CN111072589B

CN111072589B - Recrystallization method and preparation method of mirabegron

Info

Publication number: CN111072589B
Application number: CN201911353104.XA
Authority: CN
Inventors: 何海晓; 张永林; 雷飞; 熊继业; 王新锋; 马士锋
Original assignee: Beijing Zhendong Guangming Pharmaceutical Research Institute Co ltd
Current assignee: Beijing Zhendong Guangming Pharmaceutical Research Institute Co ltd
Priority date: 2019-12-25
Filing date: 2019-12-25
Publication date: 2022-03-22
Anticipated expiration: 2039-12-25
Also published as: CN111072589A

Abstract

The invention relates to the technical field of chemical drug purification, in particular to a recrystallization method and a preparation method of mirabegron. The recrystallization method of the mirabegron comprises the following steps: dissolving the crude mirabegron in a mixed solvent at a reflux temperature, cooling and crystallizing, and collecting a solid; the mixed solvent comprises an alcohol solvent and dichloromethane. According to the recrystallization method, through regulation and control of the mixed solvent, the beta-crystal form mirabegron can be quickly converted into the alpha-crystal form after being dissolved in the specific mixed solvent, the solubility of the beta-crystal form mirabegron in the specific mixed solvent system is reduced after crystal conversion, the beta-crystal form mirabegron is slowly separated out, and other impurity components are separated from the mirabegron, so that the aim of purification is fulfilled; particularly, the content of the impurity imA in the product can be reduced aiming at imA impurities in the crude mirabegron, the crude mirabegron obtained on the basis of the original process route is subjected to simple crystallization purification, the operation process is simple, the production cost is low, and the method has important significance for research and development and application of the mirabegron medicine.

Description

Recrystallization method and preparation method of mirabegron

Technical Field

The invention relates to the technical field of chemical drug purification, in particular to a recrystallization method and a preparation method of mirabegron.

Background

Mirabegron is a drug used for treating urgency, frequency and incontinence of urine caused by overactive bladder, and is first marketed in japan in 2011. The united states Food and Drug Administration (FDA) approved for the treatment of overactive bladder (OAB) in adults on day 6, month 28, 2012. Mirabegron: c₂₁H₂₄N₄O₂S, Chinese cultural name: (R) -2- (2-aminothiazol-4-yl) -4' - [2- [ (2-hydroxy-2-phenylethyl) amino group]Ethyl radical]The structure of the acetanilide is shown as the formula (III):

the synthesis route of mirabegron mainly comprises two routes:

scheme 1: (R) -styrene oxide and 4-nitrophenylethylamine are used as starting materials, and after dehydration condensation and palladium carbon hydrogenation reduction of nitro, the starting materials and 2-aminothiazole-4-acetic acid are subjected to dehydration condensation to obtain mirabegron;

scheme 2: (R) -mandelic acid and 4-nitrophenylethylamine are used as starting materials, and the milaberon is obtained by dehydration condensation, borane reduction amide, palladium carbon hydrogenation reduction nitro and dehydration condensation with 2-aminothiazole-4-acetic acid.

In the two synthetic routes, because both the two synthetic routes need reduction reaction, primary amine obtained by nitro reduction and secondary amine obtained by amido bond reduction can participate in the condensation reaction of the next step, an impurity imA condensed with two molecules of 2-aminothiazole-4-acetic acid can be generated, and the impurity imA is very similar to the chemical polarity of mirabegron and is a key impurity in the mirabegron. The chemical formula of the impurity imA is as follows:

for this reason, researchers have developed some new synthesis processes for mirabegron to avoid the production of impurity imA. However, in order to avoid the formation of the impurity imA, the new process steps are relatively cumbersome and the raw material cost is high.

Therefore, on the basis of obtaining the crude mirabegron by the original four-step reaction, if the impurity imA in the crude mirabegron can be removed, the method has important significance for drug development.

In view of the above, the present invention is particularly proposed.

Disclosure of Invention

The first purpose of the invention is to provide a recrystallization method of mirabegron, which can remove the impurity imA in the mirabegron crude product with high efficiency.

The second object of the present invention is to provide a method for producing mirabegron, which can further increase the purity of mirabegron and reduce the content of the impurity imA by subjecting the crude mirabegron obtained by the above recrystallization.

In order to achieve the above purpose of the present invention, the following technical solutions are adopted:

the recrystallization method of the mirabegron comprises the following steps:

dissolving the crude mirabegron in a mixed solvent at a reflux temperature, cooling and crystallizing, and collecting a solid;

the mixed solvent comprises an alcohol solvent and dichloromethane.

According to the recrystallization method, through regulation and control of the mixed solvent, beta-crystal-form mirabegron can be quickly converted into alpha-crystal form after being dissolved in the specific mixed solvent, the solubility of the beta-crystal-form mirabegron in a specific mixed solvent system is reduced after crystal conversion, the beta-crystal-form mirabegron is slowly separated out, other impurity components are separated from the mirabegron, the purpose of purification is achieved, the solubility of the impurity imA in the mixed solvent is higher, and therefore the content of the impurity imA in the product is further reduced.

In a preferred embodiment of the present invention, the volume ratio of the alcohol solvent to dichloromethane is 1: 10 to 40.

In various embodiments, the ratio of alcohol solvent to dichloromethane can be 1: 10, 1: 15, 1: 20, 1: 25, 1: 30, 1: 35, 1: 40, and so on.

In a preferred embodiment of the present invention, the volume ratio of the alcohol solvent to dichloromethane is 1: 10 to 30.

By adopting the mixed solvent with the proportion, the purity, imA removal rate and product yield of the recrystallized product can be further considered.

In a preferred embodiment of the invention, the ratio of the crude mirabegron to the mixed solvent is 1 g: 10-60 mL, preferably 1 g: 10-50 mL, and more preferably 1 g: 10-40 mL.

By regulating the dosage relation of the crude mirabegron and the mixed solvent within the range, the dosage of the mixed solvent can be reduced as much as possible while the purification of the mirabegron is considered, and the content of the impurity imA is reduced.

In a preferred embodiment of the invention, the ratio of the crude mirabegron to the mixed solvent is 1 g/20-30 mL, preferably 1 g/25-30 mL, and more preferably 1 g/30 mL.

When the dosage of the mixed solvent is too small, in the process of dissolving the crude mirabegron, the mirabegron in the beta crystal form is transformed into the alpha crystal form and then is quickly crystallized, and the stirring is hindered, so that the post-treatment is inconvenient.

In a preferred embodiment of the present invention, the alcoholic solvent is selected from any one or more of methanol, ethanol and isopropanol. Preferably, the alcoholic solvent is methanol.

By adopting the specific alcohol, the transformation of the mirabegron from a beta crystal form to an alpha crystal form can be triggered, the solubility of the mirabegron is changed, meanwhile, the dichloromethane is matched to ensure the solubility difference of the mixed solvent to the alpha crystal form mirabegron and impurities, particularly the impurity imA, the separation of the mirabegron and the impurities is promoted, the product purity is improved, and the content of the impurity imA is reduced.

Meanwhile, the solubility of mirabegron in ethanol and isopropanol is poor, and the mirabegron can be dissolved only under the condition of heating and refluxing, but the boiling point of dichloromethane is relatively low, and the dissolution of the ethanol/dichloromethane and isopropanol/dichloromethane system on the crude mirabegron is not as good as that of the methanol/dichloromethane system.

When methanol and dichloromethane are used in combination, the recrystallization effect can be further improved, and the content of the impurity imA can be further reduced to be less than 0.1 percent of the limit.

In a preferred embodiment of the present invention, the alcohol solvent includes methanol and dichloromethane; the volume ratio of the methanol to the dichloromethane is 1: 10-40, preferably 1: 20-30.

In a preferred embodiment of the present invention, the reflux temperature may be 30 to 40 ℃.

In one embodiment of the present invention, the recrystallization method comprises the following steps:

(a) uniformly mixing an alcohol solvent and dichloromethane, heating to reflux temperature, such as 30-40 ℃, adding a crude mirabegron, and stirring for dissolving;

(b) naturally cooling and crystallizing the system obtained in the step (a), and filtering and collecting solids.

And collecting the obtained solid, and drying at normal temperature, such as air drying, to obtain recrystallized mirabegron pure product.

In a specific embodiment of the present invention, the temperature reduction is natural temperature reduction at room temperature.

In a specific embodiment of the invention, in the step (b), the system obtained in the step (a) is stirred at room temperature for 2-4 hours for crystallization, and the solid is collected by filtration.

The invention also provides a preparation method of the mirabegron, which comprises the step of carrying out recrystallization treatment on the mirabegron crude product by adopting any one of the recrystallization methods.

The synthetic route of the crude mirabegron can be as follows:

and/or the presence of a gas in the gas,

Compared with the prior art, the invention has the beneficial effects that:

according to the recrystallization method, through regulation and control of the mixed solvent, the beta-crystal form mirabegron can be quickly converted into the alpha-crystal form after being dissolved in the specific mixed solvent, the solubility of the beta-crystal form mirabegron in the specific mixed solvent system is reduced after crystal conversion, the beta-crystal form mirabegron is slowly separated out, and other impurity components are separated from the mirabegron, so that the aim of purification is fulfilled; particularly, the content of the impurity imA in the product can be reduced aiming at imA impurities in the crude mirabegron, the crude mirabegron obtained on the basis of the original process route is subjected to simple crystallization purification, the operation process is simple, the production cost is low, and the method has important significance for research and development and application of the mirabegron medicine.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.

FIG. 1 is a liquid phase analysis spectrum of a crude mirabegron of example 1 of the present invention;

FIG. 2 is an enlarged view of the liquid phase analysis spectrum of FIG. 1;

FIG. 3 is a liquid phase analysis spectrum of the mirabegron pure product prepared in example 1 of the present invention;

FIG. 4 is an enlarged view of the liquid phase analysis spectrum of FIG. 3;

fig. 5 is a powder X-ray diffraction pattern of the mirabegron pure product prepared in each embodiment of the present invention, wherein the powder X-ray diffraction patterns of the mirabegron pure product prepared in embodiments 1-8 correspond from top to bottom, respectively;

FIG. 6 is a powder X-ray diffraction pattern of the mirabegron alpha crystal form;

fig. 7 is a powder X-ray diffraction pattern of mirabegron beta crystal form.

Detailed Description

The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings and the detailed description, but those skilled in the art will understand that the following described embodiments are some, not all, of the embodiments of the present invention, and are only used for illustrating the present invention, and should not be construed as limiting the scope of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

In the embodiments of the present invention, the purity of mirabegron is detected by using high performance liquid chromatography, and the detection conditions are as follows:

a chromatographic column: phenomenex Luna, C18, 250 x 4.6mm, 5 μm;

flow rate: 1 mL/min;

detection wavelength: 220 nm;

column temperature: 35 ℃;

sample introduction amount: 20 mu L of the solution;

mobile phase A: a mixture of 10mmol/L sodium heptanesulfonate +20mmol/L potassium dihydrogen phosphate (pH adjusted to 3.0 with phosphoric acid) in water and acetonitrile in a volume ratio of 9: 1;

mobile phase B: acetonitrile;

the gradient elution conditions (volume ratio) are as follows in table 1:

TABLE 1 gradient elution conditions

T(min)	A(％)	B(％)
			0	100	0
8	82	18
			15	82	18
25	45	55
			25.1	100	0
40	100	0

The specifications of part of the mirabegron crude products used in the inventive examples and comparative examples are as follows:

crude product 20190114, manufactured by Toguanming pharmaceutical research institute Co., Ltd, Beijing, under the batch number MLBL-API-20190114-CP, the purity thereof was 98.08%, and the imA content thereof was 0.65%;

crude product 20190122, manufactured by Toguanming pharmaceutical research institute Co., Ltd, Beijing, intermediate product lot MLBL-API-20190122-CP, with a purity of 99.03% and a content of imA of 0.19%;

crude product 20190115, manufactured by Toguanming pharmaceutical research institute Co., Ltd, Beijing, under the batch number of MLBL-API-20190115-CP, had a purity of 99.42% and a imA content of 0.25%.

Examples 1 to 4

400mL of water and 6.15g of concentrated hydrochloric acid were put into a 1L three-necked flask, and after stirring them uniformly, 100g of (R) -2- (4-aminophenylethylamino) -1-phenylethanol dihydrochloride, 48g of 2-aminothiazole-4-acetic acid, and 70g of EDCI were added in this order, followed by stirring at room temperature for 1 hour. The reaction was complete as monitored by HPLC. And (3) transferring the mixture to a 2L beaker, adding 400mL of water, stirring uniformly, slowly dropwise adding a 20% NaOH solution in mass fraction, separating out a white solid, adjusting the pH value to 9-10, stirring for 30min, and filtering. Pulping the filter cake by using 2L of ethanol water solution with volume fraction of 15%, filtering, and drying by blowing at 45-50 ℃ to obtain 114.2g of crude mirabegron, wherein the yield is 94.8%, and the purity is as follows: 99.62%, imA content: 0.21 percent. The liquid phase analysis spectrum of the crude mirabegron is shown in figure 1, and figure 2 is an enlarged view of the liquid phase analysis spectrum of figure 1.

Embodiments provide a recrystallization method of mirabegron, comprising the steps of:

and adding a mixed solvent into a 5L three-necked bottle, heating the mixed solvent to the reflux temperature, adding 100g of the crude mirabegron under the mechanical stirring condition of 150rpm, stirring and dissolving, separating out a white solid, naturally cooling to room temperature, stirring for 3h, filtering, collecting the solid, and drying the solid by blowing at room temperature to obtain the pure mirabegron.

Wherein, the components and the dosage of the mixed solvent adopted in the recrystallization processes of different embodiments, the quantity of the obtained mirabegron pure product, the yield of the mirabegron pure product, the purity of the mirabegron pure product and the content information of imA impurities in the mirabegron pure product are shown in table 2.

TABLE 2 operating conditions of the different examples and results of the pure mirabegron obtained by recrystallization

Taking example 1 as an example, fig. 3 is a liquid phase analysis spectrum of the mirabegron pure product prepared in example 1 of the invention, and fig. 4 is an enlarged view of the liquid phase analysis spectrum of fig. 3.

Examples 5 to 8

adding a mixed solvent into a three-necked bottle, heating the mixed solvent to a reflux temperature, adding the crude mirabegron under the mechanical stirring condition of 150rpm, stirring and dissolving, separating out a white solid, naturally cooling to room temperature, stirring for 3h, filtering, collecting the solid, and drying the solid by blowing at room temperature to obtain the pure mirabegron.

Wherein, in the recrystallization processes of different embodiments, the types and the amounts of the adopted crude products, the components and the amounts of the mixed solvents, the amount of the obtained mirabegron pure product, the yield of the mirabegron pure product, the purity of the mirabegron pure product and the content information of imA impurities in the mirabegron pure product are shown in tables 3-4.

TABLE 3 operating conditions of the different examples

TABLE 4 results of pure mirabegron obtained by recrystallization of various examples

Numbering	Pure quantity (g)	Yield of pure product (%)	Purity of pure product (%)	imA content (%)
					Example 5	0.4	60.0	99.84	0.09
Example 6	0.67	67.0	99.82	0.09
					Example 7	1.53	69.5	99.69	0.03
Example 8	0.31	62.0	99.75	0.09

The powder X-ray diffraction pattern of the mirabegron pure product prepared in examples 1-8 of the present invention is shown in fig. 5, and the powder X-ray diffraction pattern of the mirabegron pure product prepared in examples 1-8 is respectively corresponded to the powder X-ray diffraction pattern of the mirabegron pure product from top to bottom in fig. 5. Fig. 6 and 7 are a powder X-ray diffraction spectrum of the mirabegron alpha crystal form and a powder X-ray diffraction spectrum of the mirabegron beta crystal form, respectively. As can be seen from the figure, mirabegron which is all alpha crystal form is obtained after recrystallization in the embodiment of the invention.

Comparative examples 1 to 6

The kinds and amounts of crude products and solvents used in the recrystallization processes of comparative examples 1 to 6, the amounts of purified mirabegron obtained, the yield of purified mirabegron, the purity of purified mirabegron, and the content of imA impurities in purified mirabegron are shown in tables 5 to 6. In which comparative examples 1 to 6 were recrystallized in the remaining operation modes referring to examples 1 to 4.

TABLE 5 operating conditions for the various comparative examples

Numbering	Solvent(s)	Kind of crude product	Crude product batch (g)
				Comparative example 1	Methanol 2mL + Water 16mL	Crude product 20190122	1.0
Comparative example 2	20mL of ethanol	Crude product 20190115	1.0
				Comparative example 3	Isopropyl alcohol 20mL	Crude product 20190115	0.5
Comparative example 4	Methanol 1.5mL + ethanol 10mL	Crude product 20190115	1.0
				Comparative example 5	90mL ethanol/water (v/v) ═ 1/1	Crude product 20190115	3.0
Comparative example 6	90mL ethanol/water (v/v) ═ 3/2	Crude product 20190115	3.0

TABLE 6 results of pure mirabegron obtained by recrystallization in various comparative examples

Numbering	Pure quantity (g)	Yield of pure product (%)	Purity of pure product (%)	imA content (%)
					Comparative example 1	0.86	86.0	99.06	0.14
Comparative example 2	0.47	47.0	99.81	0.12
					Comparative example 3	0.25	50.0	99.83	0.12
Comparative example 4	0.67	67.0	99.61	0.15
					Comparative example 5	2.18	72.67	99.80	0.12
Comparative example 6	1.78	59.32	99.90	0.10

Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. The recrystallization method of mirabegron is characterized by comprising the following steps:

the mixed solvent is methanol and dichloromethane;

the volume ratio of the methanol to the dichloromethane is 1: 10-30;

the ratio of the crude mirabegron to the mixed solvent is 1g to (10-50) mL;

the reflux temperature is 30-40 ℃.

2. The recrystallization method according to claim 1, wherein the ratio of the crude mirabegron to the mixed solvent is 1 g: 10-40 mL.

3. The recrystallization method according to claim 2, wherein the ratio of the crude mirabegron to the mixed solvent is 1 g: 20-30 mL.

4. The recrystallization method according to claim 2, wherein the ratio of the crude mirabegron to the mixed solvent is 1 g: 25-30 mL.

5. The recrystallization method according to claim 2, wherein the ratio of the crude mirabegron to the mixed solvent is 1 g/30 mL.

6. The recrystallization method according to claim 1, wherein the temperature reduction is natural temperature reduction at room temperature.

7. The recrystallization method according to claim 1, wherein the recrystallization method comprises the steps of:

(a) mixing the mixed solvent with the crude mirabegron, and stirring and dissolving at the reflux temperature;

(b) cooling and crystallizing the system obtained in the step (a), and filtering and collecting solids.

8. The recrystallization method according to claim 7, wherein in the step (b), the system obtained in the step (a) is stirred at room temperature for 2-4 h for crystallization, and the solid is collected by filtration.

9. The method for preparing mirabegron, which is characterized by comprising the step of carrying out recrystallization treatment on a crude mirabegron by using the recrystallization method as described in any one of claims 1 to 8.