JP6147432B2 - Method for producing type II crystals of sarpogrelate hydrochloride - Google Patents

Description

  The present invention relates to a method for producing type II crystals of sarpogrelate hydrochloride.

  Sarpogrelate hydrochloride represented by the following general formula (1) has an action mechanism that selectively antagonizes platelet and vascular serotonin receptors (5-HT). Specifically, sarpogrelate hydrochloride has an antiplatelet action and a vasoconstriction inhibitory action, so it is clinically used as an agent for inhibiting and treating ischemic diseases such as ulcers, pain and cold feeling due to chronic arterial occlusion. Yes.

A method for producing sarpogrelate hydrochloride is first disclosed in Example 2 of Patent Document 1. According to Patent Document 1, 2- [2-hydroxy-3-dimethylaminopropoxy] -3′-methoxybibenzyl hydrochloride is produced as an intermediate through a multi-stage production process. The hydrochloride is neutralized to remove the salt and converted to the 2- [2-hydroxy-3-dimethylaminopropoxy] -3′-methoxybibenzyl form, reacted with succinic anhydride, and then hydrogen chloride— Sarpogrelate hydrochloride was prepared by reacting with an ethyl acetate solution. In Patent Document 1, no particular mention is made regarding the crystalline form of sarpogrelate hydrochloride.
Patent Document 2 clarified that the sarpogrelate hydrochloride produced in Patent Document 1 has two crystals of type I and type II. Moreover, it is disclosed that the sarpogrelate hydrochloride produced in Example 2 of Patent Document 1 is a polycrystalline compound having a form I of 30 mol% and a form II of 70 mol%. In Patent Document 2, sarpogrelate hydrochloride (hereinafter referred to as crude crystal) produced in Example 2 of Patent Document 1 is dissolved by heating in acetone, xylene, water or a mixed solvent of acetone and water and heated to 25 ° C. It discloses a method for producing type II by cooling and cooling the produced crystals after cooling. However, since the solvent used in the method disclosed in Patent Document 2 has a low solubility of the crude crystals and must be used in an excess of 10 times or more, it is a large scale in order to use the method industrially. Manufacturing equipment is required, and it is difficult to dispose of the solvent.
In Patent Document 3, crude crystals were dissolved in water-containing acetone or water-containing methyl ethyl ketone, and acetone or methyl ethyl ketone cooled to 10 ° C. or lower was added dropwise to obtain a crystal mixture containing 70 to 90 mol% of type II. According to the crystallization method proposed in Patent Document 3, there is an advantage that the content of type II crystals is further increased and the amount of crystallization solvent used is reduced. However, since water is used as the crystallization solvent, sarpogrelate The succinic acid ester is hydrolyzed and a compound represented by the following general formula (2) is produced as an impurity, which reduces the purity and yield of the type II crystal.

The compound represented by the general formula (2) is a decomposition product, which is produced when recrystallization is performed using water or alcohols, and has a great influence on the purity of the target crystalline compound.
As described above, as shown in the prior art, a small amount of a crystallization solvent is used to obtain a type II crystal from a crude crystal of sarpogrelate hydrochloride, and is represented by the general formula (2). Therefore, it is necessary to develop a new crystallization method that does not use water or alcohols that cause generation of decomposition products as crystallization solvents.

US Registered Patent No. 4,599,419 Korean Patent Publication No. 2006-93677 Japanese Patent Publication No. 2008-285445

The inventors of the present invention have been investigating a method by which a pure type II crystal can be produced from a crude crystal of Sarpogrelate hydrochloride using a recrystallization process from a simple and economical process. As a result, acetonitrile (AN) has excellent solubility in sarpogrelate hydrochloride, and does not induce the formation of the decomposition product represented by the general formula (2) in the recrystallization process. Thus, the present invention was completed by finding that it is effective as a recrystallization solvent for crude crystals.
Accordingly, an object of the present invention is to provide a method for obtaining type II crystals with high purity from crude crystals of sarpogrelate hydrochloride using acetonitrile as a recrystallization solvent.

The present invention relates to a sarpogrelate hydrochloride comprising a step of heating and dissolving a crude crystal of sarpogrelate hydrochloride in acetonitrile, and a step of cooling a solution of the crude crystal to a temperature of 0 to 20 ° C. and filtering the produced crystal. The production method of type II crystal is characterized.
Further, the present invention is characterized by a rod-shaped sarpogrelate hydrochloride type II crystal.

According to the recrystallization method of the present invention, since the hydrolyzate represented by the general formula (2) is hardly contained as an impurity, the yield and purity of the type II crystal can be improved. .
According to the recrystallization method of the present invention, the yield and purity of type II crystals are high and there is no inconvenience in the process, which is effective for mass production of type II crystals.
According to the recrystallization method of the present invention, there is an effect that the content ratio of the type I crystal and the type II crystal can be easily adjusted by adjusting the conditions in the process of warming dissolution and cooling of the starting material.

2 is an electron micrograph (magnified 300 times) of a type II crystal of sarpogrelate hydrochloride produced in Example 1. FIG. 2 is an infrared (IR) spectroscopic spectrum for sarpogrelate hydrochloride type II crystals prepared in Example 1. FIG. FIG. 2 is an X-ray diffraction analysis diagram for type II crystals of sarpogrelate hydrochloride prepared in Example 1. 2 is an infrared (IR) spectroscopic spectrum related to a crude crystal of sarpogrelate hydrochloride (type I crystal / type II crystal = 3/7 molar ratio) used as a raw material in Example 1. FIG. FIG. 3 is an X-ray diffraction analysis chart of crude crystals of sarpogrelate hydrochloride (type I crystal / type II crystal = 3/7 molar ratio) used as a raw material in Example 1.

The results of X-ray diffraction analysis (XRD), differential scanning calorimetry (DSC), infrared (IR) spectroscopic analysis, and nuclear magnetic resonance spectroscopic analysis (NMR) for the type II crystal of sarpogrelate hydrochloride produced in the present invention are disclosed in Patent Literature It was in agreement with the analysis result disclosed in 2.
Moreover, the II type crystal manufactured by the conventional methods, such as patent document 2, was obtained as crystalline powder (powder) close to amorphous. However, as can be seen from the electron micrograph of FIG. 1, the type II crystal produced by the production method according to the present invention is obtained as a rod-like crystal form. This is because the purity of the type II crystal is further increased. It is judged that there is a reason.
In addition, it should be confirmed from the following experimental examples that the rod-shaped type II crystal produced by the production method according to the present invention is more stable than the powdery type II crystal produced by the conventional method. Can do.
Therefore, the production method of the present invention is a method for increasing the yield and purity of type II crystals, and for the first time, the present invention revealed that the crystal structure of type II crystals is a rod-like crystal form.

The method for producing the type II crystal of the present invention will be described in detail according to the process as follows.
First, the crude crystals are dissolved by heating in acetonitrile.
Specifically, the crude crystals of sarpogrelate hydrochloride are mixed with acetonitrile and heated to a temperature of 30 to 80 ° C. to dissolve. In this case, acetonitrile is used in a range of 1: 2 to 8 times by weight, more preferably 3 to 5 times by weight with respect to the weight of the crude crystals. In order to increase the content of type II crystals, it is preferable to dissolve the crude crystals sufficiently. In order to dissolve the crude crystals sufficiently, there are methods such as increasing the amount of solvent used, increasing the heating temperature, or lengthening the stirring time in the heated state. According to the experiments by the present inventors, it was confirmed that the content of type II crystals decreased when a small amount of solvent was used and the stirring time was kept short. Preferably, the minimum amount of the solvent is used and the mixture is heated at an appropriate temperature and an appropriate stirring time. The stirring time varies depending on the reaction volume and the type of the reactor, but it is within about 10 hours, preferably 3 to 5 hours. In addition, a sample can be taken during the reaction and IR analysis can be easily performed to appropriately adjust the stirring time.
In addition to acetonitrile, one or more polar solvents selected from acetone, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMAc), and dimethyl sulfoxide (DMSO) are used to increase the solubility of the crude crystals. Can further be included. In this case, the polar solvent can be used in a range of 1: 0.01 to 0.5 volume times, more preferably 0.1 to 0.5 volume times based on acetonitrile.

Next, the crude crystal solution is cooled, and the produced crystals are filtered to obtain type II crystals.
Specifically, a sufficiently dissolved crude crystal solution is cooled to a temperature of 0 to 20 ° C., and the crystal produced by cooling is filtered to obtain the type II crystal targeted by the present invention. The cooling temperature is more preferably maintained at 0 to 10 ° C. When left standing in the cooled state, crystals are gradually precipitated, but the standing time in the cooled state is suitably about 1 to 5 hours, more preferably 1 to 3 hours.

  The type II crystal produced by the production method described above was obtained as a rod-like crystal form [see the electron micrograph of FIG. 1]. The reason why the type II crystal was obtained as a rod-like crystal form instead of a powder is considered to be because the purity of the type II crystal is high. In particular, according to the present invention, a type II crystal having a molar ratio of type II crystal / type I crystal of 98% or more can be produced as a crystal of sarpogrelate hydrochloride.

  The present invention will be described in more detail with reference to the following examples and experimental examples, but the present invention is not limited thereto.

[Example]
Example 1. Production of type II crystals of sarpogrelate hydrochloride In this example, crude crystals (Molar ratio of type I crystals: type II crystals = 30: 70, purity 99.3% by the production method disclosed in Example 2 of Patent Document 1) ) Was manufactured.
10 g of crude crystals were placed in 100 mL of acetonitrile and stirred at reflux for 5 hours, then cooled to 10 ° C. and left for 2 hours. The produced crystals were filtered, washed with acetonitrile and dried to give 9.3 g of type II crystals (yield 93%, HPLC purity 99.93%, type II crystal / type I crystal molar ratio of 98% or more) )
The electron micrograph, infrared (IR) spectroscopic spectrum and X-ray diffraction analysis diagram for the type II crystal prepared in Example 1 (type II crystal / type I crystal molar ratio of 98% or more) are shown in FIGS. Show.
Infrared (IR) spectrum and X-ray diffraction analysis diagrams for the crude crystals (type I crystal / type II crystal = 3/7 molar ratio) used as the raw material in Example 1 are shown in FIGS. Show.

Examples 2-7 and Comparative Examples 1-3. Production of type II crystals of sarpogrelate hydrochloride Recrystallization of crude crystals (Molar ratio of type I crystals: type II crystals = 30: 70, purity 99.3%) by the method of Example 1 except that recrystallization conditions The solvent type, the amount of solvent used, the recrystallization temperature, and the recrystallization time were made different.

  The recrystallization conditions and the yield, purity and crystal shape of the manufactured product are summarized in Table 1 below.

[Experimental example]
Experimental Example 1 Test of stability of type II crystals of sarpogrelate hydrochloride In order to compare the stability against heat and moisture in the type II crystals produced in Example 1 and Comparative Example 1, experiments were conducted under the following conditions. The results are shown in Table 2 below.
<Experimental conditions>
-Storage equipment: Constant Temp & Humid Chamber SH-201S (Manufacturer: ACT)
-Storage conditions: accelerated test-temperature 40 ± 1 ° C, relative humidity 75%
Long-term storage test-temperature 25 ± 1 ° C, relative humidity 60%
-Analytical instrument: HPLC
-Manufacture of standard solution and test solution 1) Standard solution: A calibration curve was prepared by preparing a type II crystal at a concentration of 0.4 mg / mL (100%).
2) Test solution: Accelerated and long-term storage test samples were prepared and analyzed at a concentration of 1 mg / mL.
3) Calculation of residual ratio: The content was calculated by comparing the area value of the type II crystal shown in the HPLC graph with the standard solution.

  According to Table 2, the type II crystal according to the present invention has a rod-like crystal structure, and is resistant to heat and moisture during storage for a long time compared to the powder type II crystal produced by the conventional method. You can see that it is stable.

Claims (4)

Mixing the acetonitrile-containing recrystallization solvent and the crude crystals of sarpogrelate hydrochloride in a weight ratio of 5 to 7: 1 , and heating and dissolving the mixture at a temperature of 30 to 80 ° C. for 3 to 10 hours;
A step of filtering the crystalline Form II of the rod-like produced by cooling said dissolved mixture to a temperature of 0 to 20 ° C., and Nde including a
The acetonitrile-containing recrystallization solvent is a mixed solvent of one or more polar solvents selected from acetone and tetrahydrofuran (THF) and acetonitrile.
A process for producing type II crystals of sarpogrelate hydrochloride.   The method for producing type II crystals of sarpogrelate hydrochloride according to claim 1, wherein the warming dissolution is performed at a temperature of 30 to 80 ° C for 3 to 5 hours. The volume ratio of the polar solvent and acetonitrile containing the recrystallization solvent used is 0.01 to 0.5: Production method of type II crystals of Sarpogrelate hydrochloride according to claim 1, characterized in that the 1. The method for producing a type II crystal of sarpogrelate hydrochloride according to any one of claims 1 to 3 , wherein the type II crystal of sarpogrelate hydrochloride has a purity of 99% or more.