CN109456277A - A kind of preparation method of Mirabegron - Google Patents
A kind of preparation method of Mirabegron Download PDFInfo
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- CN109456277A CN109456277A CN201811269400.7A CN201811269400A CN109456277A CN 109456277 A CN109456277 A CN 109456277A CN 201811269400 A CN201811269400 A CN 201811269400A CN 109456277 A CN109456277 A CN 109456277A
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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
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Abstract
The invention discloses a kind of preparation methods of Mirabegron, it is related to field of medicine preparing technology, the following steps are included: R-MA and p-nitrophenyl ethamine occur at high temperature it is amide condensed react, obtain intermediate (R) -2- hydroxy-n-(4- nitrophenethyl) -2- phenyl-acetamides;Again through diisobutyl aluminium hydride reducing amide carbonyl, intermediate (R) -2- ((4- nitrophenethyl) amino) -1- phenylethanol hydrochloride is obtained;Again through ammonium formate-Pd/C reduction system reducing nitro, intermediate (R) -2- ((4- aminophenethyl) amino) -1- phenylethanol is obtained;Condensation reaction finally occurs with aminothiazole acid, obtains Mirabegron.The Mirabegron purity that the present invention is prepared is good, high income, and synthetic line step is few, mild condition is controllable, easy to operate, at low cost, be suitble to industrialized production, has broad prospects and industrial application value.
Description
Technical field
The present invention relates to field of medicine preparing technology more particularly to a kind of preparation methods of Mirabegron.
Background technique
Mirabegron be by Japanese Astellas pharmaceuticals (Astellas) research and develop, Yamanouchi Pharmaceutical Co., Ltd in
On October 17th, 1997, the compound patent in Japanese publication Mirabegron, and protected preparation method, at present
Patent protection is applied in multiple countries and regions such as the U.S., Europe and China, on September 16th, 2011, Mirabegron is in day
This list marketing, in June, 2012 list through U.S. FDA approval in the U.S..As first for treating overactive bladder
Orally active 3 adrenoceptor agonists class drug of β, the successful listing of Mirabegron have been filled up beta-2 adrenoceptor and have been swashed
Dynamic blank of the agent in terms for the treatment of overactive bladder.
Presently disclosed synthetic route mainly has several following:
Synthetic route one: patent WO9920607A1 reports a kind of using R- styrene oxide as the synthesis side of starting material
Method, the route p-nitrophenyl ethamine and R- styrene oxide elder generation ring-opening reaction, then secondary amine is protected with protective agent, using palladium charcoal
Catalysis reduction, is most condensed afterwards and deprotection obtains Mirabegron.
The route is the earliest synthetic route about Mirabegron.The route needs multistep to carry out column chromatography for separation, step
Length, yield are low, at high cost, it is difficult to realize industrialized production.
Synthetic route two: patent WO2015044965A1 reports a kind of synthetic method of Mirabegron, with R-MA
For starting material, successively warp is condensed with p-nitrophenyl ethylamine hydrochloride, borine-Tetrahydrofuran System reducing amide carbonyl, palladium charcoal
Catalysis reduction nitro, is finally condensed to yield Mirabegron with aminothiazole acid.
Only four-step reaction obtains Mirabegron to the route, and seeming is the industrialized route with bright prospects, still
Reaction has used expensive condensation reagent, has used the borine that toxicity is big and risk is high, has used condensation reagent twice
EDCl, cost are excessively high, it is difficult to realize industrialization large-scale production.
Synthetic route three: Chinese patent CN103232352A reports the synthesis that an equal amido phenenyl alcohol is starting material
Route, the route successively through amido protecting, alcohol oxidation, condensation, reduction, deprotection, are finally condensed to yield with aminothiazole acid
Mirabegron.
The route is completely new route, but since route oxidation has used the potassium permanganate and starting material of high pollution
It is not easy to obtain and be difficult to realize industrialized production.
By above-mentioned summary it is found that at present about the synthesis of Mirabegron or because synthetic route it is too long, yield it is low or because
To use expensive reagent cost height, or use to be difficult to the starting material obtained and be difficult to realize industrialized production, therefore develop
Raw material is cheap and easy to get, reaction step is few, and the synthetic route of Mirabegron at low cost has broad prospects.
Summary of the invention
Technical problems based on background technology, the invention proposes a kind of preparation method of Mirabegron, starting is former
Expect cheap and easy to get, reaction condition is controllable, and synthetic route step is few, at low cost, and the Mirabegron purity being prepared is good, yield
It is high.
A kind of preparation method of Mirabegron proposed by the present invention, synthetic route are as follows:
The following steps are included:
S1, R-MA (formula II) and p-nitrophenyl ethamine occur at high temperature it is amide condensed react, obtain intermediate
(R) -2- hydroxy-n-(4- nitrophenethyl) -2- phenyl-acetamides (formula III);
S2, intermediate (R) -2- hydroxy-n-(4- nitrophenethyl) -2- phenyl-acetamides (formula III) are hydrogenated through diisobutyl
Aluminium reducing amidocarbonylation obtains intermediate (R) -2- ((4- nitrophenethyl) amino) -1- phenylethanol hydrochloride (formula IV);
S3, intermediate (R) -2- ((4- nitrophenethyl) amino) -1- phenylethanol hydrochloride (formula IV) are through ammonium formate -
Pd/C reduction system reducing nitro obtains intermediate (R) -2- ((4- aminophenethyl) amino) -1- phenylethanol (formula V);
S4, intermediate (R) -2- ((4- aminophenethyl) amino) -1- phenylethanol (formula V) and aminothiazole acid are sent out
Raw condensation reaction, obtains Mirabegron (formula I).
Preferably, in S1, the molar ratio of R-MA and p-nitrophenyl ethamine is 1-2:1, preferably 1.2:1;Preferably, acyl
The reaction temperature of amine condensation reaction is 140-160 DEG C, reaction time 7-10h.
Preferably, in S1, the solvent of amide condensed reaction is dimethylbenzene.
Preferably, in S2, intermediate (R) -2- hydroxy-n-(4- nitrophenethyl) -2- phenyl-acetamides and diisobutyl
The molar ratio of aluminum hydride is 1:1-2, preferably 1:1.2;Preferably, the reaction temperature of amidocarbonylation reduction reaction is -78-30 DEG C,
Reaction time is 1-5h, and preferable reaction temperature is 0-10 DEG C, reaction time 2h.
Preferably, in S2, the solvent of amidocarbonylation reduction reaction is toluene, methylene chloride, tetrahydrofuran, one in ether
Kind or more than one, preferred tetrahydrofuran.
Preferably, in S3, the temperature of nitro-reduction reaction is 10-65 DEG C, reaction time 2-8h, and preferable reaction temperature is
50 DEG C, reaction time 6h.
Preferably, in S4, intermediate (R) -2- ((4- aminophenethyl) amino) -1- phenylethanol and aminothiazole acid
The molar ratio that condensation reaction occurs is 1:1-2;Preferably, reaction time 5-7h, preferably 6h.
Preferably, in S4, the condensation reagent of condensation reaction is 4-dimethylaminopyridine.
The invention also provides a kind of Mirabegrons prepared using the above method.
The utility model has the advantages that used raw material is cheap and easy to get the invention discloses a kind of preparation method of Mirabegron, rise
Beginning raw material mandelic acid and the reaction of p-nitrophenyl ethamine are using dimethylbenzene as solvent directly progress condensation reaction under the high temperature conditions, nothing
Condensation reagent need to be added, the condensation reagent for needing addition expensive in traditional preparation methods is avoided;Amido carboxyl reduction reaction uses
Diisobutyl aluminium hydride reduction method, go back original reagent is cheap and easy to get, relatively environment-friendly, avoids conventional method and uses the toxicity such as borine
Go back original reagent that is high, having explosion risk;Nitro-reduction reaction uses ammonium formate method, compares and carries out reduction safety using hydrogen
Controllably;Condensation reaction with aminothiazole acid uses cheap DMAP catalyzing and condensing, at low cost, high income.Present invention preparation
Obtained Mirabegron purity is good, high income, and synthetic line step is few, mild condition is controllable, easy to operate, at low cost, suitable
Industrialized production, has broad prospects and industrial application value.
Specific embodiment
Embodiment
A kind of preparation method of Mirabegron proposed by the present invention, synthetic route are as follows:
The following steps are included:
S1, R-MA (formula II) and p-nitrophenyl ethamine occur at high temperature it is amide condensed react, obtain intermediate
(R) -2- hydroxy-n-(4- nitrophenethyl) -2- phenyl-acetamides (formula III);
S2, intermediate (R) -2- hydroxy-n-(4- nitrophenethyl) -2- phenyl-acetamides (formula III) are hydrogenated through diisobutyl
Aluminium reducing amidocarbonylation obtains intermediate (R) -2- ((4- nitrophenethyl) amino) -1- phenylethanol hydrochloride (formula IV);
S3, intermediate (R) -2- ((4- nitrophenethyl) amino) -1- phenylethanol hydrochloride (formula IV) are through ammonium formate -
Pd/C reduction system reducing nitro obtains intermediate (R) -2- ((4- aminophenethyl) amino) -1- phenylethanol (formula V);
S4, intermediate (R) -2- ((4- aminophenethyl) amino) -1- phenylethanol (formula V) and aminothiazole acid are sent out
Raw condensation reaction, obtains Mirabegron (formula I).
It should be noted that in above-mentioned steps S1-S4 simultaneously can be added it is other for collect product, improve yield,
The additional step of product purity, removal impurity etc. is improved, such as is filtered, washed, extracts, purifying, drying common supplementary means.
In the following, technical solution of the present invention is described in detail by specific embodiment.
Embodiment 1
The synthesis of S1, intermediate (R) -2- hydroxy-n-(4- nitrophenethyl) -2- phenyl-acetamides
Sequentially added in four mouthfuls of reaction flasks of 3000mL participate in reaction p-nitrophenyl ethamine 273g (1.64mol,
1.0eq), (R)-mandelic acid 250g (1.64mol, 1.0eq), dimethylbenzene 1500mL (mandelic acid V/m be 6) rise under nitrogen protection
Temperature to 140 DEG C flow back, insulation reaction 7 hours, sampling HPLC monitoring reaction progress, raw material p-nitrophenyl ethamine fully reacting,
Stirring condition decline warms to room temperature, filter, obtained solid methylene chloride dissolved clarification, respectively 5% dilute hydrochloric acid through 500mL*2 and
5% sodium hydroxide of 500mL*2 washs, and organic phase is dried over anhydrous sodium sulfate, and methylene chloride is removed under reduced pressure, after drying
To product (R) -2- hydroxy-n-(4- nitrophenethyl) -2- phenyl-acetamides about 429g, yield 87.2%, purity 99.2%.
The synthesis of S2, intermediate (R) -2- ((4- nitrophenethyl) amino) -1- phenylethanol hydrochloride
Intermediate (R) -2- hydroxy-n-(4- nitrophenethyl) -2- phenyl-acetamides are sequentially added in four mouthfuls of reaction flasks
400g (1.33mol, 1.0eq), toluene 800mL, ether 800mL are cooled to -78 DEG C under nitrogen protection, 1.0M (first are slowly added dropwise
Benzene solvent) diisobutyl aluminium hydride 1330mL (1.33mol, 1.0eq), be added dropwise process control reaction temperature be not higher than -20
DEG C, insulation reaction 1 hour, the process of HPLC monitoring reaction, will be above-mentioned anti-to raw material fully reacting at -78 DEG C after being added dropwise
It answers liquid to be poured slowly into the dilute hydrochloric acid of 3000mL 5%, then adjusts pH to 12 or so through 10% sodium hydroxide.Through 2000mL*3
Ethyl acetate extraction, anhydrous sodium sulfate is dry, is concentrated to give grease, and the isopropanol dissolution of 400mL is added 50mL concentrated hydrochloric acid, 0
DEG C crystallization is stayed overnight, and has a large amount of light yellow solids to be precipitated, and product is through filtering, dry off-white powder intermediate (R) -2- ((4- nitre
Base phenethyl) amino) -1- phenylethanol hydrochloride 343g, yield 80.3%, purity 98.2%.
The synthesis of S3, intermediate (R) -2- ((4- aminophenethyl) amino) -1- phenylethanol
Intermediate (R) -2- ((4- nitrophenethyl) ammonia for participating in reaction is once added in the four-hole boiling flask of 5000mL
Base) -1- phenylethanol hydrochloride 322g (1.0mol, 1.0eq), methanol 2800mL, ammonium formate 220g (3.5mol, 3.5eq),
4% Pd/C about 13g (0.04meq) is warming up to 10 DEG C and reacts 2 hours, and HPLC monitoring reaction conversions are complete, filtering, and filtrate is dense
It is reduced to dry.Water 1500mL is added into the residue after concentration, 10% sodium hydroxide adjusts pH to 10, there are a large amount of white solids to analyse
Out, product is filtered, dries to obtain off-white powder intermediate (R) -2- ((4- aminophenethyl) amino) -1- phenylethanol
229g, yield 89.5%, purity 98.1%.
The synthesis of S4, Mirabegron
In a kettle, intermediate (R) -2- ((4- aminophenethyl) amino) -1- phenylethanol 220g is added
(0.86mol, 1.0eq), aminothiazole acid 136g (0.86mol, 1.0eq) sequentially add concentrated hydrochloric acid under mechanical stirring
Reaction 5 hours, 10% sodium hydroxide tune pH to 12 or so is stirred at room temperature in 100mL, DMAP 52g (0.43mol, 0.5eq), greatly
It measures solid to be precipitated, filters to obtain off-white powder, the recrystallisation from isopropanol through 800ml obtains white solid Mirabegron 253g, yield
74.4%, purity 99.5%.
Embodiment 2
The synthesis of S1, intermediate (R) -2- hydroxy-n-(4- nitrophenethyl) -2- phenyl-acetamides
Sequentially added in four mouthfuls of reaction flasks of 3000mL participate in reaction p-nitrophenyl ethamine 273g (1.64mol,
1.0eq), (R)-mandelic acid 499g (3.28mol, 2.0eq), dimethylbenzene 1750mL (mandelic acid V/m be 3.5), under nitrogen protection
160 DEG C of reflux are warming up to, insulation reaction 10 hours, the progress of sampling HPLC monitoring reaction, raw material p-nitrophenyl ethamine reacted
Entirely, stirring condition decline warms to room temperature, and filters, obtained solid methylene chloride dissolved clarification, respectively 5% dilute hydrochloric acid through 500mL*2
Sodium hydroxide with the 5% of 500mL*2 washs, and organic phase is dried over anhydrous sodium sulfate, and methylene chloride is removed under reduced pressure, after drying
Obtain product (R) -2- hydroxy-n-(4- nitrophenethyl) -2- phenyl-acetamides about 450g, yield 91.5%, purity 99.3%.
The synthesis of S2, intermediate (R) -2- ((4- nitrophenethyl) amino) -1- phenylethanol hydrochloride
Intermediate (R) -2- hydroxy-n-(4- nitrophenethyl) -2- phenyl-acetamides are sequentially added in four mouthfuls of reaction flasks
400g (1.33mol, 1.0eq), methylene chloride 1800mL are cooled to 30 DEG C under nitrogen protection, and 1.0M is slowly added dropwise, and (toluene is molten
Agent) diisobutyl aluminium hydride 2660mL (2.66mol, 2.0eq), be added dropwise process control reaction temperature be not higher than 30 DEG C, drop
Insulation reaction 5 hours, the process of HPLC monitoring reaction delay above-mentioned reaction solution to raw material fully reacting at 30 DEG C after adding
Slowly it pours into the dilute hydrochloric acid of 3000mL 5%, then adjusts pH to 12 or so through 10% sodium hydroxide.Acetic acid through 2000mL*3
Ethyl ester extraction, anhydrous sodium sulfate is dry, is concentrated to give grease, and 50mL concentrated hydrochloric acid, 0 DEG C of crystallization is added in the isopropanol dissolution of 400mL
Overnight, a large amount of light yellow solids are precipitated, product is through filtering, dry off-white powder intermediate (R) -2- ((4- nitrobenzene second
Base) amino) -1- phenylethanol hydrochloride 386g, yield 90.4%, purity 98.0%.
The synthesis of S3, intermediate (R) -2- ((4- aminophenethyl) amino) -1- phenylethanol
Intermediate (R) -2- ((4- nitrophenethyl) ammonia for participating in reaction is once added in the four-hole boiling flask of 5000mL
Base) -1- phenylethanol hydrochloride 322g (1.0mol, 1.0eq), methanol 3000mL, ammonium formate 378g (6.0mol, 6.0eq),
6% Pd/C about 19g (0.06meq) is warming up to 65 DEG C and reacts 8 hours, and HPLC monitoring reaction conversions are complete, filtering, and filtrate is dense
It is reduced to dry.Water 1500mL is added into the residue after concentration, 10% sodium hydroxide adjusts pH to 10, there are a large amount of white solids to analyse
Out, product is filtered, dries to obtain off-white powder intermediate (R) -2- ((4- aminophenethyl) amino) -1- phenylethanol
240g, yield 93.8%, purity 98.6%.
The synthesis of S4, Mirabegron
In a kettle, intermediate (R) -2- ((4- aminophenethyl) amino) -1- phenylethanol 220g is added
(0.86mol, 1.0eq), aminothiazole acid 272g (1.72mol, 2.0eq) sequentially add concentrated hydrochloric acid under mechanical stirring
Reaction 7 hours, 10% sodium hydroxide tune pH to 12 or so is stirred at room temperature in 100mL, DMAP 72g (0.60mol, 0.7eq), greatly
It measures solid to be precipitated, filters to obtain off-white powder, the recrystallisation from isopropanol through 800ml obtains white solid Mirabegron 266g, yield
78.2%, purity 99.2%.
Embodiment 3
The synthesis of S1, intermediate (R) -2- hydroxy-n-(4- nitrophenethyl) -2- phenyl-acetamides
Sequentially added in four mouthfuls of reaction flasks of 3000mL participate in reaction p-nitrophenyl ethamine 273g (1.64mol,
1.0eq), (R)-mandelic acid 375g (2.46mol, 1.5eq), dimethylbenzene 1875mL (mandelic acid V/m be 5) rise under nitrogen protection
Temperature to 150 DEG C flow back, insulation reaction 9 hours, sampling HPLC monitoring reaction progress, raw material p-nitrophenyl ethamine fully reacting,
Stirring condition decline warms to room temperature, filter, obtained solid methylene chloride dissolved clarification, respectively 5% dilute hydrochloric acid through 500mL*2 and
5% sodium hydroxide of 500mL*2 washs, and organic phase is dried over anhydrous sodium sulfate, and methylene chloride is removed under reduced pressure, after drying
To product (R) -2- hydroxy-n-(4- nitrophenethyl) -2- phenyl-acetamides about 454g, yield 92.3%, purity 99.2%.
The synthesis of S2, intermediate (R) -2- ((4- nitrophenethyl) amino) -1- phenylethanol hydrochloride
Intermediate (R) -2- hydroxy-n-(4- nitrophenethyl) -2- phenyl-acetamides are sequentially added in four mouthfuls of reaction flasks
400g (1.33mol, 1.0eq), tetrahydrofuran 2000mL are cooled to 10 DEG C under nitrogen protection, and 1.0M is slowly added dropwise, and (toluene is molten
Agent) diisobutyl aluminium hydride 2000mL (2.0mol, 1.5eq), be added dropwise process control reaction temperature be not higher than 20 DEG C, be added dropwise
After at 10 DEG C insulation reaction 3 hours, HPLC monitoring reaction process to raw material fully reacting, above-mentioned reaction solution is slow
It pours into the dilute hydrochloric acid of 3000mL 5%, then adjusts pH to 12 or so through 10% sodium hydroxide.Acetic acid second through 2000mL*3
Ester extraction, anhydrous sodium sulfate is dry, is concentrated to give grease, and 50mL concentrated hydrochloric acid, 0 DEG C of crystallization mistake is added in the isopropanol dissolution of 400mL
Night has a large amount of light yellow solids to be precipitated, and product is through filtering, dry off-white powder intermediate (R) -2- ((4- nitrobenzene second
Base) amino) -1- phenylethanol hydrochloride 390g, yield 91.3%, purity 98.5%.
The synthesis of S3, intermediate (R) -2- ((4- aminophenethyl) amino) -1- phenylethanol
Intermediate (R) -2- ((4- nitrophenethyl) ammonia for participating in reaction is once added in the four-hole boiling flask of 5000mL
Base) -1- phenylethanol hydrochloride 322g (1.0mol, 1.0eq), methanol 3200mL, ammonium formate 346g (5.5mol, 5.5eq),
5% Pd/C about 16g (0.05meq) is warming up to 40 DEG C and reacts 5 hours, and HPLC monitoring reaction conversions are complete, filtering, and filtrate is dense
It is reduced to dry.Water 1500mL is added into the residue after concentration, 10% sodium hydroxide adjusts pH to 10, there are a large amount of white solids to analyse
Out, product is filtered, dries to obtain off-white powder intermediate (R) -2- ((4- aminophenethyl) amino) -1- phenylethanol
240g, yield 93.8%, purity 98.6%.
The synthesis of S4, Mirabegron
In a kettle, intermediate (R) -2- ((4- aminophenethyl) amino) -1- phenylethanol 220g is added
(0.86mol, 1.0eq), aminothiazole acid 204g (1.29mol, 1.5eq) sequentially add concentrated hydrochloric acid under mechanical stirring
Reaction 6 hours, 10% sodium hydroxide tune pH to 12 or so is stirred at room temperature in 100mL, DMAP 52g (0.43mol, 0.5eq), greatly
It measures solid to be precipitated, filters to obtain off-white powder, the recrystallisation from isopropanol through 800ml obtains white solid Mirabegron 271g, yield
79.7%, purity 99.0%.
Embodiment 4
The synthesis of S1, intermediate (R) -2- hydroxy-n-(4- nitrophenethyl) -2- phenyl-acetamides
Sequentially added in four mouthfuls of reaction flasks of 3000mL participate in reaction p-nitrophenyl ethamine 273g (1.64mol,
1.0eq), (R)-mandelic acid 300g (1.97mol, 1.2eq), dimethylbenzene 1500mL (mandelic acid V/m be 5) rise under nitrogen protection
Temperature to 140 DEG C flow back, insulation reaction 8 hours, sampling HPLC monitoring reaction progress, raw material p-nitrophenyl ethamine fully reacting,
Stirring condition decline warms to room temperature, filter, obtained solid methylene chloride dissolved clarification, respectively 5% dilute hydrochloric acid through 500mL*2 and
5% sodium hydroxide of 500mL*2 washs, and organic phase is dried over anhydrous sodium sulfate, and methylene chloride is removed under reduced pressure, after drying
To product (R) -2- hydroxy-n-(4- nitrophenethyl) -2- phenyl-acetamides about 453g, yield 92.1%, purity 99.4%.
The synthesis of S2, intermediate (R) -2- ((4- nitrophenethyl) amino) -1- phenylethanol hydrochloride
Intermediate (R) -2- hydroxy-n-(4- nitrophenethyl) -2- phenyl is sequentially added in four mouthfuls of reaction flasks of 5000mL
Acetamide 400g (1.33mol, 1.0eq), tetrahydrofuran 2000mL are cooled to 0 DEG C under nitrogen protection, 1.0M (first are slowly added dropwise
Benzene solvent) diisobutyl aluminium hydride 1600mL (1.6mol, 1.2eq), be added dropwise process control reaction temperature be not higher than 10 DEG C,
Insulation reaction 2 hours, HPLC monitor the process of reaction to raw material fully reacting, by above-mentioned reaction solution at 0 DEG C after being added dropwise
It is poured slowly into the dilute hydrochloric acid of 3000mL 5%, then adjusts pH to 12 or so through 10% sodium hydroxide.Second through 2000mL*3
Acetoacetic ester extraction, anhydrous sodium sulfate is dry, is concentrated to give grease, and 50mL concentrated hydrochloric acid, 0 DEG C of analysis is added in the isopropanol dissolution of 400mL
Crystalline substance overnight, has a large amount of light yellow solids to be precipitated, and product is through filtering, dry off-white powder intermediate (R) -2- ((4- nitrobenzene
Ethyl) amino) -1- phenylethanol hydrochloride 389g, yield 91.1%, purity 98.5%.
The synthesis of S3, intermediate (R) -2- ((4- aminophenethyl) amino) -1- phenylethanol
Intermediate (R) -2- ((4- nitrophenethyl) ammonia for participating in reaction is once added in the four-hole boiling flask of 5000mL
Base) -1- phenylethanol hydrochloride 322g (1.0mol, 1.0eq), methanol 3200mL, ammonium formate 315g (5.0mol, 5.0eq),
5% Pd/C about 16g (0.05meq) is warming up to 50 DEG C and reacts 6 hours, and HPLC monitoring reaction conversions are complete, filtering, and filtrate is dense
It is reduced to dry.Water 1500mL is added into the residue after concentration, 10% sodium hydroxide adjusts pH to 10, there are a large amount of white solids to analyse
Out, product is filtered, dries to obtain off-white powder intermediate (R) -2- ((4- aminophenethyl) amino) -1- phenylethanol
241g, yield 94.1%, purity 98.6%.
The synthesis of S4, Mirabegron
In four mouthfuls of reaction flasks of 5000mL, in a kettle, intermediate (R) -2- ((4- aminophenethyl) ammonia is added
Base) -1- phenylethanol 220g (0.86mol, 1.0eq), aminothiazole acid 136g (0.86mol, 1.0eq), under mechanical stirring
Concentrated hydrochloric acid 100mL is sequentially added, reaction 6 hours, 10% sodium hydroxide tune is stirred at room temperature in DMAP 52g (0.43mol, 0.5eq)
PH to 12 or so, a large amount of solids are precipitated, and filter to obtain off-white powder, and the recrystallisation from isopropanol through 800ml obtains the drawing of white solid rice
The grand 269g yield 79.1% of shellfish, purity 99.6%.
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto,
Anyone skilled in the art in the technical scope disclosed by the present invention, according to the technique and scheme of the present invention and its
Inventive concept is subject to equivalent substitution or change, should be covered by the protection scope of the present invention.
Claims (9)
1. a kind of preparation method of Mirabegron, which is characterized in that synthetic route is as follows:
The following steps are included:
S1, R-MA (formula II) and p-nitrophenyl ethamine occur at high temperature it is amide condensed react, obtain intermediate (R) -2-
Hydroxy-n-(4- nitrophenethyl) -2- phenyl-acetamides (formula III);
S2, intermediate (R) -2- hydroxy-n-(4- nitrophenethyl) -2- phenyl-acetamides (formula III) through diisobutyl aluminium hydride also
Former amidocarbonylation obtains intermediate (R) -2- ((4- nitrophenethyl) amino) -1- phenylethanol hydrochloride (formula IV);
S3, intermediate (R) -2- ((4- nitrophenethyl) amino) -1- phenylethanol hydrochloride (formula IV) through ammonium formate-Pd/C also
Former reduction system nitro obtains intermediate (R) -2- ((4- aminophenethyl) amino) -1- phenylethanol (formula V);
S4, intermediate (R) -2- ((4- aminophenethyl) amino) -1- phenylethanol (formula V) contract with aminothiazole acid
Reaction is closed, Mirabegron (formula I) is obtained.
2. the preparation method of Mirabegron according to claim 1, which is characterized in that in S1, R-MA and to nitro
The molar ratio of phenyl ethylamine is 1-2:1, preferably 1.2:1;Preferably, the reaction temperature of amide condensed reaction is 140-160 DEG C, reaction
Time is 7-10h.
3. the preparation method of Mirabegron according to claim 1 or 2, which is characterized in that in S1, amide condensed reaction
Solvent is dimethylbenzene.
4. the preparation method of Mirabegron according to claim 1-3, which is characterized in that in S2, intermediate
(R) molar ratio of -2- hydroxy-n-(4- nitrophenethyl) -2- phenyl-acetamides and diisobutyl aluminium hydride is 1:1-2, preferably
1:1.2;Preferably, the reaction temperature of amidocarbonylation reduction reaction is -78-30 DEG C, reaction time 1-5h, preferable reaction temperature
It is 0-10 DEG C, reaction time 2h.
5. the preparation method of Mirabegron according to claim 1-4, which is characterized in that in S2, amidocarbonylation
The solvent of reduction reaction be one of toluene, methylene chloride, tetrahydrofuran, ether or more than one, preferred tetrahydrofuran.
6. the preparation method of Mirabegron according to claim 1-5, which is characterized in that in S3, nitro reduction
The temperature of reaction is 10-65 DEG C, reaction time 2-8h, and preferable reaction temperature is 50 DEG C, reaction time 6h.
7. the preparation method of Mirabegron according to claim 1-6, which is characterized in that in S4, intermediate
(R) it is 1:1- that the molar ratio of condensation reaction, which occurs, for -2- ((4- aminophenethyl) amino) -1- phenylethanol and aminothiazole acid
2;Preferably, reaction time 5-7h, preferably 6h.
8. the preparation method of Mirabegron according to claim 1-7, which is characterized in that in S4, condensation reaction
Condensation reagent be 4-dimethylaminopyridine.
9. a kind of Mirabegron is prepared by any one of claim 1-8 the method.
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