CN1025998C - 3-(1,2,5,6-四氢吡啶基)-吡咯并吡啶类的制备方法 - Google Patents
3-(1,2,5,6-四氢吡啶基)-吡咯并吡啶类的制备方法 Download PDFInfo
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- CN1025998C CN1025998C CN90100888A CN90100888A CN1025998C CN 1025998 C CN1025998 C CN 1025998C CN 90100888 A CN90100888 A CN 90100888A CN 90100888 A CN90100888 A CN 90100888A CN 1025998 C CN1025998 C CN 1025998C
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- MTXPFWNUKVMJLO-UHFFFAOYSA-N 3-(3,6-dihydro-2h-pyridin-1-yl)-1h-pyrrolo[3,2-b]pyridine Chemical class C1C=CCCN1C1=CNC2=CC=CN=C12 MTXPFWNUKVMJLO-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- -1 4Be hydrogen Chemical class 0.000 claims description 44
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 40
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 30
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 239000003513 alkali Substances 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 6
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
- 239000012442 inert solvent Substances 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 14
- 150000002500 ions Chemical class 0.000 claims 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-O oxonium Chemical compound [OH3+] XLYOFNOQVPJJNP-UHFFFAOYSA-O 0.000 claims 5
- 150000004820 halides Chemical class 0.000 claims 3
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 2
- YUGDKEWUYZXXRU-UHFFFAOYSA-N 2-(4-chlorophenoxy)acetonitrile Chemical compound ClC1=CC=C(OCC#N)C=C1 YUGDKEWUYZXXRU-UHFFFAOYSA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 150000007524 organic acids Chemical class 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 5
- 208000024891 symptom Diseases 0.000 abstract description 4
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- 230000016571 aggressive behavior Effects 0.000 abstract description 3
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 58
- 239000007787 solid Substances 0.000 description 58
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 52
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 42
- 238000005160 1H NMR spectroscopy Methods 0.000 description 40
- 239000000203 mixture Substances 0.000 description 38
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 35
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 34
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 31
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 30
- 238000010828 elution Methods 0.000 description 29
- 239000000741 silica gel Substances 0.000 description 28
- 229910002027 silica gel Inorganic materials 0.000 description 28
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 26
- 239000000284 extract Substances 0.000 description 24
- 230000008016 vaporization Effects 0.000 description 23
- 239000012299 nitrogen atmosphere Substances 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 230000035484 reaction time Effects 0.000 description 19
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 238000003818 flash chromatography Methods 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 239000012298 atmosphere Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- XWIYUCRMWCHYJR-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyridine Chemical compound C1=CC=C2NC=CC2=N1 XWIYUCRMWCHYJR-UHFFFAOYSA-N 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 8
- 239000007810 chemical reaction solvent Substances 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 239000007868 Raney catalyst Substances 0.000 description 6
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 6
- 229910000564 Raney nickel Inorganic materials 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- 150000003222 pyridines Chemical class 0.000 description 5
- XLKDJOPOOHHZAN-UHFFFAOYSA-N 1h-pyrrolo[2,3-c]pyridine Chemical compound C1=NC=C2NC=CC2=C1 XLKDJOPOOHHZAN-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
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- 238000002425 crystallisation Methods 0.000 description 4
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- 229910052763 palladium Inorganic materials 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- LHASZEBEQGPCFM-CJFMBICVSA-N 2-amino-4-[(1r)-1-[[(6r)-6-[(5-chloro-2-methoxyphenyl)methyl]-7-oxo-3-(phenoxyamino)-5,6-dihydro-2h-1,4-diazepine-1-carbonyl]amino]propyl]benzoic acid Chemical compound C([C@@H]1CNC(CN(C1=O)C(=O)N[C@H](CC)C=1C=C(N)C(C(O)=O)=CC=1)=NOC=1C=CC=CC=1)C1=CC(Cl)=CC=C1OC LHASZEBEQGPCFM-CJFMBICVSA-N 0.000 description 3
- OVDGUTHABMXVMI-UHFFFAOYSA-N 3-nitro-4-(propylamino)benzoic acid Chemical compound CCCNC1=CC=C(C(O)=O)C=C1[N+]([O-])=O OVDGUTHABMXVMI-UHFFFAOYSA-N 0.000 description 3
- 241000675108 Citrus tangerina Species 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
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- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 2
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- C—CHEMISTRY; METALLURGY
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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Abstract
本发明涉及制备由下列所代表的化合物和药物上可接受的它们的盐的方法,
其中A、B、D、E、R1、R2、R3、R4、R5和R6的限定范围如说明书所述,
本发明的化合物在精神病治疗中有作用并可用于治疗肥胖症,抑郁症和以侵犯行为为症状的错乱。
Description
本发明涉及的是某些吡咯并吡啶,制备这些化合物的方法,包含这些化合物的药物组合物和这些化合物用于治疗肥胖症,抑郁症和以侵犯行为为症状的错乱的用途(例如:精神分裂症)。
美国专利4,232,031和4,278,677谈到四氢吡啶基吲哚,这些化合物具有抗抑郁,抗呕吐,抗震颤性麻痺和致类神经病症状的作用。
美国专利3,993,764和4,196,209谈到具有抗抑制,抗呕吐和抗震颤性麻痺作用的哌啶基吲哚。
J.Guillaume等〔欧洲药物化学(Eur.J.Med.Chem.),22,33-43(1987)〕提到具有5-羟色胺和抗多巴胺性能的四氢吡啶基吲哚。
K.Freter[有机化学(J.Org.Chem.),40,2525-2529(1975)]提到环酮与吲哚反应来制备3-环烯基吲哚。
G.H.Kennet等[欧洲药物学(European Journal of Pharmacology),141,429-435(1987)],C.Bendotti等[生命科学(Life Sciences),41,635-642(1987)],M.Carli等[精神病药物学(Psychopharmacology),94,359-364(1988)]和P.H.Hutson等[精神病药物学(Psychopharmacology),95,550-552(1988)]提到Ru24969(5-甲氧基-3(1,2,3,6-四氢-4-吡啶基)-1H-吲哚)作为5-羟基色胺的兴奋剂的效应,它的潜在的抗焦虑效应和抗抑制效应,和它对哺乳的效应。
本发明涉及的是由下式所表示的化合物
其中A,B,D和E之一是N,余下的三个原子是C;
R1和R2各自独立地选自氢和C1至C6烷基;而R3,R4,R5和R6各自独立地选自氢,卤素,羟基,C1-C6烷基,C1-C8烷氧基,苯基-C1-C6烷氧基,苯氧基,-NR7R8,其中R7和R8各自独立地选自氢,C1-C6烷基,C1-C6烷酰基,和COOR9,其中R9是氢或C1-C6烷基,氰基,COOR10,其中R10是氢或C1-C6烷基和CONR11R12其中R11和R12各自独立地选自氢和C1-C6烷基和药物上可接受的它们的盐。
式Ⅰ表示化合物中吡咯并[3,2-b]吡啶是优选的,其中R1,R2,R5和R6是氢,R3空缺,R4的限定范围同上,A是N,B,D和E是C。特别优选的化合物,是在前述的化合物中,其中的R4是氢,C1-C6烷氧基(例如,甲氧基)或羟基。
除非特别指明,这里提到的烷基,以及这里提到的其它基团中的烷基部分(例如,烷氧基和烷酰基),可为直链或带有支链。它们还可以成环或者是直链或有支链的并含有成环部分。
式Ⅰ化合物的制备是在碱存在的条件下,使哌啶酮一水合卤化氢(优选的是氯化氢)与式Ⅱ表示的化合物反应
其中A,B,D,E,R2,R3,R4,R5和R6的限定范围同上。适宜的碱包括烷醇钠或钾和烷基镁卤化物。一种优选的碱是甲醇钠。溶剂应为惰性溶剂。适宜的溶剂包括醇,二甲基甲酰胺和四氢呋喃。优选的溶剂是甲醇。反应在温度为约60°至约120℃时进行,优选的约为65°至约70℃,最优选的是溶剂的回流温度。压力要求不严格,总的来说,在约0.5至约2个大气压的压力下进行反应,优选的是环境压力(约1个大气压)。
式Ⅰ的化合物可以转换成无机或有机酸的盐,优选的是药物中可接受的盐,这种转换是通过大体上为化学计量的碱和酸相互反应来实现的。这些盐的实例是盐酸盐,氢溴酸盐,硝酸盐,硫酸盐,磷酸盐,乙酸盐,草酸盐,马来酸盐,延胡索酸盐,酒石酸盐,乳酸盐,苹果酸盐,丙二酸盐,柠檬酸盐,水杨酸盐,甲磺酸盐,苯磺酸盐,甲苯磺酸盐和萘磺酸盐。
该新化合物的这些或其它盐,例如苦味酸盐,还可以用来纯化所得到的游离碱,通过将游离的碱转换成盐,将盐分离并且如果合适的话,将其再结晶或通过另一手段将其纯化,然后重新从该盐中将碱释放出来。
当R2、R5和R6是氢,R3空缺、R4的限定范围同上,A是N,B,D和E是C时,式Ⅱ的化合物是新的。具体的新的化合物如下:
5-羟基吡咯并[3,2-b]吡啶;
5-二甲胺基吡咯并[3,2-b]吡啶;
5-乙氧基吡咯并[3,2-b]吡啶;
5-丙氧基吡咯并[3,2-b]吡啶;
5-丁氧基吡咯并[3,2-b]吡啶;
5-异丙氧基吡咯并[3,2-b]吡啶;
5-叔丁氧基吡咯并[3,2-b]吡啶;
5-苄氧基吡咯并[3,2-b]吡啶;
5-环戊氧基吡咯并[3,2-b]吡啶;
5-甲基吡咯并[3,2-b]吡啶。
式Ⅱ的新化合物的制备是在强碱存在的条件下,在适宜的极性溶剂中,通过2-(4-氯苯氧基)乙腈与下式的化合物相互反应来实现的,
其中R4的限定范围同上。(见Makosza等[李比希化学年鉴(Liebigs Ann.Chem.),1988,203])。适宜的碱包括钠或钾的叔醇盐,优选的碱是钾的叔丁醇盐。适宜的溶剂包括四氢呋喃,二乙醚,和二甲基甲酰胺,优选的溶剂是四氢呋喃。进行反应的温度为约-78℃至约
25℃,优选的是-10℃。压力的要求不严格,一般地进行反应的压力为约0.5至约2个大气压,优选的是环境压力(约1个大气压)。将这一反应得到的产物进行纯化,用矿物酸优选的是稀盐酸中和反应混合物,然后用标准的萃取法将其分离,使用乙酸乙酯,二乙醚,或二氯甲烷,优选的是二乙醚。萃取后的有机滤物在氢气氛和适宜的溶剂中与金属催化剂反应,反应的温度在约0℃至约70℃之间,最优选的是室温(约20℃)。适宜的溶剂包括甲醇,乙醇,丙醇,乙酸乙酯,二甲基甲酰胺和乙酸,乙酸是优选的溶剂。适宜的金属催化剂包括钯在碳中的混合物,氧化钯,和阮内镍,优选的催化剂是10%的钯在碳中的混合物。反应的氢的压力应维持在约1个大气压至约5个大气压之间,优选的是约3个大气压。
本发明还涉及式Ⅰ的化合物和它们的药物中可接受的盐在治疗和预防下述疾病方面的用途,这些疾病是肥胖症,抑郁症和以侵犯行为为症状的精神错乱。这些化合物的效果可以按给老鼠服用该化合物并测量其体重的减小的方法来测定。式Ⅰ的化合物或它的药物中可接受的盐可以单独服用,也可以与适宜的赋形剂混合服用。这些混合物可以含有一种或多种式Ⅰ的化合物或它们的药物中可接受的盐,含量可为约0.1至约99.9%。成人的标准剂量范围是从约1mg至约500mg。式Ⅰ化合物或它的药物中可接受的盐的准确剂量要依病人的年龄、体重、和条件以及病情严重程度这些因素而定。但总的来说,式Ⅰ化合物或它的药物中可接受的盐的治疗有效剂量范围为每天从约0.1至约20mg/kg治疗主体体重,优选的是约2至约10mg/kg每天,分每达4次服用。
可行的剂型包括所有专家所熟悉的那些剂型,如举例来说,栓
剂,粉剂,颗粒,片剂,胶囊,糖衣药丸,用于口服的悬浮液和溶液,注射用溶液和皮下系统。固体、半固体或液体赋形剂或稀释剂可以用来制备药物剂型。这些试剂包括粘合剂、润滑剂,乳化剂及类似物。这些试剂的实例有:淀粉,例如土豆淀粉和谷类淀粉,糖,例如乳糖,蔗糖,葡萄糖,甘露糖醇和山梨糖醇,纤维素,例如结晶纤维素,甲基纤维素,羧甲基纤维素钙,羧甲基纤维素钠,和羟基丙基纤维素,无机物,例如磷酸钾,硫酸钙,碳酸钙,滑石,明胶,阿拉伯树胶,聚乙烯吡咯烷酮,硬脂酸镁,可可脂,表面活性物质,例如脂肪酸甘油脂,脂肪酸脱水山梨糖酯,脂肪酸的蔗糖酯和聚甘油,以及其它。
本发明的化合物的制备由以下的实施例来说明。熔点未进行较正,核磁共振(NMR)数据是报导的()中的百万分之一,并且参比的是标样溶剂的氘锁峰信号。起始物质吡咯并〔3,2-b〕吡啶(V.A.Azimov等,Khim.Geterotsikl Soedin.,10,1425(1977)),吡咯并〔3,2-C〕吡啶(J.R.Dormoy等,Fr.Demande FR 2,564,836(1985年11月29日)),吡咯并〔2,3-C〕吡啶(A.A.Prokopov等,Khim.Getero-tsikl Soedin.,8,1135(1977)),吡咯并〔2,3-b〕吡啶(Aldrich化学公司。),5-甲氧基吡咯并〔3,2-b〕吡啶(M.Makoska等,李比希化学年鉴(Liebigs Ann.Chem.),203(1988)),和4-甲基-5-硝基-1H-吡啶-2-酮(H.E.Baumgarten等,JACS,74,3828(1952))在商业上可得到或按照已公开的方法可以制备。
实施例1
A.合成3-(1,2,5,6-四氢吡啶基)吡咯并吡啶的总的步骤;化合物1a-1m,2,3a,3b,3c和4
在室温的条件下,向Na(2,53g,110mmol,11当量
(eq))在纯甲醇(50ml)的溶液中,在搅拌的同时加入适宜的吡咯并吡啶(10.00mmol)和派啶酮一水合氯化氢(4.60g,30.0mmol 3.0当量(eq))。将得到的混合物在氮气氛中在回流的温度下按照作用物加热2-24小时。然后冷却得到的反应混合物,并在剧烈搅拌的条件下滴加浓盐酸(37%,9.0ml,110mmol)。接着在降低的压力下蒸发得到的反应混合物,将残余的浆状物置入水中(50ml)。用乙酸乙酯(5×50ml)萃取这一水溶液混合物,将萃取物混合在一起,干燥(Na2SO4),在减压条件下蒸发。或者直接将残余物捣碎,或者使用硅胶(约100g)采用柱色谱法分析,并用适宜的溶剂体系洗提,得到的是所需的3-(1,2,5,6-四氢吡啶基)吡咯并吡啶,是化合物1a-1m或化合物2,3a,3b,3c,或4之一。
B.3-(1,2,5,6-四氢吡啶基)吡咯并[3,2-b]吡啶(化合物1a)
反应时间是4小时,对萃取残余物进行闪蒸色谱法分离,使用硅胶(约200g)并用5%在甲醇中的三乙胺洗提,得到的是呈淡黄色固体的化合物1a(44%):熔点(mp),198-200℃;IR(KBr)3220,3100-2740,1650,1615,1550,1500,1460,1430,1260,1040cm-1;1HNMR(DMSO-d6)8.33(dd,J=4.7和1.2Hz,1H),7.72(dd,J=8.3和0.8Hz,1H),7.55(s,1H),7.11(br m,1H),7.09(dd,J=8.3和4.7Hz,1H),3.39(d,J=2.6 Hz,2H),2.92(t,J=5.8Hz,2H),2.36(br m,2H);13C NMR(DMSO-d6)143.6,142.0,129.5,128.2,125.0,121.6,118.4,116.3,116.0,44.8,42.8,27.2;LRMS(m/z,相对强度)200(30),199(M+,100),198(92),170(75),169(39),155(15),131(35);HRMS对C12H13N3的计算值:199.1110,测定值199.1096。
C.5-甲氧基-3-(1,2,5,6-四氢吡啶基)吡咯并〔3
,2,-b〕吡啶(化合物1b)
反应时间是6小时。对萃取残余物用闪蒸色谱法分离,使用硅胶(约100g)并用10%在甲醇中的三乙胺洗提,然后在1∶1二氯甲烷/乙醚中将再生的油(比移值(Rf)=0.15在10%的在甲醇中的三乙胺溶液中)结晶,得到呈浅黄色固体的化合物1b(39%):熔点(mp),208-210℃;IR(KBr)3300,3120-2730,1650,1620,1580,1490,1435,1410,1250cm-1;1H NMR(CDCl3)8.66(brs,1H),7.50(d,J=9.0Hz,1H),7.25(br m,1H),7.20(s,1H),6.58(d,J=9.0Hz,1H),3.98(s,3H)3.63-3.60(m,2H),3.14(t,J=5.7Hz,2H),2.47-2.43(m,2H),1.78(brs,1H);13C NMR(成对质子,CDCl3)160.0(s),140.1(s),128.5(s),125.4(s),122.7(d),122.0(d),121.8(d),117.0(s),105.5(d),53.2(q),45.5(t),43.4(t),27.4(t);LRMS(m/z相对强度)230(27),229(M+,100),228(38),214(49),212(22),199(22),197(42),187(26),186(33),185(32),171(41);C13H15N3O的HRMS计算值:229.1215,测定值229.1185
D.5-乙氧基-3-(1,2,5,6-四氢吡啶基)吡咯并〔3,2,-b〕吡啶(1C)
反应时间是5小时。闪蒸色谱法分离使用硅胶和10%在甲醇中的三乙胺洗提,得到呈黄色粉末的化合物1C(48%):溶点(mp)186-189℃;IR(KBr)3430-2810,1645,1610,1575,1480,1475,1435,1410,1275,1230cm-1;1H NMR(DMSO-d6)11.2(br s,1H),7.68(d,J=8.8Hz,1H),7.45(s,1H),7.06(br m,1H),6.54(d,J=8.7Hz,1H),4.4(br s,1H),4.33(q,J=7.0Hz,1H),3.47(br m,2H),2.99(br m,2H),2.41(br m,2H),1.35(t,J=7.0Hz,6H);13C NMR(DMSO-d6)158.3,139.4
,128.6,125.4,124.2,122.5,119.5,115.1,104.6,60.5,44.4,42.4,26.8,14.7;LRMS(m/z,相对强度)244(M+,100),214(81),197(94),185(33),171(49);C14H17N3O的HRMS计算值:243.1372,测定值243.1367。
E.5-丙氧基-3-(1,2,5,6-四氢吡啶基)吡咯并〔3,2,-b〕吡啶(1d)
反应时间6小时,闪蒸色谱法分离使用的是硅胶和10%在甲醇中的三乙胺洗提,得到的是呈黄色泡沫的化合物1d(78%:溶点(mp),170-173℃;IR(KBr)1640,1620,1575,1470,1455,1410,1270,1235cm-1;1H NMR(DMSO-d6)11.1(br s 1H),7.67(d,J=8.8Hz 1H,),7.42(s,1H),7.06(br s 1H),6.55(d,J=8.7Hz,1H),4.24(q,J=6.6Hz,1H),3.41(br m,2H),2.93(t,J=5.6Hz,2H),2.36(br m,2H),1.82-1.71(m,2H),0.98(t,J=7.4Hz,6H);13C NMR(DMSO-d6)158.5,139.5,128.5,125.4,123.9,122.4,120.8,115.4,104.6,66.4,45.0,42.9,27.3,22.0,10.7;LRMS(m/z,相对强度),258(20),257(M+,95),215(20),214(91),198(26),197(100),185(38),172(20),171(53),169(28);HRMS对C15H19N3O的计算值为257.1528,测定值257.1536。
F.5-异丙氧基-3-(1,2,5,6-四氢吡啶基)吡咯并〔3,2,-b〕吡啶(化合物1e)
反应时间为6小时。对萃取残余物的闪蒸色谱法分离,使用硅胶(约100g)并用5%的在甲醇中的三乙胺洗提,得到呈浅黄色泡沫的化合物1e(60%):IR(KBr)3400-2800(br),1650,1615,1580,1470,1415,1385,1370cm-1;1H NMR(DMSO-d6)7.64(d,J=8.5 Hz,1H)(br m,1H),7.03(br m,1H),6.47(d,J=8.6Hz,1H),5.25(Sept,J=6.3Hz,1H),
3.40(br m,2H),3.04(br s,1H),2.93(t,J=5.2Hz,2H),2.36(br m,2H),1.31(d,J=6.3 Hz,6H);13C NMR(DMSO-d6)157.8,139.5,128.6,125.2,124.0,122.4,120.4,115.3,105.1,66.7,44.9,42.8,27.2,22.0;LRMS(m/z,相对强度)258(10),257(M+,69),214(79),197(100),185(22),172(22);C15H19N3O的HRMS计算值为257.1528,测定值257.1535。
G.5-丁氧基-3-(1,2,5,6-四氢吡啶基)吡咯并〔3,2,-b〕吡啶(1f)
反应时间为19小时。闪蒸色谱法分离使用硅胶并用5%在甲醇中的三乙胺洗提,得到黄色固体。向这一固体中加入冷的甲醇以形成浆。将未溶解的固体过滤出,得到呈黄色粉末的化合物1f(29%):熔点(mp),158-160℃;IR(kBr)2950-2620,1640,1620,1575,1500,1470,1450,1440,1410,1380cm-1;1H NMR(DMSO-d6)11.1(br s,1H),7.66(d,J=8.7 Hz,1H),7.42(s,1H),7.07(br m,1H),6.53(d,J=8.7 Hz,1H),4.29(t,J=6.6Hz,1H),3.41(br m,2H),2.93(br t,2H),2.36(br m,2H),1.78-1.68(m,2H),1.50-1.38(m,2H),0.94(t,J=7.4Hz,6H);13C NMR(DMSO-d6)158.4,139.5,128.5,125.4,123.9,122.4,120.8,115.4,104.6,64.5,45.0,42.9,30.7,27.2,19.0,13.8;LRMS(m/z,相对强度)272(54),271(98,M+),270(23),243(13),228(11),215(28),214(100),212(30),198(35),197(97),187(21),185(43),172(28),171(62),169(34);C16H21N3O分析的计算值:C70.82;H,7.80;N,15.48;测定值C,70.17;H,7.86;N,15.26.
H.5-叔丁氧基-3-(1,2,5,6-四氢吡咯基)吡咯并[3,2-b]吡啶(1g)
反应时间为18小时。闪蒸色谱法分离使用的是硅胶,并用5%
在甲醇中的三乙胺洗提,得到的是黄色泡沫状的化合物1g(48%):IR(kBr)1650,1610,1575,1480,1450,1410,1180cm-1;1H NMR(DMSO)d611.5(br s,1H),7.67(d,J=8.8Hz,1H),7.58(s,1H),6.99(br s,1H),6.48(d,J=8.7Hz,1H),3.73(br m,2H),3.28(br t,2H),2.74(br m,2H)1.58(s,9H);LRMS(m/z,相对强度)271(M+,16),215(71),214(86),198(43),197(75),186(25),185(38),173(32),172(100),171(25),169(20);C16H21N3O的HRMS计算值:271.1685,测定值:271.1681。
I.5-苯氧基-3-(1,2,5,6-四氢吡啶基)吡咯并〔3,2,-b〕吡啶(1h)
反应时间为6小时。闪蒸色谱法分离使用的是硅胶,并用5%在甲醇中的三乙胺洗提,得到的是呈黄色固体的化合物1h(40%),它然后被转换成它的马来酸盐;熔点(mp),185-187℃;IR(kBr)1645,1610,1580,1480,1465,1415,1365,1275cm-1;1H NMR(DMSO-d6)11.4(br s,1H),8.9(br s,2H),7.76(d,J=8.8Hz,1H),7.62(d,J=2.9Hz,1H),7.49-7.47(m,2H),7.40-7.28(m,3H),7.05(br s,1H),6.68(d,J=8.7Hz,1H),6.05(s,2H),5.39(s,2H),3.81(br m,2H),3.36(t,J=6.0Hz,2H),2.71(br m,2H),13C NMR(DMSO-d6)167.3,158.3,139.1,138.2,136.1,128.5,128.3,127.8,127.5,125.6,125.4,123.0,113.2,112.9,105.2,66.7,41.7,40.4,23.1;LRMS(m/z,相对强度)305(M+,4),264(3),228(8),214(96),197(100),91(75),72(28);C19H19N3O的HRMS计算值:305.1528,测定值:305.1542。
J.5-环戊氧基-3-(1,2,5,6-四氢吡啶基)吡咯并〔3,2,-b〕吡啶(1i)
反应时间为24小时。闪蒸色谱法分离使用的是硅胶,并用5%
在甲醇中的三乙胺洗提,得到是呈黄色固体的化合物1i(78%),它然后被转化成它的马来酸盐:熔点(mp),210-211℃;1H NMR(DMSO-d6)11.3(br s,1H),8.8(br s,2H),7.70(d,J=8.8Hz,1H),7.60(d,J=2.9Hz,1H),7.10(br m,1H),6.54(d,J=8.8Hz,1H),6.05(s,2H),5.40-5.35(m,1H),3.82(br m,2H),3.37(t,J=6.0Hz,2H),2.73(br m,2H),2.02-1.93(m,2H),1.80-1.57(m,6H);13C NMR(DMSO-d6)167.3,158.4,139.4,136.1,128.8,125.3,125.2,122.8,113.2,112.6,105.6,76.8,41.7,32.6,23.8,23.1)LRMS(m/z,相对强度)283(26),215(24),214(100),198(38),197(83),185(28),173(23),172(71),171(26),169(23),121(30),72(50);C17H21N3O的HRMS计算值:283.1684,测定值:283.1684。
K.5-羟基-3-(1,2,5,6-四氢吡啶基)吡咯并〔3,2,-b〕吡啶(化合物1j)
反应时间为6小时。萃取残余物的闪蒸色谱法分离使用的是硅胶(约100g),并用10%在甲醇中的三乙胺洗提,得到的是白色泡沫。将这泡沫在5%甲醇/乙酸乙酯中粉碎,得到了呈灰白色固体的化合物1j(65%):熔点(mp),248.0℃分解;IR(kBr)3280,1620,1450,1415,1385,1340cm-1;1H NMR(DMSO-d6)11.1(br s,1H),7.56(d,J=9.3Hz,1H),7.23(s,1H),6.39(br m,1H),6.15(d,J=8.9Hz,1H),3.33(br m,2H),2.88(t,J=5.6Hz,2H),2.26(br m,2H);13CNMR(DMSO-d6)161.0,132.3,127.7,126.2,122.6,121.8,121.2,112.9,109.4,44.7,42.8,27.8;LRMS(m/z,相对强度)216(27),215(M+,100),214(25),198(30),197(52),186(36),185(49),173(29),172(75),171(34),147(21);C12H13N3O的HRMS计算值:215.1058,测定值215.1032。
L.5-氯-3-(1,2,5,6-四氢吡啶基)吡咯并〔3,2,-b〕吡啶(化合物1k)
反应时间为6小时,萃取残余物的闪蒸色谱法分离使用的是硅胶(约100g),并用10%在甲醇中的三乙胺洗提,然后用乙酸乙酯对再生的油状物进行结晶,得到了呈浅黄色固体的化合物1K(38%);熔点(mp),178°-180℃;IR(kBr)3400,3120-2600,1650,1620,1555,1490,1410,1425cm-1;1H NMR(DMSO-d6)11.54(br s,1H),7.81(d,J=8.6Hz,1H),7.66(s,1H),7.14(d,J=8.0Hz,1H),6.95(br m,1H),3.39(br m,2H),3.25(br s,1H),2.92(t,J=5.6Hz,2H),2.36(br m,2H);LRMS(m/z,相对强度)235(21),234(17),233(M+,74),232(33),218(25),217(20),215(27),205(32),204(36),203(41),192(43),191(47),190(100),167(21),165(36),98(28);C12H12N3Cl的HRMS计算值:233.0720,测定值:233.0681。
M.5-二甲胺基-3-(1,2,5,6-四氢吡啶基)吡咯并-〔3,2,-b〕吡啶(化合物1l)
反应时间为6小时。用乙酸乙酯将萃取残余物研磨,得到了呈浅黄色粉末的化合物1l(17%):熔点(mp),在120℃分解;IR(kBr)1610,1580,1490,1405,1365cm-1;1H NMR(DMSO-d6)7.53(d,J=8.9Hz,1H),7.31(s,1H),7.13(br m,1H),6.54(d,J=8.9Hz,1H),4.02(br m,2H),3.44(br m,2H),3.01(s,6H),2.38(br m,2H);LRMS(m/z,相对强度)243(20),242(M+,100),227(32),214(20),210(24),209(23),196(22),184(24);C14H18N4的HRMS计算值:242.1532,测定值:242.1536。
N.5-甲基-3-(1,2,5,6-四氢吡啶基)吡咯并[3,2,-b〕吡啶(化合物1m)
反应时间为23小时。闪蒸色谱法分离使用的是硅胶,并用5%
在甲醇中的三乙胺洗提,得到了呈黄色玻璃状的化合物1m(49%),它然后被转化成它的马来酸盐;熔点(mp),158-159℃开始分解;IR(kBr)1640,1610,1570,1510,1415,1385,1370cm-1;1H NMR(DMSO-d6)11.3(br s,1H),8.8(br s,2H),7.69-7.67(m,2H),7.23(br m,1H),7.03(d,J=8.3Hz,1H),6.04(s,2H),3.82(br m,2H),3.36(br m,2H),2.73(br m,2H),2.56(s,3H);LRMS(m/z,相对强度)214(12),213(M+,100),212(39),198(26),185(28),184(32),183(36),171(32),170(56),72(34);C13H15N3的HRMS计算值:213.1258,测定值:213.1268。
O.3-(1,2,5,6-四氢吡啶基)吡咯并〔3,2,-c〕吡啶(化合物2)
反应时间为2小时。萃取残余物的闪蒸色谱法分离使用的是硅胶(约200g),并用5%在甲醇中的三乙胺洗提,得到了呈浅黄色固体的化合物2(8%):熔点(mp),200-202℃;IR(kBr)3400,3240-2740,1640,1575,1535,1470,1445,1350cm-1;1H NMR(DMSO-d6)11.7(br s,1H),9.17(s,1H),8.22(d,J=8.5Hz,1H),7.45(s,1H),7.36(d,J=8.5Hz,1H),6.29(br s,1H),3.42(br m,2H),2.95(br m,2H),2.40(br m,2H);13C NMR(DMSO-d6)142.8,140.3,140.1,129.2,123.1,121.9,121.3,116.7,106.9,44.7,42.6,27.9;LRMS(m/z,相对强度)200(34),199(M+,100),198(84),171(29),170(74),189(36),155(20),143(13),131(42),119(19);C12H13N3的HRMS计算值:199.1110,测定值:199.1071。
P.3-(1,2,5,6-四氢吡啶基)吡咯并[2,3-c]吡啶(化合物3a)
反应时间为4小时。萃取残余物的闪蒸色谱法分离使用的是硅胶
(约200g),并用5%在甲醇中的三乙胺洗提,得到了呈浅黄色固体的化合物3a(28%):熔点(mp),208-210℃;IR(kBr)3220,3120-2740,1640,1500,1460,1430,1260,1140cm-1;1H NMR(DMSO-d6)8.71(d,J=1.7Hz,1H),8.09(d,J=5.6Hz,1H),7.74(dd,J=1.6和5.6Hz,1H),7.59(s,1H),6.19(br m,1H),3.39(d,J=3.0Hz,2H),3.28(br s,1H),2.92(t,J=5.8Hz,2H),2.38(br m,2H);13C NMR(DMSO-d6)138.1,134.8,134.0,129.3,128.6,126.0,120.6,116.2,114.6,44.7,42.7,27.9;LRMS(m/z,相对强度)200(14),199(M+,100),198(76),170(49),169(25),156(10),142(10),131(23);C12H13N3的HRMS计算值:199.1110,测定值:199.1100。
Q.5-甲氧基-3-(1,2,5,6-四氢吡啶基)吡咯并-〔2,3,-c〕吡啶(化合物3b)
反应时间为4小时。用二氯甲烷对萃取残余物进行研磨得到了浅黄色固体。将该固体用甲醇/二氯甲烷溶解,并向该溶液中加入马来酸(1.05当量(eq))。加入乙醚研磨呈浅黄色粉末的化合物3b的马来酸盐(40%):熔点(mp),170℃分解;IR(kBr)3100-2600,1720,1630,1480,1370,1230cm-1;1H NMR(DMSO-d6)11.57(br s,1H),8.87(br s,2H),8.40(s,1H),7.75(s,1H),7.14(s,1H),6.14(br m,1H),6.09(s,2H),3.85(s,3H),3.78(br m,2H),3.36(br t,2H),2.71(br m,2H);13C NMR(DMSO-d6)167.3,157.9,135.4,132.9,131.5,130.6,129.8,129.3,113.3,112.4,97.3,53.6,41.6,23.9;LRMS(m/z,相对强度)230(19),229(M+,100),228(77),212(24),201(63),200(65),199(27),185(46),150(20),114(33),99(54),87(21),57(78);C13H15N3O的HRMS计算值:229.1215,测定值:229.1232。
R.5-氯-3-(1,2,5,6-四氢吡啶基)吡咯并〔2,3,-c〕吡啶(化合物3c)
反应时间为9小时。对萃取残余物用乙酸乙酯进行研磨,得到呈浅黄色粉末的化合物3c(54%):熔点(mp),230-233℃;IR(kBr)3420,3240,1610,1545,1450cm-1;1H NMR(DMSO-d6)8.52(s,1H),7.77(s,1H),7.71(s,1H),6.16(br m,1H),3.38(br m,2H),3.20(br s,1H),2.91(t,J=5.3Hz,2H),2.35(br m,2H);13C NMR(DMSO-d6)139.4,134.0,133.4,131.8,128.7,128.6,121.8,116.3,113.7,44.8,42.7,28.1;LMRS(m/z,相对强度)235(48),234(53),233(M+,100),232(94),206(21),204(53),169(27),165(24);C12H12N3Cl的HRMS的计算值:233.0720,测定值:233.0671。
S.3-(1,2,5,6-四氢吡啶基)吡咯并〔2,3,-b〕吡啶(化合物4)
反应时间为4小时。用乙酸乙酯对萃取残余物进行研磨,得到是呈浅黄色固体的化合物4(63%):熔点(mp),199.0-202。0℃;IR(kBr)3280,3100-2740,1650,1595,1570,1520,1495,1450,1415,1330,1240cm-1;1H NMR(DMSO-d6)11.65(br s,1H),8.20(d,J=6.7Hz,1H),7.47(s,1H),7.08-7.03(m,2H),6.18(br m,1H),3.39-3.34(br m,2H),2.92(br m,2H),2.37(br m,2H);LRMS(M/z,相对强度)200(21),199(M+,100),198(77),171(22),170(87),169(36),155(22),143(22),142(23),131(67),80(23);C12H13N3的HRMS计算值:199.1110,测定值:199.1059。
实施例2
(6-氯-3-硝基-2-吡啶基)乙腈(化合物5a和(6-
氯-3-硝基-4-吡啶基)乙腈(化合物6)
向施以搅拌的叔丁醇钾(24.69g,220mmol,2.2当量(ep))在无水四氢呋喃(150ml)的溶液中,在氮气氛和-50℃条件下,滴加下述溶液,该溶液是2-氯-5-硝基吡啶(15.85g,100mmol)放(4-氯代苯氧基)乙腈(E.Grochowski等,Bull.Acad.Pol.Sci.Ser.Sci.Chim.11,443(1963))(18.44g,110mmol,1.1当量(ep))在无水四氢呋喃(150ml)中形成的,控制滴加速度,以使反应温度在以干冰/乙酮浴冷却的条件下保持在-40℃至-50℃。在-78℃氮气氛中搅拌得到的紫色反应混合物1小时,在这段时间内向该反应中加入冰醛酸(20ml,0.35mol,3.5当量(ep)),并允许该混合物升热至室温。向反应混合物中加入5%HCl(100ml)溶液,用乙醚(100ml)萃取该水溶液混合物,然后用二氯甲烷(2×100ml)萃取。将萃取物混合,干燥(MgSO4),并穿过硅胶过滤器(约150g),然后使二氯甲烷(1200ml)穿过硅胶。将过滤物在减压下蒸发,余下的油用硅胶9约300g)经色谱法分离,并用25%在二氯甲烷中的己烷洗提,得到了一种油状物(Rf=0.52在二氯甲烷中),将该油状物在冷的无水醚中研磨,得到了呈白色结晶固体的化合物5a(1.37g,7%):熔点(mp),121.5-123.5℃;IR(kBr)3070,2240,1600,1560,1525,1430,1390,1370,1345,1185cm-1;1HNMR(CDCl3)8.45(d,J=8.6Hz,1H),4.38(s,2H);13C NMR(CDCl3)155.5,146.8,143.2,136.2,125.5,114.4,26.7;LRMS(m/z,相对强度)199(10),198(12),197(M+,30),170(23),151(39),126(75),125(20),124(100),116(29),115(54),112(23),99
(49),88(24),79(75);C7H4ClN3O2分析的计算值为C,42.55;H,2.04;N,21.27;测定值:C,42.52;H,1.89;N,20.95。
进一步的洗提得到了另外一种油状物(Rf=0.48在二氯甲烷中),在冷的无水乙醚中将其研磨,得到了呈白色结晶态固体的化合物6(1.87g,9%):熔点(mp),87-89℃;IR(kBr)3080,2240,1600,1545,1520,1450,1390,1340,1135cm-1;1H NMR(CDCl3)9.17(s,1H),7.76(s,1H),4.27(s,2H);13C NMR(CDCl3)157.4,147.3,137.7,125.5,114.4,22.5;LRMS(m/z,相对强度)199(39),197(N+,100),182(28),180(70),153(29),152(31),151(67),127(29),126(61),125(35),124(64),116(32),115(47),114(35),99(33),98(21),97(46);C7H4ClN3O2分析的计算值:C,42.55;H,2.04;N,21.27,测定值:C,42.35 H,1.95;N,20.94。
实施例3
(6-氯-3-硝基-2-吡啶基)乙腈(化合物5a)
向施加搅拌的NaH(60%,1.84g,46mmol,2.3当量(eq))和氰基乙酸乙酯(4.90ml,46mmol,2.3当量(eq))在无水四氢呋喃(30ml)中的溶液中,在0℃,滴加下述溶液,该溶液是由2,6-二氯-3-硝基吡啶(3.86g,20.0mmol)在无水四氢呋喃(20ml)中形成的。在0℃氮气氛的条件下将得到的反应混合物搅拌90分钟,在这段时间内反应物的颜色慢慢地由黄变至深红。然后向反应混合物中加入5%HCl溶液(40ml),并用醚(40ml)然后用二氯甲烷(40ml)萃取该水溶液混合物。将萃取物混合,干燥(MgSO4),在减压下蒸发。将残余的油状物穿过硅胶过滤器(约200g),然后使10%乙酸乙酯/己烷(1.5
L),2∶1己烷/乙酸乙酯(2L)和1∶1乙酸乙酯/己烷(1L)穿过该过滤器。将最后3L的滤液在减压下蒸发,得到一种纯净的浅黄色油状物(7.2g)。将该油状物置入2M HI水溶液(30ml)中,并在回流温度下加热该混合物5小时。用二氯甲烷(3×30ml)萃取得到的反应混合物,并将这些萃取物混合、干燥(MgSO4),并穿过硅胶过滤器(约150g),然后使二氯甲烷(1L)穿过该过滤器,在减压下蒸发这一滤液,把残余的固体放在冷的无水乙醚中搅拌。将未溶解的固体滤出,得到呈灰白色结晶态固体的化合物5a(1.16g,5.87mmol,29%总共):熔点(mp),119-121℃。该固体的物理和光谱特性与实施例2中叙述的化合物5a的相应特性相同。
实施例4
6-苄氧基-3-硝基-2-吡啶基)乙腈(化合物5b)
向叔丁醇钾(12.34g,110mmol,2.2当量(eq))在无水二甲基甲酰胺(100ml)中所形成的溶液中,在施加搅拌的条件下,在-10℃滴加下述溶液,该溶液是(4-氯代苯氧基)乙腈(9.22g,55mmol,1.1当量(eq))和2-苄氧基-5-硝基吡啶[H.L.Friedman等,美国化学会志(J.Am.Chem.Soc.),69,1204(1947)](11.51g,50.0mmol)在无水二甲基甲酰胺(50ml)中混合而成的。得到的深紫色溶液在-10℃氮气氛中搅拌1小时。然后在0℃向反应溶液中滴加5%HCl水溶液(85ml),将沉淀的固体滤出并干燥,得到的是褐色固体(13.4g)。该固体被溶于二氯甲烷(50ml)中,并将该溶液穿过硅胶过滤器(约500g),然后用二氯甲烷(4L)洗提。将滤液减压蒸发,余下的油状物在乙醚/己烷(1∶1)中结晶,得到了呈灰白色固体
的化合物5b(11.15g,41.4mmol,83%):熔点(mp),63.0-67.0℃;IR(kBr)2260,1590,1515,1470,1455,1450,1420,1350,1295cm-1;1H NMR(CDCl3)8.41(d,J=8.8Hz,1H),7.56-7.31(m,5H),6.90(d,J=8.8Hz,1H),5.60(s,2H),4.43(s,2H);LRMS(m/z,相对强度)270(12),269(M+,55),107(29),92(39),91(100),65(55)。C14H11N3O3分析的计算值:C,62.45;H,4.12;N,15.61;测定值:C,62.19;H,4.05;N,15.55。
实施例5
(6-二甲胺基-3-硝基-2-吡啶基)乙腈(化合物5c)
在-10℃搅拌条件下,向叔丁醇钾(12.34g,110mmol,2.2当量(eq))在无水二甲基甲酰胺(100ml)中形成的溶液中滴加下述溶液,该溶液是(4-氯代苯氧基)乙腈(9.22g,55mmol,1.1当量(eq))和2-二甲基胺基-5-硝基吡啶(Pfaltz和Bauer公司,8.36g,50.0mmol)在无水二甲基甲酰胺(50ml)中形成的。将得到的深紫色溶液在-10℃氮气氛中搅拌1小时。然后在0℃向反应溶液中滴加5%HCl水溶液(85ml),将沉淀的固体滤出、干燥得到呈黄色固体的化合物5c(8.60g,41.7mmol,83%):溶点(mp),156.0-158.0℃;IR(kBr)2240,1600,1580,1530,1485,1420,1385,1335cm-1;1H NMR(CDCl3)8.25(d,J=9.0Hz,1H,6.45(d,J=9.6Hz,1H),4.38(s,2H),3.25(br s,6H);LRMS(m/z,相对强度)207(13),206(M+,100),191(54),189(26),177(88),160(35),159(22),145(94),134(30),131(24),119(29),118(59),93(27)。对C9H10N4O2分析的计算值C,52.42;H,4.89;N,27.17;测定值:C,52.19;H,4.93;N,26.93。
实施例6
5-氯代吡咯并[3,2-b]吡啶(化合物7a)
将500mg阮内镍(用纯乙醇彻底清洗、化合物5(1.70g,8.60mmol)和1∶1纯乙醇/乙酸(30ml)的混合物在氢气氛中(3大气压(atm))摇动2小时。将反应混合物过滤,在减压下蒸发滤液。把残余的油状物置于碳酸氢钠饱和溶液(10ml)中,用二氯甲烷(3×25ml)萃取这一水溶液混合物。将萃取物混合、干燥(MgSO4)并减压蒸发。把残余的固体置入冷的无水乙醚中搅拌,将未溶解的固体滤出,得到是呈白色固体的化合物7a(0.65g,4.26mmol,50%):熔点(mp),200-203℃;IR(kBr)3140-2700,1620,1555,1500,1460,1450,1415,1335cm-1;1H NMR(CDCl3)8.92(br,s 1H),7.67(d,J=8.0Hz,1H)7.48(t,J=2.9Hz,1H),7.11(d,J=7.9Hz,1H),6.67-6.65(m,1H);LRMS(m/z,相对强度)154(46),153(17),152(M+,100),117(81),90(17),63(15);C7H5ClN2的HRMS计算值:152.0141,测定值:152.0131(偏差1.0ppm)。
实施例7
A.5-烷氧基吡咯并〔3,2,-b〕吡啶(化合物7x)
在冷却至-10℃氮气氛中,向施以搅拌的叔丁醇钾(12.34g,110mmol,2.2当量(eq))在无水二甲基甲酰胺或四氢呋喃(在下面做为反应介质时提到)中所形成的溶液中滴加下述溶液,该溶液是由(4-氯代苯氧基)乙腈(9.22g,55mmol,1.1当量(eq))和2-烷氧基-5-硝基吡啶(50mmol)在无水二甲基甲酰胺或四氢呋喃(所有2-烷氧基-5-硝基吡啶使用H.L.Friedman等[美国化学会志(J.Am.Chem.Soc.),69,1204(1947)]的方法制备,对反应时间、温度和纯化方法做微小改动)中所形成的
。得到的深紫色反应溶液在-10℃氮气氛中保持1小时。加入盐酸水溶液(80ml,5%HCl),使得到的混合物升温至室温。用二氯甲烷(3×50ml)萃取反应混合物,把萃取物混合、干燥(MgSO4)并减压蒸发。残余的油状物穿过硅胶过滤器(约200g),然后使二氯甲烷/己烷(1∶1,2L)穿过该过滤器。减压蒸发这一滤液,把残余的油状物(含有要得到的(6-烷氧基-3-硝基-2-吡啶基)-乙腈)溶于乙酸中,并加入10%钯/碳(油状物重量的10%)。该混合物在3大气压氢气氛中加氢6小时。得到的反应混合物通过硅藻土((商标)Celite)过滤,并减压蒸发滤液。把残余的油状物置于水(50ml)中,加入碳酸钠调整pH至10。用二氯甲烷(2×100ml)萃取该混合物,将萃取物混合、干燥(MgSO4)、并减压蒸发。用硅胶(约200g)按照色谱法分离,并用适宜的溶剂体系洗提,得到要制备的5-烷氧基吡咯并[3,2-b]吡啶(化合物7x)。在下面对制备的化合物进行具体的叙述。
B.5-乙氧基吡咯并〔3,2,-b〕吡啶(化合物7b)
反应溶剂是四氢呋喃,先用二氯甲烷然后用二氯甲烷/乙醚(9∶1)洗提,得到了呈黄色固体的化合物7b(19%):熔点(mp),156-157.5℃;IR(kBr)1620,1570,1485,1470,1445,1410,1390,1365,1340,1305cm-1;1H NMR(CDCl3)8.35(br s,1H),7.55(d,J=8.5Hz,1H),7.28(t,J=3.2Hz,1H),6.58(d,J=9.0Hz,1H),6.57-6.55(m,1H),4.41(q,J=7.0Hz,2H),1.40(t,J=7.1Hz,3H);LRMS(m/z,相对强度)163(32),162(M+,89),147(100),134(85),119(22),118(75),117(31),106(83),105(48),79(49);对C9C10N2O分析的计算值:C,66.65;H,6.21;N,17.27;测定值:C,66.31;H,6.18;N,17.15。
C.5-丙氧基吡咯并〔3,2-b〕吡啶(化合物7c)
反应溶剂是四氢呋喃,先用二氯甲烷然后用1%在二氯甲烷中的甲醇洗提,得到呈黄色固体的化合物7C(23%):熔点(mp),114-116℃;IR(kBr)1615,1610,1585,1475,1410,1380,1305 cm-1;1H NMR(CDCl3)8.1(br s,1H),7.57(d,J=8.7Hz,1H),7.31-7.29(m,1H),6.60(d,J=8.9Hz,1H),6.59-6.57(m,1H),4.31(t,J=6.8Hz,2H),1.88-1.76(m,2H),1.04(t,J=7.4Hz,3H);13C NMR(CDCl3)158.8,142.4,127.6,124.2,122.3,104.6,100.9,66.4,22.1,10.6;对C10H12N2O分析的计算值:C,68.16;H,6.86;N,15.90;测定值:C,67.56;H,6.43;N,15.71。
D.5-异丙氧基吡咯并〔3,2-b〕吡啶(化合物7d)
反应溶剂是四氢呋喃,先用醚/己烷(1∶2,4000ml)然后用醚/己烷(1∶1)洗提,得到了化合物7d(16%从离析的(6-异丙氧基-3-硝基-2-吡啶基)乙腈中),呈灰白色固体:熔点(mp),104.5-107.5℃;IR(kBr)1620,1575,1480,1455,1410,1390,1335,1310cm-1;1H NMR(CDCl3)8.77(br m,1H),7.54(d,J=9.0Hz,1H),7.28(t,J=2.9Hz,1H),6.54(d,J=8.4Hz,1H),6.52(br m,1H),5.38(sept,J=6.3Hz,1H),1.35(d,J=6.3Hz,6H);13C NMR(CDCl3)159.4,142.8,126.6,124.3,122.0,106.5,102.4,67.7,22.2;LRMS(m/z,相对强度)177(7),176(M+,51),161(30),134(100),106(57),79(20)。C10H12N2O分析的计算值:C,68.16;H,6.86;N,15.90;测定值:C,67.95;H,6.77;N,15.81。
E.5-丁氧基吡咯并〔3,2-b〕吡啶(7e)
反应溶剂是四氢呋喃,用1-3%在二氯甲烷中的甲醇试剂洗提,得到了呈灰白色固体的化合物7e(36%):熔点(mp),92
-93℃;IR(kBr)2960-2750,1620,1570,1490,1460,1415,1395,1340,1320cm-1;1H NMR(CDCl3)8.5(br s,1H),7.56(d,J=8.9Hz,1H),7.30(t,J=3.0Hz,1H),6.60(d,J=8.8Hz,1H),6.57(m,1H),4.35(t,J=6.7Hz,2H),1.82-1.72(m,2H),1.55-1.42(m,2H),0.96(t,J=7.4Hz,3H);13C NMR(CDCl3)160.1,142.5,126.4,124.1,121.8,106.0,102.7,65.7,31.4,19.4,14.0;LRMS(相对强度)191(26),190(67,M+),160(35),147(52),135(25),134(100),118(21),117(32),106(60),105(28),78(19);C11H14N2O分析的计算值:C,69.45;H,7.42;N,14.72;测定值:C,69.20;H,7.33;N,14.58。
F.5-叔-丁氧基吡咯并〔3,2-b〕吡啶(化合物7f)
反应溶剂是四氢呋喃,先用二氯甲烷再用1%在二氯甲烷中的甲醇洗提,得到一种混合物,使用硅胶(约100g)对该混合物进行再次色谱法分离,并用乙醚/己烷(1∶1)洗提,得到了呈灰白色固体的化合物7f(15%):熔点(mp),109-110℃;IR(kBr)1615,1570,1470,1450,1410,1390,1365,1300cm-1;1H NMR(CDCl3)8.1(br s,1H),7.52(d,J=8.8Hz,1H),7.29-7.27(m,1H),6.56(d,J=8.5Hz,1H),6.55-6.53(m,1H),1.57(s,9H);13C NMR(CDCl3)159.1,143.1,126.6,124.6,121.1,109.4,103.0,79.2,29.0;LRMS(m/z,相对强度)190(M+,17),135(31),134(100),106(57),105(22),79(22);C11H14N2O分析的计算值:C,69.45;H,7.42;N,14.72;测定值:C,69.37;H,7.48;N,14.49。
G.5-苄氧基吡咯并〔3,2-b〕吡啶(化合物7g)
反应溶剂是二甲基甲酰胺。用阮内镍(用乙醇洗涤)代替在碳上的钯。用二氯甲烷洗提得到了呈灰白色固体的化合物7g(27%从
离析的(6-苄氧基-3-硝基-2-吡啶基)乙腈):熔点(mp),146.0-148.0℃;IR(kBr)1605,1580,1500,1470,1450,1410,1300cm-1;1H NMR(CDCl3)8.47(br m,1H),7.57(d,J=9.0Hz,1H),7.50-7.48(m,2H),7.39-7.27(m,4H),6.67(d,J=8.4Hz,1H),6.60-6.58(m,1H),5.45(s,2H);13C NMR(CDCl3)159.7,142.6,137.8,128.4,128.0,127.7,126.7,124.5,122.1,106.0,102.6,67.7;LRMS(m/z,相对强度)225(38),224(M+,89),223(40),207(20),147(61),119(31),118(75),105(30),92(22),91(100),65(36)。C14H12N2O分析的计算值:C,74.98;H,5.39;N,12.49;测定值:C,74.80;H,5.22;N,12.42。
H.5-环戊氧基吡咯并〔3,2-b〕吡啶(化合物7h)
反应溶剂是四氢呋喃,用在二氯甲烷中2.5%的甲醇洗提,得到了一种混合物,在乙醚中研磨该混合物,把未溶解的固体滤出,得到了呈白色固体的化合物7h(29%):熔点(mp),99-101℃;IR(kBr)1610,1580,1480,1445,1510,1360,1320,1300cm-1;1H NMR(CDCL3)8.1(br s,1H),7.55(d,J=8.8Hz,1H),7.29(t,J=2.9H2,1H),6.58-6.56(m,1H),6.55(d,J=8.7Hz,1H),5.52-5.47(m,1H),2.05-1.92(m,2H),1.88-1.75(m,4H),1.70-1.55(m,2H);LRMS(m/z,相对强度)203(30),202(M+,62),174(11),159(15),135(40),134(100),133(20),117(28),106(64),105(35),79(38);C14H12N2O[0.25H2O)分析的计算值:C,69.71;H,7.07;N,13.54;测定值:C,69.81;H,6.66;N,12.30。
实施例8
5-羟基吡咯并〔3,4-b〕吡啶(化合物7i)
在氢气氛中(3大气压),摇动5-苄氧基吡咯并[3,4-b]吡啶(化合物7f,1.38g,6.15mmol)、5%pd/c(0.30g)
和纯乙醇(25ml)的混合物30分钟。将得到的混合物通过硅藻土(Celite(商标)过滤,并减压蒸发滤液。在乙醚中研磨余下的固体,得到呈灰白色结晶态固体的化合物7i(0.80g,5.96mmol,97%):熔点(mp),280.0-282.0℃;IR(kBr)1640,1615,1605,1455,1430,1400,1380,1365cm-1;1H NMR(DMSO-d6)11.4(br m,2H),7.56(d,J=9.7Hz,1H),7.16(d,J=3.1Hz,1H),6.01-5.93(m,2H);13C NMR(DMSO-d6)162.0,131.9,127.9,125.0,118.2,112.2,94.5;LRMS(m/z,相对强度)135(41),134(M+,100),106(66),105(42),79(59),53(31),52(52)。C7H6N2O分析的计算值:C,62.68;H,4.51;N,20.88;测定值:C,62.40;H,4.40;N,20.76。
实施例9
5-二甲基胺基吡咯并〔3,2-b〕吡啶(化合物7j)
在氢气氛中(3大气压)摇动(6-二甲基氨基-3-硝基-2-吡啶基)-乙腈(化合物5c,2.06g,10.0mmol)、阮内镍(0.70g,用纯乙醇彻底洗涤)和纯乙醇/乙酸(4∶1.50ml)的混合物3小时。将得到的混合物通过硅藻土(Celite(商标))过滤,并减压蒸发滤液。把残余的油状物溶于水中(25ml),用碳酸钠调整pH至10,并用二氯甲烷(3×25ml)萃取该混合物。将萃取物混和、干燥(MgSO4)并减压蒸发,得到一种油状物。把这一油状物溶于乙酸乙酯(10ml)中,将该溶液穿过氧化铝(碱性)过滤器(约100g),然后使乙酸乙酯(1500ml)穿过该过滤器。减压蒸发得到的滤液,制得呈白色固体的化合物7j(0.44g,2.73mmol,27%):熔点(mp),149.0-151.0℃;IR(kBr)1620,1590,1505,1475,1455,1410cm-1;1H NMR
(CDCl3)8.68(br m,1H),7.47(d,J=8.8Hz,1H),7.21(t,J=3.0Hz,1H),6.50(d,J=8.8Hz,1H),6.49-6.47(m,1H),3.10(s,6H);13C NMR(CDCl3)156.6,144.3,126.4,120.8,102.7,102.0,39.3;LRMS(m/z,相对强度)162(21),161(M+,99),160(23),146(80),132(100),119(36),118(82),117(81),90(19)。对C9H11N3分析的计算值:C,67.06;H,6.88;N,26.08;测定值:C,66.69;H,6.81;N,25.94。
实施例10
5-甲基吡咯并〔3,2-b〕吡啶(化合物7k)
在0℃氮气氛中,向施加搅拌的氢化钠(60%在油中,18.2g,455mmol,2.0当量(eq))在无水四氢呋喃(250ml)中形成的浆状物中滴加下述溶液,该溶液是由丙二酸二丁酯(97.9g,453mmol,2.0当量(eq))在无水四氢呋喃(150ml)中形成的。使混合物升温至室温,然后在45℃加热30分钟。然后使反应混合物冷却至室温,并把呈固体的2-氯代-5-硝基吡啶(35.9g,226mmol)一次全部加入到反应混合物中。在回流温度(66℃)氮气氛中加热得到的混合物2小时。然后使反应物冷却,置入分液漏斗中,加入水(200ml),用10%HCl调整pH至6,加入乙醚(200ml),并将有机层移出。用乙醚(200ml)萃取余下的水溶液层一次,然后将有机萃取物混合、干燥(MgSO4)并减压蒸发。将得到的固体/油混合物在乙醚/己烷(1∶1,300ml)中搅拌,把未溶解的固体滤出,得到的是呈白色结晶态固体的(2-叔丁氧基羰基)-(5-硝基-2-吡啶基)乙酸叔丁酯(46.0g,135mmol,60%):熔点(mp),105-106℃;IR(kBr)1740,1730,1600,1575,1520,1460,1390,1370,1365,1330,1310cm-1;1H NMR(CDCl3)
9.36(d,J=2.6Hz,1H),8.48(dd,J=2.6和8.7Hz,1H),7.75(d,J=8.6Hz,1H),4.89(s,1H),1.47(s,18H);LRMS(m/z,相对强度)227(11),209(49),182(52),164(33),57(100);对C16H22N2O6分析的计算值:C,56.80;H,6.55;N,8.28;测定值:C,56.72;H,6.57;N,8.14。
在-10℃氮气氛中,向施以搅拌的叔丁醇钾(11.0g,97.6mmol,3.3当量(eq))在无水四氢呋喃(100ml)中形成的溶液中滴加下述溶液,该溶液是(4-氯代苯氧基)乙腈(5.45g,32.5mmol,1.1当量(eq))和(2-叔丁氧基羰基)-(5-硝基-2-吡啶基)乙酸叔丁酯(10.0g,29.6mmol)在无水四氢呋喃(75ml)中所形成的。在氮气氛中室温的条件下搅拌得到的深紫色反应混合物64小时。向反应溶液中加入5%HCl(72ml),并用乙酸乙酯(3×200ml)萃取得到的水溶液混合物。把这些萃取物合并、干燥(MgSO4)并减压蒸发得到一种油状物。用硅胶(约300g)对该油状物进行柱色谱法分离,并用乙醚/己烷试剂(在己烷中有10-40%乙醚)洗提,得到呈透明的、浅黄色油状物的(3-硝基-6-(二羰-叔丁氧基甲基)-2-吡啶基)乙腈(5.14g,13.6mmol,46%):IR(CHCl3)3670,2970,2925,2255,1725,1600,1580,1520,1450,1395,1370,1350,1320cm-1;1H NMR(CDCl3)8.49(d,J=8.6Hz,1H),7.81(d,J=8.6Hz,1H),4.92(s,1H),4.40(s,2H),1.48(s,18H);13C NMR(CDCl3)165.4,158.8,145.0,143.4,133.9,125.0,115.1,83.5,62.3,27.9,26.8;LRMS(m/z,相对强度)322(3),265(19),248(24),221(75),204(23),203(47),57(100);C18H24N3O6([M+]+H)的HRMS计算值:378.1665,测定值:378.1637;对C18H23N3O6分析的计算值:C,57.29;H,6.14;N,11.13;测定值:C,56.96;H,6.10;N,10.97。
将(3-硝基-6-(二羰-叔丁氧甲基)-2-吡啶基)乙腈(6.85g,18.2mmol)、二恶烷(150ml)和2M硫酸(25ml)的混合物在回流温度下加热12小时。将得到的溶液冷却、用碳酸钠中和并用乙酸乙酯(3×50ml)萃取。把这些萃取物合并,干燥(MgSO4),并减压蒸发,得到一种油状物。将该油状物和二氯甲烷先后通过硅胶过滤器(约100g)。将该滤液减压蒸发,得到了呈灰白色固体的(6-甲基-3-硝基-2-吡啶基)乙腈(1.91g,10.8mmol,59%):熔点(mp),70-72℃;IR(kBr)2245,1595,1580,1515,1450,1370,1340cm-1;1H NMR(CDCl3)8.38(d,J=8.4Hz,1H),7.37(d,J=8.4Hz,1H),4.39(s,2H),2.70(s,3H);13C NMR(CDCl3)164.7,145.3,142.1,133.8,123.9,115.1,27.1,24.7;LRMS(m/z,相对强度)178(29),177(M+,93),160(16),132(26),131(92),105(37),104(100),92(32),79(50),78(51),77(81),63(54);HRMS3.98;N,23.72;测定值:C,53.90;H,3.95;N,23.47。
在氢气氛中摇动(6-甲基-3-硝基-2-吡啶基)-乙腈(1.83g,10.3mmol)、阮内镍(0.20g)和乙酸/乙醇(3∶7)的混合物4小时。将得到的混合物过滤并减压蒸发滤液。将残余油状物在饱和碳酸氢钠(25ml)和乙酸乙酯(25ml)中分配。移出有机物层,并用乙酸乙酯(2×25ml)萃取水溶液层。把有机萃取物合并、干燥(MgSO4)并减压蒸发,得到黄色固体。用硅胶(约50g)对这一固体进行柱色谱法分离,并用在二氯甲烷中5%的甲醇洗提,得到呈棕黄色固体的化合物7K(0.32g,2.4mmol,24%):熔点(mp),200-202℃;IR(kBr)1610,1570,1465,1445,
1405,1290cm-1;1H NMR(DMSO-d6)11.15(br s,1H),7.65(d,J=8.5Hz,1H),7.54(m,1H),6.95(d,J=8.5Hz,1H),6.45(br m,1H),2.51(s,3H);13C NMR(DMSO-d6)150.0,145.7,128.5,126.6,118.7,116.0,101.1,24.2;对C8H8N2分析的计算值:C,72.70;H,6.10;N,21.20;测定值:C,72.22;H,6.19;N,21.25。
实施例11
5-氯代吡咯并〔2,3-c〕吡啶(化合物8)
在氢气氛中(3大气压)摇动200mg阮内镍(用纯乙醇彻底清洗),化合物6(2.35g,11.89mmol)和1∶1纯乙醇/乙酸(50ml)组成的混合物2小时。过滤反应混合物,减压蒸发滤液。把残余的油状物置入饱和碳酸氢钠溶液(25ml)中,并用二氯甲烷(3×25ml)萃取这一水溶液混合物。把这些萃取物合并,干燥(MgSO4)并减压蒸发。将残余的固体在冷的无水醚中搅拌,并滤出未溶解的固体,得到呈白色结晶态固体的化合物8(0.80g,5.24mmol,44%):熔点(mp),192-194℃;IR(kBr)3400,3080-2750,1610,1565,1495,1455,1290cm-1;1H NMR(CDCl3)9.55(br s,1H),8.59(s,1H),7.56(s,1H),7.48(t,J=2.8Hz,1H),6.53-6.51(m,1H);13C NMR(DMSO-d6)138.8,135.4,133.6,132.6,132.0,113.8,100.5;LRMS(m/z,相对强度)154(34),153(13),152(M+,100),117(68),90(19),63(14);C7H5ClN2的HRMS计算值:152.0141,测定值:152.0136。
实施例12
5-甲氧基吡咯并〔2,3-c〕吡啶(化合物9)
将4-甲基-5-硝基-1H-吡啶-2-酮(5.00g,
32.44mmol)、亚硫酰氯(20ml)和两滴二甲基甲酰胺所组成的混合物在氮气氛中回流温度下加热52小时。减压蒸发上述得到的桔色溶液,并加入少量的无水甲苯,然后通过减压蒸发将其除去以达到除去残留的亚硫酰氯的目的。将余下的油状物和二氯甲烷(11)先后通过硅胶过滤器(在150℃真空中干燥一夜,约100g)。减压蒸发该滤液得到呈桔色油状物的2-氯-4-甲基-5-硝基吡啶(5.30g,30.71mmol,95%),该油状物在0℃以下结晶;IR(CHCl3)1605,1550,1520,1450,1360,1345cm-1;1H NMR(CDCl3)9.03(s,1H),7.83(s,1H),2.60(s,3H);LRMS(m/z,相对强度)174(25),173(19),172(M+,68),157(74),155(100),128(27),101(47),100(55),99(74),90(43),75(36)。
在0℃、搅拌的条件下,向钠(2.30g,100mmol,3.8当量(eq))在纯甲醇(75ml)中形成的溶液中快速滴加下述溶液,该溶液是2-氯-4-甲基-5-硝基吡啶(4.50g,26.07mmol)在纯甲醇(15ml)中所形成的。将得到的黑色溶液在室温搅拌30分钟,然后通过减压蒸发将其浓缩为固体。将该固体置于水中(25ml),用浓HCl将pH调整至6,并用乙酸乙酯(2×25ml)萃取该水溶液混合物。把萃取物合并、干燥(MgSO4)并减压蒸发,得到呈桔色固体的2-甲氧基-4-甲基-5-硝基吡啶(4.30g,25.57mmol,98%):熔点(mp),70-72℃;1H NMR(DMSO-d6)8.94(s,1H),6.97(s,1H),3.99(s,3H),2.58(s,3H);LRMS(m/z,相对强度)168(M+,98),167(100),151(34),138(24),80(17)。
由2-甲氧基-4-甲基-5-硝基吡啶(4.30g,25.57
mmol)和二甲基甲酰胺二甲基乙缩醛(35ml)所组成的溶液在氮气氛中回流温度下加热40小时。向该溶液中加入乙酸乙酯(150ml),并用水(150ml)洗涤该混合物。用乙酸乙酯(100ml)反萃取该水溶液萃取物,把有机萃取物合并、干燥(Na2SO4)并减压蒸发,得到紫色固体。把该固体溶于纯乙醇中(200ml),并加入在碳上5%的钯(3.0g)在氢气氛(3大气压)摇动该溶液3小时。把得到的反应混合物过滤,并减压蒸发该滤液。残余物进行闪蒸色谱法分离,得到呈白色结晶态固体的化合物9(2.05g,13.84mmol,54%最后一步,50%总体):熔点(mp),123-124℃;IR(kBr)1625,1580,1490,1460,1320,1150cm-1;1H NMR(DMSO-d6)11.28(br s,1H),8.37(s,1H),7.57(t,J=2.8Hz,1H),6.86(s,1H),6.33(br m,1H),3.82(s,3H);13C NMR(DMSO-d6)157.2,136.4,131.5,130.7,130.0,99.6,96.8,53.4;LRMS(m/z,相对强度)149(20),148(M+,98),147(100),119(46),118(79),117(26),105(31),91(15),70(16);C8H8N2O的HRMS计算值:148.0657;测定值:148.0613。
实施例13
已适应动物器具约6天的雄性CD-1老鼠(初到时17-19g),8只装入一个盒子。将老鼠称重并在上午和下午间隔至少六小时服用对比物或本发明的化合物(药)两天。在第三天的上午,给动物称重。化合物1a-1m,2和3a-3c的任一种证明,相对于服用对比物的动物,服用药物的动物体重至少减少5%(与第1天上午的体重相比),剂量是32mg/kg。
Claims (11)
1、一种制备下式化合物或它们的可作药用的盐的方法
其中A,B,D和E之一是氮,其余三个原子是碳;R1和R2是各自独立地选自氢和C1至C6烷基;R3、R4、R5和R6是各自独立地选自氢,卤素,羟基,C1-C6烷基,C1-C8烷氧基,苯基-C1-C6烷氧基,苯氧基,-NR7R8基其中R7和R8是各自独立地选自氢、C1-C6烷基、C1-C6烷酰基、和COOR9其中R9是氢或C1-C6烷基,氰基,COOR10其中R10是氢或C1-C6烷基,和CONR11R12而其中R11和R12是独立地选自氢和C1-C6烷基,其条件是当A是氮时则不存在R3,当B是氮时则不存在R4,当D是氮时则不存在R5,以及当E是氮时则不存在R6,该方法包括使哌啶酮-水合氢卤化物与下式的化合物反应,
其中A、B、D、E、R2、R3、R4、R5和R6的限定范围同上;
并且,通过能生成可用作药物的盐的无机酸或有机酸与式Ⅰ的化合物反应,把该化合物任意地转化成它的药物中可接受的盐。
2、根据权利要求1所述的方法,其中所述式Ⅰ的化合物中,其中R1、R2、R5和R6是氢;R3是空缺;R4是一个选自下列的基,团:氢,卤素,羟基,C1-C6烷基,C1-C8烷氧基,苯基-C1-C6烷氧基,苯氧基,-NR7R8基其中R7和R8是各自独立地选自氢、C1-C6烷基、C1-C6烷酰基、以及其中的R9是氢或C1-C6烷基的COOR9基,氰基,其中的R10是氢或C1-C6烷基的COOR10基,其中的R11和R12是各自独立地选自氢和C1-C6烷基的CONR11R12基;A是氮而B、D和E是碳,该化合物是通过哌啶酮-水合氢卤化物与所述式Ⅱ的化合物反应来制备的,在式Ⅱ中,R2、R5和R6是氢;R3是空缺;R4是一个选自下列的基团:氢,卤素,羟基,C1-C6烷基,C1-C8烷氧基,苯基-C1-C6烷氧基,苯氧基,-NR7R8基其中R7和R8是各自独立地选自氢、C1-C6烷基、C1-C6烷酰基、以及其中的R9是氢或C1-C6烷基的COOR9,氰基,其中的R10是氢或C1-C6烷基的COOR10基,其中的R11和R12是各自独立地选自氢和C1-C6烷基的CONR11R12基;A是氮而B、D和E是碳。
3、根据权利要求1或权利要求2所述的方法,在所述式Ⅰ的化合物中,其中R4是氢、甲氧基、乙氧基、丙氧基、丁氧基或羟基,该化合物是通过哌啶酮一水合氢卤化物与所述式Ⅱ的化合物反应来制备的,在式Ⅱ中,R4是氢、甲氧基、乙氧基、丙氧基、丁氧基或羟基。
4、根据权利要求1的方法,其中所述的哌啶酮一水合氢卤化物与在一种碱存在下与式Ⅱ的化合物反应。
5、根据权利要求2的方法,其中使所说的式Ⅱ化合物在一种碱存在下与哌啶酮一水合氢卤化物反应。
6、根据权利要求1的方法,其中使所说的式Ⅱ的化合物在一种惰性溶剂中与哌啶酮一水合氢卤化物反应。
7、根据权利要求2的方法,其中所说的式Ⅱ化合物在一种惰性溶剂中与哌啶酮一水合氢卤化物反应。
8、根据权利要求1的方法,其中R2、R5、和R6是氢;R3是空缺;A是氮;B、D和E是碳;而R4是选自氢,卤素,羟基,C1-C6烷基,C1-C8烷氧基,苯基-C1-C6烷氧基,苯氧基其中R7和R8是独立地选自氢、C1-C6烷基、C1-C6烷酰基的-NR7R8基和其中R9是氢或C1-C6烷基的COOR9基,氰基,其中R10是氢或C1-C6烷基的COOR10基,以及其中R11和R12是独立地选自氢和C1-C6烷基的CONR11R12基的式Ⅱ化合物是由下式的化合物与2-(4-氯苯氧基)-乙腈反应制备
式中R4的定义如上。
9、根据权利要求8所述的方法,其中2-(4-氯代苯氧基)乙腈在一种碱存在下与式Ⅲ化合物反应。
10、根据权利要求8或权利要求9所述的方法,其中2-(4-氯代苯氧基)乙腈在极性溶剂中与所述的式Ⅲ化合物反应。
11、根据权利要求9的方法,其中所述的式Ⅲ化合物在一种极性溶剂中与2-(4-氯苯氧基)乙腈反应。
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Cited By (3)
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CN107074882A (zh) * | 2014-10-23 | 2017-08-18 | 詹森药业有限公司 | 作为nik抑制剂的新的吡唑并嘧啶衍生物 |
CN107074882B (zh) * | 2014-10-23 | 2019-07-30 | 詹森药业有限公司 | 作为nik抑制剂的新的吡唑并嘧啶衍生物 |
AU2015334915B2 (en) * | 2014-10-23 | 2019-09-19 | Janssen Pharmaceutica Nv | New pyrazolopyrimidine derivatives as NIK inhibitors |
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