CN107056706B - Method for preparing ivabradine hydrochloride α crystal form - Google Patents
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- CN107056706B CN107056706B CN201611164488.7A CN201611164488A CN107056706B CN 107056706 B CN107056706 B CN 107056706B CN 201611164488 A CN201611164488 A CN 201611164488A CN 107056706 B CN107056706 B CN 107056706B
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- C07D223/16—Benzazepines; Hydrogenated benzazepines
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Abstract
The invention relates to a method for preparing an ivabradine hydrochloride α crystal form, in particular to a method for preparing the ivabradine hydrochloride α crystal form shown in a formula I, which is characterized in that the amorphous form or other crystal forms of the ivabradine hydrochloride are stirred at a high temperature in high-boiling-point poor solvents such as toluene, butyl acetate or 4-methyl-2-pentanone and the like for crystal transformation.
Description
Technical Field
The invention relates to a method for preparing an ivabradine α crystal form, and the ivabradine hydrochloride prepared by the method can be used as an active ingredient for producing pharmaceutical preparations.
Background
Ivabradine hydrochloride (Ivabradine hydrochloride), the chemical name of which is 3- [3- [ [ [ (7S) -3, 4-dimethoxybicyclo [4.2.0] octa-1, 3, 5-trien-7-yl ] methyl ] methylamino ] propyl ] -1,3,4, 5-tetrahydro-7, 8-dimethoxy-2H-3-benzazepin-2-one hydrochloride, the structural formula is shown as the formula (I):
ivabradine hydrochloride has extremely high pharmacological and therapeutic properties, in particular with respect to the slowing of the heart rate, making it useful for the treatment or prevention of various clinical symptoms of myocardial ischemia, such as angina pectoris, myocardial infarction and concomitant rhythm disorders, and for the treatment or prevention of various pathologies involving rhythm disorders, in particular supraventricular rhythm disorders.
The first patent reported on the preparation of this compound is EP0534859 (related patent US5296482), which describes the preparation of ivabradine and its addition salts with a pharmaceutically acceptable acid, including in particular the preparation of its hydrochloride salt, but which does not claim any of the crystal forms involved. Because ivabradine hydrochloride has extremely high medicinal value, subsequent patent applications disclose a large number of related research techniques, including multiple crystal form patent applications.
CN1305856C discloses an ivabradine hydrochloride α crystal form, which is obtained by crystallization and separation by taking a toluene/1-methyl-2-pyrrolidone mixture as a solvent.
CN1827600B discloses an ivabradine hydrochloride β crystal form, wherein the ivabradine hydrochloride is heated and dissolved in water or a mixed solvent of water and isopropanol, cooled and crystallized, and crystals are collected to obtain tetrahydrate.
CN100404512C discloses ivabradine hydrochloride β d crystal form, which is formed by heating β crystal form to 80 ℃ at 5 ℃/min and dehydrating.
CN100402502C discloses an ivabradine hydrochloride gamma crystal form, wherein the ivabradine hydrochloride is heated and dissolved in 2-ethoxyethanol, cooled and crystallized, and the crystal is collected by filtration to be a monohydrate.
CN100432057C discloses an ivabradine hydrochloride gamma-d crystal form formed by heating the gamma-crystal form to 80 ℃ at a temperature of 5 ℃/min and dehydrating.
CN1948292A discloses an ivabradine hydrochloride delta crystal form, wherein the ivabradine hydrochloride is heated and dissolved in acetonitrile, cooled and crystallized, and crystals are collected by filtration, and the water content of the product is 2.8%.
CN1948293A discloses a delta d crystal form of ivabradine hydrochloride, which is formed by heating the delta crystal form to 85 ℃ at a temperature of 10 ℃/min and dehydrating.
EP2460797A discloses crystalline form I of ivabradine hydrochloride, the salt-forming crystallization of the free base of ivabradine in HCl/acetonitrile.
EP2780327A discloses two crystal forms of Ivabradine hydrochloride, i.e. II and III, wherein the Ivabradine hydrochloride is respectively dissolved in a methyl ethyl ketone/tetrahydrofuran mixed solvent and methyl ethyl ketone, cooled, crystallized, filtered and dried.
EP2773620A discloses Ivabradine hydrochloride IV crystal form, wherein Ivabradine hydrochloride is pulped in toluene, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethanol, ethyl acetate, isopropyl acetate or their mixed solvent, filtered to collect crystal and dried.
EP2534135A discloses ivabradine hydrochloride Z, X, K in three crystal forms, wherein ivabradine hydrochloride is dissolved in isopropanol and crystallized to obtain crystal form Z, the crystal form Z is vacuum-dried at 22 ℃ to obtain crystal form X, and the crystal form Z is vacuum-dried at 70 ℃ to obtain crystal form K.
WO2012025940 discloses an ivabradine ζ crystal form of hydrochloride, which is recrystallized in acetonitrile, after collecting the crystals, dried under controlled humidity.
EP2781509A discloses the crystalline form of ivabradine epsilon hydrochloride, slurrying ivabradine hydrochloride in aqueous 3-pentanone or 2-butanone, filtering to collect the crystals, and drying.
CN101805289A discloses an ivabradine hydrochloride omega crystal form, which is lyophilized after dissolving in water.
CN101768117B discloses an ivabradine hydrochloride W crystal form, wherein the ivabradine hydrochloride is heated and dissolved in a mixed solvent of methanol and acetone, and then is subjected to standing crystallization and filtration.
CN103864690A discloses an Ivabradine hydrochloride S crystal form, and Ivabradine hydrochloride delta or delta d crystal form is pulped and crystal transformed in tetrahydrofuran.
CN101353325B discloses a new crystal form of ivabradine hydrochloride, which is prepared by heating and dissolving ivabradine hydrochloride in 2-butanone, standing for crystallization and filtering.
CN102731400A discloses a new crystal form of ivabradine hydrochloride, which is prepared by heating and dissolving ivabradine hydrochloride in ethanol or a mixed solvent of ethanol and ethyl acetate, and cooling and crystallizing.
CN103012269B discloses an Ivabradine hydrochloride C crystal form, wherein the Ivabradine hydrochloride is heated and dissolved in ethanol, and ethyl acetate is added for cooling and crystallization.
CN103183639A discloses a II crystal form of ivabradine hydrochloride containing 0.5 crystal water, wherein the ivabradine hydrochloride is refluxed in acetone or a mixed solvent of tetrahydrofuran and ethyl acetate, dissolved by dropping water, cooled and crystallized.
CN102304088B discloses ivabradine hydrochloride monohydrate, which is dissolved in hot water, gradually cooled to low temperature for crystallization, collected crystals, and dried under the control of temperature and humidity.
EP2773621A discloses a process for the preparation of the delta crystalline form of ivabradine hydrochloride which is crystallized in a mixed solvent of ethanol and n-pentane, n-heptane or cyclohexane.
CN102050784B discloses a preparation method of amorphous ivabradine hydrochloride, which is to dissolve ivabradine hydrochloride in ethanol or acetone to form a solution, then add the solution into ether or cyclohexane, stir and cool.
It is known that solid drugs in different crystal forms lead to different bioavailability, and ultimately affect the therapeutic effect of the drug in the body. The stable crystal form has small solubility, slow dissolution rate and low bioavailability; the unstable crystal forms are opposite in nature; and the metastable crystal form is between the two. Generally, according to the thermodynamic law, an unstable crystal form is transformed into a metastable crystal form, and the metastable crystal form is transformed into a stable crystal form. In view of the importance of the crystal form and the stability of the solid medicine in clinical treatment, it is very important for pharmaceutical researchers to find advantageous solid medicine raw materials suitable for preparing medicaments.
In the existing ivabradine hydrochloride crystal forms, the α crystal form is generally known to be relatively stable, and the pharmaceutical preparation is produced by using the raw material medicine of the crystal form in original Uygur corporation, however, according to the prior published technology, the α crystal form is prepared by heating and dissolving in a mixed solvent of toluene and N-methyl pyrrolidone, cooling and crystallizing, because the boiling point of the N-methyl pyrrolidone is very high (about 203 ℃), the residual solvent is not easy to remove when the product is dried, and in order to meet the quality requirement of solvent residue, the product is dried at higher temperature and longer time, and the product purity is easy to lower due to long-time high-temperature action.
In view of the extremely high pharmaceutical value and stable pharmaceutical characteristics of the ivabradine hydrochloride α crystal form pharmaceutical preparation, it is necessary to deeply research and develop a process for efficiently producing the α crystal form ivabradine hydrochloride.
Disclosure of Invention
The invention aims to provide a preparation method of an ivabradine hydrochloride α crystal form, so as to overcome the defects of the prior art.
The invention provides a preparation method of an ivabradine hydrochloride α crystal form shown in formula I, which is characterized in that amorphous ivabradine hydrochloride or other crystal forms are stirred at a high temperature in a poor solvent with a high boiling point to be transformed into crystals, then the crystals are cooled, filtered and collected to form crystals, and the crystals are dried.
Wherein, the high boiling point poor solvent is a solvent with a boiling point of more than 100 ℃ and in which the ivabradine hydrochloride solid is not easy to dissolve (slightly soluble, insoluble or insoluble), preferably a solvent with a boiling point of 100-200 ℃, and comprises toluene, xylene (ortho, meta, para), aromatic hydrocarbons such as ethylbenzene and the like, esters such as butyl acetate and the like, ketones such as 4-methyl-2-pentanone and the like, and one or more of 1, 4-dioxane, and can convert amorphous or other crystal forms of ivabradine hydrochloride into α crystal form, and because too high a boiling point of the solvent can cause the product to be difficult to dry, one or more of toluene, butyl acetate and 4-methyl-2-pentanone with moderate boiling points are preferably selected when the solvent is selected.
The dosage of the solvent used in the method is proper, preferably 10-100 times (V/W) of the mass of the ivabradine hydrochloride, more preferably 10-50 times (V/W); the crystal transformation process is that the mixture of the ivabradine hydrochloride and the solvent is stirred at the temperature of 100-200 ℃, preferably at the temperature of 100-150 ℃, and finally cooled and filtered; the stirring time in the crystal transformation process is more than 0.5h, and preferably 0.5-2 h.
The term "V/W" refers to the ratio of solvent volume (in mL) to feedstock mass (in g).
The detailed experimental data and the actual experimental results lead to a satisfactory conclusion, which proves the original conception of the inventor and finally forms the technology disclosed by the invention.
The ivabradine hydrochloride α crystal form is prepared by the method, the efficiency is high, the convenience is realized, reaction raw materials are basically suspended in a solvent and are not dissolved, the raw materials are uniformly heated, other crystal forms can be completely converted into a α crystal form, the yield is high, the residual solvent of a product after crystal conversion is easy to remove, the post-treatment is convenient, for example, the delta d crystal form of the ivabradine hydrochloride is refluxed in toluene for 0.5h, the solid is completely converted into a α crystal form, and the obtained product has good crystal form purity, high solid dispersion degree, no agglomeration and easy drying.
The method skillfully solves the problems in the prior art, and provides a new green, environment-friendly, economical and efficient way for preparing the ivabradine hydrochloride α crystal form.
Drawings
Figure 1 XRD pattern of ivabradine hydrochloride α crystalline form.
Detailed Description
The present invention will be explained in detail below with reference to specific examples so that those skilled in the art can more fully understand the present invention, and the specific examples are only for illustrating the technical scheme of the present invention and do not limit the present invention in any way.
Example 1:
10.0g of ivabradine hydrochloride (delta crystal form) obtained according to the method described in patent specification EP0534859 was added to 100mL (10 times, V/W) of toluene, heated to reflux, stirred for 0.5h, cooled to room temperature, filtered under reduced pressure, and then dried under vacuum at 60 ℃ for 6h to give 9.7g of white solid powder with a yield of 97.0%.
Analyzing the results of the measurement
Example 2:
10.0g of ivabradine hydrochloride (delta d crystal form) obtained according to the method described in patent specification EP0534859 was added to 100mL (10 times, V/W) of toluene, heated to reflux, stirred for 0.5h, cooled to room temperature, filtered under reduced pressure, and then dried under vacuum at 60 ℃ for 6h to give 9.8g of white solid powder with a yield of 98.0%.
Analyzing the results of the measurement
Example 3:
10.0g of ivabradine hydrochloride (β crystal form) obtained according to the method described in patent specification CN1827600B was added to 100mL (10 times, V/W) of toluene, heated to reflux, stirred for 1.5h, cooled to room temperature, filtered under reduced pressure, and then dried under vacuum at 60 ℃ for 6h to obtain 9.8g of white solid powder with a yield of 98.0%.
Analyzing the results of the measurement
Example 4:
to 100mL (10 times, V/W) of toluene was added 10.0g of ivabradine hydrochloride (form K) obtained according to the method described in patent specification EP2534135A, heated to reflux, stirred for 0.5h, cooled to room temperature, filtered under reduced pressure, and then dried under vacuum at 60 ℃ for 6h to obtain 9.7g of white solid powder with a yield of 97.0%.
And (4) according to crystal form determination results, XRD shows α crystal forms.
Example 5:
10.0g of ivabradine hydrochloride (delta crystal form) obtained according to the method described in patent specification EP0534859 was added to 100mL (10 times, V/W) of xylene, heated to 120 ℃, stirred for 0.5h, cooled to room temperature, filtered under reduced pressure, and then dried under vacuum at 60 ℃ for 6h to give 9.6g of white solid powder with a yield of 96.0%.
And (4) according to crystal form determination results, XRD shows α crystal forms.
Example 6:
to 100mL (10 times, V/W) of ethylbenzene was added 10.0g of ivabradine hydrochloride (delta form) obtained according to the method described in patent specification EP0534859, heated to 120 ℃, stirred for 0.5h, cooled to room temperature, filtered under reduced pressure, and then dried under vacuum at 60 ℃ for 6h to give 8.5g of white solid powder with a yield of 85.0%.
And (4) according to crystal form determination results, XRD shows α crystal forms.
Example 7:
to 100mL (10 times, V/W) of 4-methyl-2-pentanone was added 10.0g of ivabradine hydrochloride (delta crystalline form) obtained according to the method described in patent specification EP0534859, heated to reflux, stirred for 0.5h, cooled to room temperature, filtered under reduced pressure, and then dried under vacuum at 60 ℃ for 6h to obtain 8.0g of white solid powder with a yield of 80.0%.
And (4) according to crystal form determination results, XRD shows α crystal forms.
Example 8:
to 100mL (10 times, V/W) of butyl acetate was added 10.0g of ivabradine hydrochloride (delta form) obtained according to the method described in patent specification EP0534859, heated to reflux, stirred for 1h, cooled to room temperature, filtered under reduced pressure, and then dried under vacuum at 60 ℃ for 6h to obtain 9.4g of white solid powder with a yield of 94.0%.
And (4) according to crystal form determination results, XRD shows α crystal forms.
Example 9:
10.0g of ivabradine hydrochloride (delta crystal form) obtained according to the method described in patent specification EP0534859 was added to 100mL (10 times, V/W) of toluene, heated to 100 ℃, stirred for 1h, cooled to room temperature, filtered under reduced pressure, and then dried under vacuum at 60 ℃ for 6h to obtain 9.7g of white solid powder with a yield of 97.0%.
And (4) according to crystal form determination results, XRD shows α crystal forms.
Example 10:
10.0g of ivabradine hydrochloride (delta crystal form) obtained according to the method described in patent specification EP0534859 was added to 100mL (10 times, V/W) of toluene, heated to 80 ℃, stirred for 0.5h, cooled to room temperature, filtered under reduced pressure, and then dried under vacuum at 60 ℃ for 6h to obtain 9.8g of white solid powder with a yield of 98.0%.
And (4) according to crystal form measurement results, XRD shows that the crystal form is consistent with the β crystal form.
Example 11:
to 20ml of anhydrous methanol was added 10.0g of ivabradine hydrochloride, and the mixture was heated to dissolve the solid, and concentrated under reduced pressure until the solvent was dried to obtain a foamy solid.
And (3) crystal form determination results: XRD showed amorphous.
100ml of toluene (10 times, V/W) was added to the above solid, heated to reflux, stirred for 0.5h, cooled to room temperature, filtered under reduced pressure, and then dried under vacuum at 60 ℃ for 6h to give 9.3g of a white solid powder with a yield of 93.0%.
Analyzing the results of the measurement
Example 12:
according to the information disclosed in patent specification CN1305856C, 10.0g of ivabradine hydrochloride obtained by the method described in patent specification EP0534859 was added to a mixed solvent of 100mL of toluene and 40mL of N-methyl-pyrrolidone (NMP), heated to reflux, stirred for 0.5h, cooled for crystallization, filtered under reduced pressure, and then dried under vacuum at 60 ℃ for 6h to obtain 8.6g of a white solid powder with a yield of 86.0%.
Analyzing and measuring results:
Claims (5)
1. a preparation method of ivabradine hydrochloride α crystal form is characterized in that amorphous form or other crystal forms of ivabradine hydrochloride are stirred at high temperature in a high boiling point poor solvent for crystal transformation, then cooled, filtered and collected to form crystals, wherein the high boiling point poor solvent is selected from toluene, the temperature for crystal transformation through high temperature stirring is 100-150 ℃,
2. the process for the preparation of the crystalline form of ivabradine α hydrochloride according to claim 1, wherein the amount of the poor solvent with high boiling point is 10-100 times (V/W) the mass of ivabradine hydrochloride.
3. The process for the preparation of the crystalline form of ivabradine α hydrochloride according to claim 2, wherein the amount of the poor solvent with high boiling point is 10-50 times (V/W) the mass of ivabradine hydrochloride.
4. The method for preparing the crystalline form of ivabradine α hydrochloride according to claim 1, wherein the stirring and crystal transformation time is more than 0.5 h.
5. The process for the preparation of the crystalline form of ivabradine α hydrochloride according to claim 1, wherein the stirring and crystal transformation time is between 0.5 and 2 h.
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