CN114539084A - Preparation method of mirabegron and intermediate thereof - Google Patents

Preparation method of mirabegron and intermediate thereof Download PDF

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CN114539084A
CN114539084A CN202011327875.4A CN202011327875A CN114539084A CN 114539084 A CN114539084 A CN 114539084A CN 202011327875 A CN202011327875 A CN 202011327875A CN 114539084 A CN114539084 A CN 114539084A
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compound
salt
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mirabegron
crystal form
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CN114539084B (en
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魏彦君
孔猛
刘希望
徐青景
邢艳平
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Weizhi Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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    • 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
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    • C07D277/40—Unsubstituted amino or imino radicals
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract

The invention discloses a preparation method of mirabegron and an intermediate thereof. The preparation method can reduce the relative dosage of the auxiliary materials, effectively reduce the cost expenditure in the aspect of the auxiliary materials, and reduce the generation and/or the residue of the dehydroxylation impurities, so that the content of the dehydroxylation impurities in the product can be kept in a very low level range, and the product quality and the safety of the mirabegron intermediate and/or the raw material medicine can be better guaranteed.

Description

Preparation method of mirabegron and intermediate thereof
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of mirabegron and an intermediate thereof.
Background
Overactive Bladder (OAB), a syndrome characterized by urgent micturition, often accompanied by frequent micturition, urinary incontinence, etc., seriously affects the daily life and social activities of patients, and has become a disease bothering people.
Mirabegron, CAS number: 223673-61-8, the structural formula is shown as follows, is a selective beta 3-adrenergic receptor stimulant and is mainly used for treating urgent micturition, frequent micturition, urinary incontinence and other symptoms caused by overactive bladder. It was first marketed in japan in 2011 and then marketed in countries or regions such as the united states and european union, and it was widely appreciated by patients because of its advantages such as good therapeutic effect and low side effects.
Figure BDA0002794815780000011
At present, one of the main flow routes for synthesizing mirabegron is: 4-nitrophenylethylamine or salt thereof and D-mandelic acid are taken as initial raw materials, and the mirabegron is obtained by dehydration condensation, amide reduction and nitro reduction, and then dehydration condensation with 2-aminothiazole-4-acetic acid. Generally, the synthesis directly obtains the beta crystal form of mirabegron, the beta crystal form shows certain hygroscopicity, the stability is relatively poor, and the alpha crystal form which does not show hygroscopicity and has better stability can be prepared by crystal transformation, see: CN 1575287A (name of the invention: alpha-type or beta-type crystal of acetanilide derivative).
CN 1575287a in the preparation method of mirabegron intermediate ((R) -2- (4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride), when borane tetrahydrofuran is used as a reducing agent, in order to reduce the occurrence of side reactions and ensure the product purity, 7.51kg (about 25mol) of 1, 3-Dimethylimidazolidinone (DMI) corresponding to (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide needs to be used to reach 23L (density of 1.056g/mL at 25 ℃, about 212.77mol), that is: the molar dosage of the 1, 3-dimethyl imidazolidinone is 8.5 times of that of the (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide, so that the problems of large auxiliary material dosage and high cost exist, the inconvenience of subsequent operation is increased, and the treatment time is greatly increased: the second addition of concentrated hydrochloric acid crystallization requires stirring overnight, which severely restricts the production efficiency of the method, is not beneficial to reducing the production cost, time cost and the like of unit product, and influences the industrial application thereof.
In order to overcome the above-mentioned drawbacks and/or disadvantages of the prior art methods, there is a need for further improvements in the process for the preparation of mirabegron or its intermediates.
Disclosure of Invention
Aiming at the problems and/or defects in the prior art, the invention aims to provide a preparation method of mirabegron and an intermediate thereof. The method can reduce the relative dosage of the auxiliary material (1, 3-dimethyl imidazolidinone) and effectively reduce the cost expenditure in the aspect of the auxiliary material, and can also reduce the generation and/or the residue of dehydroxylation impurities (such as 337008 and the like), so that the content of the dehydroxylation impurities in the product can be kept in a very low level range, and the method is favorable for better ensuring the product quality and the safety of the mirabegron or the intermediate thereof.
The invention provides a preparation method of a compound B or a salt thereof, which comprises the following steps:
Figure BDA0002794815780000021
the compound A or the salt thereof is subjected to oxygen removal from the carbonyl group (which can be simply referred to as "decarbonylation oxygen reaction") in the presence of 1, 3-dimethyl imidazolidinone, borane dimethyl sulfide and a solvent with or without inert gas protection to form a compound B or a salt thereof.
Further, in the above-mentioned case,
in the above-mentioned process for producing compound B or a salt thereof,
the molar ratio of the compound A or the salt thereof to the 1, 3-dimethylimidazolidinone can be 1:0.1 to 7.5 (e.g., 1:0.5, 1:1, 1:1.5, 1:2, etc.), preferably 1:2.5 to 5;
and/or the presence of a gas in the gas,
the molar ratio of the compound A or the salt thereof to the borane dimethylsulfide can be 1: 2-5 (such as 1:2.1, 1:2.3 and 1:2.5), and is preferably 1: 2-3;
and/or the presence of a gas in the gas,
the molar ratio of borane dimethyl sulfide to 1, 3-dimethyl imidazolidinone can be 1:1.05 to 3.5 (including but not limited to: 1:1.1, 1:1.5, 1:2, 1:2.2, 1:2.5, 1:3, etc.), preferably 1:1.05 to 2.4.
Further, in the above-mentioned case,
in the above-mentioned process for producing compound B or a salt thereof,
the solvent may be a common solvent for such reactions, including but not limited to: ether solvents and the like, preferably tetrahydrofuran;
and/or the presence of a gas in the gas,
the solvent is used in an amount that meets the reaction requirements, for example: the amount of the solvent used per mole of the compound A or the salt thereof may be 2 to 5kg (e.g., 2.5kg, 3kg, 3.5kg, 4kg, etc.);
and/or the presence of a gas in the atmosphere,
the reaction temperature for removing the oxygen on the carbonyl group can be-10-70 ℃, and is preferably 55-65 ℃;
and/or the presence of a gas in the gas,
the borane dimethyl sulfide can be added at the temperature of-10 to 70 ℃, preferably at the temperature of-5 to 5 ℃;
and/or the presence of a gas in the gas,
the reaction end point of the decarbonylation reaction can be controlled and determined by the reaction time and/or the remaining amount of the starting material (compound A or a salt thereof) in the reaction solution (monitored by TLC, HPLC or the like), for example, the reaction time is 4 to 10 hours, or the compound A or a salt thereof is substantially disappeared (the remaining amount in the reaction solution is less than or equal to 2%) as the reaction end point;
and/or the presence of a gas in the gas,
the method also comprises the following post-treatment steps: after the reaction of removing the oxygen on the carbonyl group of the compound A or a salt thereof is completed, methanol and an inorganic acid (the mass ratio of the methanol to the inorganic acid is about 1:2) are added into a reaction solution at the temperature of below 5 ℃ (for example, -5 to 5 ℃), concentrated, an organic solvent (an ester solvent, a haloalkane solvent and the like, such as ethyl acetate and the like) and an alkaline aqueous solution (a potassium carbonate aqueous solution or a sodium carbonate aqueous solution and the like with the concentration of about 25 wt%) are added into the reaction solution, liquid separation is carried out, an organic phase is taken out, the organic phase is washed by a saline solution (a sodium chloride aqueous solution or a potassium chloride aqueous solution with the concentration of about 10 wt%) and concentrated, isopropanol and an inorganic acid (concentrated hydrochloric acid and the like) are added (the mass ratio of the isopropanol to the inorganic acid is about 1:0.07), the mixture is stirred for 1.5 to 3 hours at the temperature of 40 to 50 ℃), the temperature is reduced to 20 to 25 ℃, a solid is precipitated, separated and dried, and the compound B or a salt thereof is obtained.
Further, in the above-mentioned case,
the above process for producing compound B or a salt thereof may further comprise the step of producing compound a or a salt thereof:
Figure BDA0002794815780000041
performing amidation reaction on the compound X or the salt thereof and D-mandelic acid (namely, the carboxyl of the D-mandelic acid reacts with the amino of the compound X or the salt thereof) in the presence of a dehydrating agent, an organic amine and a solvent with or without inert gas protection to generate a compound A or a salt thereof;
preferably, the first and second liquid crystal materials are,
the above-mentioned step for preparing compound A or its salt can meet one or more of conditions of (r) - (r):
the dehydrating agent is a carbodiimide dehydrating agent, and includes but is not limited to: n, N-Dicyclohexylcarbodiimide (DCC), N' -Diisopropylcarbodiimide (DIC), 1-ethyl- (3-dimethylaminopropyl) carbodiimides hydrochloride (EDC), etc., preferably N, N-dicyclohexylcarbodiimide;
the organic amine is selected from triethylamine and/or diisopropylethylamine, and triethylamine is preferred;
③ said solvent may be a solvent commonly used in such amidation reactions, including but not limited to: amide solvents and the like, for example: n, N-dimethylformamide, N-dimethylacetamide and the like, preferably N, N-dimethylformamide;
the ratio between compound X or a salt thereof and the dehydrating agent may be a conventional ratio, for example: the molar ratio of the compound X or a salt thereof to the dehydrating agent is 1:0.5 to 2, preferably 1:1 to 1.5 (e.g., 1:1.05, 1:1.1, 1:1.2, etc.);
the proportion between the compound X or the salt thereof and the organic amine may be conventional, for example: the molar ratio of the compound X or the salt thereof to the organic amine is 1: 0.5-2, preferably 1: 1.1-1.5 (e.g., 1:1.15, 1:1.2, 1:1.25, etc.);
the ratio between compound X or its salt and the solvent may be conventional, for example: the amount of the solvent used per mole of the compound X or a salt thereof is 1 to 5kg (e.g., 1.2kg, 1.5kg, 2kg, 2.5kg, 3kg, 3.5kg, 4kg, etc.);
the ratio between compound X or its salt and D-mandelic acid can be conventional, for example: the molar ratio of the compound X or the salt thereof to the D-mandelic acid is 1: 0.5-2, preferably 1: 1-1.5 (e.g., 1:1.05, 1:1.1, 1:1.2, etc.);
the amidation reaction can be further carried out in the presence of 1-hydroxybenzotriazole, and the proportion of the compound X or the salt thereof to the 1-hydroxybenzotriazole can be conventional, such as: the molar ratio of the compound X or the salt thereof to the 1-hydroxybenzotriazole is 1: 0.5-2, preferably 1: 1-1.5 (for example, 1:1.05, 1:1.1, 1:1.2, etc.);
ninthly, the temperature of the amidation reaction can be adjusted according to actual needs (considering factors such as reaction rate, side reaction occurrence, energy consumption and the like), and is preferably 2-40 ℃ (for example, 10 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃ and the like); the end point of the amidation reaction can be controlled and determined by the reaction time and/or the remaining amount of the starting material (compound X or a salt thereof) in the reaction solution (monitored by HPLC or the like), for example, the reaction time is 4 to 10 hours, or the compound X or a salt thereof is substantially disappeared (the remaining amount in the reaction solution is not more than 2%) as the end point of the reaction;
and R, further comprising a post-processing step: after the amidation reaction is finished, adding an organic solvent (such as an ester solvent, a halogenated alkane solvent and the like, for example, ethyl acetate and the like) and water, filtering, separating liquid, washing an organic phase with an acid (such as 3.6-3.8 wt% of diluted hydrochloric acid), washing with an alkaline aqueous solution (such as a potassium carbonate aqueous solution or a sodium carbonate aqueous solution with the concentration of about 20 wt%), washing with a saline aqueous solution (such as a sodium chloride aqueous solution or a potassium chloride aqueous solution with the concentration of about 28 wt%), concentrating, adding toluene, stirring, refluxing, cooling to 15-25 ℃, precipitating a solid, separating and drying to obtain the compound A or a salt thereof.
The invention also provides a preparation method of the mirabegron alpha crystal form, which comprises the following steps:
Figure BDA0002794815780000061
carrying out a condensation reaction on the compound D or a salt thereof and 2-aminothiazole-4-acetic acid in the presence of a condensing agent, an acid and a solvent with or without inert gas protection, crystallizing to obtain a product containing the beta crystal form of mirabegron (such as the beta crystal form of mirabegron, a mixture of the beta crystal form and the alpha crystal form of mirabegron and the like), and then recrystallizing with a mixed solvent to obtain the alpha crystal form of mirabegron;
wherein the mixed solvent is
Figure BDA0002794815780000062
And water, R is C2～C3Hydrocarbyl (hydrocarbyl includes alkyl, alkenyl, alkynyl, etc.); preferably, R is C3Alkyl (including n-propyl and isopropyl), and more preferably, R is isopropyl.
Further, in the above-mentioned case,
in the above preparation method of the mirabegron alpha crystal form,
Figure BDA0002794815780000063
the mass ratio of the water to the water is 0.5-15: 1; preferably, the first and second liquid crystal materials are,
Figure BDA0002794815780000064
the mass ratio of the water to the water is 0.5-7: 1 or 8-15: 1; more preferably, it is a mixture of more preferably,
Figure BDA0002794815780000065
the mass ratio of the water to the water is 0.8-6.7: 1 or 9.5-13: 1 (for example, 1:1, 5:1, 10:1, 12.5:1, etc.).
Further, in the above-mentioned case,
in the preparation method of the mirabegron alpha crystal form, the recrystallization adopts a cooling crystallization method and/or a concentration crystallization method;
preferably, the first and second liquid crystal materials are,
the cooling crystallization method comprises the following steps: dissolving a product containing the mirabegron beta crystal form in a mixed solvent, heating to 65-80 ℃, then cooling to 5-35 ℃, stirring, separating out a solid, separating and drying to obtain the mirabegron alpha crystal form; more preferably, the cooling rate of cooling from 65-80 ℃ to 5-35 ℃ is 5 +/-0.5 ℃/10 min;
and/or the presence of a gas in the gas,
the concentration crystallization method comprises the following steps: dissolving a product containing the mirabegron beta crystal form in a mixed solvent, concentrating, separating out a solid, separating, and drying to obtain the mirabegron alpha crystal form;
wherein the proportion of the product containing the mirabegron beta crystal form to the mixed solvent, or the concentration of the product containing the mirabegron beta crystal form in the mixed solvent meets the requirement of complete dissolution; in the examples, 20kg of mirabegron beta crystal form is dissolved in 396kg of mixed solvent (e.g., 360kg of isopropyl acetate and 36kg of purified water), namely: the mass ratio of the two is 1:19.8, and the ratio may be selected from the range of 1:9 to 999 (e.g., 1:10, 1:12, 1:15, 1:19, 1:20, 1:25, 1:30, 1:40, 1:100, 1:200, 1:500, etc.), and is preferably 1:15 to 49. When the concentration of the product containing the beta crystal form of the mirabegron in the mixed solvent is too low, the product can be properly concentrated and then crystallized; when the concentration is too high to dissolve a small amount of solid, a certain amount of solvent may be added and/or the undissolved solid may be filtered before crystallization.
Further, in the above-mentioned case,
in the preparation method of the mirabegron alpha crystal form, one or more than two of the conditions a-h are met:
a. the condensing agent is a carbodiimide dehydrating agent, and includes but is not limited to: n, N-Dicyclohexylcarbodiimide (DCC), N' -Diisopropylcarbodiimide (DIC), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), etc., preferably 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride;
b. the acid can be inorganic acid (such as hydrochloric acid, sulfuric acid and the like) and/or organic acid (such as tartaric acid, citric acid and the like), and is preferably concentrated hydrochloric acid;
c. the solvent can be a solvent conventionally used in the condensation reaction, and is preferably water;
d. the ratio between the compound D or a salt thereof and the condensing agent may be a conventional ratio, for example: the molar ratio of the compound D or a salt thereof to the condensing agent is 1: 0.5-2, preferably 1: 1-1.5 (e.g., 1:1.05, 1:1.1, 1:1.2, etc.);
e. the ratio between compound D or a salt thereof and the acid may be a conventional ratio, for example: compound D or a salt thereof with an acid (as H)+In terms of moles) of 1:0.5 to 2, preferably 1:1 to 1.2 (for example: 1:1.05, 1:1.1, etc.);
f. the ratio between compound D or a salt thereof and the solvent may be a conventional ratio, for example: the amount of the solvent used per mole of the compound D or the salt thereof is 2 to 5kg (for example, 2.5kg, 3kg, 3.5kg, 4kg, etc.);
g. the ratio between compound D or a salt thereof and 2-aminothiazole-4-acetic acid may be a conventional ratio, for example: the molar ratio of the compound D or the salt thereof to the 2-aminothiazole-4-acetic acid is 1: 0.5-2, preferably 1: 1-1.2 (for example, 1:1.05, 1:1.1, etc.);
h. the temperature of the condensation reaction can be adjusted according to actual needs (considering factors such as reaction rate, side reaction occurrence, energy consumption, etc.), and is preferably 2 to 40 ℃ (for example, 10 ℃, 15 ℃, 20 ℃, 30 ℃, 35 ℃, etc.); the end point of the condensation reaction can be controlled and determined by the reaction time and/or the remaining amount of the starting material (compound D or a salt thereof) in the reaction solution (monitored by TLC, HPLC or the like), and for example, the reaction time is 3 to 10 hours, or the compound D or a salt thereof is substantially disappeared (the remaining amount in the reaction solution is 1% or less) as the end point of the reaction.
Further, in the above-mentioned case,
in the preparation method of the mirabegron alpha crystal form, the crystal comprises the following steps: after the condensation reaction is finished, adding inorganic base (such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like) and water, stirring, separating out solid, separating and drying to obtain the mirabegron beta crystal form;
the amount of the inorganic base is determined by the total amount of the compound D salt (e.g., hydrochloride salt) and the acid, i.e.: OH of inorganic base-A molar amount at least equal to or greater than the total H of said compound D salt and said acid+Molar amount, the total molar amount of compound D salt (hydrochloride) and acid (concentrated hydrochloric acid) (total H) used in the examples of the present invention+) The inorganic base (sodium hydroxide) is used in a molar amount of 1.05 to 1.3 equivalents (for example: 1.07 equivalents, 1.17 equivalents, 1.27 equivalents, etc.).
Further, in the above-mentioned case,
the preparation method of the mirabegron alpha crystal form further comprises the following steps of:
Figure BDA0002794815780000081
compound B or a salt thereof can be produced by any of the aforementioned production methods, and then subjected to a reduction reaction as described above to produce compound D or a salt thereof;
preferably, the first and second liquid crystal materials are,
the reduction reaction can be carried out in the presence of a catalyst, a reducing agent and a solvent;
more preferably, it is a mixture of more preferably,
in the step of producing compound D or a salt thereof, one or two or more of the conditions i to vii are satisfied:
i. the catalyst is palladium carbon catalyst, and the Pd content and/or the water content of the palladium carbon catalyst can be selected according to the conditions of commercial products and the actual needs of the reactions, such as: pd content 5 wt% and water content 46.5 wt% were used in the examples;
ii. The reducing agent can be a reducing agent commonly used in the reduction reaction, and is preferably hydrogen;
iii, the solvent may be an alcoholic solvent, for example: methanol;
iv, the ratio between compound B or a salt thereof and the catalyst may be conventional ratios, for example: the mass ratio of the compound B or the salt thereof to the catalyst is 1: 0.01-0.1, namely: the amount of the catalyst is 1 to 10% by mass, preferably 1 to 5% by mass (for example, 2%, 2.5%, 3%, 3.5%, 4% by mass, etc.) of the compound B or a salt thereof;
v, the ratio between compound B or a salt thereof and the solvent may be a conventional ratio, for example: the mass ratio of the compound B or a salt thereof to the solvent is selected within the range of 1:5 to 20, preferably 1:10 to 15 (for example, 1:11, 1:12, etc.);
vi, the temperature of the reduction reaction can be adjusted according to actual needs, for example: selecting at 5-40 ℃, preferably 20-30 ℃; the end point of the reduction reaction can be controlled and determined by the time of introducing hydrogen gas and/or the remaining amount of the starting material (compound B or a salt thereof) in the reaction solution (monitored by HPLC, etc.), for example, the time of introducing hydrogen gas is 4 to 10 hours, or the compound B or a salt thereof substantially disappears (the remaining amount in the reaction solution is 0.5%) as the end point of the reaction;
vii, further comprising a post-treatment step: after the reduction reaction is finished, filtering, distilling, adding an alcohol solvent and methyl tert-butyl ether, stirring for 0.8-2 h at the temperature of 5-35 ℃, separating out a solid, separating and drying to obtain a compound D or a salt thereof; preferably, the alcohol solvent is methanol; and/or the mass ratio of the alcohol solvent to the methyl tert-butyl ether is 1: 3-5 (such as 1:3.5, 1:4, 1:4.5, etc.); and/or the temperature for stirring and separating out the solid is 5-25 ℃ (for example, 15 ℃, 20 ℃ and the like).
In the present invention, the salt may be a salt conventional in the art, for example: hydrochloride, sulfate, tartrate, and the like; since the structural formula of the mirabegron and the intermediate (such as the compound A, the compound B, the compound D and the like) comprises a basic group: imino (NH) and/or amino groups(NH2) And the like, and thus easily reacts with hydrochloric acid, sulfuric acid, tartaric acid, and the like to form a salt.
In the present invention, the first and second liquid crystal display panels,
the mirabegron alpha crystal form has characteristic peaks at diffraction angles 2 theta of 5.22 +/-0.2, 7.99 +/-0.2, 15.20 +/-0.2, 17.80 +/-0.2, 18.96 +/-0.2, 20.10 +/-0.2, 23.05 +/-0.2 and 24.22 +/-0.2 degrees in an X-ray powder diffraction manner;
the mirabegron beta crystal form has characteristic peaks at diffraction angles 2 theta of 9.56 +/-0.2, 19.52 +/-0.2, 20.58 +/-0.2, 21.88 +/-0.2 and 23.34 +/-0.2 through X-ray powder diffraction.
The beneficial effects of the invention are specifically explained as follows:
(1) the invention uses the combination of 1, 3-dimethyl imidazolidinone and borane dimethyl sulfide;
on one hand, the relative dosage of the auxiliary material (1, 3-dimethyl imidazolidinone) can be reduced, and the cost expenditure in the aspect of the auxiliary material is effectively reduced: when the dosage of the 1, 3-dimethyl imidazolinone (DMI) is 7.5 equivalents, the auxiliary material cost is reduced to 88% (namely: 7.5/8.5) of the original expenditure relative to 8.5 equivalents in the prior art, and when the dosage of the 1, 3-dimethyl imidazolinone (DMI) is 5 equivalents and 2.5 equivalents, the auxiliary material cost is respectively reduced to 58.8 percent and 29.4 percent of the original expenditure, and the borane dimethylsulfide is cheap relative to the borane tetrahydrofuran, so that the economic benefit is obvious, the market competitiveness of the mirabegron or the intermediate thereof can be well improved, and the commercial success is facilitated;
on the other hand, the generation and/or residue of dehydroxylation impurities (such as 337008 and the like) can be reduced, so that the content of the dehydroxylation impurities in the product can be kept in a very low level range, and the product quality and safety of the mirabegron or the intermediate thereof can be better guaranteed;
(2) the present invention has found, through intensive studies, that, in the case of the beta crystal form of mirabegron, both isopropyl acetate solvents (for example:
Figure BDA0002794815780000101
) Or water, and the single one as a solvent has poor solubility, which is the case of poor solubility；
But surprisingly, if two solvents, namely an isopropyl acetate solvent and water, are combined together, the mirabegron beta crystal form can be completely dissolved under certain conditions, which is possibly related to a phase diagram of a binary solvent and the interaction between the solvent combination and the mirabegron beta crystal form, the invention utilizes the property newly found by the solvent combination and uses the solvent combination as a crystal transformation solvent for the mirabegron crystal transformation, and the mirabegron alpha crystal form with better stability is quite unexpectedly obtained;
(3) according to the invention, through the specific solvent combination of the isopropyl acetate solvent and water, not only can the complete dissolution of the mirabegron beta crystal form be realized, but also the successful conversion of the mirabegron beta crystal form to the mirabegron alpha crystal form can be realized, so that the mirabegron alpha crystal form can be prepared under the condition of no crystal seed;
in addition, the solvent combination can effectively remove the residue of dehydroxylation impurities (337010) in the mirabegron product, so that the content of the dehydroxylation impurities can be reduced to be below 50% of the original level, and the product quality and safety of the mirabegron raw material medicine can be better guaranteed;
(4) the method has the advantages of mild process conditions, convenient operation and control, remarkably improved production efficiency, high yield and purity, low energy consumption, low cost, safety, environmental protection and suitability for industrial production.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of crystalline product B of the present invention.
FIG. 2 is an X-ray powder diffraction pattern of crystalline product A of the present invention.
FIG. 3 is an X-ray powder diffraction pattern of a crystalline product obtained using isopropanol/purified water (mass ratio of 6.7:1) as a solvent.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention thereto.
In the present invention, those who do not specify the conditions are performed according to the conventional conditions or the conditions recommended by the manufacturer, and the reagents or apparatuses used are not specified by the manufacturer, and can be obtained by purchasing commercially available products or prepared by known methods.
With respect to definitions of terms used in the present disclosure, the initial definitions provided for the terms herein apply to the terms throughout, unless otherwise indicated; terms not specifically defined herein should be given their meanings to those skilled in the art in light of the disclosure and/or the context.
Ca～CbHydrocarbyl, denotes any hydrocarbyl group containing a to b carbon atoms, such as: c2～C3Hydrocarbyl means hydrocarbyl containing 2 or 3 carbon atoms, for example: ethyl, n-propyl, isopropyl, allyl, and the like; the hydrocarbon group includes an alkyl group, an alkenyl group (alkenyl group), and the like.
In the present invention, the classification and/or explanation of the solvent can be made with reference to the "solvent handbook" by Chenglin (4 th edition, Beijing: chemical industry Press).
Some of the schemes and examples below may omit some details of common reactions, isolation techniques and analytical procedures, and some may omit secondary products from chemical reactions. In addition, in some cases, the reaction intermediate may be used in a subsequent step without isolation and/or purification.
In general, the chemical transformations described in the specification may be carried out using substantially stoichiometric amounts of the reactants, although certain reactions may benefit from the use of an excess of one or more of the reactants. Any description herein of stoichiometry, temperature, etc., whether or not the term "range" is used explicitly, is intended to include the endpoints as recited.
Example 1
1. Preparation of Compound 3
Figure BDA0002794815780000121
The method comprises the following steps:
adding 26.02kg (about 171mol) of D-mandelic acid (compound 1), 31.5kg (about 155.45mol) of 4-nitrophenylethylamine hydrochloride (compound 2), 23.12kg (about 171mol) of 1-hydroxybenzotriazole, 35.28kg (about 171mol) of N, N-dicyclohexylcarbodiimide and 18.84kg (about 186mol) of triethylamine into 240kg of N, N-dimethylformamide, stirring for 5 hours at the reaction temperature of 20-25 ℃, and obtaining a reaction solution after the reaction is basically complete (the residual amount of the compound 2 is less than or equal to 2%) by High Performance Liquid Chromatography (HPLC);
adding 360kg of ethyl acetate and 604.8kg of purified water into the reaction solution, stirring, filtering with diatomite, standing, separating, taking an organic phase, extracting the lower aqueous phase twice with ethyl acetate (285kg and 171kg), merging the organic phases, adding a mixed solution of 32.82kg of concentrated hydrochloric acid (mass fraction 36-38 wt%) and 285kg of purified water (equivalent to 317.82kg of dilute hydrochloric acid with concentration of about 3.6-3.8 wt%), stirring for 4 hours, filtering with diatomite, standing, separating, taking an organic phase, adding a purified water (277.5kg) solution of potassium carbonate (69.3kg) (equivalent to 346.8kg of potassium carbonate aqueous solution with concentration of about 20 wt%), stirring for 1 hour, standing, separating, taking an organic phase, adding 285kg of purified water, stirring for 2 hours, filtering with diatomite, adding 15.75kg of sodium chloride into the filtrate, stirring for 1 hour, standing, separating, taking an organic phase, adding a purified water (150kg) solution of sodium chloride (58.3kg) (equivalent to 208.3kg of a sodium chloride aqueous solution with the concentration of about 28 wt%), stirring for 1h, standing, separating, taking an organic phase, then distilling under reduced pressure (the vacuum degree is less than or equal to-0.09 MPa and the temperature is 35-45 ℃) until no fraction is produced, adding 24kg of toluene, continuing distilling under reduced pressure (the vacuum degree is less than or equal to-0.09 MPa and the temperature is 45-60 ℃) until no fraction is produced, then adding 109.5kg of toluene, heating to 105-115 ℃, stirring and refluxing for 0.5h, then cooling to 15-25 ℃, stirring for 1h, precipitating a solid, centrifuging, drying under vacuum (the vacuum degree is less than or equal to-0.09 MPa and the temperature is 45-50 ℃) to obtain the compound 3((R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide), the yield is 80.31%, and the purity is 99.50% by HPLC.
2. Preparation of Compound 4
Figure BDA0002794815780000131
The method comprises the following steps:
i. under the protection of inert gas (such as nitrogen), adding 24kg (about 80mol) of compound 3((R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide) and 45.6kg (about 399.5mol) of 1, 3-dimethyl imidazolidinone (DMI) into 53.36kg of tetrahydrofuran, then dropwise adding a tetrahydrofuran solution of borane dimethyl sulfide (184 mol of borane dimethyl sulfide and 142.92kg of tetrahydrofuran), controlling the temperature to be-5 ℃ in the dropwise adding process, heating to 55-65 ℃ after the addition is finished, stirring for reacting for 4 hours, and obtaining a reaction solution after the reaction is basically complete (the residual amount of the compound 3 is less than or equal to 2%) through Thin Layer Chromatography (TLC) or High Performance Liquid Chromatography (HPLC);
ii. Cooling the reaction liquid to-5 ℃, adding 9.51kg of methanol to quench the reaction, stirring for 0.5h, adding 19.66kg of concentrated hydrochloric acid (mass fraction is 36-38 wt%), heating to 55-65 ℃, stirring for 1h, then cooling to 35-45 ℃, starting reduced pressure distillation (vacuum degree is less than or equal to-0.09 MPa) until no fraction is generated basically, adding 128.57kg of ethyl acetate, stirring for dissolving, then adding 115.70kg of purified water (equivalent to 154.1kg of potassium carbonate aqueous solution with concentration of about 25 wt%), stirring for 1h, standing, separating, taking an organic phase, extracting the lower aqueous phase twice with ethyl acetate (64.3kg and 42.9kg), merging the organic phase, then adding 14.48kg of sodium chloride and 130.2kg of purified water (equivalent to 144.68kg of sodium chloride aqueous solution with concentration of about 10 wt%), stirring for 1h, standing, separating, and (3) taking an organic phase, then carrying out reduced pressure distillation (the vacuum degree is less than or equal to-0.09 MPa, and the temperature is 35-45 ℃) until no fraction is produced, adding 20.0kg of isopropanol, continuing reduced pressure distillation until no fraction is produced, adding 123.2kg of isopropanol, stirring for dissolving, adding 8.86kg of concentrated hydrochloric acid, stirring for 2 hours at 40-50 ℃, then cooling to 20-25 ℃, separating out a solid, filtering, and carrying out vacuum drying (the vacuum degree is less than or equal to-0.09 MPa, and the temperature is 45-50 ℃) to obtain a compound 4((R) -2- (4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride), wherein the yield is 88.7%, and the HPLC purity is 99.6%.
3. Preparation of Compound 5
Figure BDA0002794815780000141
The method comprises the following steps:
a. adding 20.4kg of compound 4((R) -2- (4-nitrophenylethyl) amino) -1-phenylethanol hydrochloride) and 0.72kg of palladium-carbon catalyst (Pd/C, 5 wt% of Pd and 46.5 wt% of water) into a reaction kettle of 242kg of methanol, introducing hydrogen, stirring and reacting for 4 hours at the reaction temperature of 20-30 ℃, and stopping introducing the hydrogen after HPLC (high performance liquid chromatography) detects that the residual amount of the compound 4 in the reaction liquid is less than or equal to 0.5% to obtain a reaction liquid;
b. and (2) filtering the reaction solution, distilling under reduced pressure (the vacuum degree is less than or equal to-0.09 MPa and 35-45 ℃) until the reaction solution becomes viscous or is turbid just before, stopping distilling under reduced pressure, supplementing 60.5kg of methanol, stirring and dissolving at 35-45 ℃, adding 240kg of methyl tert-butyl ether (MTBE), stirring for 1h at the temperature of 5-15 ℃ after the addition is finished, separating out a solid, centrifuging, and drying under vacuum (the vacuum degree is less than or equal to-0.09 MPa and 45-50 ℃) to obtain a compound 5((R) -2- (4-aminophenylethyl) amino) -1-phenylethanol hydrochloride), wherein the yield is 87.5% and the HPLC purity is 99.80%.
4. Preparation of mirabegron beta crystal form
Figure BDA0002794815780000151
I. Under the protection of inert gas (such as nitrogen), 187.0kg of purified water, 5.6kg of concentrated hydrochloric acid (the mass fraction is 36-38 wt%, the HCl content is about 57.5mol), 16kg (about 54.6mol) of compound 5((R) -2- (4-aminophenylethyl) amino) -1-phenylethanol hydrochloride) and 9.08kg (about 57.4mol) of 2-aminothiazole-4-acetic acid are added into a reaction kettle, then a water (23kg) solution of 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (11.52kg, about 60mol, EDC) is added, the temperature is controlled to be 2-10 ℃ in the adding process, the temperature is raised to 20-30 ℃ after the adding is finished, the reaction is kept for 3 hours, and a reaction liquid is obtained after the residual amount of the compound 5 in the reaction liquid is less than or equal to 1% by HPLC detection;
II. Adding 162kg of purified water into the reaction solution, uniformly stirring, then adding a purified water (80kg) solution of sodium hydroxide (5.25kg, about 131.2mol), controlling the temperature to be 20-35 ℃ in the adding process, stirring for 1h after the adding is finished, separating out crystals, centrifuging, drying in vacuum (the vacuum degree is less than or equal to-0.09 MPa, 55-60 ℃), obtaining a crystallization product B, wherein the yield is 98.0%, and the HPLC purity is 99.54%;
the crystalline product B obtained above was subjected to X-ray powder diffraction (XRD) detection under the following test conditions:
SCAN：3.0/60.0/0.02/0.15(sec)，Cu(40kV,40mA)，I(cps)＝1766；
PEAK：47-pts/Parabolic Filter，Threshold＝3.0，Cutoff＝0.1％，BG＝3/1.0，Peak-top＝summit；
NOTE: intensity ═ CPS, 2T (0) ═ 0.0(deg), for calculation of lattice spacing
Figure BDA0002794815780000152
Figure BDA0002794815780000153
(Cu/K-alpha1)；
The results are shown in Table 1 and FIG. 1.
TABLE 1X-ray powder diffraction (XRD) detection results of crystalline product B
Figure BDA0002794815780000161
The results show that the crystalline product B obtained in the present invention has characteristic peaks at diffraction angles 2 θ of 9.559, 19.520, 20.580, 21.880 and 23.340 degrees (°), which are consistent with the characteristic peaks of the β -type crystal described in CN 1575287a (title of the invention: α -type or β -type crystal of acetanilide derivative), and thus it can be confirmed that the crystalline product B prepared in the present invention is the β -type crystal form of mirabegron.
5. Transformation of mirabegron beta crystal form into alpha crystal form
Adding 20kg of the crystallized product B (beta crystal form) into 396kg of mixed solvent (360kg of isopropyl acetate and 36kg of purified water), heating to 68-78 ℃ while stirring, cooling to 15-25 ℃ (the cooling rate is 5 ℃/10min) after complete dissolution, stirring for 1h, separating out crystals, centrifuging, and drying in vacuum (the vacuum degree is less than or equal to-0.09 MPa, 55-60 ℃) to obtain a crystallized product A, wherein the yield is 85.9%, and the HPLC purity is 99.81%;
the crystalline product A obtained above was subjected to X-ray powder diffraction (XRD) detection under the following test conditions:
SCAN：3.0/60.0/0.02/0.15(sec)，Cu(40kV,40mA)，I(cps)＝2041；
PEAK：47-pts/Parabolic Filter，Threshold＝3.0，Cutoff＝0.1％，BG＝3/1.0，Peak-top＝summit；
NOTE: intensity ═ CPS, 2T (0) ═ 0.0(deg), for calculation of lattice spacing
Figure BDA0002794815780000171
Figure BDA0002794815780000172
(Cu/K-alpha1)；
The results are shown in Table 2 and FIG. 2.
TABLE 2X-ray powder diffraction (XRD) examination of crystalline product A
Figure BDA0002794815780000173
The results show that the crystalline product a obtained in the present invention has characteristic peaks at diffraction angles 2 θ of 5.221, 7.999, 15.200, 17.800, 18.960, 20.100, 23.059, 24.220 degrees (°), which are consistent with the characteristic peaks of the α -type crystal described in CN 1575287a (title of the invention: α -type or β -type crystal of acetanilide derivative), and thus it can be confirmed that the crystalline product a obtained by converting the β -type crystal form of mirabegron in the present invention is the α -type crystal form of mirabegron.
Examples 2 to 4
In step i of the preparation method of the compound 4, the amount of 1, 3-Dimethylimidazolidinone (DMI) used was changed to 0mol, 200mol, and 600mol, respectively, that is: compound 4 was prepared with the amounts of 1, 3-Dimethylimidazolidinone (DMI) 0 equivalent, 2.5 equivalents, and 7.5 equivalents, respectively, based on compound 3(mol), and other process conditions were unchanged (same as in example 1), and the yield, HPLC purity, and impurity content thereof are shown in table 3.
Figure BDA0002794815780000181
TABLE 3 influence of the amount of 1, 3-Dimethylimidazolidinone (DMI) used on the preparation of Compound 4
Example 2 Example 3 Example 1 Example 4
DMI amount/equivalent 0 2.5 5 7.5
Yield of 83.0％ 86.6％ 88.7％ 89.2％
HPLC purity 96.7％ 99.61％ 99.6％ 99.44％
Impurity (337008) 3.1％ ND ND ND
ND means not detected, meaning that the content is below the detection limit.
Examples 5 to 6
In step i of the preparation method of the compound 4, the dosage of borane dimethyl sulfide is changed to 168mol and 200mol respectively, namely: the borane dimethylsulfide was used in an amount of 2.1 equivalents and 2.5 equivalents, respectively, based on the compound 3(mol), and other process conditions were unchanged (same as in example 1), to prepare the compound 4, the yield, HPLC purity, and impurity content of which are shown in table 4.
TABLE 4 influence of the amount of borane dimethylsulfide on the preparation of Compound 4
Example 5 Example 1 Example 6
Borane dimethyl sulfide dosage/equivalent 2.1 2.3 2.5
Yield of 86.0％ 88.7％ 88.5％
HPLC purity 99.76％ 99.6％ 99.73％
Impurity (337008) ND ND ND
Examples 7 to 9
In the step i of the preparation method of the compound 4, the temperature is controlled to be 30 +/-2 ℃, 40 +/-2 ℃ and 50 +/-2 ℃ respectively in the process of dropwise adding the tetrahydrofuran solution of borane dimethylsulfide, other process conditions are not changed (the same as the example 1), and the compound 4 is prepared, wherein the yield, the HPLC purity and the impurity content are shown in Table 5.
TABLE 5 influence of temperature control during dropping on the preparation of Compound 4
Example 1 Example 7 Example 8 Example 9
Temperature of -5～5℃ 30±2℃ 40±2℃ 50±2℃
Yield of 88.7％ -- -- --
HPLC purity 99.6％ 99.64％ 99.63％ 98.81％
Impurity (337008) ND ND ND ND
Examples 10 to 12
In step a of the preparation method of compound 5, the amount of palladium on carbon catalyst (Pd/C, Pd content 5 wt%, water content 46.5 wt%) was changed to 0.4kg, 0.51kg, 0.61kg, respectively, that is: the palladium-carbon catalyst was used in amounts of 2%, 2.5% and 3% by mass of compound 4, and other process conditions were not changed (same as in example 1), and compound 5 was obtained, and the yield, HPLC purity and impurity content thereof are shown in table 6.
Figure BDA0002794815780000191
TABLE 6 Effect of palladium on carbon catalyst amount on the preparation of Compound 5
Figure BDA0002794815780000192
Figure BDA0002794815780000201
Examples 13 to 14
In step b of the preparation method of compound 5, the mixture was stirred at 20 ± 2 ℃ and 30 ± 2 ℃ for 1 hour to precipitate a solid, and other process conditions were not changed (same as example 1), so as to prepare compound 5, wherein the yield, HPLC purity and impurity content are shown in table 7.
TABLE 7 influence of the temperature at which the solid precipitates on the preparation of Compound 5
Example 1 Example 13 Example 14
Temperature of precipitated solid 5～15℃ 20±2℃ 30±2℃
Yield of 87.5％ 86.9％ 84.7％
HPLC purity 99.80％ 99.71％ 99.76％
Impurity (337009) 0.04％ 0.09％ 0.06％
Examples 15 to 16
In step I of the mirabegron beta crystal form preparation method, the dosage of the 2-aminothiazole-4-acetic acid is respectively changed into 54.6mol and 60mol, namely: based on the compound 5(mol), the amount of 2-aminothiazole-4-acetic acid used was 1 equivalent and 1.1 equivalent, and other process conditions were unchanged (same as in example 1), to obtain a reaction solution, and the content of mirabegron and the content of impurities in the reaction solution were measured, and the results are shown in table 8.
Figure BDA0002794815780000202
TABLE 8 Effect of 2-aminothiazole-4-acetic acid dosage on Mirabegron preparation
Example 15 Example 1 Example 16
2-aminothiazole-4-acetic acid dosage/equivalent 1.0 1.05 1.1
HPLC purity 97.05％ 97.84％ 96.18％
Impurity (337010) 0.08％ 0.07％ 0.08％
Examples 17 to 18
In step I of the preparation method of the mirabegron beta crystal form, the dosage of the concentrated hydrochloric acid is respectively changed to 5.34kg (the HCl content is about 54.6mol) and 5.87kg (the HCl content is about 60mol), that is: based on the compound 5(mol), the amounts of HCl used were 1 equivalent and 1.1 equivalent, respectively, and other process conditions were unchanged (same as in example 1), to obtain a reaction solution, and the content of mirabegron and the content of impurities in the reaction solution were measured, and the results are shown in table 9.
TABLE 9 Effect of concentrated HCl dosage on Mirabegron preparation
Example 17 Example 1 Example 18
HCl amount/equivalent 1.0 1.05 1.1
HPLC purity 97.29％ 97.84％ 96.53％
Impurities (337010) 0.09％ 0.07％ 0.10％
Examples 19 to 21
In step I of the preparation method of the mirabegron beta crystal form, the dosage of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) is respectively changed to 54.6mol, 57.3mol and 65.5mol, namely: the amount of EDC used was 1 equivalent, 1.05 equivalent, and 1.2 equivalent, respectively, based on the compound 5(mol), and other process conditions were not changed (the same as in example 1), so that a reaction solution was obtained, and the content of mirabegron and the content of impurities in the reaction solution were measured, and the results are shown in table 10.
TABLE 10 Effect of EDC amount on Mirabegron preparation
Figure BDA0002794815780000211
Examples 22 to 23
In the step I of the mirabegron beta crystal form preparation method, the reaction temperature is respectively changed into 15 +/-2 ℃ and 35 +/-2 ℃ for heat preservation reaction for 3 hours, other process conditions are not changed (the same as the example 1), reaction liquid is obtained, and the content of the mirabegron and the content of impurities in the reaction liquid are detected, and the results are shown in a table 11.
TABLE 11 influence of reaction temperature on the preparation of mirabegron
Example 22 Example 1 Example 23
Reaction temperature 15±2℃ 20～30℃ 35±2℃
HPLC purity 97.28％ 97.84％ 97.38％
Impurities (337010) 0.10％ 0.07％ 0.10％
Examples 24 to 25
In step II of the mirabegron β crystal form preparation method, the amounts of sodium hydroxide are changed to 120.1mol and 142mol, respectively, that is: based on the total molar amount (about 112.1mol) of the compound 5 and the concentrated hydrochloric acid, the amount of sodium hydroxide is 1.07 equivalent and 1.27 equivalent, and other process conditions are unchanged (same as example 1), so as to prepare a crystalline product B (determined as a beta crystal form by X-ray powder diffraction detection), wherein the yield, HPLC purity and impurity content of the crystalline product B are shown in table 12.
TABLE 12 influence of sodium hydroxide dosage on the preparation of mirabegron beta Crystal form
Example 24 Example 1 Example 25
Sodium hydroxide amount/equivalent 1.07 1.17 1.27
Yield of 96.3％ 98.0％ 98.8％
HPLC purity 99.60％ 99.54％ 99.53％
Impurity (337010) 0.08％ 0.09％ 0.09％
Examples 26 to 29
In the method for converting the beta crystal form of the mirabegron into the alpha crystal form, the using amount (396kg) of the mixed solvent is unchanged, the mass ratio of the isopropyl acetate to the purified water is respectively changed into 1:1, 5:1 (namely, 330kg of isopropyl acetate and 66kg of purified water), 6.7:1 and 12.5:1, other process conditions are unchanged (the same as example 1), the crystalline product A (alpha crystal form) is prepared, and the test results are shown in Table 13.
TABLE 13 influence of solvent ratio on the preparation of mirabegron alpha Crystal form
Figure BDA0002794815780000221
Figure BDA0002794815780000231
X-ray powder diffraction (XRD) detection confirms that the crystal products obtained in examples 26-29 are all mirabegron alpha crystal forms, such as:
the crystalline product of example 26: the X-ray powder diffraction has characteristic peaks at diffraction angles 2 theta of 5.280, 8.020, 15.260, 17.840, 18.926, 20.180, 23.100 and 24.300 degrees;
crystalline product of example 28: the X-ray powder diffraction has characteristic peaks at diffraction angles 2 θ of 5.320, 8.080, 15.300, 17.899, 19.003, 20.220, 23.141, and 24.360 degrees.
In addition, in the relevant experimental studies, the inventors of the present application also found that:
(1) purified water is singly used for pulping, the raw material is beta-crystal form, and the obtained product is still beta-crystal form: the X-ray powder diffraction has characteristic peaks at diffraction angles 2 theta of 9.540, 19.600, 20.600, 21.801 and 23.321 degrees, and cannot convert the peaks into an alpha crystal form;
(2) the isopropyl acetate is singly used (other process conditions are the same), and the problems exist that the beta crystal form can not be completely dissolved, more insoluble solids exist by naked eyes, and the residual insoluble solids (beta crystal form) can be used as seed crystals in the subsequent crystallization process, so that the obtained product is still in the beta crystal form and can not be converted into the alpha crystal form;
(3) using isopropanol/purified water (mass ratio of 6.7:1) as a solvent, under the same other process conditions, the raw material is in a beta crystal form, and the obtained product is still in the beta crystal form: the X-ray powder diffraction has characteristic peaks at diffraction angles 2 θ of 9.540, 19.600, 20.600, 21.820 and 23.300 degrees, see fig. 3, and cannot convert the crystals into the α crystal form.
Example 30
In the method for converting the beta crystal form of mirabegron into the alpha crystal form, the crystallization method is changed from the cooling crystallization method of example 1 into a concentration crystallization method, and the specific method comprises the following steps: completely dissolving the crystalline product B (beta crystal form) in isopropyl acetate/purified water (mass ratio is 6.7:1), concentrating, precipitating crystals, centrifuging (or filtering), and drying in vacuum (vacuum degree is less than or equal to-0.09 MPa, 55-60 ℃) to obtain the crystalline product A, wherein the HPLC purity is 99.86%, and characteristic peaks exist at diffraction angles of 2 theta, 5.280, 8.039, 15.260, 17.860, 19.056, 20.179, 23.100 and 24.300 ℃ by X-ray powder diffraction, so that the obtained crystalline product A is confirmed to be an alpha crystal form.
Examples 31 to 32
In the method for converting the beta crystal form of mirabegron into the alpha crystal form, the temperature of the precipitated crystal is respectively changed to 10 +/-2 ℃ and 30 +/-2 ℃, other process conditions are unchanged (the same as the example 1), and a crystal product A (alpha crystal form) is prepared, wherein the yield, HPLC purity and impurity content are shown in a table 14.
TABLE 14 influence of temperature of precipitated crystals on the preparation of mirabegron alpha Crystal form
Example 31 Example 1 Example 32
Temperature of 10±2℃ 15～25℃ 30±2℃
Yield of 89.8％ 85.9％ 83.5％
HPLC purity 99.73％ 99.81％ 99.82％
Impurity (337010) 0.03％ 0.02％ 0.02％
。

Claims (10)

1. A process for the preparation of compound B or a salt thereof, comprising the steps of:
Figure FDA0002794815770000011
removing oxygen from the carbonyl of the compound A or the salt thereof in the presence of 1, 3-dimethyl imidazolidinone, borane dimethyl sulfide and a solvent with or without inert gas protection to generate a compound B or a salt thereof.
2. The process for producing compound B or a salt thereof according to claim 1,
the molar ratio of the compound A or the salt thereof to the 1, 3-dimethyl imidazolidinone is 1: 0.1-7.5, preferably 1: 2.5-5;
and/or the presence of a gas in the gas,
the molar ratio of the compound A or the salt thereof to the borane dimethyl sulfide is 1: 2-5, preferably 1: 2-3;
and/or the presence of a gas in the gas,
the molar ratio of the borane dimethyl sulfide to the 1, 3-dimethyl imidazolidinone is 1: 1.05-3.5, preferably 1: 1.05-2.4.
3. The process for producing compound B or a salt thereof according to claim 1 or 2,
the solvent is an ether solvent, preferably tetrahydrofuran;
and/or the presence of a gas in the gas,
the dosage of each mole of the compound A or the salt thereof corresponding to the solvent is 2-5 kg;
and/or the presence of a gas in the gas,
the reaction temperature for removing the oxygen on the carbonyl is-10-70 ℃, and the preferable temperature is 55-65 ℃;
and/or the presence of a gas in the gas,
the borane dimethyl sulfide is added at the temperature of-10 to 70 ℃, preferably at the temperature of-5 to 5 ℃;
and/or the presence of a gas in the gas,
further comprises the following post-treatment steps: after the reaction of removing the carbonyl oxygen of the compound A or the salt thereof is finished, adding methanol and inorganic acid into a reaction solution at the temperature of-5 ℃, concentrating, adding an organic solvent and an alkaline aqueous solution, separating, taking an organic phase, washing with a saline solution, concentrating, then adding isopropanol and inorganic acid, stirring for 1.5-3 h at the temperature of 40-50 ℃, then cooling to 20-25 ℃, precipitating a solid, separating, and drying to obtain the compound B or the salt thereof.
4. The process for producing compound B or a salt thereof according to claim 1 or 2, further comprising the step of producing compound a or a salt thereof:
Figure FDA0002794815770000021
carrying out amidation reaction on the compound X or the salt thereof and D-mandelic acid in the presence of a dehydrating agent, an organic amine and a solvent with or without inert gas protection to generate a compound A or a salt thereof;
preferably, the first and second liquid crystal materials are,
the above-mentioned step for preparing compound A or its salt satisfies one or more of the conditions of (i) - (R):
the dehydrating agent is a carbodiimide dehydrating agent, preferably N, N-dicyclohexylcarbodiimide;
the organic amine is selected from triethylamine and/or diisopropylethylamine, and triethylamine is preferred;
the solvent is an amide solvent, preferably N, N-dimethylformamide;
the molar ratio of the compound X or the salt thereof to the dehydrating agent is 1: 0.5-2, preferably 1: 1-1.5;
the mol ratio of the compound X or the salt thereof to the organic amine is 1: 0.5-2, preferably 1: 1.1-1.5;
sixthly, the dosage of each mole of the compound X or the salt thereof corresponding to the solvent is 1-5 kg;
the molar ratio of the compound X or the salt thereof to the D-mandelic acid is 1: 0.5-2, preferably 1: 1-1.5;
the amidation reaction is further carried out in the presence of 1-hydroxy benzotriazole, and the molar ratio of the compound X or the salt thereof to the 1-hydroxy benzotriazole is 1: 0.5-2, preferably 1: 1-1.5;
ninthly, controlling the temperature of amidation reaction to be 2-40 ℃;
and R, further comprising a post-processing step: and after the amidation reaction is finished, adding an organic solvent and water, filtering, separating liquid, taking an organic phase, carrying out acid washing, washing with an alkaline aqueous solution, washing with a salt aqueous solution, concentrating, then adding toluene, stirring and refluxing, cooling to 15-25 ℃, separating out a solid, separating and drying to obtain the compound A or the salt thereof.
5. The preparation method of the mirabegron alpha crystal form is characterized by comprising the following steps:
Figure FDA0002794815770000031
with or without inert gas protection, under the condition that a condensing agent, acid and a solvent exist, carrying out condensation reaction on the compound D or the salt thereof and 2-aminothiazole-4-acetic acid, crystallizing to obtain a product containing a mirabegron beta crystal form, and then recrystallizing by using a mixed solvent to obtain a mirabegron alpha crystal form;
wherein the mixed solvent is
Figure FDA0002794815770000032
And water, R is C2～C3A hydrocarbyl group; preferably, R is C3Alkyl, more preferably, R is isopropyl.
6. The method for preparing mirabegron alpha crystal form according to claim 5,
Figure FDA0002794815770000033
the mass ratio of the water to the water is 0.5-15: 1; preferably, the first and second liquid crystal materials are,
Figure FDA0002794815770000034
the mass ratio of the water to the water is 0.5-7: 1 or 8-15: 1; more preferably, it is a mixture of more preferably,
Figure FDA0002794815770000035
the mass ratio of the water to the water is 0.8-6.7: 1Or 9.5-13: 1.
7. The method for preparing mirabegron alpha crystal form according to claim 5 or 6, characterized in that the recrystallization adopts a cooling crystallization method and/or a concentration crystallization method;
preferably, the first and second liquid crystal materials are,
the cooling crystallization method comprises the following steps: dissolving a product containing the mirabegron beta crystal form in a mixed solvent, heating to 65-80 ℃, then cooling to 5-35 ℃, stirring, separating out a solid, separating and drying to obtain the mirabegron alpha crystal form; more preferably, the temperature of the mirabegron solution is reduced from 65-80 ℃ to 5-35 ℃ at the rate of 5 +/-0.5 ℃/10 min;
preferably, the first and second liquid crystal materials are,
the concentration crystallization method comprises the following steps: dissolving a product containing the mirabegron beta crystal form in a mixed solvent, concentrating, separating out a solid, separating, and drying to obtain the mirabegron alpha crystal form; wherein the mass ratio of the product containing the mirabegron beta crystal form to the mixed solvent is 1: 9-999, and the preferable mass ratio is 1: 15-49.
8. The method for preparing mirabegron alpha crystal form according to claim 5 or 6, characterized in that one or more than two of the conditions a-h are satisfied:
a. the condensing agent is a carbodiimide dehydrating agent, preferably 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride;
b. the acid is inorganic acid and/or organic acid, preferably concentrated hydrochloric acid;
c. the solvent is water;
d. the molar ratio of the compound D or the salt thereof to the condensing agent is 1: 0.5-2, preferably 1: 1-1.5;
e. the molar ratio of the compound D or the salt thereof to the acid is 1: 0.5-2, preferably 1: 1-1.2;
f. the dosage of each mole of the compound D or the salt thereof corresponding to the solvent is 2-5 kg;
g. the molar ratio of the compound D or the salt thereof to the 2-aminothiazole-4-acetic acid is 1: 0.5-2, preferably 1: 1-1.2;
h. the temperature of the condensation reaction is 2-40 ℃.
9. The process for the preparation of the alpha crystalline form of mirabegron, according to claims 5 or 6, characterized in that said crystallization comprises the following steps: after the condensation reaction is finished, adding inorganic base and water, stirring, separating out solid, separating and drying to obtain the mirabegron beta crystal form;
preferably, the first and second liquid crystal materials are,
the inorganic alkali is sodium hydroxide, potassium hydroxide or lithium hydroxide;
and/or the presence of a gas in the gas,
as the total H of said compound D or salt thereof and said acid+Molar amount of OH of inorganic base-The molar amount is 1.05-1.3 equivalents.
10. The process for preparing mirabegron alpha crystal according to claim 5 or 6, characterized by further comprising the step of preparing compound D or its salt:
Figure FDA0002794815770000051
preparing a compound B or a salt thereof according to the preparation method of any one of claims 1 to 4, and carrying out the reduction reaction on the compound B or the salt thereof to generate a compound D or a salt thereof;
preferably, the first and second liquid crystal materials are,
the reduction reaction is carried out in the presence of a catalyst, a reducing agent and a solvent;
more preferably, it is a mixture of more preferably,
the step of producing the compound D or a salt thereof described above satisfies one or two or more of the conditions i to vii:
i. the catalyst is a palladium carbon catalyst;
ii. The reducing agent is hydrogen;
iii, the solvent is an alcohol solvent, preferably methanol;
iv, the dosage of the catalyst is 1 to 10 percent of the mass of the compound B or the salt thereof, and preferably 1 to 5 percent;
v, the mass ratio of the compound B or the salt thereof to the solvent is 1: 5-20, preferably 1: 10-15;
vi, the temperature of the reduction reaction is 20-30 ℃;
vii, further comprising a post-treatment step: after the reduction reaction is finished, filtering, distilling, adding an alcohol solvent and methyl tert-butyl ether, stirring for 0.8-2 h at the temperature of 5-35 ℃, separating out a solid, separating and drying to obtain a compound D or a salt thereof; preferably, the alcohol solvent is methanol; and/or the mass ratio of the alcohol solvent to the methyl tert-butyl ether is 1: 3-5; and/or the temperature for stirring and separating out the solid is 5-25 ℃.
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