CN86108424A - 硝噻烯啶的合成方法 - Google Patents
硝噻烯啶的合成方法 Download PDFInfo
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- CN86108424A CN86108424A CN198686108424A CN86108424A CN86108424A CN 86108424 A CN86108424 A CN 86108424A CN 198686108424 A CN198686108424 A CN 198686108424A CN 86108424 A CN86108424 A CN 86108424A CN 86108424 A CN86108424 A CN 86108424A
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- nizatidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/26—Radicals substituted by sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/28—Radicals substituted by nitrogen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- Thiazole And Isothizaole Compounds (AREA)
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Abstract
本发明提供了一个制备硝噻烯啶的方法,该方法包括使4—[[(2—氨乙基)硫]甲基]—N,N—二甲基—2—噻唑甲胺与1—烷氧基—N—甲基—2—硝基乙烯胺反应。
Description
根据Pioch的美国专利第4,375,547号所述,硝噻烯啶
(Nizatidine)是N-[2-[[[2-[(二甲氨基)甲基]-4-噻唑基]-甲基]硫]乙基]-N′-甲基-2-硝基-1,1-乙烯二胺化合物的俗名,它是一种抗溃疡的化合物。该专利公开了硝噻烯啶的合成,方法是使4-[[(2-氨乙基)硫]-甲基]-N,N-二甲基-2-噻唑甲胺与1,1-二甲基硫-2-硝基乙烯反应以制得相应的2-硝基-1-甲基硫-1-乙烯胺衍生物,然后,该衍生物与甲胺反应,便转化成硝噻烯啶。上述专利所公开的制备方法产生了副产品甲硫醇气体,从所周知,这种气体会产生一种难闻的气味,这就要求采用额外的提纯设备来把它除去。
本发明提供了一个制备硝噻烯啶的方法,方法包括使1-烷氧基-N-甲基-2-硝基乙烯胺与4-[[2-氨乙基)硫]-甲基]-N,N-二甲基-2-噻唑甲胺在水中反应。本发明的方法不会产生甲硫醇气体,因此对于把成本作为一个重要考虑因素的硝噻烯啶的大规模生产特别有价值。
本发明提供了一个制备具有下面结构式的硝噻烯啶的方法,
该方法包括使结构式(式中R为C1-4烷基)为:
的1-烷氧基-N-甲基-2-硝基乙烯胺与结构式为
的4-[[(2-氨乙基)硫]-甲基]-N,N-二甲基-2-噻唑甲胺反应。
在一个适当的反应容器内,使1-烷氧基-N-甲基-2-硝基乙烯胺与4-[[(2-氨乙基)硫]甲基]-N,N-二甲基-2-噻唑甲胺在极性溶剂,如水中,化合就可以实现本发明的方法。最好是把噻唑甲胺加入到硝基乙烯胺在水中的悬浮液中。
在本发明的方法中最好用水作溶剂。水的用量没有严格规定,但不要多于为使原料噻唑甲胺和硝基乙烯胺悬浮而所需要的水的用量。
本方法中每摩尔当量的噻唑甲胺所需用的1-烷氧基-N-甲基-2-硝基乙烯胺的用量约为1至2个摩尔当量。这两种起始反应物以约等克分子量使用较好。
本反应在约10℃至100℃的温度下进行约10分钟至24小时后便基本完成,若在约15℃至60℃的温度下反应约30分钟至约4小时则较好。
R为甲基或乙基较佳。
可用常规方法分离本方法的产品。一般说来,可用适当的碱(例如碳酸氢钠)中和溶液,然后用一种不与水混溶的有机溶剂(例如二氯甲烷)萃取中和后的混合物。分离有机相,然后一般在真空下蒸发溶剂。如有需要,可采用常规技术最后提纯剩留物,如用普通溶剂进行结晶,或用固体载体如硅胶或铝土进行净化。
现已发现按本发明的方法生产的产品纯度总是高的,因此不需要另外的昂贵的纯化步骤就可使用。在工业化生产中本方法还有一个优点,即不会产生带有难闻气味的付产物甲硫醇,因此不需要特殊的设备、处理步骤和适当的排出装置来消除恶臭。
本方法中所使用的起始原料是本技术领域中熟知的,并可采用先有技术的方法很容易地制得。噻唑甲胺已在美国专利第4,375,547中公开。1-烷氧基-N-甲基-2-硝基乙烯胺类最好是由四氟硼酸三烷基氧鎓和N-甲基-2-硝基乙酰胺在对质子有惰性的溶剂中反应制得。
以下的实例进一步说明本发明的方法。这些实施例无论从那方面来看都不是对本发明的范围的限制,也不应作这样的理解。
实例1
硝噻烯啶的合成
A.1-甲氧基-N-甲基-2-硝基乙烯胺的合成:
将3.33克(0.028摩尔)N-甲基-2-硝基乙酰胺和4.8克(0.032摩尔)四氟硼酸三甲基氧鎓溶于100毫升二氯甲烷中的溶液,在约25℃下搅拌约二十小时。然后把100毫升冷的饱和碳酸氢钠溶液加进上述混合物中。把各层分离,用30毫升二氯甲烷萃取含水相。将有机萃取物合并,并用无水硫酸镁干燥。然后过滤混合物,在真空下蒸发挥发性组分,可得1.30克黄色固体状的1-甲氧基-N-甲基-2-硝基乙烯胺。产率是35.2%。产品的结构是由质子核磁共振(NMR)测定的。
B.在室温下,把1.17克(0.005摩尔)4-[[(2-氨乙基)硫]甲基]-N,N-二甲基-2-噻唑甲胺加入到含有5毫升水与0.66克(0.005摩尔)1-甲氧基-N-甲基-2-硝基乙烯胺的悬浮混合物中。当把固体成份加入到溶液中时会出现轻微的温升。在室温下,搅拌反应混合物2.5小时,然后加入10毫升饱和的碳酸氢钠溶液,用二氯甲烷萃取混合物两次,每次用10毫升。将有机萃取物合并,用无水硫酸镁干燥,在真空下,把有机溶液浓缩,可得到一种油状物。把乙醇加到这种油中,然后将所得溶液再浓缩成油状物。把这种油溶解在乙醇和乙酸乙酯中,然后把硝噻烯啶的晶种加进该溶液中。把溶液冷却,用真空过滤法收集沉淀后的固体物,可得1.31克硝噻烯啶。该固体物的薄层色谱显示只有微小的的杂质存在。用乙醇把固体物重结晶,可制得0.65克硝噻烯啶,薄层色谱分析表明该化合物基本上是纯净的,产率为39.3%。
实例2
硝噻烯啶的合成。
把含0.48克(0.035摩尔)浓度为95%的4-[[(2-氨乙基)硫]甲基]-N,N-二甲基-2-噻唑甲胺,8.03克(0.056摩尔)1-乙氧基-N-甲基-2-硝基乙烯胺和200毫升水的混合物在约55℃下加热搅拌约4小时。反应的进度由高效液相色谱(HPLC)测定。把反应混合物的温度升高至65℃,并再维持90分钟,然后升温至75℃,并维持60分钟。把1克碳酸钾加进反应混合物中,把所制得的混合物在约50℃加热约15分钟。高效液相色谱分析表明,混合物中含有88.8%(摩尔)的硝噻烯啶。将反应混合物应冷却,用100毫升二氯甲烷稀释。然后加入40克氯化钠。把有机相分离,先后用100毫升二氯甲烷和50毫升二氯甲烷萃取含水相。合并各有机相,然后用无水硫酸镁干燥。在真空下蒸发有机相,使其体积减少至100毫升。把该二氯甲烷溶液与100毫升乙醇混合,在真空下浓缩所得的溶液直至干燥为止。把90毫升乙酸乙酯加入到剩留物中,然后在室温下把所得的混合物搅拌约20分钟。在室温下让混合物静置一夜。用真空过滤法收集沉淀出的固体物,然后用50毫升新鲜乙酸乙酯洗涤,经过真空干燥后可得6.25克硝噻烯啶。据高效液相色谱分析,产品的纯度为95%。产率是53.9%。
Claims (2)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US81013685A | 1985-12-18 | 1985-12-18 | |
US810,136 | 1985-12-18 |
Publications (1)
Publication Number | Publication Date |
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CN86108424A true CN86108424A (zh) | 1987-08-05 |
Family
ID=25203102
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN198686108424A Pending CN86108424A (zh) | 1985-12-18 | 1986-12-17 | 硝噻烯啶的合成方法 |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP0230127A1 (zh) |
JP (1) | JPS62155268A (zh) |
KR (1) | KR890002427B1 (zh) |
CN (1) | CN86108424A (zh) |
AU (1) | AU582932B2 (zh) |
CA (1) | CA1277325C (zh) |
DK (1) | DK605386A (zh) |
FI (1) | FI865117A (zh) |
HU (1) | HU196385B (zh) |
IL (1) | IL80961A0 (zh) |
NZ (1) | NZ218647A (zh) |
PH (1) | PH21924A (zh) |
PT (1) | PT83938B (zh) |
ZA (1) | ZA869438B (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102329282A (zh) * | 2011-07-15 | 2012-01-25 | 海南灵康制药有限公司 | 一种尼扎替丁化合物及其制法 |
CN101462969B (zh) * | 2009-01-09 | 2012-04-25 | 福建深纳生物工程有限公司 | 1-甲氨基-1-甲氧基-2-硝基乙烯的合成方法 |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2038922B1 (es) * | 1991-12-30 | 1994-04-16 | Fermentaciones Y Sintesis Espa | Procedimiento para la obtencion de nizatidina. |
US5470865A (en) * | 1994-08-30 | 1995-11-28 | Eli Lilly And Company | Pharmaceutical composition |
KR100980612B1 (ko) * | 2008-09-02 | 2010-09-07 | 한국항공우주연구원 | 유량조절밸브 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4200578A (en) * | 1978-12-18 | 1980-04-29 | Bristol-Myers Company | Thiazole derivatives |
US4375547A (en) * | 1980-10-02 | 1983-03-01 | Eli Lilly And Company | N-Methyl-N'-2-([(2-dimethylaminomethyl)-4-thiazolyl]methylthio)ethyl 2-nitro-1,1-ethenediamine |
US4474794A (en) * | 1982-03-19 | 1984-10-02 | Eli Lilly And Company | N-Thiazolylmethylthioalkyl-N1 -alkenyl (or alkynyl)guanidines and related compounds |
ZA84869B (en) * | 1983-02-07 | 1985-09-25 | Lilly Co Eli | The synthesis of nizatidine |
-
1986
- 1986-12-15 IL IL80961A patent/IL80961A0/xx unknown
- 1986-12-15 EP EP86309739A patent/EP0230127A1/en not_active Ceased
- 1986-12-15 CA CA000525300A patent/CA1277325C/en not_active Expired - Lifetime
- 1986-12-15 ZA ZA869438A patent/ZA869438B/xx unknown
- 1986-12-16 FI FI865117A patent/FI865117A/fi not_active Application Discontinuation
- 1986-12-16 NZ NZ218647A patent/NZ218647A/xx unknown
- 1986-12-16 AU AU66603/86A patent/AU582932B2/en not_active Ceased
- 1986-12-16 PT PT83938A patent/PT83938B/pt not_active IP Right Cessation
- 1986-12-16 DK DK605386A patent/DK605386A/da not_active Application Discontinuation
- 1986-12-17 KR KR1019860010822A patent/KR890002427B1/ko not_active IP Right Cessation
- 1986-12-17 HU HU865269A patent/HU196385B/hu not_active IP Right Cessation
- 1986-12-17 CN CN198686108424A patent/CN86108424A/zh active Pending
- 1986-12-17 PH PH34608A patent/PH21924A/en unknown
- 1986-12-17 JP JP61302768A patent/JPS62155268A/ja active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101462969B (zh) * | 2009-01-09 | 2012-04-25 | 福建深纳生物工程有限公司 | 1-甲氨基-1-甲氧基-2-硝基乙烯的合成方法 |
CN102329282A (zh) * | 2011-07-15 | 2012-01-25 | 海南灵康制药有限公司 | 一种尼扎替丁化合物及其制法 |
Also Published As
Publication number | Publication date |
---|---|
ZA869438B (en) | 1988-07-27 |
HU196385B (en) | 1988-11-28 |
CA1277325C (en) | 1990-12-04 |
NZ218647A (en) | 1989-02-24 |
PT83938A (en) | 1987-01-01 |
KR870006024A (ko) | 1987-07-08 |
AU6660386A (en) | 1987-06-25 |
EP0230127A1 (en) | 1987-07-29 |
IL80961A0 (en) | 1987-03-31 |
DK605386A (da) | 1987-06-19 |
FI865117A (fi) | 1987-06-19 |
AU582932B2 (en) | 1989-04-13 |
PT83938B (pt) | 1989-06-30 |
DK605386D0 (da) | 1986-12-16 |
FI865117A0 (fi) | 1986-12-16 |
KR890002427B1 (ko) | 1989-07-03 |
JPS62155268A (ja) | 1987-07-10 |
PH21924A (en) | 1988-04-08 |
HUT45033A (en) | 1988-05-30 |
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