HU0300475A2 - Thiazolidinediones new, stable crystalline form and a process for its preparation - Google Patents

Thiazolidinediones new, stable crystalline form and a process for its preparation Download PDF

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Publication number
HU0300475A2
HU0300475A2 HU0300475A HU0300475A HU0300475A2 HU 0300475 A2 HU0300475 A2 HU 0300475A2 HU 0300475 A HU0300475 A HU 0300475A HU 0300475 A HU0300475 A HU 0300475A HU 0300475 A2 HU0300475 A2 HU 0300475A2
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Prior art keywords
crystals
methyl
ι
process
krp
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HU0300475A
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Hungarian (hu)
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HU0300475A3 (en
Inventor
Michiro Oonoda
Kazuo Orita
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Kyorin Pharmaceutical Co., Ltd.
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Priority to JP2000124006 priority Critical
Application filed by Kyorin Pharmaceutical Co., Ltd. filed Critical Kyorin Pharmaceutical Co., Ltd.
Priority to PCT/JP2001/003450 priority patent/WO2001081327A1/en
Publication of HU0300475A2 publication Critical patent/HU0300475A2/en
Publication of HU0300475A3 publication Critical patent/HU0300475A3/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D277/00Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34Oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C30CRYSTAL GROWTH
    • C30BSINGLE-CRYSTAL-GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
    • C30B7/00Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions

Abstract

The present invention relates to 5 - [(2,4-dioxothiazolidin-5-yl) methyl] -2-methoxy-N - {[4- (trifluoromethyl) phenyl] methyl} benzamide, i.e., KRP-297, having a high stability and a homogeneous crystalline form. It applies. The new crystal of AKRP-297 is prepared by crystallization from an alcoholic solvent. The diffraction angles (2q) determined by X-ray powder diffraction are at least 9.7 °, 15.0 ° and 22.5 °. HE

Description

COPIES

97807-3301 FO / TÉ

TIAZOLIDINDION ORIGINS NEW, STABILIZED BODY FORM AND PROCEDURE FOR PRODUCTION THEREOF

The present invention relates to a stable crystalline form of 5 - [(2,4-dioxothiazolidin-5-yl) methyl] -2-methoxy-N - [[4- (trifluoromethyl) phenyl] methyl} benzamide (KRP-297) of formula (1) and it relates to a method for producing it.

The compound KRP-297 exhibits excellent glucose lowering activity and can be used as a hypoglycemic agent and as an insulin sensitizer (Nomura, M. et al., Bioorg. Med. Chem. Lett .; 9, 533-538 (1999). Initially, Japanese Kokai

He was prepared according to the method described in Hei 9-48771.

It is an object of the present invention to research and formulate a crystalline form of homogeneous and excellent stability for the production of KRP-297 on an industrial scale.

During the development of the process for the preparation of KRP-297, it has been discovered that novel crystals other than those obtained by the conventional method (Japanese Kokai Hei 9-48771) can be produced, which leads to the recognition of the present invention. Thus, we have shown that KRP-297 crystals produced by the conventional method (crystals of the previous form, e.g.

By recrystallization from a suitable solvent, Kokai Hei 9-48771 is transformed into a more homogeneous and stable new crystal than usual.

The new crystals of KRP-297 are characterized by X-ray powder diffraction, with diffraction angles (2Θ) of at least 9.7 °, 15.0 ° and 22.5 °.

The novel crystals of the KRP-297 according to the invention are generally capable of being reproduced by recrystallization of the crude crystals obtained after completion of the reaction from a suitable solvent.

The solvents used in the recrystallization include lower alcohols, such as ethanol, low-alcohol alcohols, conventional organic solvents, optionally solvent mixtures and the like. A preferred solvent is ethanol or isopropyl alcohol.

The novel crystals of the present invention are non-hygroscopic and can be produced in a stable manner, which is very advantageous for the production of KRP-297 by industrial methods.

Fig. 1 is an X-ray powder diffraction diagram of the novel crystals of the present invention; Figure 2 is an X-ray powder diffraction diagram of conventional crystals; Figure 3 is a thermal analysis diagram of the novel crystals of the present invention; FIG. 1B shows a thermal analysis diagram of the crystals obtained by the conventional method.

Examples

The present invention is illustrated in detail by the following examples, but is not intended to limit the scope of the invention.

Example 1 To a solution of dichloromethane (ml) was added 6.30 g of triethylamine and 7.00 g of 5 - [(2,4-dioxothiazolidin-5-yl) methyl] -2-methoxybenzoic acid. After addition of 2.71 g of ethyl chlorocarbonate, the mixture was stirred for 10 minutes. 4.59 g of 4-trifluoromethylbenzylamine was added and the mixture was stirred for 1 hour. The reaction mixture was washed with water, the solvent was distilled off and the residue was added to 109 ml of water and 33 ml of ethanol, dropwise added with a 1N hydrochloric acid solution to adjust its pH to 2.0. The precipitated crystals were collected by filtration and washed with water to give 10.25 g of crude crystals. The crude crystals (10.25 g) were recrystallized from 90% ethanol to give 6.49 g

5 - [(2,4-dioxothiazolidin-5-yl) methyl] -2-methoxy-N - {[4- (trifluoromethyl) phenyl] methyl} benzamide (KRP-297) was prepared. Yield 61.3%, mp 193-195 ° C.

EXAMPLE 2 Dissolve 5.00 g of 5 - [(2,4-dioxothiazolidin-5-yl) methyl] -2-methoxybenzoic acid in isopropyl alcohol (4.50 g) with dropwise stirring at -5 ° C to 0 ° C. triethylamine, 2.12 g of ethyl chlorocarbonate was added. The mixture was stirred for 10 minutes at -5 ° C to 0 ° C, and 3.27 g of 4-trifluoromethylbenzylamine was added dropwise to the mixture at -5 ° C to 0 ° C in 15 ml of isopropyl alcohol. After the addition is complete, the mixture is heated and stirred for 1 hour at 25 ° C to 35 ° C. The temperature was then raised to 60 ° C and a solution of 24.8% aqueous sodium hydroxide (4.83 ml) was added, the mixture was cooled to 3 ° C and the precipitated sodium salt was collected by filtration and washed with 15 ml isopropyl alcohol.

The sodium salt obtained was dissolved in a mixture of water (78 ml) and isopropyl alcohol (59 ml) and the pH of the solution was adjusted to pH 6.98 with 1 M hydrochloric acid. This was cooled to 6 ° C and the precipitated crystals were collected by filtration and washed with water (23 mL). Dry at 40 ° C to give 6.59 g of crude crystals. Yield 84.6%.

The crude crystals were recrystallized from 132 ml of 90% ethanol and dried at 40 ° C under reduced pressure to give 6.02 g of KRP-297. Yield: 77.3%, mp 195-196 ° C.

Example 3

5.20 kg of 5 - [(2,4-dioxothiazolidin-5-yl) methyl] -2-methoxybenzoic acid and 4.68 kg of triethylamine are dissolved in 36.31 of isopropyl alcohol, with stirring dropwise addition of 2.11 kg of ethyl chlorocarbonate. while maintaining the temperature between -5 ° C and 0 ° C. After stirring for 10 minutes at -5 ° C to 0 ° C, 3.24 kg of 4-trifluoromethylbenzylamine in 15.61 isopropyl alcohol are added dropwise at the same temperature. After the drip is complete, the mixture is heated and stirred at 25 ° C to 35 ° C for 1 hour. 20.8 L of isopropyl alcohol was added followed by 5.0 L of a 24.5% aqueous sodium hydroxide solution. The mixture was cooled to 10 ° C, stirred for 1.5 hours and the precipitated sodium salt was collected by filtration and washed with 15.6 L of isopropyl alcohol. As a result of the loss of drying, the sodium salt of KRP-297 was 7.78 kg. Yield 91.4%.

The sodium salt obtained was dissolved in a mixture of water (77.8 L) and isopropyl alcohol (72.9 L), and a 1 M solution of hydrochloric acid was added dropwise at 0 ° C to 10 ° C to adjust its pH to 2.0.

The solution was stirred at 0 ° C to 10 ° C for 1.5 hours and the precipitated crystals were collected by filtration and washed with water (81.1 L). As a result of the drying loss, 6.12 kg of KRP-297 is obtained. Yield 75.5%.

These crude crystals were added to a mixture of 28.6 L of water and 122 L of isopropyl alcohol and heated to a temperature above 70 ° C, then filtered hot and washed with a solution of 2.4 L of water and 9.8 L of isopropyl alcohol. The mixed solutions were combined, allowed to cool to room temperature and stirred for 15 hours. The precipitated crystals were washed with 18.4 isopropyl alcohol, sucked and dried at 40 ° C under reduced pressure to give 5.32 kg of KRP-297. Yield 65.6%, mp 195-196 ° C.

Example 4

KRP-297 crystals of the prior art (Japanese Kokai Hei 9-48771, Example 39) (5.97 kg) (m.p. 176.0-177.5 ° C) were dissolved in ethanol (1191) · · · under heating. . After filtering off, the residue was washed with 12 L of 90% ethanol and the filtrates were cooled to room temperature.

The precipitated crystals were collected by filtration and washed with 18 L of ethanol. Drying at 40 ° C to 60 ° C to give 5.11 g of new KRP-297 crystals. Yield 85.6%, mp 195 ° C.

Example 5

X-ray powder diffraction determination

X-ray powder diffraction was performed using CuKa radiation using a model X-ray diffractometer (Rigaku Co.). The diffraction angle (20) and relative intensity (cps) of the crystals of the example compound are shown in Figure 1. The X-ray powder diffraction of the crystals prepared by the conventional method is shown in Figure 2. The results show that at least the following angles 20 at 9,7 °, 15,0 ° and 22,5 ° are diffraction patterns of the crystals produced by the example of the present invention, which are different from those of conventional crystals.

Example 6

Thermal analysis

The thermal stability of the crystals was analyzed using a Rigaku Denki TAS-200 thermal analyzer.

The thermal analysis of the new KRP-297 crystals is shown in Figure 3, and the thermal analysis of the crystals obtained by the conventional method is shown in Figure 4.

In the new crystals, an endothermic phenomenon is observed from 194.8 ° C, with an endothermic peak at 186.3 ° C.

This shows that the new crystal is more thermally stable than the conventional crystal.

Recrystallization of the KRP-297 crystals prepared by the conventional method from a suitable alcoholic solvent gave homogeneous and more stable new crystals. The homogeneous and more stable novel crystals of the present invention are non-hygroscopic and stable during production, which is very advantageous for industrial production of KRP-297.

• · • · · ·

Claims (5)

  1. Claims
    1. New Crystals of 5 - [(2,4-dioxothiazolidin-5-yl) methyl] -2-methoxy-N - {[4- (trifluoromethyl) phenyl] methyl} benzamide having diffraction angles on X-ray powder diffraction (20) le5 appear at most 9.7 °, 15.0 ° and 22.5 °.
  2. A process for preparing the novel crystals of claim 1, which is recrystallized from a suitable solvent.
  3. The process for preparing the novel crystals according to claim 2, characterized in that the recrystallization is carried out from a lower alcohol or a low carbon alcohol containing water.
    The proxy:
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    PUBLICATION EXAMPLE ·· · ····
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    183.1¾
HU0300475A 2000-04-25 2001-04-23 Novel stable crystal of thiazolidinedione derivative and process for producing the same HU0300475A3 (en)

Priority Applications (2)

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JP2000124006 2000-04-25
PCT/JP2001/003450 WO2001081327A1 (en) 2000-04-25 2001-04-23 Novel stable crystal of thiazolidinedione derivative and process for producing the same

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US (1) US6770133B2 (en)
EP (1) EP1277745A4 (en)
KR (1) KR20030007548A (en)
CN (1) CN1426402A (en)
AU (1) AU4882801A (en)
BG (1) BG107200A (en)
BR (1) BR0110258A (en)
CA (1) CA2407349A1 (en)
CZ (1) CZ20023502A3 (en)
EA (1) EA004244B1 (en)
EE (1) EE200200601A (en)
HU (1) HU0300475A3 (en)
IL (1) IL152224D0 (en)
IS (1) IS6586A (en)
MA (1) MA25664A1 (en)
MX (1) MXPA02010545A (en)
NO (1) NO20025069L (en)
PL (1) PL365533A1 (en)
SK (1) SK15142002A3 (en)
WO (1) WO2001081327A1 (en)
YU (1) YU80302A (en)
ZA (1) ZA200208293B (en)

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AT340168T (en) * 2000-02-01 2006-10-15 Kyorin Seiyaku Kk Alkalimetal salt of thiazolidin-2,4-dion derivatives
JPWO2003062214A1 (en) * 2002-01-23 2005-05-19 杏林製薬株式会社 New stable crystal benzyl thiazolidinedione derivatives and their preparation
DE10308352A1 (en) 2003-02-27 2004-09-09 Aventis Pharma Deutschland Gmbh Arylcycloalkylderivate with branched side chains, to processes for their preparation and their use as medicaments
DE10308351A1 (en) 2003-02-27 2004-11-25 Aventis Pharma Deutschland Gmbh 1,3-substituted cycloalkyl derivatives having acidic, mostly heterocyclic groups, processes for their preparation and their use as medicaments
DE10308353A1 (en) 2003-02-27 2004-12-02 Aventis Pharma Deutschland Gmbh Diarylcycloalkylderivate, processes for their preparation and their use as medicaments
DE10308355A1 (en) 2003-02-27 2004-12-23 Aventis Pharma Deutschland Gmbh Aryl-cycloalkyl substituted alkane acid derivatives, processes for their preparation and their use as medicaments
US7148246B2 (en) 2003-02-27 2006-12-12 Sanofi-Aventis Deutschland Gmbh Cycloalkyl derivatives having bioisosteric carboxylic acid groups, processes for their preparation and their use as pharmaceuticals
RU2422450C2 (en) 2003-11-19 2011-06-27 Метабазис Терапеутикс, Инк. New phosphorus-containing thymomimetic drugs
EP1586573B1 (en) 2004-04-01 2007-02-07 Sanofi-Aventis Deutschland GmbH Oxadiazolones, processes for their preparation and their use as pharmaceuticals
DE102005026762A1 (en) 2005-06-09 2006-12-21 Sanofi-Aventis Deutschland Gmbh Azolopyridin-2-one derivatives as inhibitors of lipases and phospholipases
TWI383008B (en) 2005-08-17 2013-01-21 Nippon Catalytic Chem Ind Production method of water-absorbent resin, water-absorbent resin, and usage of water-absorbent resin
TW200838512A (en) 2007-02-08 2008-10-01 Daiichi Sankyo Co Ltd Crystalline forms of a thiazolidinedione compound and manufacturing methods thereof
US20120046364A1 (en) 2009-02-10 2012-02-23 Metabasis Therapeutics, Inc. Novel Sulfonic Acid-Containing Thyromimetics, and Methods for Their Use

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CN1003445B (en) * 1984-10-03 1989-03-01 武田药品工业株式会社 Process for the production of thiazolidiredions derivative and use
AR240698A1 (en) * 1985-01-19 1990-09-28 Takeda Chemical Industries Ltd Process for the preparation of 5-(4-(2-(5-ethyl-2-pyridil)-ethoxy)benzyl)-2,4-thiazolodinedione and their salts
JP3053490B2 (en) 1991-02-25 2000-06-19 杏林製薬株式会社 Thiazolidine-2,4-dione derivatives and their salts and preparation
JPH04270273A (en) 1991-02-25 1992-09-25 Kyorin Pharmaceut Co Ltd Thiazolidine-2,4-dione derivative and its salt and production thereof
JP3644998B2 (en) 1995-02-09 2005-05-11 塩野義製薬株式会社 Selective method of obtaining crystals of benzylidene derivative
JP3144624B2 (en) * 1995-06-02 2001-03-12 杏林製薬株式会社 N- benzyl-dioxo-thiazolyl Gilles benzamide derivatives and their preparation
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EP1277745A1 (en) 2003-01-22
IS6586A (en) 2002-10-21
EA004244B1 (en) 2004-02-26
US6770133B2 (en) 2004-08-03
EP1277745A4 (en) 2004-09-15
NO20025069D0 (en) 2002-10-22
BG107200A (en) 2003-11-28
CZ20023502A3 (en) 2003-06-18
CA2407349A1 (en) 2002-10-24
EE200200601A (en) 2004-04-15
MXPA02010545A (en) 2004-05-14
US20030101925A1 (en) 2003-06-05
NO20025069L (en) 2002-10-22
SK15142002A3 (en) 2003-04-01
EA200201055A1 (en) 2003-06-26
YU80302A (en) 2005-11-28
IL152224D0 (en) 2003-05-29
MA25664A1 (en) 2002-12-31
CN1426402A (en) 2003-06-25
KR20030007548A (en) 2003-01-23
PL365533A1 (en) 2005-01-10
HU0300475A3 (en) 2004-10-28
AU4882801A (en) 2001-11-07
WO2001081327A1 (en) 2001-11-01
BR0110258A (en) 2003-01-07
ZA200208293B (en) 2003-10-06

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