CN106083758A - 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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- CN106083758A CN106083758A CN201610462336.9A CN201610462336A CN106083758A CN 106083758 A CN106083758 A CN 106083758A CN 201610462336 A CN201610462336 A CN 201610462336A CN 106083758 A CN106083758 A CN 106083758A
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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 the high-efficiency synthesis method of a kind of Mirabegron, concretely comprise the following steps: para orientation nitration, under the catalytic action of palladium calcium carbonate catalyst, obtains p-aminophenyl ethamine through nitro reduction and itrile group reduction reaction in hydrazine hydrate；(R) 1 phenyl 1,2 ethylene glycol and mesyl chloride react under the catalytic action of base catalyst piperidines or triethylamine and obtain (R) 1 phenyl 1 hydroxyl 2 mesyl ethane；(R) 1 phenyl 1 hydroxyl 2 mesyl ethane and p-aminophenyl ethamine react under the catalytic action of base catalyst potassium carbonate or triethylamine and obtain (R) 2 ((4 aminophenethyl amino) 1 phenethanol；(R) 2 ((4 aminophenethyl amino) 1 phenethanol and 2 aminothiazole 4 ethyl acetate condensation reactions under the effect of Feldalat KM obtain Mirabegron.Operation is simple for the present invention, cheaper starting materials is easy to get, reaction efficiency is higher and reproducible.
Description
Technical field
The invention belongs to the synthesis technical field of chemicals, be specifically related to the high-efficiency synthesis method of a kind of Mirabegron.
Background technology
Mirabegron (Myrbetriq, Mirabegron) is that FDA (Food and Drug Adminstration) (FDA) was June 28 in 2012
Day approval is also used for the medicine that the overactive bladder (OAB) of urge incontinence, urgent micturition, frequency symptoms is mixed in treatment.
The English name of Mirabegron: 2-Amino-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethy] amino]
Ethyl] pheny]-4-thiazoleacetamide, chemical constitution is:
In prior art, the synthetic method for Mirabegron mainly has following several:
As Europatent (EP1440969) relates to the synthetic method of Mirabegron, the synthetic route of this synthetic method
As follows:
But, above-mentioned synthetic method uses expensive monoborane-tetrahydrofuran solution and 1,3-dimethyl-2-imidazoles
Quinoline ketone, monoborane-tetrahydrofuran solution foul smelling, to wet sensitive sense, meet water reaction and acutely and release inflammable gas, blast can be formed
Property peroxide, and eyes, respiratory system and skin are had stimulation, the most unfavorable to operator and ecological environment, 1,3-diformazan
Base-2-imidazolone is not easily recycled to be applied mechanically, and causes raw material and post processing cost to increase, is unfavorable for industrialized production.
Chinese patent (CN 105198830A) report with (R)-1-phenyl-1，2-ethandiol as initiation material, elder generation and sulphur
Chloride compounds mesyl chloride or paratoluensulfonyl chloride obtain under the catalytic action of base catalyst piperidines or triethylamine (R)-
1-phenyl-1,2-hydroxy-sulfonic acids ester compounds；Again with p-nitrophenyl ethamine in base catalyst potassium carbonate or the catalysis of triethylamine
(R)-2-((4-nitrophenethyl) amino)-1-phenethanol is obtained under effect；Obtain through reduced iron powder catalysis nitro reduction amino again
To compound (R)-2-((4-aminophenethyl) amino)-1-phenethanol；Last and thiazolamine-4-acetic acid is at coupling reagent
Effect under obtain Mirabegron.The route that this route uses is simple, but uses reduced iron powder to carry out nitro reduction, reduced iron
The consumption of powder is very big, and solid waste processes and is difficult to, and can cause serious pollution problem, indirectly improve and produce into
This.
The route that Chinese patent (CN 105111165A) is reported comprises the following steps: a, amido protecting, p-aminophenyl acetonitrile
React protection with Bis(tert-butoxycarbonyl)oxide to obtain bit amino to Boc aminopheny-lacetonitrile；B, itrile group reduce, to Boc aminobenzene second
Nitrile hydrogenating reduction itrile group under the effect of reducing catalyst Raney's nickel or palladium carbon obtains Boc aminobenzene ethamine；C, condensation reaction,
(R)-styrene oxide obtains (R)-2-((4-Boc aminophenethyl) amino)-1-benzene second with reacting Boc aminobenzene ethamine
Alcohol；D, deprotection, Boc group sloughed under trifluoroacetic acid effect by (R)-2-((4-Boc aminophenethyl) amino)-1-phenethanol
Obtain (R)-2-((4-aminophenethyl) amino)-1-phenethanol；E, amine ester condensation, (R)-2-((4-aminophenethyl) ammonia
Base)-1-phenethanol and thiazolamine-4-acetic acid is condensed to yield target product Mirabegron under the effect of coupling reagent.Should
Raw material (R)-styrene oxide that route is used is much more expensive, and uses under the effect of reducing catalyst Raney's nickel or palladium carbon
Hydrogenating reduction itrile group obtains needing to use autoclave to Boc aminobenzene ethamine, high to equipment requirements condition.
Summary of the invention
Present invention solves the technical problem that there is provided that a kind of operation is simple, cheaper starting materials is easy to get, reaction efficiency relatively
The high-efficiency synthesis method of high and reproducible Mirabegron.
The present invention solves that above-mentioned technical problem adopts the following technical scheme that, the high-efficiency synthesis method of a kind of Mirabegron,
It is characterized in that concretely comprising the following steps:
Step (1), para orientation nitration is under the catalytic action of palladium calcium carbonate catalyst, in hydrazine hydrate through nitro also
Former and itrile group reduction reaction obtains p-aminophenyl ethamine；
Step (2), (R)-1-phenyl-1，2-ethandiol and mesyl chloride are in base catalyst piperidines or the catalysis of triethylamine
The lower reaction of effect obtains (R)-1-phenyl-1-hydroxyl-2-mesyl-ethane；
Step (3), (R)-1-phenyl-1-hydroxyl-2-mesyl-ethane and p-aminophenyl ethamine are at base catalyst carbon
React under the catalytic action of acid potassium or triethylamine and obtain (R)-2-((4-aminophenethyl amino)-1-phenethanol；
Step (4), after ethyl acetoacetate is heated to reflux processing except water in hexamethylene, pyrrolidine and p-methyl benzenesulfonic acid,
Hexamethylene and pyrrolidine are evaporated off, add anhydrous pyridine and elemental sulfur, under the conditions of 0 DEG C, add cyanamide, after dripping, be warming up to 90
DEG C reaction obtains thiazolamine-4-ethyl acetate；
Step (5), ((4-aminophenethyl amino)-1-phenethanol and thiazolamine-4-ethyl acetate are in first for (R)-2-
Under the effect of potassium alcoholate, condensation reaction obtains Mirabegron.
Further preferably, the concrete building-up process of step (1) is: be dissolved in by 32g p-aminophenyl acetonitrile in reaction vessel
In 200mL methanol, add 3.2g palladium calcium carbonate catalyst, under nitrogen protective condition, drip 32g hydrazine hydrate, after adding in
40 DEG C of reaction 12h, TLC monitoring raw material reactions are complete, and filtering reacting liquid, rotation is evaporated off solvent methanol, adds dichloromethane, uses
Water washs three times, and organic facies is spin-dried for obtaining p-aminophenyl ethamine.
Further preferably, the concrete building-up process of step (2) is: by 20g (R)-1-phenyl-1,2-second in reaction vessel
Glycol and 25g piperidines join in 200mL dichloromethane, add 100mL at 0 DEG C molten dissolved with the dichloromethane of 18g mesyl chloride
Liquid, is warmed to room temperature reaction 1h, TLC monitoring raw material reaction complete, separates organic facies after adding water washing after dripping, aqueous phase is with two
Chloromethanes extracts, and merges organic facies and is spin-dried for obtaining (R)-1-phenyl-1-hydroxyl-2-methanesulfonic acid base-ethane.
Further preferably, the concrete building-up process of step (3) is: by 20g p-aminophenyl ethamine, 32g in reaction vessel
(R)-1-phenyl-1-hydroxyl-2-methanesulfonic acid base-ethane and 44g base catalyst triethylamine join in 300mL toluene, heating
To 100 DEG C of reaction 15h, complete through TLC monitoring raw material reaction, reactant liquor is cooled to-5 DEG C, has a large amount of solid to separate out, sucking filtration solid
And wash with cold toluene solution, filter cake obtains (R)-2-((4-aminophenethyl amino)-1-phenethanol after drying.
Further preferably, the concrete building-up process of step (4) is: by 32.5g second in equipped with the reaction vessel of water knockout drum
Ethyl acetoacetic acid ethyl ester joins in 300mL hexamethylene, adds 20g pyrrolidine and 0.5g mono-is hydrated p-methyl benzenesulfonic acid, heat up back
Flow and remove water, be cooled to room temperature, filtering reacting liquid after reaction 5h, steam the hexamethylene in filtrate and pyrrolidine, obtained
Product after distillation joins in 500mL anhydrous pyridine, adds 16g elemental sulfur, and reaction temperature is set as 0 DEG C, drips 50mL
Dissolved with the pyridine solution of 21g cyanamide, it is warming up to 90 DEG C of reaction 60min, TLC monitoring raw material reactions after dripping complete, is cooled to
Room temperature, has a large amount of solid to separate out, sucking filtration reactant liquor, and filter cake ether washing post-drying obtains flaxen product 2-amino thiophene
Azoles-4-ethyl acetate.
Further preferably, the concrete building-up process of step (5) is: by 20g (R)-2-((4-aminobenzene in reaction vessel
Ethylamino)-1-phenethanol, 16g thiazolamine-4-ethyl acetate and 14g Feldalat KM join 300mL N, N-dimethyl
In Methanamide, room temperature reaction 10h, TLC monitoring raw material reaction is complete, adds 600mL saturated common salt aqueous solution and wash in reactant liquor
Wash reactant liquor, then with the dichloromethane extractive reaction liquid three times of 300mL, merge organic facies, then use 200mL distilled water wash, have
Machine is spin-dried for obtaining product Mirabegron mutually.
The synthetic route of the Mirabegron of the present invention is as follows:
The present invention compared with prior art has the advantages that 1, have very abundant porous knot due to calcium carbonate
Structure, the surface area that unit mass is had is very big, therefore uses palladium calcium carbonate as catalyst, and under hydrazine hydrate effect, energy is same
Time reduction nitro and itrile group, simplify reaction scheme than using palladium calcium；2, use (R)-1-phenyl-1,2-ethylene glycol as raw material
Reaction cost is directly reduced than using (R)-styrene oxide；3, novel method synthesis thiazolamine-4-acetic acid second is used
Ester, not only cheaply but also yield is the highest for raw material；4, using Feldalat KM to replace coupling reagent, operation is simple, cheaper starting materials is easy
, reaction efficiency higher and reproducible.
Detailed description of the invention
By the following examples the foregoing of the present invention is described in further details, but this should be interpreted as this
The scope inventing above-mentioned theme is only limitted to below example, and all technology realized based on foregoing of the present invention belong to this
Bright scope.
Embodiment 1
In 500mL reaction bulb, 32g p-aminophenyl acetonitrile (0.2mol) is dissolved in 200mL methanol, adds 3.2g palladium
Calcium catalyst, is slowly added dropwise 32g hydrazine hydrate under nitrogen protective condition, anti-in 40 DEG C of reaction 12h, TLC monitoring raw materials after adding
Should be complete, filtering reacting liquid, rotation is evaporated off solvent methanol, is adding a certain amount of dichloromethane, is washing three times with water, organic facies
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 bulb, by 20g (R)-1-phenyl-1，2-ethandiol (0.145mol) and 25g piperidines
(0.29mol) join in 200mL dichloromethane, under the conditions of 0 DEG C, be slowly added to 100mL dissolved with 18g mesyl chloride
(0.16mol) dichloromethane solution, is warmed to room temperature reaction 1h, TLC monitoring raw material reaction complete, adds a certain amount of after dripping
Water washing after separate organic facies, aqueous phase dichloromethane extracts, merge organic facies be spin-dried for obtaining (R)-1-phenyl-1-hydroxyl-
2-methanesulfonic acid base-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
Equipped with in the reaction bulb of water knockout drum, ethyl acetoacetate 32.5g (0.25mol) is added in hexamethylene 300mL,
Adding pyrrolidine 20g (0.275mol) and hydration p-methyl benzenesulfonic acid 0.5g (2.63mmol), temperature rising reflux also removes water, instead
It is cooled to room temperature, filtering reacting liquid after answering 5h, steams the hexamethylene in filtrate and pyrrolidine, the product after obtained distillation
Joining in 500mL anhydrous pyridine, add 16g (0.5mol) elemental sulfur, reaction temperature is set as 0 DEG C, is slowly added dropwise 50mL
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, being cooled to room temperature has a large amount of solid to separate out, sucking filtration reactant liquor, and filter cake ether (200mL × 3) washs post-drying, obtains
45g flaxen product thiazolamine-4-ethyl acetate, yield is 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 bulb, by 20g p-aminophenyl ethamine (0.147mol), 32g (R)-1-phenyl-1-hydroxyl-2-first
Sulfonic group-ethane (0.147mol) and 44g base catalyst triethylamine (0.441mol) join in 300mL toluene, are heated to
100 DEG C of reaction 15h, complete through TLC monitoring raw material reaction, reactant liquor is cooled to-5 DEG C, gradually has a large amount of solid to separate out, and sucking filtration is solid
Body, and wash with a certain amount of cold toluene, filter cake obtains (R)-2-((4-aminophenethyl amino)-1-phenethanol 45g after 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 bulb, by 20g (R)-2-((4-aminophenethyl amino)-1-phenethanol (0.078mol),
16g thiazolamine-4-ethyl acetate (0.086mol) and 14g Feldalat KM (0.2mol) join 300mL N, N-dimethyl
In Methanamide, room temperature reaction 10h, TLC monitoring raw material reaction is complete, adds 600mL saturated common salt aqueous solution and wash in reactant liquor
Wash reactant liquor, then with the dichloromethane extractive reaction liquid three times of 300mL, merge organic facies, then with 200mL distilled water wash one
Secondary, organic facies 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 ultimate principle of the present invention, principal character and advantage, the technical staff of the industry should
Understanding, the present invention is not restricted to the described embodiments, and the simply explanation present invention's described in above-described embodiment and description is former
Reason, under the scope without departing from the principle of the invention, the present invention also has various changes and modifications, and these changes and improvements each fall within
In the scope of protection of the invention.
Claims (6)
1. the high-efficiency synthesis method of a Mirabegron, it is characterised in that concretely comprise the following steps:
Step (1), para orientation nitration under the catalytic action of palladium calcium carbonate catalyst, in hydrazine hydrate through nitro reduction and
Itrile group reduction reaction obtains p-aminophenyl ethamine；
Step (2), (R)-1-phenyl-1，2-ethandiol and mesyl chloride are in base catalyst piperidines or the catalytic action of triethylamine
Lower reaction obtains (R)-1-phenyl-1-hydroxyl-2-mesyl-ethane；
Step (3), (R)-1-phenyl-1-hydroxyl-2-mesyl-ethane and p-aminophenyl ethamine are at base catalyst potassium carbonate
Or reaction obtains (R)-2-((4-aminophenethyl amino)-1-phenethanol under the catalytic action of triethylamine；
Step (4), after ethyl acetoacetate is heated to reflux processing except water in hexamethylene, pyrrolidine and p-methyl benzenesulfonic acid, is evaporated off
Hexamethylene and pyrrolidine, add anhydrous pyridine and elemental sulfur, adds cyanamide under the conditions of 0 DEG C, is warming up to 90 DEG C instead after dripping
Thiazolamine-4-ethyl acetate should be obtained；
Step (5), ((4-aminophenethyl amino)-1-phenethanol and thiazolamine-4-ethyl acetate are at Feldalat KM for (R)-2-
Effect under condensation reaction obtain Mirabegron.
The high-efficiency synthesis method of Mirabegron the most according to claim 1, it is characterised in that specifically synthesizing of step (1)
Cheng Wei: be dissolved in 200mL methanol by 32g p-aminophenyl acetonitrile in reaction vessel, adds 3.2g palladium calcium carbonate catalyst,
Under nitrogen protective condition, drip 32g hydrazine hydrate, complete in 40 DEG C of reaction 12h, TLC monitoring raw material reactions after adding, filter reaction
Liquid, rotation is evaporated off solvent methanol, adds dichloromethane, wash three times with water, and organic facies is spin-dried for obtaining p-aminophenyl ethamine.
The high-efficiency synthesis method of Mirabegron the most according to claim 1, it is characterised in that the concrete synthesis of step (2)
Process is: join in 200mL dichloromethane by 20g (R)-1-phenyl-1，2-ethandiol and 25g piperidines in reaction vessel,
Add the 100mL dichloromethane solution dissolved with 18g mesyl chloride at 0 DEG C, be warmed to room temperature reaction 1h, TLC monitoring after dripping former
Material reaction completely, separates organic facies after adding water washing, and aqueous phase dichloromethane extracts, and merges organic facies and is spin-dried for obtaining (R)-1-
Phenyl-1-hydroxyl-2-methanesulfonic acid base-ethane.
The high-efficiency synthesis method of Mirabegron the most according to claim 1, it is characterised in that the concrete synthesis of step (3)
Process is: in reaction vessel by 20g p-aminophenyl ethamine, 32g (R)-1-phenyl-1-hydroxyl-2-methanesulfonic acid base-ethane and
44g base catalyst triethylamine joins in 300mL toluene, is heated to 100 DEG C of reaction 15h, complete through TLC monitoring raw material reaction
Entirely, reactant liquor is cooled to-5 DEG C, has a large amount of solid to separate out, and sucking filtration solid also washs with cold toluene solution, and filter cake obtains after drying
(R)-2-((4-aminophenethyl amino)-1-phenethanol.
The high-efficiency synthesis method of Mirabegron the most according to claim 1, it is characterised in that specifically synthesizing of step (4)
Cheng Wei: in equipped with the reaction vessel of water knockout drum, 32.5g ethyl acetoacetate is joined in 300mL hexamethylene, add 20g
Pyrrolidine and 0.5g mono-are hydrated p-methyl benzenesulfonic acid, and temperature rising reflux, also except water, is cooled to room temperature after reaction 5h, filtering reacting liquid,
Steam the hexamethylene in filtrate and pyrrolidine, the product after obtained distillation is joined in 500mL anhydrous pyridine, adds
16g elemental sulfur, reaction temperature is set as 0 DEG C, and 50mL is dissolved with the pyridine solution of 21g cyanamide in dropping, is warming up to 90 DEG C after dripping
Reaction 60min, TLC monitoring raw material reaction is complete, is cooled to room temperature, has a large amount of solid to separate out, sucking filtration reactant liquor, filter cake ether
Washing post-drying obtains flaxen product thiazolamine-4-ethyl acetate.
The high-efficiency synthesis method of Mirabegron the most according to claim 1, it is characterised in that the concrete synthesis of step (5)
Process is: by 20g (R)-2-((4-aminophenethyl amino)-1-phenethanol, 16g thiazolamine-4-in reaction vessel
Ethyl acetate and 14g Feldalat KM join in 300mL DMF, and room temperature reaction 10h, TLC monitor raw material reaction
Completely, in reactant liquor, add 600mL saturated common salt aqueous solution washing reaction liquid, then with the dichloromethane extractive reaction of 300mL
Liquid three times, merges organic facies, then uses 200mL distilled water wash, and organic facies is spin-dried for obtaining product Mirabegron.
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| 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 |
| 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 |
| 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 |
| CN110117263A (en) * | 2019-06-11 | 2019-08-13 | 湖南中医药大学 | 2- amino -5- acyl group thiazole and its synthetic method |
| CN110862359A (en) * | 2019-11-19 | 2020-03-06 | 苏州永健生物医药有限公司 | Synthesis method of mirabegron |
| CN110862359B (en) * | 2019-11-19 | 2022-04-19 | 苏州永健生物医药有限公司 | Synthesis method of mirabegron |
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