KR101585189B1 - Process for preparing crystalline form of Sarpogrelate hydrochloride - Google Patents

Process for preparing crystalline form of Sarpogrelate hydrochloride Download PDF

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KR101585189B1
KR101585189B1 KR1020130084677A KR20130084677A KR101585189B1 KR 101585189 B1 KR101585189 B1 KR 101585189B1 KR 1020130084677 A KR1020130084677 A KR 1020130084677A KR 20130084677 A KR20130084677 A KR 20130084677A KR 101585189 B1 KR101585189 B1 KR 101585189B1
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hydrochloride
crystal
crystalline form
acetonitrile
hours
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KR1020130084677A
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KR20150010128A (en
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민연식
심성보
배관후
이형철
김병수
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주식회사 대희화학
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Priority to PCT/KR2014/006226 priority patent/WO2015008973A1/en
Priority to JP2016527915A priority patent/JP6147432B2/en
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    • 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
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B63/00—Purification; Separation; Stabilisation; Use of additives

Abstract

More particularly, the present invention relates to a method for efficiently producing crystalline Form II having a purity of 99% or more by using acetonitrile as a recrystallization solvent from crude crystals of a sapoglylate hydrochloride .

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for preparing crystalline form II of saporoglate hydrochloride (Process for preparing crystalline form II of Sarpogrelate hydrochloride)

The present invention relates to a process for preparing saporylate hydrochloride crystal Form II.

Sarpogrelate hydrochloride represented by the following formula (1) has a mechanism of selectively antagonizing the serotonin receptor (5-HT) of platelets and blood vessels. Specifically, since saponylate hydrochloride exhibits anti-platelet action and vasoconstrictor inhibitory action, it is clinically used as an agent for inhibiting and treating ischemic symptoms such as ulcer, pain and cold sensation caused by chronic arterial occlusion

[Chemical Formula 1]

Figure 112013064812942-pat00001

A method for the preparation of Sarpogrelate hydrochloride was first introduced in Example 2 of U.S. Patent No. 4,599,419. According to the above US patent, 2- [2-hydroxy-3-dimethylaminopropoxy] -3'-methoxybibenzyl hydrochloride was prepared as an intermediate through several steps of production, and then hydrochloric acid salt of the prepared intermediate The reaction mixture was neutralized to remove salts and converted into 2- [2-hydroxy-3-dimethylaminopropoxy] -3'-methoxybibenzyl form, followed by reaction with succinic anhydride, followed by reaction with a solution of hydrogen chloride and ethyl acetate, Lt; / RTI > hydrochloride. The crystal form of the sapogrelate hydrochloride is not specifically mentioned in the above-mentioned US patent.

In Korean Patent Laid-Open No. 2006-93677, it was later revealed that the sapogrelate hydrochloride prepared in the above-mentioned U.S. Patent No. 4,599,419 has two crystals of type I and II. In addition, the sapogenate hydrochloride prepared in Example 2 of U.S. Patent No. 4,599,419 discloses a polycrystalline compound having 30 mol% of I-form and 70 mol% of II-form. Korean Patent Laid-Open Publication No. 2006-93677 discloses a process for preparing a crude saponite salt (hereinafter referred to as "coarse crystal") prepared in Example 2 of US Pat. No. 4,599,419 in acetone, xylene, water or a mixed solvent of acetone and water And cooling the solution to 25 DEG C, and filtering and washing the resultant crystals to produce a II-form. However, since the solvent used in the method disclosed in Korean Patent Laid-Open Publication No. 2006-93677 is used in an excess amount of 10 times or more since the solubility of the crude crystals is low, a large-scale production facility is required to industrially use the method Further, there is a problem that it is difficult to dispose of the solvent.

In Japanese Patent Application Laid-Open No. 2008-285445, crude crystals are dissolved in hydrous acetone or methyl ethyl ketone, and acetone or methyl ethyl ketone cooled to 10 ° C or lower is added dropwise thereto to obtain a solution containing 70 to 90 mol% To obtain a crystal mixture. According to the crystallization method proposed in Japanese Patent Application Laid-Open No. 2008-285445, there is an advantage of increasing the content of crystalline II and reducing the amount of crystallization solvent. However, since water is used as a crystallization solvent, a succinic ester moiety of saponylate The compound represented by the following formula (2) is produced as an impurity to degrade the purity and the yield of the crystalline form II.

(2)

Figure 112013064812942-pat00002

The compound represented by the above formula (2) is produced as a decomposition product by recrystallization using water or alcohols, and has a great influence on the purity of a desired crystal compound.

As described in the above-mentioned prior art, in order to obtain Crystalline Form II more efficiently from crude crystals of Sarpogrelate hydrochloride, a small amount of crystallization solvent is used, and the generation of the decomposition product represented by Formula 2 There is a need to develop a new crystallization method that does not use water or alcohols as a crystallization solvent.

The inventors of the present invention have studied a method for producing a pure crystalline Form II from a crude crystal of Sarpogrelate hydrochloride by a simple and economical process through a recrystallization process. As a result, it has been found that acetonitrile (AN) is excellent in solubility in the hydrochloride salt of sarpogrelate, and unreacted starting material or other impurities can be obtained without inducing the generation of decomposition products represented by the above formula (2) It can be easily removed, and therefore it is found that it is useful as a recrystallization solvent of crude crystals, thereby completing the present invention.

Accordingly, it is an object of the present invention to provide a process for obtaining crystalline Form II in high purity from crude crystals of a sarpogrelate hydrochloride using acetonitrile as a recrystallization solvent.

In order to solve the above-mentioned problems, the present invention provides a process for preparing a crude saponate, comprising the steps of dissolving crude crystals of saponyl nitrate hydrochloride in acetonitrile by heating; And cooling the coarse crystal solution to a temperature of 0 to 20 占 폚 to filter the resulting crystals; Characterized in that it comprises a process for the preparation of saporoglyloate hydrochloride crystal form II.

Further, the present invention is characterized by a rod-like sapoglillate hydrochloride crystal type II.

According to the recrystallization method of the present invention, since the hydrolyzate represented by the formula 2 is hardly contained as impurities, the yield and purity of the crystalline form II are improved.

According to the recrystallization method of the present invention, since the yield and purity of crystalline II are high and there is no troubles in the process, it is useful for mass production of crystalline II.

According to the recrystallization method of the present invention, the content ratio of the crystalline form I and the crystalline form II can be easily controlled by controlling the conditions during the dissolving and cooling of the starting material.

1 is an electron micrograph (300-fold magnification) of the saponyl nitrate hydrochloride crystal form II prepared in Example 1. Fig.
2 is an infrared (IR) spectroscopy spectrum of the saponyl nitrate hydrochloride crystal form II prepared in Example 1. Fig.
Fig. 3 is an X-ray diffraction analysis chart of the saponyl nitrate hydrochloride crystal form II prepared in Example 1. Fig.
4 is an infrared (IR) spectroscopic spectrum of a crude sapogrelate hydrochloride salt crystal (crystal form I / II = 3/7 molar ratio) used as raw material in Example 1. FIG.
FIG. 5 is an X-ray diffraction analysis chart of a crude sapogrelate hydrochloride salt crystal (crystal form I / II = 3/7 molar ratio) used as raw material in Example 1. FIG.

(XRD), differential scanning calorimetry (DSC), infrared (IR) spectroscopy, nuclear magnetic resonance spectroscopy (NMR) results of the saponyl nitrate hydrochloride crystal form II prepared in the present invention, Which is consistent with the analysis results disclosed in 2006-93677.

In addition, the crystalline Form II prepared by the conventional method such as Korean Patent Publication No. 2006-93677 was obtained as a crystalline powder close to amorphous. However, as shown in the electron micrograph of FIG. 1, the crystal form II prepared by the process of the present invention was obtained in the form of a rod-shaped crystal, which is considered to have a reason for the higher purity of the crystalline form II.

In addition, it was confirmed from the following experimental examples that the rod-shaped crystalline Form II prepared by the production method according to the present invention is more excellent in stability than the powder crystalline Form II prepared by the conventional method.

Therefore, the present invention is also the first to disclose that the crystal structure of crystal form II is a bar-shaped crystalline form, as a method of increasing the yield and purity of crystalline Form II.

The manufacturing method of the crystalline Form II of the present invention will be described below in more detail.

First, the crude crystals are dissolved in acetonitrile by heating.

That is, the crystalline sapphagelerate hydrochloride salt is mixed with acetonitrile and heated to a temperature of 30 to 80 캜 to dissolve. At this time, acetonitrile is used in a range of 1: 2 to 8 parts by weight, preferably 3 to 5 parts by weight, based on the weight of the crude crystal. In order to increase the content of the crystalline form II, it is preferable to sufficiently dissolve the crude crystals. In order to sufficiently dissolve the coarse crystal, there may be a method of increasing the amount of the solvent used, raising the heating temperature, or lengthening the stirring time in the warmed state. According to the experiments of the present inventors, it was confirmed that when the stirring time was shortened while using a small amount of solvent, the content of crystalline type II was reduced. It is preferable to use a minimum amount of solvent to warm the reaction mixture at an appropriate temperature and an appropriate stirring time. The stirring time may vary depending on the reaction capacity or the kind of the reactor, but it is about 10 hours or less, preferably about 3 to 5 hours. In addition, the sample can be collected during the reaction, and the stirring time can be appropriately adjusted through IR analysis.

In order to improve solubility of crude crystals, at least one polar solvent selected from acetone, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMAc) and dimethylsulfoxide (DMSO) As shown in FIG. At this time, the polar solvent may be used in the range of 1: 0.01-0.5 volume times, more preferably 0.1-0.5 volume times, based on acetonitrile.

The crude crystals solution is then cooled and the resulting crystals are filtered to give crystalline Form II.

That is, the crude crystalline solution which has been sufficiently dissolved is cooled to a temperature of 0 to 20 占 폚, cooled, and the resulting crystals are filtered to obtain crystal form II of the present invention. The cooling temperature is preferably maintained at 0 to 10 占 폚. When it is left in a cooled state, crystals precipitate slowly. The time for leaving in a cooled state is preferably about 1 to 5 hours, more preferably for 1 to 3 hours.

 Crystalline Form II prepared through the above-described preparation method was obtained in the form of a stick-like crystal. (See the electron micrograph of FIG. 1) It is considered that the reason why the crystal form II was obtained in the form of a bar-like crystal instead of the powder form is that the crystal form II has high purity. Particularly, according to the present invention, crystal form II having a crystal form II / I molar ratio of 98% or more can be prepared as a sapphyrylate hydrochloride crystal.

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 Preparation of Sapphyrylate Hydrochloride Crystalline Form II

In this Example, crude crystals (crystal form I: crystal form II molar ratio = 30: 70, purity: 99.3%) were prepared by the production method disclosed in Example 2 of U.S. Patent No. 4,599,419.

The crude crystals (10 g) were added to 100 mL of acetonitrile, refluxed and stirred for 5 hours, cooled to 10 DEG C, and left for 2 hours. The resulting crystals were filtered, washed with acetonitrile, and dried to obtain 9.3 g of crystalline Form II (yield 93%, HPLC purity 99.93%, molar ratio of crystalline II / I of 98% or more).

An electron microscope photograph, an infrared (IR) spectroscopic spectrum and an X-ray diffraction diagram of the crystalline Form II (the crystalline form II / I molar ratio of 98% or more) prepared in Example 1 are shown in FIGS.

Infrared (IR) spectroscopy and X-ray diffraction analysis of crude crystals (crystalline type I / II = 3/7 molar ratio) used as raw materials in Example 1 were shown in FIGS. 4 to 5, respectively.

Examples 2 to 7 and Comparative Examples 1 to 3. Preparation of Sapphyrylate Hydrochloride Crystalline Type II

The crude crystals (crystalline form I: crystal form II molar ratio = 30:70, purity: 99.3%) were recrystallized in the same manner as in Example 1 except that the type of solvent, the amount of solvent used, the recrystallization temperature, Respectively.

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

division Recrystallization solvent Recrystallization condition Cooling
Temperature product Kinds Usage a) II / I b) yield
(%) water
(%) c) decision
shape Example 1 AN 5 times Reflux 5 hours 10 ℃ > 98 93 99.93 rod
shape Example 2 AN 5 times Reflux 2 hours 10 ℃ ~ 80 92 99.92 rod
shape Example 3 AN / acetone
(5/2) 7 times Reflux 5 hours 10 ℃ > 98 95 99.93 rod
shape Example 4 AN / DMF
(5 / 0.2) 5 times Reflux 5 hours 10 ℃ > 98 90 99.95 rod
shape Example 5 AN / DMAc
(5 / 0.2) 5 times Reflux 5 hours 10 ℃ > 98 91 99.94 rod
shape Example 6 AN / THF
(1 / 0.4) 5 times Reflux 5 hours 10 ℃ > 98 95 99.8 rod
shape Example 7 AN / DMSO
(1 / 0.2) 5 times Reflux 5 hours 10 ℃ > 98 90 99.91 rod
shape Comparative Example 1 Acetone 400 times Reflux 20 hours 10 ℃ ~ 80 90 99.5 powder Comparative Example 2 Acetone / water (1 / 0.05) 30 times Reflux 10 hours 10 ℃ > 98 80 98.5 powder Comparative Example 3 Acetone /
MeOH
(7/3) 10 times Reflux 7 hours 10 ℃ ~ 70 83 99.5 powder a) Weight ratio: weight ratio of recrystallization solvent based on crude crystal weight
b) the molar ratio of crystalline form II / I in the product
c) purity analyzed by HPLC

[Experimental Example]

Experimental Example 1. Stability Test of Sapphyrylate Hydrochloride Crystalline Form II

In order to compare the stability against heat and moisture with respect to the crystalline Form II prepared 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 device: Constant Temp & Humid Chamber SH-201S (Manufacturer: ACT)

- Storage conditions: Acceleration test - Temperature 40 ± 1 ℃, relative humidity 75%

             Long term storage test - Temperature 25 ± 1 ℃, relative humidity 60%

- Analytical instrument: HPLC

- Preparation of standard and test solutions

1) Standard solution: Crystalline type II 0.4 mg / mL concentration (100%) was prepared and calibration curve was prepared.

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 of the crystalline form II in the HPLC graph was compared with the standard solution to calculate the content.

Experimental compound Storage conditions Remaining rate (%) 1 day 6 days 28th 58 days 200 days Comparative Example 1
(Powder shape) Accelerated test 99.92 99.92 99.91 99.85 99.65 Long term preservation
exam 99.92 99.92 99.92 99.89 99.89 Example 1
(Rod shape) Accelerated test 99.93 99.93 99.92 99.90 99.90 Long term preservation
exam 99.93 99.93 99.93 99.92 99.92

Table 2 shows that the crystalline Form II according to the present invention has a rod-shaped crystal structure and is stable to heat and moisture when stored for a long time as compared with the crystalline Form II prepared according to the conventional method.

Claims (8)

Mixing acetonitrile in a ratio of 1: 2 to 7 times by weight with respect to the weight of the coarse crystal to a coarse crystal of a saponitrate hydrochloride, and melting the mixture at a temperature of 30 to 80 DEG C for 3 to 10 hours; And
Cooling the crude crystal solution to a temperature of 0 to 20 캜 and filtering out the resulting bar-shaped crystalline Form II; / RTI &gt;
In the X-ray powder diffraction analysis, the X-ray powder diffraction analysis showed that 9.461, 10.173, 10.960, 13.720, 14.240, 15.039, 15.579, 16.097, 17.079, 17.379, 18.381, 19.078, 19.602, 21.201, 21.521, 22.641, 23.698, 24.340, 25.180, 26.018, 26.900, A process for producing sapomellate hydrochloride crystal form II having a 2? Diffraction angle of 31.640 °.
The method according to claim 1,
Wherein the heat dissolution is carried out at a temperature of 30 to 80 캜 for 3 to 5 hours.
The method according to claim 1,
Wherein the amount of acetonitrile used is 1: 3-5 times the weight of crude crystals.
The method according to claim 1,
Characterized in that the acetonitrile further comprises at least one polar solvent selected from acetone, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMAc) and dimethylsulfoxide (DMSO) 0.0 &gt; II &lt; / RTI &gt;
The method of claim 4,
Wherein the polar solvent is used in an amount of 1: 0.01 to 0.5 volume times the volume of acetonitrile.
6. The method according to any one of claims 1 to 5,
Wherein the sapphirlylate hydrochloride crystal form II has a purity of 99% or more.
delete In the X-ray powder diffraction analysis, the X-ray powder diffraction analysis showed that 9.461, 10.173, 10.960, 13.720, 14.240, 15.039, 15.579, 16.097, 17.079, 17.379, 18.381, 19.078, 19.602, 21.201, 21.521, 22.641, 23.698, 24.340, 25.180, 26.018, 26.900, Characterized in that it has a 2? Diffraction angle of 31.640 DEG, and is a sapphirlylate hydrochloride crystal Form II having a purity of 99% or more.
KR1020130084677A 2013-07-18 2013-07-18 Process for preparing crystalline form of Sarpogrelate hydrochloride KR101585189B1 (en)

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PCT/KR2014/006226 WO2015008973A1 (en) 2013-07-18 2014-07-10 Method for preparing sarpogrelate hydrochloride crystal form ii
JP2016527915A JP6147432B2 (en) 2013-07-18 2014-07-10 Method for producing type II crystals of sarpogrelate hydrochloride

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JP2007217333A (en) * 2006-02-16 2007-08-30 Ohara Yakuhin Kogyo Kk Crystal form of sarpogrelate hydrochloride and method for producing the same
JP2008285445A (en) 2007-05-18 2008-11-27 Hidekazu Takada Industrial method for producing sarpogrelate hydrochloride

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KR101393178B1 (en) * 2005-02-22 2014-05-08 미쓰비시 타나베 파마 코퍼레이션 Crystal of (±)2-(Dimethylamino)-1-｛[O-(m-methoxyphenethyl)phenoxy]methyl｝ethyl Hydrogen Succinate Hydrochloride
JP5090770B2 (en) * 2007-04-06 2012-12-05 ダイト株式会社 Industrial production method of sarpogrelate hydrochloride
KR100881890B1 (en) * 2007-05-03 2009-02-04 주식회사 엔지켐 Process for preparation of Sarpogrelate HCl salt
JP4849374B2 (en) * 2007-05-18 2012-01-11 株式会社Ｄｎｐファインケミカル福島 (±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride mixed crystal of Form I and Form II crystals
KR100911720B1 (en) * 2009-04-10 2009-08-10 주식회사 한서켐 A process for preparing crystal foam of sarpogrelate hcl
KR20100118747A (en) * 2009-04-29 2010-11-08 제일약품주식회사 Improved preparation method of sarpogrelate hydrochloride
KR101027945B1 (en) * 2009-05-06 2011-04-12 주식회사 한서켐 Recrystallization process of sarpogrelate HCl
JP6130701B2 (en) * 2012-04-01 2017-05-17 エシャシ ファーマ リミテッドＥｓｈｙａｓｉ Ｐｈａｒｍａ Ｌｉｍｉｔｅｄ Industrial production method of (2RS) -1-dimethylamino-3- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} propan-2-yl hydrogen succinate hydrochloride

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Publication number Priority date Publication date Assignee Title
JP2007217333A (en) * 2006-02-16 2007-08-30 Ohara Yakuhin Kogyo Kk Crystal form of sarpogrelate hydrochloride and method for producing the same
JP2008285445A (en) 2007-05-18 2008-11-27 Hidekazu Takada Industrial method for producing sarpogrelate hydrochloride

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