CN86103227A - 制备2-吡咯烷酮衍生物的方法 - Google Patents
制备2-吡咯烷酮衍生物的方法 Download PDFInfo
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- CN86103227A CN86103227A CN86103227.6A CN86103227A CN86103227A CN 86103227 A CN86103227 A CN 86103227A CN 86103227 A CN86103227 A CN 86103227A CN 86103227 A CN86103227 A CN 86103227A
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- pyrrolidone
- butyl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/38—2-Pyrrolones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/50—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
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- Pain & Pain Management (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
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Abstract
一类新型的2-吡咯烷酮衍生物,其中包括3-(3,5-二叔丁基-4-羟基苄叉)-2-吡咯烷酮,以及其N位取代物。该取代基包括烷基,烷氧基,炔基,苯基烷基,羟基烷基,及氨基烷基,该物质具有有效的消炎、镇痛、解热性能,并且有可靠的安全性。
Description
上面用于定义R,R1,R2时所用的“低级烷基”包括1~6个碳原子的直链或者支链烷基,例如甲基,乙基,正丙基,异丙基,正丁基,异丁基,1-甲基丙基,叔丁基,正戊基,1-乙基丙基,异戊基和正己基。
上述的低级烷氧基和低级炔基是从上述低级烷基衍生物生出来的。
本发明的化合物(I),如果需要可以被转变成相应的钠盐和钾盐。当R是式
的基团时,它可以进一步与无机酸或有机酸生成药用盐,这些无机酸例如盐酸,氢溴酸,氢碘酸;有机酸例如顺丁烯二酸,反丁烯二酸,琥珀酸,丙二酸,醋酸,柠檬酸或甲磺酸。
(R按上面定义)
即3,5-二叔丁基-4-羟基苯甲醛(II)与维狄希试剂(III)反应,以通常的方法获得目的产物(I)。在这个反应中可以应用不参加反应的任何溶剂,较好的溶剂例如二甲基甲酰胺(DMF),二甲基亚砜,(DMSO),乙醇,乙酸乙酯和苯。该反应在大约0~150℃下进行,最好在30~100℃下进行。
即3,5-二叔丁基-4-羟基苯甲醛(II)与碱约存在下与维狄希试剂(III)进行维狄希反应,给出化合物(I),碱可用有机碱如三乙胺和吡啶和无机碱如碳酸钠和碳酸钾。反应中可应用不参加反应的任何溶剂,较好的溶剂是二甲基甲酰胺(DMF),二甲基亚砜(DMSO),乙醇,乙酸乙酯和苯,该反应可在大约0~150℃下进行,最好在30℃~100℃下进行。
Y是囟素或是有机磺酰氧基,X是囟素,R是低级烷氧基。
在上述的方法中,化合物(VII)是在碱的作用下通过环合反应而得到的,碱可用氢化钠,碳酸钾和醇钠,该反应在溶剂如乙醇和苯中进行,反应温度为-50℃~+100℃,化合物(IV)是通过与三苯基膦反应制得,在这个步骤中亚磷酸三乙酯也可以用来制备维狄希试剂。
(R同上,Y代表囟素原子或有机磺酰氧基例如甲磺酰氧基或甲苯磺酰氧基)
即化合物(V)作为一种烷基化剂与本发明的化合物(VI)在碱的存在下反应生成目的化合物(I),这些碱例如氢化钠,氨化钠或叔丁氧化钾。在反应中可使用不参加反应的任何溶剂,较好的溶剂如二甲基酰胺(DMF),二甲亚砜(DMSO),苯,四氢呋喃(THF)和叔丁醇。反应在大约-20℃~100℃下进行,更好的是0~30℃下进行。
为了进一步说明本发明,下面给出了本发明化合物的典型离子,但并不限制本发明的范围。
N-甲基-3-(3,5-二叔丁基-4-羟基苄叉)-2-吡咯烷酮,
N-乙基-3-(3,5-二叔丁基-4-羟基苄叉)-2-吡咯烷酮,
3-(3,5-二叔丁基-4-羟基苄叉)-2-吡咯烷酮,
N-甲氧基-3-(3,5-二叔丁基-4-羟基苄叉)-2-吡咯烷酮,
N-(2-二甲氨基乙基)-3-(3,5-二叔丁基-4-羟基苄叉)-2-吡咯烷酮,
N-苄基-3-(3,5-二叔丁基-4-羟基苄叉)-2-吡咯烷酮,
N-炔丙基-3-(3,5-二叔丁基-4-羟基苄叉)-2-吡咯烷酮,
N-(2-羟乙基)-3-(3,5-二叔丁基-4-羟基苄叉)-2-吡咯烷酮,
N-正丁基-3-(3,5-二叔丁基-4-羟基苄叉)-2-吡咯烷酮,
N-(2-二乙氨基乙基)-3-(3,5-二叔丁基-4-羟基苄叉)-2-吡咯烷酮,
N-乙氧基-3-(3,5-二叔丁基-4-羟基苄叉)-2-吡咯烷酮,
N-己基-3-(3,5-二叔丁基-4-羟基苄叉)-2-吡咯烷酮,
N-正丁氧基-3-(3,5-二叔丁基-4-羟基苄叉)-2-吡咯烷酮。
本发明提供的每一种2-吡咯烷酮衍生物都是一种新型的化合物,这些化合物在任何文献上从未报道过,它们都有低毒性及显著的消炎作用。
消炎剂可以粗略地分为以下四类:甾族激素,非甾族剂,消炎酶和避免抑制剂。在这四类中非甾族剂是最重要的,近来引起了全世界关注并试图发展非甾族消炎剂。现在常用的非甾族剂包括吲哚乙酸衍生物。例如吲哚甲阿辛;苯乙酸衍生物,例如对异丁苯基醋酸和布洛芬;水杨酸衍生物,例如阿司匹林,水杨酸和水杨醯水杨酸;邻氨基苯甲酸衍生物,例如甲灭酸和氟灭酸;吡咯烷二酮衍生物,例如苯丁唑啉(保泰松),羟基保泰松和丁酮唑酮;和碱性药物例如消炎灵,嘧吡啶和替诺端丁。然而这些非甾族剂从临床观点看有一个严重的缺点,有使胃和肾功能紊乱的副作用,因此世界上仍然试图发展较好的非甾族消炎剂,在这种情况下我们长时间研究了新的消炎剂,因而发现了通式(I)的2-吡咯烷酮衍生物,这化合物有与平常用的非甾族消炎剂不同的化学结构,并具有极好的消炎作用。
本发明的每一种化合物作为很安全的消炎,止痛的和解热的药物是有价值的。并且具有下列药理特征。
(1)比常用消炎剂如吲哚甲阿辛,布洛芬,炎痛喜康具有更宽的安全范围。
(2)另外,它对脂氧合酶具有抑制作用和抗氧化作用,这些作用在常用的非甾族抗类剂中从未观察到。
本发明化合物可以应用常用消炎剂可应用的疾病,这些疾病是:关节炎,风湿病,神精炎,关节痛,神经痛,感冒综合症,急性慢性支气管炎,外伤和手术后的炎症,以及发热,牙痛和头痛。
下面叙述的药理实验将详细阐述本发明化合物的有用性。
药理实验1:降低炎症部位局部表面温度的作用。
(1)实验方法:
将0.5ml升乳杆菌的液体石腊(10mg/ml)悬浮液,注入年龄为六周的雄性大白鼠右后脚底部引起炎症。3至7天后,炎症脚表面温度比正常脚一直高8~10℃,将下文所述的实验化合物和对照化合物(即吲哚甲阿辛,炎痛喜康)分别悬浮于5%的阿拉伯树胶水溶液中,按5ml/kg体重的剂量,口服给药。根据H.Shirota等的方法(cf.J.rharmacal method 12,35~43(1984)),在2,4,6小时后,测定炎症部位局部表面温度。通过二只动物的平均数据来计算比未给药之前至少降低表面温度2℃所用的剂量,并测定每个实验化合物的消炎率。
(2)实验化合物
A.N-甲基-3-(3,5-二叔丁基-4-羟苄叉)-2-比咯烷酮。
B.N-甲氧基-3-(3,5-二叔丁基-4-羟苄叉)-2-吡咯烷酮。
C.3-(3,5-二叔丁基-4-羟苄叉)-2-比咯烷酮。
(3)实验结果如表1所示:
表1
化合物 炎症部位局部温度至少降低2℃所需量(mg/kg)
A 1
B 0.3
C 0.3
吲哚甲阿辛 0.3
炎痛喜康 0.3
药理实验2:抑制脚底角叉菜胶水肿作用。
(1)实验方法:
年龄为五周雄性大白鼠每5只为一组,实验化合物悬浮于5%的阿拉伯胶水溶液中,按0.5mg/100g体重剂量给药一小时后,用1%角叉菜胶溶液注射到动物右后脚底部,使之产生炎症。注射三小时后,通过测量脚底的体积来计算注入角叉菜胶的脚底的体积增加。得到数据与对照组进行比较,从而测定出化合物抑制率。实验用的化合物与实验1相同。
(2)实验结果如表2所示
表2
化合物 剂量(mg/kg) 抑制率
A 10 36.1
B 10 36.4
C 10 38.5
吲哚甲阿辛 10 37.7
药理实验3:引起胃溃疡作用。
(1)实验方法:
年龄为七周的雄性大白鼠饥饿24小时,然后用悬浮于5%的阿拉伯胶水溶液中的实验化合物使其口服。六小时后,观察胃粘膜出血点,计算化合物引起50%溃疡度的剂量。
(2)结果如表3所示
表3
化合物 UD50*(mg/kg)
B 473.0
C 75.8
吲哚甲阿辛 7.8
炎痛喜乐 23.1
U50*:引起50%溃疡面的剂量。
上述三个药理结果清楚表明:本发明的每个化合物都具有强的抗炎作用,同时很少有引起胃功能紊乱的副作用,而常用抗炎剂却常常存在着这样的副作用,因此,本发明的化合物作为优良的抗炎剂,将会连续使用很长的时间。
急性毒性实验
使用大白鼠、小白鼠进行急性研究,测定化合物B的LD50值,结果列入表4。
表4 LD50和可信范围。
大白鼠 小白鼠给药途径
雄 雌 雄 雌口服 354.2 161.2* 4000~2000 6873腹腔 86.7* 46.9* 1069 805.4
523~2270 443.9~1549.3皮下 806.4* 291 >4000 >4000
124~476
注*:数值是按照Behrems-krber方法进行计算的。饥饿17~24小时后,口服给药。
可以看出,发明有很高的价值。
本发明的化合物用于抗炎药物,可用口服给药和其它途径给药(肌注,皮下,静脉或栓剂)。根据病人个体差异,年龄,症状使用不同剂量,对成年病人来说一般大约在1~500mg/日,较好为5~300mg/日,最好是10~100mg/日。
根据通常的技术,发明化合物可制成片剂,颗粒,粉末,胶囊,注射液,栓剂,外用制剂如油膏。
口服固体药物的制备,根据需要,在活性成分中加入赋形剂,粘合剂,崩解剂,润滑剂,着色剂和去味剂(调味剂)然后混合物均匀,做成片剂,包衣片,颗粒,粉末或胶囊。
可用的赋形剂例如乳糖,玉米淀粉,白糖,葡萄糖,山梨醇,结晶纤维素及二氧化硅。
用作粘合剂的例如聚乙烯基醇,聚乙烯基醚,乙基纤维素,甲基纤维素,阿拉伯胶,黄蓍胶,明胶,紫胶片,羟丙基纤维素,羟甲基丙基纤维素,羟丙基淀粉,聚乙烯基吡咯烷酮,白糖及山梨醇。
崩解剂如淀粉,琼脂,明胶粉,结晶纤维素,碳酸钙,碳酸氢钠,柠檬酸钙,糊精及果胶。
润滑剂可以使用例如硬脂酸镁,滑石粉,聚乙二醇,二氧化硅及硬化菜籽油。着色剂是可以加到药中的物质。去味剂可用可可粉,薄荷醇,芳香粉,薄荷油,冰片及肉桂粉。药片,颗粒可用糖,明胶进行适当包衣。
在口服液体药物的制备中,若需要可向活性成分中加入去味剂,缓冲液,稳定剂等,然后混合均匀,进行处理则成为例如糖浆之类的药剂。
在注射液的制备中,若需要的话,可向活性成分中加pH调节剂,缓冲剂,混悬剂,增溶剂,等渗剂和防腐剂,混合均匀,然后制成皮下,肌肉注射液或静脉注射液。
悬浮剂可以利用的有例如甲基纤维素,多乙氧基醚,羟乙基纤维素,阿拉伯胶,黄蓍胶粉,羧基甲基纤维素钠,聚氧化乙烯山梨糖醇酐单月桂酸酯。
增溶剂可使用的有例如聚氧化乙烯硬化蓖麻油,多乙氧基醚,烟酰胺,聚氧化山梨糖醇酐单月桂酸酯,聚乙二醇(Macrogol),蓖麻油及脂肪酸乙酯。
稳定剂可用例如亚硫酸钠,焦亚硫酸钠和醚。防腐剂可用对羟基苯甲酸甲酯,对羟基苯甲酸乙酯,己二烯〔2,4〕酸,酚,甲酚,氯甲酚。
本发明将通过下述实例进行进一步阐明,但这并不限制本发明的范围。
例1:N-甲基-3-(3,5-二叔丁基-4-羟苄叉)-2-吡咯烷酮。
取1.2g的3,5-二叔丁基-4-羟苯甲醛,2.5g(N-甲基-2-吡咯烷酮基-3)溴化三苯基鏻和1.0ml三乙胺,在乙醇中加热回流2小时。然后蒸出乙醇,残留物溶于氯仿,用水洗涤,再用饱和盐水洗,用无水硫酸镁干燥。蒸出氯仿,剩余物用硅胶进行柱层析,苯-丙酮洗脱,用乙酸乙酯己烷混合液进行重结晶,获得1g题目产物。
m.p:185℃
NMR(δ,CDCl3):1.46(18H,S),
3.50(2H,t,J=6Hz),
3.01(3H,S),5.43(1H,S),
7.30(1H,t,J=3Hz),
和7.36(2H,S)
例2~4:根据例1方法制备下列化合物
例2:N-乙基-3-(3,5-二叔丁基-4-羟苄叉)-2-吡咯烷酮。
m.p:186.5℃
NMR(δ,CDCl3):1.45(18H,S),
2.9-3.1(2H,m),3.3-3.6(4H,m),
5.40(1H,S),
7.26(1H,t,J=3Hz)
和7.32(2H,S)
例3:N-甲氧基-3-(3.5-二叔丁基-4-在羟苄叉)-2-吡咯烷酮。
取3,5-二叔丁基-4-羟基甲醛27.6g,(N-甲氧基-2-吡咯烷酮基-3)溴化三苯基鏻和33.0ml三乙胺在乙醇中50℃下加热四小时,然后蒸出乙醇,残留物溶于氯仿,用水洗涤,再用饱和盐水洗,用无水硫酸镁干燥。蒸出氯仿,剩余物用硅胶进行柱层析用苯/乙酮洗脱,用乙酸乙酯和己烷混合液进行重结晶,给出26.5g题目产物。
m.p:169℃
NMR(δ,CDCl3):1.46(18H,S),
3.05(2H,dt,J=3Hz,7Hz),
3.66(2H,t,J=7Hz,
3.88(3H,S),5.44(1H,S),
7.30(2H,S)和
7.35(1H,t,J=3Hz)
例4:3-(3,5-二叔丁基-4-羟基苄叉)-2-吡咯烷酮:
m.p:210℃(分解)
NMR(δ,CDCl3):1.46(18H,S),
3.13(2H,宽,dt,J=3Hz,6Hz),
3.52(2H,t,J=6Hz),
5.45(1H,S),6.98(1H,宽),
7.32(1H,t,J=2Hz)
和7.37(2H,S)
例5:N-(2-二甲氨基乙基)-3-(3,5-二叔丁基-4-羟苄叉)-2-吡咯烷酮。
取3-(3,5-二叔丁基-4-羟基苄叉)-2-吡咯烷酮500mg溶于5ml二甲基甲酰胺中,在冰冷却下相继加入0.2g氢化钠和0.2g二甲氨基乙基氯。反应混合物于室温放置1小时。反应物用乙酸乙酯提取,水洗涤,在用饱和盐水洗,无水硫酸镁干燥,回收乙酸乙酯后,残留物用硅胶进行柱层析,用苯/丙酮作洗脱剂,用乙酸乙酯/己烷进行重结晶,得到300mg题目产物。
m.p:150℃
NMR(δ,CDCl3):1.46(18H,S),2.26(6H,S),
2.50(2H,t,J=7Hz),
2.90-3.1(2H,t,m),
3.54(4H,t,J=7Hz),
5.37(1H,S),
7.26(1H,t,J=3Hz)和
7.31(2H,S)
例6~8:下面化合物是按照例5方法制备的。
例6:N-苄基-3-(3,5-二叔丁基-4-羟苄叉)-2-吡咯烷酮。
m.p:160℃
NMR(δ,CDCl3):1.46(18H,S),2.9-3.1(2H,m),
3.38(2H,t,J=6Hz),
4.62(2H,S),5.41(1H,S)和
7.3-7.5(8H,7.31,7.36)
例7:N-炔丙基-3-(3,5-二叔丁基-4-羟苄叉)-2-吡咯烷酮。
m.p:212℃
NMR(δ,CDCl3):1.46(18H,S),
2.23(1H,t,J=3Hz),
2.9-3.2(2H,m),
3.59(2H,t,J=7Hz),
4.26(2H,d,J=3Hz),
5.41(1H,S)和7.2-7.4(3H,m)
例8:N-(2-羟乙基)-3-(3,5-二叔丁基-4-羟苄叉)-2-吡咯烷酮。
取N-2-(2-四氢吡喃氧基)乙基-3-(3,5-二叔丁基-4-羟苄叉)-2-吡咯烷酮300mg,按照例5的方法,用盐酸甲醇溶液进行水解,得到150mg的题目产品。
m.p:191℃
NMR(δ,CDCl3):1.45(18H,S),2.9-3.2(2H,m),
3.38(1H,t),3.5-3.7(4H,m)
3.84(2H,q,J=6Hz),
5.41(1H,S)和7.2-7.4(3H,m)
2,4-二溴丁酰氯(2)
取γ-丁内酯500g与10ml三溴化磷的混合液加热至100℃,然后在搅拌,保持温度在110~115℃下慢慢滴入250ml溴(不要暴露在空气中),大约需6小时。加毕后,反应物在相同温度继续搅拌1小时。冷却到90℃,加入0.5ml二甲氨基甲酰胺(DMF)。在油浴90℃下,滴加500ml亚硫酰氯,约2小时加毕。在相同温度下继续搅3小时。然后将产物液体60~150℃/1mmHg下进行减压蒸馏,得到1.0kg产品(2)。
N-甲氧基-2,4-二溴丁酰胺(3)
取520g乙酰胺,1升水,5升氯仿的混合物,用冰盐浴冷至-5℃。然后加入1450g2,4-二溴丁酰氯和1升氯仿的混合液,再滴加500g氢氧化钠溶于1升水中的溶液,反应温度保持不超过10℃。加毕后,反应物在相同温度进行搅拌1小时。分出氯仿相,并先用0.5N盐酸洗涤,再用饱和碳酸氢钠溶液洗,最后用饱和盐水洗,用硫酸镁干燥,蒸出氯仿,得1400g油状物,供下步使用。
N-甲氧基-3-溴-2-吡咯烷酮(4)
粗品N-甲氧基-2,4-二溴丁酰胺1400g溶于5升苯中,反应混合物在用冰水冷却的同时,在15~20℃下慢慢地加入氢化钠125g。反应完毕后,剩余氢化钠用冰分解,反应物用饱和盐水洗涤,用硫酸镁干燥,蒸出苯后,产品用硅柱层纯化,苯和丙酮混合液作洗脱剂,得到500g产品(4)。
NMR(δ,CDCl):
3-CH4.38(1H,dd.J=3.6Hz,7.2Hz)
4-CH2 2.2-2.9(2H,m)
5-CH2 3.4-3.9(2H,m)
1-CH30 3.82(3H,S)
溴化(N-甲氧基-2-吡咯烷酮基-3)三苯基(5)。
取75g N-甲氧基-3-溴-2-吡咯烷酮,105g三苯基膦及700ml四氢呋喃的混合物加热回流24小时,冷却后,析出沉淀,滤集产品,用四氢呋喃洗,干燥,得到54g化合物(5)。
化合物(5)以例3所述方法进行反应,得到本发明的2-吡咯烷酮衍生物。
Claims (12)
4.权利要求1或2或3所述的方法,其中R为氢原子。
5.权利要求1或2或3所述的方法,其中R为低级烷基。
6.权利要求1或2或3所述方法,其中R为低级烷氧基。
7.权利要求1或2或3所述的方法,其中R为低级炔基。
8.权利要求1或2或3所述的方法。其中R为甲氧基。
9.权利要求1或2或3所述的方法,其中R为甲基。
11.权利要求10所述的方法,其中R为低级烷氧基。
12.权利要求10所述的方法,其中R为甲氧基,X为溴。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP60096799A JPH066571B2 (ja) | 1985-05-09 | 1985-05-09 | 2−ピロリドン誘導体 |
JP96799/85 | 1985-05-09 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN86103227A true CN86103227A (zh) | 1987-01-21 |
CN1014058B CN1014058B (zh) | 1991-09-25 |
Family
ID=14174668
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN86103227A Expired CN1014058B (zh) | 1985-05-09 | 1986-05-09 | 制备2-吡咯烷酮衍生物的方法 |
Country Status (19)
Country | Link |
---|---|
US (1) | US4833160A (zh) |
EP (1) | EP0204964B1 (zh) |
JP (1) | JPH066571B2 (zh) |
KR (1) | KR910004789B1 (zh) |
CN (1) | CN1014058B (zh) |
AT (1) | ATE66673T1 (zh) |
AU (1) | AU581078B2 (zh) |
CA (1) | CA1264762A (zh) |
DE (1) | DE3681076D1 (zh) |
DK (1) | DK213286A (zh) |
ES (1) | ES8800148A1 (zh) |
FI (1) | FI84172C (zh) |
HU (2) | HU199117B (zh) |
MX (1) | MX162717A (zh) |
NO (1) | NO861820L (zh) |
NZ (1) | NZ216092A (zh) |
PH (2) | PH23189A (zh) |
PT (1) | PT82540B (zh) |
ZA (1) | ZA863352B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103342672A (zh) * | 2013-07-02 | 2013-10-09 | 扬州大学 | 取代吡咯烷-2-酮的新合成方法 |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5356917A (en) * | 1985-08-09 | 1994-10-18 | Eli Lilly And Company | Aryl-substituted rhodanine derivatives |
US5691367A (en) * | 1985-08-09 | 1997-11-25 | Eli Lilly And Company | Aryl-substituted rhodanine derivatives |
US5202341A (en) * | 1987-03-11 | 1993-04-13 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Hydroxystyrene compounds having tyrosine kinase inhibiting activity |
JP2539504B2 (ja) * | 1987-03-11 | 1996-10-02 | 鐘淵化学工業株式会社 | ヒドロキシスチレン誘導体 |
US5089516A (en) * | 1987-03-11 | 1992-02-18 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | 1-phenyl-3,5-pyrazolidinedione hydroxystyrene compounds which have tyrosine kinase inhibiting activity |
US5216002A (en) * | 1989-12-21 | 1993-06-01 | Eli Lilly And Company | Method of treating inflammatory bowel disease |
US5143928A (en) * | 1990-03-27 | 1992-09-01 | Warner-Lambert Company | 3,5-di-tertiarybutyl-4-hydroxyphenylmethylene derivatives of 2-substituted thiazolidinones, oxazolidinones, and imidazolidinones as antiinflammatory agents |
CA2078790C (en) * | 1991-01-21 | 1998-10-06 | Susumu Kamata | 3-benzylidene-1-carbamoyl-2-pyrrolidone analogues |
WO1992017447A1 (en) * | 1991-04-05 | 1992-10-15 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Phenoxybenzene derivative |
DK0595546T3 (da) * | 1992-10-28 | 1996-04-15 | Shionogi & Co | Benzylidenderivater |
US5358964A (en) * | 1993-07-26 | 1994-10-25 | Warner-Lambert Company | Benzylidene-lactone and their thiocarbonyl analogs as inhibitors of proteoglycan degradation |
GB9704499D0 (en) | 1997-03-05 | 1997-04-23 | Glaxo Wellcome Spa | Method of manufacture |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
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US3714153A (en) * | 1970-06-22 | 1973-01-30 | Roussel Uclaf | Novel cyclopropanecarboxylic acids |
DE2329308A1 (de) * | 1972-03-03 | 1975-01-02 | Gruenenthal Chemie | Neue lactame |
AU518986B2 (en) * | 1977-10-11 | 1981-10-29 | Takeda Chemical Industries Ltd. | Lactams |
US4138495A (en) * | 1978-05-19 | 1979-02-06 | Stauffer Chemical Company | N-Substituted pyrrolidones and their use as miticides |
JPS5879944A (ja) * | 1981-11-09 | 1983-05-13 | Kanegafuchi Chem Ind Co Ltd | 3,5−ジ・タ−シヤリ−・ブチルスチレン誘導体及び抗炎症、鎮痛、解熱剤並びに血小板凝集阻害剤 |
US4431656A (en) * | 1981-02-05 | 1984-02-14 | Kanegafuchi Chemical Industry Company Limited | 3,5-di-Tert-butylstyrene derivatives, salts thereof, and pharmaceutical compositions containing the same as an active ingredient |
US4440784A (en) * | 1981-02-05 | 1984-04-03 | Kanegafuchi Chemical Industry Company, Ltd. | Anti-inflammatory, analgesic, and antipyretic pharmaceutical composition |
JPS57130950A (en) * | 1981-02-05 | 1982-08-13 | Kanegafuchi Chem Ind Co Ltd | 3,5-di-tert-butyl-4-hydroxystyrene derivative and anti- inflammatory, analgesic, antipyretic agent and inhibitor for blood platelet aggregation |
DE3326724A1 (de) * | 1983-07-25 | 1985-02-07 | Boehringer Ingelheim KG, 6507 Ingelheim | In 1-stellung substituierte 4-hydroxymethyl-pyrrolidinone, verfahren zu ihrer herstellung, pharmazeutische zusammensetzungen und zwischenprodukte |
JPS6112660A (ja) * | 1984-06-27 | 1986-01-21 | Kanegafuchi Chem Ind Co Ltd | 新規2−ピロリドン誘導体及び抗炎症剤 |
JPH0623194B2 (ja) * | 1985-03-23 | 1994-03-30 | 鐘淵化学工業株式会社 | 新規ラクタム誘導体及び抗炎症剤 |
JPS6412660A (en) * | 1987-07-07 | 1989-01-17 | Canon Kk | Original reader |
JP3611676B2 (ja) * | 1996-06-24 | 2005-01-19 | アサマ化成株式会社 | パン生地の改良剤およびパンの製造方法 |
-
1985
- 1985-05-09 JP JP60096799A patent/JPH066571B2/ja not_active Expired - Lifetime
-
1986
- 1986-04-22 FI FI861698A patent/FI84172C/fi not_active IP Right Cessation
- 1986-04-23 US US06/856,068 patent/US4833160A/en not_active Expired - Fee Related
- 1986-04-28 AU AU56766/86A patent/AU581078B2/en not_active Ceased
- 1986-04-30 PH PH33721A patent/PH23189A/en unknown
- 1986-05-05 ZA ZA863352A patent/ZA863352B/xx unknown
- 1986-05-07 DK DK213286A patent/DK213286A/da not_active Application Discontinuation
- 1986-05-07 AT AT86106249T patent/ATE66673T1/de active
- 1986-05-07 NO NO861820A patent/NO861820L/no unknown
- 1986-05-07 EP EP86106249A patent/EP0204964B1/en not_active Expired - Lifetime
- 1986-05-07 HU HU872041D patent/HU199117B/hu not_active IP Right Cessation
- 1986-05-07 DE DE8686106249T patent/DE3681076D1/de not_active Expired - Fee Related
- 1986-05-08 ES ES554775A patent/ES8800148A1/es not_active Expired
- 1986-05-08 CA CA000508748A patent/CA1264762A/en not_active Expired - Fee Related
- 1986-05-08 MX MX2417A patent/MX162717A/es unknown
- 1986-05-08 HU HU861911A patent/HU196749B/hu not_active IP Right Cessation
- 1986-05-08 PT PT82540A patent/PT82540B/pt not_active IP Right Cessation
- 1986-05-08 NZ NZ216092A patent/NZ216092A/xx unknown
- 1986-05-09 CN CN86103227A patent/CN1014058B/zh not_active Expired
- 1986-05-09 KR KR1019860003628A patent/KR910004789B1/ko not_active IP Right Cessation
-
1987
- 1987-05-27 PH PH35306A patent/PH23225A/en unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103342672A (zh) * | 2013-07-02 | 2013-10-09 | 扬州大学 | 取代吡咯烷-2-酮的新合成方法 |
Also Published As
Publication number | Publication date |
---|---|
DK213286D0 (da) | 1986-05-07 |
PH23189A (en) | 1989-05-29 |
EP0204964A1 (en) | 1986-12-17 |
HUT43040A (en) | 1987-09-28 |
DK213286A (da) | 1986-11-10 |
FI861698A (fi) | 1986-11-10 |
PT82540B (pt) | 1988-08-17 |
JPS61257967A (ja) | 1986-11-15 |
NO861820L (no) | 1986-11-10 |
PH23225A (en) | 1989-06-06 |
CA1264762A (en) | 1990-01-23 |
FI861698A0 (fi) | 1986-04-22 |
NZ216092A (en) | 1988-08-30 |
HUT45493A (en) | 1988-07-28 |
MX162717A (es) | 1991-02-18 |
KR860008973A (ko) | 1986-12-19 |
PT82540A (en) | 1986-06-01 |
EP0204964B1 (en) | 1991-08-28 |
US4833160A (en) | 1989-05-23 |
FI84172B (fi) | 1991-07-15 |
KR910004789B1 (ko) | 1991-07-13 |
AU581078B2 (en) | 1989-02-09 |
DE3681076D1 (de) | 1991-10-02 |
ES8800148A1 (es) | 1987-11-01 |
ZA863352B (en) | 1986-12-30 |
ATE66673T1 (de) | 1991-09-15 |
CN1014058B (zh) | 1991-09-25 |
HU196749B (en) | 1989-01-30 |
HU199117B (en) | 1990-01-29 |
FI84172C (fi) | 1991-10-25 |
JPH066571B2 (ja) | 1994-01-26 |
ES554775A0 (es) | 1987-11-01 |
AU5676686A (en) | 1986-11-13 |
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