Salt of proline derivative, solvate thereof, and production method thereof
View Patent ↗The present invention provides 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine (compound I) useful as a dipeptidyl peptidase-IV inhibitor, which has superior properties of stability and hygroscopicity, and reproducible crystal structure, and a production method thereof.
1. The compound that is either 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine 2.5 hydrobromide or a hydrate thereof.
2. A method of producing 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine 2.5 hydrobromide or a hydrate thereof,
which comprises eliminating 1,1-dimethylethyloxycarbonyl from 3-{(2S,4S)-1-(1,1-dimethylethyloxycarbonyl)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine with hydrobromic acid, and simultaneously forming a salt.
3. A method of producing 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine 2.5 hydrobromide or a hydrate thereof,
which comprises crystallizing 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine 2.5 hydrobromide from water and/or a solvent selected from ethanol, 1-propanol, 2-propanol, ethyl acetate, and acetone.
4. The method of claim 2 , wherein the hydrate is a 1.0 to 2.0hydrate.
5. The method of claim 3 , wherein the hydrate is a 1.0 to 2.0 hydrate.
6. The compound of claim 1 , which is a hydrate of 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine 2.5 hydrobromide.
7. The compound of claim 6 , wherein the hydrate is a 1.0 to 2.0 hydrate.
8. The compound of claim 7 , which has peaks at diffraction angles represented by 2θ of 5.4°, 13.4° and 14.4° (each ±0.2°) in a powder X-ray diffraction pattern.