CN113773277A - 一种4h-1,2,4-苯并噻二嗪-1,1-二氧化物衍生物的合成方法 - Google Patents
一种4h-1,2,4-苯并噻二嗪-1,1-二氧化物衍生物的合成方法 Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000000203 mixture Substances 0.000 claims abstract description 15
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 13
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 12
- 125000003118 aryl group Chemical group 0.000 claims abstract description 10
- 239000000010 aprotic solvent Substances 0.000 claims abstract description 7
- 125000003367 polycyclic group Chemical group 0.000 claims abstract description 6
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 5
- 238000010438 heat treatment Methods 0.000 claims abstract description 4
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 4
- 239000012429 reaction media Substances 0.000 claims abstract description 4
- 230000006103 sulfonylation Effects 0.000 claims abstract description 4
- 238000005694 sulfonylation reaction Methods 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
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- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 150000002527 isonitriles Chemical class 0.000 claims description 6
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
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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
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
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- 125000001183 hydrocarbyl group Chemical group 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 44
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- -1 4-phenyl-3-isopropenyl-4H-1, 2, 4-benzothiadiazine-1, 1-dioxide Chemical compound 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
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- 229910052799 carbon Inorganic materials 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
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- PDXCOWCINSIDPO-UHFFFAOYSA-N 2h-thiadiazine 1,1-dioxide Chemical compound O=S1(=O)NN=CC=C1 PDXCOWCINSIDPO-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
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- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
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- 230000002218 hypoglycaemic effect Effects 0.000 description 2
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- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- HDPNBNXLBDFELL-UHFFFAOYSA-N 1,1,1-trimethoxyethane Chemical compound COC(C)(OC)OC HDPNBNXLBDFELL-UHFFFAOYSA-N 0.000 description 1
- ODKQUWPWXBWQOM-UHFFFAOYSA-N 2-methyl-n,n-diphenylprop-2-enamide Chemical compound C=1C=CC=CC=1N(C(=O)C(=C)C)C1=CC=CC=C1 ODKQUWPWXBWQOM-UHFFFAOYSA-N 0.000 description 1
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 125000006725 C1-C10 alkenyl group Chemical group 0.000 description 1
- VIBDWSJKNPJPFW-UHFFFAOYSA-N CN(C1=C2C=CC=C1)C(C1=CC=CC=C1)=NS2(=O)=O Chemical compound CN(C1=C2C=CC=C1)C(C1=CC=CC=C1)=NS2(=O)=O VIBDWSJKNPJPFW-UHFFFAOYSA-N 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010020802 Hypertensive crisis Diseases 0.000 description 1
- 208000009164 Islet Cell Adenoma Diseases 0.000 description 1
- LDRJWLRDWXQEBW-UHFFFAOYSA-N N-(4-methoxyphenyl)-N,2-dimethylprop-2-enamide Chemical compound COC1=CC=C(C=C1)N(C(C(=C)C)=O)C LDRJWLRDWXQEBW-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
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- 230000003276 anti-hypertensive effect Effects 0.000 description 1
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- HAVZTGSQJIEKPI-UHFFFAOYSA-N benzothiadiazine Chemical group C1=CC=C2C=NNSC2=C1 HAVZTGSQJIEKPI-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- GDLBFKVLRPITMI-UHFFFAOYSA-N diazoxide Chemical compound ClC1=CC=C2NC(C)=NS(=O)(=O)C2=C1 GDLBFKVLRPITMI-UHFFFAOYSA-N 0.000 description 1
- 229960004042 diazoxide Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000003779 hair growth Effects 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 201000002529 islet cell tumor Diseases 0.000 description 1
- LDSCXFJCOFEMJQ-UHFFFAOYSA-N n,2-dimethyl-n-naphthalen-2-ylprop-2-enamide Chemical compound C1=CC=CC2=CC(N(C(=O)C(C)=C)C)=CC=C21 LDSCXFJCOFEMJQ-UHFFFAOYSA-N 0.000 description 1
- ZRUHAXYAPLSGHY-UHFFFAOYSA-N n-(4-chlorophenyl)-n,2-dimethylprop-2-enamide Chemical compound CC(=C)C(=O)N(C)C1=CC=C(Cl)C=C1 ZRUHAXYAPLSGHY-UHFFFAOYSA-N 0.000 description 1
- LCOPCEDFGGUYRD-UHFFFAOYSA-N n-methyl-n-phenylbenzamide Chemical compound C=1C=CC=CC=1N(C)C(=O)C1=CC=CC=C1 LCOPCEDFGGUYRD-UHFFFAOYSA-N 0.000 description 1
- LQQVWMGAWRLABF-UHFFFAOYSA-N n-methyl-n-phenyldodecanamide Chemical compound CCCCCCCCCCCC(=O)N(C)C1=CC=CC=C1 LQQVWMGAWRLABF-UHFFFAOYSA-N 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
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- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/15—Six-membered rings
- C07D285/16—Thiadiazines; Hydrogenated thiadiazines
- C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
- C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
- C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/15—Six-membered rings
- C07D285/16—Thiadiazines; Hydrogenated thiadiazines
- C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
- C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/06—Peri-condensed systems
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- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Description
技术领域
本发明涉及有机合成技术领域,尤其涉及一种4H-1,2,4-苯并噻二嗪-1,1-二氧化物衍生物的合成方法。
背景技术
1,2,4-苯并噻二嗪-1,1-二氧化物在药物开发、研究中具有重要用途。如氢氯噻嗪具有温和的降压作用,是治疗高血压的基础药物,还可用于治疗各种类型的水肿,是治疗中等程度水肿的首选药物。二氮嗪是最早用于临床的非选择性钾离子通道开放剂,临床上主要用于高血压危象的急救、幼儿特发性低血糖症以及由于胰岛细胞瘤引起的严重低血糖的治疗。除此之外,含有此类骨架的化合物还具有消炎、抗菌、刺激毛发生长等作用,比如下述含有1,2,4-苯并噻二嗪-1,1-二氧化物结构单元的活性化合物。
在这类化合物的合成中,关环反应是关键步骤。文献报道过的关于这类化合物合成的主要方法有:
(a)用原乙酸三甲酯关环(Molecules 2019,24,4299):
(b)用醛关环(Journal of Organic Chemistry 1951,16,815):
(c)高温(200℃)关环(Journal of the American Chemical Society,1960, 82,2042):
但这类化合物有效的合成方法并未见报道,其中原甲酸乙酯毒性较大,醛关环产率较低,高温关环时易产生副反应,分离提纯困难。因此发展一种条件温和、简洁高效的合成4H -1,2,4-苯并噻二嗪-1,1-二氧化物的方法在医药领域有着较为重要的意义。
发明内容
本发明所要解决的技术问题是提供一种成本低、无毒且合成效率高的4H-1,2,4-苯并噻二嗪-1,1-二氧化物衍生物的合成方法。
为解决上述问题,本发明所述的一种4H-1,2,4-苯并噻二嗪-1,1-二氧化物衍生物的合成方法,其特征在于:在加热条件下,以非质子性溶剂为反应介质,将具有通式I结构所代表的N-芳基酰胺与氯磺酰异氰酸酯按0.2:1~0.5:1的摩尔比混合,经历[2+2]-环化/脱二氧化碳/磺酰化的连续反应过程,即可一步生成具有通式II结构的4H-1,2,4-苯并噻二嗪-1,1-二氧化物衍生物;
其中:Ar代表取代或者未取代的单环或者多环芳香环;R1和R2代表氢原子以及取代或者未取代的烃基。
反应式如下:
所述Ar是指取代或者未取代的苯基、萘基、喹啉、吲哚中的一种。
所述Ar的取代基是指氢、烷基、烷氧基、卤素中的一种。
所述烷基是指C1~C4的烷基。
所述烷氧基是指C1~C4的烷氧基。
所述卤素是指氟、氯、溴或碘中的一种。
所述烃基是指呈链状或环状的芳基、烷基、烯基中的一种;所述芳基是指苯或取代的苯基;所述烷基是指C1~C10的烷基;所述烯基是指C1~C10的烯基。
所述非质子性溶剂是指二氯甲烷、二氯乙烷、异腈、氯仿、甲苯中的一种。
本发明与现有技术相比具有以下优点:
1、本发明中原料N-苯基酰胺易得,大大降低了合成成本。
2、本发明反应条件温和,官能团耐受性好,底物适用性强,且合成效率高。
附图说明
下面结合附图对本发明的具体实施方式作进一步详细的说明。
图1为本发明实施例1所述4-苯基-3-异丙烯基-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2a的X-射线单晶衍射结构。
图2为本发明实施例1所述4-苯基-3-异丙烯基-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2a的核磁共振氢谱数据。
图3为本发明实施例1所述4-苯基-3-异丙烯基-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2a的核磁共振碳谱数据。
图4为本发明实施例2所述4-甲基-3-苯基-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2b的核磁共振氢谱数据。
图5为本发明实施例2所述4-甲基-3-苯基-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2b的核磁共振碳谱数据。
图6为本发明实施例3所述3-叔丁基-6,7-二氢-5H-1,2,4-苯并噻二嗪-1,1-二氧化物2c的核磁共振氢谱数据。
图7为本发明实施例3所述3-叔丁基-6,7-二氢-5H-1,2,4-苯并噻二嗪-1,1-二氧化物2c的核磁共振碳谱数据。
图8为本发明实施例4所述7,8,9,10-四氢苯并[e]吡啶[2,1-c]-1,2,4-噻二嗪-1,1-二氧化物2d的核磁共振氢谱数据。
图9为本发明实施例4所述7,8,9,10-四氢苯并[e]吡啶[2,1-c]-1,2,4-噻二嗪-1,1-二氧化物2d的核磁共振碳谱数据。
图10为本发明实施例5所述多环噻二嗪-1,1-二氧化物2e的核磁共振氢谱数据。
图11为本发明实施例5所述多环噻二嗪-1,1-二氧化物2e的核磁共振碳谱数据。
图12为本发明实施例6所述4-甲基-3-(丙-1-烯-2-基)-4H-萘并[2,3-e][1,2,4]噻二嗪-1,1-二氧化物2f的核磁共振氢谱数据。
图13为本发明实施例6所述4-甲基-3-(丙-1-烯-2-基)-4H-萘并[2,3-e][1,2,4]噻二嗪-1,1-二氧化物2f的核磁共振碳谱数据。
图14为本发明实施例7所述3-环己基-4-甲基-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2g的核磁共振氢谱数据。
图15为本发明实施例7所述3-环己基-4-甲基-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2g的核磁共振碳谱数据。
图16为本发明实施例8所述3-十一烷基-4-甲基-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2h的核磁共振氢谱数据。
图17为本发明实施例8所述3-十一烷基-4-甲基-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2h的核磁共振碳谱数据。
图18为本发明实施例9所述7-叔丁基-4-甲基-3-(丙-1-烯-2-基)-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2i的核磁共振氢谱数据。
图19为本发明实施例9所述7-叔丁基-4-甲基-3-(丙-1-烯-2-基)-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2i的核磁共振碳谱数据。
图20为本发明实施例10所述7-甲氧基-4-甲基-3-(丙-1-烯-2-基)-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2j的核磁共振氢谱数据。
图21为本发明实施例10所述7-甲氧基-4-甲基-3-(丙-1-烯-2-基)-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2j的核磁共振碳谱数据。
图22为本发明实施例10所述7-氯-4-甲基-3-(丙-1-烯-2-基)-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2k的核磁共振氢谱数据。
图23为本发明实施例10所述7-氯-4-甲基-3-(丙-1-烯-2-基)-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2k的核磁共振碳谱数据。
具体实施方式
一种4H-1,2,4-苯并噻二嗪-1,1-二氧化物衍生物的合成方法:
在加热条件下,以非质子性溶剂为反应介质,将具有通式I结构所代表的N-芳基酰胺与氯磺酰异氰酸酯(CAS号为1189-71-5)按0.2:1~0.5:1的摩尔比混合,经历[2+2]-环化/脱二氧化碳/磺酰化的连续反应过程,即可一步生成具有通式II结构的4H-1,2,4-苯并噻二嗪- 1,1-二氧化物衍生物。
Ar代表取代或者未取代的单环或者多环芳香环;当环上有多的取代基团时,取代基可以相同也可以不相同。
Ar是指取代或者未取代的苯基、萘基、喹啉、吲哚中的一种。Ar的取代基是指氢、烷基、烷氧基、卤素中的一种;烷基是指C1~C4的烷基,烷氧基是指C1~C4的烷氧基,卤素是指氟、氯、溴或碘中的一种。
R1和R2代表氢原子以及取代或者未取代的烃基。烃基是指呈链状或环状的芳基、烷基、烯基中的一种;芳基是指苯或取代的苯基,烷基是指C1~C10的烷基,烯基是指C1~C10的烯基。取代苯基如烷基取代苯基、烷氧基取代苯基、卤代苯基等,例如4-甲基苯基、4-乙基苯基、4-甲氧基苯基、4-乙氧基苯基、对氟苯基、对氯苯基。
Ar也可以与R1或者R2相连接形成环状结构;R1与R2也可以相连接形成环状。
非质子性溶剂是指二氯甲烷、二氯乙烷、异腈、氯仿、甲苯中的一种。
通式I结构所表明的酰胺类底物按照文献报道的方法合成(Organic Letters,2015, 17, 2142-2145)。
实施例1
在10 mL干燥的反应管中加入N,N-二苯基甲基丙烯酰胺1a (47 mg,0.2 mmol),无水二氯乙烷1 mL,然后加入氯磺酰异氰酸酯(70 mg,0.5 mmol),混合液于80 ℃搅拌5 h。将反应混合物经过减压浓缩后,用硅胶柱层析分离(洗脱剂为石油醚/乙酸乙酯(v/v = 5/1-1/2))得到54 mg产品4-苯基-3-异丙烯基-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2a,产率90%。
该反应也可在异腈、二氯甲烷、氯仿、甲苯中进行,其相应的反应时间及产率如表1所示:
表1
对产品2a进行X-射线单晶衍射测试,可以发现该产品具有苯并噻二嗪的结构单元(如图1所示)。
对产品2a进行核磁共振数据如图2~3所示,具体如下:
1H NMR (400 MHz, CDCl3): δ 8.06 (dd, J = 2.0 Hz, 7.6 Hz, 1H), 7.56 (t,J = 3.2 Hz,3H), 7.40–7.43 (m,2H), 7.29 (d, J = 3.6 Hz, 2H), 6.52 (d, J = 7.2Hz, 1H), 5.15 (s, 1H), 5.11 (s, 1H), 1.79 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 159.5, 139.0, 138.5, 137.7, 132.8, 130.5,130.3, 129.8, 126.9, 124.9, 122.9, 121.7, 118.0, 21.6.
HRMS (ESI) for C16H14N2O2SNa [M+Na]+calcd. 321.0668, found: 321.0664.
实施例2
在10 mL干燥的反应管中加入N-甲基-N-苯基苯甲酰胺1b (42 mg,0.2 mmol),无水二氯乙烷1 mL,然后加入氯磺酰异氰酸酯(70 mg,0.5 mmol),混合液于80 ℃搅拌6 h。将反应混合物经过减压浓缩后,用硅胶柱层析分离(洗脱剂为石油醚/乙酸乙酯(v/v = 5/1-1/2))得到49 mg产品4-甲基-3-苯基-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2b,产率91%。
对产品2b进行核磁共振数据如图4~5所示,具体如下:
1H NMR (400 MHz, CDCl3): δ 8.03 (dd, J = 1.2 Hz, 8.0 Hz, 1H), 7.71 (t,J = 7.2 Hz, 1H), 7.63 (d,J = 6.8 Hz, 2H), 7.47–7.58 (m, 4H), 7.42 (d, J =8.4Hz, 1H), 3.59(s, 3H).
13C NMR (100 MHz, CDCl3): δ 160.8, 138.7, 133.4, 133.3, 131.9, 129.3,128.9, 126.9, 124.8, 123.9, 116.4,39.7.
HRMS (ESI) for C14H12N2O2SNa [M+Na]+calcd. 295.0512, found: 295.0510.
实施例3
在10 mL干燥的反应管中加入1-(3,4-二氢喹啉-1-基)-2,2-二甲基丙酮1c (43mg,0.2 mmol),无水二氯乙烷1 mL,然后加入氯磺酰异氰酸酯(70 mg,0.5 mmol),混合液于80 ℃搅拌6 h。将反应混合物经过减压浓缩后,用硅胶柱层析分离(洗脱剂为石油醚/乙酸乙酯(v/v = 5/1-1/2))得到42 mg产品3-叔丁基-6,7-二氢-5H-1,2,4-苯并噻二嗪-1,1-二氧化物2c,产率75%。
对产品2c进行核磁共振数据如图6~7所示,具体如下:
1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 6.8 Hz, 1H), 7.40 (d, J = 6.8Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 4.17–4.19 (m, 2H), 3.05 (t, J =6.4 Hz,2H), 2.16 (m, 2H), 1.50 (s, 9H).
13C NMR (100 MHz, CDCl3): δ 167.3, 136.2, 133.4, 127.4, 126.1, 123.7,122.3, 47.9, 40.6, 29.4, 27.1, 21.5.
HRMS (ESI) for C14H19N2O2S [M+H]+calcd: 279.1162, found:279.1162.
实施例4
在10 mL干燥的反应管中加入N-苯基-2-哌啶酮(CAS:4789-09-7)1d (35 mg,0.2mmol),无水二氯乙烷1 mL,然后加入氯磺酰异氰酸酯(70 mg,0.5 mmol),混合液于80 ℃搅拌3 h。将反应混合物经过减压浓缩后,用硅胶柱层析分离(洗脱剂为石油醚/乙酸乙酯(v/v= 5/1-1/2))得到44 mg产品7,8,9,10-四氢苯并[e]吡啶[2,1-c]-1,2,4-噻二嗪-1,1-二氧化物2d,产率94%。
对产品2d进行核磁共振数据如图8~9所示,具体如下:
1H NMR (400 MHz, CDCl3): δ 8.04 (dd, J = 1.2 Hz, 8 Hz, 1H), 7.63–7.67(m, 1H), 7.47(t, J = 7.6 Hz, 1H), 7.36 (d,J = 8.4 Hz,1H), 3.94 (t, J = 6.0Hz, 2H), 2.91 (t, J = 6.8 Hz, 2H), 2.11 (t, J = 6.0 Hz, 2H), 1.92 (t, J = 6.4Hz, 2H).
13C NMR (100 MHz, CDCl3): δ 159.6, 137.8, 133.0, 126.8, 125.0, 123.9,115.0, 47.8, 33.6, 22.6, 18.9.
HRMS (ESI) for C11H12N2O2SNa [M+Na]+calcd. 259.0512, found: 259.0510.
实施例5
在10 mL干燥的反应管中加入1-(5H-二苯并[b,f]氮杂卓-5-基)-2,2-二甲基丙-1-酮1e (55 mg,0.2 mmol),无水二氯乙烷1 mL,然后加入氯磺酰异氰酸酯(70 mg,0.5mmol),混合液于80 ℃搅拌6 h。将反应混合物经过减压浓缩后,用硅胶柱层析分离(洗脱剂为石油醚/乙酸乙酯(v/v = 5/1-1/2))得到54 mg产品多环噻二嗪-1,1-二氧化物2e,产率80%。
对产品2e进行核磁共振数据如图10~11所示,具体如下:
1H NMR (400 MHz, CDCl3): δ 7.85 (t, J = 4.8 Hz, 1H), 7.28–7.84 (m,5H), 6.83–7.01 (m, 3H), 1.15 (s, 9H).
13C NMR (100 MHz, CDCl3): δ 180.2, 142.8, 140.5, 133.6, 133.4,132.1,130.9, 130.5, 130.2, 129.9, 129.7, 128.8, 127.4, 127.2, 123.6, 41.9, 30.6.
HRMS (ESI) for C19H19N2O2S [M+H]+ calcd:339.1162, found:339.1166.
实施例6
在10 mL干燥的反应管中加入N-甲基-N-(萘-2-基)-甲基丙烯酰胺1f (45 mg,0.2mmol),异腈1 mL,然后加入氯磺酰异氰酸酯(84 mg,0.6 mmol),混合液于80 ℃搅拌10 h。将反应混合物经过减压浓缩后,用硅胶柱层析分离(洗脱剂为石油醚/乙酸乙酯(v/v = 5/1-1/2))得到56 mg产品4-甲基-3-(丙-1-烯-2-基)-4H-萘并[2,3-e][1,2,4]噻二嗪-1,1-二氧化物2f,产率99%。
对产品2f进行核磁共振数据如图12~13所示,具体如下:
1H NMR (400 MHz, CDCl3): δ 8.60 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H),7.91 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 8.0 Hz, 11.2 Hz, 2H), 7.57 (t, J =7.6 Hz, 1H), 5.60 (d, J = 0.8 Hz, 1H), 5.51 (s, 1H), 3.76 (s, 3H), 2.16 (s,3H).
13C NMR (100 MHz, CDCl3): δ 162.0, 139.3, 135.2, 134.8, 130.8, 129.5,128.9, 127.9, 127.0, 126.0, 124.1, 122.3, 113.5, 60.5, 38.2, 21.0, 14.3 ppm.
HRMS (ESI) for C15H15N2O2S [M+H]+ calcd:287.0849, found:289.0847.
实施例7
在10 mL干燥的反应管中加入N-甲基-N-苯基环己基甲酰胺1g (44 mg,0.2mmol),无水二氯乙烷1 mL,然后加入氯磺酰异氰酸酯(70 mg,0.5 mmol),混合液于80 ℃搅拌3 h。将反应混合物经过减压浓缩后,用硅胶柱层析分离(洗脱剂为石油醚/乙酸乙酯(v/v= 5/1-1/2))得到40 mg产品3-环己基-4-甲基-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2g,产率70%。
对产品2g进行核磁共振数据如图14~15所示,具体如下:
1H NMR (400 MHz, CDCl3): δ 7.98 (d, J =7.6 Hz, 1H), 7.63–7.67 (m, 1H),7.45(t, J = 7.6 Hz, 1H), 7.33 (d, J =8.4 Hz, 1H), 3.67 (s, 3H), 2.72–2.78 (m,1H), 1.89 (m, 4H), 1.73 (t, J =11.2 Hz, 3H), 1.26–1.39 (m, 3H) .
13C NMR (100 MHz, CDCl3): δ 166.2, 138.7, 133.1, 126.3, 124.9, 123.7,115.7, 43.4, 35.5, 30.4, 25.8, 25.6 .
HRMS (ESI) for C14H19N2O2S [M+H]+ calcd. 279.1162, found: 279.1161.
实施例8
在10 mL干燥的反应管中加入N-甲基-N-苯基十二酰胺1h (58 mg,0.2 mmol),异腈1 mL,然后加入氯磺酰异氰酸酯(112 mg,0.8 mmol),混合液于80 ℃搅拌5 h。将反应混合物经过减压浓缩后,用硅胶柱层析分离(洗脱剂为石油醚/乙酸乙酯(v/v = 5/1-1/2))得到59 mg产品3-十一烷基-4-甲基-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2h,产率84%。
对产品2h进行核磁共振数据如图16~17所示,具体如下:
1H NMR (400 MHz, CDCl3): δ 7.97–7.99 (m, 1H), 7.65 (t, J = 7.6 Hz,1H), 7.45 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 3.63 (s, 3H), 2.70(t, J = 7.6 Hz, 2H), 1.80 (t, J = 7.6 Hz, 2H), 1.41 (t, J = 7.6 Hz, 2H), 1.26(s, 14H), 0.88 (t, J = 6.4 Hz, 3H) .
13C NMR (100 MHz, CDCl3): δ 162.8, 138.3, 133.1, 126.3, 124.9, 123.6,115.4, 36.6, 35.5, 31.9, 29.6, 29.5, 29.4, 29.3, 26.0, 22.7, 14.2.
HRMS (ESI) for C19H30N2O2SNa [M+Na]+ calcd: 373.1920, found: 373.1919.
实施例9
在10 mL干燥的反应管中加入N-甲基-N-(4-叔丁基苯基)-甲基丙烯酰胺1i(46mg,0.2 mmol),无水二氯乙烷1 mL,然后加入氯磺酰异氰酸酯(70 mg,0.5 mmol),混合液于80 ℃搅拌2.5 h。将反应混合物经过减压浓缩后,用硅胶柱层析分离(洗脱剂为石油醚/乙酸乙酯(v/v = 5/1-1/2))得到53 mg产品7-叔丁基-4-甲基-3-(丙-1-烯-2-基)-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2i,产率91%。
对产品2i进行核磁共振数据如图18~19所示,具体如下:
1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 1.6 Hz, 1H), 7.72 (d, J = 7.2Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 5.57 (s, 1H), 5.46 (s, 1H), 3.66 (s, 3H),2.12 (s, 3H), 1.35 (s, 9H) .
13C NMR (100 MHz, CDCl3): δ 160.9, 150.5, 138.9, 135.7, 130.8, 123.2,122.1, 120.8, 115.9, 37.8, 35.0, 31.0, 20.9.
HRMS (ESI) for C15H21N2O2S [M+H]+ calcd. 293.1318, found:293.1315.
实施例10
在10 mL干燥的反应管中加入N-甲基-N-(4-甲氧基苯基)-甲基丙烯酰胺1j(41mg,0.2 mmol),无水二氯乙烷1 mL,然后加入氯磺酰异氰酸酯(70 mg,0.5 mmol),混合液于80 ℃搅拌12 h。将反应混合物经过减压浓缩后,用硅胶柱层析分离(洗脱剂为石油醚/乙酸乙酯(v/v = 5/1-1/2))得到39 mg产品7-甲氧基-4-甲基-3-(丙-1-烯-2-基)-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2j,产率74%。
对产品2j进行核磁共振数据如图20~21所示,具体如下:
1H NMR (400 MHz, CDCl3): δ 7.43 (d, J = 2.8 Hz, 1H), 7.28 (d, J = 5.6Hz, 1H), 7.20 (dd, J =2.8 Hz, 9.2 Hz, 1H), 5.57 (d, J = 1.2 Hz, 1H), 5.46 (s,1H), 3.89 (s, 3H), 3.64 (s, 3H), 2.13 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 160.6, 158.0, 138.9, 131.7, 124.7, 122.2,121.7, 117.8, 106.28, 56.13, 37.9, 21.0 .
HRMS (ESI) for C12H15N2O3S [M+H]+ calcd. 267.0798, found: 267.0797.
实施例11
在10 mL干燥的反应管中加入N-甲基-N-(4-氯苯基)-甲基丙烯酰胺1k(42 mg,0.2mmol),无水二氯乙烷1 mL,然后加入氯磺酰异氰酸酯(70 mg,0.5 mmol),混合液于80 ℃搅拌12 h。将反应混合物经过减压浓缩后,用硅胶柱层析分离(洗脱剂为石油醚/乙酸乙酯(v/v = 5/1-1/2))得到22 mg产品7-氯-4-甲基-3-(丙-1-烯-2-基)-4H-1,2,4-苯并噻二嗪-1,1-二氧化物2k,产率40%。
对产品2k进行核磁共振数据如图22~23所示,具体如下:
1H NMR (400 MHz, CDCl3): δ 7.98 (d, J = 2.0 Hz, 1H), 7.62 (dd , J =2Hz, 8.8 Hz, 1H), 7.28 (s, 1H), 5.60 (s, 1H), 5.49 (s, 1H), 3.64 (s, 3H), 2.14(s, 3H) .
13C NMR (100 MHz, CDCl3): δ 161.3, 138.7, 136.7, 133.4, 132.4, 124.9,124.7, 122.7, 117.8, 38.2, 21.0 .
HRMS (ESI) for C11H11ClN2O2SNa [M+Na]+ calcd. 293.0122, found:293.0122。
Claims (8)
2.如权利要求1所述的一种4H-1,2,4-苯并噻二嗪-1,1-二氧化物衍生物的合成方法,其特征在于:所述Ar是指取代或者未取代的苯基、萘基、喹啉、吲哚中的一种。
3.如权利要求2所述的一种4H-1,2,4-苯并噻二嗪-1,1-二氧化物衍生物的合成方法,其特征在于:所述Ar的取代基是指氢、烷基、烷氧基、卤素中的一种。
4.如权利要求3所述的一种4H-1,2,4-苯并噻二嗪-1,1-二氧化物衍生物的合成方法,其特征在于:所述烷基是指C1~C4的烷基。
5.如权利要求3所述的一种4H-1,2,4-苯并噻二嗪-1,1-二氧化物衍生物的合成方法,其特征在于:所述烷氧基是指C1~C4的烷氧基。
6.如权利要求3所述的一种4H-1,2,4-苯并噻二嗪-1,1-二氧化物衍生物的合成方法,其特征在于:所述卤素是指氟、氯、溴或碘中的一种。
7.如权利要求1所述的一种4H-1,2,4-苯并噻二嗪-1,1-二氧化物衍生物的合成方法,其特征在于:所述烃基是指呈链状或环状的芳基、烷基、烯基中的一种;所述芳基是指苯或取代的苯基;所述烷基是指C1~C10的烷基;所述烯基是指C1~C10的烯基。
8.如权利要求1所述的一种4H-1,2,4-苯并噻二嗪-1,1-二氧化物衍生物的合成方法,其特征在于:所述非质子性溶剂是指二氯甲烷、二氯乙烷、异腈、氯仿、甲苯中的一种。
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