CN1029230C - 新的异羟肟酸和n-羟基脲衍生物的制备方法 - Google Patents
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Abstract
本发明涉及制备下式的新的羟肟酸和N-羟基脲衍生物的方法,所述化合物能抑制脂氧合酶,可用于治疗哺乳动物的炎症、变态反应和心血管病。
式中R1、R4、A、B、Ar、m、n、p和q的定义同说明书。
Description
本发明涉及新的异羟肟酸及N-羟基脲衍生物。本发明的化合物能抑制脂氧合酶并用于治疗或减轻哺乳动物的炎症、变态反应及心血管疾病。本发明还涉及含有这些化合物的药用组合物以及使用这些化合物治疗哺乳动物的炎症,变态反应和心血管疾病。本发明还涉及制备上述化合物的方法。
已知花生四烯酸是几组内源性代谢产物,包括前列环素的前列腺素、凝血噁烷和白三烯(leukotrienes)的生物前体。花生四烯酸代谢的第一步是通过磷脂酶的作用,从膜磷脂中释放出花生四烯酸和有关的不饱和脂肪酸,游离的脂肪酸,然后由环氧酶代谢生成前列腺素和凝血噁烷,或者由脂氧合酶代谢产生可进一步转化成白三烯的氢过氧化脂肪酸。白三烯涉及包括风湿性关节炎、痛风、气喘、局部缺血再灌注损伤、牛皮癣和肠炎等炎症的病理生理学。人们期待任何抑制脂氧合酶的药物能对急性和慢性两种炎症提供显著的新疗效。
近来发表了几篇有关脂氧合酶抑制剂的综述(参看H.Masamune et al.,Ann、Rep、Med.Chem,24,71-80(1989)和B.J.Fitzsimmons et al.,Leukotrienes and Lipoxygenases,427-502(1989))。
与本发明化合物属于同总类的化合物公开在EP 279263 A2,EP 196184 A2,JP 63502179和U.S.Patent,No.4,822,809中。
本发明提供了下式表示的新异羟肟酸及N-羟基脲衍生物:
式中n是0或1;m是0-3;P是1-6;q是1或2;R1是氢,C1-C4烷基,C2-C4链烯基、烷硫基烷基,烷氧基烷基或NR2R3,式中R2和R3各自独立为氢,C1-C4烷基、羟基、芳基、或者被一个或多个下述基团取代的芳基,所述基团选自卤素、硝基、氰基、C1-C12烷基、C1-C12烷氧基,C1-C12卤代烷基,C1-C12羟基取代的烷基,C1-C12烷氧基羰基,氨基羰基,C1-C12烷氧基羰基、二C1-C12烷氨基羰基和C1-C12烷基磺酰基,条件是R2和R3不都是羟基;R4是氢,药学上可接受的阳离子,芳酰基,或C1-C6烷酰基;A是C1-C6亚烷基或C2-C6亚链烯基;每一个B独自为氢、卤素、硝基、氰基、-SH、羟基、C1-C6烷基,C1-C6卤代烷基,C2-C6链烯基,C1-C6烷氧基,C1-C6硫代烷基,C1-C12氨基羰基,C1-C6烷氨基羰基,二C1-C6烷氨基羰基或C2-C12烷氧基烷基;每个Ar独自地为苯基、萘基、吡啶基、喹啉基、噻吩基、呋喃基或苯氧基苯基,或者任何具有一个或多个取代基的上述基团,所述取代基选自羟基、卤素、硝基、氰基,-SH,C1-C12烷基,C1-C12烷氧基,C1-C12卤代烷基、C1-C12羟基取代的烷基、C1-C12烷氨基,二C1-C12烷基氨基,C1-C12烷氧基羰基,氨基羰C1-C12烷氨基羰基,二C1-C12烷氨基羰基和C1-C12烷基磺酰基。基团Ar、B和连接基团A可以连接在环上任何合适的位置。A和B可结合在一起,与其相连的碳原子一起形成环。化学式中的虚线表示可以是双键。
本发明还涉及药用组合物,该组合物含有药物上可接受的载体或稀释剂以及本发明的化合物或其药学上可接受的盐。本发明还涉及治疗哺乳动物炎症、变态反应和心血管疾病的方法,该方法包括施用上述化合物或组合物。
本文中使用了如下定义:
“卤代”和“卤素”,是指由元素氟、氯、溴和碘衍生的基团。
“烷基”是指直链或支链饱和烃基,例如甲基、乙基、正丙基和异丙基。
“链烯基”是指直链或支链不饱和(双键)烃基,例如乙烯基,1-或2-丙烯基,2-甲基-1-丙烯基和1-或2-丁烯基。
“亚烷基”是指直链和支链饱和烃基,例如:
-CH2-,-CH(CH3)-,-C(CH3)2-,-CH2CH2-,-CH2CH(CH3)-,
-CH(C2H5)-,-C(CH3)2C(CH3)2-and-CH2CH2CH2-
“亚链烯基”是指直链或支链不饱和(双键)烃基,例如:
-CH=CH-,-CH=CHCH2,
-CH=CHCH(CH3)-,-C(CH3)=CHCH2-and-CH2CH=CHCH2-.
“烷氧基”是指-OR5,其中R5是烷基,例如甲氧基、乙氧基、丙氧基,异丙氧基和丁氧基。
“烷氧烷基”是指-R6OR7,其中R6和R7独自为烷基,例如甲氧甲基,甲氧乙基,乙氧甲基和乙氧乙基。
“硫代烷基”是指-SR8,其中R8是烷基,例如甲硫基,乙硫基,丙硫基和丁硫基。
“烷氧基”是指-NHR9,其中R9是烷基,例如甲氨基,乙氨基,丙氨基和丁氨基。
“二烷氨基”是指-NR9R10,其中R9和R10是烷基,例如二甲氨基,甲基乙氨基和二乙氨基。
“烷硫基烷基”是指-R11SR12,其中R11和R12分别是烷基,例如甲硫基甲基,乙硫基乙基,甲硫基乙基。
“烷酰基”是指-COR13,其中R13是烷基,例如甲酰基、乙酰基、丙酰基,丁酰基和异丁酰基。
“芳基”是指芳香基,例如苯基、萘基、吡啶基、喹啉基、噻吩基、呋喃基和苯氧基苯基。
“芳酰基”是指-COR14,其中R14是芳基,例如苯甲酰基和萘甲酰基。
“烷氧羰基”是指-C(=0)R15,其中R15是烷氧基,例如甲氧羰基,乙氧羰基和丙氧羰基。
“烷氨基羰基”是指-C(=0)NHR16,其中R16是烷基,例如甲氨基羰基,乙氨基羰基和丙氨基羰基。
“二烷氨基羰基”是指-C(=0)NR17R18,其中R17和R18独自为烷基,例如二甲氨基羰基,二乙氨基羰基和甲基乙氨基羰基。
“烷基磺酰基”是指-SO2R19,其中R19是烷基,例如甲磺酰基和乙磺酰基。
“卤代烷基”是指如上所述用1或多个卤素取代的烷基,例如氯甲基,三氟甲基和2,2,2,-三氯乙基。
“羟基取代的烷基”是指如上所述用1或多个羟基取代的烷基,例如羟甲基,二羟乙基和三羟丙基。
“药学上可接受的阳离子”是指基于碱金属和碱土金属的无毒阳离子,例如钠、锂、钾、钙和镁,以及无毒铵,季铵,和胺阳离子,例如铵、四甲基铵、甲基胺、二甲基胺、三甲基胺、乙基胺、二乙基胺和三乙基胺。
制备方法
本发明的化合物可用许多合成方法制备。例如参看JP申请案No.105048/90中的相似方法。如下列反应路线中所用,Q是:
A、B、Ar、m、n和P的定义同上。尽管下述的路线1和2中,R1分别是甲基和NH2,但R1为上述定义的其它基团的化合物也可用类似的方法制备。
在一个实施例中,式Ⅲ的化合物按照路线1中拟出的反应步骤制备。
反应路线1
在步骤1中,联乙酰化合物(Ⅱ)用本技术领域所周知的标准方法制备。例如,将羟基胺(Ⅰ)与乙酰氯或乙酸酐在适宜的碱存在下于反应惰性溶剂中进行反应。优选的碱是氢化钠,三乙基胺和吡啶,后两种尤其好。适宜的反应惰性溶剂包括二氯甲烷,氯仿,四氢呋喃、苯和甲苯。反应通常在0℃-环境温度下进行,反应时间一般为30分钟至几小时。产物可用普通方法,如重结晶或色谱法分离和纯化。
步骤2涉及联乙酰基化合物(Ⅱ)用适宜碱的选择性水解。典型的碱包括氢氧化铵、氢氧化钠、氢氧化钾和氢氧化锂,最好采用甲醇、乙醇、异丙醇或水为溶剂,但是二元溶剂系统如醇-水,四氢呋喃-水等也可采用。反应温度一般在约-10℃至环境温度范围内,反应通常在几分钟至几小时内完成。式Ⅲ产物用标准方法分离,并可用普通方法如重结晶和色谱法进行纯化。
在另一实施例中,式Ⅳ的化合物按路线2中所示方法制备。
反应路线2
在这一步骤中,一般于反应惰性溶剂中在室温至回流温度下,用三甲基甲硅烷异氰酸酯处理羟基胺(Ⅰ)。不与反应物和/或产物反应的适宜溶剂包括:例如四氢呋喃、二噁烷、二氯甲烷和苯。另一种方法是羟基胺(Ⅰ)在反应惰性溶剂如苯或甲苯中用气态氯化氢处理,随后用光气处理。反应温度通常在室温至溶剂沸点温度范围内。中间产物氨基甲酰氯不分离、而直接(即,就地)与氨水反应。由此获得的式Ⅳ产物用标准方法分离,并可用普通方法,例如重结晶和色谱法提纯。
上述羟基胺(Ⅰ)很容易用标准的合成方法由易购的羰基化合物(例如酮类、醛类)、醇类和囟代化合物的制得。请参看例如R.L.Danheiser et al.Tetrahedron Lett.28,3299(1987);M,Kolobielski et al.J.Am.Chem,Soc,79,5820(1957);Y.Kobayashi et al.,J,Org.Chem,47,3232(1982)和Fieser et al.J.Am.Chem Soc.70 3147(1948)。例如,合适的羰基化合物转化成它的肟,然后用合适的还原剂还原成需要的羟基胺(Ⅰ),例如,请参看R.F.Borch et al,J.Am,Chem,Soc,93,2897(1971)。优选的还原剂包括氰氢硼化钠和甲硼烷复合物如硼-吡啶,硼-三乙胺和硼-二甲基硫;还可采用三乙硅烷的三氟乙酸溶液。
另一种方法是,在Mitsunobu型反应条件下用N,O-双(叔丁氧羰基)羟基胺处理相应的醇,然后该N,O-保护的中间产物经过酸催化水解也能制得羟基胺(Ⅰ)(参看JP 1045344)。值得注意的是,可采用N,O-联乙酰羟基胺代替N,O-双(叔丁氧羰基)羟基胺制备N,O-联乙酰基化合物(Ⅱ),从而为式(Ⅲ)产物提供了捷径。
上述羟基胺(Ⅰ)还可通过用适宜的囟代化合物与O-保护的羟基胺反应,随后去保护而制得。请参看W.P.Jackson等,J.Med,Chem,31,499(1988)。优选的O-保护羟基胺包括0-四氢吡喃基羟胺,O-三甲基甲硅烷基羟胺和0-苄基羟基胺。
由上述所示方法制得的式(Ⅰ)羟基胺用标准方法分离,并可用普通方法例如重结晶和色谱法提纯。
本发明之新化合物的药学上可接受的盐很容易由下述方法制得:在水溶液或适宜的有机溶剂中将所述化合物与化学计量(无毒阳离子)的适宜金属氢氧化物或醇盐或胺接触。制备无毒酸成盐时,可使用适宜的无机酸或有机酸的水溶液或适宜有机溶液。然后可通过沉淀或蒸发溶剂获得盐。
生物活性
本发明之化合物能抑制脂氧合酶,这种抑制作用通过检测大鼠腹腔存在的细胞而得到证实,所述方法能测定本发明这些化合物对花生四烯酸代谢的影响。
按照“Synthesis of leukotrienes by peritoneal macrophages”Jap.J.Inflammation,7,145-150(1987)中所述的方法对实施例1-14的化合物进行了试验,结果表明它们是脂氧合酶抑制剂。在该试验中,某些优选的化合物对于脂氧合酶的抑制作用具有低的IC50值,约为0.5-30μm。
本发明之化合物对脂氧合酶的抑制能力使它们可用于控制哺乳动
物体内由花生四烯酸引起的内源性代谢产物导致的症状。因此,这些化合物在预防和治疗这些症状时是很有价值,在这些疾病中花生四烯酸代谢产物的累积是致病因素,例如变应支气管气喘,皮肤病、风湿性关节炎、骨关节炎和血栓形成。
化学式所示本发明化合物及其药学上可接受的盐特别适用于预防和治疗人体内各种炎症、变态反应和心血管疾病。
施药方法
对于上述各种症状的治疗,本发明的化合物及其药学上可接受的盐,根据标准的药物实践,可单独,或者最好是与药学上可接受的载体或稀释剂组合成组合物施予人体。化合物可通过各种惯用的施药方法(包括口服、非肠道给药和吸入)施用。当化合物口服施用时,以待治疗者的体重为基准,其剂量范围一般约为0.1-20mg/kg/天,最好是约0.1-1.0mg/kg/天,一次或分次给药。如果希望非肠道施用,有效剂量一般约为0.1-1.0mg/kg/天。某些情况下,可能需要使用超出这些限制范围的剂量,因为剂量随患者的年龄、体重和反应以及患者症状的严重程度和被施用的特定化合物的效力而变化。
对于口服给药,本发明之化合物及其药学上可接受的盐可以以各种形式施用,如片剂、粉剂、锭剂、糖浆剂或胶囊,或作为水溶液或悬浮液施用。用于口服的片剂,通常使用的载体包括乳糖和玉米淀粉。通常添加润滑剂,如硬脂酸镁。胶囊的情况下,有用的稀释剂是乳糖和干燥的玉米淀粉。当需要口服的水混悬液时,可将活性成分与乳化剂和混悬剂组合。如果需要,还可添加某些甜味剂和/或芳香剂。
就肌肉内、腹腔内、皮下和静脉应用而言,通常将活性成分制备成灭菌溶液,溶液的PH值应经过合适的调节和缓冲。对于静脉使用,应控制溶液的总浓度使制剂为等渗溶液。
实施例
用以下实施例说明本发明,但应理解为本发明并不限于这些实施例的具体描述。在270MHz测定核磁共振(NMR)光谱(除另有说明),峰值的位置以四甲基硅烷为内标以每百万分之一(PPm)表示。峰形表示如下:S,单峰;d,双峰;t,三峰;q,四峰;m,多峰;Br,宽峰。
实施例1N-羟基-N-[(反式-2-苯基-1-环丙基)甲基]脲
步骤1,反式-2-苯基-1-环丙基甲醇
在0℃搅拌下将氢硼化钠(567mg,15mmol)添加到2-苯环丙烷羧酸(1.62g,10mmol)的THF(80ml)的冷溶液中。向该混合物中滴加三氟化硼合乙醚(2.13g,15mmol),在0℃将反应混合物搅拌1小时,然后在室温下搅拌一夜。混合物仔细用水稀释并用EtOAc(200ml)提取。EtOAc层用水(70ml)和盐水(80ml)洗涤。溶液用MgSO4干燥并真空浓缩,获得1.49g(产率100%)产物(1),无色油状物。
1.77(IR(neat)v 3350,1605,1490,1090,1035,1020,695cm-1.
1H NMR(CDCl3)δ 7.05-7.29(m,5H),3.62(d,J=7Hz,2H),2.28(br s,1H),1.81(m,1H),1.46(m,1H),0.95(m,2H).
步骤2,N,O-双(叔丁氧羰基)-反式-2-苯基-1-环丙烷甲基羟基胺
通氮和在-75℃搅拌下,向上述步骤1的产品(1.5g,10mmol),N,O-双(叔丁氧羰基)羟基胺(2.563g,11mmol)和三苯膦(3.93g,15mmol)的无水甲苯(35ml)冷却溶液中滴加偶氮二羧酸二乙酯(2.612g,15mmol)的无水甲苯(10ml)溶液。然后将该混合物加温至室温,搅拌1小时并除去挥发物。层析纯化残余物(SiO2,100g,用EtOAc-正己烷(1∶5)洗脱),获得3.24g(产率89.3%)产物(2),浅黄色油状物。
1H NMR(TMS/CDCl3)δ7.05-7.26(m,5H),3.62(m,2H),1.85(m,1H),1.50(m,1H),1.46(s,9H),1.48(s,9H),0.97(m,2H).
步骤3,反式-2-苯基-1-环丙烷甲基羟基胺
搅拌下向上述步骤2的产物(3.16g,8.71mmol)的CH2Cl2(85ml)溶液中添加三氟乙酸(22ml),在室温下将该反应混合物搅拌一夜(18小时)。减压下除去挥发物并添加EtOAc(200ml)。用水(50ml)、饱和NaHCO3溶液,水(50ml)和盐水(50ml)洗涤有机层。溶液用MgSO4干燥,真空浓缩,生成的油用硅胶纯化(150g,CHCl3-EtOH(40∶1)),获得932mg(产率65.6%)产物(3),无色油状物。
IR(neat)v 3250,3050,1605,1495,1455,1300,1090,1030,755cm-1.
1H NMR(CDCl3)δ7.04-7.27(m,5H),2.90(dd,J=1.1,6.9Hz,2H),1.77(m,1H),1.34(m,1H),0.94(m,2H).
步骤4,N-羟基-N-[(反式-2-苯基-1-环丙基)甲基]脲
在室温搅拌下,向上述步骤3的产物(906mg,5.56mmol)的THF(20ml)溶液中添加三甲基甲硅烷异氰酸酯(961mg,8.34mmol)。反应混合物搅拌1.5小时,真空除去挥发物,将生成的无色固体用正己烷研制,得到756mg(产率65.9%)标题化合物的无色结晶,m.p.145.5-147.5℃。
IR(nujol) v 1610,1560,1145,1090,750,690cm-1.
1H NMR(CDCl3)δ9.24(s,1H),7.0-7.3(m,5H),5.55(s,2H),3.60(dd,J=7.4,15Hz,1H),3.45(dd,J=7.4,15Hz,1H),1.92(m,1H),1.50(m,1H),0.95(m,2H).
实施例2 N-羟基-N-([反式-2-(-3-苯氧苯基)-1-环丙基]甲基)脲
用适当的原料,按照实施例1的方法制备了实施例2的标题化合物,油状物。
IR(neat)v 3200,1650,1580,1450,1415,1250,1220,1165,1150,760cm-1.
1H NMR(CDCl3)δ 7.66(s,1H),7.05-7.34(m,4H),6.98(m,2H),6.78(m,3H),5.31(s,2H),3.57(dd,J=7.3,14.7Hz,1H),3.42(dd,J=7.3,14.7Hz,1H),1.84(m,1H),1.42(m,1H),0.94(m,2H).
实施例3 N-羟基-N-[反式-2-(3-苯氧苯基)-1-环丙基]甲基)乙酰胺
用适当的原料,按照实施例1的方法制备了实施例3的标题化合物,油状物。
IR(neat)v 3160,2900,1610,1580,1490,1250,1220cm-1.
1H NMR(CDCl3)δ 8.38(br s,1H),6.97-7.36(m,6H),6.79(m,3H),3.65(m,2H),2.13(s,3H),1.87(m,1H),1.42(m,1H),1.00(m,2H).
实施例4 N-[(2,2-二氟-反式-3-苯基-1-环丙基)甲基]-N-羟基脲
步骤1,N,O-二叔丁氧羰基-N-[(2,2-二氟-反式-3-苯基-1-环丙基)甲基]羟基胺
在室温下将KOH(2.60g,40mmol)和乙酸(2,2-二氟-反式-3-苯基-1-环丙基)甲基酯(4.52g,20mmol,按照Y.KoBayashi等人在J.Org Chem,47,3232(1982)发表的方法制备)溶于甲醇(20ml)、四
氢呋喃(20ml)和水(50ml)的混合物中并搅拌14小时,用硫酸镁干燥。蒸发掉溶剂,得到(2,2-二氟-反式-3-苯基-1-环丙基)甲醇(定量产率)。
氮气氛中-78℃、搅拌下20分钟内,向上述制得的醇(3.39g,18.4mmol),N,O-二-叔丁氧羰基羟基胺(5.36g,23.0mmol)和三苯膦(6.03g,23.0mmol)的甲苯(40ml)溶液中滴加偶氮二羧酸二乙酯(4.01g,23.0mmol)的甲苯(5ml)溶液。搅拌30分钟后,移去冷却浴,在室温下搅拌反应混合物4小时。滤掉沉淀物,减压下浓缩滤液。残余物用硅胶(300g)柱层析,用10%乙酸乙酯作为洗脱剂,得到7.03g(17.6mmol,产率96%)标题化合物,静置固化,m.p.62-64℃。
IR(KBr)v 1782,1724cm-1.
1H NMR(CDCl3)δ 7.36-7.21(m,5H),3.99(ddd,J=2.20,7.70,15.02Hz,1H),3.79(dd,J=7.70,15.02Hz,1H),2.62(dd,J=7.70,14.65Hz,1H),2.21(dq,J=7.70,14.65Hz,1H),1.49(s,9H),1.48(s,9H).
步骤2,N-[(2,2-二氟-反式-3-苯基-1-环丙基)甲基]-N-羟基脲
在0℃搅拌下,向上述步骤1制得的羟基胺(7.03g,17.6mmol)的二氯甲烷(50ml)溶液中缓慢添加三氟乙酸(13.6ml)。在0℃至室温下搅拌13.5小时,溶剂蒸发掉。将残余物添加到饱和碳酸氢钠溶液(50ml)中,用乙酸乙酯(2x100ml)提取。合并提取物用饱和碳酸氢钠液(50ml)和盐水(50ml)洗涤,用硫酸镁干燥。蒸发掉溶剂,得到3.02g N-[(2,2-二氟-反式-3-苯基-1-环丙基)甲基]羟基胺粗品。
搅拌下向上述获得的羟基胺的四氢呋喃(50ml)溶液中添加三甲基甲硅烷异氰酸酯(85%,3.08g,22.7mmol),在室温下将反应混合物搅拌4小时。搅拌下向反应混合物中添加甲醇(30ml),10分钟后蒸发掉溶剂。用异丙醚和正己烷的混合物研制残余物,得到2.41g固体,
用含10%乙醇的异丙醚溶液重结晶,得到1.34g(5.5mmol,产率31%)标题化合物,m.p.139-140℃。
IR(KBr)v 3460,3350,3200,1604,1584cm-1.
1H NMR(DMSO-d6)δ 9.52(s,1H),7.38-7.24(m,5H),6.44(s,2H),3.75(ddd,J=2.56,7.70,14.65Hz,1H),3.53(dd,J=7.70,14.65Hz,1H),2.85(dd,J=7.70,14.65Hz,1H),2.28(dq,J=7.70,14.65Hz,1H).
计算值C11H12F2N2O2:C,54.54;H,4.90;N,11.56.测定值C,57.78;H,5.11;N,11.59.
实施例5 N-羟基-N-(顺式-4-苯基环己烷-1-基)脲
步骤1
将4-苯基环己酮(5.00g,29mmol)和羟胺盐酸盐(5.20g,75mmol)溶解在甲醇(40ml)和吡啶(10ml)的混合物中,在环境温度下搅拌一夜。将反应混合物真空浓缩,生成的残余物用1N HCl(100ml)稀释并用乙酸乙酯提取三次。合并有机层用MgSO4干燥并真空浓缩,得到5.97g(定量产率)肟(1),白色针状物。
步骤2
将上述步骤1制得的肟(5.45g,28.8mmol)溶解在乙酸(20ml)中,
在1小时内分批添加氰基硼氢化钠(5.66g,90mmol)。反应完成后,将反应混合物小心地注入冰冷却的K2CO3溶液中,调节PH至9。用乙酸乙酯提取混合物,用MgSO4干燥并真空浓缩,获得羟基胺的非对映体混合物。用硅胶柱分离,含10%二异丙醚的己烷溶液洗脱,得1.61g(产率29%)顺式-羟基胺(2,Rf=0.4)和2.7g(产率49%)反异构体(Rf=0.2),两者均为白色结晶。
1H NMR(CDCl3,顺式异构体)δ7.36-7.14(m,5H),3.30-3.19(m,1H),2.65-2.48(m,1H),2.00-1.91(m,1H),1.83-1.55(m,6H).
1H NMR(CDCl3,反式异构体)δ7.35-7.14(m,5H),2.98-2.87(m,1H),2.57-2.45(m,1H),2.16-1.88(m,4H),1.63-1.42(m,2H),1.34-1.16(m,2H).
步骤3 N-羟基-N-(顺式-4-苯基环己烷-1-基)脲
将上述步骤2制得的顺式-羟基胺(1.43g,7.5mmol)与三甲基甲硅烷异氰酸酯(2.19g,19mmol)的四氢呋喃(20ml)溶液一起搅拌1小时。将反应产物真空浓缩,残余物用乙酸乙酯重结晶,获得0.452g(产率26%)标题化合物,细白粉末,m.p.161.4-162.2℃。
IR(KBr)v3500,3200,2950,1660,1630,1560,1490,1440,1160cm-1.
1H NMR(DMSO-d6)δ 8.87(s,1H),7.48-7.30(m,4H),7.22-7.10(m,1H),6.18(s,2H),4.07-3.92(m,1H),2.86-2.77(m,1H),2.25-2.09(m,2H),1.79-1.62(m,4H),1.56-1.41(m,2H).
以下实施例6-10的化合物按照相似方法制备。
实施例6 N-羟基-N-(反式-4-苯基环己烷-1-基)脲
m.p.161.9-162.6℃.
IR(KBr)v 3470,3300,3100,2920,2860,1680,1630,1570,1470,1450,1160cm-1.
1H NMR(DMSO-d6)δ8.94(s,1H),7.36-7.13(m,5H),6.24(s,2H),4.03-3.83(m,1H),2.53-2.36(m,1H),1.89-1.76(m,2H),1.73-1.41(m,6H).
实施例7 N-羟基-N-(顺式-3-苯基环己烷-1-基)脲
m.p.144.1-144.9℃.
IR(KBr)v 3450,3300,2910,1655,1640,1460,1440cm-1.
1H NMR(DMSO-d6)δ 8.92(s,1H),7.36-7.10(m,5H),6.24(s,2H),4.08-3.90(m,1H),2.68-2.50(m,1H),1.92-1.25(m,8H).
实施例8 N-羟基-N-(反式-3-苯基环己烷-1-基)脲
m.p.132.9-133.7℃.
IR(KBr)v 3500,3370,2940,2870,1630,1560,1450,1160cm-1.
1H NMR(DMSO-d6)δ 9.00(s,1H),7.38-7.25(m,4H),7.20-7.11(m,1H),6.24(s,2H),4.19-4.05(m,1H),3.26-3.15(m,1H),1.99-1.83(m,3H),1.75-1.46(m,4H),1.44-1.26(m,1H).
实施例9 N-羟基-N-(顺式-2-苯基环己烷-1-基)脲
m.p.125.5-125.9℃.
IR(KBr)v 3520,3490,3400,2930,2920,2850,1640,1620,1550,1460cm-1.
1H NMR(DMSO-d6)δ 8.86(s,1H),7.34-7.07(m,5H),5.84(s,2H),4.56-4.48(m,1H),2.95-2.82(m,1H),2.39-2.19(m,1H),2.08-1.65(m,3H),1.64-1.32(m,2H).
实施例10 N-羟基-N-(反式-2-苯基环己烷-1-基)脲
m.p.163.1-164.1℃.
IR(KBr) v 3480,3280,3190,2920,1660,1580,1440cm-1.
1H NMR(DMSO-d6)δ 8.68(s,1H),7.35-7.07(m,5H),5.91(s,2H),4.22(td,J=11.5Hz,1H),2.26(td,J=13,4Hz,1H),1.86-1.57(m,5H),1.55-1.12(m,3H).
实施例11 N-羟基-N-[(3-苯基-2-环丁烯)-1-基]脲
按照实施例5的方法,由3-苯基-环丁烯-1-酮(1)制备了标
题化合物[按照R.L.Danheiser et al.,Tetrahedron Lett.28,3299(1987)的方法制备3-苯基-环丁烯-1-酮],m.p.130-131℃。
IR(Nujol) v 3200,1620,1570,1240,1160,1070,760cm-1.
1H NMR(CDCl3)δ 9.02(s,1H),7.35(m,5H),6.29(s,1H),5.78(br s,2H),5.23(s,1H),3.00(br s,2H).
实施例12 N-羟基-N-(3-苯基环戊烷-1-基)脲
按照实施例5的方法,由3-苯基环戊酮制备了标题化合物(3-苯基环戊酮是按M.Kolobielski et.al.J.Am,Chem.Soc,79,5820(1957)的方法由3-苯基环戊烯酮制得)。
实施例13 N-羟基-N-[2-(4-苯基-1-环己烯-1-基)乙基]脲
步骤1(4-苯基环己烷-1-亚基)乙酸乙酯
将三乙基膦酰基乙酸酯(17.85g,76mmol)添加到60%NaH(30g,76mmol)的THF(10ml)的混悬液中,并搅拌0.5小时。室温下向混合物中添加4-苯基环己酮(13.2g,76mmol)的THF(50ml)溶液,搅拌2小时。小心地将水(100ml)添加到混合物中,然后用AcOEt(200ml)提取。合并有机层,用MgSO4干燥,真空浓缩,得到19.7g(定量产率)产物(1),无色油状物。
步骤2,(4-苯基-1-环己烯-1-基)乙酸乙酯
将上述步骤1制得的未饱和酯(19.7g,76mmol)溶解在EtOH(100ml)中,添加催化量的乙醇钠。混合物在回流下加热3小时,然后除去挥发物,残余物用AcOEt(100ml)稀释。有机层用水(50ml)洗涤,用MgSO4干燥并真空浓缩。硅胶层析分离,得到3.75g(产率21%)产物(2);回收得6.07g(产率35%)外烯烃(1),无色油状物。
1H NMR(CDCl3)δ 7.16-7.34(m,5H),5.64-5.68(m,1H),4.16(q,J=7Hz,2H),3.00(s,2H),2.70-2.85(m,1H),2.05-2.43(m,4H),1.91-2.03(m,1H),1.72-1.88(m,1H),1.27(t,J=7Hz,3H).
步骤3,(4-苯基-1-环己烯-1-基)乙醛
充Ar下于-78℃向步骤2制得的酯(2)(3.7g,16mmol)的无水甲苯(60ml)冷却溶液(-78℃)中滴加1.02M DIBAL的无水甲苯(15.7ml,16mmol)溶液,在该温度下搅拌1小时。小心地添加水(2ml),反应混合物搅拌0.5小时。生成的混悬液通过硅藻土垫过滤,有机层真空浓缩,得到3.0g(产率94%)期望的醛(3)无色油状物。
步骤4 N-羟基-N-[2-(4-苯基-1-环己烯-1-基)乙基]脲
按照实施例5的方法,由上述步骤3制得的醛制备了标题化合物(m.p.131.8-132.6℃)。
IR(KBr)v 3450,3200,2900,1640,1580,1475cm-1.
1H NMR(DMSO-d6)δ 9.21(s,1H),7.33-7.10(m,5H),6.23(s,2H),5.50(s,1H),3.57-3.35(m,1H),2.77-2.60(m,1H),2.29-1.92(m,6H),1.89-1.56(m,2H).
实施例14 N-羟基-N-[(4-苯基-1-环己烯-1-基)乙基]脲
步骤1,1-羟基-4-苯基环己烷甲腈
在0℃,向4-苯基环己酮(11.4g,65.5mmol)和氰化钠(3.53g,72mmol)的MeOH(25ml)溶液中滴加乙酸(5.0g,8.3mmol)。反应混合物在室温下搅拌2小时,然后减压除去挥发物。残余物用水(50ml)稀释并用Et2O(100ml)提取。有机层用MgSO4干燥并真空浓缩,得到13.5(定量产率)产物(4)的黄色结晶。
步骤2,4-苯基-1-环己烯甲腈
在0℃,向上述步骤1制备的氰基醇(13.5g,65.5mmol)的吡啶(40ml)溶液中滴加磷酰氯(7.2g,50mmol)。混合物在80℃加热2小时。反应混合物倒入冰(100g)中,用Et2O(200ml)提取。有机层用盐水洗涤,用MgSO4干燥并真空浓缩,得到11.5g(产率96%)期望的产物(5),黄色结晶。
步骤3,4-苯基-1-环己烯基甲醛
按照实施例13,步骤3中所述的方法,用DIBAL(0.96M的甲苯溶液,51ml,48mmol)的CH2Cl2(100ml)溶液,处理上述步骤2制备的腈(7.3g,40mmol)。以85%产率制得醛(6),浅黄色油状物。
步骤4,N-羟基-N-[(4-苯基-1-环己烯-1-基)甲基]脲
按照实施例5的方法,由上述步骤3制得的醛制备了标题化合物(m.p.142.3-143.1℃)。
IR(KBr)v 3480,3430,3400,2910,1610,1550cm-1.
1H NMR(DMSO-d6)δ 9.15(s,1H),7.33-7.14(m,5H),6.24(s,2H),5.66-5.57(m,1H),3.90(s,2H),2.78-2.64(m,1H),2.32-1.95(m,4H),1.92-1.79(m,1H),1.79-1.60(m,1H).
实施例15 N-羟基-N-[外-(1,1a,6,6a-四氢环丙烷并[a]茚-
1-基)甲基]脲
步骤1,N,O-二叔丁氧羰基-N-[外-(1,1a,6,6a-四氢环丙烷并[a]茚-1-基)甲基]羟胺
充氮和搅拌下,于-42℃用10分钟向外-1-羟甲基-1,1a,6,6a-四氢环丙烷并[a]茚(1)[1.53g,9.6mmol,按S.S.Hixon et al.,J.Am Chem Soc.110,3601(1988)的方法制备],N,O-二-叔丁氧羰基羟胺(3.36g,14.4mmol)和三苯膦(3.78g,14.4mmol)的甲苯(20ml)溶液中,滴加偶氮二羧酸二乙酯(2.51g,14.4mmol)的甲苯(5ml)溶液。反应混合物在-42℃至室温下搅拌17.5小时。滤出沉淀物,减压浓缩滤液。残余物用硅胶(300g)柱层析,用含5%乙酸乙酯的正己烷溶液作为洗脱剂,得到3.33g(8.9mmol,产率93%)标题化合物(2)。
IR(KBr)v 1786,1711cm-1.
1H NMR(CDCl3)δ 7.29-7.27(m,1H),7.14-7.05(m,3H),3.64(dd,J=6.96,15.02Hz,1H),3.50(dd,J=6.96,15.02Hz,1H),3.14(dd,J=6.96,16.85Hz,1H),2.97(d,J=16.85Hz,1H),2.38-2.33(m,1H),1.85-1.78(m,1H),1.52(s,9H),1.49(s,9H),0.76(tt,J=3.45,6.96Hz,1H).
步骤2,N-羟基-N-[外-(1,1a,6,6a-四氢环丙烷并[a]茚-1-基)甲基]脲
在0℃搅拌下,向上述步骤1制备的羟胺(2)(3.29g,8.8mmol)的二氯甲烷(40ml)溶液中缓慢添加三氟乙酸(6.8ml)。0℃至室温下搅拌27小时后,蒸发掉溶剂。向残余物中加入饱和碳酸氢钠液(50ml),用乙酸乙酯(2x100ml)提取。合并提取液,用饱和碳酸氢钠液(50ml)和盐水(50ml)洗涤,用硫酸镁干燥。蒸发掉溶剂,得到1.51gN-[(外-1,1a,6,6a-四氢环丙烷并[a]茚-1-基)甲基]羟胺粗品。
搅拌下,向上述制备的羟胺的四氢呋喃(50ml)溶液中添加三甲基甲硅烷异氰酸酯(95%,1.17g,9.7mmol),反应混合物在室温下搅拌3.5小时。向搅拌的反应混合物中添加甲醇(10ml),10分钟后蒸掉溶剂。用乙酸乙酯重结晶,得到1.11g(5.1mmol,产率58%标题化合物,m.p.139-140℃。
IR(KBr)v 3475,3347,3280,1616,1601,1576cm-1.
1H NMR(DMSO-d6)δ 9.30(s,1H),7.27-7.26(m,1H),7.15-7.01(m,3H),6.28(s,2H),3.34(dd,J=6.96,15.02Hz,1H),3.31(dd,J=6.96,15.02Hz,1H),3.08(dd,J=6.96,16.85Hz,1H),2.90(d,J=16.85Hz,1H),2.38-2.30(m,1H),1.99-1.75(m,1H),0.62-0.56(m,1H).
计算值 C12H14N2O2;C,66.03;H,6.46;N,12.83.测定值:C,65.79;H,6.51;N,12.71.
实施例16,N-羟基-N-[内-(1,1a,6,6a-四氢环丙烷并[a]
茚-1-基)甲基]脲
按照实施例15的方法制备了标题化合物(m.p.151-152℃)。
IR(KBr)v 3480,3310,3160,1640,1570cm-1.
1H NMR(DMSO)δ9.12(s,1H),7.26-7.21(m,1H),7.10-7.04(m,1H),6.19(s,1H),3.05(dd,J=6.96,17.58Hz,1H),2.95(d,J=17.58Hz,1H),2.82(dd,J=5.86,14.29Hz,1H),2.79(dd,J=7.69,14.29Hz,1H),2.26(ddd,J=1.62,6.96,7.96Hz,1H),1.19(dddd,J=1.62,6.60,6.96,7.96Hz,1H),1.41(ddd,J=5.86,6.60,6.96,7.69Hz,1H).
实施例17,N-[(2,2-二氯-反式-3-苯基环丙基)甲基]-N-羟基脲
步骤1,乙酸(2,2-二氯-反式-3-苯基-1-环丙基)甲基酯
在120℃至135℃,用1小时将三氯乙酸钠(27.8g,150mmol)的二甘醇二甲醚(20ml)溶液滴加到乙酸反式肉桂酯(8.81g,50mmol)的二甘醇二甲醚(80ml)溶液中,反应混合物在120℃至125℃加热1小时。反应混合物冷却至室温,倒入水(300ml)中,用正己烷(300ml+3x50ml)提取并用MgSO4干燥。除去溶剂,真空下蒸馏残余物,得到标题化合物(11.0g,产率76%,b.p.104-105℃(0.15mmHg))。
IR(film)v 1740cm-1.
1H NMR(CDCl3)δ 7.40-7.23(m,5H),4.47(dd,J=6.23,12.29Hz,1H),4.30(dd,J=8.42,12.09Hz,1H),2.71(d,J=8.42Hz,1H),2.34(dt,J=6.23,8.06Hz,1H),2.13(s,3H).
步骤2,N,O-二叔丁氧羰基-N-[(2,2-二氯-反式-3-苯基环丙基)甲基]羟基胺
室温下,将KOH(3.36g,60mmol)和上述步骤1产物(10.36g,40mmol)溶于甲醇(30ml)、四氢呋喃(30mol)和水(90ml)的混合物中,搅拌3小时。反应混合物用1N盐酸水溶液中和,用二乙醚(100ml+2x50ml)提取。合并有机相,用饱和碳酸氢钠水溶液(2x50ml)和盐水(50ml)洗涤,然后用MgSO4干燥。蒸发掉溶剂,得到(2,2-二氯-反式-3-苯基环丙基)甲醇(定量产率)。充氮气和搅拌下,向冷却至-42℃的上述制得之醇(4.34g,20mmol)、N,O-二-叔丁氧羰基羟基胺(5.83g,25mmol)和三苯膦(6.56g,25mmol)的甲苯(40ml)溶液中滴加偶氮二羧基二乙酯(4.35g,25mmol)的甲苯(5ml)溶液,15分钟滴完。使反应混合物升温至室温过夜。滤除不溶物质并减压浓缩滤液。所得残余物用柱层析(SiO2,300g;含8%乙酸乙酯的正己烷溶液)纯化,得标题化合物8.09g(产率94%)。
IR(KBr)v 1783,1717cm-1.
1H NMR(CDCl3)δ7.38-7.24(m,5H),4.01(dd,J=6.60,15.39Hz,1H),3.98(dd,J=6.60,15.39Hz,1H),2.69(d,J=8.43,6.60Hz,1H),1.48(s,18H).
步骤3,N-[(2,2-二氯-反式-3-苯基环丙基)甲基]-N-羟基脲
搅拌下,向上述步骤2产物(3.75g,8.7mmol)的冷却至0℃的二氯甲烷(40ml)溶液中缓慢滴加三氟乙酸(6.7ml)反应混合物升温至室温
过夜,蒸发掉溶剂。所得残余物用饱和碳酸氢钠水溶液(50ml)溶解并用乙酸乙酯(2x100ml)提取。合并提取液,用饱和碳酸氢钠水溶液(50ml)和盐水(50ml)洗涤,然后用MgSO4干燥。蒸发溶剂,得3.02gN-[(2,2-二氯-反式-3-苯基环丙基)甲基]羟基胺粗品。搅拌下,向获得的羟基胺的四氢呋喃(50ml)溶液中添加三甲基甲硅烷异氰酸酯(85%,1.77g,13.1mmol),反应混合物在室温下搅拌1.5小时。添加甲醇(10ml),10分钟后蒸发掉溶剂。用柱层析(SiO2,300g,含10%正己烷的乙酸乙酯溶液),纯化得到1.90g白色固体。用50%乙酸乙酯的正己烷溶液重结晶,得到1.41g(产率59%)标题化合物,m.p.128-130℃。
IR(KBr)v 3459,3360,3170,2890,1624,1566cm-1.
1H NMR(DMSO-d6)δ 9.58(s,1H),7.40-7.27(m,5H),6.47(s,2H),3.78(dd,J=6.96,14.29Hz,1H),3.67(dd,J=6.96,14.29Hz,1H),2.88(d,J=8.43Hz,1H),2.34(dt,J=6.96,8.43Hz,1H).
计算值C11H12Cl2N2O2:C,48.02;H,4.39;N,10.18.测定值C,47.84;H,4.35;N,10.09.
实施例18 N-羟基-N-([反式-2-(3-甲硫基苯基)环丙基)甲基]脲
步骤1,[2-反式-(3-甲硫基苯基)环丙基]甲醇
在低于-70℃和搅拌下,向1.7M叔丁基锂的戊烷溶液(2.1ml,3.5mmol)和乙醚(10ml)的混合物中添加[2-反式-(3-溴苯基)环丙基]甲醇(277mg,1mmol)的乙醚(5ml)溶液,5分钟加完。在-78℃搅拌1小时后,缓慢添加二甲基二硫化物(207mg,2,2mmol),使反应混合物升温至室温过夜。所得混合物用水(20ml)骤冷并用乙醚(20ml+10ml)提取。合并有机相,用盐水洗涤,MgSO4干燥并蒸发。残余物
用柱层析(SiO2,50g;20%乙酸乙酯的正己烷溶液)纯化,蒸发洗脱剂,得标题化合物(148mg,产率76%)。
IR(film)ν 3375,1594,1022cm-1.
1H NMR(CDCl3)δ7.18(t,J=7.70Hz,1H),7.08-7.03(m,1H),7.00-6.98(m,1H),6.58-6.81(m,1H),3.62(dd,J=5.86,6.23Hz,2H),2.47(s,3H),1.85-1.77(m,1H),1.50-1.44(m,1H),1.42(t,J=5.86Hz,1H),1.01-0.89(m,2H).
步骤2,N-O-二叔丁氧羰基-N-([2-反式-(3-甲硫基苯基)环丙基]甲基)羟基胺
用实施例15,步骤1所述方法,由上述步骤1的产物制备了标题化合物(产率75%)。
IR(KBr)v 1784,1714cm-1.
1H NMR(CDCl3)δ7.15(t,J=7.70Hz,1H),7.06-7.02(m,1H),6.99-6.97(m,1H),6.84-6.80(m,1H),3.71(dd,J=6.60,14.66Hz,1H),3.57(dd,J=6.60,14.66Hz,1H),2.33(s,3H),1.86-1.83(m,1H),1.50-1.37(m,1H),1.48(s,9H),1.47(s,9H),0.98-0.85(m,2H).
步骤3,N-羟基-N-([2-反式-(3-甲硫基苯基)环丙基]甲基)脲
按照实施例15,步骤2描述的方法,将步骤2制备的羟基胺转化成标题化合物。粗产品用乙酸乙酯重结晶,得标题化合物(产率58%,m.p.126-127℃)。
IR(KBr)v 3465,3350,3180,3000,2994,1602,1583,1505,1480,1443,1425cm-1.
1H NMR(DMSO-d6)δ 9.29(s,1H),7.17(t,J=7.70Hz,1H),7.03-6.89(m,1H),6.95-6.92(m,1H),6.83-6.78(m,1H),6.27(s,2H),3.38(dd,J=6.60,14.66Hz,1H),3.34(dd,J=6.60,14.66Hz,1H),2.45(s,3H),1.99-1.80(m,1H),1.39-1.28(m,1H),0.92-0.86(m,2H).
计算值 C12H16N2O2S:C,57.12;H,6.39;N,11.10.测定值C,56.97;H,6.48;N,10.74.
用上述实施例的类似方法制备了下列化合物。
实施例19 N-羟基-N-[(2-甲基-反式-2-苯基环丙基)-甲基]脲
m.p.86-87℃.
IR(KBr)v 3475,3340,3185,1621,1566,1474,1443,1428cm-1.
1H NMR(DMSO-d6)δ9.28(s,1H),7.30-7.10(m,5H),6.28(2,2H),3.61(dd,J=7.69,14.29Hz,1H),3.44(dd,J=7.69,14.29Hz,1H),1.36(s,3H),1.25(ddt,J=7.69,9.16,5.85Hz,1H),1.04(dd,J=4.77,9.16Hz,1H),0.54(dd,J=4.77,5.86Hz,1H).
实施例20 N-羟基-N-[(2-甲基-顺式-2-苯基环丙基)甲基]脲
m.p.151-152℃.
IR(KBr)v 3475,3310,3245,3160,1637,1640,1571,1495,1444,1420cm-1.
1H NMR(DMSO-d6)δ 9.19(s,1H),7.33-7.15(m,5H),6.23(s,2H),3.25(dd,J=4.03,13.92Hz,1H),2.45(d,J=4.03,13.92Hz,1H),1.32(s,3H),
1.29-1.18(m,1H),0.93(dd,J=4.76,5.13Hz,1H),0.75(dd,J=4.76,8.06Hz,1H).
实施例21 N-[(3,3-二甲基-反式-2-苯基环丙基)甲基]-N-羟基脲
m.p.132.5-133℃.
IR(KBr)v 3505,3470,3385,3345,1637,1458cm-1.
1H NMR(DMSO-d6)δ 9.27(s,1H),7.28-7.14(m,5H),6.27(s,2H),3.58(dd,J=6.96,14.29Hz,1H),3.46(dd,J=6.96,14.29Hz,1H),1.72(d,J=5.86Hz,1H),1.35(dt,J=5.86,6.96Hz,1H),1.20(s,3H),0.75(s,3H).
实施例22 N-羟基-N-[(1-甲基-反式-2-苯基环丙基)甲基]脲
m.p.119-120℃.
IR(KBr)v 3475,3360,3305,1668,1640,1578cm-1.
1H NMR(DMSO-d6)δ9.23(s,1H),7.30-7.12(m,5H),6.23(s,2H),3.49(d,J=14.29Hz,1H),3.29(d,J=14.29Hz,1H),2.04(dd,J=6.60,8.06Hz,1H),0.91-0.77(m,2H),0.72(s,3H).
实施例23 N-羟基-N-[(反式-2-(2-甲苯基)环丙基)甲基]
脲
m.p.106-106.5℃.
IR(KBr)v 3480,3365,3165,2885,1661,1627,1575,1493,1457,1434cm-1.
1H NMR(DMSO-d6)δ9.31(s,1H),7.13-7.00(m,3H),6.92-6.88(m,1H),6.26(s,2H),3.35(dd,J=6.96,15.02Hz,1H),3.41(dd,J=6.96,15.02Hz,1H),2.35(s,3H),1.89-1.81(m,1H),1.30-1.19(m,1H),0.91-0.80(m,2H).
实施例24 N-[(2,2-二苯基环丙基)甲基]-N-羟基脲
m.p.164-165℃(dec.).
IR(KBr)v 3465,3310,3110,3080,3030,2900,2830,1631,1577,1489,1441cm-1.
1H NMR(DMSO-d6)δ9.33(s,1H),7.39-7.09(m,10H),6.27(s,2H),3.49(dd,J=4.40,13.92Hz,1H),2.71(dd,J=4.77,13.92Hz,1H),1.89-1.82(m,1H),1.37(dd,J=4.76,5.86Hz,1H),1.24(dd,J=4.76,8.79Hz,1H).
实施例25 N-羟基-N-([反式-2-(3-甲苯基)环丙基]甲基)脲
m.p.113-114℃.
IR(KBr)v 3460,3350,3180,1605,1580,1505,1491,1444,1427cm-1.
1H NMR(DMSO-d6)δ9.27(s,1H),7.10(dd,J=7.33,7.69Hz,1H),6.94-6.90(m,1H),6.87-6.81(m,2H),6.26(s,2H),3.34(d,J=6.96Hz,2H),2.24(s,3H),1.84-1.76(m,1H),1.33-1.27(m,1H),0.90-0.82(m,2H).
实施例26 N-羟基-N-([反式-2-(4-甲苯基)环丙基]甲基)脲
m.p.149-150℃.
IR(KBr)v 3450,3335,3165,2920,2880,1613,1572,1498,1435cm-1.
1H NMR(DMSO-d6)δ9.26(s,1H),7.10(d,J=8.43Hz,2H),6.93(d,J=8.43Hz,2H),6.26(s,2H),3.34(d,J=6.96Hz,2H),2.23(s,3H),1.83-1.76(m,1H),1.32-1.21(m,1H),0.89-0.78(m,2H).
实施例27 N-([反式-2-(3-溴苯基)环丙基]甲基)-N-羟基脲
m.p.96-96.5℃.
IR(KBr)v 3465,3350,3185,1643,1603,1583,1505,1481,1446,1426cm-1.
1H NMR(DMSO-d6)δ9.30(s,1H),7.30-7.16(m,3H),7.07-7.03(m,1H),6.28(s,2H),3.40(dd,J=6.96,14.92Hz,1H),3.32(dd,J=6.96,14.92Hz,1H),1.90-1.83(m,1H),1.37-1.28(m,1H),0.95-0.90(m,2H).
实施例28 N-([反式-2-(4-溴苯基)环丙基]甲基)-N-羟基脲
m.p.130-131℃.
IR(KBr)v 3445,3335,3255,3160,2935,2880,1615,1572,1491,1437cm-1.
1H NMR(DMSO-d6)δ9.29(s,1H),7.41(d,J=8.43Hz,2H),6.27(s,2H),3.38(dd,J=7.33,15.02Hz,1H),3.30(dd,J=7.33,15.02Hz,1H),1.89-1.81(m,1H),1.38-1.26(m,1H),0.96-0.84(m,2H).
实施例29 N-羟基-N-([反式-2-(2-萘基)环丙基]甲基)脲
m.p.162-162.5℃.
IR(KBr)v 3460,3340,1627,1599,1577,1434cm-1.
1H NMR(DMSO-d6)δ9.32(s,1H),7.85-7.7(m,3H),7.59-7.55(m,1H),7.49-7.37(m,2H),7.23(dd,J=1.93,8.43Hz,1H),6.29(s,2H),3.45(dd,J=6.60,14.65Hz,1H),3.41(dd,J=6.60,14.65Hz,1H),2.06-1.99(m,1H),1.50-1.43(m,1H),1.06-0.95(m,2H).
实施例30 N-羟基-N-([顺式-2-苯基环丙基)甲基]脲
m.p.100.6-101.4℃.
IR(KBr)v 3500,3200,2900,1670,1640,1580,1500,1280,1160cm-1.
1H NMR(CDCl3)δ8.17(s,1H),7.28-7.13(m,5H),5.28(s,2H),3.33(dd,J=5.1,14.7Hz,1H),2.96(dd,J=8.8,14.7Hz,1H),2.23-2.15(m,1H),1.48-1.37(m,1H),1.04-0.94(m,2H).
实施例31 N-羟基-N-([反式-2-苯基环丙基)甲基]乙酰胺
m.p.-(油).
IR(KBr)v 3200,2900,1620,1460,1360,1260,1180cm-1.
1H NMR(CDCl3)δ7.30-7.05(m,5H),3.71-3.60(m,2H),2.14(s,3H),1.95-1.88(m,1H),1.62(s,1H),1.49-1.37(m,1H),1.03-0.92(m,2H).
实施例32(1R*、1′S*、2′S*)-N-羟基-N-[1-(2′-苯基环丙基)乙基]脲
m.p.144.0-144.6℃.
IR(KBr)v 3450,3350,3200,1660,1440cm-1.
1H NMR(DMSO-d6)δ8.97(s,1H),7.24-6.99(m,5H),6.26(s,2H),3.70-3.59(m,1H),1.98-1.88(m,1H),1.38-1.25(m,1H),1.15(d,J=7.0Hz,3H),0.91-0.80(m,2H).
实施例33(1S*、1′S*、2′S*)-N-羟基-N-[1-(2′-苯基环丙基)乙基]脲
m.p.135.3-135.8℃.
IR(KBr)v 3480,3200,1640,1570,1450,1150cm-1.
1H NMR(DMSO-d6)δ9.02(s,1H),7.27-7.02(m,5H),6.27(m,2H),3.65-3.57(m,1H),1.84-1.77(m,1H),1.27-1.20(m,1H),1.14(d,J=6.6Hz,3H),1.01-0.92(m,1H),0.86-0.75(m,1H).
实施例34 N-([反式-2-(2-氯苯基)环丙基]甲基)-N-羟基脲
m.p.105.6-105.9℃.
IR(KBr)v 3490,3200,2900,1665,1630,1580,1480cm-1.
1H NMR(DMSO-d6)δ9.31(s,1H),7.39(dd,J=1.5,7.7Hz,1H),7.26-7.17(m,2H),7.03(dd,J=2.0,7.7Hz,1H),6.27(s,2H),3.50(dd,J=6.6,
14.3Hz,1H),3.41(dd,J=5.1,12.1Hz,1H),2.10-2.04(m,1H),1.43-1.33(m,1H),1.02-0.85(m,2H).
实施例35 N-([反式-2-(3-氯苯基)环丙基]甲基)-N-羟基脲
m.p.109.9-110.7℃.
IR(KBr)v 3460,3350,3180,1600,1580,1520,1450,1430cm-1.
1H NMR(CDCl3)δ7.20-6.92(m,4H),5.29(br s,2H),3.67(dd,J=6.2,14.7Hz,1H),3.45(dd,J=7.7,14.7Hz,1H),1.85-1.91(m,1H),1.61(br s,1H),1.51-1.40(m,1H),1.05-0.93(m,2H).
实施例36 N-([反式-2-(4-氯苯基)环丙基]甲基)-N-羟基脲
m.p.115.0-115.7℃.
IR(KBr)v 3450,3330,3170,2900,1620,1575,1500cm-1.
1H NMR(DMSO-d6)δ9.30(s,1H),7.27(d,J=8.4Hz,2H),7.07(d,J=8.8Hz,2H),6.28(s,2H),3.44-3.28(m,2H),1.90-1.83(m,1H),1.41-1.30(m,1H),0.96-0.86(m,2H).
实施例37 N-羟基-N-([反式-2-(2-三氟甲苯基)环丙基]甲基)脲
m.p.103.5-104.4℃.
IR(KBr)v 3450,3370,2820,1660,1630,1590,1540,1460,1370,1265,1210cm-1.
1H NMR(DMSO-d6)δ9.30(s,1H),7.64(d,J=7.7Hz,1H),7.55(t,
J=7.7Hz,1H),7.35(t,J=7.7Hz,1H),7.18(d,J=7.7Hz,1H),6.27(s,2H),3.53-3.29(m,2H),2.07-1.96(m,1H),1.52-1.38(m,1H),1.06-0.94(m,2H).
实施例38 N-羟基-N-([反式-2-(3-三氟甲苯基)环丙基]甲基)脲
m.p.101.5-102.3℃.
IR(KBr)v 3500,3300,2900,1630,1460,1360,1330,1130cm-1.
1H NMR(CDCl3)δ7.68(br s,1H),7.40-7.20(m,4H),5.38(br s,2H),3.61(dd,J=6.4,14.7Hz,1H),3.46(dd,J=7.3,14.7Hz,1H),1.97-1.90(m,1H),1.49-1.43(m,1H),1.05-0.95(m,2H).
实施例39 N-羟基-N-([反式-2-(4-三氟甲苯基)环丙基]甲基)脲
m.p.136.3-136.8℃.
IR(KBr)v 3500,3330,2900,1670,1635,1560,1480,1330,1160,1120cm-1.
1H NMR(DMSO-d6)δ9.31(s,1H),7.57(d,J=8.1Hz,2H),7.27(d,J=8.1Hz,2H),6.28(s,2H),3.47-3.34(m,2H),2.00-1.94(m,1H),1.48-1.35(m,1H),1.04-0.94(m,2H).
实施例40 N-([反式-2-(3-氟苯基)环丙基]甲基)-N-羟基脲
m.p.123.5-124.0℃.
IR(KBr)v 3480,3300,2900,1630,1580,1460,1135cm-1.
1H NMR(DMSO-d6)δ9.30(s,1H),7.30-7.21(m,1H),6.95-6.83(m,3H),6.28(s,2H),3.44-3.28(m,2H),1.89-1.85(m,1H),1.36-1.31(m,1H),0.95-0.90(m,2H).
实施例41 N-([反式-2-(4-氟苯基)环丙基]甲基)-N-羟基脲
m.p.139.8-140.5℃.
IR(KBr)v 3450,3320,3180,2900,1630,1580,1455cm-1.
1H NMR(CDCl3)δ7.05-6.90(m,4H),6.28(br s,1H),5.27(br s,2H),3.66(dd,J=6.2,14.7Hz,1H),3.48(dd,J=7.7,14.7Hz,1H),1.93-1.85(m,1H),1.46-1.35(m,1H),1.00-0.88(m,2H).
实施例42 N-羟基-N-([反式-2-(3-甲氧苯基)环丙基]甲基脲
m.p.109.5-110.0℃.
IR(KBr)v 3450,3300,2900,1640,1605,1580,1495,1450,1405,1355,1260,1090cm-1.
1H NMR(DMSO-d6)δ9.29(s,1H),7.16-7.10(m,1H),6.70-6.61(m,3H),6.26(s,2H),3.72(s,3H),3.45-3.31(m,2H),1.83-1.78(m,1H),1.33-1.28(m,1H),0.91-0.85(m,2H).
实施例43 N-羟基-N-([反式-2-(3-硝基苯基)环丙基]甲基)脲
m.p.123.5-124.5℃.
IR(KBr)v 3475,3380,3180,1640,1530,1460cm-1.
1H NMR(DMSO-d6)δ9.33(s,1H),8.01-7.93(m,1H),7.88(s,1H),7.60-7.46(m,2H),6.29(s,2H),3.50-3.29(m,2H),2.08-2.00(m,1H),1.48-1.39(m,1H),1.07-0.96(m,2H).
实施例44 N-([反式-2-(3,4-二氯苯基)环丙基]甲基)-N-羟基脲
m.p.-(油).
IR(KBr)v 3475,3350,3200,2900,1630,1575,1480,1235cm-1.
1H NMR(CDCl3)δ7.34(br s,1H),7.28(d,J=8.0Hz,1H),7.12(d,J=2.2Hz,1H),6.88(dd,J=2.0,8.2Hz,1H),5.35(s,2H),3.61(dd,J=6.2,14.7Hz,1H),3.42(dd,J=7.5,14.5Hz,1H),1.88-1.83(m,1H),1.46-1.34(m,1H),1.03-0.89(m,2H).
实施例45 N-([反式-2-(3-氯-4-氟-苯基)环丙基]甲基)-N-羟基脲
m.p.82.3-82.9℃.
IR(KBr)v 3480,3350,1605,1580,1505,1430cm-1.
1H NMR(DMSO-d6)δ9.30(s,1H),7.30-7.21(m,2H),7.10-7.03(m,1H),6.28(s,2H),3.45-3.24(m,2H),1.90-1.84(m,1H),1.32-1.28(m,1H),0.94-0.87(m,2H).
以下示出各种苯基环丁基衍生物的立体选择性合成的通用反应路线:
产率(%)
实施例 R 步骤1 步骤2 步骤3
46 H 68.2 定量 16.0
47 CH374.9 定量 8.7
48 正丙基 45.0 定量 49.7
实施例46 N-羟基-N-(3-苯基-2-环丁烯基)脲
m.p.130-131℃(dec.).
IR(nujol)v 3200,1620,1570,1240,1160,1070,760cm-1.
1H NMR(CDCl3-DMSO-d6)δ9.02(br s,1H),7.35(m,5H),6.29(s,1H),5.78(br s,2H),5.23(s,1H),3.00(br s,2H).
实施例47 N-羟基-N-(2-甲基-3-苯基-2-环丁烯基)脲
m.p.138-139℃(dec.).
IR(nujol)v 3190,1640,1635,1565,1180,1080,695cm-1.
1H NMR(CDCl3)δ8.97(s,1H),7.28(s,5H),5.95(s,2H),5.11(br s,1H),2.82(br s,2H),2.00(s,3H).
实施例48 N-羟基-N-(3-苯基-2-丙基-2-环丁烯基)脲
m.p.132-133.5℃(dec.).
IR(nujol)v 3470,3170,1630,1565,1190,1080,765cm-1.
1H NMR(CDCl3-DMSO-d6)δ8.67(s,1H),7.35(m,5H),5.44(br s,2H),5.27(d,J=2.5Hz,1H),2.85(m,2H),2.44(m,2H),1.60(m,2H),0.90(t,J=7.4Hz,3H).
以下示出各种苯基环丁基衍生物的立体选择性合成的另一通用反应路线。
顺式 反式 X 步骤1 步骤2 步骤3 步骤4 步骤5
49 50 H 54 60 32 74 25
51 52 对-F 64 77 11 69 27
53 54 间-Cl 92 定量 28 76 26
55 56 对-Cl- 75 76 25 87 23
58 57 对-Br 70 82 22 90 30
60 59 对-CF379 92 20 71 20
61 对-OCH327 67 26
62 苯乙烯基 94 59 定量 24
63 间-PhO-Ph 定量 90 定量 37
实施例49 N-羟基-N-(顺式-3-苯基环丁基)脲
m.p.136-138℃.
IR(nujol)v 3450,3200,1615,1570,1150,1060,745 695cm-1.
1H NMR(DMSO-d6)δ9.19(s,1H),7.28(s,5H),5.60(s,2H),5.20(m,1H),3.47(m,1H),2.87(m,2H),2.33(m,2H).
实施例50 N-羟基-N-(反式-3-苯基环丁基)脲
m.p.169-171℃.
IR(nujol)v 3450,3200,1620,1575,1165,750cm-1.
1H NMR(CDCl3-DMSO-d6)δ9.13(s,1H),7.28-7.16(m,5H),5.76(br s,2H),4.77(m,1H),3.06(m,1H),2.48(m,4H).
实施例51,N-[顺式-3-(4-氟苯基)环丁基]-N-羟基脲
步骤1,N-[顺式-3-(4-氟苯基)环丁基]-N-羟基脲-3-(4-氟苯基)环丁酮
在500ml配有磁搅拌器的锥形瓶中装锌粉(49.2g,0.75g原子)和40ml 3%盐酸。混合物快速搅拌1分钟,然后滗去上清液。以同样方式,依次用下列物质洗涤锌粉:三份40ml 3%盐酸,五份100ml蒸馏水,二份75%ml 2%硫酸铜水溶液,五份100ml蒸馏水,四分100ml无水乙醇和五份100ml无水醚。最终将偶合物转移至瓷漏斗,用另外的无水醚洗涤,用橡胶封片封盖并抽吸干燥直到它达到室温。将得到的锌-铜偶合物在五氧化二磷的真空干燥器中贮存一夜,然后备用。
将装有冷凝器,加料漏斗,磁搅拌器和N2进口的2000ml三口烧瓶在充N2下经火焰干燥。冷却后,烧瓶装填35g(0.287mol)4-氟苯乙烯,20.6g(0.315mol)锌-铜偶合物和500ml无水醚。在充N2下搅拌混悬液,用1.5小时滴加33.6ml(54.8g,0.301mol)Cl3CCOCl和27.8ml(45.7g,0.298mol)POCl3的240ml无水醚溶液。完成添加后,混合物回流并搅拌2小时。然后反应混合物通过硅藻土填料过滤,未反应的锌用350ml醚洗涤。醚溶液真空浓缩成约为其原料体积的25%,添加等量(500ml)戊烷,将该溶液搅拌几分钟以沉淀锌盐。从残余物中滗出溶液,并依
次用冰水(700ml)、冷的饱和NaHCO3水溶液(300ml)、水(300ml)和盐水(500ml)洗涤,用MgSO4干燥并真空除去溶剂,留下61g粗品的浅黄色油状物,无需进一步纯化直接用于下步反应。
在10℃搅拌下,向上述制得粗品(61g)的250ml乙酸溶液中添加51.3g锌粉(放热反应)。于50-70℃搅拌30分钟后,混合物通过硅藻土填料过滤,未反应的锌用乙酸(50ml)和乙醚(50ml)洗涤。将水(800ml)添加到该混合物中,用乙醚(2x500ml,1x100ml)提取。有机层用饱和NaHCO3水溶液(300ml)、水(300ml)和盐水(300ml)洗涤、然后用MgSO4干燥并真空蒸发,得39.5g标题化合物(由4-氟苯乙烯计算,产率94.7%)。
1H NMR(CDCl3)δ7.26(m,2H),7.04(m,2H),3.65(m,1H),3.55(m,2H),3.23(m,2H).
步骤2 顺式-3-(4-氟丙基)环丁醇
充氮和搅拌下,向LiAl[O(CH3)3H(73.4g,0.289mol)的冷却至-73℃的THF(500ml)溶液中,添加39.5g上述步骤1制得的环丁酮(0.241gmmol)的THF(150ml)溶液。反应混合物在-70℃搅拌一夜,加入冷的饱和NH4Cl水溶液(100ml)。添加MgSO4(30g),混合物通过硅藻土过滤,用乙酸乙酯(4x50ml)洗涤,滤液经真空蒸发,得粗品。添加乙酸乙酯(300ml),溶液用MgSO4干燥并真空浓缩,得38.5g(产率96.3%)标题化合物,顺式-环丁醇,浅黄色油状物。
1H NMR(CDCl3)δ7.17(m,2H),6.98(m,2H),4.28(m,1H),2.92(m,1H),2.75(m,2H),2.00(m,2H),1.80(br s,1H).
步骤3,苯甲酸-反式-3-(4-氟苯基)环丁基酯
搅拌下,向上述步骤2制得的顺式-环丁醇(28.25g,0.23mol)和Ph3P(69.43g,0.265mol)的THF(236ml)溶液中,一次加入苯甲酸(32.32g,0.265mol),然后在10℃和充氮下滴加DEAD(46.1g,0.265mol)的THF(80ml)溶液(放热反应)。室温下搅拌1.5小时之后,真空蒸发挥发物。将Et2O(200ml)和正己烷(50ml)添加到残余物中,滤除不溶解物质,将滤液真空浓缩。重复两次上述处理过程,得到87.3g黄色油状的标题苯甲酸酯粗品,无需进一步纯化就可使用。
1H NMR(CDCl3)δ8.1-7.1(m,9H),5.41(m,1H),3.74(m,1H),2.68(m,4H).
步骤4 反式-3-(4-氟苯基)环丁醇
室温搅拌下,向上述步骤3制得的苯甲酸酯粗品(87g)的THF(200ml)和MeOH(200ml)混合溶液中滴加KOH(42g)的水溶液(300ml)。室温搅拌1.5小时后,蒸发掉溶剂,用乙酸乙酯(2x400ml,1x150ml)提取。有机层用水(300ml)和盐水(500ml)洗涤,然后用MgSO4干燥并真空蒸发,得到约61g粗品。蒸馏(b.P.87-88℃(1.2mmHg))后获得33.88g(由顺式醇计算的产率88.6%)标题的反式-醇,无色油状物。
1H NMR(CDCl3)δ7.18(m,2H),6.99(m,2H),4.53(m,1H),3.62(m,1H),2.44(m,4H).
步骤5,N-O-双(叔丁氧羰基)-N-〔顺式-3-(4-氟苯基)环丁基〕羟胺
充氮和室温搅拌下,向上述步骤4制得的反式-醇(33.5g,0.202mol),Ph3(60.85g,0.232mol)和N,O-双(叔丁氧羰基)
羟胺(54.06g,0.232mol)的THF(200ml)溶液中,添加DEAD(36.5ml,0.232mol)的THF(70ml)溶液(放热反应)。减压除去挥发物。将Et2O(200ml)和正己烷(100ml)的混合物添加到生成的油中,滤除不溶解物,真空浓缩滤液。重复该处理过程,得到123g标题化合物粗品,黄色油状物,用闪层析(SiO2,1.2Kg,用正己烷/乙酸乙酯(15∶1)洗脱)纯化,得到64.33g(产率83.8%)标题化合物。
1H NMR(CDCl3)δ7.18(m,2H),6.98(m,2H),4.59(m,1H),3.12(m,1H),2.63(m,4H),1.55(s,9H),1.48(s,9H).
步骤6 N-[顺式-3-(4-氟苯基)环丁基]-N-羟基脲
在5℃搅拌下,向上述步骤5制得的化合物(64.3g,0.164mol)的CH2Cl2(330ml)溶液中滴加三氟乙酸(81.4ml)。搅拌4小时后,真空除去挥发物。添加饱和NaHCO3水溶液(300ml),用乙酸乙酯(2x400ml,1x200ml)提取。有机层用水(200ml)和盐水(400ml)洗涤,然后用MgSO4干燥并真空蒸发,得到27.0g(产率90.8%)相应的羟胺。充氮室温和搅拌下,向上述羟胺(27.0g,0.149mol)的THF(300ml)溶液中,添加三甲基甲硅烷异氰酸酯(23.5g,0.203mol)。搅拌过夜后,加MeOH(150ml)以停止反应。真空除去挥发物,所得固体用异丙醇重结晶。得到12.92g(产率38.6%,第一次产物),5.01g(产率15.1%,第二次产物)和0.76g(产率2.3%,第三次产物)标题化合物,无色片状物。总产率为56.0%。
m.p.155-157℃.
IR(nujol)v 3450,3200,1620,1577,1240,1160,830cm-1.
1H NMR(DMSO-d6)δ9.14(s,1H),7.19(m,2H),7.05(m,2H),6.23(s,2H),4.58(m,1H),3.00(m,1H),2.30(m,4H).
实施例52 N-[反式-3-(4-氟苯基)环丁基]-N-羟基脲
m.p.134-136℃.
IR(nujol)v 3450,3200,1615,1570,1510,1245,1150,830,770cm-1.
1H NMR(CDCl3/DMSO-d6)δ9.22(s,1H),7.25(t,J=8.8Hz,2H),6.98(t,J=8.8Hz,2H),5.85(s,2H),4.98(m,1H),3.43(m,1H),2.87(m,2H),2.28(m,2H).
实施例53 N-[顺式-3-(3-氯苯基)环丁基]-N-羟基脲
m.p.157-158℃(dec.).
IR(nujol)v 3450,3340,1645,1570,1155,1090,870,860,785,690cm-1.
1H NMR(DMSO-d6)δ9.24(s,1H),7.35(m,4H),6.35(s,2H),4.70(m,1H),3.15(m,1H),2.38(m,4H).
实施例54 N-[反式-3-(3-氯苯基)环丁基]-N-羟基脲
m.p.127-128℃.
IR(nujol)v 3430,1640,1585,1205,1165,1090,1070,920,870,770,690cm-1.
1H NMR(DMSO-d6)δ9.14(s,1H),7.26-7.13(m,4H),5.51(br s,2H),5.02(m,1H),3.44(m,1H),2.87(m,2H),2.31(m,2H).
实施例55 N-[顺式-3-(4-氟苯基)环丁基]-N-羟基脲
m.p.155-157℃(dec.).
IR(nujol)v 3450,3200,1618,1577,820cm-1.
1H NMR(DMSO-d6)δ9.02(s,1H),7.17(dd,J=8.4Hz,2H),7.26(d,J=8.4Hz,2H),6.11(s,2H),4.46(dt,J=8.1Hz,1H),2.89(dt,J=8.1Hz,1H),2.15(m,4H).
实施例56 N-[反式-3-(4-氯苯基)环丁基]-N-羟基脲
m.p.147-148℃.
IR(nujol)v 1645,1570,1240,1195,1095,820,770cm-1.
1H NMR(DMSO-d6)δ9.07(s,1H),7.14(d,J=8.8Hz,4H),6.13(s,2H),4.59(m,1H),3.15(m,1H),2.46(m,2H),1.93(m,2H).
实施例57 N-[反式-3-(4-溴苯基)环丁基]-N-羟基脲
m.p.162-164℃(dec.).
IR(nujol)v 2900,1640,1565,1460,1380,815cm-1.
1H NMR(DMSO-d6)δ9.27(s,1H),7.48(d,J=8.4Hz,2H),7.26(d,J=8.4Hz,2H),6.33(s,2H),4.78(m,1H),3.40(m,1H),2.69(m,2H),2.14(m,2H).
实施例58 N-[顺式-3-(4-溴苯基)环丁基]-N-羟基脲
m.p.164.5-166℃.
IR(nujol)v 3460,1640,1570,1195,810,770cm-1.
1H NMR(DMSO-d6)δ9.19(s,1H),7.48(d,J=8.4Hz,2H),7.19(d,J=8.4Hz,2H),6.29(s,2H),4.64(m,1H),3.06(m,1H),2.33(m,4H).
实施例59 N-羟基-N-[反式-3-(4-三氟甲苯基)环丁基]脲
m.p.157.5-159.5℃.
IR(nujol)v 3470,3180,1645,1570,1330,1160,1120,850,830,770cm-1.
1H NMR(DMSO-d6)δ9.31(s,1H),7.68(d,J=8.1Hz,2H),7.54(d,J=8.1Hz,2H),6.35(s,2H),4.83(m,1H),3.49(m,1H),2.76(m,2H),2.20(m,2H).
实施例60 N-羟基-N-[顺式-3-(4-三氟甲苯基)环丁基]脲
m.p.151-153℃
IR(nujol)v 3530,3150,1630,1580,1330,1170,1120,1070,835cm-1.
1H NMR(DMSO-d6)δ9.21(s,1H),7.68(d,J=8.1Hz,2H),7.54(d,J=8.1Hz,2H),6.31(s,2H),4.70(m,1H),3.09(m,1H),2.38(m,4H).
实施例61 N-羟基-N-[反式-3-(4-甲氧 苯基)环丁基]脲
m.p.139-139.6℃(dec.).
IR(nujol)v 1615,1570,1515,1465,1250,1030cm-1.
1H NMR(DMSO-d6)δ9.24(s,1H),7.21(d,J=8.4Hz,2H),6.87(d,J=8.4Hz,2H),6.31(s,2H),4.77(m,1H),3.73(s,3H),3.30(m,1H),2.67(m,2H),2.10(m,2H).
实施例62 N-羟基-N-[顺式-3-(α-苯乙烯基)环丁基]脲
m.p.183.5-184℃.
IR(nujol)v 3460,3180,1610,1580,1190,1090,960,745cm-1.
1H NMR(DMSO-d6)δ9.12(s,1H),7.30(m,6H),6.32(s,2H),6.30(d,J=17.6Hz,1H),4.57(m,1H),2.67(m,1H),2.18(m,4H).
实施例63 N-羟基-N-[顺式-3-(3-苯氧基苯基)环丁基]脲
m.p.127-129℃.
IR(nujol)v 3450,3200,1640,1580,1490,1380,1250,750cm-1.
1H NMR(DMSO-d6)δ9.16(s,1H),7.40-6.70(m,9H),6.27(s,2H),4.63(m,1H),3.10(m,1H),2.32(m,4H).
实施例64 N-([顺式-3-(4-氯苯基)环丁基]甲基)-N-羟基脲
步骤1,3-(4-氯苯基)-顺式-3-羟基环丁烷基甲酸乙酯
按照Caputo et.al.,J.Org.Chem,33,1959(1968)的方法,由3-氧代环丁烷基甲酸乙酯(3.10g,22mmol)和4-氯苯基溴化镁(23mmol)制得标题化合物。用柱层析(SiO2,300g,12.5%乙酸乙酯的己烷溶液)得标题化合物(4.03g,产率72%)。
1H NMR(CDCl3)δ7.44(d,J=8.43Hz,2H),7.35(d,J=8.43Hz,2H),4.21(q,J=6.96Hz,2H),3.25(br s,1H),2.88-2.80(m,3H),2.66-2.59(m,2H),1.30(t,J=6.96Hz,3H).
步骤2 顺式-3-(4-氟苯基)环丁烷基甲酸乙酯
按照Caputo et.al.,的方法,由3-(4-氯苯基)-顺式-3-羟基环丁烷基甲酸乙酯(1.42g,4.84mol)制得标题化合物。用柱层析
(SiO2,200g,5%乙酸乙酯的正己烷溶液)得标题化合物(0.47g,产率48%)。
1H NMR(CDCl3)δ7.26(d,J=8.43Hz,2H),7.16(d,J=8.43Hz,2H),4.15(q,J=6.96Hz,2H),3.45-3.37(m,1H),3.14-3.02(m,1H),2.66-2.55(m,2H),2.43-2.30(m,2H),1.27(t,J=6.96Hz,3H).
步骤3[顺式-3-(4-氯苯基)环丁基]甲醇
按照实施例67,步骤3中所述方法将上述步骤2制得之羧酸酯(0.52g,2.2mmol)转变成标题化合物。
1H NMR(CDCl3)δ7.25(d,J=8.43Hz,2H),7.13(d,J=8.43Hz,2H),3.61(d,J=6.59Hz,2H),3.47-3.36(m,1H),2.56-2.39(m,3H),1.93-1.80(m,2H).
步骤4 N,O-二叔丁氧羰基-N-([顺式-3-(4-氯苯基)环丁基]甲基)羟胺
按照实施例15,步骤1中所述方法将上述步骤3制得的甲醇(0.40g,2.0mmol)转化成标题化合物(1.99g,产率99%)。
1H NMR(CDCl3)δ7.25(d,J=8.43Hz,2H),7.11(d,J=8.43Hz,2H),3.61(d,J=6.59Hz,2H),3.37-3.31(m,1H),2.64-2.43(m,3H),1.89-1.77(m,2H),1.53(s,9H),1.48(s,9H).
步骤5 N-([顺式-3-(4-氯苯基)环丁基]甲基)-N-羟基脲
按照实施例15,步骤2中所述方法将上述步骤4制得之羟基胺(0.82g,1.99mmol)转化成标题化合物。粗品用30%乙酸乙酯的二异丙醚溶液重结晶,得到标题化合物(0.37g,产率73%),m.p.127.5-128℃。
IR(KBr)v 3505,3350,3180,1646,1633,1567,1490cm-1.
1H NMR(DMSO-d6)δ9.20(s,1H),7.33(d,J=8.43Hz,2H),7.23(d,J=8.43Hz,2H),6.22(br s,2H),3.37(d,J=6.59Hz,2H),3.35-3.28(m,1H),2.51-2.34(m,3H),1.81-1.70(m,2H).
计算值C12H15ClN2O2:C,56.59;H,5.94;N,11.00.测定值C,56.96;H,5.90;N,10.99.
实施例65 N-([顺式-3-(4-氟苯基)环丁基]甲基-N-羟基脲
步骤1,[顺式-3-(4-氟苯基)环丁基]甲醇
按照Escale et.al.,Ecer.J.Med.Chem,13,449(1978)的方法,将顺式-3-(4-氟苯基)环丁基甲酸乙酯(3.31g,14.9mol)转化为标题化合物(2.53g,产率94%)
1H NMR(CDCl3)δ7.20-7.11(m,2H),7.02-6.94(m,2H),3.61(d,J=6.59Hz,2H),3.43-3.35(m,1H),2.54-2.40(m,3H),1.90-1.79(m,2H).
步骤2 N,O-二叔丁氧羰基-N-([顺式-3-(4-氯苯基)-1-环丁基]甲基)羟基胺
按照实施例15,步骤1中所述方法将上述步骤1制得的化合物(2.53g,14mmol)转化成标题化合物(5.54g,定量产率)。
1H NMR(CDCl3)δ7.16-7.10(m,2H),7.01-6.92(m,2H),3.62(d,
J=6.59Hz,2H),3.39-3.32(m,1H),2.63-2.43(m,3H),1.89-1.77(m,2H),1.52(s,9H),1.48(s,9H).
步骤3,N-([顺式-3-(4-氟苯基)环丁基]甲基)-N-羟基脲
按照实施例15,步骤2中所述方法将上述步骤2制得的羟基胺(5.54g,14mmol)转化成标题化合物。粗品用二异丙醚重结晶,得到标题化合物(1.40g,产率42%),m.p.102-103℃。
IR(KBr)v 3475,3185,2930,1621,1566,1508,1466cm-1.
1H NMR(DMSO-d6)δ9.21(s,1H),7.27-7.21(m,2H),7.14-7.06(m,2H),6.22(br s,2H),3.37(d,J=6.59Hz,2H),3.34-3.27(m,1H),2.54-2.34(m,3H),1.82-1.70(m,2H).
计算值C12H15FN2O2:C,60.49;H,6.35;N,11.76.测定值C,60.60;H,6.58;N,11.76.
实施例66 N-羟基-N-[(顺式-3-苯基环丁基)甲基]脲
步骤1,N,O-二叔丁氧羰基-N-[(顺式-3-苯基环丁基)甲基)羟基胺
按照实施例15,步骤1中所述方法,由(顺式-3-苯基环丁基)甲醇(0.49g,3.0mmol)制得标题化合物(1.00g,产率88%)。
1H NMR(CDCl3)δ7.21-7.25(m,2H),7.21-7.14(m,3H),3.62(d,J=6.59Hz,2H),3.43-3.36(m,1H),2.62-2.45(m,3H),1.93-1.81(m,2H),1.53(s,9H),1.48(s,9H).
步骤2 N-羟基-N-[(顺式-3-苯基环丁基)甲基]脲
按照实施例15,步骤2中所述方法,将上述步骤1制得的羟基胺
(1.00g,2.6mmol)转化成标题化合物。粗品用二异丙醚重结晶,得到标题化合物(0.27g,产率47%),m.p.100-100.5℃。
IR(KBr)v 3475,3185,1624,1569,1492,1466cm-1.
1H NMR(DMSO-d6)δ9.18(s,1H),7.32-7.13(m,5H),6.23(br s,2H),3.38(d,J=6.59Hz,2H),3.33-3.25(m,1H),2.56-2.34(m,3H),1.84-1.72(m,2H).
计算值C12H16N2O2:C,65.43;H,7.32;N,12.72.测定值:C,65.64;H,7.39;N,12.65.
实施例67 N-羟基-N-[(顺式-3-(4-三氟甲苯基)环丁基)甲基]脲
步骤1,顺式-3-羟基-3-(4-三氟苯基)环丁基甲酸甲酯
按照Caputo et.al.,的方法,由3-氧代环丁基甲酸甲酯(2.56g,20mmol)和4-三氟甲苯基溴化镁(20mmol)制得该化合物。经柱层析(SiO2,200g,30%乙酸乙酯的正己烷溶液)获得标题化合物(3.21g,产率58%)。
1H NMR(CDCl3)δ7.64(d,J=8.43Hz,2H),7.62(d,J=8.43Hz,2H),3.77(s,3H),3.00-2.84(m,3H),2.71-2.59(m,2H).
步骤2,顺式-3-(4-三氟甲苯基)环丁基甲酸甲酯
按照Caputo et.al.,的方法,由步骤1的产物(3.21g,11.7mmol)制得上述化合物。经柱层析(SiO2,200g,10%乙醚的正己烷溶液)得标题化合物(2.63g,产率87%)。
1H NMR(CDCl3)δ7.56(d,J=8.43Hz,2H),7.34(d,J=8.43Hz,2H),3.70(s,3H),3.55-3.47(m,1H),3.20-3.09(m,1H),2.71-2.60(m,2H),2.50-2.36(m,2H).
步骤3,[顺式-3-(4-三氟甲苯基)环丁基]甲醇
充氮和室温下,用30分钟将上述步骤2制得的化合物(1.29g,5mmol)的乙醚(100ml)溶液滴加到搅拌的LiAlH4(0.23g,6mmol)乙醚(20ml)混悬液中。反应混合物搅拌3小时,冷却至0℃,过量的氢化物通过添加水(2.5ml)破坏。向所得混合物中添加20%硫酸水溶液(20ml),分离有机相。水相用乙醚(2x20ml)提取,合并的提取液,用水(20ml),饱和碳酸氢钠水溶液(20ml)和盐水(20ml)洗涤,然后用MgSO4干燥。溶剂蒸发,得到纯净的无色液体(定量产率),无需进一步纯化就可使用。
1H NMR(CDCl3)δ7.54(d,J=8.43Hz,2H),7.33(d,J=8.43Hz,2H),3.63(t,J=6.59Hz,2H),3.55-3.45(m,1H),2.66-2.44(m,3H),1.99-1.86(m,2H),1.32(t,J=5.13Hz,1H).
步骤4 N,O-二叔丁氧羰基-N-[(顺式-3-(4-三氟甲苯基)环丁基]甲基)羟基胺
按照实施例15,步骤1中所述方法,将上述步骤3制得的化合物(0.69g,5mmol)转化为标题化合物(1.80g,产率68%)。
1H NMR(CDCl3)δ7.57(d,J=8.43Hz,2H),7.29(d,J=8.43Hz,2H),3.62(d,J=6.59Hz,2H),3.48-3.41(m,1H),2.68-2.48(m,3H),1.95-1.82(m,2H),1.53(s,9H),1.48(s,9H).
步骤5,N-羟基-N-[(顺式-3-(4-三氟甲苯基)环丁基]甲基)脲
按照实施例15,步骤2中所述方法,将上述步骤4制得的羟基胺(1.51g,3.4mmol)转化为标题化合物。粗品用乙醚/正己烷重结晶,得到标题化合物(0.30g,产率31%),m.p.144-146℃。
IR(KBr)v 3510,3195,1649,1577,1475,1459cm-1.
1H NMR(DMSO-d6)δ9.16(s,1H),7.64(d,J=8.43Hz,2H),7.43(d,J=8.43Hz,2H),6.23(br s,2H),3.47-3.38(m,1H),3.37(d,J=6.59Hz,2H),2.58-2.38(m,3H),1.88-1.76(m,2H).
计算值 C13H15F3N2O2:C,54.17;H,5.24;N,9.72.测定值C,54.12;H,5.28;N,9.66.
实施例68 N-羟基-N-(1-[顺式-3-(4-三氟甲苯基)环丁基]乙基)脲
将3-(4-三氟甲苯基))环丁烷基甲酸乙酯(1.85g,6.8mmol)溶解在EtOH(70ml)中,并与过量KOH(0.56g,在30ml H2O中)水溶液一起回流4小时。减压除去挥发物,残余物用Et2O提取以除去非酸性杂质。然后用2N HCl水溶液酸化水相并用CHCl3提取。合并提取液用水洗涤,用MgSO4干燥,真空浓缩,得到1.47g相应羧酸,白色结晶。
氩气氛中,向冷的(0℃)由上述制得的羧酸(1.45g,6.0mmol)的无水Et2O(20ml)溶液中滴加1.10M甲基锂的无水Et2O(10.9ml,12.0mmol)溶液,混合物在室温下搅拌一夜。通过添加饱和NH4Cl水溶液使反应停止并用Et2O提取。合并有机层,用水和盐水洗涤,用MgSO4干燥并真空浓缩,得到1.24g相应的甲基酮,无色油状物。
10分钟内,向冷的(0℃)上述制得的酮(1.24g,5.1mmol)的MeOH(30ml)溶液中,小份添加NaBH4(0.39g,10mmol)。室温下反应混合物搅拌2小时,然后减压除去挥发物。残余物用H2O稀释并用乙酸乙酯提取。有机层用MgSO4干燥并真空浓缩。层析纯化(SiO2,用己烷/乙酸
乙酯(5∶1)洗脱后,获得0.96g(产率78%)相应的醇,无色油状物。
1H NMR(CDCl3)δ7.54(d,J=8.1Hz,2H),7.30(d,J=8.1Hz,2H),3.77-3.57(m,1H),3.45-3.28(m,1H),2.56-2.22(m,3H),2.05-1.80(m,2H),1.40(br s,1H),1.13(d,J=6.2Hz,3H).
按照实施例67所述方法将上述制得的醇转化为标题化合物,m.p.146.9-147.8℃。
IR(KBr)v3460,1670,1460,1330,1270,1240,1170cm-1.
1H NMR(CDCl3)δ8.83(s,1H),7.64(d,J=7.7Hz,2H),7.42(d,J=8.1Hz,2H),6.22(s,2H),4.11-3.94(m,1H),3.40-3.25(m,1H),2.50-2.33(m,3H),1.84-1.72(m,2H),0.93(d,J=6.6Hz,3H).
实施例69 N-羟基-N-[(顺式-3-(4-氟苯基)环丁基]硫脲
室温、搅拌下,向顺式-3-(4-氟苯基)环丁基羟基胺(1.81g,10mmol)的THF(30ml)溶液中添加三甲基甲硅烷异硫氰酸酯(1.58g,12mmol)。于70℃搅拌3小时后,添加MeOH(20ml),真空除去挥发物,残余物用乙酸乙酯/正己烷/EtOH重结晶,得到1.34g(产率55.8%)标题化合物,m.p.156-158℃。
IR(nujol)v 2850,1620,1610,1510,1490,1350,1220,1110,880,835cm-1.
1H NMR(DMSO-d6)δ9.69(s,1H),7.25(m,2H),7.00(m,4H),5.80(m,1H),3.12(m,1H),2.48(m,4H).
实施例70 N′-[顺式-3-(4-氟苯基)环丁基]-N′-羟基脲
基乙酸乙酯
搅拌下,向顺式-3-(4-氟苯基)环丁基羟基胺(0.9g,5mmol)的THF(20ml)溶液中添加异氰酸根合乙酸乙酯(0.71g,5.5mol)。搅拌10分钟后,添加EtOH。真空除去挥发物,所得残余物用乙酸乙酯/正己烷重结晶,得到1.10g(产率71%)标题化合物的无色针状物,m.p.130-132℃。
IR(nujol)v3180,1740,1645,1600,1510,1300,1220,1190,1125,830cm-1.
1H NMR(DMSO-d6)δ7.25(s,1H),7.19(m,2H),6.97(m,2H),6.46(t,J=5.8Hz,1H),4.77(m,1H),4.20(q,J=7.0Hz,2H),3.99(d,J=5.8Hz,2H),3.08(m,1H),2.47(m,4H),1.28(t,J=7.0Hz,3H).
实施例71 N-[(顺式-3-(4-氟苯基)环丁基]-N-羟基-N′-对甲苯磺酰脲
室温、搅拌下,向顺式-3-(4-氟苯基)环丁基羟基胺(0.9g,3mmol)的THF(20ml)溶液中添加对甲苯磺酰基异氰酸酯(1.085g,5.5mmol)。生成的沉淀物通过过滤收集并用乙酸乙酯/EtOH重结晶,得到1.68g(产率89%)标题化合物的无色固体,m.p.177-178℃(分解)。
IR(nujol)v2950,1640,1515,1350,1170,880,830cm-1.
1H NMR(DMSO-D6)δ9.68(s,1H),7.79(d,J=7.5Hz,2H),7.37(d,J=7.5Hz,2H),7.16(m,5H),4.58(m,1H),3.32(s,3H),3.08(m,1H),2.35(m,4H).
实施例72 N′-[(顺式-3-(4-氟苯基)环丁基]-N′-羟基脲基乙酸
搅拌下,向上述实施例71中制得的化合物(1.03g,3.32mmol)的
THF/MeOH(5ml/5ml)溶液中滴加KOH(0.285g,4.32mmol)的H2O(7ml)溶液。搅拌一夜后,真空除去挥发物,添加Et2O/H2O(40ml/30ml)混合物。分离出水相并用10%HCl水溶液酸化,用乙酸乙酯(2x50ml)提取,用水和盐水洗涤,然后用MgSO4干燥并真空蒸发。所得固体用Et2O/正己烷混合物研制,得到0.74g期望产物的无色固体,m.p.137-139℃(分解)。
IR(nujol)v3100,1715,1625,1540,1510,1235,1115,910,830cm-1.
1H NMR(DMSO-d6)δ9.34(s,1H),7.19(m,5H),4.61(m,1H),3.65(d,J=4Hz,2H),3.05(m,1H),2.30(m,4H).
实施例73 2-[顺式-3-(4-氟苯基)环丁基]-1,2,4-偶氮异噁唑嗪-3,5-二酮
室温,搅拌下,向顺式-3-(4-氟苯基)环丁基羟基胺(0.09g,5mmol)的THF(20ml)溶液中添加N-(氯羰基)异氰酸酯(0.55g,5mmol)。搅拌30分钟后,真空除去挥发物,所得残余物用EtOH重结晶,得到0.36g(产率29%)期望产物的无色针状物,m.p.167-168.5℃。(分解)。
IR(nujol)v1910,1830,1605,1560,1215,1145,990,960,840cm-1.
1H NMR(DMSO-d6)δ12.45(s,1H),7.22(m,4H),4.56(m,1H),3.25(m,1H),2.62(m,2H),2.31(m,2H).
实施例74 N-乙氧羰基氧基-N-[顺式-3-(4-氟苯基)环丁基]脲
室温,搅拌下,向上述实施例51制得的化合物(0.448g,2mmol)的CH2Cl2(10ml)溶液中添加三乙胺(0.223g,2,2mmol)和氯甲酸乙酯(0.24g,2,2mmol)。搅拌20分钟后,添加饱和NaCl水溶液,用乙酸乙
酯(3x30ml)提取。有机层用水(30ml)和盐水(30ml)洗涤,然后用MgSO4干燥,真空蒸发。所得残余物用乙酸乙酯重结晶,得到290mg(产率49%)标题化合物的无色片状物。m.p.124-126℃。
IR(neat)v3360,1590,1550,1255,1160,1110,750,690cm-1.
1H NMR(DMSO-d6)δ7.20(m,4H),6.84(s,2H),4.63(m,1H),4.25(q,J=6.9Hz,2H),3.13(m,1H),2.50(br s,4H),1.27(t,J=6.9Hz,3H).
实施例75 N-羟基-N-[顺式-3-(4-苯氧基苯基)环丁基]脲
m.p.187-188℃.
IR(KBr)v3450,3200,1620,1580,1510,1260cm-1.
1H NMR(DMSO-d6)δ9.18(s,1H),7.40-7.33(m,2H),7.26-7.22(m,2H),7.11(dddd,J=7.69,7.69,1.10,1.10Hz,1H),6.99-6.94(m,4H),6.29(s,2H),4.67-4.61(m,1H),3.09-3.03(m,1H),2.39-2.25(m,4H).
实施例76 N-羟基-N-[反式-3-(4-苯氧基苯基)环丁基]脲
m.p.163-165℃.
IR(KBr)v3450,1620,1570,1510,1260cm-1.
1H NMR(DMSO-d6)δ9.26(s,1H),7.41-7.30(m,4H),7.11(dddd,J=7.51,7.51,1.10,1.10Hz,1H),7.01-6.94(m,4H),6.32(s,2H),4.83-4.77(m,1H),3.41-3.34(m,1H),2.75-2.64(m,2H),2.20-2.11(m,2H).
实施例77 N-([顺式-3-(2-苯并呋喃基)-3-甲基]环丁基)-N-羟基脲
m.p.190-192℃(dec.).
IR(KBr)v3500,3300,1630,1560,1460cm-1.
1H NMR(DMSO-d6)δ9.20(s,1H),7.56-7.49(m,2H),7.26-7.16(m,2H),6.56(d,J=1.1Hz,1H),6.33(s,2H),4.90-4.84(m,1H),2.78-2.70(m,2H),2.07(ddd,J=8.42,8.42,2.56Hz,2H),1.48(s,3H).
实施例78 N-([反式-3-(2-苯并呋喃基)-3-甲基]环丁基)-N-羟基脲
m.p.160-162℃.
IR(KBr)v3420,2970,1640,1580,1460cm-1.
1H NMR(DMSO-d6)δ9.27(s,1H),7.57-7.52(m,2H),7.27-7.17(m,2H),6.72(d,J=0.74Hz,1H),6.33(s,2H),4.82-4.76(m,1H),2.44-2.36(m,4H),1.55(s,3H).
实施例79 N-[顺式-3-(4-联苯基)环丁基]-N-羟基脲
m.p.205-207℃(dec.).
IR(KBr)v3450,1620,1570,1470cm-1.
1H NMR(DMSO-d6)δ9.23(s,1H),7.65-7.58(m,4H),7.47-7.42(m,2H),7.36-7.31(m,3H),6.29(s,2H),4.70-4.64(m,1H),3.28-3.08(m,1H),2.36-2.33(m,4H).
实施例80 N-[反式-3-(4-联苯基)环丁基]-N-羟基脲
m.p.196-197℃(dec.).
IR(KBr)v3450,1620,1570cm-1.
1H NMR(DMSO-d6)δ9.29(s,1H),7.67-7.61(m,4H),7.48-7.31(m,5H),6.34(s,2H),4.88-4.82(m,1H),3.45-3.39(m,1H),2.78-2.67(m,2H),2.25-2.15(m,2H).
实施例81 N-[顺式-3-(3,4-二氟苯基)环丁基]-N-羟基脲
m.p.154-155℃.
IR(KBr)v3500,3200,1640,1520,1480cm-1.
1H NMR(DMSO-d6)δ9.22(s,1H),7.40-7.20(m,2H),7.08-7.05(m,1H),6.30(s,2H),4.66-4.59(m,1H),3.18-3.05(m,1H),2.43-2.21(m,4H).
实施例82 N-[顺式-3-(3,4-二氟苯基)环丁基]-N-羟基脲
m.p.124-126℃.
IR(KBr)v3500,1650,1570,1520cm-1.
1H NMR(DMSO-d6)δ9.30(s,1H),7.40-7.30(m,2H),7.18-7.10(m,1H),6.33(s,2H),4.80-4.74(m,1H),3.48-3.18(m,1H),2.72-2.61(m,2H),2.21-2.11(m,2H).
实施例83 N-羟基-N-[顺式-3-(4-甲苯基)环丁基]脲
m.p.177-179℃.
IR(KBr)v3470,3200,1620,1570,1460cm-1.
1H NMR(DMSO-d6)δ9.16(s,1H),7.10(s,4H),6.25(s,2H),4.65-4.59(s,1H),3.04-2.98(m,1H),2.39-2.22(m,7H).
实施例84 N-羟基-N-[反式-3-(4-甲苯基)环丁基]脲
m.p.165-166℃.
IR(KBr)v3480,1650,1570,1430cm-1.
1H NMR(DMSO-d6)δ9.24(s,1H),7.20-7.10(m,4H),6.30(s,2H),4.82-4.76(m,1H),3.41-3.27(m,1H),2.73-2.62(m,2H),2.27(s,3H),2.16-2.07(m,2H).
实施例85 N-[顺式-3-(2-氟苯基)环丁基]-N-羟基脲
m.p.154-156℃.
IR(KBr)v3500,3300,3200,1660,1640,1570,1490,1450cm-1.
1H NMR(DMSO-d6)δ9.16(s,1H),7.34-7.07(m,4H),6.29(s,2H),4.72-4.66(m,1H),3.32-3.22(m,1H),2.39-2.31(m,4H).
实施例86 N-[反式-3-(4-叔丁基苯基)环丁基]-N-羟基脲
m.p.157-158℃.
IR(KBr)v3500,3200,2950,1640,1580,1340cm-1.
1H NMR(DMSO-d6)δ9.25(s,1H),7.35-7.20(m,4H),6.31(s,2H),4.82-4.76(m,1H),3.40-3.26(m,1H),2.73-2.62(m,2H),2.18-2.09(m,2H),1.27(s,9H).
实施例87 N-[顺式-3-(4-叔丁基苯基)环丁基]-N-羟基脲
m.p.165℃(dec.).
IR(KBr)v3500,3300,2950,2800,1635,1560,1450cm-1.
1H NMR(DMSO-d6)δ9.17(s,1H),7.32-7.13(m,4H),6.28(s,2H),4.70-4.57(m,1H),3.05-2.95(m,1H),2.39-2.24(m,4H),1.26(s,9H).
实施例88 N-[顺式-3-(4-叔丁基苯基)环丁基]-N-羟基硫脲
m.p.165-167℃(dec.).
IR(KBr)v3280,1600,1490cm-1.
1H NMR(DMSO-d6)δ9.77(s,1H),7.56-7.14(m,4H),6.26(s,2H),5.77-5.67(m,1H),3.09-2.99(m,1H),2.51-2.28(m,4H),1.26(s,9H).
实施例89 N-[(顺式-3-苄氧基环丁基)甲基]-N-羟基脲
m.p.92.6-92.8℃.
IR(KBr)v3460,1620,1575,1500,1460,1150,1090cm-1.
1H NMR(DMSO-d6)δ9.15(s,1H),7.39-7.25(m,5H),6.21(s,2H),4.34(s,2H),3.90-3.34(m,1H),3.40-3.26(m,2H),2.35-2.21(m,2H),2.11-1.94(m,1H),1.64-1.51(m,2H).
实施例90 N-[(反式-3-苄氧基环丁基)甲基]-N-羟基脲
m.p.100.6-101.5℃.
IR(KBr)v3460,2900,1680,1580,1500,1165,1130cm-1.
1H NMR(DMSO-d6)δ9.19(s,1H),7.39-7.25(m,5H),6.21(s,2H),4.34(s,2H),4.18-4.04(m,1H),3.40-3.27(m,2H),2.51-2.39(m,1H),2.09-1.90(m,4H).
实施例91 N-(顺式-3-环己基环丁基)-N-羟基脲
m.p.161-162℃.
IR(KBr)v3490,3350,3220,2930,2855,1605,1585,1458cm-1.
1H NMR(DMSO-d6)δ9.03(s,1H),6.20(br s,2H),4.50-4.37(m,1H),2.03-1.92(m,2H),1.89-1.75(m,2H),1.71-1.40(m,6H),1.25-0.99(m,4H),0.82-0.67(m,2H).
实施例92 N-[顺式-3-(3-环己烯基)环丁基]-N-羟基脲
m.p.154-155℃.
IR(KBr)3500,3350,1610,1460cm-1.
1H NMR(DMSO-d6)δ9.02(s,1H),6.19(s,2H),5.63(s,2H),4.49-4.42(m,1H),2.03-1.80(m,8H),1.64-1.46(m,2H),1.40-1.27(m,1H),1.12-1.00(m,1H).
实施例93 N-羟基-N-(1-[3-(4-三氟甲苯基)环丁基]乙基)脲
反式∶顺式=2∶1
m.p.137.2-137.8℃.
IR(KBr)v3460,1670,1575,1480,1330,1130,1070cm-1.
1H NMR(DMSO-d6)δ8.82(s)and 8.79(s,1H),7.66(d,J=8.1Hz)and 7.63(d,J=7.9Hz,2H),7.49(d,J=8.4Hz)and 7.42(d,J=8.4Hz,2H),6.22(s,2H),4.34-4.20(m)and 4.07-3.95(m,1H),3.65-3.49(m)and 3.40-3.25(m,1H),2.50-2.33(m)and 2.29-2.03(m)and 1.83-1.71(m,5H),0.97(d,J=6.6Hz)and 0.92(d,J=6.6Hz,3H).
实施例94 N-羟基-N-([3-(4-三氟甲苯基)环丁基]甲基)脲
反式∶顺式=6∶1
m.p.127.8-128.7℃.
IR(KBr)v3500,3350,1640,1570,1500,1470,1330,1165,1120,1070cm-1.
1H NMR(DMSO-d6)δ9.23(s,1H),7.65(d,J=8.0Hz,2H),7.48(d,J=8.4Hz,2H),6.24(s,2H),3.73-3.57(m,1H),3.40-3.26(m,2H),2.64-2.51(m,1H),2.25-2.08(m,4H).
实施例95 N-[顺式-3-(3-氟苯基)环丁基]-N-羟基脲
m.p.152-153℃.
IR(KBr)v3465,3340,3200,1616,1589,1572,1470cm-1.
1H NMR(DMSO-d6)δ9.21(s,1H),7.39-7.30(m,1H),7.09-6.96(m,3H),6.32(br s,2H),4.73-4.59(m,1H),3.18-3.04(m,1H),2.45-2.25(m,4H).
实施例96 N-(顺式-3-苄基环丁基)-N-羟基脲
m.p.169-170℃.
IR(KBr)v3455,3335,3190,1615,1571,1474cm-1.
1H NMR(DMSO-d6)δ9.11(s,1H),7.30-7.13(m,5H),6.22(br s,2H),4.52-4.41(m,1H),2.62(d,J=6.59Hz,2H),2.12-1.86(m,5H).
实施例97 N-羟基-N-[顺式-3-(2-苯氧基苯基)环丁基]脲
m.p.155-157℃.
IR(KBr)3500,3350,1660,1580,1485cm-1.
1H NMR(DMSO-d6)δ9.13(s,1H),7.40-7.12(m,5H),7.09-7.03(m,1H),6.90-6.83(m,3H),6.26(s,2H),4.60-4.53(m,1H),3.19-3.12(m,1H),2.32-2.22(m,4H).
实施例98 N-[3-(2-呋喃基)环丁基甲基]-N-羟基脲
步骤1,[3-(2-呋喃基)-3-羟基]环丁基甲酸乙酯
将呋喃(1.67ml,23mmol)的THF(20ml)溶液冷却至-78℃,用正丁基锂(1.55M己烷液,14.8ml,23mmol)处理。所得溶液升温至-10至0℃之间并保持该温度1小时。然后将混合物冷却至-78℃,搅拌下于-78℃添加3-氧代环丁烷基甲酸乙酯(3.0g,21mmol)的THF(30ml)溶液。于-78℃搅拌0.5小时后,用氯化氨水溶液使混合物终止反应,产物用醚提取并用硫酸镁干燥。除去溶剂得到油状物,用硅胶柱(EtOAc/正己烷(1∶5)纯化,得到标题化合物(1.39g,产率31.5%),无色油状物。
步骤2,3-(2-呋喃基)环丁基甲酸乙酯
充氮和搅拌下,将四碘化二磷(2.50g,4.4mmol)的无水苯(40ml)混悬液加热几分钟,得到橙色溶液,向其中一次性添加上述步骤1制得的化合物(1.54g,7.3mmol)的无水苯(20ml)溶液。所得混合物于80℃加热15分钟,然后用碳酸氢钠水溶液终止反应。有机相用醚提取,提取液用亚硫酸钠液、水和盐水洗涤。有机相用硫酸钠干燥。除去溶剂,得到标题化合物(1.42g,产率99.8%),黄色油状物。
步骤3,N-[3-(2-呋喃基)环丁基甲基]-N-羟基脲
按照实施例15所述的方法,将上述步骤2制得的化合物转化为标题化合物。粗品用乙酸乙酯/正己烷重结晶,得到标题化合物(199g,产率12.5%),m.p.89-100℃。
IR(KBR)v3460,3300,1640,1560,1510cm-1.
1H NMR(DMSO-d6)9.19(s,0.4H),9.16(s,0.6H),7.52-7.49(m,1H),
6.36-6.32(m,1H),6.21(s,1H),6.16-6.08(m,1H),3.48(d,J=7.33Hz,0.8H),3.36(d,J=6.96Hz,1.2H),3.49-3.29(m,1H),2.37-2.27(m,2H),2.17-2.06(m,1H),1.89-1.78(m,2H).
实施例99 N-[反式-3-(3-氟苯基)环戊基]-N-羟基脲
按照实施例100所述方法,由顺式-3-(3-氟丙基)环戊烷-1-醇制备了标题化合物(用乙酸乙酯/己烷重结晶),m.p.113.0-114.0℃。
IR(KBr)v3500,3200,2950,2850,1640,1580,1450cm-1.
1H NMR(DMSO-d6)δ9.12(s,1H),7.34(m,1H),7.13(m,3H),6.29(br s,2H),4.74(m,1H),3.17(m,1H),2.06-1.72(m,5H),1.51(m,1H).
Anal.Calc.for C12H15N2O2F:C,60.49;H,6.34;N,11.76.Found:C,60.31;H,6.44;N,11.82.
实施例100 N-[顺式-3-(3-氟丙基)环戊基]-N-羟基脲
步骤1,3-(3-氟苯基)环戊-2-烯-1-酮
将1-(3-氟苯基)-1,4-戊二酮(23g,0.12mmol)溶解在氢氧化钠(11g)的水(550ml)溶液中,溶液在100℃搅拌3小时。冷却至0℃后,过滤收集所得之棕色结晶,用水洗涤。用己烷重结晶得标题化合物(9g,产率45%)的黄色固体。
1H NMR(CDCl3)δ7.44(m,2H),7.33(m,1H),7.20(m,1H),6.57(m,1H),3.03(m,2H),2.61(m,2H).
步骤2,1-顺式-(叔丁基二甲基甲硅烷氧基)-3-(3-氟苯基)环戊烷
向上述步骤1产物(0.82g,4.6mmol)和氯化铈(Ⅲ)七水合物(1.7g,
4.6mmol)及MeOH(10ml)的混合物中,分批添加NaBH4(0.17g,4.6mmol)固体。混合物搅拌10分钟,用冷水骤冷,然后用乙酸乙酯(3x10ml)提取。合并提取液,用MgSO4干燥,真空除去溶剂,得到相应烯丙基醇的黄色固体。向烯丙醇(0.8g)的无水DMF(2ml)溶液中依次添加咪唑(0.75g,10mmol)和叔丁基二甲基甲硅烷氯化物(0.80g,5.5mmol)。在室温下将混合物搅拌3小时,添加水(10ml),反应混合物用乙酸乙酯提取并用1N HCl水溶液、饱和Na2HCO3水溶液和盐水洗涤。合并的提取液用MgSO4干燥并浓缩,得到相应甲硅烷基化的烯丙基醇的棕色油状物。
充氢气下搅拌甲硅烷基化的烯丙基醇、5%Pd/c(0.2g)和无水EtOH(5ml)的混悬液18小时,过滤除去催化剂。减压浓缩反应混合物,硅胶[乙酸乙酯/己烷(1∶9)]层析纯化,得到1.8g(产率80%)标题化合物的浅黄色油状物。
1H NMR(CDCl3)δ7.22(m,1H),7.03(m,2H),6.85(m,1H),4.35(m,1H),3.01(m,1H),2.32(m,1H),2.01(m,1H),1.88-1.55(m,4H).
步骤3,顺式-3-(3-氟苯基)环戊烷-1-醇
将上述步骤2制得的化合物(9.4g,30mmol)的THF(100ml)溶液冷却至0℃,添加正Bu4NF(1M的THF溶液,60ml)。将反应混合物升温至室温并搅拌1小时。混合物用乙酸乙酯稀释,用盐水洗涤,MgSO4干燥并真空浓缩。用硅胶柱层析(乙酸乙酯/己烷(1∶7))纯化,得到标题化合物(4.5g,产率83%)透明油状物。
1H NMR(CDCl3)δ7.24(m,1H),7.18(m,2H),6.87(m,1H),4.44(m,1H),3.03(m,1H),2.46(m,1H),2.08-1.78(m,3H),1.64(m,2H).
步骤4,1-反式-苯甲酰氧-3-(3-氟苯基)环戊烷
0℃下,向上述步骤3制得之化合物(4.5g,25mmol)和PPh3(7.2g,27.5mmol)的THF(15ml)溶液中依次添加苯甲酸(3.35g,27.4mmol,溶于10ml THF中)和二乙偶氮二羧酸酯(4.3ml,27.5mmol,溶于10ml THF中)。混合物升温至室温并搅拌2小时。溶液蒸发掉,残余物用硅胶柱层析[乙酸乙酯/己烷(1∶7)],得到标题化合物(6.2g,产率87%)。
1H NMR(CDCl3)δ8.05(m,2H),7.57(m,1H),7.45(m,2H),7.26(m,1H),6.96(m,3H),5.57(m,1H),3.43(m,1H),2.35(m,3H),2.00(m,2H),1.68(m,1H).
步骤5,反式-3-(3-氟苯基)-环戊烷-1-醇
向上述步骤4制得之化合物(6.10g,20mmol)的MeOH(25ml)和THF(25ml)溶液中,添加KOH(6g,0.11mol)和水(1ml)。搅拌2小时后,反应混合物用CH2Cl2提取,并用1N HCl水溶液,饱和HaHCO3水溶液和盐水洗涤,MgSO4干燥并浓缩。用硅胶柱层析(乙酸乙酯/己烷(1;6)),得到标题化合物(3.5g,产率97%)。
1H NMR(CDCl3)δ7.24(m,1H),7.01-6.83(m,3H),4.54(m,1H),4.45(br s,1H),3.40(m,1H),2.31-2.04(m,3H),1.86-1.57(m,3H).
步骤6,N-[顺式-3-(3-氟苯基)环戊基]羟基胺
向上述步骤5制得之化合物(3.2g,17mmol)和PPh3(6.06g,22mmol)和N,O-二叔丁氧羰基羟基胺(4.5g,18mmol)的THF溶液(冷却至-40℃)中,滴加二乙基偶氮二羧酸酯(3.8ml,22mmol)的THF(10ml)溶液。反应混合物升温至室温过夜,减压除去溶剂。硅胶柱层析(乙酸乙酯/己烷(1∶9)),得到6.7g粗品N,O-二叔丁氧羰基-N-[顺式-3-
(3-氟苯基)环戊基]羟基胺。搅拌下,向冷却至0℃的上述获得之保护的羟基胺的CH2Cl2(40ml)溶液中,缓慢添加三氟乙酸(12.5ml)。反应混合物升温至室温反应6小时。然后蒸除溶剂。所得残余物用饱和NaHCO3(50ml)水溶液溶解,用CH2Cl2(2x100ml)提取。合并的提取液用盐水(50ml)洗涤,MgSO4干燥,减压除去溶剂。硅胶柱层析(乙酸乙酯/己烷(1∶2)),得标题化合物(1.9g,产率64%),黄色固体。
1H NMR(CDCl3)δ8.44(br s,2H),7.22(m,1H),6.93(m,3H),3.76(m,1H),3.02(m,1H),2.42(m,1H),1.99(m,3H),1.86-1.61(m,2H).
步骤7,N-[顺式-3-(3-氟苯基)-环戊基]-N-羟基脲
搅拌下,向上述步骤6制得化合物(2.4g,12mmol)的THF(10ml)溶液中,添加三甲基甲硅烷基异氰酸酯(85%,2.4ml,18mmol),反应混合物在室温下搅拌1.5小时。加入甲醇(10ml),10分钟后减压除去溶剂,得白色固体。用IPE/己烷重结晶,得到标题化合物(1.6g,产率57%)的无色固体,m.p.104.2-105.7℃。
IR(KBr)v3500,2950,2900,1620,1570,1470,1150,880cm-1.
1H NMR(DMSO-d6)δ9.10(s,1H),7.32(m,1H),7.04(m,3H),6.29(s,2H),4.67(m,1H),3.00(m,1H),2.12-1.58(m,6H).
Anal.Calc.for C12H15N2O2F:C,60.49;H,6.34;N,11.76.Found:C,60.45;H,6.50;N,11.72.
实施例101 N-羟基-N-[反式-3-(4-苯氧基苯基)环戊基]脲
反式∶顺式=>20∶1
m.p.130.9-131.6℃.
IR(KBr)v3520,3400,3200,1650,1560,1510,1485,1440,1235cm-1.
1H NMR(DMSO-d6)δ9.10(s,1H),7.37(t,J=7.9Hz,2H),7.24(d,J=8.4Hz,2H),7.11(t,J=7.3Hz,1H),7.02-6.91(m,4H),6.27(s,2H),4.82-4.69(m,1H),3.23-3.06(m,1H),2.13-1.65(m,5H),1.58-1.40(m,1H).
实施例102 N-[3-(4-氟苯基)环戊基]甲基-N-羟基脲
步骤1,3-(4-氟苯基)环戊酮
按照M.KoloBielski et.al.,J.Am.Chem,Soc,79,5820(1957)的方法,使3-(4-氟苯基)环戊-2-烯-酮氢化而制得。
1H NMR(CDCl3)δ7.22(m,2H),7.02(m,2H),3.38(m,1H),2.66(dd,J=8.06Hz,1H),2.52-2.23(m,4H),1.95(m,1H).
步骤2,3-(4-氟苯基)环戊烷基甲醛
按照G.L.Grunewald,J.Med,Chem,32,478(1989)方法制备了标题化合物。
1H NMR(CDCl3)δ9.70(s,1H),7.19(m,2H),6.98(m,2H),2.98(m,2H),2.29-1.59(m,6H).
步骤3,3-(4-氟苯基)环戊基甲醇
将上述步骤2制得的甲醛(2.8g,14mmol)的MeOH(30ml)溶液冷却至0℃,缓慢添加NaBH4固体(0.54g,14mmol)。反应混合物升温至室温,搅拌30分钟,然后用冰水骤冷。反应混合物用乙酸乙酯(3x20ml)提取,合并的提取液用MgSO4干燥,减压除去挥发物,残余物用硅胶柱层析(乙酸乙酯/己烷(1∶7)),得到标题化合物(2.6g,产率92%)。
1H NMR(CDCl3)δ7.18(m,2H),6.96(m,2H),3.60(m,2H),3.05(m,1H),2.30-1.55(m,8H).
步骤4,N-[3-(4-氟苯基)环戊基]甲基-N-羟基脲
按照实施例100所述的方法,由上述步骤3产物制备了标题化合物(用MeOH/己烷重结晶),m.p.138.9-140℃。
IR(KBr)v3500,3350,3200,2860,1640,1570,1510,1470,1160cm-1.
1H NMR(DMSO-d6)δ9.21(s,1H),7.27(m,2H),7.08(m,2H),6.20(br s,2H),3.33(m,2H),3.06(m,1H),2.45(m,1H),2.09-1.21(m,6H).
计算值C13H17N2O2F:C,61.89;H,6.79;N,11.10.测定值C,61.68;H,6.95;N,11.04.
实施例103 N-[反式-3-(4-氟苯基)环戊基]-N-羟基脲
m.p.143.0-144.2℃.
IR(KBr)v3500,3200,2950,2850,1660,1580,1440,1180,1100,770cm-1.
1H NMR(DMSO-d6)δ9.12(s,1H),7.29(m,4H),6.28(br s,2H),4.72(m,1H),3.14(m,1H),1.95(m,5H),1.72(m,1H).
实施例104 N-[顺式-(3,4-二氟苯基)环戊基]-N-羟基脲
m.p.107.2-108.5℃.
IR(KBr)v3490,3200,2950,2850,1660,1570,1520,1450,1370,770cm-1.
1H NMR(DMSO-d6)δ9.10(s,1H),7.32(m,2H),7.10(m,1H),6.30(br s,2H),4.67(m,1H),2.97(m,1H),1.83(m,6H).
实施例105 N-[顺式-3-(2-氟苯基)环戊基]-N-羟基脲
m.p.118.2-119.3℃
IR(KBr)v3500,3200,2950,2870,1660,1640,1580,1490,1450,1220,750cm-1.
1H NMR(DMSO-d6)δ9.11(s,1H),7.36(m,1H),7.17(m,3H),6.28(br s,2H),4.66(m,1H),3.20(m,1H),1.84(m,6H).
实施例106 N-[反式-(3,4-二氟苯基)环戊基]-N-羟基脲
m.p.100.7-101.8℃
IR(KBr)v3500,3200,2950,2850,1650,1520,1440cm-1.
1H NMR(DMSO-d6)δ9.10(s,1H),7.31(m,2H),7.08(m,1H),6.27(br s,2H),4.74(m,1H),3.13(m,1H),1.86(m,5H),1.48(m,1H).
实施例107 N-羟基-N-[反式-3-(4-三氟甲苯基)环戊基]脲
m.p.135.1-136.3℃
IR(KBr)v3500,3450,2950,1640,840cm-1.
1H NMR(DMSO-d6)δ9.15(s,1H),7.63(d,J=8.06Hz,2H),7.46(d,J=8.06Hz,2H),6.28(br s,2H),4.75(m,1H),3.27(m,1H),1.91(m,5H),1.52(m,1H).
实施例108 N-羟基-N-(反式-2-苯基环戊基)脲
m.p.148.2-149.9℃.
IR(KBr)v3490,3200,1670,1580,1450,1160,790cm-1.
1H NMR(DMSO-d6)δ9.07(s,1H),7.26(m,4H),7.16(m,1H),6.18(br s,2H),4.58(m,1H),3.18(m,1H),2.25(m,1H),1.62(m,5H).
实施例109 N-[反式-3-(2,4-二氟苯基)环戊基]-N-羟基脲
m.p.113.0-114.1℃.
IR(KBr)v3500,3200,1620,1570,1420,1140,970cm-1.
1H NMR(DMSO-d6)δ9.13(s,1H),7.37(m,1H),7.14(m,1H),7.02(m,1H),6.30(br s,2H),4.74(m,1H),3.32(m,1H),2.04-1.50(m,6H).
实施例110 N-羟基-N-(顺式-2-苯基环戊基)脲
m.p.118.8-120.0℃.
IR(KBr)v3500,3350,3190,1650,1620,1460,800cm-1.
1H NMR(DMSO-d6)δ8.75(s,1H),7.29-7.08(m,5H),5.72(br s,2H),4.92(m,1H),3.05(m,1H),2.10-1.89(m,5H),1.54(m,1H).
实施例111 N-羟基-N-[顺式-3-(4-三氟甲苯基)环戊基]脲
m.p.124.2-125.5℃.
IR(KBr)v3490,3200,2990,2910,1660,1570,1440,1320,1120cm-1.
1H NMR(DMSO-d6)δ9.13(s,1H),7.49(d,J=8.06Hz,2H),7.48(d,J=8.06Hz,2H),6.29(br s,2H),4.70(m,1H),3.06(m,1H),2.11-1.61(m,6H).
实施例112 N-[顺式-3-(2,4-二氟苯基)环戊基]-N-羟基脲
m.p.125.2-126.0℃.
IR(KBr)v3490,3350,1610,1590,1510,1470,980cm-1.
1H NMR(DMSO-d6)δ9.10(s,1H),7.39(m,1H),7.15(m,1H),7.03(m,1H),6.29(br s,2H),4.67(m,1H),3.14(m,1H),2.06-1.61(m,6H).
实施例113 N-[顺式-3-(4-氟苯基)环戊基]-N-羟基脲
m.p.122.5-123.3℃.
IR(KBr)v3490,3200,2950,2850,1620,1570,1510,1250,930cm-1.
1H NMR(DMSO-d6)δ9.09(s,1H),7.28(m,2H),7.09(m,2H),6.28(s,2H),4.67(m,1H),2.93(m,1H),2.09-1.55(m,6H).
实施例114 N-羟基-N-[顺式-3-苯基环戊基]脲
m.p.132.0-134.3℃.
IR(KBr)v3470,3200,2870,1620,1570,1470,1150,800cm-1.
1H NMR(DMSO-d6)δ9.10(s,1H),7.26(m,5H),6.28(s,2H),4.70(s,1H),2.91(m,1H),2.06-1.58(m,6H).
实施例115 N-[顺式-3-(4-氯苯基)环戊基]-N-羟基脲
m.p.143.0-144.3℃.
IR(KBr)v3500,320,2950,1660,1630,1570,1450,830cm-1.
1H NMR(DMSO-d6)δ9.10(s,1H),7.31(m,4H),6.29(br s,2H),4.67(m,1H),2.96(m,1H),1.56-2.07(m,6H).
实施例116 N-羟基-N-[反式-3-苯基环戊基]脲
m.p.122.4-123.6℃.
IR(KBr)v3500,3350,3200,3000,2850,1610,1570,1500-1400,800cm-1.
1H NMR(DMSO-d6)δ9.11(s,1H),7.3-7.15(m,5H),6.28(s,2H),4.74(m,1H),3.14(m,1H),2.11-1.46(m,6H).
实施例117 N-[反式-3-(2-氟苯基)环戊基]-N-羟基脲
m.p.78.5-80.5℃.
IR(KBr)v3500,3300,2950,2850,1650,1560,1490,1220,750cm-1.
1H NMR(DMSO-d6)δ9.14(s,1H),7.22(m,4H),6.29(br s,2H),4.74(m,1H),3.46(m,1H),1.79(m,6H).
实施例118 N-[反式-3-(4-氟苯基)环戊基]-N-羟基脲
m.p.121.7-122.8℃.
IR(KBr)v3490,3350,3200,1610,1580,1510,1240,840cm-1.
1H NMR(DMSO-d6)δ9.11(s,1H),7.26(m,2H),7.08(m,2H),6.28(br s,2H),4.74(m,1H),3.14(m,1H),1.87(m,5H),1.47(m,1H).
实施例119 N-羟基-N-[顺式-3-(3-甲苯基)环戊基]脲
顺式∶反式=>20∶1
m.p.112.0-113.0℃.
IR(KBr)v3490,3350,3200,2950,1610,1585,1465,1425cm-1.
1H NMR(DMSO-d6)δ9.08(s,1H),7.16(t,J=7.3Hz,1H),7.09-6.92(m,3H),6.28(s,2H),4.7304.59(m,1H),2.94-2.83(m,1H),2.27(s,3H),2.07-1.55(m,6H).
实施例120 N-羟基-N-[反式-3-(3-甲苯基)环戊基]脲
反式∶顺式=>20∶1
m.p.109.9-110.8℃.
IR(KBr)v3475,3400,3200,2950,2870,1620,1570,1440cm-1.
1H NMR(DMSO-d6)δ9.10(s,1H),7.15(t,J=7.3Hz,1H),7.06-6.93(m,3H),6.28(s,2H),4.79-4.68(m,1H),3.17-3.04(m,1H),2.27(s,3H),2.14-1.64(m,5H),1.57-1.42(m,1H).
实施例121 N-羟基-N-[顺式-3-(4-甲苯基)环戊基]脲
顺式∶反式=>20∶1
Cis∶trans=>20∶1.
m.p.149.8-150.4℃.
IR(KBr)v3470,3250,2980,1660,1575,1520,1420,1140cm-1.
1H NMR(DMSO-d6)δ9.07(s,1H),7.15-7.06(m,4H),6.25(s,2H),4.72-4.59(m,1H),2.95-2.82(m,1H),2.25(s,3H),2.05-1.53(m,6H).
实施例122 N-羟基-N-[反式-3-(4-甲苯基)环戊基]脲
反式∶顺式=>20∶1
m.p.135.2-135.8℃.
IR(KBr)v3500,3340,3200,1660,1580,1460,1440cm-1.
1H NMR(DMSO-d6)δ9.10(s,1H),7.16-7.03(m,4H),6.27(s,2H),4.80-4.65(m,1H),3.18-3.02(m,1H),2.25(s,3H),2.10-1.61(m,5H),1.55-1.37(m,1H).
实施例123 N-羟基-N-[3-(3-甲氧苯基)环戊基]脲
顺式∶反式=9∶1
m.p.-(油)
IR(Liquid Cell)v3200,3020,2900,2875,1660,1585,1565,1440,1220,1210cm-1.
1H NMR(DMSO-d6)δ9.11(s,1H),7.19(t,J=7.7Hz,1H),6.40-6.21(m,3H),6.84(s,2H),4.75-4.59(m,1H),3.73(s,3H),3.00-2.82(m,1H),2.13-1.48(m,6H).
实施例124 N-羟基-N-[3-甲氧苯基)环戊基]脲
反式∶顺式=9∶1
m.p.-(油)
IR(Liquid Cell)v3025,2800,1670,1560,1520,1480,1430,1220,1210cm-1.
1H NMR(DMSO-d6)δ9.10(s,1H),7.18(t,J=7.9Hz,1H),6.86-6.68(m,3H),6.28(s,2H),4.81-4.67(m,1H),3.73(s,3H),3.19-3.04(m,1H),2.10-1.63(m,5H),1.58-1.40(m,1H).
实施例125 N-羟基-N-[顺式-3-(4-甲氧苯基)环戊基]脲
顺式∶反式=>20∶1
m.p.139.4-140.3℃.
IR(KBr)v3475,3350,3200,1620,1575,1520,1470,1260cm-1.
1H NMR(DMSO-d6)δ9.11(s,1H),7.16(d,J=8.4Hz,2H),6.84(d,J=8.4Hz,2H),6.28(s,2H),4.73-4.59(m,1H),3.71(s,3H),2.95-2.82(m,1H),2.05-1.56(m,6H).
实施例126 N-羟基-N-[反式-3-(4-甲氧苯基)环戊基]脲
反式∶顺式=>20∶1
m.p.133.7-134.6℃.
IR(KBr)v3475,3350,2950,2880,1610,1585,1515,1460,1445,1250cm-1.
1H NMR(DMSO-d6)δ9.08(s,1H),7.13(d,J=8.8Hz,2H),6.83(d,J=8.8Hz,2H),6.27(s,2H),4.80-4.64(m,1H),3.71(s,3H),3.17-3.02(m,1H),2.08-1.62(m,5H),1.55-1.36(m,1H).
实施例127 N-羟基-N-[顺式-3-(3-苯氧基苯基)环戊基]脲
顺式∶反式=20∶1
m.p.103.0-103.6℃.
IR(KBr)v3475,3325,3150,2900,1655,1580,1490,1250,1220,1165cm-1.
1H NMR(DMSO-d6)δ9.07(s,1H),7.38(dd,J=8.4,7.3Hz,2H),7.29(t,J=8.1Hz,1H),7.13(t,J=7.3Hz,1H),7.05-6.97(m,3H),6.92(d,J=1.8Hz,1H),6.79(dd,J=2.4,7.9Hz,1H),6.26(s,2H),4.72-4.50(m,1H),3.00-2.80(m,1H),2.05-1.51(m,6H).
实施例128 N-羟基-N-[反式-3-(3-苯氧基苯基)环戊基]脲
反式∶顺式=>20∶1
m.p.-(油)
IR(Liquid Cell)v3700,3550,3420,3020,1670,1650,1580,1560,1490,1440,1220cm-1.
1H NMR(DMSO-d6)δ9.11(s,1H),7.38(t,J=7.3Hz,2H),7.28(t,J=7.7Hz,1H),7.12(t,J=7.1Hz,1H),6.99(d,J=7.0Hz,3H),6.88(s,1H),6.77(d,7.7Hz,1H)6.29(s,2H),4.80-4.65(m,1H),3.21-3.04(m,1H),2.12-1.61(m,5H),1.58-1.38(m,1H).
实施例129 N-羟基-N-[顺式-3-(4-苯氧基苯基)环戊基]脲
顺式∶反式=>20∶1
m.p.139.0-139.8℃.
IR(KBr)v3475,3330,3200,2960,2880,1620,1575,1510,1490,1260cm-1.
1H NMR(DMSO-d6)δ9.09(s,1H),7.37(t,J=7.5Hz,2H),7.27(d,J=8.1Hz,2H),7.10(t,J=7.7Hz,1H),6.95(t,J=8.1Hz,4H),6.27(s,2H),4.72-4.60(m,1H),3.01-2.87(m,1H),2.09-1.54(m,6H).
实施例130 N-[(1-苯并环丁基)甲基]-N-羟基脲
m.p.119-121℃.
IR(nujol)v3450,3190,1670,1575,1340,1150,765,750cm-1.
1H NMR(CDCl3)δ9.15(s,1H),7.11(m,4H),5.50(s,2H),3.83(s,2H),3.83(m,1H),3.33(m,1H),2.98(d,J=4.3Hz,1H).
Claims (5)
1、制备下式化合物的方法,
式中,
R1是C1-C4烷基,NR2R3;
R2是氢和R3是氢,C1-C4烷基、芳基、或者由一个或多个选自下述取代基的取代的芳基,这些基团为卤素、C1-C6烷基、和C1-C6烷基磺酰基;
R4是氢;
A是C1-C2亚烷基;
每一个B独立地为卤素、硝基、氰基、-SH、羟基,C1-C6烷基,C1-C6烷氧基,卤代C1-C6烷基,或C1-C6硫代烷基;
每个Ar独立地为苯基、萘基、呋喃基、苯氧基苯基、或者被一个或多个选自下列取代基取代的任何前述基团,这些取代基选自羟基、卤素、C1-C6烷基,C1-C6烷氧基,C1-C6卤代烷基、和C1-C6烷基磺酰基;
Ar和B以及与它们相连接的碳原子一起可形成环;
n是0或1;
m是0-3;
p是1-4;
q是1或2;和
……表示可选择的化学键;
该方法包括:
(Ⅰ)在包括反应温度为-10℃至环境温度的条件下,用选自氢氧化铵、氢氧化钠、氢氧化钾和氢氧化锂的碱于溶剂体系统中选择性氢化下式的化合物:
式中Q是
(Ⅱ)在包括反应温度为环境温度至回流温度的条件下,于反应惰性溶剂中将下式之化合物与三甲基甲硅烷基异氰酸酯反应:
式中Q的定义同上;或者
(Ⅲ)在包括反应温度为环境温度至溶剂沸点温度的反应条件下,于反应惰性溶剂中将下式之化合物与氯化氢气体反应,随后用光气处理,
式中Q的定义同上。
2、根据权利要求1的方法,其中:
当采用方法(Ⅰ)时,所述溶剂体系选自下述的一种或多种溶剂,所述溶剂包括水、甲醇、乙醇、丙醇和四氢呋喃;
当采用方法(Ⅱ)时,所述反应惰性溶剂选自四氢呋喃、二噁烷、二氯甲烷和苯;和
当采用方法(Ⅲ)时,所述反应惰性溶剂选自苯和甲苯。
3、根据权利要求1或2的方法,它还包括所述制得化合物的分离步骤。
4、根据权利要求1-3中任一权项的方法,其中R4是氢。
5、根据权利要求4的方法,其中:
R1是氨基;
n是0;
m是0;
p是2或3;
q是1;
Ar是苯基、氟苯基或苯氧基苯基;
……代表没有化学键。
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JP2323814A JP3007138B2 (ja) | 1990-11-27 | 1990-11-27 | 新規なヒドロキサム酸とn―ヒドロキシ尿素誘導体およびそれらの組成物 |
JP323814/90 | 1990-11-27 |
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US5434151A (en) * | 1992-08-24 | 1995-07-18 | Cytomed, Inc. | Compounds and methods for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase |
US5552419A (en) * | 1993-01-06 | 1996-09-03 | Ciba-Geigy Corporation | Arylsulfonamido-substituted hydroxamic acids |
US5506242A (en) * | 1993-01-06 | 1996-04-09 | Ciba-Geigy Corporation | Arylsufonamido-substituted hydroxamic acids |
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WO1994018158A1 (en) * | 1993-02-15 | 1994-08-18 | Pfizer Inc. | Spiroalkylhydroxyureas for use as lipoxygenase inhibitors |
ES2116591T3 (es) * | 1993-04-07 | 1998-07-16 | Pfizer | Cicloalquilhidroxiureas y su uso como inhibidores de la lipoxigenasa. |
DK0710233T3 (da) * | 1993-07-20 | 2000-01-03 | Pfizer | Heteroarylcycloalkenylhydroxyurinstoffer |
TW418089B (en) * | 1993-08-19 | 2001-01-11 | Pfizer | Pharmaceutical composition comprising phenoxyphenyl cyclopentenyl hydroxyureas (the dextrorotary isomers) |
WO1995017379A1 (en) * | 1993-12-22 | 1995-06-29 | Pfizer Inc. | Phenylthiophenyl cycloalkenyl hydroxyureas as lipoxygenase inhibitors |
US5703093A (en) * | 1995-05-31 | 1997-12-30 | Cytomed, Inc. | Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders |
US5750565A (en) | 1995-05-25 | 1998-05-12 | Cytomed, Inc. | Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders |
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WO1996016054A1 (en) * | 1994-11-18 | 1996-05-30 | Pfizer Pharmaceuticals Inc. | Cycloalkenyl-n-hydroxyureas |
CA2210905A1 (en) * | 1995-02-02 | 1996-08-08 | Nikken Chemicals Co., Ltd. | N-hydroxyurea derivatives |
CA2176854A1 (en) * | 1995-06-07 | 1996-12-08 | Daniel J. Keavy | N-acyl-2 aryl cyclopropylmethylamine derivatives as melatonergics |
US6828460B2 (en) | 1999-03-22 | 2004-12-07 | Pfizer Inc. | Resorcinol derivatives |
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FI89709C (fi) | 1985-03-16 | 1993-11-10 | Wellcome Found | Foerfarande foer framstaellning av terapeutiskt anvaendbara arylderivat |
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DE4124345A1 (de) * | 1991-07-23 | 1993-01-28 | Gruenenthal Gmbh | Substituierte 3,4-dihydronaphthaline, diese verbindungen enthaltende arzneimittel und verfahren zur herstellung dieser verbindungen und arzneimittel |
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