KR20190073121A - Crystallizine Sapogrelate Hydrochloride and a method for forming the same - Google Patents

Abstract

Disclosed are sarpogrelate hydrochloride crystals used an anticoagulant. A method to produce the sarpogrelate hydrochloride crystals by the present invention includes: a step of making 2-[2-hydroxy-3-dimethylaminopropoxy]-3′-methoxybenzyl hydrochloride represented by chemical formula 3 react with succinic anhydride represented by chemical formula 4 in the presence of an organic base; a step of removing the hydrochloride of the generated organic base after completion of the reaction; and a step of adding aqueous hydrochloric acid solution to filtrate from which the hydrochloride of the organic base is removed. The sarpogrelate hydrochloride crystals include 60-80 wt% of sarpogrelate hydrochloride form I crystals and 20-40 wt% of sarpogrelate hydrochloride form II crystals. The present invention is able to solve the mixing problem of the sarpogrelate hydrochloride form II crystals.

Description

Crystallizine Sapogrelate Hydrochloride and a Method for Forming the Same

More particularly, the present invention relates to a crystal of sapogrelate hydrochloride used as an anti-blood coagulant and a method for producing the same.

Sarpogrelate.HCl represented by the following formula (1) increases the activity of prostaglandins I2 and is effectively used for the inhibition and treatment of thrombosis.

[Chemical Formula 1]

A conventional method for preparing the above sapogrelate hydrochloride is disclosed in U.S. Patent No. 4,599,419 issued to Mitsubishi Chemical Industries, Inc. (July 8, 1986).

In the method disclosed in the above-mentioned US Patent, 2- [2-hydroxy-3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride was prepared as an intermediate through various steps, The reaction mixture was neutralized to remove salts and converted into the form of 2- [2-hydroxy-3-dimethylaminopropoxy] -3'-methoxybibenzyl, then reacted with succinic anhydride, and anhydrous hydrochloric acid gas was collected in ethyl acetate A 20% ethyl acetate solution of hydrochloric acid was prepared and added to the reaction mixture to prepare the sapogrelate hydrochloride.

On the other hand, in Korean Patent Laid-Open Publication No. 2006-93677 (published on August 25, 2006), there are two different crystal forms of hydrochloric acid sapoglylate, namely, I and II crystals, It is described that the type is more useful as a pharmaceutical. The saponification of hydrochloric acid prepared according to Example 2 of Japanese Patent Laid-Open No. 58-32847 is a polymorphous compound having about 70 mol% of I-form and about 30 mol% of II-form crystal, It is disclosed that the crystal transition temperatures of I-form and II-form ranges from about 20 to 40 캜. In addition, I-form crystals are physicochemically stable at temperatures lower than 25 ° C, and II-form crystals are stable at temperatures higher than 35 ° C.

Korean Kokai Patent Application No. 10-1393178 uses a method of preparing a mixture of Ⅰ form crystals and Ⅱ type crystals and then containing ≧ 75% of Ⅱ form crystals. However, this method requires manufacturing of the Ⅰ-type crystal and the Ⅱ-type crystal, respectively, so that the manufacturing cost is increased and the productivity is lowered.

Korean Patent Laid-Open No. 10-2010-0120558 discloses a process for producing a product having a molar ratio of I-form crystal and II-form crystal of 7: 3 by the method of Mitsubishi Chemical Industry, Is obtained. However, this method is disadvantageous in that it takes a lot of time and cost in pretreatment for the reaction when manufacturing the goods.

Accordingly, it is an object of the present invention to provide a pharmaceutical composition which comprises a mixture of 60 to 80% of I-form crystals and 20 to 40% of II-form crystals to solve the problem of mixing of the sulfogrelate hydrochloride II- .

In order to accomplish the above object, the present invention provides a process for preparing a 2-hydroxy-3-dimethylaminopropoxy-3'-methoxybenzyl chloride salt represented by the following formula (3) and a succinic anhydride represented by the following formula In the presence of a base, after completion of the reaction, removing the hydrochloride of the produced organic base and adding an aqueous hydrochloric acid solution to the filtrate from which the hydrochloride of the organic base has been removed, The hydrochloride crystals provide a process for the preparation of the sapphogelate hydrochloride crystals comprising 60 to 80% by weight of the sapogrelate hydrochloride Form I crystals and 20 to 40% by weight of the sapphorellate hydrochloride II-form crystals.

(3)

[Chemical Formula 4]

The sapphorzelate hydrochloride crystals according to the present invention can obtain saprophile crystal hydrochloride crystals in which 60-80% of I-form crystals and 20-40% of II-form crystals are mixed.

Fig. 1 shows the results of differential scanning calorimetry (DSC) analysis of the mixed sapogrelate hydrochloride Ⅰ and Ⅱ crystals prepared in Example 1. Fig.
FIG. 2 is a powder X-ray diffraction (XRD) analysis result of the mixed sapogrelate hydrochloride I and II crystals prepared in Example 1. FIG.
Fig. 3 is a result of powder X-ray diffraction (XRD) analysis of Form I crystal disclosed in Korean Patent No. 10-1393178.
Fig. 4 is a powder X-ray diffraction (XRD) analysis result of the Ⅱ type crystal disclosed in Korean Patent No. 10-1393178.

Hereinafter, the present invention will be described in more detail with reference to the accompanying drawings.

(±) -2- [2- (3-Carboxypropionyloxy) -3-dimethylaminopropoxy] -3'-methoxybenzyl chloride hydrochloride, 3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride (hereinafter referred to as "sapogrelate hydrochloride") exist in two different crystal forms, namely, I-form and II-form crystals.

The I-form and II-form crystals are crystalline polymorphs of the sapogrelate hydrochloride represented by the following formula (1), both of which have different physicochemical characteristics. The crystalline polymorph means one of a plurality of different crystal forms of the same compound (see Korean Patent No. 10-1393178).

[Chemical Formula 1]

The I-form crystals of the sapogrelate hydrochloride have an endothermic peak at 152 ± 2.0 ° C in differential scanning calorimetry (DSC) and 9.3 ± 0.1 °, 10.7 ± 0.1 ° and 16.5 ° in powder X-ray diffraction (XRD) And has a diffraction peak at ± 0.1 °. The I-form crystal preferably has diffraction peaks at Bragg angles (2?) Of 10.7 ± 0.1 ° and 16.5 ± 0.1 ° in the case of powder X-ray diffraction, and in this case also Bragg angles (2θ) of 9.3 ± 0.1 °, 12.8 0.1 °, 13.0 ± 0.1 °, 18.1 ± 0.1 ° and 24.1 ± 0.1 °, and diffraction peaks at Bragg angles (2θ) of 10.7 ± 0.1 ° and 16.5 ± 0.1 ° , And may have diffraction peaks at 9.3 ± 0.2 °, 12.8 ± 0.2 ° and 13.0 ± 0.2 °. (2 &thetas;) at Bragg's angles (2 [theta]) of 10.7 + - 0.2 DEG and 16.5 + 0.2 DEG, and at 9.3 + 0.2 DEG, 12.8 + 0.2 DEG, 13.0 + 0.2 DEG, 18.1 + 0.2 DEG Deg.] And 24.1 [deg.] - 0.2 [deg.]. In order to more reliably form I-form crystals of high purity, it is preferable that Bragg's angles (2?) Of 11.0 ± 0.1 ° and 19.2 ± 0.1 ° do not have a diffraction peak at all. The above-mentioned I-form crystals are excellent in formulation but are unstable and difficult to be used alone.

The II-form crystals of the sapogrelate hydrochloride had an endothermic peak at 157 ± 2.0 ° C in the differential scanning calorimetry (DSC) measurement and 9.5 ± 0.1 °, 11.0 ± 0.1 ° and 11.5 ° in the powder X-ray diffraction (XRD) And has a diffraction peak at 19.15 ± 0.1 °. Further, the II-form crystal can have diffraction peaks at one or more selected from Bragg angles (2?) Of 16.2 占 0.1 占 19.7 占 0.1 占 22.8 占 0.1 占 and 23.8 占 0.1 占 in powder X-ray diffraction , In this case, the diffraction peaks at Bragg angles (2?) Of 9.5 ± 0.2 °, 11.0 ± 0.2 ° and 19.15 ± 0.2 ° and at 16.2 ± 0.2 °, 19.7 ± 0.2 °, 22.8 ± 0.2 ° and 23.8 ± 0.2 ° And may have a diffraction peak. Or a powder X-ray diffraction spectrum, the diffraction peaks at Bragg angles (2?) Of 9.5 ± 0.2 °, 11.0 ± 0.2 ° and 19.15 ± 0.2 °, and 16.2 ± 0.2 °, 19.7 ± 0.2 °, 22.8 ± 0.2 ° and It is preferable to have a diffraction peak at 23.8 ± 0.2 °. In order to more reliably form II crystals of high purity, it is preferable that they do not have diffraction peaks at Bragg angles (2?) Of 9.3 0.1, 10.7 0.1 and 16.5 0.1. The II-form crystals are in powder form, which is advantageous in that the hydrolyzate production rate is low, and is suitable for use as a pharmaceutical product. However, there is a problem in that the dissolution rate is faster than that of the control drug when compared with the conventional I- In order to solve this problem, sapogrelate hydrochloride mixed with type I and type II crystals is used.

The sapogrelate hydrochloride according to the present invention is a polymorphic compound, and the polymorphic compound refers to a compound in which an I-form crystal and a II-form crystal are mixed. Specifically, the sapogrelate hydrochloride according to the present invention has crystals mixed with 60 to 80% by weight of I-form crystals and 20 to 40% by weight of II-form crystals.

In the differential scanning calorimetry (DSC) of the sapropharylactate hydrochloride crystals according to the present invention, the endothermic onset temperature is 148 ± 2 ° C and 152 ± 2 ° C, and has an endothermic peak at 150 ± 2 ° C and 154 ± 2 ° C. Further, in the powder X-ray diffraction (XRD) analysis, it has diffraction peaks of 9.184 占 0.2 占 9.494 占 0.2 占 10.138 占 0.2 占 10.61 占 0.2 占 and 10.971 占 0.2 占. The crystals of the sapogrelate hydrochloride according to the present invention are specified by the physicochemical properties described in this specification, but each spectral data is not strictly interpreted because it can be changed somewhat in nature.

As a method for producing a crystal according to the present invention, there can be mentioned a method of producing a crystal of 2- [2-hydroxy-3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride (2- [ 3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride, succinic anhydride and an organic base are reacted in an organic solvent.

(2)

Specifically, the hydrochloride salt of 2- [2-hydroxy-3-dimethylaminopropoxy] -3'-methoxybenzyl hydrochloride represented by the following formula (3) and succinic anhydride of the following formula In the presence of an organic base which can be formed, in a nonpolar, aprotic reaction solvent which can be mixed with water.

(3)

[Chemical Formula 4]

In Formula 2, the amount of succinic anhydride is preferably 1.0 to 1.2 equivalents based on 1 equivalent of 2- [2-hydroxy-3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride compound. If the amount of the succinic anhydride is less than 1.0 equivalent, the reaction is not completed. If the amount of the succinic anhydride exceeds 1.2 equivalent, the succinic anhydride is economically disadvantageous without any special benefit.

The reaction solvent may be a non-polar, aprotic solvent that can be mixed with water without limitation. For example, an organic solvent such as acetone may be used, and acetone is preferable. The volume ratio of the solvent is preferably 4 to 10 times (ml / g) to the weight of the 2- [2-hydroxy-3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride. If the amount of the solvent used is too small, stirring may become difficult, and if the amount of the solvent used is too large, it is economically disadvantageous without special benefit.

As the organic base, an organic base capable of forming a hydrochloride which is insoluble in the reaction solvent used in the present invention may be used without limitation, and organic bases such as triethylamine may be preferably used. The triethylamine hydrochloride is not dissolved in an organic solvent such as acetone, but is easily removed by filtration, and there is no contamination to the final product.

On the other hand, when an inorganic base such as sodium carbonate, potassium carbonate or the like is used, water (H2O) generated by neutralization after the desalting reaction of the inorganic base hydrochloride is not preferable because it reacts with succinic anhydride, and tributylamine, DBU -Diazabicyclo [5.4.0] undec-7-ene, etc., the use of an organic base in which the hydrochloride salt thereof is dissolved in an organic solvent does not cause any particular problem, but in the solution in which these salts are dissolved , And hydrochloric acid is added to precipitate the sapogrelate hydrochloride crystals, so that there is a possibility that the final product is contaminated with these salts. Therefore, it is preferable to use an organic base which does not dissolve the hydrochloride of the organic base such as triethylamine in the reaction solvent, since an additional process such as the use and purification of relatively expensive organic base is required.

The amount of the organic base to be used is preferably 0.1 to 1.0 equivalent based on 2- [2-hydroxy-3-dimethylaminopropoxy] -3'-methoxybenzyl hydrochloride. If the amount of the organic base is less than 0.1 equivalent, the reaction time becomes very long and the reaction is difficult to complete. If the organic base is used in excess of 1.0 equivalent, 1.0 equivalent or more of the organic base is present in the solution. As a result, these salts are present in the reaction solution, and the final product may be contaminated.

The reaction can be carried out by heating under reflux, and the reaction time is suitably 1 to 2 hours. If the reaction time is too short, the reaction is difficult to complete, and if the reaction time is too long, there is no particular advantage and is economically disadvantageous. When the reaction is completed, the hydrochloride of the generated organic base is removed by filtration, and an aqueous hydrochloric acid solution is added to the filtrate, and filtration is performed if necessary to obtain the sapogrelate hydrochloride crystals.

The aqueous hydrochloric acid solution may be a concentrated hydrochloric acid aqueous solution, and the amount of the hydrochloric acid aqueous solution used is 1 to 1.1 equivalents, preferably 1 equivalent, relative to 1 equivalent of the resulting sapogrelate. If the amount of the hydrochloric acid aqueous solution used is too small, there is a fear of unreacted. In addition, it is preferable that the temperature when the aqueous hydrochloric acid solution is added is maintained at 15 to 25 캜. When the temperature is 15 ° C or lower, it is precipitated by itself and the yield is lowered. When the temperature is 25 ° C or higher, the crystal type ratio can be changed.

In the method for producing a saprophile hydrochloride salt according to the present invention, the yield of a target sapogrelate hydrochloride salt is usually 94 to 95%. The process for preparing a saprophile salt hydrochloride according to the present invention can obtain a target with a very simple process and a high purity in a high yield compared with the conventional process. The present invention also relates to a process for the preparation of a compound of formula (I), which comprises reacting 2- [2-hydroxy-3-dimethylaminopropoxy ] -3'-methoxybibenzyl hydrochloride as it is in the hydrochloride salt form, and instead of producing hydrochloride of sapogrelate by collecting hydrochloric acid gas in ethyl acetate as in the conventional method, a concentrated hydrochloric acid aqueous solution Can be used as it is.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited by the following Examples.

EXAMPLES Preparation of Sapphagelate Hydrochloride Crystals

(20 mmol) of succinic anhydride and 2.0 g (20 mmol) of succinic anhydride were placed in 60 ml of acetone and 2.79 ml (20 mmol) of triethylamine was added thereto, And the mixture was heated under reflux for 1 hour. After cooling the reaction solution to room temperature, the resulting triethylamine hydrochloride was removed by filtration, and 1.74 ml of concentrated hydrochloric acid was added dropwise to the filtrate while maintaining the temperature at 15 to 25 ° C. The resulting crystals were filtered and dried at 60 ° C To obtain 8.82 g (yield: 94.6%) of the desired compound as white.

Differential scanning calorie ( DSC ) analysis

The differential scanning calorimetry (DSC) was analyzed with the sapogrelate hydrochloride prepared in Example 1 and described in FIG. Referring to the differential scanning calorie of FIG. 1, the endothermic initiation temperature of the differential scanning calorie (DSC) is 148 2 ° C and 152 2 ° C, and has an endothermic peak at 150 2 ° C and 154 2 ° C.

Powder X-ray diffraction ( XRD ) analysis

Powder X-ray diffraction (XRD) analysis of the sapogrelate hydrochloride prepared in Example 1 above was described in FIG. Referring to the XRD analysis of FIG. 2, the sapogrelate hydrochloride has a diffraction peak at 9.184 ± 0.2 °, 9.494 ± 0.2 °, 10.138 ± 0.2 °, 10.61 ± 0.2 ° and 10.971 ± 0.2 °. 3 and 4 show the results of powder X-ray diffraction (XRD) analysis of the type I crystals and the type II crystals disclosed in Korean Patent No. 10-1393178, the crystals of the sapogrelate hydrochloride of the present invention were identified as Form I and II Type crystals are mixed.

Claims (6)

Reacting 2- [2-hydroxy-3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride represented by the following formula (3) with succinic anhydride represented by the following formula (4) in the presence of an organic base;
(3)

[Chemical Formula 4]

Removing the hydrochloride of the generated organic base after completion of the reaction; And
And adding an aqueous hydrochloric acid solution to the filtrate from which the hydrochloride of the organic base has been removed, wherein the aqueous solution contains 60 to 80% by weight of the saponite hydrochloride type I crystal and 20 to 40% by weight of the sapphire salt hydrochloride type II crystal ≪ / RTI > 2. The process according to claim 1, wherein the organic base is triethylamine. The method according to claim 1, wherein the aqueous hydrochloric acid solution is added at a temperature of 15 to 25 ° C. The sapogrelate hydrochloride crystals having an endothermic initiation temperature of 148 ± 2 ° C. and 152 ± 2 ° C. and having an endothermic peak at 150 ± 2 ° C. and 154 ± 2 ° C. in the differential scanning calorimetry (DSC) of the sapogrelate hydrochloride crystals. Wherein the powder X-ray diffraction (XRD) of the sapogrelate hydrochloride crystals has a diffraction peak of 9.184 ± 0.2 °, 9.494 ± 0.2 °, 10.138 ± 0.2 °, 10.61 ± 0.2 ° and 10.971 ± 0.2 °, Hydrochloride crystals. 5. The crystalline sapogenate hydrochloride according to claim 4 or 5, which comprises 60 to 80% by weight of the I-form crystal and 20 to 40% by weight of the II-form crystal.

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