WO2003062214A1

WO2003062214A1 - Novel stable crystal of benzylthiazolidinedione derivative and method for preparation thereof

Info

Publication number: WO2003062214A1
Application number: PCT/JP2003/000529
Authority: WO
Inventors: Hiroya Satou; Noriyuki Yoshida; Shintarou Kanazawa
Original assignee: Kyorin Pharmaceutical Co., Ltd.
Priority date: 2002-01-23
Filing date: 2003-01-22
Publication date: 2003-07-31
Also published as: JPWO2003062214A1

Abstract

Novel two types of N-cyclohexylmethyl-5-(2,4-dioxothiazolidine-5-yl)methyl-2-methoxybenzamide crystal (compound 1), characterized in that they exhibit, in X-ray powder diffraction, respective characteristic diffraction patterns at 2θ (diffraction angle) = 6.52˚, 22.2˚ and 24.0˚ (crystal A) and 2θ (diffraction angle) = 10.9˚, 20.3˚ and 23.2˚ (crystal B), and also exhibit respective single endothermic peaks in the thermal analysis (DTA); and a method for preparing the novel two types of crystal which comprises recrystallizing from solvents suitable for respective types of crystal. The novel two types of crystal of the compound 1 are uniform and are excellent in stability and thus can be advantageously used for producing the compound 1 on a commercial scale.

Description

Satsuki Itoda: A new stable crystal of benzylthiazolidinedione derivative and its preparation

Technical field

The present invention relates to the formula (e)

N-cyclohexylmethyl-5- (2,4-dioxothiazolidine represented by

O-5-yl) methyl-2-methoxybenzamide (hereinafter referred to as compound (I)) in two single and stable crystal forms and their selective production methods.

Background art

Compound (I) is used as a peroxisome proliferator-activated receptor (PPAR) agonist, which is a nuclear receptor, and particularly as a human PPAR agonist, for preventing and treating metabolic diseases such as diabetes and hyperlipidemia. It is known that the compound is useful for the pharmaceutical use of the compound, and was disclosed in WO 01/14350 together with a method for producing the compound.

In order to develop compound (I) as a pharmaceutical product, it is strongly desired to find homogeneous and stable crystals and to establish a production method on an industrial scale. Disclosure of the invention

With the research and development of the production method of compound (I), the crystals obtained by the conventional method (WO 01/14350) may be a mixture of two stable new types of crystals (referred to as A and B). The inventors have found a method for isolating and identifying each crystal and uniformly producing each crystal on an industrial scale, thereby completing the present invention. That is, as a result of recrystallizing a crude crystal of the compound (I) · obtained by the conventional method (WO 01/14350) with various solvents and examining its physical properties, it has not been known until now. The existence of two types of new crystals (referred to as A and B) was found, and it was clarified that the crystals obtained by the conventional method were a mixture of these new crystals A and B. It was confirmed that the new crystals A and B obtained here were more homogeneous and physically stable than the conventional crystals. Further, in the production of such a new type of crystal, it has become clear that type A and type B can be separately formed by selecting a recrystallization solvent and a final treatment method, and the present invention has been completed. Furthermore, the present invention also shows that the crude or recrystallized (old crystal) obtained by the conventional method can be converted to a homogeneous and more stable new crystal A or B by recrystallization or final treatment with a similar suitable solvent. It is a feature of.

The new crystal of compound (I) has at least 6.52 ° and 22.2 in powder X-ray diffraction. The crystal A and the powder X-ray diffraction, which are characterized by exhibiting a diffraction angle (26>) at 24.0 ° and a single endothermic peak in differential thermal analysis (DTA) at least, Crystal B characterized by showing diffraction angles (2-0) at 10.9 °, 20.3 ° and 23.2 °, and at the same time showing a single endothermic peak in differential thermal analysis (DTA). It is.

The new crystals A and B of the compound (I) of the present invention are usually obtained after completion of the reaction. The obtained crude crystals can be selectively obtained with good reproducibility by recrystallizing them with an appropriate solvent.

Suitable solvents used for recrystallization include lower alcohols such as ethanol, hydrated lower alcohols, and acid bases. In the case of the crystal A as a preferred solvent, it is 8% aqueous ethanol or 80% aqueous isopropyl alcohol. After dissolving in the alcohol first, water may be added. In the case of crystal B, an acid monobase (dissolved in a common inorganic base, preferably sodium hydroxide or an aqueous hydration solution) and cooled, preferably at a temperature of 10 ° C or lower. Neutralized with a common acid, preferably hydrochloric acid, and the precipitated crystals are filtered and washed with water), 50% aqueous ethanol or 50% aqueous isopropyl alcohol.

The new crystals A and B of the present invention are both stable and have no hygroscopicity, and can be supplied separately and stably by the production method of the present invention. The present invention is extremely useful for industrial production of compound (I). BEST MODE FOR CARRYING OUT THE INVENTION

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

[Example 1]

N-cyclohexylmethyl-5- (2,4-dioxothiazolidin-1-5-yl) methyl-2-methoxybenzamide (Crystal B of compound (I))

5- (2,4-dioxothiazolidine-1-yl) methyl-2-methoxybenzoic acid (5.00 g, 17.8 mmol), isopropyl alcohol 5 mL, ethyl acetate 20 mL, and triethylamine 4.50 g (44.5 mmol) 2.03 g (18.7 mmol) of ethyl ethyl formate at -5 ° C to 0 ° C under ice-water cooling. Was added dropwise over 5 minutes. After stirring for 15 minutes, a solution of 2.11 g (18.6 mmol) of cyclohexylmethylamine in ethyl acetate (20 mL) was added dropwise at -5 ° C to 0 ° C over 10 minutes, and then at 25 ° C to 29 ° C for 30 minutes Stirred. The reaction solution was washed with water (25 mL) and extracted with 40 mL of 0.5 mol / L sodium hydroxide aqueous solution. Then, 20 mL of isopropyl alcohol and 251 mg of activated carbon (5% by weight) were added to the aqueous layer, and the mixture was added at 25 ° C The mixture was stirred for 30 minutes at 29 ° C. The activated carbon was separated by filtration, washed (purified water 10 mL), and the filtrate was cooled to 10 C or lower, and 4 mol / L hydrochloric acid was added to this solution until crystals were precipitated ( At the start of dropping: 3 ° C, pH 10.6 [measurement is performed at pH and pH at the same time. Use the same equipment for pH measurement below.] At the start of crystal precipitation: 4 ° C; pH 8.30 _s After stirring for 10 minutes, 4 mol / L hydrochloric acid was added again (at the start of dropping: 3 ° C, ρΗ9 · 18, at the end of dropping: 5 ° C, pH 2.00, total dropping volume: 9.0 mL). After stirring for 30 minutes, the precipitated crystals were collected by filtration, washed (20 mL of 20% aqueous isopropyl alcohol), and dried under reduced pressure at 50 ° C for 3 hours to obtain 5,59 g (83%) of a slightly yellow-brown solid. This solid is Was added to 56 mL of cold purified water (3 ° C), and the mixture was stirred for 30 minutes at 10 ° C or lower.The precipitated solid was washed with 20% aqueous isopropyl alcohol (llmL), The crystals were dried under reduced pressure for 3 hours to obtain 5.40 _g (81%) of crystal B of compound (I) as white crystals.

-Differential thermal analysis (DTA): 183 ° C (one heat absorption peak)

• Mass spectrometry (EI-MS) m / z: 264 (Base Peak), 376 (M ⁺ ).

■ Elemental analysis _{_{_{_{C 19 H 24 N 2 0 4}}}} S:. Calculated (%); 0,60.62; H, 6.43; N, 7.44 Found (%); 0,60.49; H, 6.23; N, 7.44.

^-1 H-NMR (CDCl ₃ , ppm ₎ 400 MHz) (5 *: 0.96-1.06 (2H, m), 1.12- 1.32 (3H _; m), 1.53-1.80 (6H, m), 3.16 (1H, dd, J = 9.3, 14.2Hz), 3.13-3.37 (2H, m), 3.51 (1H, dd, J-4.4, 14.2Hz), 3.97 (3H, s), 4.56 (1H, dd, J = 4.4, 9.3Hz ), 6.94 (lH, d, J = 8.8Hz), 7.29 (lH, dd, J = 2A, 8.3Hz), 7.95 (1H, t, J = 5.4Hz), 8.09 (1H, d, J = 2.4Hz) ), 8.89 (1H, br s),

[Example 2]

N-cyclohexylmethyl-15- (2,4-dioxothiazolidine-15-yl) methyl-2-methylethoxybenzamide (Crystal B of the compound (I) B) 5— (2,4-geo Oxothiazolidine-1-5-yl) Methyl-2-methoxybenzoic acid 40.0 g (142 mmol), isopropyl alcohol 280 mL and triethylamine 36.0 g (356 mmol) were added and dissolved. C; at 0 ° C, 16.2 g (149 mmol) of ethyl chloroformate was added dropwise over 10 minutes. After stirring for 25 minutes, a solution of 16.9 g (149 mmol) of cyclohexanemethylamine in isopropyl alcohol (120 mL) was added dropwise at -4 ° C to 0 ° C, and the mixture was further stirred at room temperature. 160 mL of isopropyl alcohol was added to the reaction solution, the temperature was raised to 40 ° C, 38.4 mL of a 24.5% aqueous sodium hydroxide solution was added, and the mixture was stirred for 1 hour. The mixture was further stirred for 1.5 hours under cooling with ice water, and the precipitated crystals were collected by filtration, washed (120 mL of isopropyl alcohol), and treated with N-cyclohexylmethyl-5- (2,4-dioxothiazolidin-15-yl) methyl-1-2- 74.4 g of wet crystals of methoxybenzamido sodium salt were obtained. Dissolve 34.7 g of the wet crystals in a mixture of 347 mL of water and 332 mL of isopropyl alcohol.Cool to 4 ° C, add 32 mL of lmol / L hydrochloric acid, stir for 30 minutes, add 82 mL of lmol / L hydrochloric acid, and stir for 1.5 hours. . The precipitate was collected by filtration, and the crystals were washed with 139 mL of water to obtain 38.6 g of wet crystals. The crystals were dried under reduced pressure at 40 ° C. for 2 hours to obtain 24.1 g of Compound (I) crystal B. Melting point: 181 ~ 184 ° C (hot plate method)

The obtained crystal showed the same pattern as the crystal obtained in Example 1 in powder X-ray diffraction.

• Mass spectrometry (EI-MS) m / z: 264 (Base Peak), 376 (M ⁺ ). [Example 3]

N-cyclohexylmethyl-5- (2,4-dioxothiazolidine-15-yl) methyl-12-methoxybenzamide (Crystal A of Compound (I)) Compound (I) obtained in Example 2 12.3 g of the wet crystals were dissolved by heating in a mixed solution of 53 mL of isopropyl alcohol and 11 mL of water, filtered, and washed with 17 mL of an aqueous 80% isopropyl alcohol pill alcohol solution. The obtained filtrate was heated to 70 ° C to dissolve the precipitate, and then stirred at 50 ° C for 1 hour, at 40 ° C for 1 hour, and further at room temperature for 16 hours. The precipitated crystals were collected by filtration and washed with 25 mL of isopropyl alcohol. The obtained crystals were dried under reduced pressure at 40 ° C. to obtain 7.75 g of Compound (I) crystal A as white crystals.

'' Differential thermal analysis (DTA): 176 ° C (one heat absorption peak)

[Example 4〗

N-cyclohexylmethyl-5- (2,4-dioxothiazolidin-5-yl) methyl: 12-methoxybenzamide (Crystal B of Compound (I)) Obtained in Example 3 After dissolving 3.00 g of the crystal A of compound (I) in 30 mL of isopropyl alcohol with heating (80 ° C), pour into 30 mL of water (9 ° C) at a stretch, and cool in an ice-water bath (1 to 10 ° C) for 1 hour. Stirred. The precipitated crystals were collected by filtration and washed with 6 mL of water. The obtained crystals were dried under reduced pressure at 40 ° C. to give 2.89 g of Compound (I) crystal B as white crystals.

'' Differential thermal analysis (DTA): 183 ° C (one heat absorption peak)

[Example 5]

N-cyclohexylmethyl-5- (2,4-dioxothiazolidin-5-yl) methyl-2-methylethoxybenzamide (crystal A of the compound (I)) A conventional method (WO 01/14350) )) And heat-dissolve 4.53 g of the crystals of compound (I) in a mixed solution of 36 mL of ethanol and 9 mL of water. The mixture was stirred for 1 hour at 40 ° C for 1 hour, and further for 15.5 hours at 25 ° C or less. The precipitated crystals were collected by filtration and washed with 14 mL of ethanol. The obtained crystals were dried at 40 ° C under reduced pressure to obtain 4.17 g of Compound (I) crystal A as white crystals.

The obtained crystal showed the same pattern as that of the crystal obtained in Example 3 in powder X-ray diffraction.

'' Differential thermal analysis (DTA): 178 ° C (one heat absorption peak)

[Example 6] N-cyclohexylmethyl-5- (2,4-dioxothiazolidin-1-yl) methyl-2-methoxybenzamide (Crystal B of Compound (I))

2.00 g of the compound (I) crystal obtained by the conventional method (WO 01/14350) was dissolved by heating in 20 mL of ethanol, poured into 20 mL of water at a stretch, and cooled to 10 ° C. in an ice bath. The precipitated crystals were collected by filtration and washed with 10 mL of water. The obtained crystal was dried under reduced pressure at 40 ° C. to obtain 1.90 g of a crystal B of the compound (I) as a white crystal.

• Differential thermal analysis (DTA): 184 ° C (one heat absorption peak)

[Experimental example 1]

X-ray powder diffraction measurement

The powder X-ray diffraction was measured by Cu K line using an X-ray diffractometer RINT2200 wide-angle goniometer manufactured by Rigaku Corporation. The diffraction angles (260 and relative intensities (cps)) of the crystals of the compound of this example are shown in Fig. 1 (Crystal A) and Fig. 2 (Crystal B). Typical crystal powder obtained by the conventional method The X-ray diffraction patterns are shown in Fig. 3. As a result, the two types of crystals obtained in the embodiment of the present invention were at least 2O2 6.52 °, 22.2 ° and 24.0 °. (Crystal A) and at least 2 O = 10.9 °, 20.3 °, and 23.2 (Characteristic B) However, it was different from conventional crystals.

[Experimental example 2]

Differential thermal analysis (DTA)

The measurement was carried out using a differential thermal analyzer (SEIKOSE DULMEN; EXTRA6000 thermal analysis system). Figure 4 shows the crystal A, Figure 5 shows the crystal B, and Figure 6 shows the thermal analysis chart of the conventional crystal. As a result, the two types of crystals obtained in the examples of the present invention each showed a single endothermic peak, while the conventional crystal (FIG. 6) showed two endothermic peaks. Industrial applicability

By recrystallizing the crude crystal of compound (I), which was conventionally obtained as a mixture of two types of crystals, with an appropriate solvent, two types of homogeneous and more stable new types of crystals A and B can be selectively obtained. How to get. The new crystals provided by the present invention are homogeneous and stable without moisture absorption. Further, the production method of the present invention can stably supply the compound (I) having a well-formed crystal form, and is extremely useful for industrial production of the compound (I). BRIEF DESCRIPTION OF THE FIGURES

Fig. 1 X-ray powder diffraction diagram of new crystal A of the present invention

Figure 2 X-ray powder diffraction diagram of the new crystal B of the present invention

Figure 3 X-ray powder diffraction pattern of conventional crystal

Figure 4 Thermal analysis (TG / DTA) of the new crystal A of the present invention

Fig. 5 Thermal analysis (TG / DTA) of new crystal B of the present invention

Figure 6 Thermal analysis (TG / DTA) of conventional crystal

Claims

Scope of Word

1. In powder X-ray diffraction, at least 6.52 °, 2.2.2. N-cyclohexylmethyl-5- (2,4-) characterized by a diffraction angle (20) at 24.0 ° and a single endothermic peak in differential thermal analysis (DTA). New crystal A of dioxothiazolidine-5-yl) methyl-2-methoxybenzamide (Compound (I)).

2. In powder X-ray diffraction, at least 10.9 °, 20.3 ° and 23.2. N-cyclohexylmethyl-5- (2,4-dioxothiazolidine-5), which shows a diffraction angle (20) and a single endothermic peak in differential thermal analysis (DTA). A new crystal B of-(yl) methyl-2-methoxybenzamide (compound (I)).

3. The method for producing a new crystal A of the compound (I) according to claim 1, wherein the recrystallization is performed from a suitable solvent such as a lower alcohol or a lower alcohol containing 80% water.

4. The method for producing a new crystal B of the compound (I) according to claim 2, wherein the recrystallization is performed from an appropriate solvent such as an acid monobase or a 50% aqueous lower alcohol.

5. A method for converting the novel crystal A of the compound (I) according to claim 1 into the new crystal B of the compound (I) according to claim 2 by a recrystallization method.

6. A pharmaceutical composition comprising the novel crystal A according to claim 1 and / or the novel crystal B according to claim 2.