CN104844538B - 一种多取代1,3,4‑噻二嗪类化合物及制备方法 - Google Patents
一种多取代1,3,4‑噻二嗪类化合物及制备方法 Download PDFInfo
- Publication number
- CN104844538B CN104844538B CN201510162591.7A CN201510162591A CN104844538B CN 104844538 B CN104844538 B CN 104844538B CN 201510162591 A CN201510162591 A CN 201510162591A CN 104844538 B CN104844538 B CN 104844538B
- Authority
- CN
- China
- Prior art keywords
- polysubstituted
- thiadiazine
- diazthiness
- dihydros
- alcohol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000002360 preparation method Methods 0.000 title claims description 29
- -1 Polysubstituted 1,3,4-thiadiazine compound Chemical class 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000001677 (2R,5R)-1,4-dithiane-2,5-diol Substances 0.000 claims abstract description 5
- YUIOPHXTILULQC-UHFFFAOYSA-N 1,4-Dithiane-2,5-diol Chemical compound OC1CSC(O)CS1 YUIOPHXTILULQC-UHFFFAOYSA-N 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000000217 alkyl 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
- 239000002798 polar solvent Substances 0.000 claims description 6
- 238000010898 silica gel chromatography Methods 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 238000007363 ring formation reaction Methods 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- CMXPERZAMAQXSF-UHFFFAOYSA-M sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate;1,8-dihydroxyanthracene-9,10-dione Chemical compound [Na+].O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O.CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC CMXPERZAMAQXSF-UHFFFAOYSA-M 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 239000012044 organic layer Substances 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 238000000638 solvent extraction Methods 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 54
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- 235000010290 biphenyl Nutrition 0.000 description 17
- 239000004305 biphenyl Substances 0.000 description 17
- 230000000052 comparative effect Effects 0.000 description 17
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 239000012265 solid product Substances 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 14
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 7
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000010189 synthetic method Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 4
- ZYMCBJWUWHHVRX-UHFFFAOYSA-N (4-nitrophenyl)-phenylmethanone Chemical class C1=CC([N+](=O)[O-])=CC=C1C(=O)C1=CC=CC=C1 ZYMCBJWUWHHVRX-UHFFFAOYSA-N 0.000 description 3
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Natural products C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- QROGIFZRVHSFLM-QHHAFSJGSA-N [(e)-prop-1-enyl]benzene Chemical compound C\C=C\C1=CC=CC=C1 QROGIFZRVHSFLM-QHHAFSJGSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000007857 hydrazones Chemical class 0.000 description 2
- 208000006278 hypochromic anemia Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- 150000008338 1,3,4-thiadiazines Chemical class 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- YIWGJFPJRAEKMK-UHFFFAOYSA-N 1-(2H-benzotriazol-5-yl)-3-methyl-8-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carbonyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound CN1C(=O)N(c2ccc3n[nH]nc3c2)C2(CCN(CC2)C(=O)c2cnc(NCc3cccc(OC(F)(F)F)c3)nc2)C1=O YIWGJFPJRAEKMK-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- KLVQAIJZDCCJRZ-UHFFFAOYSA-N 2h-1,3,4-thiadiazine Chemical compound C1SC=CN=N1 KLVQAIJZDCCJRZ-UHFFFAOYSA-N 0.000 description 1
- 208000035126 Facies Diseases 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- VCUFZILGIRCDQQ-KRWDZBQOSA-N N-[[(5S)-2-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3-oxazolidin-5-yl]methyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC2=C(NC(O2)=O)C=C1)CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F VCUFZILGIRCDQQ-KRWDZBQOSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- JZFICWYCTCCINF-UHFFFAOYSA-N Thiadiazin Chemical compound S=C1SC(C)NC(C)N1CCN1C(=S)SC(C)NC1C JZFICWYCTCCINF-UHFFFAOYSA-N 0.000 description 1
- JAWMENYCRQKKJY-UHFFFAOYSA-N [3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-ylmethyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl]-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]methanone Chemical compound N1N=NC=2CN(CCC=21)CC1=NOC2(C1)CCN(CC2)C(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F JAWMENYCRQKKJY-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- VQGHOUODWALEFC-UHFFFAOYSA-N alpha-Phenylpyridine Natural products C1=CC=CC=C1C1=CC=CC=N1 VQGHOUODWALEFC-UHFFFAOYSA-N 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- PNALOBAQBMAHBZ-UHFFFAOYSA-N benzenecarbothiohydrazide Chemical class NNC(=S)C1=CC=CC=C1 PNALOBAQBMAHBZ-UHFFFAOYSA-N 0.000 description 1
- WARCRYXKINZHGQ-UHFFFAOYSA-N benzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1 WARCRYXKINZHGQ-UHFFFAOYSA-N 0.000 description 1
- 230000037237 body shape Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- JVZRCNQLWOELDU-UHFFFAOYSA-N gamma-Phenylpyridine Natural products C1=CC=CC=C1C1=CC=NC=C1 JVZRCNQLWOELDU-UHFFFAOYSA-N 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003863 metallic catalyst Substances 0.000 description 1
- JGOAZQAXRONCCI-SDNWHVSQSA-N n-[(e)-benzylideneamino]aniline Chemical compound C=1C=CC=CC=1N\N=C\C1=CC=CC=C1 JGOAZQAXRONCCI-SDNWHVSQSA-N 0.000 description 1
- SFMJNHNUOVADRW-UHFFFAOYSA-N n-[5-[9-[4-(methanesulfonamido)phenyl]-2-oxobenzo[h][1,6]naphthyridin-1-yl]-2-methylphenyl]prop-2-enamide Chemical compound C1=C(NC(=O)C=C)C(C)=CC=C1N1C(=O)C=CC2=C1C1=CC(C=3C=CC(NS(C)(=O)=O)=CC=3)=CC=C1N=C2 SFMJNHNUOVADRW-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
本发明提供一种多取代1,3,4‑噻二嗪类化合物,通过将易化学合成的α‑氯代腙类化合物与2,5‑二羟基‑1,4‑二噻烷在室温下反应生成。本发明方法设计合理、操作简单方便、条件温和、收率高、原料廉价易得,本发明为高效合成1,3,4‑噻二嗪类化合物提供了一种简单易行的方法。所述的多取代1,3,4‑噻二嗪类化合物的通式如下:
Description
技术领域
本发明属化合物的合成方法,主要涉及多取代1,3,4-噻二嗪类化合物及其制备方法发。
背景技术
噻二嗪作为一类六元芳杂环化合物,在医药、农药等众多领域均有着广泛的应用。特别是1,3,4-噻二嗪类化合物是一类非常重要的噻二嗪类化合物,作为一个优异的合成砌块,其在众多抗细菌、抗真菌、抗高血压药物合成中起着至关重要的作用。
由于1,3,4-噻二嗪类化合物具有非常重要的应用价值,因此其合成方法一直是合成领域的热点,最近几年新的方法层出不穷,其中比较有代表性的有以下几种。
(1)Matsubara, Yoshio等提出的酰化环合1,3,4-噻二嗪合成法(Matsubara,Yoshio et al,Phosphorus and Sulfur and the Related Elements, 22(1), 41-7;1985)。
该方法需先合成末端带羧基的硫取代的腙类化合物,然后以此为原料然后进行酰化反应从而得到1,3,4-噻二嗪,整个过程比较复杂,不适合规模化的大量生产。
(2)Trepanier, Donald L. and Krieger, Paul E等以β-巯基肼和原甲酸三甲酯为原料合成了一系列1,3,4-噻二嗪类化合物(Trepanier, Donald Let al. Journal ofHeterocyclic Chemistry, 4(2), 254-8; 1967)。
该反应需要在185℃高温条件下反应,条件较为苛刻。
(3) Matsubara, Yoshio等通过运用Lawesson试剂,将苯甲酰肼变成N-硫代苯甲酰肼,然后在缩合剂作用下与溴乙酸环合生成了1,3,4-噻二嗪类化合物(Matsubara,Yoshio et al. Chemistry Express, 6(6), 411-14; 1991)。
该方法中原料N-硫代苯甲酰肼的获得需要用到昂贵的Lawesson试剂,且反应产生的副产物不利于环境的保护。
(4) Abdel-Rahman, Taha M等用1.2-二溴乙烷与硫代甲酰肼发生环合反应,生成了一类新型1,3,4-噻二嗪类化合物(Abdel-Rahman, Taha M et al. Phosphorus, Sulfurand Silicon and the Related Elements, 181(8), 1737-1754; 2006)。
该方法需在强碱条件下加热回流,且只能生成单一取代的1,3,4-噻二嗪类化合物。
尽管1,3,4-噻二嗪类化合物的合成报道较多,但是已知的合成方法仍然存在着原料不易获得、使用毒性较大的催化剂、产品收率低、对于不同官能团适用性差等问题,以上因素使开发一种新型的1,3,4-噻二嗪类化合物的制备方法成为当务之急。
发明内容
本发明的目的是提供一种多取代1,3,4-噻二嗪类化合物,该取代1,3,4-噻二嗪类化合物的结构通式Ⅳ:
其中:R1为单取代或多取代芳环(取代基可为卤素、烷氧基、烷基)、杂环、C1-C5链烷烃、苯丙烯。
R2为单取代或多取代芳环(取代基可为卤素、硝基、烷氧基、烷基)。
本发明的另一个目的是提供多取代1,3,4-噻二嗪类化合物的制备方法,将α-氯代腙类化合物(Ⅰ)与2,5-二羟基-1,4-二噻烷(Ⅱ)以及碱(Ⅲ)在相应的溶剂中进行萃取反应过夜,从而得到多取代1,3,4-噻二嗪类化合物(Ⅳ),反应在室温(25℃)下进行,所得目标产物通过硅胶色谱柱层析的方法纯化(石油醚/乙酸乙酯为洗脱剂)。反应式为:
其中:
R1为单取代或多取代芳环(取代基可为卤素、烷氧基、烷基)、杂环、C1-C5链烷烃、苯丙烯。
R2为单取代或多取代芳环(取代基可为卤素、硝基、烷氧基、烷基)。
具体制备步骤如下:
(1)将α-氯代腙Ⅰ与2,5-二羟基-1,4-二噻烷Ⅱ及碱Ⅲ在溶剂中进行环合反应,反应在室温(25℃)进行,反应时间为3~12小时,其中α-氯代腙、2,5-二羟基-1,4-二噻烷、碱的摩尔比为1:1.5:2;所用碱可以是无机碱和有机碱,通常是用三乙胺。
(2)步骤(1)所得的反应液用溶剂萃取后,所得的有机层(位于下层)经洗涤(用饱和食盐水洗涤)后干燥,过滤,旋转蒸发仪浓缩;所用的溶剂可以是非极性溶剂和极性溶剂,极性溶剂通常为二氯甲烷、甲醇、乙腈、1,4-二氧六环、N,N-二甲基甲酰胺等;非极性溶剂通常为乙醚、四氯化碳等;
(3)将步骤(2)所得浓缩物进行硅胶柱层析分离,得到多取代1,3,4-噻二嗪类化合物Ⅳ。硅胶柱层析条件为:洗脱液体积比为石油醚:乙酸乙酯=5:1。
反应式如下:
其中R1和R2的定义同上。
所述的多取代1,3,4-噻二嗪类化合物为如下任一化合物:
2,4-二苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇(实施例1)
2-(4-溴苯基)-4-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇(实施例2)
2-(4-氯苯基)-4-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇(实施例3)
2-(4-硝基苯基)-4-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇(实施例4)
2-(4-甲氧基苯基)-4-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇(实施例5)
4-(4-氯苯基)-2-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇(实施例6)
4-(4-溴苯基)-2-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇(实施例7)
2-(3-溴苯基)-4-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇(实施例8)
(E)-4-苯基-2-苯乙烯-5,6-二氢-4H-1,3,4-噻二嗪-5-醇(实施例9)
2-(呋喃-2-基)-4-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇的制备(实施例10)
4-(4-甲氧基苯基)-2-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇的制备(实施例11)
4-苯基-2-丙基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇的制备(实施例12)
4-苯基-2-(吡啶-3-基) -5,6-二氢-4H-1,3,4-噻二嗪-5-醇的制备(实施例13)。
发明人通过将α-氯代腙类化合物与2,5-二羟基-1,4-二噻烷以及碱在室温条件下进行一锅法反应,合成了一系列1,3,4-噻二嗪类化合物(如通式所示)。本合成方法条件温和,收率高,原料廉价易得,为高效合成1,3,4-噻二嗪类化合物提供了一种简单易行的方法,本发明的合成方法未见文献报道。
本发明所提供的是一类简单、快速、多元化的构建1,3,4-噻二嗪类化合物的方法,即将α-氯代腙类化合物与2,5-二羟基-1,4-二噻烷以及碱在室温条件下进行反应。与现有的1,3,4-噻二嗪类化合物的合成方法相比较,该方法有以下优点:
(1)反应所用原料α-氯代腙类化合物很容易制备,2,5-二羟基-1,4-二噻烷及碱均廉价易得;
(2)反应条件温和,无需高温高压及惰性气体保护,只需在室温搅拌即可反应;
(3)反应无需任何昂贵添加剂(例如各类金属催化剂等),只需使用价格低廉且比较常见的有机碱三乙胺提供反应所需的碱性条件即可;
(4)反应适用范围广泛,不仅能够应用到芳香环1,3,4-噻二嗪类化合物的合成,而且能够应用到杂环及脂肪族1,3,4-噻二嗪类化合物的合成;
(5)反应为“一锅法”,步骤简单易操作。
(6)反应收率高,绝大多数反应产率在85%以上。
具体实施方式
本发明结合实施例作进一步的说明。
实施例1:2,4-二苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇的制备
1、原料(Z)-N'-苯基氯代苯腙的制备:
在250ml圆底烧瓶中加入N-氯代琥珀酰亚胺1.33g(10mmol),氮气保护下加入干燥的二氯甲烷70ml,冰浴搅拌,然后用注射器加入二甲基硫醚1.1g(18mmol),反应体系中立刻有白色沉淀产生,继续搅拌5min后将体系冷却至-40℃,然后用注射器加入苯甲醛苯腙1.2g(6mmol)的二氯甲烷溶液30ml,TLC监测反应终点。结束反应后,将体系置于冰水浴中继续反应1h,再用冰水淬灭。淬灭后的反应液用二氯甲烷(25mlx3)萃取,有机相用饱和食盐水(25mlx2)洗涤,无水硫酸钠干燥,过滤,滤液旋干后经柱层析分离得到N-苯基氯代苯腙0.95g,产率69%。白色固体。mp. 240-243°C; 1H NMR (400 MHz, CDCl3) δ7.60 (q,2H),7.30 (d,3H),7.02-7.04 (m ,J=2,8 Hz, 2H),7.00(m,1H), 6.62 (t ,1H),6.46 (t ,2H); 13C NMR (100MHz,CDCl3) δ155.0,143.3,131.2,129.4,128.9,118.4,116.3;IR(KBr): 3304, 3051, 1598, 752。
2、2,4-二苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇的制备:
将(Z)-N'-苯基氯代苯腙230mg(1.0mmol),2,5-二羟基-1,4-二噻烷228mg(1.5mmol),三乙胺0.28ml(2.0 mmol)加至反应瓶中,再加入5ml二氯甲烷,室温(25℃)搅拌8h,待薄层层析色谱(TLC)检测原料消失,减压蒸除溶剂,粗产品经柱层析纯化(洗脱剂:石油醚/乙酸乙酯=5:1)得到白色固体257mg,产率95%。
该2,4-二苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇的结构式为:
1H NMR (500 MHz, CDCl3) δ 7.90 (dd, J = 5.3, 3.4 Hz, 2H), 7.52 (d, J =7.9 Hz, 2H), 7.44-7.37 (m, 5H), 7.06 (t, J = 7.3 Hz, 1H), 5.78-5.71 (m, 1H),3.29 (dd, J = 12.7, 3.5 Hz, 1H), 3.23 (d, J = 11.3 Hz, 1H), 3.13 (dd, J =12.7, 1.7 Hz, 1H).13C NMR (125 MHz, CDCl3) δ 146.33, 137.34, 131.77, 129.16,129.04, 128.47, 125.66, 122.07, 115.86, 70.34, 30.18. HRMS (ESI): m/z calcdfor C15H15N2OS[M+H]+:271.0900, found: 271.0906。
以下为不同条件的对照实验:
对比例1-1、将25℃搅拌反应过夜改成0℃搅拌反应8h,其余同实施例1。得到白色固体状产物2,4-二苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇95mg,产率35%。
对比例1-2、将25℃搅拌反应过夜改成45℃搅拌反应8h,其余同实施例1。得到白色固体状产物2,4-二苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇257mg,产率95%。
对比例1-3、将三乙胺由2当量改成1当量,其余同实施例1。得到白色固体状产物2,4-二苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇246mg,产率91%。
对比例1-4、将三乙胺由2当量改成3当量,其余同实施例1。得到白色固体状产物2,4-二苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇257mg,产率95%。
对比例1-5、用N,N-二甲基甲酰胺代替二氯甲烷,其余同实施例1。得到白色固体状产物2,4-二苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇216 mg,产率80%。
对比例1-6、用1,4-二氧六环代替二氯甲烷,其余同实施例1。得到白色固体状产物2,4-二苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇0mg,产率为0。
对比例1-7、用甲醇代替二氯甲烷,其余同实施例1。得到白色固体状产物2,4-二苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇243mg,产率90%。
对比例1-8、用乙腈代替二氯甲烷,其余同实施例1。得到白色固体状产物2,4-二苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇221mg,产率82%。
对比例1-9、反应体系中不加入三乙胺,其余同实施例1。得到白色固体状产物2,4-二苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇13mg,产率5%。
对比例1-10、用碳酸钾(2.0 mmol)代替三乙胺,其余同实施例1。得到白色固体状产物2,4-二苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇194mg,产率72%。
对比例1-11、用碳酸铯(2.0 mmol)代替三乙胺,其余同实施例1。得到白色固体状产物2,4-二苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇203mg,产率75%。
对比例1-12、用氢氧化钠(2.0 mmol)代替三乙胺,其余同实施例1。得到白色固体状产物2,4-二苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇248mg,产率92%。
对比例1-13、用氢化钠(2.0 mmol)代替三乙胺,其余同实施例1。得到白色固体状产物2,4-二苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇224mg,产率83%。
对比例1-14、用甲醇钠 (2.0 mmol)代替三乙胺,其余同实施例1。得到白色固体状产物2,4-二苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇238mg,产率88%。
对比例1-15、用有机碱DBU (2.0 mmol)代替三乙胺,其余同实施例1。得到白色固体状产物2,4-二苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇217mg,产率78%。
对比例1-16、反应2h替代反应8h,其余同实施例1。得到白色固体状产物2,4-二苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇103mg,产率38%。
对比例1-17、反应6h替代反应8h,其余同实施例1。得到白色固体状产物2,4-二苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇221mg,产率82%。
实施例2、2-(4-溴苯基)-4-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇的制备
以(Z)-4-溴-N'-苯基氯代苯腙代替(Z)-N'-苯基氯代苯腙,摩尔量不变,其余同实施例1。得到2-(4-溴苯基)-4-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇323 mg,收率93%。
其结构式为:
1H NMR (500 MHz, DMSO) δ 7.61 (s, 1H), 7.58 (dd, J = 8.1, 1.0 Hz,2H), 7.39 (dd, J = 10.7, 4.9 Hz, 2H), 7.25-7.19 (m, 1H), 2.76 (q, J = 7.5 Hz,2H), 1.22 (t, J = 7.5 Hz, 3H).13C NMR (125 MHz, DMSO) δ 134.78, 134.52,128.88, 126.60, 126.19, 19.49, 14.61. HRMS (ESI): m/z calcd for C15H14BrN2OS[M+H]+:349.0005, found: 349.0007.
实施例3、2-(4-氯苯基)-4-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇的制备
以(Z)-4-氯-N'-苯基氯代苯腙代替(Z)-N'-苯基氯代苯腙,摩尔量不变,其余同实施例1。得到2-(4-氯苯基)-4-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇271 mg,收率89%。
其结构式为:
1H NMR (500 MHz, CDCl3) δ 7.87-7.76 (m, 2H), 7.50 (d, J = 7.9 Hz, 2H),7.44-7.31 (m, 4H), 7.07 (t, J = 7.3 Hz, 1H), 5.74 (ddd, J = 11.2, 3.4, 1.7Hz, 1H), 3.29 (dd, J = 12.8, 3.5 Hz, 1H), 3.19 (d, J = 11.2 Hz, 1H), 3.12(dd, J = 12.7, 1.7 Hz, 1H).13C NMR (125 MHz, CDCl3) δ 146.20, 135.81, 134.84,130.53, 129.20, 128.63, 126.81, 122.30, 115.94, 70.36, 30.09. HRMS (ESI): m/zcalcd for C15H14ClN2OS[M+H]+:305.0510, found: 305.0506。
实施例4、2-(4-硝基苯基)-4-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇的制备
以(Z)-4-硝基-N'-苯基氯代苯腙代替(Z)-N'-苯基氯代苯腙,摩尔量不变,其余同实施例1。得到2-(4-硝基苯基)-4-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇的制备283 mg,收率90%。其结构式为:
1H NMR (500 MHz, CDCl3) δ 8.30-8.22 (m, 2H), 8.07-7.99 (m, 2H), 7.52(dd, J = 8.7, 0.9 Hz, 2H), 7.46-7.38 (m, 2H), 7.12 (dd, J = 10.5, 4.1 Hz,1H), 5.77 (ddd, J = 11.2, 3.4, 1.7 Hz, 1H), 3.34 (dt, J = 12.6, 6.3 Hz, 1H),3.21 (d, J = 11.3 Hz, 1H), 3.13 (dd, J = 12.8, 1.7 Hz, 1H).13C NMR (125 MHz,CDCl3) δ 147.60, 145.97, 143.11, 129.30, 128.92, 125.92, 123.77, 123.05,116.36, 70.67, 29.76.HRMS (ESI): m/z calcd for C15H14N3O3S[M+H]+:316.0750,found:316.0757。
实施例5、2-(4-甲氧基苯基)-4-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇的制备
以(Z)-4-甲氧基-N'-苯基氯代苯腙代替(Z)-N'-苯基氯代苯腙,摩尔量不变,其余同实施例1。得到2-(4-甲氧基苯基)-4-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇246 mg,收率82%。其结构式为:
1H NMR (500 MHz, CDCl3) δ 7.85-7.80 (m, 2H), 7.50 (d, J = 7.9 Hz, 2H),7.38 (dd, J = 10.7, 5.3 Hz, 2H), 7.04 (t, J = 7.3 Hz, 1H), 6.97-6.94 (m, 2H),5.76-5.71 (m, 1H), 3.99-3.98 (m, 1H), 3.87 (s, 3H), 3.27 (dd, J = 12.7, 3.5Hz, 1H), 3.20 (d, J = 11.2 Hz, 1H), 3.14 (dd, J = 12.7, 1.7 Hz, 1H). 13C NMR(125 MHz, CDCl3) δ 160.45, 146.42, 131.83, 130.18, 129.12, 127.07, 121.81,115.72, 113.83, 70.28, 55.41, 30.42. HRMS (ESI): m/z calcd for C16H17N2S2O[M+H]+:301.1005 found: 301.1015。
实施例6、4-(4-氯苯基)-2-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇的制备
以N'-(4-氯苯基)氯代苯腙代替(Z)-N'-苯基氯代苯腙,摩尔量不变,其余同实施例1。得到4-(4-氯苯基)-2-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇261 mg,收率86%。其结构式为:
1H NMR (500 MHz, CDCl3) δ 7.90-7.85 (m, 2H), 7.46-7.39 (m, 5H), 7.35-7.30 (m, 2H), 5.67 (d, J = 9.7 Hz, 1H), 3.27 (dd, J = 12.8, 3.5 Hz, 1H), 3.24(d, J = 11.3 Hz, 1H), 3.13 (dd, J = 12.8, 1.8 Hz, 1H). 13C NMR (125 MHz,CDCl3) δ 144.95, 137.12, 132.71, 129.25, 129.02, 128.51, 127.09, 125.69,117.02, 70.43, 30.22.HRMS (ESI): m/z calcd for C15H14ClN2OS[M+H]+: 305.0510,found: 305.0510。
实施例7、4-(4-溴苯基)-2-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇的制备
以(Z)-N'-(4-溴苯基)氯代苯腙代替(Z)-N'-苯基氯代苯腙,摩尔量不变,其余同实施例1。得到4-(4-溴苯基)-2-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇310 mg,收率89%。其结构式为:
1H NMR (500 MHz, CDCl3) δ 7.90-7.81 (m, 2H), 7.50-7.36 (m, 7H), 5.67(ddd, J = 11.4, 3.1, 1.6 Hz, 1H), 3.27 (dd, J = 12.8, 3.5 Hz, 1H), 3.22 (d, J= 11.5 Hz, 1H), 3.13 (dd, J = 12.8, 1.8 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ145.39, 137.10, 132.83, 131.94, 129.28, 128.52, 125.71, 117.40, 114.58,70.37, 30.23.HRMS (ESI): m/z calcd for HRMS (ESI): m/z calcd for C15H14BrN2OS[M+H]+:349.0005, found: 349.0011。
实施例8、2-(3-溴苯基)-4-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇的制备
以(Z)-3-溴-N'-苯基氯代苯腙代替(Z)-N'-苯基氯代苯腙,摩尔量不变,其余同实施例1。得到2-(3-溴苯基)-4-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇296 mg,收率85%。其结构式为:
1H NMR (500 MHz, CDCl3) δ 8.03 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.50(d, J = 8.0 Hz, 3H), 7.40 (t, J = 7.9 Hz, 2H), 7.28 (dd, J = 9.4, 6.4 Hz,1H), 7.09 (t, J = 7.3 Hz, 1H), 5.76-5.67 (m, 1H), 3.26 (dd, J = 9.8, 2.6 Hz,1H), 3.24 (d, J = 5.4 Hz, 1H), 3.09 (dd, J = 12.7, 1.0 Hz, 1H). 13C NMR (125MHz, CDCl3) δ 146.17 (s), 139.34, 131.80, 130.12, 129.92, 129.23, 128.53,124.20, 122.76, 122.44, 116.07, 70.49, 30.00.HRMS (ESI): m/z calcd forC15H14BrN2OS[M+H]+:349.0005, found: 349.0015。
实施例9、(E)-4-苯基-2-苯乙烯-5,6-二氢-4H-1,3,4-噻二嗪-5-醇的制备
以(Z)-N'-苯基氯代肉桂腙代替(Z)-N'-苯基氯代苯腙,摩尔量不变,其余同实施例1。得到(E)-4-苯基-2-苯乙烯-5,6-二氢-4H-1,3,4-噻二嗪-5-醇181 mg,收率61%。其结构式为:
1H NMR (500 MHz, CDCl3)1H NMR (500 MHz, CDCl3) δ 7.54-7.47 (m, 4H),7.38 (dd, J = 11.8, 4.3 Hz, 4H), 7.32-7.29 (m, 1H), 7.07 (dd, J = 10.5, 4.1Hz, 1H), 7.02 (s, 2H), 5.70 (ddd, J = 11.4, 3.4, 1.7 Hz, 1H), 3.27 (d, J =11.5 Hz, 1H), 3.22 (dd, J = 12.8, 3.5 Hz, 1H), 3.08 (dd, J = 12.8, 1.7 Hz,1H). 13C NMR (125 MHz, CDCl3) δ 146.07, 136.37, 132.69, 131.06, 129.15,128.78, 128.20, 127.97, 126.82, 122.40, 116.12, 71.03, 29.67. HRMS (ESI): m/zcalcd for C17H17N2OS[M+H]+:297.1056, found: 297.1050。
实施例10、2-(呋喃-2-基)-4-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇的制备
以(Z)-N'-苯基呋喃-2-氯代腙代替(Z)-N'-苯基氯代苯腙,摩尔量不变,其余同实施例1。得到2-(呋喃-2-基)-4-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇226 mg,收率87%。其结构式为:
1H NMR (500 MHz, CDCl3) δ 7.50 (ddd, J = 9.6, 5.1, 0.7 Hz, 3H), 7.40-7.36 (m, 2H), 7.09-7.03 (m, 1H), 6.74 (dd, J = 3.4, 0.7 Hz, 1H), 6.50 (dd, J= 3.4, 1.8 Hz, 1H), 5.73 (d, J = 7.9 Hz, 1H), 3.25 (d, J = 3.2 Hz, 1H), 3.23(d, J = 3.3 Hz, 1H), 3.15 (d, J = 12.8 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ150.47, 146.10, 143.19, 129.18, 124.12, 122.28, 116.02, 111.55, 108.14,70.87, 30.01. HRMS (ESI): m/z calcd for C13H13N2O2S [M+H]+ :261.0692, found:261.0690。
实施例11、4-(4-甲氧基苯基)-2-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇的制备
以(Z)-N'-(4-甲氧基苯基)氯代苯腙代替(Z)-N'-苯基氯代苯腙,摩尔量不变,其余同实施例1。得到4-(4-甲氧基苯基)-2-苯基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇310 mg,收率92%。其结构式为:
1H NMR (500 MHz, CDCl3) δ 7.84-7.75 (m, 2H), 7.43-7.34 (m, 4H), 7.00(d, J = 2.8 Hz, 1H), 6.90 (dd, J = 8.8, 2.8 Hz, 1H), 5.37 (d, J = 4.6 Hz,1H), 3.83 (s, 3H), 3.67 (dd, J = 12.2, 1.8 Hz, 1H), 3.28 (dd, J = 12.2, 3.8Hz, 1H), 3.19 (d, J = 9.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 158.10, 137.87,137.16, 134.32, 129.29, 129.09, 128.82, 128.37, 125.37, 115.09, 113.62,70.54, 55.80, 31.27. HRMS (ESI): m/z calcd for C16H17N2O2S [M+H]+ :301.1005,found: 301.1008。
实施例12、4-苯基-2-丙基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇的制备
以(Z)-N'-苯基氯代丁腙代替(Z)-N'-苯基氯代苯腙,摩尔量不变,其余同实施例1。得到4-苯基-2-丙基-5,6-二氢-4H-1,3,4-噻二嗪-5-醇208 mg,收率88%。其结构式为:
1H NMR (500 MHz, CDCl3) δ 7.40-7.27 (m, 4H), 7.01 (dd, J = 9.6, 4.3Hz, 1H), 5.69-5.56 (m, 1H), 3.22-3.08 (m, 3H), 2.50-2.32 (m, 2H), 1.82-1.69(m, 2H), 1.06-0.98 (m, 3H). 13C NMR (125 MHz, CDCl3) δ 146.52, 136.21, 129.10,121.59, 115.79, 69.32, 41.35, 30.34, 20.72, 13.63.HRMS (ESI): m/z calcd forC12H17N2OS [M+H]+ :237.1056, found: 237.1066。
实施例13、4-苯基-2-(吡啶-3-基) -5,6-二氢-4H-1,3,4-噻二嗪-5-醇的制备
以(Z)-N'-苯基吡啶-3-氯代腙代替(Z)-N'-苯基氯代苯腙,摩尔量不变,其余同实施例1。得到4-苯基-2-(吡啶-3-基) -5,6-二氢-4H-1,3,4-噻二嗪-5-醇203 mg,收率85%。其结构式为:
1H NMR (500 MHz, CDCl3) δ 8.91 (d, J = 2.2 Hz, 1H), 8.37 (dd, J = 4.8,1.5 Hz, 1H), 8.05-7.87 (m, 1H), 7.52-7.45 (m, 2H), 7.36 (t, J = 8.0 Hz, 2H),7.19 (dd, J = 7.9, 4.9 Hz, 1H), 7.05 (t, J = 7.3 Hz, 1H), 5.78 (dd, J = 3.2,1.6 Hz, 1H), 5.48 (s, 1H), 3.29 (dd, J = 12.7, 3.3 Hz, 1H), 3.10 (dd, J =12.7, 1.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 148.92, 146.54, 146.13, 133.20,132.75, 129.39, 129.18, 123.16, 122.19, 115.80, 70.24, 30.13. HRMS (ESI): m/zcalcd for C14H14N3OS [M+H]+ :272.0852, found: 272.0856。
Claims (3)
1.一种多取代1,3,4-噻二嗪类化合物的制备方法,其特征在于,通过将α-氯代腙类化合物(Ⅰ)与2,5-二羟基-1,4-二噻烷(Ⅱ)以及碱(Ⅲ)在溶剂中进行萃取反应过夜,得到多取代1,3,4-噻二嗪类化合物(Ⅳ),反应温度25℃,所用碱是无机碱或有机碱,所用的溶剂是非极性溶剂或极性溶剂,所得化合物Ⅳ通过硅胶色谱柱层析的方法纯化,石油醚/乙酸乙酯为洗脱剂,反应式为:
其中:
R1为单取代或多取代芳环、杂环、C1-C5链烷烃,其中单取代或多取代的取代基选用卤素、烷氧基或烷基;
R2为单取代或多取代芳环,取代基选用卤素、硝基、烷氧基或烷基。
2.根据权利要求1所述的一种多取代1,3,4-噻二嗪类化合物的制备方法,其特征在于,具体通过以下步骤实现:
(1)将α-氯代腙Ⅰ与2,5-二羟基-1,4-二噻烷Ⅱ及碱Ⅲ在溶剂中进行环合反应,反应温度25℃,反应时间为3~12小时,其中α-氯代腙、2,5-二羟基-1,4-二噻烷、碱的摩尔比为1:1.5:2;
(2)步骤(1)所得的反应液用溶剂萃取后,所得的有机层经用饱和食盐水洗涤后干燥,过滤,旋转蒸发仪浓缩;所用的溶剂选用非极性溶剂或极性溶剂;
(3)将步骤(2)所得浓缩物进行硅胶柱层析分离,得到多取代1,3,4-噻二嗪类化合物Ⅳ,硅胶柱层析洗脱液体积比为石油醚:乙酸乙酯=5:1,
反应式如下:
其中R1和R2的定义同权利要求1。
3.根据权利要求2所述的一种多取代1,3,4-噻二嗪类化合物的制备方法,其特征在于,步骤(2)极性溶剂选用二氯甲烷、甲醇、乙腈、1,4-二氧六环或N,N-二甲基甲酰胺,非极性溶剂选用乙醚或四氯化碳。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510162591.7A CN104844538B (zh) | 2015-04-08 | 2015-04-08 | 一种多取代1,3,4‑噻二嗪类化合物及制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510162591.7A CN104844538B (zh) | 2015-04-08 | 2015-04-08 | 一种多取代1,3,4‑噻二嗪类化合物及制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104844538A CN104844538A (zh) | 2015-08-19 |
CN104844538B true CN104844538B (zh) | 2017-04-12 |
Family
ID=53844574
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510162591.7A Expired - Fee Related CN104844538B (zh) | 2015-04-08 | 2015-04-08 | 一种多取代1,3,4‑噻二嗪类化合物及制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN104844538B (zh) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102040595B (zh) * | 2009-10-22 | 2012-12-12 | 北京协和药厂 | 1,3,4-噻二嗪衍生物,其制备方法和用途 |
-
2015
- 2015-04-08 CN CN201510162591.7A patent/CN104844538B/zh not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
CN104844538A (zh) | 2015-08-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2018136001A1 (en) | Process for preparing apalutamide | |
CN109081807B (zh) | 一种制备三取代4-氨基咔唑类和二取代1-氨基二苯并[b,d]噻吩类化合物的方法 | |
CN107954906A (zh) | 一种芳基磺酰叔胺类化合物的合成方法 | |
JP2009522210A (ja) | 2,2’,6,6’−テトラオキサゾリンビフェニル配位子およびその調製方法 | |
CN104817515A (zh) | 一种苯取代恶二唑化合物的制备方法 | |
CN104844538B (zh) | 一种多取代1,3,4‑噻二嗪类化合物及制备方法 | |
JP2009046408A (ja) | ジハロ多環芳香族化合物、ピロリル多環芳香族化合物、及びそれらの製造方法 | |
CN104829547A (zh) | 一种取代三唑化合物的制备方法 | |
CN104592144A (zh) | 制备噁唑衍生物的新方法 | |
CN109503547B (zh) | 苯并二硫环戊二烯衍生物的制备方法 | |
CN108929337B (zh) | 一种4,5-二氢噻唑并[5,4-c]喹啉-2-胺的制备方法 | |
CN115286594B (zh) | 一种以s8为原料合成醌并噻唑类化合物的方法 | |
JP5209426B2 (ja) | 1,2,4−オキサジアゾール誘導体の製造方法 | |
CN105001117A (zh) | 一种含氯叠氮化合物的合成方法 | |
KR102689384B1 (ko) | 엔잘루타미드를 제조하는 방법 | |
JP2010202523A (ja) | 芳香族化合物の製造方法 | |
CN105228987A (zh) | 用于制备哒嗪化合物的方法 | |
CN110563658B (zh) | 一种1,5-苯并二氮杂卓类化合物的合成方法 | |
CN116253697B (zh) | 一种二氯萘醌和甲胺类化合物为原料合成醌并噻唑类化合物的方法 | |
JP5900675B2 (ja) | ピロリル多環芳香族化合物の製造方法 | |
CN113372344B (zh) | 一种氯代六元含氮杂环并咪唑类化合物的合成方法 | |
CN116253697A (zh) | 一种二氯萘醌和甲胺类化合物为原料合成醌并噻唑类化合物的方法 | |
Okada et al. | NAPHTHO [l, Ze][l, 4] DITHIEPlNS AND NAPHTH0 | |
CN104974095B (zh) | 2,4,5‑多取代咪唑类化合物及制备方法 | |
CN114249677B (zh) | 一种利鲁唑中间体化合物及其制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
EXSB | Decision made by sipo to initiate substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20170412 Termination date: 20190408 |