CN111662246A - Mirabegron impurity compound and preparation method and application thereof - Google Patents

Mirabegron impurity compound and preparation method and application thereof Download PDF

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CN111662246A
CN111662246A CN202010411397.9A CN202010411397A CN111662246A CN 111662246 A CN111662246 A CN 111662246A CN 202010411397 A CN202010411397 A CN 202010411397A CN 111662246 A CN111662246 A CN 111662246A
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王兴斌
郭正友
赖正茂
贠盼行
王晓龙
卢粤
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Jiangxi Qingfeng Pharmaceutical Co ltd
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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
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • 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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    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
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    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
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    • G01N2030/045—Standards internal

Abstract

The invention discloses a mirabegron impurity compound and a preparation method and application thereof; the mirabegron impurity compound disclosed by the invention is high in purity, and can be used as a reference substance to effectively identify impurities generated in the synthesis of the mirabegron, so that the medicine quality of the mirabegron is controlled.

Description

Mirabegron impurity compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of chemical drug synthesis, and particularly relates to a mirabegron impurity compound and a preparation method and application thereof.
Background
Mirabegron, chemical name (R) -2- (2-aminothiazol-4-yl) -N- (4- {2- [ (2-hydroxy-2-phenylethyl) amino ] ethyl } phenyl) acetamide, molecular formula C21H24N4O2S, molecular weight 396.51, CAS registry No. 223673-61-8, is a novel selective β 3 adrenergic receptor agonist developed by japan intra-mountains pharmaceutical company for oral administration, marketed in japan for the first time in 2011, approved by the FDA for the treatment of adult overactive bladder (OAB) at 6 months 2012, and has the structure shown below:
Figure BDA0002493386660000011
patent CN1711085A reports that the synthesis method of mirabegron is as follows: r-mandelic acid and p-nitroacetophenone are taken as starting materials, a compound shown in a formula 8 is prepared by amide condensation, then a compound shown in a formula 9 is prepared by borane reduction, a compound shown in a formula 7 is prepared by catalytic hydrogenation reduction, and finally the compound is condensed with 2-aminothiazole-4-acetic acid to prepare the mirabegron, wherein the specific synthetic route is as follows:
Figure BDA0002493386660000012
the process can generate a dimeric process impurity which has the property very similar to that of the mirabegron, the impurity is difficult to remove by conventional purification methods such as recrystallization, and the existence of the impurity has great influence on the quality of the mirabegron, so that the effective control and removal of the dimeric impurity are the key points of the quality control of the mirabegron.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a mirabegron impurity compound or a salt thereof, a preparation method and application thereof.
The inventor finds through a large number of experiments that the quality control of the mirabegron needs to be positioned by using a dimerization process impurity reference substance in the establishment of an analysis method, so that the dimerization process impurity is a necessary product for the quality control of the mirabegron; in addition, the presence of impurities may also cause serious side reactions, and there is a strong need in the art for effective identification of impurities produced in the synthesis of mirabegron.
The present invention finally solves the above technical problems by the following technical solutions.
The invention provides a mirabegron impurity compound shown as a formula I or a salt thereof:
Figure BDA0002493386660000021
preferably, the salt is formed by the mirabegron impurity compound shown in the formula I and acid, and the acid is inorganic acid or organic acid; the inorganic acid is preferably hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid; the organic acid is preferably formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, malic acid, fumaric acid, lactic acid, citric acid, tartaric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc.
The invention also provides a preparation method of the mirabegron impurity compound shown in the formula I or the salt thereof, which comprises the following steps: the compound of formula 6 or the active ester thereof and the compound of formula 7 or the salt thereof are subjected to condensation reaction in a solvent under the action of a condensing agent, and the reaction formula is as follows:
Figure BDA0002493386660000022
preferably, the solvent is water and/or an organic solvent; more preferably, when the compound of formula 7 is reacted in the form of a hydrochloride, the solvent is water; more preferably, the organic solvent is one or more of an amide solvent, a ketone solvent and a sulfoxide solvent; further preferably, the amide solvent is N, N-dimethylformamide and/or N, N-dimethylacetamide;
preferably, the condensing agent is one or more of Dicyclohexylcarbodiimide (DCC), Diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI. HCl), Carbodiimide (CDI), diphenylphosphoryl azide (DPPA) and Diethylphosphorylcyanide (DEPC);
preferably, the molar ratio of the condensing agent to the compound of formula 6 or the active ester thereof is 1: 1-2: 1;
preferably, the molar ratio of the condensing agent to the compound of formula 7 or the hydrochloride thereof is 1:1 to 2: 1;
preferably, the volume-to-mass ratio of the solvent to the compound of formula 7 or the hydrochloride thereof is 5mL/g to 50mL/g, preferably 10mL/g to 20 mL/g;
preferably, the reaction temperature is 20-30 ℃;
preferably, the active ester of formula 6 is an ester formed by the compound of formula 6 and 1-hydroxybenzotriazole or 1-hydroxy-7-azobenzotriazol;
preferably, the method comprises the steps of: mixing a compound shown in a formula 6, a compound shown in a formula 7, a condensing agent and a solvent, adding an acid to adjust the pH value to 2-4, stirring at 10-40 ℃ for reaction, adding an alkali to adjust the pH value to 8-11, stirring, filtering and drying; preferably, further comprises a refining step, such as refining with ethanol; the condensing agent is preferably EDCI & HCl; the solvent is preferably water; the acid is preferably concentrated hydrochloric acid; the base is preferably sodium hydroxide;
the reaction process can be monitored by a conventional detection method (such as TLC, HPLC or NMR) in the field, and generally, the reaction time is 0.5-3 hours, wherein the reaction end point is the time when the compound shown as the formula 7 or the hydrochloride thereof disappears.
Further, the present invention provides a method for preparing the compound of formula 6, comprising the steps of: in an organic solvent, under the action of an acid reagent, the compound of the formula 5 is subjected to an acid stripping Boc reaction, and the reaction equation is as follows:
Figure BDA0002493386660000031
preferably, the organic solvent is one or more of an ether solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent (such as dichloromethane), an amide solvent, an ester solvent, a sulfoxide solvent and an alcohol solvent;
more preferably, the ether solvent is one or more of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dioxane and 2-methyl tetrahydrofuran;
more preferably, the aromatic hydrocarbon solvent is one or more of benzene, toluene and xylene. The halogenated hydrocarbon solvent is one or more of dichloromethane, trichloromethane and 1, 2-dichloroethane;
more preferably, the amide solvent is N, N-dimethylformamide and/or N, N-dimethylacetamide;
more preferably, the ester solvent is selected from one or more of ethyl acetate, isopropyl acetate and isoamyl acetate;
more preferably, the sulfoxide solvent is dimethyl sulfoxide;
more preferably, the alcohol solvent is methanol, ethanol or isopropanol;
preferably, the acid reagent can be one or more of inorganic acid or organic acid which is conventional in the field;
more preferably, the inorganic acid is one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid;
more preferably, the organic acid is one or more of formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, citric acid, tartaric acid, carbonic acid, methanesulfonic acid, ethanesulfonic acid or trifluoroacetic acid.
Preferably, the volume-to-mass ratio of the solvent to the compound of formula 5 is 3mL/g to 20mL/g, preferably in the range of 3mL/g to 8 mL/g;
preferably, the volume-to-mass ratio of the acid reagent to the compound of the formula 5 is 2-5 mL/g;
preferably, the temperature of the Boc acid stripping reaction is 10-40 ℃, and the preferable range is 20-30 ℃;
preferably, the preparation method of the compound of formula 6 comprises the following steps: dissolving the compound shown in the formula 5 in an organic solvent, adding an acid reagent, stirring at 10-40 ℃ for reaction, removing the organic solvent, adding an alkali solution, stirring at room temperature, filtering, adjusting the pH of the filtrate to 4-6 with an acid, separating out a solid, filtering and drying; the base is preferably saturated sodium carbonate; the acid is preferably hydrochloric acid (e.g., 1mol/L hydrochloric acid); the acid reagent is preferably trifluoroacetic acid; the organic solvent is preferably removed by vacuum extraction.
The reaction process can be monitored by a conventional detection method (such as TLC, HPLC or NMR) in the field, the reaction end point is generally the time when the compound shown as the formula 5 disappears, and the reaction time is preferably 1-4 hours.
Further, the present invention provides a method for preparing the compound of formula 5, comprising the steps of: the compound of formula 4 is obtained by ester hydrolysis reaction in solvent under the action of alkali reagent, and the reaction equation is as follows:
Figure BDA0002493386660000041
preferably, the solvent is water and/or an organic solvent;
more preferably, the organic solvent is one or more of an ether solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an amide solvent, an ester solvent, a sulfoxide solvent and an alcohol solvent;
further preferably, the ether solvent is one or more of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dioxane and 2-methyl tetrahydrofuran;
further preferably, the aromatic hydrocarbon solvent is one or more of benzene, toluene and xylene;
further preferably, the halogenated hydrocarbon solvent is one or more of dichloromethane, trichloromethane and 1, 2-dichloroethane;
further preferably, the amide solvent is N, N-dimethylformamide and/or N, N-dimethylacetamide;
further preferably, the ester solvent is selected from one or more of ethyl acetate, isopropyl acetate and isoamyl acetate; more preferably, the sulfoxide solvent is dimethyl sulfoxide;
further preferably, the alcohol solvent is methanol, ethanol or isopropanol;
more preferably, the solvent is water and ethanol;
preferably, the alkali agent can be one or more of inorganic alkali or organic alkali which is conventional in the field;
more preferably, the inorganic base is one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydroxide, LiOH or hydrate thereof, sodium hydroxide and lithium hydroxide; further preferably, the inorganic base is LiOH or a hydrate thereof;
more preferably, the organic base is one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, diisopropylethylamine, triethylamine, pyridine, and 4-Dimethylpyridine (DMAP).
Preferably, the volume-to-mass ratio of the solvent to the compound of formula 4 is 2mL/g to 5 mL/g;
preferably, the molar ratio of the alkali reagent to the compound of formula 4 is 2: 1-4: 1;
preferably, the temperature of the hydrolysis reaction is 30-50 ℃;
preferably, the preparation method of the compound of formula 5 comprises the following steps: mixing the compound shown in the formula 4, inorganic base and an organic solvent, and stirring and reacting for 1-6 h at the temperature of 30-50 ℃; preferably, a post-treatment step is also included, including but not limited to: diluting the reaction solution with water, adjusting the pH value to 5-6 with acid, stirring, filtering, washing and drying; the inorganic base is preferably LiOH monohydrate; the acid is preferably glacial acetic acid; the pH adjusting step is preferably carried out in an ice bath; the acid is preferably glacial acetic acid; the washing is preferably with water.
The reaction process can be monitored by a conventional detection method (such as TLC, HPLC or NMR) in the field, the reaction end point is generally the time when the compound shown as the formula 4 disappears, and the reaction time is preferably 3-6 hours.
Further, the present invention provides a method for preparing the compound of formula 4, comprising the steps of: the compound of formula 2 and the compound of formula 3 or the active ester thereof are subjected to condensation reaction in a solvent under the action of a condensing agent, and the reaction equation is as follows:
Figure BDA0002493386660000051
preferably, the solvent is water and/or an organic solvent, and the organic solvent is preferably one or more of an ether solvent, an amide solvent, a ketone solvent and a sulfoxide solvent;
more preferably, the ether solvent is one or more of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dioxane and 2-methyl tetrahydrofuran;
more preferably, the amide solvent is preferably N, N-Dimethylformamide (DMF) and/or N, N-dimethylacetamide;
more preferably, the ketone solvent is N-methylpyrrolidone;
more preferably, the sulfoxide solvent is dimethyl sulfoxide;
preferably, the condensing agent is one or more of dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI & HCl), carbonyldiimidazole, diphenylphosphoryl azide and diethylphosphoryl cyanide; more preferably, the condensing agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI & HCl);
preferably, the molar ratio of the condensing agent to the compound of formula 3 is 1: 1-1: 2;
preferably, the volume-to-mass ratio of the solvent to the compound of formula 3 is 2-20 mL/g, and the preferred range is 3-8 mL/g;
preferably, the temperature of the condensation reaction is 40-60 ℃;
preferably, the active ester of the compound of formula 3 is an ester of the compound of formula 3 with 1-hydroxybenzotriazole or 1-hydroxy-7-azobenzotriazole;
preferably, the preparation method of the compound of formula 4 comprises the following steps: mixing a compound shown in a formula 3, a compound shown in a formula 2, a condensing agent (such as EDCI & HCl) and an organic solvent, and stirring for reaction at 40-60 ℃; preferably, a post-treatment step is also included, the post-treatment step includes but is not limited to dilution, extraction, washing, drying, solvent extraction, and more preferably, the dilution is water; ethyl acetate is adopted for extraction; washing with hydrochloric acid and saturated salt solution; the solvent is pumped out under reduced pressure; the organic solvent is preferably an amide solvent (such as DMF).
The reaction process can be monitored by a conventional detection method (such as TLC, HPLC or NMR) in the field, and generally, the reaction time is 24-28 hours, wherein the reaction end point is the time when the compound shown as the formula 3 or the hydrochloride thereof disappears.
Further, the present invention provides a method for preparing the compound of formula 3, comprising the steps of: the compound of formula 2 is reacted with Boc anhydride (di-tert-butyl dicarbonate) in a solvent under the action of a base, and the reaction formula is as follows:
Figure BDA0002493386660000071
preferably, the solvent is water and/or an organic solvent; the organic solvent is one or more of an ether solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an amide solvent, an ester solvent, a sulfoxide solvent and an alcohol solvent;
more preferably, the ether solvent is one or more of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dioxane and 2-methyl tetrahydrofuran;
more preferably, the aromatic hydrocarbon solvent is one or more of benzene, toluene and xylene;
more preferably, the halogenated hydrocarbon solvent is one or more of dichloromethane, trichloromethane and 1, 2-dichloroethane;
more preferably, the amide solvent is N, N-dimethylformamide and/or N, N-dimethylacetamide;
more preferably, the ester solvent is selected from one or more of ethyl acetate, isopropyl acetate and isoamyl acetate;
more preferably, the sulfoxide solvent is dimethyl sulfoxide;
more preferably, the alcohol solvent is methanol, ethanol or isopropanol.
Preferably, the base may be one or more of inorganic bases and/or organic bases conventional in the art;
more preferably, the inorganic base is one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydroxide, sodium hydroxide and lithium hydroxide;
more preferably, the organic base is one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, diisopropylethylamine, triethylamine, pyridine, and 4-Dimethylpyridine (DMAP).
Preferably, the mole ratio of the Boc anhydride to the compound of the formula 2 is 1: 1-2: 1;
preferably, the molar ratio of the base to the compound of formula 2 is 1: 1-3: 1;
preferably, the mass ratio of the volume of the solvent to the compound shown in the formula 2 is 3-20 mL/g, and the preferable range is 5-8 mL/g;
preferably, the condensation reaction temperature is 10-40 ℃, and more preferably 20-30 ℃;
preferably, the preparation method of the compound of formula 3 comprises the following steps: dissolving the compound shown in the formula 2 and alkali in an organic solvent, adding Boc anhydride (di-tert-butyl dicarbonate), and stirring at 10-40 ℃ for reaction; preferably, a post-treatment step is also included, including but not limited to: washing, drying, removing the solvent, adjusting the pH value (for example to 5-6), and stirring.
The reaction process can be monitored by a conventional detection method (such as TLC, HPLC or NMR) in the field, the reaction end point is generally the time when the compound shown as the formula 2 disappears, and the reaction time is preferably 3-10 hours.
The present invention also provides a process for preparing a compound of formula I, comprising the steps of preparing a compound of formula 3 from a compound of formula 2, preparing a compound of formula 4 from a compound of formula 3, preparing a compound of formula 5 from a compound of formula 4, preparing a compound of formula 6 from a compound of formula 5, preparing a compound of formula 7 from a compound of formula 6, and preparing a compound of formula I from a compound of formula 7, wherein the reaction equation is as follows:
Figure BDA0002493386660000081
preferably, the steps of preparing the compound of formula 3 from the compound of formula 2, preparing the compound of formula 4 from the compound of formula 3, preparing the compound of formula 5 from the compound of formula 4, preparing the compound of formula 6 from the compound of formula 5, preparing the compound of formula 7 from the compound of formula 6, and preparing the compound of formula I from the compound of formula 7 are as described above.
In another aspect, the invention also provides the use of a compound of formula i as a control for an impurity compound for the quality control of mirabegron or for the impurity identification of mirabegron.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
1. the invention provides a brand-new mirabegron impurity compound, which has high purity, can be used as an impurity compound reference substance for quality control of mirabegron, can effectively identify impurities generated in the synthesis of the mirabegron, and can quantitatively control the impurity compound.
2. The preparation method has mild reaction conditions, simple operation, less side reactions, higher product yield and purity, and can quickly obtain high-quality products at low cost.
Drawings
FIG. 1 is an HPLC chromatogram of a refined mirabegron prepared in example 14 and a blank control
FIG. 2 shows HPLC spectra of the compound of formula I from example 9, crude mirabegron from example 14 and refined mirabegron
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The following examples1H-NMR spectra were obtained using a Bruker-400 NMR spectrometer with tetramethylsilane as internal standard and chemical shifts (ppm); agilent6210 liquid chromatography-time-of-flight mass spectrometry combined for mass spectrometryProvided is an instrument.
EXAMPLES 1-2 preparation of Compounds of formula 3
Figure BDA0002493386660000091
Example 1
Compound 2(20.00g, 107mmol) and 4-dimethylaminopyridine (16.00g, 131mmol) were dissolved in 100mL of dichloromethane, di-tert-butyl dicarbonate (28.20g, 129mmol) was added dropwise with stirring at 20 ℃ and the reaction was stirred at 20 ℃ after completion of the reaction, and after the reaction, the reaction was washed successively with 100mL of 1mol/L hydrochloric acid and saturated brine, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the resulting residue was mixed with LiOH monohydrate (9.00g, 214mmol), 50mL of ethanol and 25mL of water and stirred at 40 ℃ for 2 hours. After the reaction is finished, 60mL of water is added for dilution, glacial acetic acid is dropwise added in an ice bath to adjust the pH value to 5-6, the mixture is concentrated to remove ethanol, 200mL of water is added, the mixture is continuously stirred for 1 hour and then filtered, 40mL of water is used for washing, and the mixture is dried to obtain 19.87g of compound 3, namely a white solid, wherein the yield is 80.5%.
Example 2
Compound 2(40.00g, 214mmol) and 4-dimethylaminopyridine (32.00g, 262mmol) were dissolved in 320mL of dichloromethane, di-tert-butyl dicarbonate (56.60g, 261mmol) was added dropwise with stirring at 30 ℃ and the reaction was stirred at 30 ℃ after completion of the reaction, and after the reaction, the reaction was washed successively with 200mL of 1mol/L hydrochloric acid and saturated brine, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the resulting residue was mixed with LiOH monohydrate (18.00g, 428mmol), 100mL of ethanol and 50mL of water and stirred at 40 ℃ for 2 hours. After the reaction is finished, 120mL of water is added for dilution, glacial acetic acid is dropwise added in an ice bath to adjust the pH value to 5-6, the mixture is concentrated to remove ethanol, 400mL of water is added, the mixture is continuously stirred for 1 hour and then filtered, 80mL of water is used for washing, and drying is carried out to obtain 40.26g of a compound 3, a white solid and the yield is 81.6%.
Examples 3-4 preparation of Compounds of formula 4
Figure BDA0002493386660000101
Example 3
Compound 3(13.87g, 54.8mmol), compound 2 (2-aminothiazole-4-acetic acid ethyl ester, 11.10g, 59.6mmol) and EDCI. HCl (9.45g, 54.8mmol) were dissolved in 42mL DMF, heated and stirred at 40 ℃ for 24h, after the reaction was completed, diluted with 80mL water, extracted with ethyl acetate (3X 50mL), and the organic phase was washed successively with 50mL of 1mol/L hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 17.56g of Compound 4 as a yellow solid in a yield of 75.1%.
Example 4
Compound 3(27.74g, 110mmol), Compound 2 (2-aminothiazole-4-acetic acid ethyl ester, 22.20g, 120mmol) and EDCI. HCl (37.80g, 220mmol) were dissolved in 220mL DMF, heated and stirred at 60 ℃ for 24h, after the reaction was completed, 160mL of water was added for dilution, ethyl acetate was extracted (3X 100mL), the organic phase was washed successively with 100mL of 1mol/L hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 35.62g of Compound 4 as a yellow solid in a yield of 76.2%.
Examples 5-6 preparation of Compounds of formula 5
Figure BDA0002493386660000102
Example 5
A250 mL reaction flask was charged with Compound 4(14.63g, 34.3mmol), and further added with LiOH monohydrate (3.75g, 89.4mmol), 35mL of ethanol, and 20mL of water, and heated and stirred at 30 ℃ for 3 h. And after the reaction is finished, adding 30mL of water for dilution, dropwise adding glacial acetic acid under an ice bath to adjust the pH value to 5-6, continuously stirring for 1h, filtering, washing with 50mL of water, and drying to obtain 12.23g of a compound 5, namely a light yellow solid, wherein the yield is 89.5%.
Example 6
To a 500mL reaction flask, Compound 4(29.26g, 68.6mmol), LiOH monohydrate (11.51g, 274mmol), 80mL of ethanol, and 50mL of water were added, and the mixture was stirred at 50 ℃ for 3 hours. And after the reaction is finished, adding 60mL of water for dilution, dropwise adding glacial acetic acid under an ice bath to adjust the pH value to 5-6, continuously stirring for 1h, filtering, washing with 100mL of water, and drying to obtain 24.21g of a compound 5, namely a light yellow solid, wherein the yield is 88.5%.
Examples 7-8 preparation of Compounds of formula 6
Figure BDA0002493386660000111
Example 7
Adding compound 5(12.23g, 30.6mmol) and 50mL dichloromethane into a 250mL reaction flask, adding 37mL trifluoroacetic acid, stirring at 20 deg.C for 2H, removing solvent under reduced pressure, adding 50mL saturated sodium carbonate solution, stirring at room temperature for 0.5H, filtering, adjusting pH of filtrate to 5 with 1mol/L hydrochloric acid, precipitating solid, filtering, washing filter cake with a little water, drying to obtain 8.68g compound 6, light yellow solid, yield 95.1%, ESI-MS (M/z):299.02[ M + H ]: 299.02]+；1H NMR(DMSO-d6):12.361(s，1H)，12.183(s，1H)，6.951(s，2H)，6.928(s，1H)，6.329(m，1H)，3.588(s，2H)，3.563(s，2H)。
Example 8
Adding the compound 5(6.12g, 15.3mmol) and 49mL of dichloromethane into a 250mL reaction flask, adding 30.6mL of trifluoroacetic acid, stirring at 30 ℃ for 2h, then removing the solvent by suction under reduced pressure, adding 30mL of saturated sodium carbonate solution, stirring at room temperature for 0.5h, filtering, adjusting the pH of the filtrate to 5 by using 1mol/L hydrochloric acid, precipitating a solid, filtering, washing a filter cake with a small amount of water, and drying to obtain 4.30g of the compound 6, namely a light yellow solid, wherein the yield is 94.2%.
Examples 9-10 preparation of Compounds of formula I
Figure BDA0002493386660000112
Example 9
A250 mL reaction flask was charged with Compound 6(2.00g, 6.70mmol), Compound 7(2.00g, 6.83mmol), EDCI. HCl (1.44g, 7.51mmol) and 20mL of water, adjusted to pH 3 with 5mL of concentrated hydrochloric acid, stirred at room temperature for 3h at 20 ℃, adjusted to pH 9 by dropwise addition of 2mol/L sodium hydroxide solution, stirred for 0.5h, filtered, washed with a small amount of water, dried, and the crude product was purified with ethanol to give 1.42g of Compound I as an off-white solid in 62.1% yield. The purity is 98.70%; ESI-MS (M/z) 537.25[ M + H]+，269.22[(M+2H)/2]+；1H NMR(DMSO-d6):10.078(s，1H)，7.520(s，1H)，7.499(s，1H)，7.285-7.344(m，4H)，7.202-7.245(m，1H)，6.932-6.942(m，3H)，6.321(s，1H)，4.622-4.654(m，1H)，3.676(s，2H)，3.563(s，2H)，2.727-2.831(m，2H)，2.644-2.708(m，4H)。
Example 10
A250 mL reaction flask was charged with Compound 6(4.00g, 13.4mmol), Compound 7(4.00g, 13.7mmol), EDCI. HCl (2.87g, 15.0mmol) and 80mL of water, the solution pH was adjusted to 3 with 7mL of concentrated hydrochloric acid, stirred at room temperature for 3h at 30 ℃, 2mol/L sodium hydroxide solution was added dropwise to adjust the pH to 9, stirring was continued for 0.5h, filtered, washed with a small amount of water, dried, and the crude product was purified with ethanol to give 1.42g of Compound I as a white solid in 97.31% yield and 98.73% purity.
EXAMPLES 11-13 preparation of salts related to Compounds of formula I
Example 11
Compound I (2.00g, 3.73mmol) and 20mL of ethanol were added to a 100mL reaction flask, and dissolved to clear with stirring, 1.0mL of concentrated hydrochloric acid was added dropwise to precipitate an off-white solid, which was filtered, washed with a small amount of ethanol, and dried to obtain 2.03g of a hydrochloride of Compound I as an off-white solid with a yield of 95.01%. The purity was 99.20%.
Example 12
Compound I (2.00g, 3.73mmol) and 20mL ethanol were added to a 100mL reaction flask, and dissolved to clear with stirring, 2.0mL 48% hydrobromic acid was added dropwise to precipitate an off-white solid, which was filtered, washed with a small amount of ethanol, and dried to give 2.12g of a hydrobromide salt of compound I as an off-white solid in 92.35% yield. The purity is 99.31%.
Example 13
Compound I (2.00g, 3.73mmol) and 20mL of ethanol were added to a 100mL reaction flask, and dissolved to clear with stirring, 1.79g of methanesulfonic acid was added dropwise to precipitate an off-white solid, which was filtered, washed with a small amount of ethanol, and dried to obtain 2.24g of a hydrochloride of Compound I as an off-white solid with a yield of 94.58%. The purity is 99.26%.
EXAMPLE 14 preparation and purification of Mirabegron
To a mixture of 8.00g of R-2- [ [2- (4-aminophenyl) ] amino ] -1-phenylethanol hydrochloride, 4.32g of 2-aminothiazole-4-acetic acid, 2.64g of concentrated hydrochloric acid and 120ml of water was added 5.76g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI.HCl) at room temperature, followed by stirring for 1 hour. Then, a mixed solution of 2.40g of sodium hydroxide and 40ml of water is added dropwise into the reaction solution for crystallization, and the generated solid, namely the crude mirabegron is filtered out and washed by water and then directly refined (the purity is 99.71%).
Heating the wet product to 80 deg.C with 90ml ethanol and 140ml water mixture to dissolve, cooling to 50 deg.C, adding 5.0% seed crystal, cooling to 20 deg.C, filtering to obtain solid, and vacuum drying at 50 deg.C to obtain white solid mirabegron refined product (purity 99.91%).
The crude mirabegron prepared in example 14 and the compound of formula I prepared in example 9 were collected and tested by hplc, and the results are shown in table 1.
In table 1, the number 1 indicates information such as retention time, peak area, relative peak area, peak height, etc. of the crude mirabegron prepared in example 14; number 2 indicates information on retention time, peak area, relative peak area, peak height, etc. of the compound of formula I obtained in example 9; numbers 3 and 4 represent information on retention time, peak area, relative peak area, peak height, etc. of the other unknown impurity A, B in the crude mirabegron prepared in example 14.
TABLE 1 information table relating compounds of formula I with crude mirabegron and other impurities
Figure BDA0002493386660000131
The purified mirabegron prepared in example 14 and the compound of formula I prepared in example 9 were collected and analyzed by hplc, and the results are shown in table 2.
In table 2, reference numeral 1 denotes information such as retention time, peak area, relative peak area, and peak height of the purified mirabegron prepared in example 14; number 2 indicates information on retention time, peak area, relative peak area, peak height, etc. of the compound of formula I obtained in example 9; numbers 3 and 4 represent information on retention time, peak area, relative peak area, peak height, and the like of other impurities in the mirabegron purified product obtained in example 14.
TABLE 2 information table relating to compounds of formula I and refined mirabegron and other impurities
Figure BDA0002493386660000141
The refined mirabegron prepared in the embodiment 14 has the HPLC purity of more than 99.91 percent and the impurity (the compound shown in the formula I) content of less than 0.05 percent, and meets the requirement of medicine quality.
HPLC detection was performed on the refined mirabegron prepared in example 14 and a blank control, and the results are shown in FIG. 1;
HPLC analysis of the compound of formula I prepared in example 9, the crude mirabegron prepared in example 14, and the refined mirabegron prepared in example 2 was performed;
as shown in the data in tables 1 and 2 and in FIGS. 1 and 2, the mirabegron related substance can effectively identify impurities generated in the synthesis of the mirabegron, so that the medicine quality of the mirabegron is controlled.

Claims (7)

1. A Mirabegron impurity compound of formula I:
Figure FDA0002493386650000011
preferably, the salt is formed by the mirabegron impurity compound shown in the formula I and acid, and the acid is inorganic acid or organic acid; the inorganic acid is preferably hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid; the organic acid is preferably formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, malic acid, fumaric acid, lactic acid, citric acid, tartaric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid.
2. A process for the preparation of a mirabegron impurity compound of formula I or a salt thereof, comprising the steps of: the compound of formula 6 or the active ester thereof and the compound of formula 7 or the salt thereof are subjected to condensation reaction in a solvent under the action of a condensing agent, and the reaction formula is as follows:
Figure FDA0002493386650000012
preferably, the first and second liquid crystal materials are,
the solvent is water and/or an organic solvent; more preferably, when the compound of formula 7 is reacted in the form of a hydrochloride, the solvent is water;
and/or the condensing agent is one or more of Dicyclohexylcarbodiimide (DCC), Diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI & HCl), carbon-based diimidazole (CDI), diphenyl phosphoryl azide (DPPA) and diethyl phosphoryl cyanide (DEPC);
and/or the molar ratio of the condensing agent to the compound shown in the formula 6 or the active ester thereof is preferably 1: 1-2: 1;
and/or the molar ratio of the condensing agent to the compound of formula 7 or the hydrochloride thereof is preferably 1:1 to 2: 1;
and/or the volume mass ratio of the solvent to the compound shown in the formula 7 or the hydrochloride thereof is 10 ml/g-20 ml/g;
and/or the reaction temperature is 20-30 ℃;
and/or the active ester of the formula 6 is an ester formed by the compound of the formula 6 and 1-hydroxybenzotriazole or 1-hydroxy-7-azobenzotriazol;
and/or, the method comprises the steps of: mixing a compound shown in a formula 6, a compound shown in a formula 7, a condensing agent and a solvent, adding an acid to adjust the pH value to 2-4, stirring at 20-30 ℃ for reaction, adding an alkali to adjust the pH value to 8-11, stirring, filtering and drying; preferably, further comprises a refining step, such as refining with ethanol; the condensing agent is preferably EDCI & HCl; the solvent is preferably water; the acid is preferably concentrated hydrochloric acid; the base is preferably sodium hydroxide.
3. The method of claim 2, wherein the compound of formula 6 is prepared by: in an organic solvent, under the action of an acid reagent, the compound of the formula 5 is subjected to an acid stripping Boc reaction, and the reaction equation is as follows:
Figure FDA0002493386650000021
preferably, the first and second liquid crystal materials are,
the organic solvent is one or more of an ether solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent (such as dichloromethane), an amide solvent, an ester solvent, a sulfoxide solvent and an alcohol solvent;
and/or, the acid reagent can be one or more of inorganic acid (such as trifluoroacetic acid) or organic acid which is conventional in the field;
and/or the volume-to-mass ratio of the solvent to the compound shown in the formula 5 is 2 mL/g-20 mL/g, preferably 3 mL/g-8 mL/g;
and/or the volume-mass ratio of the acid reagent to the compound shown in the formula 5 is 2-5 mL/g;
and/or the temperature of the acid stripping Boc reaction is 10-40 ℃, and the preferable range is 20-30 ℃;
and/or, the preparation method of the compound of formula 6 comprises the following steps: dissolving the compound shown in the formula 5 in an organic solvent, adding an acid reagent, stirring at 10-40 ℃ for reaction, removing the organic solvent, adding an alkali solution, stirring at room temperature, filtering, adjusting the pH of the filtrate to 4-6 with an acid, precipitating a solid, filtering and drying; the base is preferably saturated sodium carbonate; the acid is preferably hydrochloric acid (e.g., 1mol/L hydrochloric acid); the acid reagent is preferably trifluoroacetic acid; the organic solvent is preferably removed by vacuum extraction.
4. The method of claim 3, wherein the compound of formula 5 is prepared by: the compound of formula 4 is obtained by ester hydrolysis reaction in solvent under the action of alkali reagent, and the reaction equation is as follows:
Figure FDA0002493386650000022
preferably, the first and second liquid crystal materials are,
the solvent is water and/or organic solvent, such as water and ethanol;
and/or, the alkali reagent can be one or more of inorganic alkali (such as LiOH or hydrate thereof) or organic alkali which is conventional in the field;
and/or the volume-mass ratio of the solvent to the compound of the formula 4 is 2 mL/g-5 mL/g;
and/or the molar ratio of the alkali reagent to the compound of formula 4 is 2: 1-4: 1;
and/or the temperature of the hydrolysis reaction is 30-50 ℃;
and/or, the preparation method of the compound of formula 5 comprises the following steps: mixing the compound shown in the formula 4, inorganic base and an organic solvent, and stirring and reacting for 1-6 h at the temperature of 30-50 ℃; preferably, a post-treatment step is also included, including but not limited to: diluting the reaction solution with water, adjusting the pH value to 5-6 with acid, stirring, filtering, washing and drying; the inorganic base is preferably LiOH monohydrate; the acid is preferably glacial acetic acid; the pH adjusting step is preferably carried out in an ice bath; the washing is preferably with water.
5. The method of claim 4, wherein the compound of formula 4 is prepared by: the compound of formula 2 and the compound of formula 3 or the active ester thereof are subjected to condensation reaction in a solvent under the action of a condensing agent, and the reaction equation is as follows:
Figure FDA0002493386650000031
preferably, the first and second liquid crystal materials are,
the solvent is water and/or an organic solvent, and the organic solvent is preferably one or more of an ether solvent, an amide solvent (such as DMF), a ketone solvent and a sulfoxide solvent;
and/or the condensing agent is one or more of dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI & HCl), carbonyldiimidazole, diphenylphosphoryl azide and diethylphosphoryl cyanide;
and/or the molar ratio of the condensing agent to the compound shown in the formula 3 is 1: 1-1: 2;
and/or the volume-mass ratio of the solvent to the compound in the formula 3 is 2-20 mL/g, and the preferable range is 3-8 mL/g.
And/or the temperature of the condensation reaction is 40-60 ℃;
and/or, the active ester of the compound of formula 3 is an ester of the compound of formula 3 with 1-hydroxybenzotriazole or 1-hydroxy-7-azobenzotriazol;
and/or, the preparation method of the compound of formula 4 comprises the following steps: mixing a compound shown in a formula 3, a compound shown in a formula 2, a condensing agent (such as EDCI & HCl) and an organic solvent, and stirring for reaction at 40-60 ℃; preferably, a post-treatment step is also included, including but not limited to dilution, extraction, washing, drying, solvent extraction; more preferably, water is used for dilution; ethyl acetate is adopted for extraction; washing with hydrochloric acid and saturated salt solution; the solvent was evacuated under reduced pressure.
6. The method of claim 5, wherein the compound of formula 3 is prepared by: the compound of formula 2 is reacted with Boc anhydride (di-tert-butyl dicarbonate) in a solvent under the action of a base, and the reaction formula is as follows:
Figure FDA0002493386650000041
preferably, the first and second liquid crystal materials are,
the solvent is water and/or an organic solvent; the organic solvent is one or more of an ether solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an amide solvent, an ester solvent, a sulfoxide solvent and an alcohol solvent;
and/or, the base may be one or more of inorganic bases and/or organic bases conventional in the art;
and/or the mole ratio of the Boc anhydride to the compound in the formula 2 is 1: 1-2: 1;
and/or the molar ratio of the alkali to the compound shown in the formula 2 is 1: 1-3: 1;
and/or the mass ratio of the volume of the solvent to the compound in the formula 2 is 3-20 mL/g, and the preferable range is 5-8 mL/g;
and/or the temperature of the condensation reaction is 20-30 ℃;
and/or, the preparation method of the compound of formula 3 comprises the following steps: dissolving the compound shown in the formula 2 and alkali in an organic solvent, adding Boc anhydride (di-tert-butyl dicarbonate), and stirring at 10-40 ℃ for reaction; preferably, a post-treatment step is also included, including but not limited to: washing, drying, removing the solvent, adjusting the pH value (for example to 5-6), and stirring.
7. Use of a compound of formula i according to claim 1 as a reference for an impurity compound for the quality control of mirabegron or for the identification of impurities in mirabegron.
CN202010411397.9A 2020-05-15 2020-05-15 Mirabegron impurity compound and preparation method and application thereof Pending CN111662246A (en)

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