CN114539084B - Preparation method of mirabegron and intermediate thereof - Google Patents

Preparation method of mirabegron and intermediate thereof Download PDF

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CN114539084B
CN114539084B CN202011327875.4A CN202011327875A CN114539084B CN 114539084 B CN114539084 B CN 114539084B CN 202011327875 A CN202011327875 A CN 202011327875A CN 114539084 B CN114539084 B CN 114539084B
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compound
salt
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mirabegron
crystal form
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CN114539084A (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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a preparation method of mirabegron and an intermediate thereof. According to the preparation method, on one hand, the relative dosage of auxiliary materials can be reduced, the cost expenditure on the aspect of the auxiliary materials is effectively reduced, and on the other hand, the generation and/or the residue of dehydroxylated impurities can be reduced, so that the content of the dehydroxylated impurities in a product can be kept within 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 ensured.

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 milbegron and an intermediate thereof.
Background
Overactive bladder (Overactive Bladder, OAB), a syndrome characterized by symptoms of urgency, often accompanied by urinary frequency, incontinence, etc., severely affecting the daily life and social activities of the patient, has become a major disorder afflicting people.
Milabagron, CAS number: 223673-61-8, the structural formula is shown below, is a selective beta 3-adrenergic receptor agonist, and is mainly used for treating urgent urination, frequent urination, urinary incontinence and other symptoms caused by overactive bladder. The traditional Chinese medicine composition is marketed in japan at the earliest 2011 and then in countries or regions such as the united states and the european union, and is widely appreciated by patients due to the advantages of good treatment effect, small side effects and the like.
Currently, one of the main routes for the synthesis of milbegron is: 4-nitrophenethylamine or salt thereof and D-mandelic acid are used as starting materials, and are subjected to dehydration condensation, amide reduction, nitro reduction and dehydration condensation with 2-aminothiazole-4-acetic acid to obtain mirabegron. In general, the mirabegron beta crystal form is directly obtained through synthesis, 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 through crystal transformation, see: CN 1575287a (title: alpha-form or beta-form crystals of an acetanilide derivative).
CN 1575287a in the preparation of milabegron intermediate ((R) -2- (4-nitrophenyl) amino) -1-phenylethanol hydrochloride) when borane tetrahydrofuran is used as reducing agent, in order to be able to reduce the occurrence of side reactions and to ensure the purity of the product, 7.51kg (about 25 mol) of (R) -2-hydroxy-N- (4-nitrophenyl) -2-phenylacetamide corresponding 1, 3-Dimethylimidazolidinone (DMI) is used in an amount up to 23L (density 1.056g/mL at 25 ℃ c., about 212.77 mol), i.e.: the molar dosage of the 1, 3-dimethyl imidazolinone is 8.5 times of that of the (R) -2-hydroxy-N- (4-nitrophenyl) 2-phenylacetamide, the problems of large auxiliary material dosage and high cost exist, meanwhile, the inconvenience of subsequent operation is increased, and the treatment time is greatly increased: the second time of adding concentrated hydrochloric acid crystallization needs stirring overnight, which severely restricts the production efficiency of the method, is unfavorable for reducing the production cost, time cost and the like of unit products, and affects the industrialized application of the unit products.
In order to overcome the above-described drawbacks and/or shortcomings of the prior art methods, there is a need for continued improvements in the preparation of mirabegron or intermediates thereof.
Disclosure of Invention
Aiming at the problems and/or the defects existing in the prior art, the invention aims to provide a preparation method of mirabegron and an intermediate thereof. According to the method, on one hand, the relative dosage of auxiliary materials (1, 3-dimethyl imidazolinone) can be reduced, the cost expenditure on the aspect of the auxiliary materials is effectively reduced, and on the other hand, the generation and/or the residue of dehydroxylation impurities (such as 337008 and the like) can be reduced, so that the content of the dehydroxylation impurities in a product can be kept within a very low level range, and the product quality and the safety of mirabegron or an intermediate thereof can be better ensured.
The invention provides a preparation method of a compound B or salt thereof, which comprises the following steps:
compound A or a salt thereof is decarbonylated with or without inert gas shielding in the presence of 1, 3-dimethylimidazolidinone, borane dimethyl sulfide, and a solvent (may be referred to simply as "decarbonyloxy reaction") to produce compound B or a salt thereof.
Further, the method comprises the steps of,
in the above-mentioned process for producing compound B or a salt thereof,
The molar ratio between compound a or a salt thereof and 1, 3-dimethylimidazolidinone may 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 number of the groups of groups,
the molar ratio between compound a or a salt thereof and borane dimethyl sulfide may be 1:2 to 5 (e.g. 1:2.1, 1:2.3, 1:2.5), preferably 1:2 to 3;
and/or the number of the groups of groups,
the molar ratio between borane dimethyl sulfide and 1, 3-dimethylimidazolidinone may 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, the method comprises the steps of,
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 number of the groups of groups,
the solvent may be used in an amount sufficient for the reaction, for example: the amount of the solvent to be used may be 2 to 5kg (for example, 2.5kg, 3kg, 3.5kg, 4kg, etc.) per mol of the compound A or a salt thereof;
and/or the number of the groups of groups,
the reaction temperature for removing oxygen on carbonyl can be-10-70 ℃, and is preferably 55-65 ℃;
and/or the number of the groups of groups,
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 number of the groups of groups,
The reaction end point of the decarbonyloxy 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 liquid (monitored by TLC or HPLC or the like), for example, the reaction time is 4 to 10 hours, or the compound A or a salt thereof substantially disappears (remaining amount in the reaction liquid. Ltoreq.2%) as the reaction end point;
and/or the number of the groups of groups,
post-processing steps may also be included: after the reaction of removing oxygen from carbonyl group of the compound A or its salt is completed, methanol and inorganic acid (the mass ratio between methanol and inorganic acid is about 1:2) are added to the reaction solution at a temperature below 5 ℃ (for example, -5 ℃), the mixture is concentrated, an organic solvent (ester solvent, haloalkane solvent, etc., for example, ethyl acetate, etc.) and an alkaline aqueous solution (for example, aqueous potassium carbonate solution or aqueous sodium carbonate solution with a concentration of about 25 wt%) are added, the organic phase is separated, washed with an aqueous salt solution (for example, aqueous sodium chloride solution or aqueous potassium chloride solution with a concentration of about 10 wt%) and concentrated, then isopropanol and inorganic acid (for example, concentrated hydrochloric acid, etc.) are added (the mass ratio between isopropanol and inorganic acid is about 1:0.07), the mixture is stirred for 1.5-3 hours at a temperature of 40-50 ℃, then the mixture is cooled to 20-25 ℃, solid is separated, and the mixture is dried, thus obtaining the compound B or its salt.
Further, the method comprises the steps of,
in the above-mentioned method for producing compound B or a salt thereof, the method may further comprise the step of producing compound a or a salt thereof:
amidation reaction of compound X or its salt with D-mandelic acid in the presence of dehydrating agent, organic amine and solvent with or without inert gas to produce compound A or its salt;
preferably, the method comprises the steps of,
the above steps for preparing compound A or a salt thereof satisfy one or more of the conditions (1) to (in):
(1) the dehydrating agent is a carbodiimide dehydrating agent, including but not limited to: n, N-Dicyclohexylcarbodiimide (DCC), N' -Diisopropylcarbodiimide (DIC), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and the like, preferably N, N-dicyclohexylcarbodiimide;
(2) said organic amine is selected from triethylamine and/or diisopropylethylamine, preferably triethylamine;
(3) the solvent may be a common solvent for such amidation reactions, including but not limited to: amide solvents, etc., for example: n, N-dimethylformamide, N-dimethylacetamide and the like, preferably N, N-dimethylformamide;
(4) The ratio between the compound X or a salt thereof and the dehydrating agent may be a conventional ratio, for example: the molar ratio between the compound X or a salt thereof and the dehydrating agent is 1:0.5-2, preferably 1:1-1.5 (e.g., 1:1.05, 1:1.1, 1:1.2, etc.);
(5) the ratio between compound X or a salt thereof and the organic amine may be a conventional ratio, for example: the molar ratio between the compound X or a salt thereof and 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.);
(6) the ratio between compound X or a salt thereof and the solvent may be a conventional ratio, for example: the amount of the solvent to be used per mole of the compound X or a salt thereof is 1 to 5kg (for example, 1.2kg, 1.5kg, 2kg, 2.5kg, 3kg, 3.5kg, 4kg, etc.);
(7) the ratio between compound X or a salt thereof and D-mandelic acid may be a conventional ratio, for example: the molar ratio between the compound X or a salt thereof and 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.);
(8) the amidation reaction may be further carried out in the presence of 1-hydroxybenzotriazole, and the ratio between the compound X or its salt and 1-hydroxybenzotriazole may be a conventional ratio, for example: the molar ratio between the compound X or a salt thereof and 1-hydroxybenzotriazole is 1:0.5-2, preferably 1:1-1.5 (e.g., 1:1.05, 1:1.1, 1:1.2, etc.);
(9) The temperature of the amidation reaction may be adjusted according to the actual requirements (considering factors such as reaction rate, occurrence of side reaction, energy consumption, etc.), and is preferably 2 to 40 ℃ (e.g., 10 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃ etc.); the reaction 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 liquid (monitored by a method such as HPLC), for example, the reaction time is 4 to 10 hours, or the compound X or a salt thereof substantially disappears (remaining amount in the reaction liquid. Ltoreq.2%) as the reaction end point;
further comprising the post-treatment steps of: after the amidation reaction is completed, adding an organic solvent (which can be an ester solvent, a halogenated hydrocarbon solvent, etc., for example, ethyl acetate, etc.) and water, filtering, separating liquid, taking an organic phase, washing with an acid (for example, 3.6wt% -3.8wt% of dilute hydrochloric acid), washing with an alkaline aqueous solution (for example, a potassium carbonate aqueous solution or a sodium carbonate aqueous solution with a concentration of about 20wt%), washing with a saline solution (for example, a sodium chloride aqueous solution or a potassium chloride aqueous solution with a concentration of about 28wt%), concentrating, then adding toluene, stirring and refluxing, cooling to 15-25 ℃, separating out solid, separating, and drying to obtain the compound A or the salt thereof.
The invention also provides a preparation method of the mirabegron alpha crystal form, which comprises the following steps:
performing condensation reaction on the compound D or a salt thereof and 2-aminothiazole-4-acetic acid in the presence of a condensing agent, acid and a solvent with or without inert gas protection, crystallizing to obtain a product containing a mirabegron beta crystal form (for example, a mirabegron beta crystal form, a mixture of the mirabegron beta crystal form and an alpha crystal form and the like), and then recrystallizing with a mixed solvent to obtain a mirabegron alpha crystal form;
wherein the mixed solvent isAnd water, R is C 2 ～C 3 Hydrocarbyl (hydrocarbyl including alkyl, alkenyl, alkynyl, etc.); preferably, R is C 3 Alkyl (including n-propyl and isopropyl), more preferably, R is isopropyl.
Further, the method comprises the steps of,
in the preparation method of the mirabegron alpha crystal form,and water in a mass ratio of 0.5-15:1; preferably, a +>And water in a mass ratio of 0.5-7:1 or 8-15:1; more preferably, the->And water in a mass ratio of 0.8 to 6.7:1 or 9.5 to 13:1 (e.g., 1:1, 5:1, 10:1, 12.5:1, etc.).
Further, the method comprises the steps of,
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 method comprises the steps of,
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 solids, separating, and drying to obtain the mirabegron alpha crystal form; more preferably, the cooling rate from 65-80 ℃ to 5-35 ℃ is 5+/-0.5 ℃/10min;
and/or the number of the groups of groups,
the concentration crystallization method comprises the following steps: dissolving a product containing the mirabegron beta crystal form in a mixed solvent, concentrating, separating out solids, separating and drying to obtain the mirabegron alpha crystal form;
the proportion between the product containing the mirabegron beta crystal form and the mixed solvent, or the concentration of the product containing the mirabegron beta crystal form in the mixed solvent, can meet the requirement of complete dissolution; in the examples 20kg of the beta crystalline form of mirabegron is dissolved in 396kg of a mixed solvent (for example: 360kg of isopropyl acetate and 36kg of purified water), namely: the mass ratio of the two is 1:19.8, and generally the ratio can be selected in 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.), preferably 1:15 to 49. When the concentration of the product containing the mirabegron beta crystal form in the mixed solvent is too low, the product can be properly concentrated and then crystallized; when the concentration is so high that a small amount of solid is not dissolved, the crystallization may be performed after a certain amount of solvent is appropriately added and/or the undissolved solid is filtered off.
Further, the method comprises the steps of,
in the preparation method of the mirabegron alpha crystal form, one or more than two conditions of a-h are satisfied:
a. the condensing agent is a carbodiimide dehydrating agent, including but not limited to: n, N-Dicyclohexylcarbodiimide (DCC), N' -Diisopropylcarbodiimide (DIC), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and the like, preferably 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride;
b. the acid may be an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.) and/or an organic acid (e.g., tartaric acid, citric acid, etc.), preferably concentrated hydrochloric acid;
c. the solvent can be a solvent conventionally used in such condensation reactions, preferably water;
d. the ratio between compound D or a salt thereof and the condensing agent may be a conventional ratio, for example: the molar ratio between the compound D or a salt thereof and 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 (in the form of H + Calculated as a mole ratio) 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 to be used is 2 to 5kg (for example, 2.5kg, 3kg, 3.5kg, 4kg, etc.) per mol of the compound D or a salt thereof;
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 between the compound D or a salt thereof and the 2-aminothiazole-4-acetic acid is 1:0.5 to 2, preferably 1:1 to 1.2 (for example: 1:1.05, 1:1.1, etc.);
h. the temperature of the condensation reaction can be adjusted according to the actual requirements (considering factors such as reaction rate, occurrence of side reaction, energy consumption, etc.), and is preferably 2 to 40 ℃ (e.g., 10 ℃, 15 ℃, 20 ℃, 30 ℃, 35 ℃ etc.); the reaction 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 liquid (monitored by TLC or HPLC or the like), for example, the reaction time is 3 to 10 hours, or the compound D or a salt thereof substantially disappears (remaining amount in the reaction liquid. Ltoreq.1%) as the reaction end point.
Further, the method comprises the steps of,
in the preparation method of the mirabegron alpha crystal form, the crystallization comprises the following steps: after the condensation reaction is completed, adding inorganic alkali (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 may be determined based on the total amount of the salt of the compound D (e.g., hydrochloride) and the acid, namely: OH of inorganic base - Molar amounts of at least equal to or greater than the total H of the salt of compound D and the acid + Molar amount of the compound D salt (hydrochloride) and the acid (concentrated hydrochloric acid) in the examples according to the invention (total H + ) Inorganic base (hydroxide)Sodium) in a molar amount of 1.05 to 1.3 equivalents (for example: 1.07 equivalents, 1.17 equivalents, 1.27 equivalents, etc.).
Further, the method comprises the steps of,
the preparation method of the mirabegron alpha crystal form further comprises the step of preparing a compound D or a salt thereof:
compound B or a salt thereof can be produced by any of the aforementioned production methods, and then compound B or a salt thereof is subjected to the reduction reaction as described above to produce compound D or a salt thereof;
preferably, the method comprises the steps of,
the reduction reaction can be carried out in the presence of a catalyst, a reducing agent and a solvent;
more preferably, the method further comprises the steps of,
in the step of preparing compound D or a salt thereof, one or two or more of the conditions of i to vii are satisfied:
i. the catalyst is a 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 the commercial products and the actual requirements of the reactions, for example: pd content 5wt% and water content 46.5wt% 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 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 catalyst is used in an amount of 1 to 10% by mass, preferably 1 to 5% by mass (e.g., 2%, 2.5%, 3%, 3.5%, 4% by mass, etc.) of the compound B or a salt thereof;
the ratio between v, compound B or a salt thereof and the solvent may be a conventional ratio, for example: the mass ratio between the compound B or a salt thereof and the solvent is selected in the range of 1:5 to 20, preferably 1:10 to 15 (e.g., 1:11, 1:12, etc.);
vi, the temperature of the reduction reaction can be adjusted according to actual needs, for example: selecting in the range of 5-40 ℃, preferably 20-30 ℃; the reaction end point of the reduction reaction can be controlled and determined by the time of hydrogen introduction and/or the remaining amount of the raw material (compound B or a salt thereof) in the reaction liquid (monitored by HPLC or the like), for example, the time of hydrogen introduction is 4 to 10 hours, or the compound B or a salt thereof substantially disappears (the remaining amount in the reaction liquid is less than or equal to 0.5%) as the reaction end point;
vii, further comprising the post-treatment step: after the reduction reaction is finished, filtering, distilling, adding an alcohol solvent and methyl tertiary butyl ether, stirring for 0.8-2 h at the temperature of 5-35 ℃, separating out solids, separating, and drying to obtain a compound D or salt thereof; preferably, the alcohol solvent is methanol; and/or the mass ratio between the alcohol solvent and the methyl tertiary butyl ether is 1:3-5 (for example, 1:3.5, 1:4, 1:4.5, etc.); and/or the temperature at which the solid is stirred and precipitated is 5 to 25 ℃ (e.g., 15 ℃, 20 ℃), etc.
In the present invention, the salt may be a salt conventional in the art, for example: hydrochloride, sulfate, tartrate, etc.; since milbegron and intermediates thereof (e.g., compound A, compound B, compound D, etc.) contain basic groups in the structural formula: imino (NH) and/or amino (NH) 2 ) And the like, and thus are easily reacted with hydrochloric acid, sulfuric acid, tartaric acid, and the like to form salts.
In the present invention,
the X-ray powder diffraction of the mirabegron alpha crystal form has characteristic peaks at diffraction angles of 2θ=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;
the powder diffraction of the mirabegron beta crystal form has characteristic peaks at diffraction angles of 2θ=9.56±0.2, 19.52±0.2, 20.58±0.2, 21.88±0.2 and 23.34±0.2 degrees.
The beneficial effects of the invention are as follows:
(1) The present invention is directed to a process for preparing a composition comprising the steps of using a combination of 1, 3-dimethylimidazolidinone and borane dimethyl sulfide;
on the one hand, the relative dosage of auxiliary materials (1, 3-dimethyl imidazolinone) can be reduced, and the cost expenditure on the aspect of auxiliary materials is effectively reduced: when the dosage of 1, 3-dimethyl imidazolinone (DMI) is 7.5 equivalents, compared with 8.5 equivalents in the prior art, the cost of the auxiliary materials is reduced to 88 percent (namely 7.5/8.5) of the original expenditure, and when the dosage of 1, 3-dimethyl imidazolinone (DMI) is 5 and 2.5 equivalents, the cost of the auxiliary materials is respectively reduced to 58.8 percent and 29.4 percent of the original expenditure, and simultaneously, the borane dimethyl sulfide is cheap relative to borane tetrahydrofuran, so that the economic benefit is obvious, the market competitiveness of Mirabegron or an intermediate thereof can be well improved, and the commercial success is facilitated;
on the other hand, the production and/or the residue of the dehydroxylated impurities (such as 337008 and the like) can be reduced, so that the content of the dehydroxylated impurities in the product can be kept in a very low level range, and the product quality and the safety of the milbegron or an intermediate thereof can be better ensured;
(2) The present invention has been found through intensive studies that, for mirabegron β crystalline form, either isopropyl acetate solvent (e.g.: ) Also water, the solubility of the single solvent is poor, and the single solvent belongs to the poor solubility condition;
surprisingly, however, if the two solvents, i.e. isopropyl acetate solvent and water, are combined together under certain conditions, the mirabegron beta crystal form can be completely dissolved, which is possibly related to the phase diagram of the binary solvent and the interaction between the solvent combination and the mirabegron beta crystal form, the invention utilizes the newly discovered property of the solvent combination and uses the solvent combination as a crystal transformation solvent for mirabegron crystal transformation, and quite unexpectedly obtains the mirabegron alpha crystal form with better stability;
(3) According to the invention, through the specific solvent combination of isopropyl acetate solvent and water, not only can complete dissolution of the mirabegron beta crystal form be realized, but also successful conversion from 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 seed crystal;
in addition, the solvent combination can also effectively remove the residue of the dehydroxylated impurity (337010) in the milberon product, so that the content of the dehydroxylated impurity can be reduced to below 50% of the original level, thereby better ensuring the product quality and safety of the milberon bulk drug;
(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 the crystalline product obtained using isopropanol/purified water (mass ratio of 6.7:1) as solvent.
Detailed Description
The invention is illustrated in further detail by way of examples which follow, but are not intended to limit the scope of the invention to the examples.
In the present invention, the specific conditions are not specified, and the reagent or the apparatus is carried out according to the conventional conditions or the conditions recommended by the manufacturer, and the reagent or the apparatus is not specified by the manufacturer, and can be obtained by purchasing commercial products or preparing the reagent or the apparatus by a known method.
In connection with the definition of terms used in the present invention, unless otherwise indicated, the initial definition provided by the terms herein applies to the term throughout; to the extent that terms are not specifically defined herein, they should be given meanings that would be able to be given to those skilled in the art in light of the disclosure and/or the context.
C a ～C b Hydrocarbyl means any hydrocarbyl group containing a to b carbon atoms, for example: c (C) 2 ～C 3 Hydrocarbyl refers to hydrocarbyl groups containing 2 or 3 carbon atoms, for example: ethyl, n-propyl, isopropyl, allyl, etc.; hydrocarbyl groups include alkyl, alkenyl (olefmic) groups, and the like.
In the present invention, classification and/or explanation of solvents can be referred to "handbook of solvents" by Cheng Nenglin (4 th edition, beijing: chemical industry Press).
Some of the schemes and examples below may omit details of common reactions, separation techniques, and analytical procedures, and some may omit secondary products from chemical reactions. In addition, in some cases, the reaction intermediates may be used in subsequent steps without isolation and/or purification.
In general, the chemical transformations described in the specification may be performed using substantially stoichiometric reactants, although some reactions may benefit from using an excess of one or more reactants. Any description of stoichiometry, temperature, etc., herein, whether or not the term "range" is used explicitly, is intended to include the endpoints as shown.
Example 1
1. Preparation of Compound 3
The method comprises the following steps:
(1) 26.02kg (about 171 mol) of D-mandelic acid (compound 1), 31.5kg (about 155.45 mol) of 4-nitroaniline hydrochloride (compound 2), 23.12kg (about 171 mol) of 1-hydroxybenzotriazole, 35.28kg (about 171 mol) of N, N-dicyclohexylcarbodiimide and 18.84kg (about 186 mol) of triethylamine were added to 240kg of N, N-dimethylformamide, and the mixture was stirred at a temperature of 20 to 25℃for 5 hours to obtain a reaction solution after the reaction was substantially complete (the remaining amount of compound 2 was not more than 2%) by High Performance Liquid Chromatography (HPLC);
(2) Adding 360kg of ethyl acetate and 604.8kg of purified water into the reaction solution, stirring, then filling up with diatomite, filtering, standing, separating, taking an organic phase, extracting a lower aqueous phase twice with ethyl acetate (285 kg, 171 kg), combining the organic phases, adding a mixed solution of 32.82kg of concentrated hydrochloric acid (36-38wt%) and 285kg of purified water (corresponding to 317.82kg of diluted hydrochloric acid with a concentration of about 3.6-3.8 wt%) to stir for 4h, filling up with diatomite, filtering, standing, separating, taking an organic phase, adding a solution of purified water (277.5 kg) of potassium carbonate (69.3 kg of a solution of potassium carbonate with a concentration of about 20 wt%) to stir for 1h, standing, separating, taking an organic phase, adding 285kg of purified water, stirring for 2h, filling up with diatomite, filtering, adding 15.75kg of sodium chloride into the filtrate, stirring for 1h, standing, separating the liquid, taking an organic phase, adding a solution of purified water (150 kg) of sodium chloride (58.3 kg) corresponding to a water solution of sodium chloride with a concentration of about 28wt percent, stirring for 1h, standing, separating the liquid, taking the organic phase, then carrying out reduced pressure distillation (vacuum degree is less than or equal to-0.09 MPa, temperature is 35-45 ℃) until no fraction is obtained, adding 24kg of toluene, continuing reduced pressure distillation (vacuum degree is less than or equal to-0.09 MPa, temperature is 45-60 ℃) until no fraction is obtained, adding 109.5kg of toluene, heating to 105-115 ℃, stirring and refluxing for 0.5h, then cooling to 15-25 ℃, stirring for 1h, precipitating solid, centrifuging, vacuum drying (vacuum degree is less than or equal to-0.09 MPa, 45-50 ℃) to obtain the compound 3 ((R) -2-hydroxy-N- (4-nitrophenyl) ethyl) -2-phenylacetamide, yield 80.31% and HPLC purity 99.50%.
2. Preparation of Compound 4
The method comprises the following steps:
i. under the protection of inert gas (such as nitrogen), 24kg (about 80 mol) of compound 3 ((R) -2-hydroxy-N- (4-nitrophenyl ethyl) -2-phenylacetamide) and 45.6kg (about 399.5 mol) of 1, 3-dimethyl imidazolidinone (DMI) are added into 53.36kg of tetrahydrofuran under the protection of inert gas (such as nitrogen), then a tetrahydrofuran solution of borane dimethyl sulfide (184 mol and 142.92kg of tetrahydrofuran) is dropwise added, the temperature is controlled to be between-5 and 5 ℃ in the dropwise adding process, the temperature is raised to 55 to 65 ℃ after the adding is finished, the stirring reaction is carried out for 4 hours, and after the Thin Layer Chromatography (TLC) or High Performance Liquid Chromatography (HPLC) detects that the reaction is basically complete (the residual amount of the compound 3 is less than or equal to 2 percent), a reaction liquid is obtained;
ii. The reaction mixture was cooled to-5℃and quenched with 9.51kg of methanol for 0.5h, then 19.66kg of concentrated hydrochloric acid (mass fraction: 36% to 38% by weight) was added, the reaction was stirred for 1h, then reduced pressure distillation was started at 35 to 45℃for about 0.09MPa, to substantially no fraction was produced, 128.57kg of ethyl acetate was added, a solution of purified water (115.70 kg) corresponding to 154.1kg of potassium carbonate aqueous solution having a concentration of about 25% by weight was added, stirred for 1h, left standing, an analytical solution was taken, an organic phase was extracted twice with ethyl acetate (64.3 kg, 42.9 kg) of an aqueous phase, then 14.48kg of sodium chloride and 130.2kg of purified water (corresponding to 144.68kg of sodium chloride aqueous solution having a concentration of about 10% by weight) were added, and then distilled for 1h, an analytical solution was stirred for about 4.80% by vacuum distillation, and then distilled for about 0.45 MPa to about 0.48 kg of isopropyl alcohol, to about 20% by vacuum concentration of ethyl alcohol, 4.80% by weight, and then distilled for about 4.40 kg of isopropyl alcohol, 4.80% by vacuum concentration of ethyl alcohol was added, and distilled solution was obtained.
3. Preparation of Compound 5
The method comprises the following steps:
a. adding 20.4kg of compound 4 ((R) -2- (4-nitrophenethyl) amino) -1-phenyl ethanol hydrochloride) and 0.72kg of palladium-carbon catalyst (Pd/C, pd content 5wt%, water content 46.5 wt%) into a reaction kettle of 242kg of methanol, introducing hydrogen and stirring for reaction for 4 hours, wherein the reaction temperature is 20-30 ℃, and stopping introducing hydrogen after HPLC detects that the residual amount of compound 4 in the reaction liquid is less than or equal to 0.5%, so as to obtain a reaction liquid;
b. the reaction solution is filtered, distilled under reduced pressure (the vacuum degree is less than or equal to minus 0.09MPa and 35-45 ℃) until the reaction solution becomes sticky or becomes turbid just before beginning, distilled under reduced pressure is stopped, 60.5kg of methanol is added, stirring and dissolving are carried out at 35-45 ℃, 240kg of Methyl Tertiary Butyl Ether (MTBE) is added, stirring is carried out for 1h at the temperature of 5-15 ℃ after the addition is finished, solids are separated out, centrifugation and vacuum drying (the vacuum degree is less than or equal to minus 0.09MPa and the vacuum degree is 45-50 ℃) are carried out, and the compound 5 ((R) -2- (4-aminophenyl) amino) -1-phenyl ethanol hydrochloride) is obtained, the yield is 87.5%, and the HPLC purity is 99.80%.
4. Preparation of mirabegron beta crystalline form
I. Under the protection of inert gas (such as nitrogen), adding 187.0kg of purified water, 5.6kg of concentrated hydrochloric acid (36-38wt% in mass fraction, with the HCl content being about 57.5 mol), 16kg (about 54.6 mol) of compound 5 ((R) -2- (4-aminophenyl) amino) -1-phenylethanol hydrochloride), 9.08kg (about 57.4 mol) of 2-aminothiazole-4-acetic acid into a reaction kettle, then adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (11.52 kg, about 60mol, EDC) of water (23 kg), controlling the temperature to be 2-10deg.C in the adding process, heating to 20-30deg.C after the adding process is completed, preserving heat for 3h, and obtaining a reaction solution after the residual amount of compound 5 in the reaction solution is detected by HPLC to be less than or equal to 1%;
II. 162kg of purified water is added into the reaction liquid, the mixture is stirred uniformly, then purified water (80 kg) solution of sodium hydroxide (5.25 kg, about 131.2 mol) is added, the temperature is controlled to be 20-35 ℃ in the adding process, the mixture is stirred for 1h after the addition is finished, crystals are separated out, the mixture is centrifuged, and vacuum drying (the vacuum degree is less than or equal to-0.09 MPa and 55-60 ℃) is carried out, so that a crystallization product B is obtained, 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 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: intelliity=CPS, 2T (0) =0.0 (deg) for calculating lattice spacing (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
The results showed that the crystalline product B obtained in the present invention has characteristic peaks at diffraction angles 2θ= 9.559, 19.520, 20.580, 21.880, 23.340 degrees (°), which are consistent with the characteristic peaks of the β -type crystals described in CN 1575287a (title: α -type or β -type crystals of an acetanilide derivative), so that it can be confirmed that the crystalline product B obtained in the present invention is the β -type crystal form of milabegron.
5. Conversion of mirabegron beta crystalline form to alpha crystalline form
Adding 20kg of a crystallization product B (beta crystal form) into 396kg of a mixed solvent (360 kg of isopropyl acetate and 36kg of purified water), heating to 68-78 ℃ while stirring, cooling to 15-25 ℃ (the cooling rate is 5 ℃/10 min) after complete dissolution, stirring for 1h, separating out crystals, centrifuging, and vacuum drying (the vacuum degree is less than or equal to-0.09 MPa and 55-60 ℃) to obtain a crystallization 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 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: intelliity=CPS, 2T (0) =0.0 (deg) for calculating lattice spacing (Cu/K-alpha1)；
The results are shown in Table 2 and FIG. 2.
TABLE 2X-ray powder diffraction (XRD) detection results of crystalline product A
The results showed that the crystalline product a obtained in the present invention has characteristic peaks at diffraction angles 2θ= 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 crystals described in CN 1575287a (title: α -type or β -type crystals of an acetanilide derivative), so that it can be confirmed that the crystalline product a obtained by conversion of the β -type crystal of mirabegron in the present invention is the α -type crystal of mirabegron.
Examples 2 to 4
In step i of the process for producing compound 4, the amount of 1, 3-Dimethylimidazolidinone (DMI) used was changed to 0mol, 200mol, 600mol, respectively, namely: the amount of 1, 3-Dimethylimidazolidinone (DMI) used was 0 equivalent, 2.5 equivalents, 7.5 equivalents, respectively, based on the compound 3 (mol), and other process conditions were unchanged (the same as in example 1), to prepare compound 4, whose yield and HPLC purity, and impurity content are shown in Table 3.
TABLE 3 influence of the amount of 1, 3-Dimethylimidazolone (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 is good 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 is not detected, and means that the content is lower than the detection limit.
Examples 5 to 6
In the step i of the preparation method of the compound 4, the dosage of the borane dimethyl sulfide is respectively changed to 168mol and 200mol, namely: the borane dimethyl sulfide 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 (the same as in example 1), to prepare compound 4, whose yield and HPLC purity, and impurity content are shown in table 4.
TABLE 4 influence of borane dimethyl sulfide usage on the preparation of Compound 4
Example 5 Example 1 Example 6
Borane dimethyl sulfide amount/equivalent 2.1 2.3 2.5
Yield is good 86.0％ 88.7％ 88.5％
HPLC purity 99.76％ 99.6％ 99.73％
Impurity (337008) ND ND ND
Examples 7 to 9
In step i of the preparation method of the compound 4, the temperature is respectively controlled at 30+/-2 ℃, 40+/-2 ℃ and 50+/-2 ℃ during the process of dropwise adding the tetrahydrofuran solution of the borane dimethyl sulfide, and other process conditions are unchanged (the same as in the example 1), so that the compound 4 is prepared, and the yield, the HPLC purity and the impurity content are shown in Table 5.
TABLE 5 influence of temperature control during the dripping on the preparation of Compound 4
Example 1 Example 7 Example 8 Example 9
Temperature (temperature) -5～5℃ 30±2℃ 40±2℃ 50±2℃
Yield is good 88.7％ -- -- --
HPLC purity 99.6％ 99.64％ 99.63％ 98.81％
Impurity (337008) ND ND ND ND
Examples 10 to 12
In the step a of the preparation method of the compound 5, the dosage of the palladium carbon catalyst (Pd/C, pd content 5wt%, water content 46.5 wt%) was changed to 0.4kg, 0.51kg, 0.61kg, respectively, namely: the palladium carbon catalyst was used in an amount of 2%, 2.5% and 3% by mass of the compound 4, and other process conditions were unchanged (the same as in example 1), to obtain a compound 5, whose yield and HPLC purity, and impurity content are shown in table 6.
TABLE 6 influence of the amount of Palladium carbon catalyst used on the preparation of Compound 5
Examples 13 to 14
In step b of the preparation method of the compound 5, the compound 5 is prepared by stirring for 1h at the temperature of 20+/-2 ℃ and 30+/-2 ℃ respectively, separating out solids, and keeping other process conditions unchanged (the same as in the example 1), wherein the yield, the HPLC purity and the impurity content are shown in Table 7.
TABLE 7 influence of the temperature at which solids are precipitated on the preparation of Compound 5
Example 1 Example 13 Example 14
Temperature at which solids precipitate 5～15℃ 20±2℃ 30±2℃
Yield is good 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 the step I of the preparation method of the mirabegron beta crystal form, the dosage of the 2-aminothiazole-4-acetic acid is respectively changed into 54.6mol and 60mol, namely: the amounts of 2-aminothiazole-4-acetic acid used were 1 equivalent and 1.1 equivalent, respectively, based on the compound 5 (mol), and other process conditions were unchanged (the same as in example 1), to obtain a reaction solution, and the milbegron content and the impurity content in the reaction solution were measured, and the results are shown in Table 8.
TABLE 8 influence of 2-aminothiazole-4-acetic acid dosage on preparation of Mirabegron
Example 15 Example 1 Example 16
2-aminothiazole-4-acetic acid quantity/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 the 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 54.6 mol) and 5.87kg (the HCl content is about 60 mol), namely: the amounts of HCl and other process conditions were not changed (same as in example 1) in terms of compound 5 (mol), respectively, 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 influence of the amount of concentrated hydrochloric acid on the preparation of Mirabegron
Example 17 Example 1 Example 18
HCl amount/equivalent 1.0 1.05 1.1
HPLC purity 97.29％ 97.84％ 96.53％
Impurity (337010) 0.09％ 0.07％ 0.10％
Examples 19 to 21
In the 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 amounts of EDC used were 1 equivalent, 1.05 equivalent and 1.2 equivalent, respectively, based on the compound 5 (mol), and other process conditions were unchanged (the 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 10.
TABLE 10 influence of EDC usage on preparation of Mirabegron
Examples 22 to 23
In the step I of the preparation method of the mirabegron beta crystal form, the reaction temperature is respectively changed to 15+/-2 ℃ and 35+/-2 ℃ for heat preservation reaction for 3 hours, other process conditions are unchanged (the same as in the example 1), a reaction liquid is obtained, and the mirabegron content and the impurity content in the reaction liquid are detected, and the result is 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％
Impurity (337010) 0.10％ 0.07％ 0.10％
Examples 24 to 25
In the step II of the preparation method of the mirabegron beta crystal form, the dosage of sodium hydroxide is respectively changed into 120.1mol and 142mol, namely: the sodium hydroxide was used in an amount of 1.07 equivalents and 1.27 equivalents, respectively, based on the total molar amount of the compound 5 and concentrated hydrochloric acid (about 112.1 mol), and other process conditions were unchanged (the same as in example 1), to obtain a crystalline product B (confirmed to be the beta crystalline form by X-ray powder diffraction detection), whose yield and HPLC purity, and impurity content are shown in table 12.
TABLE 12 influence of sodium hydroxide dosage on preparation of milbegron beta crystal form
Example 24 Example 1 Example 25
Sodium hydroxide amount/equivalent 1.07 1.17 1.27
Yield is good 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 mirabegron beta crystal form into the alpha crystal form, the dosage of the mixed solvent (396 kg) is unchanged, the mass ratio of isopropyl acetate to purified water is respectively changed to 1:1, 5:1 (namely 330kg of isopropyl acetate and 66kg of purified water), 6.7:1 and 12.5:1, and other process conditions are unchanged (the same as in the example 1), so that a crystal product A (alpha crystal form) is prepared, and the test results are shown in Table 13.
TABLE 13 influence of solvent ratio on preparation of Mirabegron alpha Crystal form
As confirmed by X-ray powder diffraction (XRD) detection, the crystalline products obtained in examples 26 to 29 were all in the form of mirabegron alpha crystals, for example:
the crystalline product of example 26: x-ray powder diffraction has characteristic peaks at diffraction angles 2θ= 5.280, 8.020, 15.260, 17.840, 18.926, 20.180, 23.100, 24.300 degrees;
the crystalline product of example 28: the X-ray powder diffraction has characteristic peaks at diffraction angles 2θ= 5.320, 8.080, 15.300, 17.899, 19.003, 20.220, 23.141, 24.360 degrees.
Furthermore, in a related experimental study, the inventors of the present application also found that:
(1) Pulping with purified water alone, the starting material is beta-crystalline, and the product obtained is still beta-crystalline: the X-ray powder diffraction has characteristic peaks at diffraction angles 2θ= 9.540, 19.600, 20.600, 21.801 and 23.321 degrees, and can not be converted into an alpha crystal form;
(2) The problem with using isopropyl acetate alone (other process conditions are the same) is that the beta-form cannot be completely dissolved, and more insoluble solids are visible to the naked eye, and the residual insoluble solids (beta-form) can be used as seed crystals in the subsequent crystallization process, so that the obtained product is still beta-form and cannot be converted into alpha-form;
(3) Using isopropanol/purified water (mass ratio of 6.7:1) as solvent, the starting material was beta crystalline form, and the product was still beta crystalline form, with otherwise identical process conditions: x-ray powder diffraction has characteristic peaks at diffraction angles 2θ= 9.540, 19.600, 20.600, 21.820, 23.300 degrees, see fig. 3, nor can it be converted to the alpha crystalline form.
Example 30
In the method for converting the mirabegron beta crystal form into the alpha crystal form, the crystallization method is changed from the cooling crystallization method of the example 1 to a concentration crystallization method, and the specific method is as follows: the crystallization product B (beta crystal form) is completely dissolved in isopropyl acetate/purified water (the mass ratio is 6.7:1), then the mixture is concentrated, crystals are separated out, and the mixture is centrifuged (or filtered) and dried in vacuum (the vacuum degree is less than or equal to-0.09 MPa and 55-60 ℃), so that the crystallization product A is obtained, the purity of the HPLC is 99.86%, and the X-ray powder diffraction has characteristic peaks at diffraction angles of 2 theta= 5.280, 8.039, 15.260, 17.860, 19.056, 20.179, 23.100 and 24.300 ℃, thereby confirming that the obtained crystallization product A is alpha crystal form.
Examples 31 to 32
In the method for converting mirabegron beta crystal form into alpha crystal form, the temperature of precipitated crystals is changed to 10+/-2 ℃ and 30+/-2 ℃ respectively, other process conditions are unchanged (the same as in example 1), and a crystal product A (alpha crystal form) is prepared, wherein the yield, the HPLC purity and the impurity content are shown in Table 14.
TABLE 14 influence of the temperature at which crystals are precipitated on the preparation of the alpha form of Mirabegron
Example 31 Example 1 Example 32
Temperature (temperature) 10±2℃ 15～25℃ 30±2℃
Yield is good 89.8％ 85.9％ 83.5％
HPLC purity 99.73％ 99.81％ 99.82％
Impurity (337010) 0.03％ 0.02％ 0.02％
。

Claims (25)

1. The preparation method of the mirabegron alpha crystal form is characterized by comprising the following steps of:
under the protection of inert gas or without inert gas, carrying out condensation reaction on the compound D or salt thereof and 2-aminothiazole-4-acetic acid in the presence of a condensing agent, acid and a solvent, crystallizing to obtain a product containing a mirabegron beta crystal form, and then recrystallizing with a mixed solvent to obtain a mirabegron alpha crystal form;
wherein the mixed solvent isAnd water, R is C 3 An alkyl group; />And water in a mass ratio of 0.5-15:1.
2. The method for preparing milbegron alpha crystal form according to claim 1, wherein R is isopropyl.
3. The process for preparing the alpha crystal form of mirabegron according to claim 1, wherein, And water in a mass ratio of 0.5-7:1 or 8-15:1.
4. A process for the preparation of crystalline form alpha of mirabegron according to claim 3,and water in a mass ratio of 0.8-6.7:1 or 9.5-13:1.
5. The process for the preparation of crystalline form α of milbegron according to any one of claims 1 to 4, characterized in that the recrystallization is carried out by a cooling crystallization process and/or a concentration crystallization process.
6. The method for preparing milbegron alpha crystal form according to claim 5, wherein when the recrystallization adopts a cooling crystallization method, the cooling crystallization method comprises the steps of: and (3) 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 solids, separating, and drying to obtain the mirabegron alpha crystal form.
7. The preparation method of the mirabegron alpha crystal form according to claim 6, wherein the temperature of the mirabegron solution is reduced from 65-80 ℃ to 5-35 ℃ at a temperature reduction rate of 5+/-0.5 ℃/10min.
8. The method for preparing milbegron alpha crystal form according to claim 5, wherein when the recrystallization adopts a concentrated crystallization method, the concentrated crystallization method comprises the steps of: dissolving a product containing the mirabegron beta crystal form in a mixed solvent, concentrating, separating out solids, 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.
9. The method for preparing milbegron alpha crystal form according to claim 8, wherein the mass ratio of the product containing milbegron beta crystal form to the mixed solvent is 1:15-49.
10. The preparation method of mirabegron alpha crystal form according to any one of claims 1 to 4, wherein one or more of conditions a to h are satisfied:
a. the condensing agent is a carbodiimide dehydrating agent;
b. the acid is inorganic acid and/or organic acid;
c. the solvent is water;
d. the mol ratio between the compound D or the salt thereof and the condensing agent is 1:0.5-2;
e. the mol ratio between the compound D or the salt thereof and the acid is 1:0.5-2;
f. the dosage of the solvent is 2-5 kg per mol of the compound D or the salt thereof;
g. the mol ratio between the compound D or the salt thereof and the 2-aminothiazole-4-acetic acid is 1:0.5-2;
h. the temperature of the condensation reaction is 2-40 ℃.
11. The preparation method of mirabegron alpha crystal form according to claim 10, wherein one or more than two of conditions a to e are satisfied:
a. the condensing agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride;
b. the acid is concentrated hydrochloric acid;
c. The mol ratio between the compound D or the salt thereof and the condensing agent is 1:1-1.5;
d. the mol ratio between the compound D or the salt thereof and the acid is 1:1-1.2;
e. the molar ratio of the compound D or the salt thereof to the 2-aminothiazole-4-acetic acid is 1:1-1.2.
12. The process for the preparation of crystalline form α of milbegron according to any one of claims 1 to 4, characterized in that the crystallization comprises the following steps: after the condensation reaction is completed, inorganic alkali and water are added, and the mixture is stirred, solid is separated out, separated and dried, thus obtaining the mirabegron beta crystal form.
13. The method for preparing milbegron alpha crystal form according to claim 12, wherein the inorganic base is sodium hydroxide, potassium hydroxide or lithium hydroxide;
or alternatively, the first and second heat exchangers may be,
with the total H of the compound D or a salt thereof and the acid + Molar amount of OH of inorganic base - The molar usage is 1.05 to 1.3 equivalent.
14. The process for the preparation of crystalline form α of milbegron according to any one of claims 1 to 4, further comprising the step of preparing compound D or a salt thereof:
the compound B or a salt thereof is subjected to the above reduction reaction to produce the compound D or a salt thereof.
15. The process for preparing crystalline form α of milbegron according to claim 14, wherein the reduction is carried out in the presence of a catalyst, a reducing agent and a solvent.
16. The process for preparing crystalline form α of milabegron according to claim 15, wherein the step of preparing compound D or a salt thereof satisfies one 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;
iv, the dosage of the catalyst is 1-10% of the mass of the compound B or the salt thereof;
v, the mass ratio of the compound B or the salt thereof to the solvent is 1:5-20;
vi, the temperature of the reduction reaction is 20-30 ℃;
vii, further comprising the post-treatment step: after the reduction reaction is finished, filtering, distilling, adding an alcohol solvent and methyl tertiary butyl ether, stirring for 0.8-2 h at the temperature of 5-35 ℃, separating out solid, separating, and drying to obtain the compound D or salt thereof.
17. The process for preparing crystalline form α of milabegron according to claim 16, wherein the step of preparing compound D or a salt thereof satisfies one or more of the conditions i to v:
i. the solvent is methanol;
ii. The dosage of the catalyst is 1% -5%;
iii, the mass ratio of the compound B or the salt thereof to the solvent is 1:10-15;
v, in the post-treatment step, the alcohol solvent is methanol;
Or the mass ratio of the alcohol solvent to the methyl tertiary butyl ether is 1:3-5;
or, the temperature of stirring and solid precipitation is 5-25 ℃.
18. Process for the preparation of crystalline form α of milabegron according to claim 14, characterized in that the compound B or a salt thereof is prepared by a process comprising the steps of:
the oxygen on the carbonyl group is removed from compound A or a salt thereof in the presence of 1, 3-dimethylimidazolidinone, borane dimethyl sulfide and a solvent with or without inert gas protection to produce compound B or a salt thereof.
19. The process for preparing a crystalline form α of mirabegron according to claim 18, wherein,
the mol ratio between the compound A or the salt thereof and the 1, 3-dimethyl imidazolinone is 1:0.1-7.5;
or alternatively, the first and second heat exchangers may be,
the molar ratio of the compound A or the salt thereof to the borane dimethyl sulfide is 1:2-5;
or alternatively, the first and second heat exchangers may be,
the molar ratio of the borane dimethyl sulfide to the 1, 3-dimethyl imidazolinone is 1:1.05-3.5.
20. The process for preparing a crystalline form α of mirabegron according to claim 19, wherein,
the mol ratio between the compound A or the salt thereof and the 1, 3-dimethyl imidazolinone is 1:2.5-5;
or alternatively, the first and second heat exchangers may be,
the molar ratio of the compound A or the salt thereof to the borane dimethyl sulfide is 1:2-3;
Or alternatively, the first and second heat exchangers may be,
the molar ratio of the borane dimethyl sulfide to the 1, 3-dimethyl imidazolinone is 1:1.05-2.4.
21. The process for preparing a crystalline form α of mirabegron according to claim 18, wherein,
the solvent is an ether solvent;
or alternatively, the first and second heat exchangers may be,
the dosage of the solvent is 2-5 kg for each mole of the compound A or the salt thereof;
or alternatively, the first and second heat exchangers may be,
the reaction temperature for removing the oxygen on the carbonyl is-10-70 ℃;
or alternatively, the first and second heat exchangers may be,
the borane dimethyl sulfide is added at the temperature of between 10 ℃ below zero and 70 ℃;
or alternatively, the first and second heat exchangers may be,
the method also comprises the following post-treatment steps: after the reaction of removing oxygen on carbonyl of the compound A or salt thereof is completed, adding methanol and inorganic acid into the reaction liquid at the temperature of minus 5-5 ℃, concentrating, adding an organic solvent and an alkaline aqueous solution, separating liquid, taking an organic phase, washing with a saline solution, concentrating, adding isopropanol and inorganic acid, stirring for 1.5-3 h at the temperature of 40-50 ℃, cooling to the temperature of 20-25 ℃, separating out solid, separating, and drying to obtain the compound B or salt thereof.
22. The process for preparing a crystalline form α of mirabegron according to claim 21, wherein,
the solvent is tetrahydrofuran;
or alternatively, the first and second heat exchangers may be,
the reaction temperature for removing the oxygen on the carbonyl is 55-65 ℃;
or alternatively, the first and second heat exchangers may be,
the borane dimethyl sulfide is added at the temperature of between 5 ℃ below zero and 5 ℃.
23. The process for the preparation of crystalline form α of milabegron according to claim 18, further comprising the step of preparing compound a or a salt thereof:
and carrying out amidation reaction on the compound X or the salt thereof and D-mandelic acid in the presence of a dehydrating agent, organic amine and a solvent with or without inert gas protection to generate a compound A or the salt thereof.
24. The process for preparing a crystalline form α of mirabegron according to claim 23,
the step of preparing the compound A or the salt thereof satisfies one or more than two conditions of (1) to (gamma):
(1) the dehydrating agent is a carbodiimide dehydrating agent;
(2) the organic amine is selected from triethylamine and/or diisopropylethylamine;
(3) the solvent is an amide solvent;
(4) the mol ratio between the compound X or the salt thereof and the dehydrating agent is 1:0.5-2;
(5) the molar ratio of the compound X or the salt thereof to the organic amine is 1:0.5-2;
(6) the dosage of the solvent corresponding to each mole of the compound X or the salt thereof is 1-5 kg;
(7) the mol ratio between the compound X or the salt thereof and the D-mandelic acid is 1:0.5-2;
(8) the amidation reaction is further carried out in the presence of 1-hydroxybenzotriazole, and the molar ratio of the compound X or the salt thereof to the 1-hydroxybenzotriazole is 1:0.5-2;
(9) The temperature of the amidation reaction is 2-40 ℃;
further comprising the post-treatment steps of: after the amidation reaction is finished, adding an organic solvent and water, filtering, separating liquid, taking an organic phase, washing with acid, washing with an alkaline aqueous solution, washing with a saline solution, concentrating, then adding toluene, stirring and refluxing, cooling to 15-25 ℃, separating out solids, separating, and drying to obtain the compound A or salt thereof.
25. The process for preparing crystalline form α of milabegron according to claim 23, wherein the step of preparing compound a or a salt thereof satisfies one or more of the conditions (1) to (7):
(1) the dehydrating agent is N, N-dicyclohexylcarbodiimide;
(2) the organic amine is selected from triethylamine;
(3) the solvent is N, N-dimethylformamide;
(4) the mol ratio between the compound X or the salt thereof and the dehydrating agent is 1:1-1.5;
(5) the molar ratio between the compound X or the salt thereof and the organic amine is 1:1.1-1.5;
(6) the mol ratio between the compound X or the salt thereof and the D-mandelic acid is 1:1-1.5;
(7) the amidation reaction is further carried out in the presence of 1-hydroxybenzotriazole, and the molar ratio of the compound X or the salt thereof to the 1-hydroxybenzotriazole is 1:1-1.5.
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