CN1169811C - 合成(3aS)-5,5-二氧代-2,3,3a,4-四氢-1H-吡咯并[2,1-c][1,2,4]苯并噻二嗪的新方法 - Google Patents
合成(3aS)-5,5-二氧代-2,3,3a,4-四氢-1H-吡咯并[2,1-c][1,2,4]苯并噻二嗪的新方法 Download PDFInfo
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Abstract
本发明涉及通过5,5-二氧代-2,3-二氢-1H-吡咯并[2,1-c][1,2,4]苯并噻二嗪的对映选择性催化氢化工业合成式(I) (3aS)-5,5-二氧代-2,3,3a,4-四氢-1H-吡咯并[2,1-c][1,2,4]苯并噻二嗪的方法。
Description
技术领域
本发明涉及工业合成式(I)(3aS)-5,5-二氧代-2,3,3a,4-四氢-1H-吡咯并[2,1-c][1,2,4]苯并噻二嗪及其与药学上可接受的酸形成的加成盐的新方法。
式(I)化合物及其盐具有强的活性,有助于谷氨酸在AMPA受体水平引起的活化,使其能用于治疗和预防与谷氨酸能(glutamatergic)神经传递功能障碍有关的病理状况,例如与老化及与焦虑和抑郁综合征有关的记忆障碍和认知障碍、进行性神经变性疾病中的记忆缺乏以及急性神经变性疾病的后遗症。
背景技术
EP 0 692 484专利说明书记载了式(I)化合物、其在治疗中的用途和它的制备方法。
考虑到对此化合物药学方面的兴趣和只有(S)异构体对AMPA的产出(flux)具有促进活性这一事实,能用有效的合成方法以好的产率和优良的纯度选择性地得到(S)异构体并能将其容易地用于工业规模制备得到此化合物具有首要的重要性。
已知两种制备式(I)化合物的方法。然而,这些方法不能用于工业规模。
-EP 0 692 484专利说明书记载了使用硼氢化钠,通过5,5-二氧代-2,3-二氢-1H-吡咯并[2,1-c][1,2,4]苯并噻二嗪的非对映选择性还原及随后用制备HPLC色谱在手性固定相上分离所得的外消旋混合物制备式(I)化合物的方法。
然而,由于此分离方法的生产率非常低,用于工业化规模不可行。
-公开文献Bioorg.Med.Chem.Lett.1996,6,3003记载了通过使用氢化铝锂手性络合物还原5,5-二氧代-2,3-二氢-1H-吡咯并[2,1-c][1,2,4]苯并噻二嗪制备式(I)化合物的方法。
然而,还原反应的低对映选择性需要费力地进行富集,以得到光学纯形式的式(I)化合物。
发明内容
本申请人现发展了一种通过5,5-二氧代-2,3-二氢-1H-吡咯并[2,1-c][1,2,4]苯并噻二嗪的对映选择性催化氢化工业化合成式(I)化合物的方法,其能直接以优良的产率及极好的化学和对映体纯度得到(S)异构体。
更具体地,本发明涉及工业合成式(I)化合物的方法,此方法的特征在于在以下反应条件下,使式(II)的5,5-二氧代-2,3-二氢-1H-吡咯并[2,1-c][1,2,4]苯并噻二嗪氢化,
在有式(III)催化剂(R)-BINAP RuCl2(R,R)-DPEN存在的条件下,
催化剂用量为0.4-2毫摩尔/摩尔式(II)化合物。
-在甲苯和异丙醇的混合物中,甲苯的比例为10-90%体积比,优选70-80%体积比,
-在氢气压力为4×105-2.5×106帕斯卡、优选1×106-1.5×106帕斯卡下,
-于温度40-90℃、优选65-75℃下,
-在有碱、例如溶解在醇溶剂如叔丁醇或异丙醇中的叔丁醇钾或叔丁醇钠的存在下,碱的用量为0.8-1.5摩尔/摩尔式(II)化合物,优选1-1.2摩尔/摩尔式(II)化合物,
经分离及随后的重结晶后直接得到对映体过量高于80%的式(I)化合物。
具体实施方式
下列实施例将说明本发明但不以任何方式限制本发明。
用HPLC色谱测定式(I)化合物的化学纯度,使用HYPERSIL BDSC18柱,水/乙腈=25/75的混合物为洗脱剂。
(检测器:210nm;炉温(oven):30℃;流速1ml/min。)
用HPLC色谱测定式(I)化合物的对映体纯度,使用CHIRALPACK AS(Daicel)柱,乙醇/庚烷=70/30的混合物为洗脱剂。
(检测器:212nm;炉温:25℃;流速1ml/min。)
缩写:
BINAP:2,2’-(双(二苯基膦基))-1,1’-联萘
DPEN:二苯基乙二胺
实施例:
(3aS)-5,5-二氧代-2,3,3a,4-四氢-1H-吡咯并[2,1-c][1,2,4]苯并噻二嗪
在高压反应釜中进行反应。
将40g 5,5-二氧代-2,3-二氢-1H-吡咯并[2,1-c][1,2,4]苯并噻二嗪溶解在450ml预先用氮气脱气的甲苯中,向其中加入90.5mg式(III)催化剂(R)-BINAP RuCl2(R,R)-DPEN,然后加入预先加热到50℃的叔丁醇钾(20.2g)的异丙醇(150ml)溶液。
用氮气吹扫后,搅拌条件下将混合物加热到70℃,然后加1.5×106帕斯卡的氢气压力20小时,同时进行搅拌。
降压和用氮气吹扫后,将反应混合物干燥,用丙酮将所得残余物重结晶。
以定量的产率直接得到式(I)化合物,其化学纯度高于90%,对映体过量为83%。
Claims (7)
1.工业合成式(I)的(3aS)-5,5-二氧代-2,3,3a,4-四氢-1H-吡咯并[2,1-c][1,2,4]苯并噻二嗪的方法,
其特征在于在以下反应条件下,使式(II)的5,5-二氧代-2,3-二氢-1H-吡咯并[2,1-c][1,2,4]苯并噻二嗪氢化,
在有式(III)催化剂(R)-BINAP RuCl2(R,R)-DPEN存在的条件下,
催化剂用量为0.4-2毫摩尔/摩尔式(II)化合物,
-在甲苯和异丙醇的混合物中,其中甲苯的比例为10-90%体积比,
-在氢气压力为4×105-2.5×106帕斯卡下,
-在温度40-90℃下,
-在有溶解在醇溶剂中的碱存在的条件下,碱的用量为0.8-1.5摩尔/摩尔式(II)化合物,
经分离及随后的重结晶后直接得到对映体过量高于80%的式(I)化合物。
2.权利要求1所述的方法,其特征在于甲苯/异丙醇混合物中甲苯的比例为70-80%体积比。
3.权利要求1或2所述的方法,其特征在于氢气压力为1×106-1.5×106帕斯卡。
4.权利要求1所述的方法,其特征在于氢化温度为65-75℃。
5.权利要求1所述的方法,其特征在于所用碱的量为1-1.2摩尔/摩尔式(II)化合物。
6.权利要求1所述的方法,其中的碱是叔丁醇钾或叔丁醇钠。
7.权利要求1所述的方法,其中的醇溶剂是叔丁醇或异丙醇。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0105226 | 2001-04-18 | ||
FR0105226A FR2823753B1 (fr) | 2001-04-18 | 2001-04-18 | Nouveau procede de synthese de la (3as)-5,5-dioxo-2,3,3a, 4-tetrahydro-1h-pyrrolo [2,1-c] [1,2,4] benzothiadiazine |
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Publication Number | Publication Date |
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CN1381455A CN1381455A (zh) | 2002-11-27 |
CN1169811C true CN1169811C (zh) | 2004-10-06 |
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CNB021057907A Expired - Fee Related CN1169811C (zh) | 2001-04-18 | 2002-04-18 | 合成(3aS)-5,5-二氧代-2,3,3a,4-四氢-1H-吡咯并[2,1-c][1,2,4]苯并噻二嗪的新方法 |
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US (1) | US6518422B2 (zh) |
EP (1) | EP1251132B1 (zh) |
JP (1) | JP4011956B2 (zh) |
KR (1) | KR100468066B1 (zh) |
CN (1) | CN1169811C (zh) |
AR (1) | AR036871A1 (zh) |
AT (1) | ATE269339T1 (zh) |
AU (1) | AU782080B2 (zh) |
BR (1) | BR0201307A (zh) |
CA (1) | CA2382405C (zh) |
DE (1) | DE60200627T2 (zh) |
DK (1) | DK1251132T3 (zh) |
EA (1) | EA004927B1 (zh) |
ES (1) | ES2223031T3 (zh) |
FR (1) | FR2823753B1 (zh) |
HK (1) | HK1049668A1 (zh) |
HU (1) | HUP0201256A3 (zh) |
MX (1) | MXPA02003639A (zh) |
NO (1) | NO20021768L (zh) |
NZ (1) | NZ518422A (zh) |
PL (1) | PL353512A1 (zh) |
PT (1) | PT1251132E (zh) |
SI (1) | SI1251132T1 (zh) |
ZA (1) | ZA200203085B (zh) |
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Publication number | Priority date | Publication date | Assignee | Title |
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FR2856065B1 (fr) * | 2003-06-13 | 2005-08-19 | Servier Lab | Nouveaux derives de benzothiazine et benzothiadiazine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
US20060014887A1 (en) * | 2004-07-19 | 2006-01-19 | 3M Innovative Properties Company | Method of hydrolyzing a dispersion of ionic fluoropolymer |
FR2879201B1 (fr) * | 2004-12-10 | 2007-02-16 | Servier Lab | Nouveaux derives de benzothiazine et benzothiadiazine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
DK2230094T3 (en) | 2009-03-20 | 2014-03-03 | Kremstal Tuerenwerk Gmbh | Process for coating of panels |
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Publication number | Priority date | Publication date | Assignee | Title |
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US3294791A (en) * | 1966-03-14 | 1966-12-27 | American Home Prod | Tetrahydro-2, 5-methano-1, 2, 5-benzothiadiazepine 1, 1-dioxide |
US3471483A (en) * | 1967-11-09 | 1969-10-07 | American Home Prod | 1 - substituted - 2,3,3a - 4 - tetrahydro - 1h-pyrrolo(2,1 - c)(1,2,4)benzothiadiazine,5,5-dioxide |
JPH06192272A (ja) * | 1992-12-24 | 1994-07-12 | Japan Tobacco Inc | 新規なトリアゾロベンゾチアジアジン及びトリアゾロベンゾチアジアゼピン誘導体 |
FR2722502B1 (fr) * | 1994-07-12 | 1996-08-23 | Adir | Nouveau derive de benzothiadiazine, son procede depreparation et les compositions pharmaceutiques qui le contiennent |
FR2812291B1 (fr) * | 2000-07-28 | 2002-12-13 | Adir | Nouveaux derives de benzothiadiazine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
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