CN1022241C - 3-酰基-2-氧代吲哚-1-羧酰胺抗炎剂的前药化合物的制备 - Google Patents
3-酰基-2-氧代吲哚-1-羧酰胺抗炎剂的前药化合物的制备 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
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- 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
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
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- Pain & Pain Management (AREA)
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- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
公开了制备下式的烯醇醚和酯类的方法,这类化合物可用作已知抗炎和止痛药物3-酰基-2-氧代吲哚-1-羧酰胺的前药形式,式中X和Y各为氢、氟或氯;R1是2-噻吩基或苄基,R是键烷酰基、环烷基羰基、苯基链烷酰基、氯苯甲酰基、甲氧基苄基、苯基、噻吩甲酰基末位烷氧羰基链烷酰基、烷氧羰基、苯氧羰基、1-烷氧基烷基、1-烷氧羰氧基烷基、烷基、烷磺酰基、甲苯磺酰基或二烷氧基氧合磷基。
Description
本发明涉及一些抗炎药物,并且特别涉及到3-酰基-2-氧代吲哚-1-羧酰胺(一类已知的非甾族抗炎药物)的烯醇酯类和醚类前药。
美国专利3634453中首次报道了将氧代吲哚用作抗炎药物,其组成是1-取代-2-氧代吲哚-3-羧酰胺。最近,美国专利4556672中公开了一系列3-酰基-2-氧代吲哚-1-羧酰胺,它们是环氧酶(CO)和脂氧合酶(LO)的抑制剂,并可用作哺乳类动物的止痛药和抗炎药。
本发明提供了下式所示的抗炎的醚类或酯类前药,
式中X和Y各为氢,氟或氯;R1是2-噻吩塞或苄基;R是2至10个碳原子的链烷酰基,5至7个碳原子的环烷基羰基,7至10个碳原子的苯基链烷酰基,氯代苯甲酰基,甲氧苯甲酰基,噻吩甲酰基,末位烷氧羰基取代的链烷酰基(所述烷氧基具有1至3个碳原子,所述链烷酰基具有3至5个碳原子);2至10个碳原子的烷氧羰基;苯氧羰基;1-(酰氧基)烷基(所述酰基具有1至4个碳原子,所述烷基具有2至4个碳原子);1-(烷氧羰氧基)烷基(所述烷氧基具有2至5个碳原子,所述烷基具有1至4个碳原子);1至3个碳原子的烷基;1至3个碳原子的烷磺酰基;甲苯磺酰基或二烷氧基氧合磷基(所述烷基各具有1至3个碳原子)。
特别优选的式(Ⅰ)化合物为其中R1是2-噻吩基,X是氯,Y是氢及R是2至10个碳原子的链烷酰基的化合物。这一组中优选的
是R为乙酰基,丙酰基和异丁酰基的化合物。
第二组优选的式(I)化合物为其中R1是2-噻吩基,X是氯,Y是氢及R是7至10个碳原子的苯基链烷酰基的化合物。这一组中特别优选的是R为苯乙酰基的化合物。
第三组优选的式(I)化合物为其中R1是2-噻吩基,X是氯,Y是氢及R是末位烷氧羰基取代的链烷酰基(所述烷氧基具有1至3个碳原子,所述链烷基具有3至5个碳原子)的化合物。这一组中特别优选的是R为末位乙氧羰基取代的丙酰基的化合物。
第四组优选的式(I)化合物为其中R1是2-噻吩基,X是氯,Y是氢及R是2至10个碳原子的烷氧羰基的化合物。这一组中特别优选的是R为甲氧羰基、乙氧羰基和正已氧羰基的化合物。
第五组优选的式(I)化合物为其中R1是2-噻吩基,X是氯,Y是氢及R是1-(烷基羰氧基)烷基(所述烷氧基具有2至5个碳原子,所述烷基具有1至4个碳原子)的化合物。这一组中特别优选的是R为1-(乙氧羰氧基)乙基的化合物。
第六组优选的式(I)化合物为其中R1是2-噻吩基,X是氯,Y是氢及R是1至3个碳原子的烷磺酰基的化合物。这一组中特别优选的是R为甲磺酰基的化合物
第七组优选的式(I)化合物为其中R1是2-噻吩基,X是氯,Y是氯及R是2至10个碳原子的链烷酰基的化合物。这一组中特别优选的是R为乙酰基、丙酰基和异丁酰基的化合物。
第八组优选的式(I)化合物为其中R1是2-噻吩基,X是氯,Y是氯及R是2至10个碳原子的烷氧羰基的化合物。这一组中特别优选的是R为甲氧羰基、乙氧羰基和正已氧羰基的化合物。
第九组优选的式(I)化合物为其中R1是苄基,X是氢,Y是氟及R是2至10个碳原子的链烷酰基的化合物。这一组中特别优选的是R为乙酰基的化合物。
第十组优选的式(I)化合物为其中R1是苄基,X是氢,Y是
氟及R是2至10个碳原子的烷氧羰基的化合物。这一组中特别优选的是R为甲氧羰基的化合物。
本发明还包括治疗哺乳动物体炎症的方法,该方法包括给所述哺乳动物服用抗炎有效量的选自式(Ⅰ)所示化合物的药物。
本发明的烯醇醚类和酯类不是烯醇酸(母体化合物则是烯醇酸),与所述母体化合物相比,它们减少了胃刺激作用。
术语“前药”是指作为药物前体的化合物,将其服用并吸收以后,经过某些代谢过程在体内释放出药物。
虽然所有常规给药途径都可用于本发明化合物,但较好的给药途径是口服。在胃肠吸收以后,本发明化合物在体内水解为相应的式(Ⅰ)(式中R是氢)的化合物或其盐。因为本发明的前药不是烯醇酸,于是就将胃肠道在酸性母体化合物中的暴露缩减到最低限度。此外,因为已经注意到胃肠道并发症是酸性非甾族抗炎药物的主要不利反应[参见例如DelFavero,“Side Effects of drugs Annual7”,Dukes and Elis,Eds.Excerpta Medica,Amsterdam,1983,P104-115],本发明化合物(Ⅰ)明显地优于母体烯醇化合物。
在将3-酰基-2-氧代吲哚-1-羧酰胺转变成式(Ⅰ)化合物时,3-位上的环外双键上的取代基可以是顺式、反式或二者的混合物。因此,结构式为
的化合物或其混合物便可用下式来表示:
各种形式的异构体都被认为是本发明的一部分。
有两种方法可用于本发明化合物的合成;第一种方法包括在0℃用比等摩尔稍微过量的所需的酰氯、氯甲酸酯、
盐或烷基化试剂处理适当的3-酰基-2-氧代吲哚-1-羧酰胺和等摩尔量的三乙胺在反应惰性溶剂如氯仿中的溶液。将反应液温热至室温并保持约2至3小时。如果起始物氧代吲哚没有完全反应,则将反应液冷至0℃,加入另外的酰化剂或烷基化剂,重复该过程,直至起始物氧代吲哚消耗掉。
先用1N盐酸洗涤,再用饱和碳酸氢钠溶液提取,然后使产物从反应溶剂中分离出来。真空除去溶剂后,剩下的产物用重结晶或层析法纯化。
用于制备本发明产物的第二种方法包括在无水的反应惰性溶剂(如丙酮)中使适当的3-酰基-2-氧代吲哚-1-羧酰胺与三倍摩尔过量的所需α-氯烷基碳酸酯、五倍摩尔过量的碘化钠和二倍摩尔过量的无水碳酸钾反应,并将反应混合物加热回流16小时。
用水稀释反应混合物,用与水不混溶的溶剂如乙醚或氯仿提取产物。将含有产物的溶液浓缩,得到粗产物,可将其用重结晶和/或层析法纯化。
所需起始原料3-酰基-2-氧代吲哚-1-羧酰胺可通过本领域熟知的方法得到,例如参见上面引用的有关这些化合物的参考文献。上面提到的其它起始试剂可由市场购得,或可以通过熟知的方法制得。
按照已知的方法,例如大鼠足水肿试验、辅药诱导的大鼠关节炎试验或苯基苯醌诱导的小鼠扭动试验,来评价式(Ⅰ)所示前药的抗炎和止痛活性,这些方法以前曾用以评价母体化合物并且叙述在上面引用的参考资料中以及其它文献中;例如参见C.A.Winter,“Progress in Drug Research”,由E.Jucker,Birkhauser Verlag,Basel编辑,
第10卷,1966,139-192页。
在用T.J.Carty等人在Prostaglandins第19卷51-59页(1980)中所述方法的改进方法进行的试验中发现,与母体3-酰基-2-氧代吲哚-1-羧酰胺比较,式(Ⅰ)的新前药对由花生四烯酸合成前列腺素的抑制能力有所减弱。在这个改进方法中,用大鼠嗜碱白血病细胞(RBL-1)培养物(由Jakschik等人在上述期刊第16卷733页(1978)中所述方法制备)代替小鼠成纤维细胞(MC5-5)和兔滑液细胞培养物。这样,本发明化合物本身作为抗炎药是相对不活泼的,但它们通过在体内的水解作用能产生一种活性抗炎化合物。因为式(Ⅰ)化合物不是烯醇酸类,并且已知水解作用发生在前药离开胃之后,因此,它们大大减弱了由于口服母体烯醇化合物而引起的胃刺激作用。
按摩尔计算,本发明前药通常按与已知的衍生该前药的3-酰基-2-氧代吲哚-1-羧酰胺相同的水平和次数给药。然而,当在抑制疼痛和炎症中需要较高剂量时,本发明化合物的非烯醇性质通常允许使用较高的耐受口服剂量。
如上面引用的参考资料所述,本发明前药的制剂方式和给药途径也与已知母体化合物的相同。较好的给药途径是口服,这样正好利用了该化合物非烯醇性质的特殊优点。
本发明通过下列实例予以说明,但并不限于这些实例的具体细节。
实例1
一般步骤
方法A
往3-酰基-2-氧代吲哚-1-羧酰胺在氯仿中形成的浆液中加入等摩尔量的三乙胺。将所得溶液冷至0℃,并加入稍微过量的适当的酰氯、氯代甲酸酯、
盐或烷基化试剂。在0℃搅拌2小时后再在室温搅拌2小时,如果3-酰基氧代吲哚-1-羧酰胺没有消耗掉,再将混合
物冷至0℃,并且加入另外的酰氯、氯代甲酰酯或
盐,将混合物在0℃搅拌2小时,再在室温搅拌2小时。可以重复进行该过程,以便让3-酰基氧代吲哚-1-羧酰胺完全消耗掉。反应完全后,将混合物过滤,用1N盐酸(2×)和饱和碳酸氢钠溶液(2×)洗涤滤液。有机层用MgSO4干燥,过滤并真空浓缩。所得产物用重结晶或层析法纯化。
方法B
将3-酰基-2-氧代吲哚-1-羧酰胺、3倍摩尔过量的适当的α-氯代烷基-或α-氯代(芳烷基)碳酸酯、5倍摩尔过量的碘化钠、和2倍摩尔过量的无水碳酸钾(在165℃和高真空下干燥1小时)在丙酮(用分子筛干燥过)中的混合物回流16小时。将混合物冷却,然后用水稀释、用乙醚提取。合并乙醚提取液,用硫酸镁干燥,过滤,真空浓缩滤液。所得粗产物用层析法和/或重结晶法纯化。
实例2
按照所述方法,由所需试剂开始,制得下述前药:
酯:
(R=-COCH3)-方法A;产率53%
(用2-丙醇重结晶后);mp 173-176℃;
质谱 m/e(相对强度)M+,362(<1.0),322(4.2),320(11.0),296(1.8),279(18.2),277(44.4),248(10.6),195(77.7),193(100),185(12.3),165(13.4),137(42.8),111(88.2),102(20.0),83(23.9);1H-NMR(CDCl3)δ 2.39,2.53(3H,2s),5.31(1H,br s),7.2-7.35(2H,m),7.48,7.55(1H,2d,J=2.1Hz),7.6-8.3(3H,m),8.54(1H,br s).分析计算 C16H11ClN2O4S(362.79):C,52.97;H,3.06;N,7.72.实测:C,52.91;H,2.95;N,7.97.
(R=-COCH2CH3)-方法A;产率18%
(用2-丙醇重结晶后);mp 183-185℃;
质谱 m/e(相对强度)M+,378,376(<1,1.2),333(0.7),322(6.4),320(18.4),279(17.8),277(44.3),250(2.3),248(9.0),195(27.0),193(100),137(7.8),111(24.1),57(30.0);1H-NMR(d6-Me2SO)δ 1.0-1.3(3H,m),2.7-3.0(2H,q,J=7.5Hz),6.9-7.6(3H,m),7.9-8.4(5H,m).分析计算 C17H13ClN2O4S(376.68):C,54.18;H,3.48;N,7.43.实测:C,53.86;H,3.33;N,7.28.
(R=-CO(CH2)5CH3)-方法A;产率29%
(用2-丙醇重结晶后);mp 189-190℃;
质谱 m/e(相对强度)M+,432(0.8),322(13.8),320(37.5),279(34.8),277(87.0),250(5.0),248(17.3),195(26.6),193(100);1H-NMR(CDCl3)δ 0.95(3H,m),1.32-1.55(6H,m),1.85(2H,五重峰,J=8Hz),2.83(2H,t,J=8Hz),5.35(1H,br s),7.25(1H,m),7.32(1H,m),7.60(1H,d),7.72(1H,m),8.27(1H,m),8.31(1H,d,J=10Hz),8.62(1H,br s).分析计算
C22H21ClN2O4S(432.91):C,58.26;H,4.89;N,6.47.实测:C,58.18;H,4.87;N,6.42.
(R=-CO(CH2)8CH3)-方法A;产率8%
(用2-丙醇重结晶后);mp 120-122℃;
质谱m/e(相对强度)M+,431(<1),322(2.9),320(8.6),279(16.8),277(42.6),262(0.9),260(2.1),250(2.4),248(9.0),195(26.4),193(100),155(7.4),137(6.3),111(18.2);1H-NMR(d6-Me2SO)δ 0.87(3H,s),1.30(13H,br s),1.50(1H,m),1.65(1H,m),2.20(1H,t,J=7.2Hz),2.70(1H,t,J=7.3Hz),7.1-8.5(7H,m).分析计算 C24H27ClN2O4S(474.75):C,60.68;H,5.73;N,5.90.实测:C,60.64;H,5.76;N,5.88.
(R=-COCH(CH3)2)-方法 A;产率37%
(用2-丙醇重结晶后);mp 189-191℃;
质谱m/e(相对强度)M+,392,390(1.2,3.5),322,320(11.7,30.2),279,277(19.2,48.7),250,248(4.6,15.5),195,193(28.7,100);1H-NMR(CDCl3)δ 1.35(3H,d,J=8Hz,异构体A),1.45(3H,d,J=8Hz,异构体B),2.93(1H,七重峰,J=8Hz,异构体A),3.05(1H,七重峰,J=8Hz,异构体B),5.38(1H,br s,异构体A),5.45(1H,br s,异构体B),7.2-7.4(2H,m),7.54(1H,d),7.7-7.8(2H,m),8.2-8.3(1H,m),8.48(1H,br s,异构体B),8.55(1H,br s,异构体A)(注:异构体A与B的比例大约是80∶20).精确质量计算 C18H15ClN2O4S:390.0449.实测:390.0462.
(R=-COC(CH3)3)-方法A;产率51%
(用2-丙醇重结晶后);mp 198-200℃;
质谱m/e(相对强度)M+,404(0.3),320(2.4),277(22.0),259(1.1),248(8.3),193(66.6),
137(6.6),111(19.1),102(2.4),85(21.1),57(100);1H-NMR(CDCl3)δ 1.39(9H,s),5.47(1H,br s),7.23(2H,m),7.50(1H,d,J=2.2Hz),7.71(1H,dd,J=1.1,5.0Hz),7.77(1H,dd,J=1.1,3.8Hz),8.25(1H,d,J=8.8Hz),8.57(1H,br s).分析计算 C19H17ClN2O4S(404.85):C,56.36;H,4.23;N,6.92.实测:C,56.05;H,4.23;N,6.86.
(R=-CO(环己基))-方法A;产率10%
(用2-丙醇重结晶后);mp 189-190℃;
质谱m/e(相对强度)M+,430(0.7),381(<1),322(2.3),320(6.5),279(8.0),277(19.8),195(16.3),193(60.0),111(67.1),83(100),55(25.8);1H-NMR(d6-Me2SO)δ 1.05-1.70(11H,一组多重峰)。6.95-7.10(1H,m),7.18(1H,t,J=4.4Hz),7.31(1H,dd,J=2.2,8.8Hz),7.4(1H,m),7.70-8.15(4H,一组多重峰),分析计算 C21H19ClN2O4S(429.72):C,58.53;H,4.44;N,6.50.实测:C,58.34;H,4.32;N,6.43.
(R=-COPh)-方法A;产率44%
(用乙酸重结晶后);mp 228-230℃;质谱 m/e(相对强度)M+,424(3.0),381(1.9),277(3.9),260(6.9),248(10.2),232(0.9),212(2.3),185(4.7),168(24.1),140(6.5),105(100),77(27.1);1H-NMR(CDCl3)δ 5.55(1H,br s),7.30(3H,m),7.55(3H,m),7.65(1H,m),7.74(1H,dd,J=1.0,5.0Hz),7.84(1H,dd,J=1.0,3.8Hz),8.2-8.3(3H,m),8.45(1H,br s).分析计算 C21H13ClN2O4S·H2O(442.87):C,56.95;H,3.41;N,6.32.实测:C,57.24;H,3.08;N,6.09.
(R=-COCH2Ph)-方法A;产率3%
(用硅胶过滤)(10∶90-甲醇/氯仿)和用2-丙醇重结晶两次以后)mp 207-208℃;质谱 m/e(相对强度)M+,438(<1),395(<1),322(9.6),320(26.4),279
(17.1),277(43.1),195(14.6),193(54.3),91(100);1H-NMR(CDCl3/d6-Me2SO)δ 3.96(2H,s),6.20(1H,br s),7.02(1H,dd,J=4.0,5.1Hz),7.15(1H,dd,J=2.2,8.8Hz),7.3-7.4(6H,m),7.57(1H,dd,J=1.2,5.1Hz),7.90(1H,dd,J=1.2,4.0Hz),8.15(1H,d,J=8.8Hz),8.30(1H,br s).分析计算 C22H15ClN2O4S(438.87):C,60.20;H,3.45;N,6.38.实测:C,60.53;H,3.38;N,6.18.
(R=-CO(CH2)3Ph)-方法A;产率13%
(用2-丙醇重结晶后);mp 168-171℃;
质谱m/e(相对强度)M+,未观察到,423(<1),322(1.0),320(2.9),279(10.2),277(25.7),250(1.5),248(5.6),195(26.7),193(100),158(0.7),147(72.1),91(99.5);1H-NMR(d6-Me2SO)δ 1.75-2.05(2H,m),2.22(1H,t,J=7.4Hz),2.55-3.00(3H,m),6.90-7.65(9H,m),7.85-8.50(4H,m).分析计算 C24H19ClN2O4S(466.75):C,61.73;H,4.10;N,5.99.实测:C,61.74;H,4.02;N,5.89.
(R=-CO(3-Cl-Ph)-方法A;产率26%(用2-丙醇/二甲基甲酰胺重结晶以后);mp210-218℃;质谱 m/e(相对强度)M+,460,458(0.5,0.6),279(1.5),277(3.9);250(0.9),248(2.8),195(1.3),193(4.6),141(43.0),139(100),113(8.8),111(32.8);1H-NMR(CDCl3)δ 5.28(1H,br s),7.25(2H,m),7.51(2H,m),7.62(1H,m),7.74(1H,dd,J=1.1,5.0Hz),7.84(1H,dd,J=1.1,3.8Hz),8.07(1H,m),8.16(1H,m),8.27(1H,d,J=8.8Hz),8.41(1H,br s).分析计算 C21H12Cl2N2O4S(459.29):C,54.91;H,2.63;N,6.10.实测:C,54.85;H,2.59;N,6.04.
(R=-CO(4-MeO-Ph)-方法A;产率11%(用硅胶过滤)(5∶95-甲醇/氯仿)(并用2-丙醇重结晶以后);mp 198-199℃;质谱 m/e(相对强度)M+,454(0.3),411(0.3),279(0.3),277(0.6),250(1.3),248(4.2),195(1.1),193(4.0),135(100);1H-NMR(CDCl3)δ 4.05,4.10(3H,2s),5.35,5.46(1H,2 br s),7.15(2H,m),7.40(3H,m)7.68(1H,d,J=2.1Hz),7.86(1H,dd,J=1.1,5.0Hz),7.97(1H,dd,J=1.1,3.8Hz),8.29(1H,m),8.41(1H,m),8.60,8.77(1H,2 br s).分析计算 C22H15ClN2O5S(454.87):C,58.09;H,3.32;N,6.16.实测:C,57.99;H,3.22;N,6.07.
(R=-CO(2-噻吩基))-方法A;产率16%
(经过两次闪式层析以后)(第一次:氯仿;第二次:0.5∶99.5的甲醇/氯仿);mp 220-222℃;
质谱 m/e(相对强度)M+,432,430(0.4,1.1),389(0.4),387(0.7),279(0.6),277(1.7),113(5.1),111(100);1H-NMR(d6-Me2SO)δ 7.3-7.5(4H,m),7.8-8.4(7H,m).精确质量计算 C19H11ClN2O4S2:429.9849.实测:429.9825.
(R=-COCH2CH2CO2Et)-方法A;产率72%
(用2-丙醇重结晶后);mp 132-140℃;
质谱m/e(相对强度)M+,448(<1),405(<1),360(<1),305(1.3),303(3.7),279(2.4),277(6.4),195(8.9),193(32.9),129(100),111(12.6),101(74.3);1H-NMR(d6-Me2SO)δ 1.15(3H,m),2.5(2H,m),2.55-3.2(2H,一组复合多重峰),4.05(2H,m),6.90-7.45(3H,一组复合多重峰),7.70(1H,m),7.85-8.45(4H,一组复合多重峰).分析计算 C20H17ClN2O6(448.87):C,53.51;H,3.82;N,6.24.实测:C,53.49;H,3.70;N,6.23.
碳酸酯:
(R=-COOCH3)-方法A;产率29%
(用2-丙醇/氯仿重结晶以后)mp 180℃软化,熔化 200℃;质谱 m/e(相对强度)M+,380,378(8.5,23.8),337(7.2),335(21.2),293(17.3),291(39.8),250(28.3),248(100),195(24.9),193(86.2),111(88.6);1H-NMR(d6-Me2SO)δ 3.90,3.95(3H,2s),7.3-7.5(3H,m),7.95-8.05(2H,m),8.15-8.25(3H,m).分析计算 C16H11ClN2O5S(378.22):C,50.73;H,2.93;N,7.39.实测:C,50.84;H,2.93;N,7.34.
(R=-COOCH2CH3)-方法A;产率24%
(用2-丙醇重结晶后);mp 170-175℃;
质谱 m/e(相对强度)M+,392(<1.0),320(1.2),305(3.9),277(22.5),259(2.6),248(17.0),193(100),185(7.2),165(4.0),111(18.8);1H-NMR(CDCl3)δ 1.42(3H,t,J=7.1Hz),4.39(2H,q,J=7.1Hz),5.41(1H,br s),7.25(2H,m),7.48,7.66(1H,2d,J=2.1和2.2Hz)7.75(1H,m),8.25(2H,m),8.57(1H,br s).分析计算 C17H13ClN2O5S(392.79):C,51.98;H,3.34;N,7.13.实测:C,51.90;H,3.26;N,6.93.
(R=-COOCH(CH3)2)-方法A;产率37%
(用2-丙醇重结晶后);mp 185-186℃;
质谱 m/e(相对强度)M+,322,320(1.8,6.5),303(1.6),279(15.2),277(41.3),250(2.2),248(8.5),193(100),167(1.7),165(2.6),139(1.3),137(4.3),111(12.4),102(8.0);1H-NMR(d6-Me2SO)δ 1.34,1.37(6H,2s),5.00(1H,七重峰,J=6.2Hz),7.35(1H,t,J=4.3Hz),7.50(1H,dd,J=8.7Hz),7.55(1H,m),7.96,8.05(2H,2 br s),8.17(2H,m),8.25(1H,m).
分析计算 C18H15ClN2O5S(406.69):C,53.14;H,3.72;N,6.89.实测:C,52.93;H,3.65;N,6.82.
(R=-COO(CH2)5CH3)-方法A;产率39%
(用2-丙醇重结晶后);mp 110-144℃;
质谱m/e(相对强度)M+,448(0.3),405(<1),322(1.7),320(4.5),279(15.9),277(39.9),195(29.8),193(100),111(14.8);1H-NMR(d6-Me2SO)δ 0.85(3H,br t,J=6.6Hz),1.3(6H,m),1.6(2H,m),4.35(2H,t,J=6.2Hz),7.35(1H,t,J=4.3),7.4-7.55(2H,m),7.95-8.05(2H,m),8.15-8.25(3H,m).分析计算 C21H21ClN2O5S(448.91):C,56.18;H,4.72;N,6.24.实测:C,56.11;H,4.60;N,6.16.
(R=-COO(CH2)8CH3)-方法A;产率21%
(用2-丙醇重结晶后);mp 118-120℃;
质谱 m/e(相对强度)M+,490(0.6),368(0.5),322(4.9),320(2.2),279(32.6),277(79.3),250(4.9),248(16.1),195(28.5),193(100);1H-NMR(CDCl3)δ 0.89(3H,m),1.2-1.5(12H,m),1.76(2H,m),4.34(2H,t,J=6.6Hz),5.33(1H,br s),7.24(1H,m),7.32(1H,dd,J=2.2,8.8Hz),7.68(1H,d,J=2.1Hz),7.74(1H,dd,J=1.2,5.1Hz),8.20(1H,dd,J=1.2,4.0Hz),8.29(1H,d,J=8.8Hz),8.58(1H,br s).分析计算C24H22ClN2O5S(490.99):C,58.71;H,5.54;N,5.71.实测:C,58.87;H,5.48;N,5.64.
(R=-COOPh)-方法A;产率8%(用2-丙醇重结晶后);mp 212-214℃;质谱 m/e(相对强度)M+,442,440(1.7,5.7),399(4.4),397(9.7),355(<1),354(<1),353(2.9),352(1.7),338(<1),336(2.5),250(13.4),248(44.3),234(9.7),232(24.0),195(8.1),193(27.7),111(100);1H-NMR(CDCl3)δ 5.90(1H,br s),7.1-7.4
(7H,m),7.74(2H,m),8.22(2H,m),8.39(1H,br s).分析计算 C21H13ClN2O5S(440.84):C,57.21;H,2.97;N,6.36.实测:C,56.99;H,2.98;N,6.38.
缩醛-酯:
(R=-CH(CH3)OCOCH3)-方法A,只是反应混合物中还包括1摩尔当量的硝酸银,并且将反应混合物回流24小时;产率9%(闪式层析两次,第一次:1∶99甲醇/氯仿,第二次:0.5∶99.5甲醇/氯仿,并且用环己烷/乙酸乙酯重结晶);mp 175-180℃;质谱m/e(相对强度)M+,408,406(<1,<1),364(2.9),362(1.2),322(12.1),320(40.2),279(25.8),277(62.6),195(43.3),193(100);1H-NMR(CDCl3)δ 1.70(3H,d,J=5.4Hz),1.94(3H,s),5.16(1H,br,s),6.31(1H,q,J=5.4Hz),7.23(1H,dd,J=3.9,5.2Hz),7.27(1H,d,J=2.2Hz),7.52(1H,dd,1.2,3.7Hz),7.69(1H,dd,J=1.1,5.1Hz),7.98(1H,d,J=2.2Hz),8.21(1H,d,J=8.8Hz),8.47(1H,br s).分析计算 C18H15ClN2O5S(406.83):C,53.14;H,3.72;N,6.89.实测:C,53.40;H,3.61;N,6.85.
缩醛-碳酸酯:
(R=-CH(CH3)OCOOCH2CH3)-方法B;产率32%
(闪式层析 (25∶75-乙酸乙酯/己烷)并用2-丙醇重结晶以后);mp 159-162℃;质谱 m/e(相对强度)M+,438,436(<1.0,1.0),393(<1.0),322(1.9),320(5.3),307(2.0),305(6.3),279(9.9),277(26.9),195(42.5),193(100);1H-NMR(CDCl3)δ 1.21(3H,t,J=7.1Hz),1.73(3H,d,J=5.3Hz),4.10(2H,q,J=5.3Hz),
5.19(1H,br s),7.26(2H,m),7.52(1H,dd,J=1.1,3.7Hz),7.71(1H,dd,J=1.1,5.0Hz),7.97(1H,d,J=2.2Hz),8.22(1H,d,J=8.7Hz),8.47(1H,br s).分析计算 C19H17ClN2O6S(436.86):C,52.23;H,3.92;N,6.41.实测:C,52.57;H,4.44;N,6.03.
(R=-CH(CH3)OCOOC(CH3)3)-方法B;产率25%(闪式层析(25∶75-乙酸乙酯/己烷)并用2-丙醇重结晶以后);mp184-187℃;质谱m/e(相对强度)M+,347(0.8),322(4.1),320(2.0),279(16.2),277(53.8),196(11.3),195(34.5),194(13.3),193(100);1H-NMR(CDCl3)δ 1.33(9H,s),1.71(2H,d,J=5.4Hz),5.21(1H,br s),6.14(1H,q,J=5.2Hz),7.26(2H,m),7.54(1H,dd,J=1.2,3.7Hz),7.70(1H,dd,J=1.2,5.0Hz),8.00(1H,d,J=2.2Hz),8.21(1H,d,J=8.7Hz),8.49(1H,br s).分析计算 C21H21ClN2O6S(464.91):C,54.25;H,4.55;N,6.03.实测:54.38;H,4.58;N,6.09.
(R=-CH(CH3)OCOOCH2Ph)-方法B;产率11%(闪式层析(25∶75-乙酸乙酯/己烷)并用乙酸乙酯/己烷重结晶以后);mp 140-145℃,软化点130℃;质谱 m/e(相对强度)M+,498(<1.0),455(<1.0),410(<1.0),195(10.3),193(32.2),111(62.9),91(100);1H-NMR(CDCl3)δ 1.72(3H,d,J=5Hz),5.00(1H,d,J=11Hz),5.04(1H,d,J=11Hz),5.28(1H,br s),6.20(1H,q,J=5Hz),7.1-7.3(7H,m),7.44(1H,m),7.61(1H,m),7.93(1H,d,J=2Hz),8.20(1H,d,J=9Hz),8.40(1H,br s).分析计算 C24H19ClN2O6S(498.92):C,57.77;H,3.84;N,5.62.实测:C,57.78;H,3.80;N,5.59.
醚类:
(R=-CH3)-方法A,用四氟硼酸三甲基
盐:产率27%(用2-丙醇重结晶以后);mp 186-188℃;质谱m/e(相对强度)M+,335(2.0),334(4.7),291(29.7),277(18.0),260(21.7),248(12.6),193(100),185(14.5),157(8.7),111(52.5);1H-NMR(CDCl3)δ 3.88(3H,s),5.25(1H,br s),7.27(3H,m),7.69(1H,d,J=5.7Hz),7.88(1H,d,J=2.2Hz),8.21(1H,d,J=8.7Hz),8.49(1H,br s).分析计算C15H11ClN2O3S(334.76):C,53.81;H,3.31;N,8.37.实测:C,54.15;H,3.48;N,8.10.
(R=CH2CH3)-方法A用四氟硼酸三乙基
盐;产率22%(用2-丙醇重结晶以后);mp 202-205℃;质谱m/e(相对强度)M+,350,348(1.5,4.6),320(<1),307(7.3),305(19.6),250(2.2),248(7.4),195(27.0),193(100),187(1.2),185(4.7),167(1.3),165(3.2),139(2.8),137(8.1),111(24.0);1H-NMR(d6-Me2SO)δ 1.40(3H,t,J=7.0Hz),4.15(2H,q,J=7.0Hz),7.30(1H,m),7.35(1H,dd,J=2.3,8.7),7.50(1H,m),7.65(1H,s),7.90(1H,d,J=2.3Hz),8.00(1H,dd,J=1.0,5.0Hz),8.05(1H,s),8.15(1H,d,J=8.7Hz).分析计算 C16H13ClN2O3S(348.67):C,55.09;H,3.76;N,8.03.实测:54.87;H,3.62;N,7.79.
磺酸酯:
(R=-SO2CH3)-方法A;产率4%
(用硅胶过滤两次(5∶95-甲醇/氯仿)并用2-丙醇重结晶以后);mp180-182℃;质谱 m/e(相对强度)M+,400,398(2.8,5.6),357(6.8),355(2.6),261(15.3),
259(45.3),250(31.0),248(100),141(15.4),139(42.9),113(6.1),111(37.7);1H-NMR(CDCl3)delta 3.02(3H,s),5.23(1H,br s),7.23(1H,m),7.37(1H,dd,J=2.2,8.8Hz),7.76(2H,m),8.16(1H,d,J=2.1Hz),8.26(1H,d,J=8.8Hz),8.33(1H,br s).分析计算 C15H11ClN2O5S2(398.83):C,45.17;H,2.78;N,7.03.实测:C.45.30;H,2.60;N,6.78.
(R=-SO2(4-Me-Ph)-方法A;产率6%
(用2-丙醇重结晶以后);mp 200-202℃;
质谱 m/e(相对强度)M+,474(<1),433(1.6),431(4.0),404(1.6),402(3.3),250(32.0),248(100),195(4.4),193(15.8),155(27.7),111(47.8),91(42.2);1H-NMR(d6-Me2SO)δ 2.40(3H,s),7.05(1H,t,J=4.5Hz),7.35-7.50(4H,m),7.65(3H,m),7.90(3H,m),8.12(1H,d,J=8.7Hz).分析计算 C21H15ClN2O5S2(474.78):C,53.10;H,3.18;N,5.89.实测:C,53.09;H,3.22;N,5.66.
磷酸酯:
(R=-PO(OCH2CH3)2)-方法A;产率14%
(用硅胶过滤(5∶95-甲醇/氯仿)并用环己烷/乙酸乙酯重结晶以后):mp180-183℃;质谱m/e(相对强度)M+,458,456(1.2,3.8),415(7.4),413(17.4),261(31.7),259(100),250(3.1),248(9.2),196(17.1),195(12.5),193(44.6);1H-NMR(CDCl3)δ 1.33(6H,dt,J=1.2,7.1Hz),4.14(4H,m),5.23(1H,br s),7.32(1H,dd,J=2.2,8.8Hz),7.70(1H,dd,J=1.2,5.0Hz),7.83(1H,dd,J=1.2,3.8Hz),
8.06(1H,d,J=2.2Hz),8.25(1H,d,J=8.8Hz),8.46(1H,br s).分析计算 C18H18ClN2O6PS(456.83):C,47.32;H,3.97;N,6.13.实测:C,47.25;H,3.83;N,6.08.
实例2
由适当的试剂开始,利用所述方法,制得下列化合物:
酯类:
(R=-COCH3)-方法A;产率16%
(用2-丙醇重结晶以后);mp 190-203℃;质谱m/e(相对强度)M+,382,380(1.6,7.7),340(36.8),338(98.1),297(16.5),295(43.4),279(<1),277(2.1),268(3.4),266(8.3),256(1.4),254(5.2),213(38.6),211(100),111(26.7);1H-NMR(d6-Me2SO)δ 1.9,2.4(3H,2s),7.09-7.40(2H,一组多重峰),7.55-7.80(1H,set of m),7.95-8.50(4H,一组多重峰)。分析计算 C16H10ClFN2O4S(380.66):C,50.47;H,2.65;N,7.36.实测:C,50.13;H,2.52;N,7.19.
(R=-COCH2CH3)-方法A;产率10%
(用硅胶过滤(5∶95-甲醇/氯仿)并用2-丙醇重结晶以后);mp182-188℃;质谱 m/e(相对强度)M+,396,394(<1,1.3),340(7.2),338(16.2),297(12.1),295(32.5),268(2.7),266(7.1),213(26.1),211(100),111(40.8),57(94.2);1H-NMR(d6-Me2SO)δ 1.18(3Ha,b,m)2.22(2Ha,q,J=7.5Hz),2.71(2Hb,q,J=7.5Hz),7.09-7.70(2Ha,b,m),7.95-8.48(5Ha,b,m).分析计算 C17H12ClFN2O4S(394.80):C,51.71;H,3.06;N,7.10.实测:51.67;H,3.01;N,6.97.
(R=-COCH(CH3)2)-方法A;产率11%
(用硅胶过滤并用2-丙醇重结晶以后);mp204-206℃;质谱 m/e(相对强度)M+,410,408(1.1,4.1),340(11.5),338(27.2),297(13.2),295(33.6),268(5.6),266(15.0),213(25.8),211(100),111(36.4);1H-NMR(d6-Me2SO)δ 1.34(6H,d,J=7.0Hz),3.25(1H,heptet,J=7.0Hz),7.33(1H,dd,J=4.0,5.1Hz),7.48(1H,d,J=9.6Hz),8.00(1H,br s),8.03(1H,br s),8.13(1H,dd,J=1.2,5.0Hz).分析计算C18H14ClFN2O4S(408.83):C,52.88;H,3.45;N,6.85.实测:C,52.48;H,3.32;N,6.86.
(R=-COCH2Ph)-方法A;产率22%(用2-丙醇重结晶以后);mp 189-199℃;
质谱 m/e(相对强度)M+,(未观察到),340(18.9),338(42.1),297(20.7),295(54.4),268(5.8),266(19.6),213(17.9),211(53.7),91(100);1H-NMR(d6-Me2SO)δ 3.98(2Ha,s),4.02(2Hb,s),5.35(1H,br s),6.99-7.45(7H,m),7.68,8.00(2H,2m),
8.42(1H,dd,J=5.1,6.9Hz),8.50(1H,br s).分析计算 C22H14ClFN2O4S(456.86):C,57.83;H,3.09;N,6.13.实测:C,57.53;H,2.98;N,6.15.
(R=-COCH2CH2COOEt)-方法A;产率26%
(2-丙醇重结晶以后);mp153-155℃;
质谱m/e(相对强度)M+,(未观察到),321(3.1),295(3.1),266(4.5),213(8.8),211(23.4),155(5.2),129(100),111(12.4),101(75.0),91(2.7);1H-NMR(d6-Me2SO)δ 1.12(3H,2t,J=7.1Hz),2.5-3.5(4H,一组复合多重峰),4.05(2H,2q,J=7.3Hz),7.15-7.40(2H,一组复合多重峰),7.70(1H,m),7.95-8.43(4H,一组复合多重峰).分析计算 C20H16ClFN2O6S(466.70):C,51.45;H,3.45;N,6.00.实测:C,51.28;H,3.26;N,5.99.
碳酸酯:
(R=-COOCH3)-方法A;产率25%
(用2-丙醇重结晶以后;mp 203-205℃;
质谱 m/e(相对强度)M+,398,396(7.5,24.5),355(4.5),353(10.6),311(23.8),309(49.1),280(26.3),278(27.9),268(30.5),266(100),252(3.5),250(6.9),240(3.4),238(7.2),213(25.2),211(56.9),203(29.4),197(5.6),182(6.8),169(6.1),157(4.5),155(12.4),142(2.1),111(45.4),97(5.3),83(5.5);1H-NMR(d6-Me2SO)δ 3.89,3.95(3H,2s),7.38(2H,m),8.00(3H,m),8.19(1H,m),8.29(1H,t,J=6.7Hz).分析计算 C16H10ClFN2O5S(396.71):C,48.43;H,2.54;N,7.06.实测:C,48.41;H,2.47;N,6.95.
(R=-COOCH2CH3)-方法A;产率57%
(用2-丙醇重结晶以后)mp164-166℃;
质谱 m/e(相对强度)M+,410(1.4),325(1.8),323(5.8),297(8.0),295(20.5),268(6.1),266
(13.7),213(37.6),211(100),203(7.9),155(7.5),111(21.0);1H-NMR(d6-Me2SO)δ1.30(3H,t,J=7.1Hz),4.32(2H,q,J=7.1Hz),7.35(2H,m),8.0(3H,m),8.20-8.35(2H,m).分析计算 C17H12ClFN2O5S(410.67):C,49.70;H,2.94;N,6.82.实测:C,49.76;H,2.85;N,6.77.
(R=-COO(CH2)5CH3)-方法A;产率85%
(用2-丙醇重结晶以后);mp 128-135℃;
质谱m/e(相对强度)M+,468,466(0.3,0.7),425(0.3),424(0.3),423(1.1),340(7.0),338(14.1),297(28.5),295(74.5),213(34.3),211(100);1H-NMR(CDCl3)δ 0.85-0.92(3H,m),1.22-1.48(6H,m),1.72(2H,五重峰 J=9Hz),4.31(2Ha,b,t),5.40(1Ha,b,br s),7.21(1Ha,b,m),7.30(1Ha,d,J=9Hz),7.47(1Hb,d,J=9Hz),7.77(2Ha,1Hb,m),8.19(1Hb,m),8.42(1Ha,d,J=8Hz),8.46(1Hb,d,J=8Hz),8.49(1Ha,br s),8.52(1Hb,br s).分析计算C21H20ClFN2O5S(466.91):C,54.02;H,4.32;N,6.00.实测:C,53.93;H,4.26;N,6.02.
磺酸酯:
(R=-SO2CH3)-方法A;产率9%
(用硅胶过滤并用环己烷/乙酸乙酯重结晶以后);mp180-185℃;质谱 m/e(相对强度)M+,418,416(3.4,7.2),375(8.4),373(21.8),296(6.8),294(6.8),294(16.0),279(7.0),277(18.5),268(42.7),266(100),111(65.4).分析计算 C15H10ClFN2O5S2(416.85):C,43.22;H,2.42;N,6.72.实测:C,43.37;H,2.30;N,6.72.
实例3
用所述方法、由所需试剂开始制得下述化合物:
酯类:
(R=-COCH3)-方法A;产率56%
(用2-丙醇重结晶以后);mp 195-197℃;
质谱 m/e(相对强度)M+,354(<1),312(32.5),269(38.6),251(4.8),221(12.2),194(1.6),178(100),121(11.1),91(23.9),65(5.9);1H-NMR(d6-Me2SO)δ 2.31(3H,s),4.51(2H,s),7.02(1H,dt,J=2.6,8.9Hz),7.33(6H,s),7.63(1H,dd,J=5.8,8.6Hz),7.95(2H,m).分析计算 C19H15FN2O4(354.19):C,64.40;H,4.27;N,7.91.实测:C,64.30;H,4.21;N,7.89.
(R=-COCH2CH3)-方法A;产率23%
(用2-丙醇重结晶以后);mp 196-198℃;
质谱 m/e(相对强度)M+,368(2),325(5),312(25),269(70),251(7),240(4),221(5),178(100),150(8),121(10),91(37),65(12),57(83);1H-NMR(d6-Me2SO)δ 1.02(3H,t,J=7.4Hz),2.61(2H,q,J=7.4Hz),4.53(2H,s),7.02(1H,dt,J=2.6,
9.2Hz),7.32(6H,m),7.61(1H,dd,J=5.8,8.6Hz),7.95(2H,m).分析计算 C20H17FN2O4(368.20):C,65.21;H,4.65;N,7.61.实测:C,64.98;H,4.44;N,7.54.
(R=-COCH(CH3)2)-方法A;产率28%
(用2-丙醇重结晶以后);mp 182-184℃;质谱 m/e(相对强度)M+,382(3.5),339(<1),312(18.6),269(18.1),178(46.2),177(17.4),91(31.8),71(100);1H-NMR(d6-Me2SO)δ 1.09(3H,d,J=7.0Hz),2.64(1H,dq,J=7.0Hz),4.65(2H,s),5.36(1H,br s),6.83(1H,dt,J=2.5,8.7Hz),7.18-7.33(5H,m),7.50(1H,dd,J=5.6,8.6Hz),8.10(1H,dd,J=2.5,10.3Hz),8.59(1H,br s).分析计算 C21H19FN2O4(382.38):C,65.96;H,5.01;N,7.33.实测:C,65.76;H,4.94;N,7.33.
(R=-COPh)-方法A;产率68%(用2-丙醇重结晶以后);mp188-190℃;质谱 m/e(相对强度)M+,416(2.7),373(3.0),242(6.1),177(6.4),121(5.2),105(100),77(17.8);1H-NMR(CDCl3)δ 4.71(2H,d),5.41(1H,br s),6.71(1H,dt,J=2.5,8.7Hz),7.26(5H,m),7.42(1H,dd,J=5.6,8.6),7.52(2H,m),7.66(1H,m),8.03(2H,d),8.10(1H,dd,J=2.5,10.3Hz),8.63(1H,br s).分析计算 C24H17FN2O4·H2O(434.41):C,66.35;H,4.40;N,6.44.实测:C,66.14;H,3.92;N,6.41.
(R=-COCH2Ph)-方法A;产率27%(用2-丙醇重结晶以后);mp 201-202℃;
质谱 m/e(相对强度)M+,430(0.9),387(0.6),312(87.5),269(100),178(64.7),91(65.6);1H-NMR(d6-Me2SO)δ 3.99(2H,s),4.48(2H,s),6.85(2H,dt,J=2.6,8.9Hz),7.28(10H,m),7.91(1H,
dd,J=2.5,10.7Hz),7.97(1H,br s),8.07(1H,br s).分析计算 C25H19FN2O4(430.25):C,69.76;H,4.45;N,6.51.实测:C,69.35;H,4.38;N,6.62.
(R=-COCH2CH2COOEt)-方法A;产率46%(用2-丙醇重结晶以后);mp159-161℃;
质谱 m/e(相对强度)M+,(未观察到),395(0.4),352(0.8),331(0.3),289(0.6),269(6.4),252(9.4),234(1.9),222(6.8),212(1.5),196(1.1),178(24.8),177(10.6),168(1.5),130(7.7),129(100),121(5.3),101(65.8),91(10.0);1H-NMR(d6-Me2SO)δ 1.15(3H,t,J=7.1Hz),2.61(2H,t,J=6.0Hz),2.88(2H,t,J=6.0Hz),4.06(2H,q,J=7.1Hz),4.46(2H,s),6.98(1H,dt,J=2.6,8.9Hz),7.32(5H,m),7.67(1H,dd,J=5.8,8.6Hz),7.93(1H,dd,J=2.5,10.7Hz),7.98(1H,br s),8.08(1H,br s).分析计算 C23H21FN2O6(440.23):C,62.72;H,4.81;N,6.36.实测:C,62.75;H,4.79;N,6.29.
碳酸酯:
(R=-COOCH3)-方法A;产率45%(用2-丙醇重结晶以后);mp 178-180℃;
质谱 m/e(相对强度)M+,370(16.7),327(3.7),294(24.0),251(100),235(11.7),222(32.9),205(0.4),204(3.8),192(29.8),178(42.5),164(2.2),149(5.8);1H-NMR(d6-Me2SO)δ 3.86(3H,s),4.58(2H,s),7.08(1H,dt,J=2.6,9.1Hz),7.32(5H,s),7.55(1H,dd,J=5.9,8.7Hz),7.95(1H,dd,J=2.5,10.6Hz),7.99(1H,br s),8.07(1H,br s).分析计算 C19H15FN2O5(370.19):C,61.62;H,4.08;N,7.56.实测:C,61.64;H,4.07;N,7.55.
(R=-COOCH2CH3)-方法A;产率52%
(用2-丙醇重结晶以后);mp 189-190℃;
质谱 m/e(相对强度)M+,384(8.8),340(3.4),312(33.2),297(57.0),269(71.1),251(47.1),240(14.9),221(33.6),212(7.1),206(10.1),178(100),150(10.6),121(14.3),91(51.5);1H-NMR(d6-Me2SO)δ 1.23(3H,t,J=7.1Hz),4.26(2H,q,J=7.1Hz),4.58(2H,s),7.08(1H,dt,J=2.5,8.9Hz),7.32(5H,m),7.53(1H,dd,J=5.8,8.6Hz),7.94(1H,dd,J=2.6,10.7Hz),7.99(1H,br s),8.07(1H,br s).分析计算 C20H17FN2O5(384.19):C,62.52;H,4.42;N,7.29.实测:C,62.59;H,4.41;N,6.98.
(R=-COO(CH2)5CH3)-方法A;产率31%(用2-丙醇重结晶以后);mp 144-145℃;
质谱m/e(相对强度)M+,440(<1),397(0.6),378(<1),353(<1),312(18.1),294(1.9),269(69.7),251(16.7),240(4.3),221(16.4),212(2.1),194(2.0),178(100),164(0.9),149(5.7),121(9.2),103(1.1),91(29.2);1H-NMR(d6-Me2SO)δ 0.85(3H,br t,J=6.6Hz),1.24(6H,m),1.58(2H,m),4.21(2H,t,J=6.4Hz),4.59(2H,s),7.06(1H,dt,J=2.5,9.0Hz),7.31(5H,m),7.54(1H,dd,J=5.8,8.6Hz),7.96(1H,dd,J=2.5,10.6Hz),8.00(1H,br s),8.07(1H,br s).分析计算 C24H25FN2O5(440.24):C,65.44;H,5.72;N,6.36.实测:C,65.31;H,5.62;N,6.38.
Claims (3)
1、制备下式所示化合物的方法
式中X和Y各选自氢、氟和氯;R1选自2-噻吩基和苄基;R选自以下(1)和(2)类基团:(1)当R为C1-C3烷基,2至10个碳原子的链烷酰基,5至7个碳原子的环烷基羰基,7至10个碳原子的苯基链烷酰基,氯代苯甲酰基,甲氧苯甲酰基,噻吩甲酰基,末位烷氧羰基取代的链烷酰基,所述烷氧基具有1至3个碳原子,所述链烷酰基具有3至5个碳原子;2至10个碳原子的烷氧羰基;苯氧羰基;1-(酰氧基)烷基,所述酰基具有2至4个碳原子,所述烷基具有1至4个碳原子;1至3个碳原子的烷磺酰基;或甲苯磺酰基和二烷氧基氧合磷基,所述烷基各具有1至3个碳原子时,该方法包括:在室温下,在含等摩尔量三乙胺的反应惰性溶剂中,使下式所示化合物与等摩尔稍稍过量的式R-Cl所示化合物反应,
直至反应基本完全;或(2)当R为1-(烷氧羰氧基)烷基,所述烷氧基具有2至5个碳原子,所述烷基具有1至4个碳原子时,该方法包括:在无水的反应惰性溶剂中,使下式所示化合物:
与三倍摩尔过量的式R-Cl化合物在五倍摩尔过量的碘化钠和二倍摩尔过量的无水碳酸钾存在下,加热回流至反应完全。
2、根据权利要求1的方法,其中当R选自(1)基团时,反应惰性溶剂是氯仿。
3、根据权利要求1的方法,其中当R选自(2)基团时,反应惰性溶剂是丙酮。
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PCT/US1988/003658 WO1990004393A1 (en) | 1988-10-18 | 1988-10-18 | Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides |
USPCT/US88/03658 | 1988-10-18 |
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CN1022241C true CN1022241C (zh) | 1993-09-29 |
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US (1) | US5118703A (zh) |
JP (1) | JPH07597B2 (zh) |
KR (1) | KR910007237B1 (zh) |
CN (1) | CN1022241C (zh) |
AP (1) | AP118A (zh) |
AR (1) | AR246519A1 (zh) |
AT (1) | ATE125794T1 (zh) |
AU (1) | AU606819B2 (zh) |
BG (1) | BG50834A3 (zh) |
CA (1) | CA1339558C (zh) |
CZ (1) | CZ278983B6 (zh) |
DD (1) | DD285604A5 (zh) |
DK (1) | DK514989A (zh) |
EG (1) | EG19887A (zh) |
FI (1) | FI95253C (zh) |
HU (1) | HU208421B (zh) |
IE (1) | IE66586B1 (zh) |
IL (1) | IL91960A (zh) |
IS (1) | IS1598B (zh) |
MA (1) | MA21657A1 (zh) |
MX (1) | MX18021A (zh) |
MY (1) | MY104238A (zh) |
NO (1) | NO178027C (zh) |
NZ (1) | NZ231044A (zh) |
OA (1) | OA09140A (zh) |
PH (1) | PH27554A (zh) |
PL (2) | PL162316B1 (zh) |
PT (1) | PT92000B (zh) |
RO (1) | RO109195B1 (zh) |
RU (1) | RU2036905C1 (zh) |
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US5059693A (en) * | 1989-10-06 | 1991-10-22 | Pfizer Inc. | Process for making 3-aroyl-2-oxindole-1-carboxamides |
KR950704727A (ko) * | 1992-11-23 | 1995-11-20 | 알렌 제이, 스피겔 | 4-클로로-2-티오펜카복실산의 위치선택적 제조 방법(regioselective synthesis of 4-chloro-2-thiophenecarboxylic acid) |
US5270331A (en) * | 1993-01-26 | 1993-12-14 | Pfizer, Inc. | Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides |
DK0683777T3 (da) * | 1993-02-09 | 1997-04-28 | Pfizer | Oxindol-1-N-(alkoxycarbonyl)carboxamider og -1-(N-carboxamido)carboxamider som antiinflammatoriske midler |
US5449788A (en) * | 1994-01-28 | 1995-09-12 | Catalytica, Inc. | Process for preparing 2-oxindole-1-carboxamides |
CN1094819C (zh) * | 1997-04-30 | 2002-11-27 | 大兴株式会社 | 环状坯料之制造装置 |
EP0984012A3 (en) * | 1998-08-31 | 2001-01-10 | Pfizer Products Inc. | Nitric oxide releasing oxindole prodrugs with analgesic and anti-inflammatory properties |
WO2001030151A1 (en) * | 1999-10-26 | 2001-05-03 | The University Of Texas Southwestern Medical Center | Methods of treating hair loss comprising administering indoline compound |
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BE558210A (zh) * | 1956-06-08 | |||
US3564009A (en) * | 1966-01-13 | 1971-02-16 | Sumitomo Chemical Co | Process for producing 1-acylindole derivatives |
BE756447A (fr) * | 1969-10-15 | 1971-03-22 | Pfizer | Oxindolecarboxamides |
US3923996A (en) * | 1972-07-31 | 1975-12-02 | Sandoz Ag | 3-Substituted-oxindoles in compositions and methods of treating obesity |
IE53102B1 (en) * | 1981-05-12 | 1988-06-22 | Ici Plc | Pharmaceutical spiro-succinimide derivatives |
EP0076606B1 (en) * | 1981-10-06 | 1986-02-05 | Imperial Chemical Industries Plc | Biochemical process |
US4556672A (en) * | 1984-03-19 | 1985-12-03 | Pfizer Inc. | 3-Substituted 2-oxindole-1-carboxamides as analgesic and anti-inflammatory agents |
US4752609A (en) * | 1985-06-20 | 1988-06-21 | Pfizer Inc. | Analgesic and antiinflammatory 1,3-diacyl-2-oxindole compounds |
UA25898A1 (uk) * | 1987-02-02 | 1999-02-26 | Пфайзер Інк. | Спосіб одержаhhя кристалічhої hатрієвої солі 5-хлор-3-(2-теhоїл)-2-оксііhдол-1-карбоксаміду |
DE68923673T2 (de) * | 1988-10-18 | 1996-01-18 | Pfizer | Prodrogen von antiinflammatorischen 3-Acyl-2-oxindol-1-carboxamiden. |
US5047554A (en) * | 1989-04-18 | 1991-09-10 | Pfizer Inc. | 3-substituted-2-oxindole derivatives |
US5059693A (en) * | 1989-10-06 | 1991-10-22 | Pfizer Inc. | Process for making 3-aroyl-2-oxindole-1-carboxamides |
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