KR20090004269A - Polymorph form ii of racemic clopidogrel carboxylic acid monohydrate, and process for the preparation it - Google Patents

Abstract

A novel crystal form II of racemic clopidogrel carboxylic acid monohydrate, and a method for preparing the crystal form are provided to obtain the crystal form II of racemic clopidogrel carboxylic acid monohydrate useful as the material for the synthesis of S-(+)-clopidogrel. A crystal form II of racemic clopidogrel carboxylic acid monohydrate is such that the specific peak values (2theta) measured by the XRD spectrum under the conditions of CuKalpha, lambda=1.54056 Å, 18 KW, 40.0 KV, and 30.0 mA are 12.54, 14.70, 17.44, 19.94, 20.54, 23.12, 25.00, 26.94, 27.36, 28.56, and 29.72±2 degrees. Preferably the crystal form II of racemic clopidogrel carboxylic acid monohydrate has a melting point of 108.0-112.0 deg.C.

Description

Polymorph form II of racemic clopidogrel carboxylic acid monohydrate, and process for the preparation it}

The present invention relates to a crystalline Form II of a novel racemic clopidogrel carboxylic acid monohydrate and a preparation method thereof.

The chemical name of S-(+)-clopidogrel is methyl (+)-S-α- (o-chlorophenyl) -6,7-dihydrothieno- [3,2-c] -pyridine-5 ( 4H ) -Acetate, a potent platelet aggregation inhibitory activity and anti-thrombotic activity, showing peripheral arterial diseases such as stroke, thrombosis and embolism and coronary artery such as myocardial infarction and angina pectoris It is known to be effective as a therapeutic agent for vascular diseases used in the treatment of diseases.

In a recent research report, S-(+)-clopidogrel has been shown to be highly effective platelet aggregation inhibitors at lower doses than aspirin and has a reduced effect on the gastrointestinal tract, resulting in highly effective platelet aggregation inhibitors. . S-(+)-Clopidogrel is currently sold under the trade name Flavix, which contains about 98 mg of S-(+)-clopidogrel hydrogen sulphate, the active ingredient 75 mg of S-(+)-clopidogrel base is contained.

Racemic clopidogrel is well known as an intermediate for S-(+)-clopidogrel synthesis.

As a general manufacturing method for synthesizing S-(+)-clopidogrel via synthesizing racemic clopidogrel as an intermediate, briefly summarized the manufacturing methods known in US Patent Nos. 4,529,596, US Patent No. 4,847,265, and US Patent No. 5,204,469, etc. It can be represented by Scheme 1.

According to the prior art method described in Scheme 1, racemic clopidogrel (g) is reacted with an optically active base to produce S-(+)-clopidogrel as an optically pure preferential (S) -isomer. After the formation of the diastereomeric salt (h), recrystallization yields the optically active acid addition salt of the preferred (S) optical isomer that does not contain the left-right (L) optical isomer, followed by removal of the optically active acid. Is performing a series of optical resolution processes.

Meanwhile, Korean Patent Application Publication No. 2006-0134541 and Patent Application No. 2005-0129717 disclose a method of preparing S-(+)-clopidogrel by performing optical cleavage and subsequent reaction of a compound of racemic clopidogrel carboxylic acid (j). It is.

The present invention has the same chemical formula as racemic clopidogrel carboxylic acid (j) used as an intermediate in the S-(+)-clopidogrel synthesis reaction, but a novel crystalline form II compound having a specific crystal structure different from the compounds published so far. It is the invention which patented it by manufacturing it.

It is an object of the present invention to provide Form II of the novel racemic clopidogrel carboxylic acid monohydrate.

It is another object of the present invention to provide a process for preparing the novel crystalline Form II compound.

In the present invention, the characteristic peak values (2θ) of the XRD spectrum measured under the conditions of CuKα, λ = 1.54056 Hz, 18KW, 40.0KV, and 30.0mA are 12.54, 14.70, 17.44, 19.94, 20.54, 23.12, 25.00, 26.94, 27.36, 28.56 , Form II of racemic clopidogrel carboxylic acid monohydrate, which is 29.72 ± 0.2 °.

The invention also features Form II of racemic clopidogrel carboxylic acid monohydrate having a DSC melting point of 108.0 ° C. to 112.0 ° C.

The invention also features Form II of racemic clopidogrel carboxylic acid monohydrate exhibiting characteristic absorbances at infrared rays (IR) spectra of 3428.6, 3708.8, 3026.9, 2875.9, 1661.7, 1647.6, 1476.6 cm ⁻¹ .

The invention also features Form II of racemic clopidogrel carboxylic acid monohydrate having a water content of 5.39 ± 1.5% as measured by Karl-Fischer method.

The invention also features Form II of racemic clopidogrel carboxylic acid monohydrate that satisfies two or more of the physicochemical properties defined above.

Schematic diagram of a method for preparing crystalline Form II of racemic clopidogrel carboxylic acid monohydrate having physicochemical properties as defined above is shown in Scheme 2 below.

In Scheme 2, M is an alkali metal atom.

Accordingly, the present invention includes the preparation method of Form II of racemic clopidogrel carboxylic acid monohydrate as described below based on Scheme 2.

That is, the present invention as shown in Scheme 2:

The racemic clopidogrel carboxylic acid alkali metal salt represented by the above formula (2) is suspended in water, the suspension is acid treated to acidify the pH to 1-5, and then filtered, and the racease represented by the above formula (4). Characterized in that the production method comprises a one-step manufacturing process comprising the step of preparing the crystalline form II of Mic Clopidogrel carboxylic acid monohydrate.

In addition, the present invention as shown in Scheme 2:

The acid is treated with the racemic clopidogrel carboxylic acid alkali metal salt represented by the above formula (2), acidified to 1-5, extracted with a solvent, and solidified, and the racemic clopidogrel carboxylic acid represented by the above formula (3). Preparing a hydrochloride salt; And suspending the racemic clopidogrel carboxylic acid hydrochloride represented by Chemical Formula 3 in water, filtering the suspension to prepare Form II of the racemic clopidogrel carboxylic acid monohydrate represented by Formula 4. Characterized by the manufacturing method consisting of the process.

In addition, the present invention as shown in Scheme 2:

Hydrolyzing the racemic clopidogrel represented by Formula 1 in the presence of a water-soluble alkali metal salt, thereby preparing a racemic clopidogrel carboxylic acid alkali metal salt represented by Formula 2; And suspending the racemic clopidogrel carboxylic acid alkali metal salt represented by Chemical Formula 2 in water, acidifying the suspension to acidity to 1 to 5, followed by filtration, followed by filtration. Characterized by a manufacturing method comprising a two-step manufacturing process comprising the step of preparing the crystalline Form II of racemic clopidogrel carboxylic acid monohydrate.

In addition, the present invention as shown in Scheme 2:

Hydrolyzing the racemic clopidogrel represented by Formula 1 in the presence of a water-soluble alkali metal salt, thereby preparing a racemic clopidogrel carboxylic acid alkali metal salt represented by Formula 2; The acid is treated with the racemic clopidogrel carboxylic acid alkali metal salt represented by the formula (2), acidify the pH to 1 to 5, extracted with a solvent, and solidified, and the racemic clopidogrel carboxylic acid hydrochloride represented by the formula (3). Preparing a salt; And suspending the racemic clopidogrel carboxylic acid hydrochloride represented by Formula 3 in water and filtering the suspension to prepare Form II of racemic clopidogrel carboxylic acid monohydrate represented by Formula 4. It is characterized by a manufacturing method consisting of a manufacturing process.

Based on the reaction scheme 2, the production method according to the present invention will be described in more detail by subdividing for each process as follows.

The racemic clopidogrel represented by Formula 1 used as a starting material in the preparation method of the present invention is commercially available 4,5,6,7-dihydro-4 H- thieno [3,2-c]. Pyridine or acid addition salts thereof and bromo- (2-chlorophenyl) acetic acid ethyl ester can be easily prepared by combining under inorganic base conditions.

In Scheme 2, in order to convert racemic clopidogrel represented by Formula 1 to racemic clopidogrel lithium carboxylate salt represented by Formula 2, a hydrolysis reaction is performed under water-soluble inorganic base conditions.

As a water-soluble inorganic base used for a hydrolysis reaction, a conventional metal salt is used, specifically, a water-soluble alkali metal salt is used, More specifically, an alkali metal hydroxide is used. The alkali metal hydroxide is selected from lithium hydroxide, sodium hydroxide and potassium hydroxide, preferably lithium hydroxide. The water-soluble alkali metal salt is used in the range of 0.5 molar equivalents to 10 molar equivalents with respect to racemic clopidogrel represented by Formula 1, and preferably 3 molar equivalents to 5 molar equivalents.

As a reaction solvent used for the hydrolysis reaction, a conventional solvent is used, and for example, water or organic solvents such as ketones, alcohols, ethers, amides, esters, hydrocarbons, halogenated hydrocarbons, nitriles, and the like. A single solvent selected from the group consisting of two or more mixed solvents may be used. As the reaction solvent, water, ethers or mixed solvents thereof are preferably used. More preferably, water, tetrahydrofuran or a mixed solvent thereof is used, and water and tetrahydrofuran are particularly preferred. A mixed solvent having a volume ratio of 10 to 10: 1 is used.

The proper temperature of the hydrolysis reaction is 20 ° C to 100 ° C, and a preferable temperature range is 70 ° C to 80 ° C. The titration time of the hydrolysis reaction is 1 hour to 48 hours, preferably 8 hours to 24 hours.

After the hydrolysis reaction is completed, a portion of the solvent used is distilled off under reduced pressure to obtain a racemic clopidogrel carboxylic acid alkali metal salt represented by Chemical Formula 2 in a solid state. Specifically, the hydrolysis reaction solution is distilled off under reduced pressure at room temperature to remove a part of the solvent, and when the solvent is removed in the range of 1 to 20% by volume, preferably 5 to 10% by volume, based on the total volume of the solvent used, The racemic clopidogrel carboxylic acid alkali metal salt represented by Formula 2 may be obtained as a solid.

In addition, the racemic clopidogrel carboxylic acid alkali metal salt represented by Formula 2 may be obtained as a solid compound having high purity by performing a conventional separation and purification process, but if necessary, the next reaction is performed without a separate separation and purification process. It can also be used. In consideration of economics, it is more preferable to omit the separation and purification process of the compound represented by Chemical Formula 2 and to be carried out in a continuous process.

In the preparation method according to the present invention, the compound represented by Chemical Formula 2 is acidified to pH 1 to 5 by acid treatment, and then filtered to form Form II of racemic clopidogrel carboxylic acid monohydrate represented by Chemical Formula 4 directly. Or, the compound represented by the formula (2) is acidified by acid treatment (acid) to pH 1-5 range, then extracted with a solvent, solidified and suspended in water and filtered to perform the process sequentially Crystalline Form II of racemic clopidogrel carboxylic acid monohydrate represented by can be prepared.

That is, according to Scheme 2, the racemic clopidogrel carboxylic acid monohydrate represented by the formula (4) is formed by acidifying the racemic clopidogrel carboxylic acid alkali metal salt represented by the formula (2) and then acidifying the suspension. Crystalline Form II can be prepared directly. More specifically, the racemic clopidogrel carboxylic acid alkali metal salt represented by Chemical Formula 2 is suspended in water, and the suspension is treated with an acid to have a pH of 1 to 5 (preferably 1 to 4, particularly preferred). In the following, it is acidified by adjusting in the range of 1 to 2) and stirred at room temperature for 2 to 4 hours, and then the acid suspension is filtered to directly prepare Form II of racemic clopidogrel carboxylic acid monohydrate represented by Chemical Formula 4 above. .

Further, according to Scheme 2, after acidifying the racemic clopidogrel carboxylic acid alkali metal salt represented by Formula 2 by acid treatment to convert the racemic clopidogrel carboxylic acid hydrochloride salt represented by Formula 3, This compound is suspended in water and filtered to prepare Form II of the racemic clopidogrel carboxylic acid monohydrate represented by the formula (4). More specifically, by adjusting the racemic clopidogrel carboxylic acid alkali metal salt represented by the formula (2) with an acid (acid) to adjust the pH to 1 to 5 (preferably 1 to 4, particularly preferably 1 to 2) After acidification, extraction with a conventional organic solvent and distillation under reduced pressure followed by solidification using an appropriate nonpolar solvent yields a racemic clopidogrel carboxylic acid hydrochloride salt represented by the formula (3). Then, the racemic clopidogrel carboxylic acid hydrochloride salt represented by the formula (3) is suspended in water, stirred at room temperature for 2 to 4 hours, and then the acidic suspension is filtered to give the racemic clopidogrel carboxylic acid represented by the formula (4). Form II of hydrate can be prepared.

The acid used to adjust the pH of the reaction solution may be appropriately selected from the group consisting of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and organic acids such as acetic acid, preferably hydrochloric acid. In addition, the acid used in the present invention for pH adjustment is more convenient to use in an aqueous solution state.

As the general organic solvent used for the extraction, a single solvent or two or more mixed solvents selected from ketones, alcohols, ethers, amides, esters, hydrocarbons, halogenated hydrocarbons and nitriles may be used. Dichloromethane, methanol, ethanol, ethyl acetate or a mixed solvent thereof are suitable.

In addition, the extracted organic solution containing racemic clopidogrel carboxylic acid hydrochloride represented by Chemical Formula 3 may be evaporated under reduced pressure as appropriate, solidified using a nonpolar solvent, filtered, and vacuum dried to obtain a solid. As the nonpolar solvent used for the solidification, a single solvent or two or more mixed solvents selected from hydrocarbons and ethers may be used, and hexane, diethyl ether, or a mixed solvent thereof is preferable.

In addition, the crystalline form II of the racemic clopidogrel carboxylic acid monohydrate represented by Chemical Formula 4 prepared by the above manufacturing method is vacuum dried at 20 ° C. to 50 ° C. for 2 to 24 hours. In addition, if necessary, a conventional purification method, for example, washing with a solvent may be performed to obtain Form II of racemic clopidogrel carboxylic acid monohydrate represented by Chemical Formula 4 as a high purity crystal compound.

The organic solvent used to carry out the preparation method according to the present invention may be selected and used from the following. C _2-10 dialkyl ketone may be used as the ketone solvent, and specifically, acetone, 2-butanone, methyl isobutyl ketone, or the like may be included. The alcohol solvent may be an aliphatic or aromatic alcohol, specifically, C _1-10 alcohol such as methanol, ethanol, isopropanol, butanol, 2-methyl-2-propanol, cyclohexanol and the like. The ether solvent may be C _2-10 ether, specifically, dioxane, tetrahydrofuran (THF), anisole, diethyl ether, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether, diethylene glycol Diethyl ether, diethyl ether and the like can be included. Amide solvents may be C _2-10 amide, specifically N, N- dimethylformamide (DMF), N, N- dimethylacetamide (DMAc), 1-methyl-2-pyrrolidone, etc. This may be included. As the ester solvent, C _2-10 ester may be used, and specifically, ethyl acetate may be included. The hydrocarbon solvent may be a C _1-10 aliphatic or aromatic hydrocarbon, and specifically, may include hexane, benzene, toluene, xylene and the like. Halogenated hydrocarbon solvents are C _1-10 hydrocarbons having 1 to 6 halogen atoms, and specifically, chloroform, dichloromethane, dichloroethane and the like may be included. As the nitrile solvent, C _2-10 nitrile may be used, and specifically, acetonitrile may be included.

Crystalline Form II of the racemic clopidogrel carboxylic acid monohydrate represented by Formula 4 prepared by the above preparation method is a novel compound.

Physical and chemical properties of the crystalline form II of racemic clopidogrel carboxylic acid monohydrate represented by the formula (4) characterized by the present invention can be confirmed from FIGS. 1 to 4.

FIG. 1 shows XRD analysis of Form II of racemic clopidogrel carboxylic acid monohydrate, which was measured using a Mac Science M18XHF diffractometer under CuKα, λ = 1.54056 Hz, 18KW, 40.0KV, and 30.0mA. Table 1 summarizes the characteristic peaks shown in the XRD analysis spectrum of FIG. 1. The error range of the characteristic peaks shown in Table 1 is ± 0.2 °.

Peak number 2θ d (Å) I / I ₀ One 12.540 7.0532 1000 2 14.700 6.0212 478 3 17.440 5.0808 274 7 19.940 4.4490 532 8 20.540 4.3205 381 9 23.120 3.8438 483 11 25.000 3.5580 574 13 26,940 3.3069 274 14 27.360 3.2571 342 15 27.360 3.3069 229 16 29.720 3.0036 146 17 30.880 2.8933 105

FIG. 2 is a differential enthalpy analysis (DSC) result of Form II of racemic clopidogrel carboxylic acid monohydrate, measured at a heating rate of 20 ° C./min in a temperature range of 50 ° C. to 200 ° C. using a Perkin Elmer DSC 7 instrument. One result. The DSC melting point of Form II identified in FIG. 2 was 182.0 ° C to 186.0 ° C.

Figure 3 is a thermogravimetric analysis (TGA) results of the Form II of racemic clopidogrel carboxylic acid monohydrate, using a Perkin Elmer TGA-7 instrument at a heating rate of 20 ℃ / min in the temperature range of 50 ℃ to 700 ℃ It is a result of a measurement.

FIG. 4 shows infrared spectroscopy of crystalline Form II of racemic clopidogrel carboxylic acid monohydrate. Fourier transform (FT IR) spectra were obtained in a wavelength range of 4000 cm ⁻¹ to 400 cm ⁻¹ using a Nicolet Magna 750 spectrometer.

FIG. 5 shows the results of nuclear magnetic resonance (NMR) spectroscopy of crystalline Form II of racemic clopidogrel carboxylic acid monohydrate, which was measured using a Varian Unity 300 FT-NMR 300 MHz instrument.

FIG. 6 is an electron scanning microscope photograph of crystalline Form II of racemic clopidogrel carboxylic acid monohydrate, using a Hitachi S-3000N instrument. Photographic observations showed that Form II is in the form of a needle or plate.

The present invention as described above has the same chemical formula as racemic clopidogrel carboxylic acid (j) used as an intermediate in the S-(+)-clopidogrel synthesis reaction, but has a specific crystal structure that has not been published so far. It has the effect of providing a novel crystalline Form II compound.

The present invention as described above will be described in more detail based on the following examples, but the present invention is not limited thereto.

Example 1 Synthesis of Racemic Clopidogrel (Formula 1)

175.7 g of 4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride and 291.4 g (1.05 molar equivalent) of bromo- (2-chlorophenyl) acetic acid ethyl ester in N, N -dimethylform After dissolving in 1.76 L of amide (DMF), 152.0 g (1.10 molar equivalents) of potassium carbonate was added thereto, and the mixture was refluxed at 90 ° C. for 8 hours. After filtration at room temperature, the mixture was concentrated under reduced pressure, and the organic layer was extracted using water and ethyl acetate. Water was removed with anhydrous sodium sulfate and concentrated under reduced pressure. Vacuum drying at room temperature for 12 hours gave 298.9 g (yield 89.0%) of the title compound as a yellow color.

Example 2 Synthesis of Racemic Clopidogrel Lithium Carboxylic Acid Salt (Formula 2)

After dissolving 335.9 g of racemic clopidogrel (Formula 1) in 3.36 L of a THF / water (4: 1) solution, 83.9 g (2.0 molar equivalents) of lithium hydroxide monohydrate was added and refluxed at 80 ° C. for 8 hours. Concentrated under reduced pressure at room temperature to remove more than 90% of the organic solvent, filtered and washed with water. Vacuum drying at room temperature for 18 hours afforded 238.4 g (yield 76.0%) of the title compound.

Example 3 Synthesis of Racemic Clopidogrel Carboxylic Acid Hydrochloride (Formula 3)

238.4 g of racemic clopidogrel lithium carboxylate (Formula 2) was suspended in 760 mL of water, adjusted to pH 1-2 with concentrated hydrochloric acid solution, 760 mL of 5% methanol / dichloromethane was added and stirred at room temperature for 2 hours. The organic layer was extracted and then extracted twice with 760 mL of 5% methanol / dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The pale yellow oil obtained was solidified using ethyl acetate and hexane and filtered. Vacuum drying at room temperature for 12 hours afforded 242.3 g (92.6%) of the title compound.

Theoretical yield 92.6%; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.74-7.77 (m, 1H), 7.55-7.60 (m, 1H), 7.43-7.49 (m, 2H), 7.36 (d, 1H, J = 5.1 Hz ), 6.85 (d, 1H, J = 5.1 Hz), 5.14 (s, 1H), 3.96-4.00 (brs, 2H), 3.16-3.21 (brs, 2H), 2.49-2.51 (brs, 2H)

Example 4 Synthesis of Racemic Clopidogrel Carboxylic Acid Hydrochloride (Formula 3)

After dissolving 335.9 g of racemic clopidogrel (Formula 1) in 3.36 L of a THF / water (4: 1) solution, 83.9 g (2.0 molar equivalents) of lithium hydroxide monohydrate was added and refluxed at 80 ° C. for 8 hours. Concentrated under reduced pressure at room temperature to remove more than 90% of the organic solvent and then 670 mL of water was added to adjust the pH 1-2 with a concentrated hydrochloric acid solution. 1.34 L of 5% methanol / dichloromethane was added and stirred at room temperature for 2 hours. The organic layer was extracted and then extracted twice with 1.34 L of 5% methanol / dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The pale yellow oil obtained was solidified using ethyl acetate and hexane and filtered. Vacuum drying at room temperature for 12 hours afforded 316.4 g (91.9%) of the title compound.

Example 5 Synthesis of Racemic Clopidogrel Carboxylic Acid Monohydrate Crystalline Form II (Formula 4)

When 31.3 g of racemic clopidogrel lithium carboxylate (Formula 2) is suspended in 100 mL of water, a suspension of pH 11-12 is added, followed by adding concentrated hydrochloric acid solution to pH 1-2 (acidic) for 2 hours in this state. Was stirred. Filter and wash twice with 20 mL of water. Vacuum drying at 50 ° C. for 12 hours gave 29.1 g (89.3%) of the title compound.

Theoretical yield 89.3%; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ7.62-7.65 (m, 1H), 7.47-7.51 (m, 1H), 7.32-7.42 (m, 2H), 7.25 (d, 1H, J = 5.1 Hz), 6.76 (d, 1H, J = 5.1 Hz), 4.73 (s, 1H), 3.65 (dd, 2H, J = 26.7 Hz, 14.1 Hz), 2.78-2.89 (m, 4H); Melting point 108.0 ° C to 112.0 ° C; Water content (Karl-Fischer method) 5.39%; XRD (CuKα, λ = 1.54056 Hz, 18 KW, 40.0 KV, 30.0 mA) 2θ = 12.54, 14.70, 17.44, 19.94, 20.54, 23.12, 25.00, 26.94, 27.36, 28.56, 29.72; FT-IR 3428.6, 3708.8, 3026.9, 2875.9, 1661.7, 1647.6, 1476.6 cm ^-1

Example 6 Synthesis of Racemic Clopidogrel Carboxylic Acid Monohydrate Crystalline Form II (Formula 4)

When 31.3 g of racemic clopidogrel lithium carboxylate (Formula 2) is suspended in 100 mL of water, a suspension of pH 11-12 is added. The mixture is concentrated to pH 3-4 (acidic) for 2 hours in this state. Was stirred. Filter and wash twice with 20 mL of water. Vacuum drying at 50 ° C. for 12 hours yielded 26.9 g (85.6%) of the title compound.

Example 7 Synthesis of Racemic Clopidogrel Carboxylic Acid Monohydrate Crystalline Form II (Formula 4)

When 344.3 g of racemic clopidogrel carboxylic acid hydrochloride (Formula 3) is suspended in 1.0 L of water, a suspension of pH 1-2 is stirred and stirred for 2 hours. Filter and wash twice with 100 mL of water. Vacuum drying at 50 ° C. for 12 h yielded 301.8 g (92.6%) of the title compound.

The present invention is characterized by the crystalline Form II of racemic clopidogrel carboxylic acid monohydrate having a novel crystal structure and the preparation method of the above-mentioned crystalline Form II compound, wherein the novel crystalline Form II compound characterized by the present invention is S-(+)- It is useful as a synthetic material of clopidogrel.

1 is an XRD analysis of Form II of racemic clopidogrel carboxylic acid monohydrate.

Figure 2 shows the results of differential enthalpy analysis (DSC) of Form II of racemic clopidogrel carboxylic acid monohydrate.

FIG. 3 shows thermogravimetric analysis (TGA) results for Form II of racemic clopidogrel carboxylic acid monohydrate. FIG.

Figure 4 shows the results of infrared (IR) spectroscopy on Form II of racemic clopidogrel carboxylic acid monohydrate.

FIG. 5 shows the results of nuclear magnetic resonance (NMR) spectroscopy on crystalline Form II of racemic clopidogrel carboxylic acid monohydrate. FIG.

6 is an electron scanning microscope (SEM) photograph of Form II of racemic clopidogrel carboxylic acid monohydrate.

Claims (23)

The characteristic peak values (2θ) of the XRD spectrum measured under the conditions of CuKα, λ = 1.54056 Hz, 18 KW, 40.0 KV, and 30.0 mA were 12.54, 14.70, 17.44, 19.94, 20.54, 23.12, 25.00, 26.94, 27.36, 28.56, 29.72 ± Crystalline Form II of Racemic Clopidogrel Carboxylic Acid Monohydrate, characterized by 2 °. Form II of racemic clopidogrel carboxylic acid monohydrate, characterized by a DSC melting point of 108.0 ° C to 112.0 ° C. Infrared (IR) spectrum shows characteristic absorbance at 3428.6, 3708.8, 3026.9, 2875.9, 1661.7, 1647.6, 1476.6 cm ^-1 , crystalline Form II of racemic clopidogrel carboxylic acid monohydrate, characterized by the above-mentioned. Crystalline form of racemic clopidogrel carboxylic acid monohydrate, characterized by a water content of 5.39 ± 1.5% measured by Karl-Fischer method II. Crystalline form of racemic clopidogrel carboxylic acid monohydrate, characterized in that it satisfies at least two of the physicochemical properties defined in any one of claims 1 to 4. The racemic clopidogrel carboxylic acid alkali metal salt represented by the following formula (2) is suspended in water, and the suspension is acid treated to acidify the pH to 1-5, followed by filtration, followed by the lactose represented by the following formula (4). Preparation of Form II of Mic Clopidogrel Carboxylic Acid Monohydrate Method for producing a racemic clopidogrel carboxylic acid crystal form comprising: [Formula 2]

In Formula 2, M is an alkali metal. [Formula 4]

The racemic clopidogrel carboxylic acid alkali metal salt represented by the following formula (2) is acidified by acid treatment to pH 1-5, extracted with a solvent and solidified, and the racemic clopidogrel carboxylic acid hydrochloride represented by the following formula (3) Process of preparing a salt; And Suspending the racemic clopidogrel carboxylic acid hydrochloride represented by the following formula (3) in water, and filtering the suspension to prepare Form II of the racemic clopidogrel carboxylic acid monohydrate represented by the following formula (4); Method for producing a racemic clopidogrel carboxylic acid crystal form comprising: [Formula 2]

In Formula 2, M is an alkali metal. [Formula 3]

[Formula 4]

The method according to claim 6 or 7, The acid treatment for pH adjustment is characterized in that using an aqueous solution of an acid selected from hydrochloric acid, sulfuric acid, nitric acid, and acetic acid. The method according to claim 6 or 7, The acidification is a production method, characterized in that to adjust the pH of the solution to 1-4. The method of claim 9, The acidification is a production method characterized in that the pH of the solution is adjusted to 1-2. The method of claim 7, wherein The solvent used for the extraction is C _2-10 ketones, C _1-10 alcohols, C _2-10 ethers, C _2-10 amides, C _2-10 esters, C _1-10 hydrocarbons, C _{1 -10} is a single solvent or a mixed solvent selected from halogenated hydrocarbons and C _2-10 nitriles. The method of claim 11, The solvent used for the extraction method is characterized in that dichloromethane, methanol, ethanol, ethyl acetate, or a mixed solvent thereof. The method of claim 7, wherein The solvent used for solidification is a C _1-10 hydrocarbons, C _2-10 ethers or a mixed solvent thereof. The method of claim 13, The solvent used for solidification is hexane, diethyl ether or a mixed solvent thereof. The method according to claim 6 or 7, The racemic clopidogrel carboxylic acid alkali metal salt represented by the formula (2) is prepared by hydrolyzing the racemic clopidogrel represented by the following formula (1) in the presence of a water-soluble alkali metal salt. [Formula 1]

The method of claim 15, The water-soluble alkali metal salt used for the said hydrolysis reaction is a manufacturing method characterized by the above-mentioned alkali metal hydroxide. The method of claim 16, A water-soluble alkali metal salt used in the hydrolysis reaction is lithium hydroxide. The method of claim 15, The amount of the water-soluble alkali metal salt used in the hydrolysis reaction is 0.5 to 10 molar equivalents relative to the racemic clopidogrel represented by the formula (1). The method of claim 18, The amount of the water-soluble alkali metal salt used in the hydrolysis reaction is characterized in that the range of 3 to 5 molar equivalents relative to the racemic clopidogrel represented by the formula (1). The method of claim 15, The solvent used for the hydrolysis reaction is water, C _2-10 ketones, C _1-10 alcohols, C _2-10 ethers, C _2-10 amides, C _2-10 esters, C _1-10 hydrocarbons And C _1-10 halogenated hydrocarbons and C _2-10 nitriles. The method of claim 20, The solvent used for the hydrolysis reaction is water, tetrahydrofuran, or a mixed solvent thereof. The method of claim 15, The temperature of the hydrolysis reaction is a manufacturing method, characterized in that 20 ℃ to 100 ℃. The method according to any one of claims 17, 19 or 21, The temperature of the hydrolysis reaction is 70 to 80 ℃ manufacturing method characterized in that.

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