CN1352643A - 新的用于制备多沙唑嗪甲磺酸盐的a型晶体变体的方法 - Google Patents
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- VJECBOKJABCYMF-UHFFFAOYSA-N doxazosin mesylate Chemical compound [H+].CS([O-])(=O)=O.C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 VJECBOKJABCYMF-UHFFFAOYSA-N 0.000 title claims abstract description 40
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- 238000000034 method Methods 0.000 claims abstract description 26
- 229960001389 doxazosin Drugs 0.000 claims abstract description 24
- RUZYUOTYCVRMRZ-UHFFFAOYSA-N doxazosin Chemical compound C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 RUZYUOTYCVRMRZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 19
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
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- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
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- 238000005169 Debye-Scherrer Methods 0.000 description 1
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Abstract
本发明涉及制备A晶型的多沙唑嗪甲磺酸盐的方法。该方法的特征在于,将多沙唑嗪和甲磺酸一起溶于质子惰性的极性有机溶剂和甲醇的混合物中。任选地消除在所生成的溶液中的任何混浊。向这样生成的澄清溶液中任选地加入A晶型的多沙唑嗪甲磺酸盐晶种,加热并在生成的产物冷却后进行分离。所述的产物用有机溶剂洗涤,干燥。
Description
本发明涉及新的用于制备多沙唑嗪甲磺酸盐的A型晶体变体的方法。
多沙唑嗪(=4-氨基-2-[4-(1,4-苯并二噁烷-2-羰基)-哌嗪-1-基]-6,7-二甲氧基喹唑啉)是已知的降低血压的物质(Merck-Index第12版,1996,No.3489)。该物质主要以单甲磺酸盐的形式使用。多沙唑嗪甲磺酸盐多型体的最早报道出现在Chinese Journal of Medicinal Chemistry 5(4),266-270(1995)。其中描述了多沙唑嗪甲磺酸盐的三种结晶型。各个晶型在所述的参考文献中被称为晶型A、B和C。通过在乙醇中将多沙唑嗪甲磺酸盐重结晶得到晶型A,分别通过在氯仿和水中重结晶多沙唑嗪甲磺酸盐得到晶型B和C。尽管所述的参考文献仅述及多沙唑嗪,但是根据公开的数据可知该物质为多沙唑嗪甲磺酸盐。
在三种晶型中只有晶型A是用于药物用途。在Chinese Journalof Medicinal Chemistry中所述的制备多沙唑嗪甲磺酸盐A晶型的方法是从乙醇中重结晶多沙唑嗪甲磺酸盐,但是尚没有一种方法可以工业规模特定地得到这种变体。
EP-A 849 266描述了一种称为晶型III的多沙唑嗪甲磺酸盐结晶变体,其与多沙唑嗪甲磺酸盐的A晶型相同。
EP-A 849 266还描述了由多沙唑嗪开始制备多沙唑嗪甲磺酸盐A晶型的方法。该方法要求优选在诸如乙酸乙酯的有机溶剂中通过与乙酸一起加热将多沙唑嗪转化为多沙唑嗪乙酸盐。过滤热的溶液,用甲磺酸处理并任选地在热时搅拌直到出现结晶。冷却后除去沉淀的溶剂加合物,在诸如甲醇或乙醇的低级醇中加热除湿气,冷却得到的溶液,移出已经分离出来的晶体(=多沙唑嗪甲磺酸盐的A晶型)。
在1998年12月18日的PCT申请PCT/EP/9808360中描述了另一种制备A晶型多沙唑嗪甲磺酸盐的方法。在该方法中的起始原料同样是多沙唑嗪。为得到A晶型的多沙唑嗪甲磺酸盐,在该方法中将多沙唑嗪和甲磺酸一起溶于例如N,N-二甲基甲酰胺和N-甲基-2-吡咯烷酮之类的质子惰性的极性有机溶剂和甲醇的混合物中,任选地消除这样得到的溶液中的混浊,搅拌得到的澄清溶液直到不再生成沉淀。除去沉淀(多沙唑嗪甲磺酸盐的D晶型),用甲醇洗涤,以用乙醇润湿的状态加热。冷却后,分离所形成的多沙唑嗪甲磺酸盐的A晶型。如果仅用甲醇溶解多沙唑嗪和甲磺酸,该方法也是成功的。
正如已经描述过的,在上述中文参考文献中指出的从乙醇中再沉淀多沙唑嗪甲磺酸盐不是可以工业规模得到特定的A晶型多沙唑嗪甲磺酸盐的方法。此外,该文献也没有指出用于制备各个晶型的作为起始原料的多沙唑嗪甲磺酸盐的制备。
上述另外两种制备多沙唑嗪甲磺酸盐A晶型的方法可能以大规模使用。但是,这两种方法非常复杂。在这两种情况下,A晶型不是简单地用甲磺酸处理多沙唑嗪来制备的。相反,EP 849 266的方法需要首先从多沙唑嗪和乙酸制备乙酸盐,将乙酸盐再在溶液中用甲磺酸处理。在该方法中,结晶出溶剂加合物并且不得不将其分离。然后只有在低级醇中加热该加合物才能得到需要的多沙唑嗪甲磺酸盐的A晶型。根据PCT/EP 9808360,首先从多沙唑嗪和甲磺酸制备称为D晶型的多沙唑嗪甲磺酸盐,其不得不被分离。只有随后在乙醇中加热该D型晶体才能制备需要的多沙唑嗪甲磺酸盐的A晶型。
尚未发现简单的可以工业规模使用的用于制备A晶型的多沙唑嗪甲磺酸盐的方法。
本发明涉及制备A晶型的多沙唑嗪甲磺酸盐的方法,其包括将多沙唑嗪和甲磺酸一起溶于质子惰性的极性有机溶剂和甲醇的混合物中,任选地过滤得到的溶液,任选地加入A晶型的多沙唑嗪甲磺酸盐晶种,加热,并于冷却后分离所形成的产物,用有机溶剂洗涤,干燥。
为了将多沙唑嗪与甲磺酸反应,两种物质以大约1∶1的摩尔比使用。优选使用摩尔量稍微过量(至多约10%)的磺酸。
适合的质子惰性的极性有机溶剂是例如N,N-二甲基甲酰胺和特别是N-甲基-2-吡咯烷酮。多沙唑嗪∶甲醇∶质子惰性极性有机溶剂(重量/体积/体积)比为约1∶(5-15)∶(1.5-4),优选约1∶(8-12)∶(2-3)。如果是将甲磺酸加入到多沙唑嗪、甲醇和质子惰性极性有机溶剂的混合物中得到的溶液是混浊的,用例如过滤的方法将混浊消除是可取的。如果用例如过滤的方法消除混浊,有利的是仅仅在过滤后加入部分甲醇。
随后,将甲磺酸加入到多沙唑嗪、甲醇和质子惰性的极性有机溶剂的混合物中得到的澄清溶液,任选地在过滤后,进行加热,优选在加入A晶型多沙唑嗪甲磺酸盐晶种后进行加热。加热优选达到回流温度。反应混合物一般在该温度加热3-9小时,优选4-6小时。
得到的晶体悬浮液随后被冷却到室温,然后在室温短暂搅拌。之后分离固体产物(多沙唑嗪甲磺酸盐的A晶型),用有机溶剂、优选低级烷醇、特别优选甲醇洗涤。用常规方法干燥,例如在真空中干燥。
该新方法以非常简单的方式提供多沙唑嗪甲磺酸盐的A晶型,并且总收率大于85%。用该新方法得到的A型晶体纯度特别高。该新方法的重要优点还在于加入甲磺酸后形成溶液。这使得能够用过滤的方法除去任何外来的颗粒。
实施例1
在搅拌下向在500ml三颈圆底烧瓶中的22.6g多沙唑嗪、45m1 N-甲基-2-吡咯烷酮和210ml甲醇的混合物中加入5.05g无水甲磺酸。在此期间,内部温度升至30℃,得到溶液。将反应混合物用0.5gA晶型的多沙唑嗪甲磺酸盐接种,这些种晶不溶解。加入晶种后,加热至回流温度(沸点68℃;未溶解),在该温度搅拌4小时,期间形成更多的晶体。然后冷却至室温,在该温度搅拌15分钟。抽滤沉淀的产物,用甲醇洗涤2次,每次50ml。在真空中在75℃干燥。得到24.6g A晶型的多沙唑嗪甲磺酸盐。基于使用的多沙唑嗪,减去用作晶种的部分,相应的收率为87.8%。
用这种方法得到的多沙唑嗪甲磺酸盐进行Debye-Scherrer X-射线衍射、示差扫描热分析和IR光谱测定,数据如附图1-3所示。
实施例2
在搅拌下向在500ml三颈圆底烧瓶中的22.6g多沙唑嗪、45ml N-甲基-2-吡咯烷酮和210ml甲醇的混合物中加入5.05g无水甲磺酸。在此期间,内部温度升至30℃,得到溶液。加入甲磺酸完成后,将混合物加热至回流温度(沸点68℃)并在该温度搅拌4小时(在回流温度进行搅拌期间形成晶体)。然后冷却至室温,在该温度搅拌15分钟。抽滤沉淀的产物,用甲醇洗涤2次,每次50ml。在真空中在75℃干燥。得到23.5g A晶型的多沙唑嗪甲磺酸盐。基于使用的多沙唑嗪,相应的收率为85.7%。
实施例3
在搅拌下向在500ml三颈圆底烧瓶中的22.6g多沙唑嗪、45ml N-甲基-2-吡咯烷酮和190ml甲醇的混合物中加入5.05g无水甲磺酸。在此期间,内部温度升至30℃,得到溶液。加入甲磺酸完成后,将反应混合物过滤到另一个500ml三颈圆底烧瓶中。然后用20ml甲醇洗涤滤器。合并的滤液加热至回流温度(沸点68℃)并在该温度搅拌4小时(在回流温度进行搅拌期间形成晶体)。在回流温度搅拌完毕后,将混合物冷却至室温并在该温度搅拌15分钟。抽滤沉淀的产物,用甲醇洗涤2次,每次50ml。在真空中在75℃干燥。得到23.4gA晶型的多沙唑嗪甲磺酸盐。基于使用的多沙唑嗪,相应的收率为85.4%。
Claims (1)
- 制备A晶型的多沙唑嗪甲磺酸盐的方法,其特征在于,将多沙唑嗪和甲磺酸一起溶于质子惰性的极性有机溶剂和甲醇的混合物中,任选地过滤所得到的溶液,任选地加入A晶型的多沙唑嗪甲磺酸盐晶种,加热,并在冷却后分离产生的产物,用有机溶剂洗涤,干燥。
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DE19912063A DE19912063A1 (de) | 1999-03-18 | 1999-03-18 | Neues Verfahren zur Herstellung von Doxazosin-Mesylat in einer als Form A bezeichneten Kristallmodifikation |
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CN109988158A (zh) * | 2018-01-03 | 2019-07-09 | 合肥立方制药股份有限公司 | X晶型、含有x晶型的多沙唑嗪甲磺酸盐及其制备方法和用途 |
CN111303130A (zh) * | 2018-12-11 | 2020-06-19 | 合肥立方制药股份有限公司 | 一种多沙唑嗪甲磺酸盐晶型、其制备方法及用途 |
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DE19912573A1 (de) * | 1999-03-19 | 2000-09-21 | Knoll Ag | Arzneimittel, enthaltend Doxazosin-Mesylat der Kristallmodifikaton D |
AU2008339652B2 (en) | 2007-12-24 | 2013-07-04 | Cipla Limited | Crystalline polymorph of doxazosin mesylate (form IV) and process for preparation thereof |
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IT1287588B1 (it) * | 1996-12-13 | 1998-08-06 | Alfa Chem Ital | Forma cristallina del doxazosin mesilato e processo per la sua produzione |
EP0849266B8 (de) * | 1996-12-20 | 2007-10-03 | Heumann PCS GmbH | Neue polymorphe Form von Doxazosinmesylat (Form III) |
DE19800214A1 (de) * | 1998-01-06 | 1999-07-15 | Knoll Ag | Verfahren zur Herstellung von Doxazosin-Mcsylat in einer als Form A bezeichneten Kristallmodifikation und ein Zwischenprodukt dafür |
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1999
- 1999-03-18 DE DE19912063A patent/DE19912063A1/de not_active Withdrawn
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2000
- 2000-03-06 JP JP2000606592A patent/JP2002540109A/ja active Pending
- 2000-03-06 IL IL14494400A patent/IL144944A0/xx unknown
- 2000-03-06 TR TR2001/02730T patent/TR200102730T2/xx unknown
- 2000-03-06 AU AU39608/00A patent/AU3960800A/en not_active Abandoned
- 2000-03-06 EP EP00918763A patent/EP1165548A1/de not_active Withdrawn
- 2000-03-06 HU HU0200663A patent/HUP0200663A2/hu unknown
- 2000-03-06 WO PCT/EP2000/001939 patent/WO2000056731A1/de not_active Application Discontinuation
- 2000-03-06 CA CA002367903A patent/CA2367903A1/en not_active Abandoned
- 2000-03-06 CZ CZ20013347A patent/CZ20013347A3/cs unknown
- 2000-03-06 PL PL00350088A patent/PL350088A1/xx unknown
- 2000-03-06 KR KR1020017011780A patent/KR20010113753A/ko not_active Application Discontinuation
- 2000-03-06 CN CN00805209A patent/CN1352643A/zh active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109988158A (zh) * | 2018-01-03 | 2019-07-09 | 合肥立方制药股份有限公司 | X晶型、含有x晶型的多沙唑嗪甲磺酸盐及其制备方法和用途 |
CN111303130A (zh) * | 2018-12-11 | 2020-06-19 | 合肥立方制药股份有限公司 | 一种多沙唑嗪甲磺酸盐晶型、其制备方法及用途 |
Also Published As
Publication number | Publication date |
---|---|
DE19912063A1 (de) | 2000-09-21 |
CA2367903A1 (en) | 2000-09-28 |
IL144944A0 (en) | 2002-06-30 |
KR20010113753A (ko) | 2001-12-28 |
WO2000056731A1 (de) | 2000-09-28 |
JP2002540109A (ja) | 2002-11-26 |
HUP0200663A2 (en) | 2002-08-28 |
EP1165548A1 (de) | 2002-01-02 |
TR200102730T2 (tr) | 2002-06-21 |
AU3960800A (en) | 2000-10-09 |
CZ20013347A3 (cs) | 2002-01-16 |
PL350088A1 (en) | 2002-11-04 |
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