Gliquidone crystal, preparation method thereof and drug containing gliquidone crystal

Abstract

The invention provides a gliquidone crystal, a preparation method thereof and a drug containing the gliquidone crystal. The gliquidone crystal is a crystal form A, a crystal form B or a crystal form Cand is determined by using a powder X-ray diffraction method; according to an X-ray powder diffraction pattern represented by a diffraction angle of 2 theta plus or minus 0.20 degree; a crystal pattern A pattern shows diffraction peaks at 10.60 degrees, 14.00 degrees, 16.10 degrees, 18.98 degrees, 20.24 degrees and 21.46 degrees; a crystal pattern B pattern shows diffraction peaks at 10.60 degrees, 14.00 degrees, 15.30 degrees, 16.10 degrees, 16.54 degrees, 17.54 degrees, 18.53 degrees, 18.98 degrees, 19.33 degrees, 20.24 degrees, 21.46 degrees, 23.24 degrees and 25.35 degrees; and a crystalpattern C pattern shows diffraction peaks at 10.70 degrees, 15.24 degrees, 18.48 degrees, 23.24 degrees and 24.74 degrees. The preparation method comprises the following steps: dissolving a gliquidonecrude product in a solvent and then crystallizing to obtain the gliquidone crystal. The invention discloses a crystal structure of glitaquinone; the glitaquinone in a crystal state has higher solubleness and stronger storage stability than a glitaquinone compound in an amorphous state; and the gliquidone crystal prepared by the preparation method provided by the invention is high in purity, highin yield, simple in preparation process, high in repeatability and suitable for industrial production.

Description

technical field

[0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a gliquidone crystal, a preparation method thereof and medicine containing the crystal. Background technique

[0002] Gliquidone, chemical name: 1-cyclohexyl-3-[[9-[2-(3,4-dihydro-7-methoxy-4,4-dimethyl-1,3-dioxy -2-(1H)-isoquinolinyl)-ethyl]phenyl]sulfonyl]urea. Its structural formula is as follows:

[0003] Gliquidone is the second-generation oral sulfonylurea hypoglycemic drug, which is a highly active pro-islet β-cell agent. It binds to specific receptors on the islet β-cell membrane and can induce the production of an appropriate amount of insulin to reduce blood sugar concentration. The highest plasma concentration is reached after 2-2.5 hours of oral administration of this product, and it will be completely absorbed soon. The plasma half-life is 1.5 hours, and the metabolism is complete. Its metabolites have no hypoglycemic effect, and most of the metaboli...

Examples

Embodiment 1

[0032] The method for the preparation of gliquidone crystals adopted in the present embodiment is as follows:

[0033] Take 10 g of crude gliquidone and put it into a three-necked flask, add 20 g of acetonitrile, start stirring and heating. Heat it to reflux, and keep it under reflux, slowly add acetonitrile dropwise until it is completely dissolved (approximately 23g can be added to dissolve completely), after the dissolution is complete, continue to reflux for 2 hours, then filter while it is hot, and lower the temperature to 0-5°C with ice-salt water , and then heat and crystallize for 4 hours, filter, and dry the obtained solid in a blast oven at 50-60° C. for 6-8 hours to obtain 9.1 g of off-white solid with a yield of 91%. The purity of the gliquidone crystal form is 98.5%. , isoquinolines not exceeding 0.6%, figure 1 for its XRPD pattern, figure 2 For its XRPD data, it can be seen from the XRPD pattern and data results that the obtained gliquidone crystal form is A c...

Embodiment 2

[0035] The method for the preparation of gliquidone crystals adopted in the present embodiment is as follows:

[0036] Take 10 g of gliquidone and add it into a three-necked flask, add 20 g of acetonitrile, start stirring and heating. Heat it to reflux, and keep it under reflux, slowly add acetonitrile dropwise until it is completely dissolved (approximately 23g can be added to completely dissolve), after the dissolution is complete, continue to reflux for 2 hours, then filter while it is hot, and lower the temperature of ice-salt water to 0-5°C , and then heat and crystallize for 6 hours, filter, and dry the obtained solid in a blast oven at 50-60° C. for 6-8 hours. 9.0 g of off-white solid was obtained, the yield was 90%, the crystal form of gliquidone had a purity of 98.3%, and the isoquinoline was no more than 0.6%. figure 1 for its XRPD pattern, figure 2 For its XRPD data, it can be seen from the XRPD pattern and data results that the obtained gliquidone crystal form i...

Embodiment 3

[0038] The method for the preparation of gliquidone crystals adopted in the present embodiment is as follows:

[0039] Take 10 g of gliquidone and add it into a three-necked flask, add 20 g of acetonitrile, start stirring and heating. Heat it to reflux, and keep it under reflux, slowly add acetonitrile dropwise until it is completely dissolved (approximately 23g can be added to completely dissolve), after the dissolution is complete, continue to reflux for 2 hours, then filter while it is hot, and lower the temperature of ice-salt water to 0-5°C , and then heat and crystallize for 4 hours, filter, and dry the obtained solid in a blast oven at 60-70° C. for 6-8 hours. 9.1 g of off-white solid was obtained with a yield of 91%, the purity of the gliquidone crystal form was 98.2%, and the isoquinoline was no more than 0.6%. figure 1 for its XRPD pattern, figure 2 For its XRPD data, it can be seen from the XRPD pattern and data results that the obtained gliquidone crystal form i...

technical field

[0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a gliquidone crystal, a preparation method thereof and medicine containing the crystal. Background technique

[0002] Gliquidone, chemical name: 1-cyclohexyl-3-[[9-[2-(3,4-dihydro-7-methoxy-4,4-dimethyl-1,3-dioxy -2-(1H)-isoquinolinyl)-ethyl]phenyl]sulfonyl]urea. Its structural formula is as follows:

[0003] Gliquidone is the second-generation oral sulfonylurea hypoglycemic drug, which is a highly active pro-islet β-cell agent. It binds to specific receptors on the islet β-cell membrane and can induce the production of an appropriate amount of insulin to reduce blood sugar concentration. The highest plasma concentration is reached after 2-2.5 hours of oral administration of this product, and it will be completely absorbed soon. The plasma half-life is 1.5 hours, and the metabolism is complete. Its metabolites have no hypoglycemic effect, and most of the metaboli...

Examples

Embodiment 1

[0032] The method for the preparation of gliquidone crystals adopted in the present embodiment is as follows:

[0033] Take 10 g of crude gliquidone and put it into a three-necked flask, add 20 g of acetonitrile, start stirring and heating. Heat it to reflux, and keep it under reflux, slowly add acetonitrile dropwise until it is completely dissolved (approximately 23g can be added to dissolve completely), after the dissolution is complete, continue to reflux for 2 hours, then filter while it is hot, and lower the temperature to 0-5°C with ice-salt water , and then heat and crystallize for 4 hours, filter, and dry the obtained solid in a blast oven at 50-60° C. for 6-8 hours to obtain 9.1 g of off-white solid with a yield of 91%. The purity of the gliquidone crystal form is 98.5%. , isoquinolines not exceeding 0.6%, figure 1 for its XRPD pattern, figure 2 For its XRPD data, it can be seen from the XRPD pattern and data results that the obtained gliquidone crystal form is A c...

Embodiment 2

[0035] The method for the preparation of gliquidone crystals adopted in the present embodiment is as follows:

[0036] Take 10 g of gliquidone and add it into a three-necked flask, add 20 g of acetonitrile, start stirring and heating. Heat it to reflux, and keep it under reflux, slowly add acetonitrile dropwise until it is completely dissolved (approximately 23g can be added to completely dissolve), after the dissolution is complete, continue to reflux for 2 hours, then filter while it is hot, and lower the temperature of ice-salt water to 0-5°C , and then heat and crystallize for 6 hours, filter, and dry the obtained solid in a blast oven at 50-60° C. for 6-8 hours. 9.0 g of off-white solid was obtained, the yield was 90%, the crystal form of gliquidone had a purity of 98.3%, and the isoquinoline was no more than 0.6%. figure 1 for its XRPD pattern, figure 2 For its XRPD data, it can be seen from the XRPD pattern and data results that the obtained gliquidone crystal form i...

Embodiment 3

[0038] The method for the preparation of gliquidone crystals adopted in the present embodiment is as follows:

[0039] Take 10 g of gliquidone and add it into a three-necked flask, add 20 g of acetonitrile, start stirring and heating. Heat it to reflux, and keep it under reflux, slowly add acetonitrile dropwise until it is completely dissolved (approximately 23g can be added to completely dissolve), after the dissolution is complete, continue to reflux for 2 hours, then filter while it is hot, and lower the temperature of ice-salt water to 0-5°C , and then heat and crystallize for 4 hours, filter, and dry the obtained solid in a blast oven at 60-70° C. for 6-8 hours. 9.1 g of off-white solid was obtained with a yield of 91%, the purity of the gliquidone crystal form was 98.2%, and the isoquinoline was no more than 0.6%. figure 1 for its XRPD pattern, figure 2 For its XRPD data, it can be seen from the XRPD pattern and data results that the obtained gliquidone crystal form i...

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