CN1040758C - 二氮杂双环壬烷的结晶形式的富马酸盐的制备方法 - Google Patents
二氮杂双环壬烷的结晶形式的富马酸盐的制备方法 Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title description 15
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- 239000012452 mother liquor Substances 0.000 description 8
- 229940095064 tartrate Drugs 0.000 description 8
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- CTIRHWCPXYGDGF-HDICACEKSA-N tedisamil Chemical compound [H][C@]12CN(CC3CC3)C[C@]([H])(CN(CC3CC3)C1)C21CCCC1 CTIRHWCPXYGDGF-HDICACEKSA-N 0.000 description 7
- 229960002926 tedisamil Drugs 0.000 description 7
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- AOIVZQPSIHOHMP-HDICACEKSA-N (1r,5s)-7-(2-methylpropyl)-3-propan-2-ylspiro[3,7-diazabicyclo[3.3.1]nonane-9,1'-cyclohexane] Chemical compound C12([C@H]3CN(C[C@@H]2CN(C3)CC(C)C)C(C)C)CCCCC1 AOIVZQPSIHOHMP-HDICACEKSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 229950002035 bertosamil Drugs 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
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- 206010013786 Dry skin Diseases 0.000 description 4
- 125000001118 alkylidene group Chemical group 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
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- 238000010438 heat treatment Methods 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- NXXZICGFHYJPGE-UHFFFAOYSA-N 3,7-bis(cyclopropylmethyl)spiro[3,7-diazabicyclo[3.3.1]nonane-9,1'-cyclopentane];dihydrochloride Chemical compound Cl.Cl.C1C(C23CCCC3)CN(CC3CC3)CC2CN1CC1CC1 NXXZICGFHYJPGE-UHFFFAOYSA-N 0.000 description 3
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
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- 125000000217 alkyl group Chemical group 0.000 description 2
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- 239000012456 homogeneous solution Substances 0.000 description 2
- -1 nonane compound Chemical class 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- PPNCOQHHSGMKGI-UHFFFAOYSA-N 1-cyclononyldiazonane Chemical compound C1CCCCCCCC1N1NCCCCCCC1 PPNCOQHHSGMKGI-UHFFFAOYSA-N 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
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- 238000003965 capillary gas chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
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- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- BITYAPCSNKJESK-UHFFFAOYSA-N potassiosodium Chemical compound [Na].[K] BITYAPCSNKJESK-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 238000000646 scanning calorimetry Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000005204 segregation Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
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- 239000012453 solvate Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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Abstract
介绍了N，N′-二低碳烷基取代-9，9-亚烷基-3，7-二氮杂双环[3，3，1]壬烷的1，5-富马酸盐，该盐以化学计量纯形式获得，应用时不吸湿。
Description
本发明涉及通式I所示的新的N，N′-二取代-9，9-亚烷基-3，7-二氮杂双环〔3，3，1〕壬烷化合物的结晶富马酸盐的制备方法：
式中A代表具有4-5个碳原子的亚烷基链，R1和R2分别代表具有3-4个碳原子的直链或支链烷基或环丙基甲基。
式(I)所示的9，9-亚烷基-3，7-二氮杂双环壬烷化合物及其药理作用在欧洲专利103833和相关的芬兰专利76338中已为人知。式(I)化合物表示的是在上述专利文献中叙述的9，9，N，N′-四取代-3，7-二氮杂双环〔3.3.1〕壬烷化合物中的一组，并可按其中所述方法制备。从上述专利文献得知，该化合物具有治疗心脏病功能并显示出特殊的节约氧气、调节心率的药效以及高的生理相容性。极小剂量的化合物便具有令人满意的抗心律不齐效果。不希望的对心脏收缩负作用影响却极小。也就是说，该化合物具有有利的抗心律不齐效果或长期的抗心脏不应期效果，而影响心脏收缩副作用却很小。正如德国专利申请P4019080(申请日1990年6月15日)所述，所述化合物具有显著的利尿效果并具有有利的钠钾离析比。
作为式(I)化合物的盐，芬兰专利76388叙述了二氢化酒石酸盐，未公开的德国专利申请号4019080叙述了N，N′-二环丙基甲基-9，9-四亚甲基-3，7-二氮杂双环〔3.3.1〕壬烷的二氢化酒石酸盐和二氢氯化物以及N-异丁基-N′-异丙基-9，9-五亚甲基-3，7-二氮杂双环〔3.3.1〕壬烷的二氢化酒石酸盐和二氢化富马酸盐。
至今使用的式(I)化合物盐有一个缺点，即所述盐不结晶，而是如氢化酒石酸盐无定形沉淀和/或如盐酸盐具有强的吸湿性。由于溶剂含量波动，若不采取特殊预防措施，则不能保证这种盐恒定的化学计量组成以及恒定的生物可利用性。
本发明的目的是提供一种结晶的、化学计量上均一的、实际上不含溶剂而且不吸湿、但在水中充分溶解的9，9，N，N′-四取代-3，7-二氮杂双环〔3.3.1〕壬烷化合物的盐的制备方法。
已经发现，这种9，9，N，N′-四取代-3，7-二氮杂双环〔3.3.1〕壬烷化合物可与富马酸以1∶1.5的摩尔比形成稳定的结晶盐，其中上述化合物在9，9-位被具有4-5个碳原子的亚烷基链取代即具有一个螺环结构，而在2个氮原子上分别被具有3-4个碳原子的亚烷基或被环丙基甲基取代。
本发明的目的是通式I所示9，9-亚烷基-3，7-二氮杂双环〔3.3.1〕壬烷化合物的相应富马酸盐的制备方法：式中A代表具有4-5个碳原子的亚烷基链，R1和R2分别代表具有3-4个碳原子的直链或支链烷基或环丙基甲基，其中每摩尔式I碱含有1.5摩尔富马酸。
作为式I化合物尤其采用N-异丁基-N′-异丙基-9，9-五亚甲基-3，7-二氮杂双环〔3，3，1〕壬烷(通用名Bertosamil)和N，N′-二环丙基甲基-9，9-四亚甲基-3，7-二氮杂双环〔3.3.1〕壬烷(通用名Tedisamil)。
本发明的式I化合物的倍半氢化富马酸盐的制备是：将式I所示碱的溶液与至少1.5倍摩尔量的富马酸在低碳醇中及较弱极性有机溶剂中混合，其中每摩尔式I碱含有1.5摩尔富马酸的盐结晶出，并分离出结晶的盐。
适宜的低碳醇例如有甲醇，乙醇或异丙醇，尤其是甲醇或乙醇。与低碳醇比较极性较弱的溶剂有低碳脂族酮，尤其是乙酮，或低碳脂族开链醚，尤其是乙醚。
为了本发明目的，富马酸对式I碱摩尔量比采用1.5-2。在采用过量富马酸的情况下，为了排除二氢富马酸盐副产物，必要时可对沉淀的盐多次结晶，直至达到一稳定的熔点为止。式I碱在醇溶液中的浓度视化合物的溶解度，溶解温度和加入量任意变化，可以在例如3-50mol/l范围内。
醇溶液与较弱极性溶剂的体积比视式I化合物在醇溶液中的浓度，结晶出的式I化合物的1.5-氢化富马酸盐的溶解度和较弱极性溶剂的种类变化，其中较弱极性溶剂的体积总是为醇溶液体积数倍。用于本发明目的的醇溶液对较弱极性溶剂的体积比在1∶15-1∶25范围内，尤其为约1∶20。为了使醇溶液与较弱极性溶剂混合，或是将较弱极性溶剂加到醇溶液中，或是将醇溶液加到较弱极性溶剂中，例如逐渐滴加。为了形成均匀溶液，可使所得混合物在回流下加热，例如至反应混合物的沸点。接着使式I化合物的1，5-氢化富马酸盐结晶出，最好在混合物冷却下如在室温和0℃之间结晶出。
结晶出的盐可利用已知的方法将其从母液中分离出，例如必要时减压过滤，然后在稍高温度如40和65℃之间干燥，最好在真空干燥器中干燥。
下面的实施例对本发明进一步阐述但不限制其范围。下例中给出的熔程利用差式扫描量热法(DSC)，使用DSC7-仪器(FirmaPerkin Elmer)进行确认，能量曲线的熔程回反射峰通过10℃/分钟的加热速率来确定。实施例中给出的干燥时的重量损失借助差式温度重量法(热重分析，TGA)，用TGA7-仪器(FirmaPerkin Elmer)，以20℃/分钟的加热速率进行测定。
实施例1
N-异丁基-N′-异丙基-9，9-五亚甲基-3，7-二氮杂双环〔3，3，1〕壬烷-1.5-氢化富马酸盐(Bertosamil-1.5-氢化富马酸盐)的制备。
于50℃将6.2kg(11.8mol)Bertosamil-二氢化富马酸盐溶解在2.6l甲醇中，然后向该溶液中加入52l丙酮并将该反应混合物回流加热7小时。然后将反应混合物慢慢冷却至室温。借助吸滤器将母液从沉淀物中吸出，沉淀物用1l丙酮洗涤，在干燥箱中于50℃干燥。得到3.6kg粗晶体，熔点为90-95℃。将该粗晶体于50℃重新溶解在2l甲醇中并向该溶液加入42l丙酮。搅拌下将反应混合物慢慢冷却至室温。用吸滤器将母液从形成的沉淀物中吸除，沉淀物用1l丙酮洗涤，并于50℃在干燥箱中干燥，得到2.82kgBertosamil-1.5-氢化富马酸盐，熔程104.5-107.4℃。在甲醇/丙酮中进一步结晶，该熔点不再变化。经滴定确定碱∶酸比例为1∶1.5。TGA测试：干燥时无重量损失。
实施例2
N，N′-二环丙基甲基-9，9-四亚甲基-3，7-二氮杂双环〔3，3，1〕壬烷-1.5-氢化富马酸盐(Tedisamil-1.5-氢化富马酸盐)的制备。
将3.7g(0.0128mol)Tedisamil溶解于25ml乙醇中，向该溶液中加入2.98g(0.0256mol)富马酸在30ml乙醇中的溶液。将得到的均匀溶液缓慢滴到500ml乙醚中，为使成盐完全，将该反应混合物置于冰箱中冰却。然后用吸滤器将母液从形成的结晶中吸除，结晶体用20ml乙醚洗涤并在干燥箱中于60℃下干燥。得到4.9g Te-disamil-1.5-氢化富马酸盐，熔程135.8-136.9。经滴定测定碱∶酸比为1∶1.5。TGA测试：干燥过程中无重量损失。
按本发明得到的实施例1和2的1.5-氢化富马酸盐的性能与相同碱的其它盐进行比较。
对比例A-G：
Bertosamil和Tedisamil与其他酸的盐(对比用)的制备。
(A)Bertosamil-二氢化富马酸盐
将6kg(20.5mol)Bertosamil溶解在14.4l乙醇中。向该溶液中加入4.76kg(41mol)固体富马酸。将反应混合物加热至80℃并在该温度下搅拌30分钟，然后搅拌下将反应混合物缓慢冷却至室温，并在冰浴中(0℃)再搅拌30分钟。通过吸滤器将母液从形成的沉淀物中吸除，沉淀物用10l冰冻的乙醇洗涤并在干燥箱中于35℃干燥。得到5.1kg Bertosamil-二氢化富马酸。由DSC测知熔程为90.2℃-96.2℃。在68-81℃温度范围出现另一峰。TGA测试干燥时重量损失达7.0％，经滴定测知碱∶酸比为1∶2.1。
(B)Bertosamil-二氢氯化物
将5.4g(0.0154mol)Bertosamil溶解在20ml异丙醇中。冰冷下，向该溶液中加入8.2ml盐酸在异丙醇中的3，8-当量溶液。然后蒸除异丙醇。将残余物溶解于少量丙酮中，并掺入乙醚直至含入的晶体被溶解。通过一吸滤器将母液从沉淀物中吸除，沉淀物在真空干燥箱中于60℃干燥。得到5g Bertosamil-二氢氯化物，熔程为180.6-183.7℃。TGA测试：干燥过程中重量损失为2.0％。经滴定测知碱∶酸比为1∶2.0。
(C)Bertosamil-二氢化酒石酸盐
将5.4g(0.018mol)Bertosamil溶解在10ml乙酸乙酯中。向该溶液中加入5.5g(0.037mol)L(+)-酒石酸在20ml中的丙酮溶液。将溶剂蒸除后，分离出8.4g无定形泡末状的Bertosamil-二氢化酒石酸盐。熔程为189.2℃-201.2℃(分解)，经滴定测知，碱∶酸比为1∶1.8。TGA测试：干燥过程中重量损失为0.1％。
(D)Bertosamil-水杨酸盐
将10.7g(0.037mol)Bertosamil溶解在40ml乙醚中。向该溶液中加入5.12g(0.037mol)水杨酸在30ml乙醚中的溶液，并将该反应混合物搅拌30分钟。通过一吸滤器将母液从沉淀物中吸除，沉淀物在真空干燥箱中于60℃下干燥。得到14.5gBertosamil-水杨酸盐，熔程为118.4-119.9℃。经滴定测知碱∶酸比为1∶1.0。TGA测试：干燥过程中无重量损失。
(E)Tedisamil-二氢氯化物
将2g(0.0069mol)Tedisamil溶解在5ml异丙醇中。在搅拌下向该溶液中加入0.53g盐酸在5ml异丙醇中的溶液。成盐后蒸除异丙醇。作为残余物遗留下的Tedisamil-二氢氯化物从丙酮中结晶，并在真空干燥箱中于60℃下干燥。得到2g Tedisamil-二氢氯化物。由DSC测知，熔程为225.7℃-240.4℃(分解)。经滴定测知，碱∶酸比为1∶2.0。TGA测试：干燥过程的重量损失为0.2％。
(F)Tedisamil-二氢酒石酸盐
将3.7g(0.0128mol)Tedisamil溶解于15ml乙酸乙酯中。向该溶液中加入3.85g(0.0256mol)L(+)-酒石酸在150ml丙酮中的溶液。将溶剂蒸除后，分离出6g无定形泡末状的Tedisamil二氢化酒石酸盐。由DSC测知，没有确定的熔程而从183℃起开始分解，TGA测试：干燥过程中的重量损失为0.5％，经滴定测知：碱∶酸比为1∶2.1。
(G)Tedisamil-水杨酸盐
将10.7g(0.037mol)Tedisamil溶解在50ml乙醚中。向该溶液中加入5.12g(0.037mol)水杨酸盐在50ml乙醚中的溶液，将反应混合物搅拌30分钟，通过吸滤器将母液从沉淀物中吸除。沉淀物在真空干燥箱于60℃下干燥。得到14.5g Tedisamil-水杨酸盐。由DSG测知，熔程为140.9-142.2℃，经滴定测定碱∶酸比为1∶1.0。TGA测试：在干燥过程中重量损失为0.1％。
按如下所述方法，测定按实施例1和2本发明方法制备的盐与按对比例A-G制备的对比盐的性能：
(1)水溶性的测定：
水溶性在室温下测定。
(2)溶剂残余含量的测定。
应用毛细管气相色谱法，使用带火焰电离检测器的Sicro-matR仪器(Siemens公司)，测定溶剂的残余含量。
(3)吸湿性的测定
在室温下将盐试样分别在相对空气湿度为55，65，76，86，92和100％下放置，直至试样重量恒定。测量试样的初始重量和放置后重量并计算重量差。化合物的吸湿性以相对初始重量的重量增加百分数计。此外，按Karl-Fischer方法，用碘滴定测定了含溶剂物质的水含量。
下表给出了按上述测试方法得到的结果，从表中可清楚看出，与对比盐相反，按本发明得到的1，5-氢化富马酸盐实际上不吸湿，但尽管如此用于药学目的仍具有足够的水溶性。
表
* Et＝乙醇，Ac＝丙酮，Di＝乙醚，Pr＝异丙醇**如果A作为溶剂化物同时产生，则在贮放过程中通过溶剂与空气湿度交换而失重。这一点反映在给出的数值上。括弧给出按Karl-Fisoher法测得的试样吸水量。
| 盐实施例号 | 水溶性g/100ml | 溶剂残余含量(GC)％(重量) | 在以下相对空气湿度下的吸湿性，以重量增加的百分数计 | ||||||||
| Et | Ac | Di | Pr | 55％ | 65％ | 76％ | 86％ | 92％ | 100％ | ||
| 1 | 4.5 | - | - | - | - | 0 | 0 | 0.04 | 0.04 | - | 0.06 |
| A**BCD | 3.6＞51501.6 | 7.8-0.7- | --1.8- | --0.02- | -0.03-- | -2.3(+2.1H2O)7.74.30.1 | -4.19.07.03.1 | -4.2139.614 | -4.2511517 | ---- | -4.0(+3.5H2O)17110235 |
| 2 | 4.4 | 0.12 | - | 0.05 | - | 0 | 0 | 0 | 0 | - | 1.1 |
| EFG | ＞190391.8 | -0.9- | -0.3- | --0.09 | 0.1-- | 0.12.50 | 306.00.04 | 43100.04 | 67160.2 | 106-- | -11829 |
Claims (2)
1.碱性N，N′-二环丙基甲基-9，9-四亚甲基-3，7-二氮杂双环〔3.3.1〕壬烷和N-异丁基-N′-异丙基-9，9-五亚甲基-3，7-二氮杂双环〔3.3.1〕壬烷的结晶性倍半富马酸盐的制备方法，其特征在于，将一种由所说碱性壬烷和一种于C1-C3-醇中的1.5-2.0倍摩尔量的富马酸组成的溶液与15-25倍体积量的一种较弱极性有机溶剂混合，所说溶剂选自脂族的二(C1-C4)-烷基酮和脂族开链二(C1-C4)-烷基醚，其中使每摩尔所说碱性壬烷含1.5摩尔富马酸的盐结晶，并分离出结晶出的盐。
2.按照权利要求1的方法，其特征在于，采用丙酮或二乙基醚作为较弱极性溶剂。
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| EP0103833A2 (de) * | 1982-09-18 | 1984-03-28 | Kali-Chemie Pharma GmbH | Diazabicyclo-(3,3,1)-nonane |
| EP0306871A2 (de) * | 1987-09-09 | 1989-03-15 | Kali-Chemie Pharma GmbH | 3,7-Diazabicyclo [3,3,1] nonan-Verbindungen sowie Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel |
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| US4971992A (en) * | 1989-03-27 | 1990-11-20 | Hoechst-Roussel Pharmaceuticals Inc. | Carbonate derivatives of eseroline |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2375235A1 (fr) * | 1976-12-23 | 1978-07-21 | Bayer Ag | Nouveaux diazabicyclo(3,3,1)nonanes, leur procede de preparation et medicament les contenant |
| EP0103833A2 (de) * | 1982-09-18 | 1984-03-28 | Kali-Chemie Pharma GmbH | Diazabicyclo-(3,3,1)-nonane |
| EP0306871A2 (de) * | 1987-09-09 | 1989-03-15 | Kali-Chemie Pharma GmbH | 3,7-Diazabicyclo [3,3,1] nonan-Verbindungen sowie Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel |
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