CN101918390B - (e)-n-{4-[3-氯-4-(2-吡啶基甲氧基)苯胺基]-3-氰基-7-乙氧基-6-喹啉基}-4-(二甲基氨基)-2-丁烯酰胺的马来酸盐及其结晶形式 - Google Patents
(e)-n-{4-[3-氯-4-(2-吡啶基甲氧基)苯胺基]-3-氰基-7-乙氧基-6-喹啉基}-4-(二甲基氨基)-2-丁烯酰胺的马来酸盐及其结晶形式 Download PDFInfo
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- CN101918390B CN101918390B CN200880118789.3A CN200880118789A CN101918390B CN 101918390 B CN101918390 B CN 101918390B CN 200880118789 A CN200880118789 A CN 200880118789A CN 101918390 B CN101918390 B CN 101918390B
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- anilino
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Abstract
Description
盐 | 酸/碱比(通过NMR测定) | 结晶度(通过XRD测定) | 结晶度(通过显微镜法测定) | DSC*(Tapex) | TGA(30-150℃) | 残留溶剂(%) | pH | 溶解度(mg/g) |
1 | 乙酸盐(非盐) | 结晶 | 结晶细针状 | 116℃,186℃ | 6.46% | 6.9 | 8.34 | <LOD |
2 | 甲磺酸盐(1∶1) | 结晶(中等) | 结晶细针状 | 88℃,141℃ | 5.03% | 0.56 | 4.29 | 10.62 |
3 | 甲苯磺酸盐(1∶1) | 结晶(低) | 结晶规则粒子 | 159℃ | 2.1% | 1.17 | 4.72 | 6.89 |
4 | 马来酸盐(1∶1) | 结晶 | 结晶规则粒子 | 195℃ | 0.5% | 1.19 | 5.11 | 0.37 |
5 | 富马酸盐(1∶1) | 无定形 | 无定形 | 不清楚 | 2.71% | 0.13 | 3.53 | 0.78 |
6 | 酒石酸盐(1∶1) | 无定形 | 无定形 | 不清楚 | 2.98% | 0.14 | 3.49 | 0.66 |
7 | 琥珀酸盐(1∶1) | 无定形W/具有结晶特征 | 无定形W/具有结晶特征 | 109℃ | 1.73% | 0.86 | 3.97 | 3.08 |
8 | 柠檬酸盐(1∶1) | 无定形 | 无定形 | 不清楚 | 2.86% | 0.56 | 3.45 | 0.30 |
9 | 硫酸盐(2∶1推定) | 无定形 | 无定形 | 149℃ | 4.42% | 0.0 | 3.01 | 1.07 |
次 | 批量 | 结晶度(显微镜法) | 粒度* | DSC(开始温度℃) | 含水率%(KF) | 残留溶剂(%) | 溶液pH | 水溶解度***(mg/g) | HPLC纯度(%) |
1 | 0.5g | 结晶细杆状 | 5-10μm | 195 | 0.59 | 1.19 | 5.11 | 0.37 | 99.38 |
2 | 6.6g | 结晶细针状 | 5-50μm | 197.6 | 0.36 | 0.1乙酸乙酯 | 5.10 | 0.50 | 99.70 |
3 | 4g | 结晶细针状 | 25-100μm | 196.3 | 0.35 | ND** | 5.15 | 0.44 | 99.52 |
实验编号 | T,℃ | 条件 | 形式,湿滤饼 | 形式,干固体(50℃和真空) |
1 | 25 | 10%水 | 水合物II形 | I+II(1小时干燥) |
2 | 45 | 10%水 | 水合物II形 | ------ |
3 | 60 | 10%水 | 水合物II形 | ------ |
4 | 可变 | 5%过量的酸+10%水 | 水合物II形 | I+II(1小时干燥) |
5 | 可变 | 10%过量的酸+10%水 | 水合物II形 | ------ |
6 | 可变 | 20%过量的酸+10%水 | 水合物II形 | ------ |
7 | 可变 | 15%水 | 水合物II形 | I+II(1小时干燥) |
8 | 25 | 13%水 | 水合物II形 | 无水I形(过夜干燥) |
9 | 25 | 13%水 | 水合物II形 | ------ |
10 | 45 | 13%水 | 水合物II形 | ------ |
11 | 45 | 13%水 | 水合物II形 | ------ |
12 | 25 | 15%水 | 水合物II形 | ------ |
13 | 25 | 15%水 | 水合物II形 | 无水I形(过夜干燥) |
14 | 45 | 15%水 | 水合物II形 | ------ |
15 | 45 | 15%水 | 水合物II形 | ------ |
实验编号 | T,℃ | 溶剂 | 形式,干固体,50℃和真空,历时1小时, |
1 | 可变 | 乙醇 | 无水I形 |
2 | 可变 | 异丙醇 | 无水I形 |
3 | 可变 | 乙酸乙酯 | 无水I形 |
4 | 可变 | 丙酮 | 无水I形 |
5 | 可变 | THF | 无水I形 |
6 | 可变 | 乙腈 | 无水I形 |
7 | 可变 | 乙酸异丙酯 | 无水I形 |
实验编号 | T,℃ | 溶剂 | 形式,湿滤饼 |
1 | 溶于5体积的T=60℃的DMSO中的盐 | 一次性加入25体积IPA | 无水I形 |
2 | 溶于5体积的T=60℃的DMSO中的盐 | 一次性加入20体积的水 | 水合物II形 |
3 | 溶于5体积的T=60℃的DMSO中的盐 | 加入2体积的水和25体积的IPA。成核过夜 | 水合物II形 |
实验编号 | 溶剂 | 形式,干样品 | |
1 | DMSO∶IPA | T=50℃真空 | 无水I形 |
2 | DMSO∶IPA | T=50℃真空 | 无水I形 |
3 | DMSO∶IPA | T=50℃真空 | 无水I形 |
4 | DMSO∶IPA | T=50℃真空 | 无水I形 |
实验编号* | 溶剂 | 初始形式 | 最终形式,湿滤饼 |
1 | 乙醇 | I | I |
2 | IPA | I | I |
3 | 乙酸乙酯 | I | I+一些II |
4 | 丙酮 | I | I |
5 | THF | I | II |
6 | 乙腈 | I | I |
7 | 甲醇 | I | I |
8 | 水 | I | II |
9 | DMSO∶IPA(1∶1) | I | I |
10 | 乙醇 | II | II |
11 | IPA | II | II |
12 | 乙酸乙酯 | II | II |
13 | 丙酮 | II | II |
14 | THF | II | II |
15 | 乙腈 | II | II |
16 | 甲醇 | II | I |
17 | DMSO∶IPA(1∶1) | II | I |
Claims (6)
Priority Applications (5)
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CN201710057547.9A CN106822127B (zh) | 2007-10-17 | 2008-10-16 | 来那替尼马来酸盐及晶形 |
CN202310691104.0A CN116715654A (zh) | 2007-10-17 | 2008-10-16 | 来那替尼马来酸盐及晶形 |
CN202310690478.0A CN116715653A (zh) | 2007-10-17 | 2008-10-16 | 来那替尼马来酸盐及晶形 |
CN201910667051.2A CN110452221A (zh) | 2007-10-17 | 2008-10-16 | (e)-n-{4-[3-氯-4-(2-吡啶甲氧基)苯胺基]-3-氰基-7-乙氧基-6-喹啉基}-4-(二甲氨基)-2-丁烯酰胺马来酸盐及晶形 |
CN202310689097.0A CN117143077A (zh) | 2007-10-17 | 2008-10-16 | 来那替尼马来酸盐及晶形 |
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US12479607P | 2007-10-17 | 2007-10-17 | |
US61/124,796 | 2007-10-17 | ||
PCT/US2008/080130 WO2009052264A2 (en) | 2007-10-17 | 2008-10-16 | Maleate salts of (e)-n-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof |
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CN202310691104.0A Division CN116715654A (zh) | 2007-10-17 | 2008-10-16 | 来那替尼马来酸盐及晶形 |
CN202310689097.0A Division CN117143077A (zh) | 2007-10-17 | 2008-10-16 | 来那替尼马来酸盐及晶形 |
CN202310690478.0A Division CN116715653A (zh) | 2007-10-17 | 2008-10-16 | 来那替尼马来酸盐及晶形 |
CN201710057547.9A Division CN106822127B (zh) | 2007-10-17 | 2008-10-16 | 来那替尼马来酸盐及晶形 |
CN201910667051.2A Division CN110452221A (zh) | 2007-10-17 | 2008-10-16 | (e)-n-{4-[3-氯-4-(2-吡啶甲氧基)苯胺基]-3-氰基-7-乙氧基-6-喹啉基}-4-(二甲氨基)-2-丁烯酰胺马来酸盐及晶形 |
CN201310576791.8A Division CN103554086A (zh) | 2007-10-17 | 2008-10-16 | (e)-n-{4-[3-氯-4-(2-吡啶甲氧基)苯胺基]-3-氰基-7-乙氧基-6-喹啉基}-4-(二甲氨基)-2-丁烯酰胺马来酸盐及晶形 |
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CN101918390A CN101918390A (zh) | 2010-12-15 |
CN101918390B true CN101918390B (zh) | 2014-06-18 |
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CN201310576791.8A Pending CN103554086A (zh) | 2007-10-17 | 2008-10-16 | (e)-n-{4-[3-氯-4-(2-吡啶甲氧基)苯胺基]-3-氰基-7-乙氧基-6-喹啉基}-4-(二甲氨基)-2-丁烯酰胺马来酸盐及晶形 |
CN201910667051.2A Pending CN110452221A (zh) | 2007-10-17 | 2008-10-16 | (e)-n-{4-[3-氯-4-(2-吡啶甲氧基)苯胺基]-3-氰基-7-乙氧基-6-喹啉基}-4-(二甲氨基)-2-丁烯酰胺马来酸盐及晶形 |
CN200880118789.3A Active CN101918390B (zh) | 2007-10-17 | 2008-10-16 | (e)-n-{4-[3-氯-4-(2-吡啶基甲氧基)苯胺基]-3-氰基-7-乙氧基-6-喹啉基}-4-(二甲基氨基)-2-丁烯酰胺的马来酸盐及其结晶形式 |
CN201710057547.9A Active CN106822127B (zh) | 2007-10-17 | 2008-10-16 | 来那替尼马来酸盐及晶形 |
CN202310691104.0A Pending CN116715654A (zh) | 2007-10-17 | 2008-10-16 | 来那替尼马来酸盐及晶形 |
CN202310690478.0A Pending CN116715653A (zh) | 2007-10-17 | 2008-10-16 | 来那替尼马来酸盐及晶形 |
CN202310689097.0A Pending CN117143077A (zh) | 2007-10-17 | 2008-10-16 | 来那替尼马来酸盐及晶形 |
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CN201310576791.8A Pending CN103554086A (zh) | 2007-10-17 | 2008-10-16 | (e)-n-{4-[3-氯-4-(2-吡啶甲氧基)苯胺基]-3-氰基-7-乙氧基-6-喹啉基}-4-(二甲氨基)-2-丁烯酰胺马来酸盐及晶形 |
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