CN103193730A - Synthesis method of mirabegron - Google Patents
Synthesis method of mirabegron Download PDFInfo
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- CN103193730A CN103193730A CN2013101327228A CN201310132722A CN103193730A CN 103193730 A CN103193730 A CN 103193730A CN 2013101327228 A CN2013101327228 A CN 2013101327228A CN 201310132722 A CN201310132722 A CN 201310132722A CN 103193730 A CN103193730 A CN 103193730A
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Abstract
The invention provides a synthesis method of mirabegron and belongs to the technical field of medicine synthesis. The synthesis method solves the problems that the synthesis method of the mirabegron is low in product yield and is not suitable for large-scale industrialized production in the prior art. The synthesis method comprises the following steps: 1) amino protection: reacting 2-aminothiazole-5-acetic acid with an amino protective agent to obtain a mirabegron intermediate product A; 2) condensation reaction: performing condensation reaction on the mirabegron intermediate product A and 4-amino phenethyl alcohol to obtain a mirabegron intermediate product B; 3) oxidation reaction: performing oxidation reaction on the mirabegron intermediate product B and an oxidant to obtain a mirabegron intermediate product C; and 4) reductive amination and protecting group removal: reacting the mirabegron intermediate product C with (R)-2-amino-1-phenethyl alcohol and removing the protecting group from the mirabegron intermediate product C to obtain the mirabegron. The synthesis method of the mirabegron is low in cost, high in product yield and suitable for large-scale industrialized production.
Description
Technical field
The present invention relates to a kind of synthetic method of Mirabegron, belong to the chemicals synthesis technical field.
Background technology
Mirabegron (Myrbetriq, Mirabegron) is FDA (Food and Drug Adminstration) (FDA) ratified and be used for the treatment of the overactive bladder (OAB) of mixing urge incontinence, urgent urination, frequent micturition symptom on June 28th, 2012 medicine.
The English name of Mirabegron: 2-Amino-N-[4-[2-[[(2R)-2-hydroxy-2-phe nylethyl] amino] ethyl] phenyl]-4-thiazoleacetamide, chemical structural formula is:
Synthetic method for Mirabegron in the prior art mainly contains following several:
As Europatent (publication number: EP1440969) with Europatent (publication number: EP1559427) relate to the synthetic method of Mirabegron, the synthetic route of described method is as follows:
Or
Yet there is following problem in above-mentioned synthetic method:
One, these two kinds of synthetic methods have been used expensive borane-tetrahydrofuran solution, 1 simultaneously, 3-dimethyl-2-imidazolone, palladium charcoal, and 1,3-dimethyl-2-imidazolone and borane-tetrahydrofuran solution are not easy to recovery of applied, cause raw material and aftertreatment cost to increase, be unfavorable for large-scale industrialization production.
Two, the first step of these two kinds of synthetic methods need be that solvent carries out recrystallization with virose toluene; Be liquid under borane-tetrahydrofuran solution normal temperature that second step used, foul smelling is to wet responsive, meeting water reacts violent and emits inflammable gas, can form explosive superoxide, and eyes, respiratory system, skin are had stimulation, all unfavorable to operator and ecotope.
Three, this two kinds of synthetic method the first steps reaction afterreaction liquid that finishes need pass through washing, pickling, alkali cleaning, the salt water washing, recrystallization just can obtain pure product, post-processing step is loaded down with trivial details and be easy to generate a large amount of three wastes, 1 of the high boiling point (boiling point is 224-226 ° of C) that used the cost height in a large number simultaneously, is difficult to remove, 3-dimethyl-2-imidazolone reagent is so this synthetic method yield is low.
Summary of the invention
The present invention is directed to the existing in prior technology defective, provide a kind of cost low, the product yield height, safe and simple Mirabegron synthetic method makes the synthetic method of this Mirabegron be fit to large-scale industrial production.
Above-mentioned purpose of the present invention can realize by following technical proposal: a kind of synthetic method of Mirabegron, and this method may further comprise the steps:
A, amido protecting: be raw material with thiazolamine-5-acetic acid, itself and amino protecting agent are reacted in solvent, obtain Mirabegron intermediate product A.
B, condensation reaction: the above-mentioned Mirabegron intermediate product A that makes is carried out condensation reaction with 4-amino-benzene ethanol under the effect of condensing agent and acid binding agent, obtain Mirabegron intermediate product B.
C, oxidizing reaction: the above-mentioned Mirabegron intermediate product B that makes is added in the solvent carries out oxidizing reaction with oxygenant, make Mirabegron intermediate product C.
D, reduction amination be the deprotection base simultaneously: will the above-mentioned Mirabegron intermediate product C that makes under the effect of reductive agent with (R)-2-amino-1-phenylethyl alcohol reacts, and sloughs the protecting group on the Mirabegron intermediate product C simultaneously, obtains Mirabegron.
In the synthetic method of above-mentioned Mirabegron; described step a specifically comprises the steps: thiazolamine-5-acetic acid is dissolved in solvent; and the adding amino protecting agent forms reaction solution in this solvent; stirring reacts completely thiazolamine-5-acetic acid and amino protecting agent, and after question response is complete that reaction solution is concentrated, recrystallization gets Mirabegron intermediate product A.
As preferably, in step a, described amino protecting agent is one or more in carbalkoxy class amino protecting group, acyl group class amino protecting group, the alkyls amino protecting group.
Wherein, described carbalkoxy class amino protecting group is one or more in carbobenzoxy-(Cbz) (Cbz), tablet held before the breast by officials methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyl ethoxycarbonyl (Teoc), first (or second) the oxygen carbonyl.
Described acyl group class amino protecting group be phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl group (Tfa), adjacent (to) in the oil of mirbane alkylsulfonyl (Ns), pivaloyl group, benzoyl one or more.
Described alkyls amino protecting group is trityl (Trt), 2,4-dimethoxy-benzyl (Dmb), in methoxy-benzyl (PMB), the benzyl (Bn) one or more.
Further preferred, in step a, described amino protecting agent is di-tert-butyl dicarbonic acid ester.This amino protecting group steric hindrance is moderate, is easy to deprotection, in reaction, introduce and slough easy, the yield height of product, and in this reaction, can not generate by product.
As preferably, in step a, described solvent is tetrahydrofuran (THF), 1,4-dioxane, methyl alcohol, the trimethyl carbinol, acetone, ethanol, n-propyl alcohol, Virahol, N, dinethylformamide, acetonitrile, 1, one or more in 2-glycol dimethyl ether, normal hexane, methylene dichloride, the water.
Further preferred, in step a, described solvent is tetrahydrofuran (THF), methyl alcohol.Tetrahydrofuran (THF) and methyl alcohol is with respect to other solvents, and it is low to have a boiling point, and cost is low, and the aftertreatment in this reaction is simple and easy to, the yield advantages of higher.
Wherein, in step a, the mol ratio of described thiazolamine-5-acetic acid and protecting group reagent is 1:(1～3).
In the synthetic method of above-mentioned Mirabegron, described step b specifically comprises the steps:
S1, Mirabegron intermediate product A and solvent be stirred under 20-25 ℃ mix the formation mixing solutions.
S2, condensing agent is dissolved in solvent forms reaction solution, be cooled to 20-25 ℃ after reaction solution is fully dissolved 30 ℃ the time, cooled reaction solution is added drop-wise in the mixing solutions among the step S1, be stirred to and react completely.
S3,4-amino-benzene ethanol and acid binding agent are dissolved in solvent form reaction solution, be cooled to 20-25 ℃ after reaction solution fully dissolved 30 ℃ the time, cooled reaction solution is added drop-wise in the mixing solutions among the step S2,30 ℃ of insulations down, continues to be stirred to and react completely.
S4, the reaction solution after reacting completely among the step S3 is cooled to room temperature, while stirring 0 ℃ wet chemical is added drop-wise in the described reaction solution, under 0 ℃, be stirred to and separate out a large amount of white solids, again the reaction solution suction filtration is got filter cake, with filter cake washing, dry that white solid is Mirabegron intermediate product B.
As preferably, in step b, solvent described in step S1, S2, the S3 is N, dinethylformamide, methylene dichloride, acetonitrile, N, dinethylformamide, N, N-methylacetamide, trichloromethane, tetrachloromethane, 1, one or more in 2-ethylene dichloride, methyl-sulphoxide, tetrahydrofuran (THF), water, ethanol, cyclohexane, ether, methyl tertiary butyl ether, N-Methyl pyrrolidone, toluene, dimethylbenzene, chlorobenzene, the dichlorobenzene.
Further preferred, in step b, the solvent described in step S1, S2, the S3 is N, dinethylformamide.N, dinethylformamide can improve the yield of reaction, can directly reaction solution be poured into freezing wet chemical and namely separate out purity greater than 99% product in aftertreatment, and directly suction filtration can obtain the product of high yield.
As preferably, among the step S2 in step b, described condensing agent is N, N-dicarbapentaborane imidazoles, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, I-hydroxybenzotriazole, N, the N'-DIC, dicyclohexylcarbodiimide, N-hydroxyl-7-azepine benzotriazole, 3,4-dihydro-3-hydroxyl-4-oxo-1,2, the 3-phentriazine, 6-chloro-I-hydroxybenzotriazole, (7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, benzotriazole-N, N, N', N'-tetramethyl-urea hexafluorophosphate, 2-(1H-benzo trisazo-L-1-yl)-1,1,3,3-tetramethyl-urea Tetrafluoroboric acid ester, block special condensing agent, two (2-oxo-3-oxazolidinyl) inferior phosphoryl chloride, 1H-benzotriazole-1-base oxygen tripyrrole alkyl hexafluorophosphate, Vinyl chloroformate, methyl-chloroformate, methyl chloroacetate, ethyl chloroacetate, isobutyl chlorocarbonate, the propane phosphoric anhydride, woodward's reagent K, diethylchlorophosphate (C2H5O)2P(O)Cl, pivaloyl chloride, in the sulfur oxychloride one or more.
As preferably, among the step S3 in step b, described acid binding agent is N-methylmorpholine, pyridine, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, methylamine, ethamine, dimethylamine, diethylamine, Trimethylamine 99, triethylamine, tripropyl amine, Tributylamine, triamylamine, tri-n-octyl amine, n-Butyl Amine 99, TBAH, N-methylmorpholine, morpholine, N, one or more in N-diisopropylethylamine, 4-Dimethylamino pyridine, salt of wormwood, yellow soda ash, cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, the potassium hydroxide.
Further preferred, among the step S3 in step b, described acid binding agent is N-methylmorpholine.Be liquid under the N-methylmorpholine normal temperature, with the reaction solution homogeneous reaction, can improve reaction yield, and easily remove after the reaction.
Wherein, the mol ratio at the Mirabegron intermediate product A described in the step b and condensing agent is 1:(0.5～2.5).
Mol ratio at the Mirabegron intermediate product A described in the step b and acid binding agent is 1:(1～3).
Mol ratio at the Mirabegron intermediate product A described in the step b and 4-amino-benzene ethanol is 1:(1～3).
Mol ratio at the 4-amino-benzene ethanol described in the step b and acid binding agent is 1:(0.5～2).
The wet chemical of step S4 also can use the aqueous sodium carbonate with isoconcentration to substitute in step b.
In the synthetic method of above-mentioned Mirabegron; described step c specifically comprises the steps: under protection of nitrogen gas; Mirabegron intermediate product B and oxygenant joined successively form reaction solution in the solvent; reaction solution refluxed to be stirred to react completely; reaction solution after reacting completely is down to room temperature earlier; suction filtration gets filter cake and filtrate again, uses the organic solvent washing filter cake, and merging, concentrated filtrate get Mirabegron intermediate product C.
As preferably, in step c, described oxygenant is adjacent iodoxybenzene formic acid, potassium permanganate, Manganse Dioxide, Dai Si-Martin's oxygenant, 2,2, in 6,6-tetramethyl piperidine oxide compound, pyridinium chloro-chromate, clorox, oxygen, nitric acid, the aluminium sesquioxide one or more.
Further preferred, in step c, described oxygenant is adjacent iodoxybenzene formic acid.Adjacent iodoxybenzene formic acid is than other oxygenants, has to be swift in response, and aftertreatment is simple, and the high side reaction of yield is few, quantitative reaction almost, the advantage that cost is low.
As preferably, in step c, described solvent is ethyl acetate, 1,4-dioxane, trichloromethane, 1, one or more in 2-ethylene dichloride, acetone, benzene, acetonitrile, tetrahydrofuran (THF), the toluene.
Further preferred, in step c, described solvent is ethyl acetate, 1, the 2-ethylene dichloride.Ethyl acetate and 1,2-ethylene dichloride and other solvent phase ratios, cost is low, in this reaction the reaction times fast, the yield height, impurity is residual few, aftertreatment is simple.
Wherein, in step c, the mol ratio of described Mirabegron intermediate product B and oxygenant is 1:(3～4).
In the synthetic method of above-mentioned Mirabegron, described steps d specifically comprises the steps: under protection of nitrogen gas, under-3～3 ℃ condition, the Mirabegron intermediate product C that will be dissolved in solvent while stirring is added drop-wise in (R)-2-amino-1-phenylethyl alcohol and forms reaction solution, under nitrogen protection, while stirring reductive agent is added in the reaction solution, reaction solution is stirred under-3～3 ℃ reacts completely; Then reaction solution is added drop-wise to and carries out the cancellation reaction in the saturated aqueous ammonium chloride, tell organic phase after washing with water, organic phase added to be stirred in the concentrated hydrochloric acid under-2～2 ℃ condition react completely, with aqueous sodium hydroxide solution the organic phase that reacts completely is regulated pH to 10, stir the back separatory, the organic phase washing, dry, concentrate, recrystallization gets the final product Mirabegron.
Wherein the cancellation reaction can be fallen by the substance reaction that specific activity is bigger, prevents side reaction.
As preferably, in steps d, described solvent is methylene dichloride, tetrahydrofuran (THF), ethanol, ethylene dichloride, methyl alcohol, Virahol, 1, one or more in 4-dioxane, normal heptane, formic acid, toluene, acetonitrile, acetic acid, hexanaphthene, the water.
As preferably, in steps d, described reductive agent is one or more in sodium borohydride, metallic nickel, hydrogen, titanium tetrachloride, Lithium Aluminium Hydride, sodium cyanoborohydride, sodium triacetoxy borohydride, borine, the tetra isopropyl titanium.
Further preferred, in steps d, described reductive agent is sodium borohydride.Sodium borohydride is used very extensive in work is produced, and it is cheap and easy to get, and active moderate, the aftertreatment in this reaction is simple.
Wherein, in steps d, the mol ratio of described (R)-2-amino-1-phenylethyl alcohol and reductive agent is 1:(1～3).
The chemical equation of synthetic method of the present invention is as follows:
In sum, the present invention has the following advantages:
1, synthetic method of the present invention is raw material with thiazolamine cheap and easy to get-5-acetic acid, do not use expensive reagent such as palladium charcoal, do not use virose toluene yet and have dangerous borane-tetrahydrofuran (THF), not only reduced cost, also realize safely cleaning production, had the very strong market competitiveness.
2, synthetic method of the present invention is that raw material condensation again behind amido protecting, oxidation, reduction amination and deprotection base can obtain Mirabegron with thiazolamine-5-acetic acid, and production process is simple and direct, is convenient to large-scale industrial production.
3, synthetic method post-reaction treatment of the present invention is simple, and do not need to use be difficult to remove 1,3-dimethyl-2-imidazolone reagent is so the side reaction of this synthetic method is less, thereby make the product yield and the purity that finally obtain higher, and quality product is better.
Description of drawings
Fig. 1 is for adopting the liquid chromatogram of synthetic method of the present invention Mirabegron processed.
Fig. 2 is for adopting the hydrogen nuclear magnetic resonance spectrogram of synthetic method of the present invention Mirabegron processed.
Embodiment
Below be specific embodiments of the invention and by reference to the accompanying drawings, technical scheme of the present invention is further described, but the present invention be not limited to these embodiment.
Embodiment 1
Under 0 ℃ the condition, the tetrahydrofuran (THF) that 1.59g2-aminothiazole-5-acetic acid is dissolved in 50mL forms reaction solution, stirs down 3.27g(Boc)
2O is added drop-wise in the reaction solution.With reaction solution rise to stirring at room made in 12 hours thiazolamine-5-acetic acid with (Boc)
2The O reaction.After the TLC detection reaction is complete reaction solution is concentrated, get crude product, crude product gets 2.5g Mirabegron intermediate product A with the ethanol/water recrystallization.
5.16g Mirabegron intermediate product A is added to the 100mL there-necked flask is dissolved in 20mLN, in the dinethylformamide, under 20 ℃, be stirred to and mix the formation mixing solutions.With 3.24gN, the N'-carbonyl dimidazoles adds an Erlenmeyer flask and is dissolved in 10mLN, and dinethylformamide is cooled to 20 ℃ after abundant the dissolving down at 30 ℃, is added drop-wise in the above-mentioned mixing solutions again, drips to finish back stirring 1.5 to TLC and HPLC demonstration complete reaction.2.33g4-amino-benzene ethanol, 1.72gN-methylmorpholine joined successively at another Erlenmeyer flask be dissolved in 5mLN, dinethylformamide, down fully be cooled to 20 ℃ after the dissolving at 30 ℃, be added to then and be added drop-wise to there-necked flask in the constant pressure funnel of 25mL and form reaction solution.Insulation is 1 hour under 30 ℃ condition, continue to stir 1 hour complete to TLC and HPLC detection reaction.Reaction solution after reacting completely is cooled to room temperature, while stirring cooled reaction solution is poured in 0 ℃ the aqueous solution of the 150mL that is dissolved with 0.4g salt of wormwood, stir 0.5 hour down to separating out a large amount of white solids at 0 ℃.The reaction solution suction filtration is got filter cake, with 90mL water washing 4 times, dry to such an extent that white solid 4.53g is Mirabegron intermediate product B at 40 ℃ filter cake.
Under protection of nitrogen gas, the adjacent iodoxybenzene formic acid of 4.53g above-mentioned Mirabegron intermediate product B and 11.2g is added the 80mL ethyl acetate successively forms reaction solution, with reaction solution reflux stir 1 hour complete to the TLC detection reaction.Reaction solution after reacting completely is down to room temperature earlier, and suction filtration gets filter cake and filtrate again, uses 20mL ethyl acetate washing leaching cake 2 times, and merging, concentrated filtrate get Mirabegron intermediate product C.
Under protection of nitrogen gas and under 0 ℃ the temperature condition, with 5.48g(R)-2-amino-1-phenylethyl alcohol adds in the there-necked flask of 100mL, and the Mirabegron intermediate product C that will be dissolved in the 50mL methylene dichloride while stirring is added drop-wise to and forms reaction solution in the there-necked flask.Under nitrogen protection, stirred 1 hour, while stirring the 3.05g sodium borohydride is added in the reaction solution.With reaction solution 0 ℃ stir down 3 hours complete to the TLC detection reaction.The reaction solution that reacts completely is added drop-wise to carries out cancellation reaction in the 10mL saturated aqueous ammonium chloride, with 40mL water washing twice, tell organic phase.With organic phase under 0 ℃ condition, add in the 10mL vitriol oil stir 0.5 hour complete to the TLC detection reaction, 20% the aqueous sodium hydroxide solution that adds 20mL is again regulated pH to 10 with the organic phase that reacts completely, and stirs separatory after 15 minutes.Organic phase with 50mL saturated common salt water washing 1 time, is used the 10g anhydrous sodium sulfate drying earlier again, concentrates, and gets crude product and gets 15.11g final product Mirabegron with first alcohol and water recrystallization.Purity is 99.0%, chiral purity 99.0%, yield 95.4%.
Embodiment 2
Under 0 ℃ the condition, the methyl alcohol that 3.16g2-aminothiazole-5-acetic acid is dissolved in 100mL forms reaction solution, stirs down 3.375g benzyloxycarbonyl amino protective material is added drop-wise in the reaction solution.Reaction solution is risen to stirring at room made thiazolamine-5-acetic acid and the reaction of benzyloxycarbonyl amino protective material in 12 hours.After the TLC detection reaction is complete reaction solution is concentrated, get crude product, crude product gets 5.67g Mirabegron intermediate product A with the ethanol/water recrystallization.
5.67g Mirabegron intermediate product A is added to the 100mL there-necked flask is dissolved in the 20mL methylene dichloride, under 22 ℃, be stirred to and mix the formation mixing solutions.With 2.97gN, the N'-carbonyl dimidazoles adds an Erlenmeyer flask and is dissolved in the 10mL methylene dichloride, is cooled to 22 ℃ after abundant the dissolving down at 30 ℃, is added drop-wise in the above-mentioned mixing solutions again, drips to finish back stirring 1.5 to TLC and HPLC demonstration complete reaction.3.06g4-amino-benzene ethanol, 1.58g pyridine joined successively at another Erlenmeyer flask be dissolved in the 5mL methylene dichloride, fully be cooled to 22 ℃ after the dissolving down at 30 ℃, be added to then and be added drop-wise to there-necked flask in the constant pressure funnel of 25mL and form reaction solution.Insulation is 1 hour under 30 ℃ condition, continue to stir 1 hour complete to TLC and HPLC detection reaction.Reaction solution after reacting completely is cooled to room temperature, while stirring cooled reaction solution is poured in 0 ℃ the aqueous solution of the 150mL that is dissolved with 0.31g yellow soda ash, stir 0.5 hour down to separating out a large amount of white solids at 0 ℃.The reaction solution suction filtration is got filter cake, with 90mL water washing 4 times, dry to such an extent that white solid 6.1g is Mirabegron intermediate product B at 40 ℃ filter cake.
Under protection of nitrogen gas, 6.1g above-mentioned Mirabegron intermediate product B and 10.24g potassium permanganate are added 80mL1 successively, the 2-ethylene dichloride forms reaction solution, with reaction solution reflux stir 1 hour complete to the TLC detection reaction.Reaction solution after reacting completely is down to room temperature earlier, and suction filtration gets filter cake and filtrate again, uses 20mL1,2-ethylene dichloride washing leaching cake 2 times, and merging, concentrated filtrate get Mirabegron intermediate product C.
Under protection of nitrogen gas and under 0 ℃ the temperature condition, with 5.48g(R)-2-amino-1-phenylethyl alcohol adds in the there-necked flask of 250mL, and the Mirabegron intermediate product C that will be dissolved in the 60mL methylene dichloride while stirring is added drop-wise to and forms reaction solution in the there-necked flask.Under nitrogen protection, stirred 1 hour, while stirring the 5.8g metallic nickel is added in the reaction solution.With reaction solution 0 ℃ stir down 3 hours complete to the TLC detection reaction.The reaction solution that reacts completely is added drop-wise to carries out cancellation reaction in the 10mL saturated aqueous ammonium chloride, with 40mL water washing twice, tell organic phase.With organic phase under 0 ℃ condition, add in the 10mL vitriol oil stir 0.5 hour complete to the TLC detection reaction, 20% the aqueous sodium hydroxide solution that adds 20mL is again regulated pH to 10 with the organic phase that reacts completely, and stirs separatory after 15 minutes.Organic phase with 50mL saturated common salt water washing 1 time, is used the 10g anhydrous sodium sulfate drying earlier again, concentrates, and gets crude product and gets 14.5g final product Mirabegron with first alcohol and water recrystallization.Purity is 99.76%, chiral purity 99.31%, total recovery 91.55%.
Embodiment 3
Under 0 ℃ the condition, the trimethyl carbinol that 2.37g2-aminothiazole-5-acetic acid is dissolved in 80mL forms reaction solution, stirs down 5.49g trityl amino protecting agent is added drop-wise in the reaction solution.Reaction solution is risen to stirring at room made thiazolamine-5-acetic acid and the reaction of trityl amino protecting agent in 12 hours.After the TLC detection reaction is complete reaction solution is concentrated, get crude product, crude product gets 8.9g Mirabegron intermediate product A with the ethanol/water recrystallization.
8.9g Mirabegron intermediate product A is added to the 100mL there-necked flask is dissolved in the 20mL acetonitrile, under 25 ℃, be stirred to and mix the formation mixing solutions.With 5.5gN, the N'-DIC adds an Erlenmeyer flask and is dissolved in the 10mL acetonitrile, is cooled to 25 ℃ after abundant the dissolving down at 30 ℃, is added drop-wise in the above-mentioned mixing solutions again, drips to finish back stirring 1.5 to TLC and HPLC demonstration complete reaction.3.3g4-amino-benzene ethanol, 1.19g sodium methylate joined successively at another Erlenmeyer flask be dissolved in the 5mL acetonitrile, fully be cooled to 25 ℃ after the dissolving down at 30 ℃, be added to then and be added drop-wise to there-necked flask in the constant pressure funnel of 25mL and form reaction solution.Insulation is 1 hour under 30 ℃ condition, continue to stir 1 hour complete to TLC and HPLC detection reaction.Reaction solution after reacting completely is cooled to room temperature, while stirring cooled reaction solution is poured in 0 ℃ the aqueous solution of the 150mL that is dissolved with 0.4g salt of wormwood, stir 0.5 hour down to separating out a large amount of white solids at 0 ℃.The reaction solution suction filtration is got filter cake, with 90mL water washing 4 times, dry to such an extent that white solid 6.1g is Mirabegron intermediate product B at 40 ℃ filter cake.
Under protection of nitrogen gas, 6.1g above-mentioned Mirabegron intermediate product B and 2.1g Manganse Dioxide are added the 80mL trichloromethane successively form reaction solution, with reaction solution reflux stir 1 hour complete to the TLC detection reaction.Reaction solution after reacting completely is down to room temperature earlier, and suction filtration gets filter cake and filtrate again, uses 20mL trichloromethane washing leaching cake 2 times, and merging, concentrated filtrate get Mirabegron intermediate product C.
Under protection of nitrogen gas and under 0 ℃ the temperature condition, with 7.3g(R)-2-amino-1-phenylethyl alcohol adds in the there-necked flask of 250mL, and the Mirabegron intermediate product C that will be dissolved in the 50mL methylene dichloride while stirring is added drop-wise to and forms reaction solution in the there-necked flask.Under nitrogen protection, stirred 1 hour, while stirring the 4.12g sodium borohydride is added in the reaction solution.With reaction solution 0 ℃ stir down 3 hours complete to the TLC detection reaction.The reaction solution that reacts completely is added drop-wise to carries out cancellation reaction in the 10mL saturated aqueous ammonium chloride, with 40mL water washing twice, tell organic phase.With organic phase under 0 ℃ condition, add in the 10mL vitriol oil stir 0.5 hour complete to the TLC detection reaction, 20% the aqueous sodium hydroxide solution that adds 20mL is again regulated pH to 10 with the organic phase that reacts completely, and stirs separatory after 15 minutes.Organic phase with 50mL saturated common salt water washing 1 time, is used the 10g anhydrous sodium sulfate drying earlier again, concentrates, and gets crude product and gets 18.7g final product Mirabegron with first alcohol and water recrystallization.Purity is 99.33%, chiral purity 99.01%, yield 88.12%.
Extract immediately and adopt the Mirabegron sample of synthetic method preparation of the present invention to detect by liquid chromatography.
Testing conditions: instrument: Agilent 1100 high performance liquid chromatographs;
Chromatographic column: Luna C18,4.6mm * 250mm, 5 μ m;
Column temperature: 25 ℃;
Flow velocity: 1.0mL/min;
Detect wavelength: 210nm;
Sampling volume: 5ul;
Mobile phase A: acetonitrile;
Mobile phase B: 0.1% phosphate aqueous solution;
Working time: 40min.
Detect the liquid chromatogram of back sample as shown in Figure 1; Analytical results is as shown in table 1.
Table 1: the Mirabegron sample chromatogram analytical results that adopts the inventive method preparation
From Fig. 1 and table 1 as can be seen: adopt the Mirabegron purity of synthetic method preparation of the present invention higher, reach 99.77%, yield is greater than 95.4%, and quality product is better.
With adopting the Mirabegron sample of synthetic method preparation of the present invention to carry out the hydrogen nuclear magnetic resonance spectrum analysis, the results are shown in accompanying drawing 2.
Specific embodiment described herein only is that the present invention's spirit is illustrated.Those skilled in the art can make various modifications or replenish or adopt similar mode to substitute described specific embodiment, but can't depart from spirit of the present invention or surmount the defined scope of appended claims.
Although the present invention has been made detailed explanation and has quoted some specific embodiments as proof, to those skilled in the art, only otherwise leave that the spirit and scope of the present invention can be done various variations or correction is obvious.
Claims (10)
1. the synthetic method of a Mirabegron is characterized in that, this method may further comprise the steps:
A, amido protecting: be raw material with thiazolamine-5-acetic acid, itself and amino protecting agent are reacted in solvent, obtain Mirabegron intermediate product A;
B, condensation reaction: the above-mentioned Mirabegron intermediate product A that makes is carried out condensation reaction with 4-amino-benzene ethanol under the effect of condensing agent and acid binding agent, obtain Mirabegron intermediate product B;
C, oxidizing reaction: the above-mentioned Mirabegron intermediate product B that makes is added in the solvent carries out oxidizing reaction with oxygenant, make Mirabegron intermediate product C;
D, reduction amination be the deprotection base simultaneously: will the above-mentioned Mirabegron intermediate product C that makes under the effect of reductive agent with (R)-2-amino-1-phenylethyl alcohol reacts, and sloughs the protecting group on the Mirabegron intermediate product C simultaneously, obtains Mirabegron.
2. the synthetic method of Mirabegron according to claim 1; it is characterized in that; in step a; specifically comprise the steps: thiazolamine-5-acetic acid is dissolved in solvent; and the adding amino protecting agent forms reaction solution in this solvent; stirring reacts completely thiazolamine-5-acetic acid and amino protecting agent, and after question response is complete that reaction solution is concentrated, recrystallization gets Mirabegron intermediate product A.
3. the synthetic method of Mirabegron according to claim 1 and 2 is characterized in that, in step a, described amino protecting agent is one or more in carbalkoxy class amino protecting group, acyl group class amino protecting group, the alkyls amino protecting group; Wherein, described carbalkoxy class amino protecting group is one or more in carbobenzoxy-(Cbz) (Cbz), tablet held before the breast by officials methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyl ethoxycarbonyl (Teoc), first (or second) the oxygen carbonyl; Described acyl group class amino protecting group be phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl group (Tfa), adjacent (to) in the oil of mirbane alkylsulfonyl (Ns), pivaloyl group, benzoyl one or more; Described alkyls amino protecting group is trityl (Trt), 2,4-dimethoxy-benzyl (Dmb), in methoxy-benzyl (PMB), the benzyl (Bn) one or more.
4. the synthetic method of Mirabegron according to claim 1 and 2, it is characterized in that, in step a, described solvent is tetrahydrofuran (THF), 1,4-dioxane, methyl alcohol, the trimethyl carbinol, acetone, ethanol, n-propyl alcohol, Virahol, N, dinethylformamide, acetonitrile, 1, one or more in 2-glycol dimethyl ether, normal hexane, methylene dichloride, the water.
5. the synthetic method of Mirabegron according to claim 1 and 2 is characterized in that, in step b, specifically comprises the steps:
S1, Mirabegron intermediate product A and solvent be stirred under 20-25 ℃ mix the formation mixing solutions;
S2, condensing agent is dissolved in solvent forms reaction solution, be cooled to 20-25 ℃ after reaction solution is fully dissolved 30 ℃ the time, cooled reaction solution is added drop-wise in the mixing solutions among the step S1, be stirred to and react completely;
S3,4-amino-benzene ethanol and acid binding agent are dissolved in solvent form reaction solution, be cooled to 20-25 ℃ after reaction solution fully dissolved 30 ℃ the time, cooled reaction solution is added drop-wise in the mixing solutions among the step S2,30 ℃ of insulations down, continues to be stirred to and react completely;
S4, the reaction solution after reacting completely among the step S3 is cooled to room temperature, while stirring 0 ℃ wet chemical is added drop-wise in the described reaction solution, under 0 ℃, be stirred to and separate out a large amount of white solids, again the reaction solution suction filtration is got filter cake, with filter cake washing, dry that white solid is Mirabegron intermediate product B.
6. the synthetic method of Mirabegron according to claim 5, it is characterized in that, in step b, solvent described in step S1, S2, the S3 is N, dinethylformamide, methylene dichloride, acetonitrile, N, N-methylacetamide, trichloromethane, tetrachloromethane, 1, one or more in 2-ethylene dichloride, methyl-sulphoxide, tetrahydrofuran (THF), water, ethanol, cyclohexane, ether, methyl tertiary butyl ether, N-Methyl pyrrolidone, toluene, dimethylbenzene, chlorobenzene, the dichlorobenzene; Condensing agent described in the step S2 is N, N-dicarbapentaborane imidazoles, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, I-hydroxybenzotriazole, N, the N'-DIC, dicyclohexylcarbodiimide, N-hydroxyl-7-azepine benzotriazole, 3,4-dihydro-3-hydroxyl-4-oxo-1,2, the 3-phentriazine, 6-chloro-I-hydroxybenzotriazole, (7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, benzotriazole-N, N, N', N'-tetramethyl-urea hexafluorophosphate, 2-(1H-benzo trisazo-L-1-yl)-1,1,3,3-tetramethyl-urea Tetrafluoroboric acid ester, block special condensing agent, two (2-oxo-3-oxazolidinyl) inferior phosphoryl chloride, 1H-benzotriazole-1-base oxygen tripyrrole alkyl hexafluorophosphate, Vinyl chloroformate, methyl-chloroformate, methyl chloroacetate, ethyl chloroacetate, isobutyl chlorocarbonate, the propane phosphoric anhydride, woodward's reagent K, diethylchlorophosphate (C2H5O)2P(O)Cl, pivaloyl chloride, in the sulfur oxychloride one or more; Acid binding agent described in the step S3 is N-methylmorpholine, pyridine, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, methylamine, ethamine, dimethylamine, diethylamine, Trimethylamine 99, triethylamine, tripropyl amine, Tributylamine, triamylamine, tri-n-octyl amine, n-Butyl Amine 99, TBAH, N-methylmorpholine, morpholine, N, one or more in N-diisopropylethylamine, 4-Dimethylamino pyridine, salt of wormwood, yellow soda ash, cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, the potassium hydroxide.
7. the synthetic method of Mirabegron according to claim 1; it is characterized in that: in step c; specifically comprise the steps: under protection of nitrogen gas; Mirabegron intermediate product B and oxygenant joined successively form reaction solution in the solvent; reaction solution refluxed to be stirred to react completely, and the reaction solution after reacting completely is down to room temperature earlier, and suction filtration gets filter cake and filtrate again; use the organic solvent washing filter cake, merging, concentrated filtrate get Mirabegron intermediate product C.
8. according to the synthetic method of claim 1 or 7 described Mirabegrons, it is characterized in that: in step c, described oxygenant is adjacent iodoxybenzene formic acid, potassium permanganate, Manganse Dioxide, Dai Si-Martin's oxygenant, 2,2, in 6,6-tetramethyl piperidine oxide compound, pyridinium chloro-chromate, clorox, oxygen, nitric acid, the aluminium sesquioxide one or more; Described solvent is ethyl acetate, 1,4-dioxane, trichloromethane, 1, one or more in 2-ethylene dichloride, acetone, benzene, acetonitrile, tetrahydrofuran (THF), the toluene.
9. the synthetic method of Mirabegron according to claim 1, it is characterized in that: in steps d, specifically comprise the steps: under protection of nitrogen gas, under-3～3 ℃ condition, the Mirabegron intermediate product C that will be dissolved in solvent while stirring is added drop-wise in (R)-2-amino-1-phenylethyl alcohol and forms reaction solution, under nitrogen protection, while stirring reductive agent is added in the reaction solution, reaction solution is stirred under-3～3 ℃ reacts completely; Then reaction solution is added drop-wise to and carries out the cancellation reaction in the saturated aqueous ammonium chloride, tell organic phase after washing with water, organic phase added to be stirred in the concentrated hydrochloric acid under-2～2 ℃ condition react completely, with aqueous sodium hydroxide solution the organic phase that reacts completely is regulated pH to 10, stir the back separatory, the organic phase washing, dry, concentrate, recrystallization gets the final product Mirabegron.
10. according to the synthetic method of claim 1 or 9 described Mirabegrons, it is characterized in that: in steps d, described solvent is methylene dichloride, tetrahydrofuran (THF), ethanol, ethylene dichloride, methyl alcohol, Virahol, 1, one or more in 4-dioxane, normal heptane, formic acid, toluene, acetonitrile, acetic acid, hexanaphthene, the water; Described reductive agent is one or more in sodium borohydride, metallic nickel, hydrogen, titanium tetrachloride, Lithium Aluminium Hydride, sodium cyanoborohydride, sodium triacetoxy borohydride, borine, the tetra isopropyl titanium.
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| CN103896872A (en) * | 2014-04-29 | 2014-07-02 | 黑龙江大学 | Method for synthesizing mirabegron |
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| JP3193706B2 (en) * | 1997-10-17 | 2001-07-30 | 山之内製薬株式会社 | Amide derivative or salt thereof |
| US7342117B2 (en) * | 2001-10-30 | 2008-03-11 | Astellas Pharma Inc. | α-form or β-form crystal of acetanilide derivative |
| MXPA05004925A (en) * | 2002-11-07 | 2005-08-18 | Yamanouchi Pharma Co Ltd | Remedy for overactive bladder comprising acetic acid anilide derivative as the active ingredient. |
| JP2011105685A (en) * | 2009-11-20 | 2011-06-02 | Astellas Pharma Inc | Crystal of phenethylamine compound |
| MX2013005242A (en) * | 2010-11-11 | 2013-06-12 | Redx Pharma Ltd | Drug derivatives. |
| JP2014518859A (en) * | 2011-05-09 | 2014-08-07 | ユニバーシタット アントウェルペン | Activity-dependent probes for urokinase plasminogen activator |
| EP2709993A4 (en) * | 2011-05-18 | 2015-02-25 | Reddys Lab Ltd Dr | Amorphous mirabegron and processes for crystal forms of mirabegron |
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| CN103304511A (en) | 2013-09-18 |
| CN103304511B (en) | 2014-11-12 |
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