CN115611894A - 一种含氮螺环化合物或其药学上可接受的盐及其制备方法和应用 - Google Patents
一种含氮螺环化合物或其药学上可接受的盐及其制备方法和应用 Download PDFInfo
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- CN115611894A CN115611894A CN202110807824.XA CN202110807824A CN115611894A CN 115611894 A CN115611894 A CN 115611894A CN 202110807824 A CN202110807824 A CN 202110807824A CN 115611894 A CN115611894 A CN 115611894A
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- Prior art keywords
- nitrogen
- pharmaceutically acceptable
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- acceptable salt
- compound
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- -1 Nitrogen-containing spiro compound Chemical class 0.000 title claims abstract description 47
- 150000003839 salts Chemical class 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title abstract description 21
- 239000001257 hydrogen Substances 0.000 claims abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 12
- 125000004185 ester group Chemical group 0.000 claims abstract description 10
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims abstract description 9
- 229910052757 nitrogen Chemical group 0.000 claims abstract description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 7
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 7
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 5
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims abstract description 5
- 150000001721 carbon Chemical group 0.000 claims abstract description 3
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- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
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- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 claims description 4
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
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- 239000000203 mixture Substances 0.000 description 17
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- 239000011734 sodium Substances 0.000 description 13
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- 239000000523 sample Substances 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 8
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- 238000003818 flash chromatography Methods 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
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- 230000002829 reductive effect Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- KAQKFAOMNZTLHT-OZUDYXHBSA-N prostaglandin I2 Chemical compound O1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-OZUDYXHBSA-N 0.000 description 4
- 101000862089 Clarkia lewisii Glucose-6-phosphate isomerase, cytosolic 1A Proteins 0.000 description 3
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 3
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- 125000004432 carbon atom Chemical group C* 0.000 description 3
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 150000003180 prostaglandins Chemical class 0.000 description 3
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- 125000001424 substituent group Chemical group 0.000 description 3
- DOGWIGUULRYFQB-UHFFFAOYSA-N 1-(2,2-dibromoethenyl)-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1C=C(Br)Br DOGWIGUULRYFQB-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
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- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
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Abstract
本发明提供了一种含氮螺环化合物或其药学上可接受的盐及其制备方法和应用，所述含氮螺环化合物具有式(4)、式(5)或式(6)所示结构：其中X为碳原子或氮原子；n选自0、1或2；R1为A环上的一个或多个基团，所述R1选自氢、卤素、C1～C6烷基、C1～C6烷氧基、三氟甲基、C1～C6酯基、C1～C6烷基胺基、氰基或苯基；当R1的数量为多个时，两个R1之间可以通过饱和或不饱和的C1～C4碳链相连；R2选自氢、苄氧羰基、叔丁氧羰基、芴甲氧羰基、邻苯二甲酰基、对甲苯磺酰基、三氟乙酰基、对甲氧基苄基、苄基或甲磺酰基；R3选自氢或C1～C6烷基。所述含氮螺环化合物或其药学上可接受的盐具有抑制COX‑2活性的功能。
Description
技术领域
本发明涉及药物化学技术领域，更具体地，涉及一种含氮螺环化合物或其药学上可接受的盐及其制备方法和应用。
背景技术
环氧酶(cyclo-oxygen-ase,COX)是前列腺素(PGs)合成所必须的酶，也是PGs合成初始步骤中的关键性限速酶，又称环氧化物水化酶，其全称为环氧化物水解酶，其作用是催化醚水解，专一作用于醚键。
分子生物学的研究发现了两种环氧合酶的存在，得以揭示传统的非甾体抗炎药的抗炎作用和消化道损伤的不良反应分别是对COX-2和COX-1的抑制，起初认为对COX-2高选择性抑制是研制新型抗炎药物的方向。其实COX-2并非单纯是炎症细胞中的诱导性酶，它也是正常组织中固有的构成酶，例如血管壁的COX-2产生的前列环素(PGI2)具有抑制血小板聚集和舒张血管的作用，PGI2与血栓烷A2的作用相反，对血管和血小板的作用相互制约，调节生理功能的平衡。过分地抑制COX-2会导致PGI2/TxA2的失衡而引起心血管事件(CannonCP,Cannon PJ.Physiology.COX-2 inhibitors and cardiovascular risk.Science,2012,336:1386_1387)。所以设计COX-2抑制剂的选择性应当适度，以抑制炎症细胞过高表达的COX-2为度，不能过分抑制，从而不干扰血管中PGI2/TxA2的平衡。因此，急需开发一种合适的化合物。
发明内容
本发明目的在于提供一种含氮螺环化合物或其药学上可接受的盐，所述含氮螺环化合物具有新的母核结构，并且具有抑制COX-2活性的功能。
本发明的另一目的在于提供所述含氮螺环化合物或其药学上可接受的盐的制备方法。
本发明的另一目的在于提供所述含氮螺环化合物或其药学上可接受的盐在制备COX-2抑制剂的应用。
为实现上述目的，本发明采用的技术方案是：
一种含氮螺环化合物或其药学上可接受的盐，所述含氮螺环化合物具有式(4)、式(5)或式(6)所示结构：
其中X为碳原子或氮原子；n选自0、1或2；
R1为A环上的一个或多个基团，所述R1选自氢、卤素、C1～C6烷基、C1～C6烷氧基、三氟甲基、C1～C6酯基、C1～C6烷基胺基、氰基或苯基；当R1的数量为多个时，两个R1之间可以通过饱和或不饱和的C1～C4碳链相连；
R2选自氢、苄氧羰基、叔丁氧羰基、芴甲氧羰基、邻苯二甲酰基、对甲苯磺酰基、三氟乙酰基、对甲氧基苄基、苄基或甲磺酰基；
R3选自氢或C1～C6烷基。
优选地，n选自0或1。
优选地，R1选自氢、氯、溴、C1～C6烷基、C1～C6烷氧基、三氟甲基、C1～C6酯基、C1～C6烷基胺基或苯基。
优选地，R2选自氢、对甲苯磺酰基或甲磺酰基。
取代基定义和一般术语
本发明使用的术语“烷基”，表示含有1至6个碳原子，饱和的直链、支链或环状的一价烃基基团。在一实施方案中，烷基基团含有1-6个碳原子；在另一实施方案中，烷基基团含有1-3个碳原子。
术语“卤素”指氟、氯、溴、碘。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。
术语“酯基”指-C(＝O)O-。所述的酯基基团可以与本发明所描述的取代基相连，形成对应的酯基取代基。酯基基团的实例包括，但并不限于，甲酯，乙酯，丙酯，丁酯等等。
优选地，所述药学上可接受的盐为氮螺环化合物与有机酸或无机酸形成的的药学上可接受的盐。
更优选地，所述药学上可接受的盐为盐酸盐、氢溴酸盐、硫酸盐、乙酸盐、乳酸盐、酒石酸盐、枸椽酸盐、三氟醋酸盐、苹果酸盐、马来酸盐、琥珀酸盐、对甲苯磺酸或甲磺酸盐。
更具体优选的，所述氮螺环化合物，部分列举如下：
本发明还提供所述含氮螺环化合物或其药学上可接受的盐的制备方法，包括如下步骤：
S1.如式(3)所示的烯基环丙烷化合物在溶剂中发生反应，得到如式(4)的化合物；
S2.将式(4)的化合物经还原得到式(5)所示化合物；或者，将式(4)的化合物在碱条件下与硅胶混合进行反应得到式(6)所示化合物。
S3.如果需要的话，将得到的式(4)所示化合物、式(5)所示化合物、式(6)所示化合物转化为药学上可接受的盐；
R1为A环上的一个或多个基团，所述R1选自氢、卤素、C1～C6烷基、C1～C6烷氧基、三氟甲基、C1～C6酯基、C1～C6烷基胺基、氰基或苯基；当R1的数量为多个时，两个R1之间可以通过饱和或不饱和的C1～C4碳链相连；
R2选自氢、苄氧羰基、叔丁氧羰基、芴甲氧羰基、邻苯二甲酰基、对甲苯磺酰基、三氟乙酰基、对甲氧基苄基、苄基或甲磺酰基；
R3选自氢或C1～C6烷基。
优选地，所述溶剂选自甲苯、氯苯、二甲基亚砜、四氢呋喃、二氯甲烷、1,2-二氯乙烷、1,4-二氧六环、甲醇、乙醇、异丙醇、乙腈、水中的一种或多种。
优选地，所述碱选自三乙胺、甲胺、二甲胺、乙二胺、异丙胺、叔丁胺、环己胺、吡啶、叔丁醇钾或叔丁醇钠。
优选地，所述加热的温度为50～120℃。
更优选地，所述加热的温度为70～90℃。
优选地，所述加热的时间为4～60h。
更优选地，所述加热的时间为4～24h。
更优选地，所述式(3)所示烯基环丙烷化合物可以购买得到，也可以参照现有的文献报道合成得到。
作为一种实施方式，式(3)所示烯基环丙烷化合物可通过如下方法制备：式(1)所示二溴代烯烃化合物与式(2)所示烯基环丙烷化合物反应，生成式(3)所示炔胺烯基环丙烷化合物。其中R1、R2、R3取代基如本发明所定义，n选自0或1。
更具体地，反应可以如下进行：在氮气氛围中，依次加入式(1)所示二溴代烯烃化合物，式(2)所示烯基环丙烷化合物，碘化亚铜，1,10-邻菲啰啉和碳酸铯，加入干燥的四氢呋喃，在室温搅拌直至原料反应完全。过滤后，在真空中蒸干溶剂，并通过快速色谱法纯化，得到式(3)所示烯基环丙烷化合物。
所述含氮螺环化合物或其药学上可接受的盐在制备COX-2抑制剂中的应用。
与现有技术相比，本发明的有益效果是：
本发明提供了一种含氮螺环化合物或其药学上可接受的盐，所述含氮螺环化合物或其药学上可接受的盐具备抑制COX-2的活性，因此可以用于制备COX-2抑制剂。本发明还公开所述含氮螺环化合物的制备方法，该方法操作简单，无需金属催化，成本低，有潜在工业化的价值。
具体实施方式
如无特殊说明，本发明所用原料、试剂及溶剂，均为商业购买未经任何处理或者可通过文献方法制得。为了更清楚地说明本发明，下面结合优选实施例对本发明做进一步的说明。本领域技术人员应当理解，下面所具体描述的内容是说明性的而非限制性的，不应以此限制本发明的保护范围。
实施例1
本实施例提供一种1-对甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4a)，制备方法具体如下：
首先制备化合物(1a)、化合物(2a)、化合物(3a)：
(1)制备化合物(1a)：将2-硝基苯甲醛(1a-s1，1.5g，10mmol，1eq)溶于二氯甲烷(50ml)中，加入四溴化碳(1.1eq)，冷却至0℃，三苯基膦(2eq)分批加入到上述混合物中，0℃搅拌，通过TLC点板监测反应完成。加入己烷(35ml)使三苯基氧膦析出。通过硅胶过滤溶液，用10％乙酸乙酯(己烷)溶液冲洗，收集滤液并真空除去溶剂，通过柱层析(石油醚:乙酸乙酯＝30:1)纯化得到化合物2-(2,2-二溴乙烯基)-1-硝基苯(1a，2.98g，97％)。
(2)制备化合物(2a)：取4-氨基-1,1-二乙氧基丁烷(3.4ml，20mmol)和三乙胺(3.5ml，25mmol)，加入二氯甲烷(100ml),在0℃下于10分钟内向上述溶液加入甲苯磺酰氯(3.8g,20mmol)，室温搅拌1小时。用饱和碳酸氢钠水溶液(100ml)洗涤，二氯甲烷萃取，硫酸钠干燥并真空浓缩，得到产物2a-s2。粗产物无需进一步纯化即可用于下一步。
取2a-s2加入二氯甲烷(80ml)，依次加入碳酸二叔丁酯(40mmol，2eq)和4-二甲氨基吡啶(10％)，室温搅拌30分钟，将反应液用水洗涤，所得溶液用二氯甲烷萃取，合并的有机层用食盐水洗涤，并经硫酸钠干燥，过滤并减压浓缩，粗产物2a-s3无需进一步纯化即可用于下一步。
取2a-s3，加入盐酸溶液(浓度36％，0.1eq)、丙酮(50ml)和水(50ml)，室温搅拌12小时，将反应混合物用碳酸氢钠溶液和水洗涤，用乙酸乙酯萃取，经硫酸钠干燥，并真空浓缩，经快速柱色谱法纯化(石油醚：乙酸乙酯＝4:1)得到2a-s4(6.3g，95％)。
在氮气氛围下，取溴化环丙基三苯膦(10.7g，1.4eq)，加入无水四氢呋喃(100ml)，冷却至0℃，用注射器在5分钟内将叔丁醇钾溶液(1M，1.1eq)缓慢滴加到上述混合物中，移至室温搅拌，1小时后，用注射器在5分钟内将2a-s4(6.3g，1eq)的四氢呋喃溶液(100ml)缓慢加入到混合物中，室温反应1小时后，加热至80℃。待反应完成后，过滤并通过真空浓缩，最后经快速柱色谱法纯化(石油醚/乙酸乙酯＝5:1)得2a-s5(5.4g，80％)。
取2a-s5，加入氢氧化钠(3eq)和乙醇(60ml)，将混合物在80℃下搅拌12小时，待反应完成后，将反应混合物用水洗涤，用乙酸乙酯萃取，干燥并真空浓缩，通过快速柱色谱法纯化(石油醚：乙酸乙酯＝5:1)得到2a(3.5g，95％)。
(3)制备化合物(3a)：在氮气氛围依次加入2-(2,2-二溴乙烯基)-1-硝基苯1a(307mg，1mmol，1.0eq)，化合物2a(1eq)，碘化亚铜(3％)，1,10-邻菲啰啉(5％)和碳酸铯(3eq)，干燥的四氢呋喃(0.25M)，室温搅拌直至原料反应完全。通过硅胶过滤后，在真空中蒸干溶剂，经柱层析(石油醚:乙酸乙酯＝5:1)纯化得到化合物3a(361mg，88％)。
1-对甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4a)，制备方法包括如下步骤：
S1.取化合物3a(0.15mmol，61mg)，加入四氢呋喃(5ml)在70℃下搅拌12小时，将反应液减压浓缩，经柱层析(石油醚:乙酸乙酯＝2:1)纯化得到化合物4a。收率74％(45mg),粉色固体,m.p.Rf＝0.3(乙酸乙酯/石油醚＝1:2).1H NMR(500MHz,CDCl3)δ7.69(d,J＝8.2Hz,2H),7.28(d,J＝4.9Hz,2H),6.73(dd,J＝9.7,5.6Hz,1H),6.53(dd,J＝18.4,9.5Hz,2H),6.29(dd,J＝9.2,5.6Hz,1H),3.33–3.27(m,2H),2.97–2.90(m,1H),2.59(ddd,J＝12.9,9.2,6.1Hz,1H),2.49–2.43(m,1H)，2.41(s,3H),2.00–1.86(m,4H),1.81–1.74(m,1H),1.70–1.58(m,1H).13C NMR(126MHz,CDCl3)δ210.5,205.6,179.6,144.1,135.9,135.4,132.9,129.4,128.5,122.7,121.4,84.7,59.2,58.0,44.3,40.3,30.9,23.4,22.0,21.6.IR(KBr,cm-1):2959,2924,1772,1718,1637,1542,1490,1386,1170,746,661,587.HRMS(ESI-TOF)/m/z:[M+Na]+calcd for C22H22N2O4SNa 433.1192；found 433.1189.
实施例2～5
实施例2～5的制备方法和原料同实施例1，其区别仅在于步骤S1中反应的温度不同，研究反应温度对产率的影响，具体结果见表1。
表1实施例2～5
| 实施例 | 反应温度/℃ | 产率/％ |
| 2 | 50 | 55 |
| 3 | 80 | 74 |
| 4 | 90 | 70 |
| 5 | 120 | 68 |
实施例6～9
实施例6～9的制备方法和原料同实施例1，其区别仅在于步骤S1中反应的时间不同，研究反应时间对产率的影响，具体结果见表2。
表2实施例6～9
| 实施例 | 反应时间/h | 产率/％ |
| 6 | 4 | 62 |
| 7 | 24 | 75 |
| 8 | 48 | 72 |
| 9 | 60 | 73 |
实施例10～15
实施例10～15的制备方法和原料同实施例1，其区别仅在于步骤S1中溶剂不同，研究不同溶剂对产率的影响，具体结果见表3。
表3实施例10～15
| 实施例 | 溶剂 | 产率/％ |
| 10 | 甲苯 | 70 |
| 11 | 二甲基亚砜 | 62 |
| 12 | 二氯乙烷 | 68 |
| 13 | 1,4-二氧六环 | 70 |
| 14 | 水 | 33 |
| 15 | 甲醇 | 40 |
实施例16
实施例16提供一种10-氟-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4b)，制备方法如下：
以4-氟-2硝基苯甲醛替代实施例1步骤(1)中的2-硝基苯甲醛，其余操作不变，得到10-氟-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4b)。收率73％(47mg),粉色固体,m.p.Rf＝0.3(乙酸乙酯/石油醚＝1:2).1HNMR(500MHz,CDCl3)δ7.71(d,J＝8.1Hz,2H),7.29(d,J＝8.1Hz,2H),6.70(dd,J＝9.8,6.5Hz,1H),6.28–6.20(m,1H),6.15(d,J＝10.0Hz,1H),3.36–3.22(m,2H),2.90(dd,J＝11.2,4.8Hz,1H),2.65–2.55(m,1H),2.48(dt,J＝12.8,6.2Hz,1H),2.42(s,3H),2.01–1.94(m,1H),1.94–1.88(m,2H),1.85–1.79(m,1H),1.66–1.58(m,2H).13C NMR(126MHz,CDCl3)δ209.1,205.4,178.1(C-F,3JC-F＝16.51Hz),178.0(C-F,3JC-F＝16.51Hz),167.5(C-F,1JC-F＝269.6Hz),165.3(C-F,1JC-F＝269.6Hz),144.2,136.0,135.9(C-F,3JC-F＝11.3Hz),135.3(C-F,3JC-F＝11.3Hz),129.5,128.4,119.7(C-F,2JC-F＝35.3Hz),119.4(C-F,2JC-F＝35.3Hz),101.4(C-F,2JC-F＝21.4Hz),101.2(C-F,2JC-F＝21.4Hz),85.1,59.2,57.8,44.2,40.1,31.5,23.4,22.1,21.6.19F NMR(471MHz,CDCl3)δ-94.1.IR(KBr,cm-1):2956,2923,1780,1644,1491,1330,1154,1010,920,785,658.HRMS(ESI-TOF)/m/z:[M+Na]+calcd forC22H21FN2O4SNa 451.1098；found 451.1099.
实施例17
实施例17提供一种10-溴-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4c)，制备方法如下：
以4-溴-2硝基苯甲醛替代实施例1步骤(1)中的2-硝基苯甲醛，其余操作不变，得到10-溴-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4c)。收率78％(57mg),粉色固体,m.p.Rf＝0.3(乙酸乙酯/石油醚＝1:3).1HNMR(500MHz,CDCl3)δ7.70(d,J＝8.2Hz,2H),7.29(d,J＝8.1Hz,2H),6.87(s,1H),6.49(d,J＝9.6Hz,1H),6.38(dd,J＝9.6,1.2Hz,1H),3.36–3.25(m,2H),2.95–2.88(m,1H),2.65–2.55(m,1H),2.49–2.43(m,1H),2.42(s,3H),2.01–1.76(m,6H),1.64–1.56(m,1H).13C NMR(126MHz,CDCl3)δ209.2,205.2,177.6,144.3,135.3,133.2,132.3,129.5,128.4,128.0,123.0,84.9,58.2,57.9,44.2,40.1,31.0,23.4,21.9,21.6.IR(KBr,cm-1):2925,1768,1630,1398,1240,1157,1089,852,788,658,614.HRMS(ESI-TOF)/m/z:[M+Na]+calcd forC22H21BrN2O4SNa 511.0298；found 511.0295.
实施例18
实施例18提供一种9-甲氧基-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4d)，制备方法如下：
以5-甲氧基-2硝基苯甲醛替代实施例1步骤(1)中的2-硝基苯甲醛，其余操作不变，得到9-甲氧基-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4d)。收率63％(42mg),粉色固体,m.p.Rf＝0.3(乙酸乙酯/石油醚＝1:2).1H NMR(500MHz,CDCl3)δ7.70(d,J＝8.2Hz,2H),7.29(d,J＝8.2Hz,2H),6.59(dd,J＝10.0,2.4Hz,1H),6.50(d,J＝10.0Hz,1H),5.43(d,J＝2.2Hz,1H),3.63(s,3H),3.32–3.24(m,2H),2.97–2.90(m,1H),2.62–2.53(m,1H),2.47–2.42(m,1H),2.41(s,3H),1.99–1.86(m,4H),1.83–1.76(m,1H),1.69–1.61(m,1H).13C NMR(126MHz,CDCl3)δ211.3,205.9,179.2,152.4,144.1,136.6,135.3,129.4,128.5,122.1,99.7,85.8,58.1,58.1,55.1,44.3,40.3,32.9,23.5,22.1,21.6.IR(KBr,cm-1):2955,2924,2855,1769,1588,1408,1277,1182,972,814,749,658.HRMS(ESI-TOF)/m/z:[M+Na]+calcd for C23H24N2O5SNa 463.1298；found 463.1295.
实施例19
实施例19提供一种10-甲氧基-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4e)，制备方法如下：
以4-甲氧基-2硝基苯甲醛替代实施例1步骤(1)中的2-硝基苯甲醛，其余操作不变，得到10-甲氧基-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4d)。收率81％(53mg),粉色固体,m.p.Rf＝0.3(乙酸乙酯/石油醚＝1:2).1H NMR(500MHz,CDCl3)δ7.73(d,J＝8.1Hz,2H),7.27(d,J＝8.1Hz,2H),6.61(d,J＝9.7Hz,1H),6.13(dd,J＝9.7,1.6Hz,1H),5.71(s,1H),3.81(s,3H),3.35(t,J＝11.7Hz,1H),3.26(d,J＝8.6Hz,1H),2.90–2.83(m,1H),2.62–2.45(m,2H),2.41(s,3H),2.01–1.87(m,4H),1.83–1.75(m,2H).13C NMR(126MHz,CDCl3)δ210.3,206.2,179.5,165.1,144.0,135.6,133.9,129.4,128.4,123.2,92.8,85.3,58.6,57.8,55.8,44.1,40.3,32.6,23.6,22.3,21.6.IR(KBr,cm-1):2956,1768,1448,1330,1231,1089,866,726,657,586.HRMS(ESI-TOF)/m/z:[M+Na]+calcd for C23H24N2O5SNa 463.1298；found 463.1296.
实施例20
实施例20提供一种1-对甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,13a-甲烷并[1,3]二氧杂环[4',5':4,5]苯并[1,2-b]吡啶并[3,2-g]氮杂
-5,14(1H)-二酮(4f)，制备方法如下：
以6-硝基苯并[d][1,3]二恶英-5-甲醛替代实施例1步骤(1)中的2-硝基苯甲醛，其余操作不变，得到1-对甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,13a-甲烷并[1,3]二氧杂环[4',5':4,5]苯并[1,2-b]吡啶并[3,2-g]氮杂
-5,14(1H)-二酮(4f)。收率76％(52mg),紫色固体,m.p.Rf＝0.3(乙酸乙酯/石油醚＝2:3).1H NMR(500MHz,CDCl3)δ7.74(d,J＝8.1Hz,2H),7.29(d,J＝8.2Hz,2H),5.93(s,1H),5.80(d,J＝10.8Hz,2H),5.77(s,1H),3.34(t,J＝11.6Hz,1H),3.24(d,J＝10.1Hz,1H),2.84(dd,J＝11.1,5.2Hz,1H),2.58–2.46(m,2H),2.42(s,3H),1.98(dt,J＝13.4,6.6Hz,1H),1.93–1.89(m,2H),1.88–1.79(m,2H),1.67–1.56(m,1H).13C NMR(126MHz,CDCl3)δ210.5,206.4,178.3,157.4,145.7,144.1,135.5,129.4,128.4,101.5,99.4,92.8,86.1,58.8,57.7,44.1,40.1,34.5,23.7,22.5,21.6.IR(KBr,cm-1):3044,2955,2924,1707,1528,1382,1203,1058,960,819,738,586.HRMS(ESI-TOF)/m/z:[M+Na]+calcd for C23H22N2O6SNa 477.1091；found 477.1086.
实施例21
实施例21提供一种9-氯-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4g)，制备方法如下：
以5-氯-2硝基苯甲醛替代实施例1步骤(1)中的2-硝基苯甲醛，其余操作不变，得到9-氯-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4g)。收率63％(42mg),白色固体,m.p.Rf＝0.3(乙酸乙酯/石油醚).δ7.72(d,J＝8.1Hz,2H),7.30(d,J＝8.1Hz,2H),6.63(dd,J＝10.0,1.7Hz,1H),6.58–6.51(m,2H),3.35(t,J＝11.2Hz,1H),3.26(d,J＝10.5Hz,1H),2.97–2.90(m,1H),2.61(ddd,J＝12.8,9.6,6.3Hz,1H),2.48–2.43(m,1H),2.42(s,3H),2.03–1.79(m,5H),1.61–1.54(m,1H13C NMR(126MHz,CDCl3)δ209.1,205.1,177.1,144.3,138.0,135.3,129.5,128.4,128.2,127.9,122.9,85.3,59.8,58.0,44.2,40.1,30.6,23.3,21.9,21.6.IR(KBr,cm-1):2954,2867,1772,1625,1402,1272,1083,858,747,666,584.HRMS(ESI-TOF)/m/z:[M+Na]+calcdfor C22H21ClN2O4SNa 467.0803；found 467.0802.
实施例22
实施例22提供一种9-氟-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4h)，制备方法如下：
以5-氟-2硝基苯甲醛替代实施例1步骤(1)中的2-硝基苯甲醛，其余操作不变，得到9-氟-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4h)。收率80％(51mg),粉色固体,m.p Rf＝0.3(乙酸乙酯/石油醚＝1:2).1HNMR(500MHz,CDCl3δ7.72(d,J＝7.7Hz,2H),7.30(d,2H),6.68–6.54(m,2H),5.99(d,J＝9.0Hz,1H),3.35(t,J＝12.1Hz,1H),3.26(d,J＝11.5Hz,1H),2.97–2.89(m,1H),2.65–2.54(m,1H),2.49–2.43(m,1H),2.42(s,3H),2.03–1.77(m,5H),1.62–1.55(m,1H).13C NMR(126MHz,CDCl3)δ209.8,205.2,177.6,156.9(C-F,1JC-F＝253.3Hz),154.9(C-F,1JC-F＝253.3Hz),144.3,135.3,132.0(C-F,2JC-F＝37.8Hz),131.7(C-F,2JC-F＝37.8Hz),129.5,128.3,123.9(C-F,3JC-F＝8.8Hz),123.8(C-F,3JC-F＝8.8Hz),108.5(C-F,2JC-F＝20.2Hz),108.4(C-F,2JC-F＝20.2Hz),85.6,58.0,58.0,44.2,40.1,31.2,23.3,21.9,21.6.19F NMR(376MHz,CDCl3)δ-115.9.IR(KBr,cm-1):2955,1772,1640,1489,1331,1154,1009,962,854,732,696,587.HRMS(ESI-TOF)/m/z:[M+Na]+calcd for C22H21FN2O4SNa 451.1098；found451.1098.
实施例23
实施例23提供一种10-甲基-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4i)，制备方法如下：
以4-甲基-2硝基苯甲醛替代实施例1步骤(1)中的2-硝基苯甲醛，其余操作不变，得到10-甲基-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4i)。收率74％(47mg),粉色固体,m.p Rf＝0.3(乙酸乙酯/石油醚＝1:2).1H NMR(500MHz,CDCl3)δ7.70(d,J＝8.0Hz,2H),7.27(d,J＝5.3Hz,3H),6.52(d,J＝9.3Hz,1H),6.30(s,1H),6.15(d,J＝9.3Hz,1H),3.36–3.23(m,2H),2.93–2.87(m,1H),2.57(ddd,J＝14.4,8.9,6.2Hz,1H),2.49–2.43(m,1H),2.41(s,3H),2.10(s,3H),1.97–1.87(m,4H),1.75(ddd,J＝14.1,8.9,5.9Hz,1H),1.66–1.58(m,1H).13C NMR(126MHz,CDCl3)δ210.7,205.9,179.8,147.0,144.0,135.5,132.1,129.4,128.4,126.9,117.9,85.0,58.5,58.0,44.2,40.3,31.5,23.5,22.8,22.1,21.6.IR(KBr,cm-1):2954,2861,1770,1585,1391,1237,1089,968,813,735,659.HRMS(ESI-TOF)/m/z:[M+H]+calcd for C23H25N2O4S425.153；found 425.1528.
实施例24
实施例24提供一种10-三氟甲基-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4j)，制备方法如下：
以4-三氟甲基-2硝基苯甲醛替代实施例1步骤(1)中的2-硝基苯甲醛，其余操作不变，得到10-三氟甲基-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4j)。收率68％(49mg),粉色固体,m.p Rf＝0.3(乙酸乙酯/石油醚＝1:4).1H NMR(500MHz,CDCl3)δ7.68(d,J＝8.1Hz,2H),7.28(d,J＝8.1Hz,3H),6.89(s,1H),6.68(d,J＝9.5Hz,1H),6.35(d,J＝9.6Hz,1H),3.39–3.26(m,2H),3.01–2.94(m,1H),2.64(ddd,J＝12.6,10.0,6.5Hz,1H),2.47–2.41(m,4H),2.42(s,3H),2.02–1.93(m,2H),1.93–1.85(m,2H),1.76(ddd,J＝13.9,9.9,6.0Hz,1H),1.64–1.55(m,1H).13C NMR(126MHz,CDCl3)δ208.8,204.6,177.2,144.4,136.54(q,J＝32.6Hz),135.2,134.7,129.5,128.3,121.15(q,J＝273.1Hz),120.59(q,J＝5.5Hz),118.2,118.2,84.9,58.9,58.2,44.3,40.1,30.1,23.2,21.7,21.6.19F NMR(471MHz,CDCl3)δ-68.4.IR(KBr,cm-1):2932,2867,1773,1634,1445,1280,1140,976,863,663,582.HRMS(ESI-TOF)/m/z:[M+H]+calcd forC23H22F3N2O4S 479.1247；found 479.1241.
实施例25
实施例25提供一种8-氟-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4k)，制备方法如下：
以6-氟-2硝基苯甲醛替代实施例1步骤(1)中的2-硝基苯甲醛，其余操作不变，得到8-氟-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4k)。收率62％(4mg),粉色固体,m.p Rf＝0.3(乙酸乙酯/石油醚＝1:1).1HNMR(500MHz,CDCl3δ7.71(d,J＝8.1Hz,2H),7.28(d,J＝8.1Hz,3H),6.74(dt,J＝9.6,6.4Hz,1H),6.39(d,J＝9.7Hz,1H),5.81(dd,J＝10.1,6.7Hz,1H),3.33–3.22(m,2H),2.95(dd,J＝9.1,7.0Hz,1H),2.77–2.67(m,1H),2.50(dt,J＝12.5,5.5Hz,1H),2.41(s,3H),2.38–2.31(m,1H),1.99–1.84(m,4H),1.65–1.56(m,1H.13C NMR(126MHz,CDCl3)δ205.9,204.6,177.8,162.6(C-F,1JC-F＝287.3Hz),160.4(C-F,1JC-F＝287.3Hz),144.3,135.9(C-F,2JC-F＝7.6Hz),135.8(C-F,2JC-F＝7.6Hz),135.2,129.5,128.4,118.3(C-F,3JC-F＝6.3Hz),118.2(C-F,3JC-F＝6.3Hz),101.9(C-F,2JC-F＝17.6Hz),101.8(C-F,2JC-F＝17.6Hz),84.4,58.6,58.4,58.3,44.2,40.3,28.9,28.9,23.1,21.6,21.4.19F NMR(471MHz,CDCl3)δ-108.0.IR(KBr,cm-1):2925,2862,1774,1633,1450,1236,1154,854,727,659,580.HRMS(ESI-TOF)/m/z:[M+H]+calcd for C22H22FN2O4S 429.1279；found 429.1272.
实施例26
实施例26提供一种甲基5,13-二氧基-1-对甲苯基-1,2,3,4,4a,5,6,7-八氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-10-羧酸盐(4l)，制备方法如下：
以4-甲酸甲酯基-2硝基苯甲醛替代实施例1步骤(1)中的2-硝基苯甲醛，其余操作不变，得到甲基5,13-二氧基-1-对甲苯基-1,2,3,4,4a,5,6,7-八氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-10-羧酸盐(4l)。收率81％(57mg),粉色固体,m.p Rf＝0.3(乙酸乙酯/石油醚＝1:2).1H NMR(500MHz,CDCl3)δ7.70(d,J＝7.6Hz,2H),7.33(s,1H),7.28(s,2H),6.75(d,J＝9.5Hz,1H),6.57(d,J＝9.5Hz,1H),3.87(s,3H),3.37(t,J＝12.0Hz,1H),3.26(d,J＝10.7Hz,1H),2.99–2.91(m,1H),2.65–2.55(m,1H),2.41(s,4H),2.01–1.85(m,4H),1.77–1.54(m,3H).13C NMR(101MHz,CDCl3)δ209.6,204.9,179.0,165.1,144.2,136.7,135.4,132.7,129.5,128.3,125.9,121.1,85.2,58.9,58.2,52.7,44.2,40.2,30.5,23.3,21.9,21.6.IR(KBr,cm-1):2925,1770,1634,1399,1251,1086,972,852,728,617.HRMS(ESI-TOF)/m/z:[M+Na]+calcd for C23H24N2O5SNa 491.1247；found 491.1246.
实施例27
实施例27提供一种9,10-二甲氧基-1-对甲苯基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4m)，制备方法如下：
以4,5-二甲氧基-2-硝基苯甲醛替代实施例1步骤(1)中的2-硝基苯甲醛，其余操作不变，得到9,10-二甲氧基-1-对甲苯基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4m)。收率68％(48mg),粉色固体,m.p Rf＝0.3(乙酸乙酯/石油醚＝1:1).1H NMR(500MHz,CDCl3)δ7.73(d,J＝8.1Hz,2H),7.27(d,J＝8.1Hz,2H),5.75(s,1H),5.55(s,1H),3.87(s,3H),3.69(s,3H),3.36–3.23(m,2H),2.90–2.83(m,1H),2.59–2.51(m,1H),2.47(dt,J＝12.9,6.4Hz,1H),2.41(s,3H),2.00–1.86(m,4H),1.81(ddd,J＝13.9,8.5,5.8Hz,1H),1.62(dt,J＝12.8,6.6Hz,1H).13C NMR(101MHz,CDCl3)13CNMR(126MHz,CDCl3)δ211.3,206.4,178.4,160.8,148.6,144.0,129.4,128.5,101.5,94.0,85.5,57.9,57.4,56.5,55.7,44.2,40.4,34.1,23.6,22.3,21.6.IR(KBr,cm-1):2955,1769,1635,1452,1331,1003,962,820,657.HRMS(ESI-TOF)/m/z:[M+H]+calcd for C24H27N2O6S471.1584；found 471.1584.
实施例28
实施例28提供一种5,13-二氧基-1-对甲苯基-1,2,3,4,4a,5,6,7-八氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-9-羧酸甲酯(4n)，制备方法如下：
以5-甲酸甲酯基-2硝基苯甲醛替代实施例1步骤(1)中的2-硝基苯甲醛，其余操作不变，得到5,13-二氧基-1-对甲苯基-1,2,3,4,4a,5,6,7-八氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-9-羧酸甲酯(4n)。收率71％(50mg),粉色固体,m.p.Rf＝0.3(乙酸乙酯/石油醚＝1:2).1H NMR(500MHz,CDCl3)δ7.67(d,J＝8.1Hz,2H),7.49(s,1H),7.29–7.26(m,2H),7.26–7.23(m,1H),6.59(d,J＝10.0Hz,1H),3.80(s,3H),3.28–3.26(m,1H),2.94(dd,J＝10.5,5.7Hz,1H),2.62(ddd,J＝12.9,9.5,6.2Hz,1H),2.45(dt,J＝12.6,5.9Hz,1H),2.40(s,3H),1.99(dd,J＝13.2,6.4Hz,1H),1.96–1.92(m,1H),1.92–1.88(m,2H),1.80–1.76(m,1H),1.75–1.71(m,1H),1.67–1.55(m,1H).13C NMR(126MHz,CDCl3)δ208.9,205.0,177.9,164.8,144.3,139.6,135.1,133.9,129.5,128.4,127.1,121.8,85.1,59.0,58.0,52.4,44.2,40.1,30.2,23.3,21.8,21.6.IR(KBr,cm-1):2955,2869,1773,1631,1441,1334,1272,1088,968,813.HRMS(ESI-TOF)/m/z:[M+H]+calcd for C24H25N2O6S 469.1428；found 469.1431..
实施例29
实施例29提供一种10-氯-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4o)，制备方法如下：
以4-氯-2硝基苯甲醛替代实施例1步骤(1)中的2-硝基苯甲醛，其余操作不变，得到10-氯-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4o)。收率77％(51mg),粉色固体,m.p Rf＝0.3(乙酸乙酯/石油醚＝1:3).1HNMR(500MHz,CDCl3)δ7.70(d,J＝7.8Hz,2H),7.30(d,J＝7.8Hz,2H),6.62(s,1H),6.57(d,J＝9.6Hz,1H),6.25(d,J＝9.6Hz,1H),3.38–3.22(m,2H),2.95–2.87(m,1H),2.65–2.53(m,1H),2.50–2.43(m,1H),2.42(s,3H),2.02–1.87(m,4H),1.84–1.75(m,1H),1.63–1.52(m,1H).13C NMR(101MHz,CDCl3)δ209.1,205.1,177.4,144.2,142.6,135.4,133.6,129.5,128.4,126.1,119.2,85.0,58.4,58.0,44.2,40.1,31.2,23.4,22.0,21.6.IR(KBr,cm-1):2925,2859,1764,1654,1397,1239,1094,788,675,522.HRMS(ESI-TOF)/m/z:[M+Na]+calcdfor C22H21ClN2O4SNa 467.0803；found 467.0802.
实施例30
实施例30提供一种1-对甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,14a-甲基萘基并[1,2-b]吡啶并[3,2-g]氮杂
-5,15(1H)-二酮(4q)，制备方法如下：
以1-硝基-2-萘甲醛替代实施例1步骤(1)中的2-硝基苯甲醛，其余操作不变，得到1-对甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,14a-甲基萘基并[1,2-b]吡啶并[3,2-g]氮杂
-5,15(1H)-二酮(4q)。收率62％(43mg),白色固体,m.p Rf＝0.3(乙酸乙酯/石油醚＝1:1).1HNMR(500MHz,CDCl3)δ7.92(d,J＝7.6Hz,1H),7.58(d,J＝7.9Hz,2H),7.53(t,J＝7.5Hz,1H),7.38(t,J＝7.5Hz,1H),7.27(d,J＝8.0Hz,1H),7.12(d,J＝8.0Hz,2H),6.64(d,J＝9.4Hz,1H),6.44(d,J＝9.4Hz,1H),3.38(d,J＝10.7Hz,1H),3.28(t,J＝11.4Hz,1H),2.98(dd,J＝12.3,3.9Hz,1H),2.63(ddd,J＝12.2,10.3,6.7Hz,1H),2.44–2.38(m,1H),2.36(s,3H),2.03–1.95(m,2H),1.89(td,J＝10.8,9.8,4.8Hz,1H),1.78–1.71(m,1H),1.70–1.62(m,2H).13C NMR(126MHz,CDCl3)δ205.5,177.9,143.9,135.2,132.7,129.2,128.7,128.4,128.2,127.8,127.0,126.4,125.7,85.7,58.3,57.4,44.5,40.4,30.4,23.3,21.5,21.4.IR(KBr,cm-1):3064,2940,2224,1956,1659,1604,1577,1415,1169,1076,737.5,672.4,571.9,546.
实施例31
实施例31提供一种1-对甲苯磺酰基-2,3,4,4a，6,7-六氢-7a，12a-甲氧基二吡啶并[2,3-b:2'，3'-g]氮杂
-5,13(1H)-二酮(4r)，制备方法如下：
以3-硝基吡啶醛替代实施例1步骤(1)中的2-硝基苯甲醛，其余操作不变，得到1-对甲苯磺酰基-2,3,4,4a，6,7-六氢-7a，12a-甲氧基二吡啶并[2,3-b:2'，3'-g]氮杂
-5,13(1H)-二酮(4r)。收率58％(36mg),黄色液体,Rf＝0.3(乙酸乙酯/石油醚＝3:1).1H NMR(500MHz,CDCl3)δ8.21(s,1H),7.77(d,J＝8.0Hz,2H),7.30(s,2H),6.93(d,J＝9.7Hz,1H),6.52(dd,J＝9.6,2.5Hz,1H),3.47(t,J＝12.2Hz,1H),3.24(d,J＝11.4Hz,1H),3.03(dd,J＝10.2,5.9Hz,1H),2.77–2.67(m,1H),2.46–2.40(m,4H),2.21–2.10(m,2H),2.00–1.89(m,3H),1.71–1.66(m,1H).13C NMR(126MHz,CDCl3)δ208.5,204.8,178.2,155.6,144.3,135.6,129.5,128.3,128.2,127.7,83.9,74.3,58.4,43.9,39.7,30.0,23.2,21.6,21.5.
实施例32
实施例32提供一种4a-乙基-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4s)，制备方法如下：
取2a-s2(630mg，2mmol)，加入盐酸溶液(浓度36％，0.1eq)、丙酮(10ml)和水(10ml)，室温搅拌12小时，将反应混合物用碳酸氢钠溶液和水洗涤，用乙酸乙酯萃取，经硫酸钠干燥，并真空浓缩，经快速柱色谱法纯化(石油醚：乙酸乙酯＝4:1)得到2s-s3(458mg，95％)。
在氮气氛围下，将2s-s3(457mg，1eq)的四氢呋喃(10ml)溶液冷却至-20℃，在15分钟内滴加乙基溴化镁溶液(1.1eq，1mol/L)，在-20℃下反应1小时后，将溶液缓慢升温至0℃，然后用饱和氯化铵溶液淬灭，并用乙酸乙酯萃取，萃取液经硫酸钠干燥并在减压下旋干，粗产物2s-s4无需进一步纯化即可用于下一步骤。
取2s-s4，加入IBX(1.5eq)和乙酸乙酯(10ml)，80℃下搅拌12小时，反应完成后，过滤，旋干溶剂，并通过快速色谱纯化(石油醚：乙酸乙酯＝2:1)得到化合物2s-s5(457mg，1.7mmol)。
在氮气氛围下，取溴化环丙基三苯膦(910mg，1.4eq)，加入无水四氢呋喃(10ml)，冷却至0℃，用注射器在5分钟内将叔丁醇钾溶液(1.0M，1.1eq)缓慢滴加到上述混合物中，移至室温搅拌，1小时后，用注射器在5分钟内将2s-s5(457mg，1.7mmol，1eq)的四氢呋喃溶液(8ml)缓慢加入到混合物中，室温反应1小时后，加热至80℃。待反应完成后，过滤并通过真空浓缩，最后经快速柱色谱法纯化(石油醚/乙酸乙酯＝5:1)得化合物2s(400mg，81％)。
以化合物2s替代实施例1步骤(3)中的2a，其余操作不变，得到4a-乙基-1-甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4s)。收率34％(22mg),白色固体,m.p Rf＝0.3(乙酸乙酯/石油醚＝1:3).1H NMR(500MHz,CDCl3)δ7.74(d,J＝8.3Hz,2H),7.28(d,J＝8.1Hz,2H),6.63(ddd,J＝9.7,5.6,1.1Hz,1H),6.45(d,J＝9.2Hz,1H),6.40(d,J＝9.7Hz,1H),6.21(dd,J＝9.2,5.6Hz,1H),3.51–3.44(m,1H),3.26(dd,J＝11.5,4.7Hz,1H),3.04–2.94(m,1H),2.42(s,3H),2.28–2.17(m,2H),2.09–2.00(m,2H),1.93–1.83(m,3H),1.81–1.73(m,1H),1.71–1.62(m,1H),0.61(t,J＝7.6Hz,3H).13C NMR(126MHz,CDCl3)δ208.7,208.3,178.5,143.8,136.5,135.0,132.9,129.4,128.1,122.4,121.4,86.6,58.6,58.4,44.5,35.8,29.4,21.6,20.9,20.7,19.1,7.1.IR(KBr,cm-1):3060,2922,1763,1632,1456,1200,968,789.HRMS(ESI-TOF)/m/z:[M+H]+calcd for C24H27N2O4S 439.1686；found 439.1683.
实施例33
实施例34提供一种5-羟基-1-甲苯磺酰基-1,2,3,4,4a,5,6,7-八氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-13-酮(5a)，制备方法如下：
实施例34
实施例34提供一种1-对甲苯磺酰基-1,2,3,3a,5,6-六氢-4H-6a，11a-甲基苯并[b]吡咯[3,2-g]氮杂
-4,12-二酮(4t)和4-羟基-1-甲苯磺酰基-2,3,3a,4,5,6-六氢-1H-6a,11a-甲基苯并[b]吡咯并[3,2-g]氮杂
-12-酮(5t)，制备方法如下：
以二乙氧基丙烷-1-胺替代实施例1步骤(2)中的4-氨基-1,1-二乙氧基丁烷，其余操作不变，可得到1-对甲苯磺酰基-1,2,3,3a,5,6-六氢-4H-6a，11a-甲基苯并[b]吡咯[3,2-g]氮杂
-4,12-二酮(4t)。
进一步地，发明人在产物4t的反应液中加入硼氢化钠(3eq)继续搅拌1小时，可将其中一个羰基还原成羟基，再进行柱层析纯化分离，得到化合物5t。收率68％(40mg),红色液体,Rf＝0.3(乙酸乙酯/石油醚＝2:1).1H NMR(500MHz,CDCl3)δ7.80(d,J＝8.1Hz,2H),7.40(d,J＝8.8Hz,1H),7.24(d,J＝8.1Hz,2H),6.26–6.21(m,1H),6.20–6.14(m,1H),6.10(d,J＝17.3Hz,1H),5.85(s,1H),5.62(d,J＝10.3Hz,1H),5.44(s,1H),3.54–3.44(m,2H),3.11–3.03(m,1H),3.01(s,6H),2.40(s,3H),1.85–1.73(m,3H),1.65–1.57(m,1H).13C NMR(126MHz,CDCl3)δ198.6,192.8,160.3,157.1,143.4,136.3,136.1,129.3,129.1,128.6,126.0,110.8,107.0,92.4,78.3,51.8,44.5,40.3,23.7,23.4,21.6.IR(KBr,cm-1):2924,1617,1396,1238,1117,989,862,790,662,564.HRMS(ESI-TOF)/m/z:[M+Na]+calcd forC24H27N3O4SNa 476.1614；found 476.1611.
实施例35
实施例35提供一种3a-甲基-1-对甲苯基-1,2,3,3a,5,6-六氢-4H-6a,11a-甲基苯并[b]吡咯并[3,2-g]氮杂
-4,12-二酮(4u)和4-羟基-3a-甲基-1-对甲苯基-2,3,3a,4,5,6-六氢-1H-6a,11a-甲基苯并[b]吡咯并[3,2-g]氮杂
-12-酮(5u)，制备方法如下：
以N-(3,3-二乙氧基丙基)-4-甲苯磺酰胺(2u-s1)和甲基溴化镁分别替代实施例19中的2a-s2和乙基溴化镁，其余操作不变，得到3a-甲基-1-对甲苯基-1,2,3,3a,5,6-六氢-4H-6a,11a-甲基苯并[b]吡咯并[3,2-g]氮杂
-4,12-二酮(4u)。
进一步地，发明人在产物4u的反应液中加入硼氢化钠(3eq)继续搅拌1小时，可将其中一个羰基还原成羟基，再进行柱层析纯化分离，得到化合物5u。收率45％(27mg),粉色固体,m.p,Rf＝0.3(乙酸乙酯/石油醚＝3:1).1H NMR(500MHz,CDCl3)δ7.73(d,J＝8.1Hz,2H),7.27(d,J＝8.1Hz,2H),6.73(dd,J＝9.6,5.6Hz,1H),6.50(d,J＝9.3Hz,1H),6.45(d,J＝9.7Hz,1H),6.29(dd,J＝9.3,5.7Hz,1H),3.78–3.69(m,2H),3.40(q,J＝9.4Hz,1H),2.93(q,J＝10.6Hz,1H),2.41(s,3H),2.12(s,1H),2.06–1.93(m,3H),1.90–1.84(m,1H),1.71(dd,J＝12.1,7.2Hz,1H),1.12(s,3H).13C NMR(126MHz,CDCl3)δ207.4,181.0,143.6,136.2,136.0,133.7,129.3,128.3,123.0,120.5,95.8,73.0,58.1,55.5,45.3,32.0,30.8,27.8,21.6,21.0.IR(KBr,cm-1):3469,2925,1771,1636,1399,1260,905,730,666.HRMS(ESI-TOF)/m/z:[M+H]+calcd for C22H23N2O4S 411.1373；found 411.1368.
实施例36
实施例36提供一种1-(甲磺酰基)-2,3,4,4a,6,7-六氢-7a,12a-甲氨基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4v)，制备方法如下：
以甲磺酰氯替代实施例1步骤(2)中的甲苯磺酰氯，其余操作不变，得到1-(甲磺酰基)-2,3,4,4a,6,7-六氢-7a,12a-甲氨基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4v)。收率78％(39mg)，白色固体，Rf＝0.3(乙酸乙酯/石油醚＝1:2)。1H NMR(500MHz,CDCl3)δ6.68(dd,J＝9.8,5.6Hz,1H),6.45(t,J＝8.3Hz,2H),6.25(dd,J＝9.3,5.6Hz,1H),3.61(dt,J＝11.5,3.6Hz,1H),3.48(td,J＝12.2,2.9Hz,1H),2.96–2.90(m,1H),2.88(s,3H),2.57(ddd,J＝12.9,9.3,6.1Hz,1H),2.47–2.40(m,1H),2.11–2.03(m,1H),2.00–1.87(m,3H),1.86–1.70(m,2H).13C NMR(126MHz,CDCl3)δ210.3,205.6,179.7,136.0,132.7,122.7,121.2,85.0,59.2,57.9,44.6,40.1,30.8,23.8,22.2.IR(KBr,cm-1):3041,2938,1770,1578,1329,1199,1055,970,745,665,521.HRMS(ESI-TOF)/m/z:[M+H]+calcd forC16H19N2O4S 335.1060；found 335.1059.
实施例37
实施例37提供一种3’-丙烯酰-1’-对甲苯基螺环[吲哚啉-2,2’-哌啶]-3-酮(6a)，制备方法如下：
取实施例1制得的1-对甲苯磺酰基-2,3,4,4a,6,7-六氢-7a,12a-甲基苯并[b]吡啶并[3,2-g]氮杂
-5,13(1H)-二酮(4a，41mg，0.1mmol)，加入二氯甲烷(1mL)、硅胶(10mg)和三乙胺(3eq)。室温搅拌并监控直至原料反应完全。随后过滤掉硅胶，用水(1mL)洗涤，二氯甲烷萃取后合并有机相，经硫酸钠干燥后经快速柱色谱法纯化(石油醚/乙酸乙酯＝1:1)得3’-丙烯酰-1’-对甲苯基螺环[吲哚啉-2,2’-哌啶]-3-酮(6a)。收率66％(24.6mg)。1HNMR(500MHz,CDCl3)δ7.73(d,J＝8.1Hz,2H),7.59(d,J＝7.7Hz,1H),7.44(t,J＝7.6Hz,1H),7.27(d,J＝8.1Hz,2H),6.88(t,J＝7.4Hz,1H),6.81(d,J＝8.2Hz,1H),6.15–6.02(m,2H),5.64(d,J＝9.9Hz,1H),5.49(s,1H),3.53–3.47(m,2H),3.08(td,J＝12.3,2.5Hz,1H),2.42(s,3H),1.89–1.77(m,3H),1.72–1.67(m,1H).13C{1H}NMR(126MHz,CDCl3)δ198.3,196.6,158.2,143.8,137.5,135.8,135.7,130.2,129.3,128.5,124.8,121.9,120.8,113.4,51.9,44.4,23.8,23.3,21.6.IR(KBr,cm-1):2924,1714,1617,1416,1315,1197,988,863,727,665,570.HRMS(ESI-TOF)/m/z:[M+Na]+calcd for C22H22N2O4SNa 433.1192；found 433.1191.
实施例38
实施例38提供一种3’-丙烯酰-6-(二甲氨基)-1’-对甲苯基螺环[吲哚啉-2,2’-哌啶]-3-酮(6p)，制备方法如下：
以4-(二甲氨基)-2-硝基苯甲醛替代实施例1步骤(1)中的2-硝基苯甲醛，其余操作不变，得到3’-丙烯酰-6-(二甲氨基)-1’-对甲苯基螺环[吲哚啉-2,2’-哌啶]-3-酮(6p)。收率58％(40mg),粉色固体,m.p Rf＝0.3(乙酸乙酯/石油醚＝1:3).1H NMR(500MHz,CDCl3)δ7.70(d,J＝7.8Hz,2H),7.30(d,J＝7.8Hz,2H),6.62(s,1H),6.57(d,J＝9.6Hz,1H),6.25(d,J＝9.6Hz,1H),3.38–3.22(m,2H),2.95–2.87(m,1H),2.65–2.53(m,1H),2.50–2.43(m,1H),2.42(s,3H),2.02–1.87(m,4H),1.84–1.75(m,1H),1.63–1.52(m,1H).13C NMR(101MHz,CDCl3)δ209.1,205.1,177.4,144.2,142.6,135.4,133.6,129.5,128.4,126.1,119.2,85.0,58.4,58.0,44.2,40.1,31.2,23.4,22.0,21.6.IR(KBr,cm-1):2925,2859,1764,1654,1397,1239,1094,788,675,522.HRMS(ESI-TOF)/m/z:[M+Na]+calcd for C22H21ClN2O4SNa467.0803；found 467.0802.
化合物的生物活性测试
1.样品的准备：取适量本发明制备的化合物，用COX-2 Assay Buffer、Milli-Q级纯水、DMSO等适当的溶剂配制成100μM浓度。
2.试剂盒的准备：
a.融解除人重组COX-2(recombinant human COX-2,rhCOX-2)以外的其它所有试剂至室温，略离心使溶液沉淀至管底，再混匀备用。COX-2探针(COX-2 Probe)、COX-2辅助因子(COX-2 Cofactor)(50X)和COX-2底物(COX-2 Substrate)(50X)配制在DMSO中，37℃水浴2min促进融解。使用完毕后立即-20℃避光保存。
b.COX-2辅助因子(COX-2 Cofactor)工作液的配制：按照每个样品需要5微升COX-2辅助因子(COX-2 Cofactor)工作液的比例配制适量的COX-2辅助因子(COX-2 Cofactor)工作液。取4微升的COX-2辅助因子(COX-2 Cofactor)(50X)，按照1:49的比例用COX-2Assay Buffer稀释。配制好的COX-2辅助因子(COX-2 Cofactor)工作液可4℃存放，仅限当日使用。
c.COX-2工作液的配制：按照每个样品需5微升COX-2工作液的比例配制适量的COX-2工作液。取适量的人重组COX-2(recombinant human COX-2,rhCOX-2)(25X)，按照1:24的比例用COX-2 Assay Buffer稀释。配制好的COX-2工作液可在冰浴上暂时保存，1小时内酶活性基本稳定。注：所有涉及COX-2的操作应在冰上进行。
d.COX-2底物(COX-2 Substrate)工作液的配制：按照每个样品需5微升COX-2底物(COX-2 Substrate)工作液的比例配制适量的COX-2底物(COX-2 Substrate)工作液。取20微升的COX-2底物(COX-2 Substrate)(50X)，加入等体积的Substrate Buffer，充分涡旋混匀，该混合物再按照1:24的比例用Milli-Q级纯水或重蒸水稀释，充分涡旋混匀。配制好的COX-2底物(COX-2 Substrate)工作液可在冰浴上暂时保存，1小时内较为稳定。
e.阳性抑制剂Celecoxib溶液的配制：试剂盒提供的阳性对照抑制剂Celecoxib浓度为100μM，配制在DMSO中。
3.样品检测：(1)参考表4，使用96孔黑板设置对照孔和样品孔，并按照下表依次加入样品和各溶液。加入待测样品后，混匀，37℃孵育10分钟。
表4数据表
(2)各孔加入COX-2Probe 5微升。
(3)各孔快速加入COX-2 Substrate工作液5微升，混匀。
d.37℃避光孵育5分钟后进行荧光测定。激发波长为560nm，发射波长为590nm。当荧光读数偏低时，也可适当延长孵育时间至10-20分钟。
4.计算:①计算每个样品孔和空白对照孔的平均荧光值，可分别记录为RFU空白对照、RFU100％酶活性对照、RFU阳性抑制剂对照和RFU样品。RFU，Relative FluorescenceUnit。②计算每个样品的抑制百分率。计算公式如下：抑制率(％)＝(RFU100％酶活性对照-RFU样品)/(RFU100％酶活性对照-RFU空白对照)×100％。
实验数据如表5：
表5化合物的抑制率
| 化合物 | 浓度 | 活性抑制率/％ |
| 4a | 100μM | 23.5 |
| 4f | 100μM | 27.2 |
| 4k | 100μM | 17.7 |
| 4j | 100μM | 21.0 |
| 4o | 100μM | 79.8 |
| 4i | 100μM | 25.3 |
| 4l | 100μM | 56.2 |
| 4e | 100μM | 35.8 |
| 4h | 100μM | 54.7 |
| 5t | 100μM | 46.8 |
实验结果表明，本发明制备的含氮螺环化合物对COX-2有一定的抑制作用，具有制备COX-2抑制剂的潜力。
显然，本发明的上述实施例仅仅是为清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明权利要求的保护范围之内。
Claims (10)
1.一种含氮螺环化合物或其药学上可接受的盐，其特征在于，所述含氮螺环化合物具有式(4)、式(5)或式(6)所示结构：
其中X为碳原子或氮原子；n选自0、1或2；
R1为A环上的一个或多个基团，所述R1选自氢、卤素、C1～C6烷基、C1～C6烷氧基、三氟甲基、C1～C6酯基、C1～C6烷基胺基、氰基或苯基；
当R1的数量为多个时，两个R1之间可以通过饱和或不饱和的C1～C4碳链相连；
R2选自氢、苄氧羰基、叔丁氧羰基、芴甲氧羰基、邻苯二甲酰基、对甲苯磺酰基、三氟乙酰基、对甲氧基苄基、苄基或甲磺酰基；
R3选自氢或C1～C6烷基。
2.根据权利要求1所述含氮螺环化合物或其药学上可接受的盐，其特征在于，n选自0或1。
3.根据权利要求1所述含氮螺环化合物或其药学上可接受的盐，其特征在于，R1选自氢、氯、溴、C1～C6烷基、C1～C6烷氧基、三氟甲基、C1～C6酯基、C1～C6烷基胺基或苯基。
4.根据权利要求1所述含氮螺环化合物或其药学上可接受的盐，其特征在于，R2选自氢、对甲苯磺酰基或甲磺酰基。
5.根据权利要求1所述含氮螺环化合物或其药学上可接受的盐，其特征在于，所述药学上可接受的盐为氮螺环化合物与有机酸或无机酸形成的的药学上可接受的盐。
6.根据权利要求1～5任一项所述含氮螺环化合物或其药学上可接受的盐的制备方法，其特征在于，包括如下步骤：
S1.如式(3)所示的烯基环丙烷化合物在溶剂中加热并进行反应，得到如式(4)的化合物；
S2.将式(4)的化合物经还原得到式(5)所示化合物；或者，将式(4)的化合物在碱条件下与硅胶混合进行反应得到式(6)所示化合物；
S3.如果需要的话，将得到的式(4)所示化合物、式(5)所示化合物、式(6)所示化合物转化为药学上可接受的盐；
R1为A环上的一个或多个基团，所述R1选自氢、卤素、C1～C6烷基、C1～C6烷氧基、三氟甲基、C1～C6酯基、C1～C6烷基胺基、氰基或苯基；当R1的数量为多个时，两个R1之间可以通过饱和或不饱和的C1～C4碳链相连；
R2选自氢、苄氧羰基、叔丁氧羰基、芴甲氧羰基、邻苯二甲酰基、对甲苯磺酰基、三氟乙酰基、对甲氧基苄基、苄基或甲磺酰基；
R3选自氢或C1～C6烷基。
7.根据权利要求6所述含氮螺环化合物或其药学上可接受的盐的制备方法，其特征在于，所述溶剂选自甲苯、氯苯、二甲基亚砜、四氢呋喃、二氯甲烷、1,2-二氯乙烷、1,4-二氧六环、甲醇、乙醇、异丙醇、乙腈、水中的一种或多种。
8.根据权利要求6所述含氮螺环化合物或其药学上可接受的盐的制备方法，其特征在于，所述加热的温度为50～120℃。
9.根据权利要求6所述含氮螺环化合物或其药学上可接受的盐的制备方法，其特征在于，所述加热的时间为4～60h。
10.权利要求1～5任一项所述含氮螺环化合物或其药学上可接受的盐在制备COX-2抑制剂中的应用。
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