyl -1- hydroxyl -2- methylsulphurs acidic group-ethane and
44g basic catalyst triethylamines are added in 300mL toluene, are heated to 100 DEG C of reaction 15h, have been reacted through TLC monitoring raw materials
Entirely, reaction solution is cooled to -5 DEG C, has a large amount of solids to be precipitated, and filters solid and is washed with cold toluene solution, is obtained after filter cake drying
(R) -2- (4- aminophenethyls amino) -1- benzyl carbinols.
5. the high-efficiency synthesis method of Mirabegron according to claim 1, it is characterised in that step（4）Specific synthesized
Cheng Wei：32.5g ethyl acetoacetates are added in 300mL hexamethylenes in the reaction vessel equipped with water knockout drum, add 20g
Pyrrolidines and 0.5g mono- are hydrated p-methyl benzenesulfonic acid, and temperature rising reflux simultaneously removes water, reaction 5h postcoolings to room temperature, filtering reacting liquid,
The hexamethylene and pyrrolidines in filtrate are steamed, the product after obtained distillation is added in 500mL anhydrous pyridines, is added
16g elemental sulfurs, reaction temperature are set as 0 DEG C, and 50mL is added dropwise dissolved with the pyridine solution of 21g cyanamides, 90 DEG C are warming up to after dripping
60min is reacted, TLC monitors raw material, and the reaction was complete, is cooled to room temperature, and there are a large amount of solids to be precipitated, and filters reaction solution, filter cake ether
Drying obtains flaxen product thiazolamine -4- ethyl acetate after washing.
6. the high-efficiency synthesis method of Mirabegron according to claim 1, it is characterised in that step（5）Specific synthesis
Process is：In the reaction vessel by 20g (R) -2- (4- aminophenethyls amino) -1- benzyl carbinols, 16g thiazolamines -4-
Ethyl acetate and 14g potassium methoxides are added in 300mL n,N-Dimethylformamide, react at room temperature 10h, and TLC monitors raw material reaction
Completely, 600mL saturated common salt aqueous solution washing reaction liquids are added into reaction solution, then reaction is extracted with the dichloromethane of 300mL
Liquid three times, merges organic phase, then distill water washing with 200mL, organic phase is spin-dried for obtaining product Mirabegron.
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| 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 |
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| CN110117263B (en) * | 2019-06-11 | 2020-12-25 | 湖南中医药大学 | 2-amino-5-acyl thiazole derivative and synthetic method thereof |
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