CN103601699A - 1,3,4-thiadiazol-2-amide derivatives and preparation method thereof - Google Patents

1,3,4-thiadiazol-2-amide derivatives and preparation method thereof Download PDF

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CN103601699A
CN103601699A CN201310541288.9A CN201310541288A CN103601699A CN 103601699 A CN103601699 A CN 103601699A CN 201310541288 A CN201310541288 A CN 201310541288A CN 103601699 A CN103601699 A CN 103601699A
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organic solvent
bromo
thiadiazoles
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朱海亮
李玉静
秦亚娟
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Nanjing University
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Nanjing University
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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
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms

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Abstract

The invention discloses 1,3,4-thiadiazol-2-amide derivatives. The 1,3,4-thiadiazol-2-amide derivatives are characterized by having the general formula which is specified in the specification, wherein R1, R2 and R3 are selected from hydrogen and methoxyl groups; R4 is selected from hydrogen and bromine; R5, R6 and R7 are selected from hydrogen, methoxyl groups and halogen; R8 is selected from hydrogen and bromine. The method for preparing the 1,3,4-thiadiazol-2-amide derivatives according to the claim 1 comprises the following steps specified in the specification.

Description

One class 1,3,4-thiadiazoles-2-amide derivatives and preparation method thereof
Technical field
The present invention relates to a class 1,3,4-thiadiazoles-2-amide derivatives and preparation method thereof.
Background technology
Styryl-1,3,4-thiadiazole micromolecular compound has active widely in chemistry and biology field, be day by day subject to people's attention.Styryl-1 being in the news, the effect such as that 3,4-thiadiazoles derivative has is antitumor, antibacterial, anti-inflammatory, antidepressant.1,3,4-thiadiazoles support is one and acts on tectonic block widely, and it has been used to synthetic various useful bioactive compoundss.The inhibition of the generation of tumour and the apoptotic signal of tumour cell own is closely bound up, therefore apoptosis plays an important role in the chemotherapy of tumour, for such compound, according to 1,3, the modification of 4-Thiadiazole, different mechanism are assigned with, wherein by reconstituted cell apoptosis reach treatment tumour object be very likely.As known, amide derivatives has biological activity widely, comprises anti-tumor activity.Therefore, by them, both combine for we, and design has been synthesized a series of 1,3, and 4-thiadiazoles-2-amide derivatives, has certain value.
Summary of the invention
The object of the present invention is to provide a class 1,3,4-thiadiazoles-2-amide derivatives and preparation method thereof.
Technical scheme of the present invention is as follows:
1. a class 1,3,4-thiadiazoles-2-amide derivatives, is characterized in that they have following general formula:
Figure BSA0000097152480000011
In formula, R 1, R 2, R 3be selected from hydrogen, methoxyl group; R 4be selected from hydrogen, bromine;
R 5, R 6, R 7be selected from hydrogen, methoxyl group, halogen; R 8be selected from hydrogen, bromine.
2. prepare a class 1,3 claimed in claim 1 for one kind, 4-thiadiazoles-2-amide derivatives method for making, they are become by the following step:
Step 1. is in stink cupboard, to the mixture that adds compound 1 and NBS (N-bromo-succinimide) in flask, be dissolved in appropriate organic solvent, heated and stirred for some time, TLC follows the tracks of reaction, after reacting completely, solution with water is washed multipass, use anhydrous desiccant dryness, pressure reducing and steaming organic solvent obtains crude product, and crude product obtains yellow crystals 2 after recrystallization.
Step 2., in stink cupboard, is mixed compound 2 obtained above and propanedioic acid, adds a certain amount of organic solvent dissolution, drip appropriate piperidines, heated and stirred for some time, TLC follows the tracks of reaction, after question response is complete, pressure reducing and steaming organic solvent, a small amount of dissolving without good solvent for remaining mixture, then pour a large amount of saturated aqueous common salts into it, by sedimentation and filtration out, with low polar solvent, wash twice again, final drying, obtains white powder 3.
Step 3., in stink cupboard, adds a certain amount of compound 3, thiosemicarbazide and POCl in flask 3mixture, heated and stirred is (TLC follows the tracks of reaction) after for some time, reaction system is cooled to room temperature, with a certain amount of frozen water cancellation, be poured in the frozen water of a large amount of volumes again, with alkali, regulate pH value to 5-10, decompress filter obtains yellow solid, dry, the method by column chromatography or recrystallization obtains white powder 4 to its purifying.
Step 4. is in stink cupboard, by synthetic compound 4, containing various substituent phenylformic acid, HoBt (I-hydroxybenzotriazole), EDCI (1-ethyl-3-(3-dimethylamine propyl) carbodiimide) is appropriate, is dissolved in appropriate organic solvent reacting by heating for some time.Reactant is washed by acid solution, and alkali lye is washed, and inorganic salt solution is washed, and uses anhydrous desiccant dryness, boils off organic solvent and obtains crude product.Finally the method by column chromatography obtains target compound 5 to its purifying.
Embodiment:
Embodiment mono-: the bromo-N-of (E)-2-(5-(2-bromo-3,4,5-trimethoxy styryl)-1,3,4-thiadiazoles-2-yl)-3,4, the preparation of 5-trimethoxy-benzamide
In stink cupboard, in 100mL single necked round bottom flask, add 3,4,5-Trimethoxybenzaldehyde (5.0g, 25.4mmoL), with the CHCl of 50mL 3dissolve, then add NBS (5.44g, 30.5mmoL) in flask, at 90 ℃, after 3h, react completely, be cooled to room temperature, solution with water is washed 3 times, with anhydrous sodium sulfate drying, and evaporated under reduced pressure, ether recrystallization.Get the solid (2g, 7.28mmoL) that above-mentioned recrystallization goes out and join in 250mL single necked round bottom flask, 50mL pyridine dissolves it completely, add propanedioic acid (0.916g, 8.80mmol), then add piperidines (90.9 μ L, 0.918mmol), be heated to 80-90 ℃, stir 24h.With oil pump, pump pyridine, with a small amount of DMF, remaining mixture is dissolved, under stirring, pouring a large amount of saturated aqueous common salts into again to it has Precipitation.By sedimentation and filtration, with normal hexane, to wash three times, last vacuum-drying, generates the styracin replacing.Get solid obtained above (1.5g, 4.73mmoL) and join in 100mL single necked round bottom flask, add the thiosemicarbazide of 0.43g, in stink cupboard to the POCl that adds 15mL in flask 3, react after about 1h at 75 ℃, standingly treat that it is cooling, then with about 20mL frozen water, carry out cancellation, and then reactant is poured in 200mL frozen water, the KOH with 50% regulates pH value to 8-9, and the solid filtering of separating out is used anhydrous alcohol solution recrystallization after drying.Get the solid (150mg, 0.4mmol) that above-mentioned recrystallization obtains, join in 50mL single necked round bottom flask, the 2-bromo-3 that the amount such as adds, 4,5-trimethoxybenzoic acid (117.3mg, 0.4mmol), EDCI (1-ethyl-3-(3-dimethylamine propyl) carbodiimide) (77.25mg, 0.4mmol), HoBt (I-hydroxybenzotriazole) (54.45mg, 0.4mmol), be dissolved in 20mL methylene dichloride, 50 ℃ of heating reflux reactions spend the night.Reactant is washed (5mL) with 1M HCl, buck is washed (3 * 5mL), and salt washing (5mL), dewaters by anhydrous sodium sulphate, after underpressure distillation, obtain crude product, crude product is through column chromatography [elutriant: V (methylene dichloride): V (ethyl acetate)=5:1] white solid of purifying to obtain.Productive rate 40.6%.m.p179～180 ℃. 1h NMR (DMSO-d 6, 300MHz) δ: 13.17 (s, 1H), 7.68 (d, J=5.4Hz, 2H), 7.44 (s, 1H), 7.24 (s, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H) .MS (ESI): 643.96 ([M+H] +) .Anal.calc.for C 23h 23br 2n 3o 7s:C, 42.81; H, 3.59; N, 6.51%; Found:C, 42.80; H, 3.60; N, 6.52%.
Embodiment bis-: (E)-N-(5-(2-bromo-3,4,5-trimethoxy styryl)-1,3,4-thiadiazoles-2-yl)-3,4, the preparation of 5-trimethoxy-benzamide
Figure BSA0000097152480000041
Preparation method is with embodiment mono-, with 3,4,5-trimethoxybenzoic acid, replaces 2-bromo-3,4, and 5-trimethoxybenzoic acid, obtains white powder target compound.Productive rate 45.5%.m.p232～233 ℃. 1hNMR (DMSO-d 6, 300MHz) δ: 13.15 (s, 1H), 7.67 (s, 2H), 7.53 (s, 2H), 7.43 (s, 1H), 3.93 (s, 3H), 3.90 (s, 6H), 3.83 (s, 3H), 3.82 (s, 3H), 3.77 (s, 3H) .MS (ESI): 567.05 ([M+H] +) .Anal.calc.for C 23h 24brN 3o 7s:C, 48.77; H, 4.27; N, 7.42%; Found:C, 48.78; H, 4.26; N, 7.45%.
Embodiment tri-: (E) preparation of N-(5-(2-bromo-3,4,5-trimethoxy styryl)-1,3,4-thiadiazoles-2-yl)-2-methoxy benzamide
Figure BSA0000097152480000051
Preparation method is with embodiment mono-, with o-methoxybenzoic acid, replaces 2-bromo-3,4, and 5-trimethoxybenzoic acid, obtains white powder target compound.Productive rate 56.3%.m.p204～205 ℃. 1h NMR (DMSO-d 6, 300MHz) δ: 12.43 (s, 1H), 7.70 (t, J=6.12Hz, 2H), 7.58～7.65 (m, 2H), 7.44 (s, 1H), 7.24 (d, J=6.24Hz, 1H), 7.11 (t, J=5.55Hz, 1H), 3.93 (s, 6H), 3.83 (s, 3H), 3.82 (s, 3H) .MS (ESI): 506.03 ([M+H] +) .Anal.calc.for C 21h 20brN 3o 5s:C, 49.81; H, 3.98; N, 8.30%; Found:C, 49.82; H, 3.97; N, 8.29%.
Embodiment tetra-: (E)-N-(5-(2-bromo-3,4,5-trimethoxy styryl)-1,3,4-thiadiazoles-2-yl)-3, the preparation of 4-dimethoxy benzamide
Preparation method is with embodiment mono-, with 3,4-dimethoxybenzoic acid, replaces 2-bromo-3,4, and 5-trimethoxybenzoic acid, obtains white powder target compound.Productive rate 59.2%.m.p262～263 ℃. 1h NMR (DMSO-d 6, 300MHz) δ: 13.01 (s, 1H), 7.82 (d, J=6.36Hz, 1H), 7.78 (s, 1H), 7.65 (s, 2H), 7.42 (s, 1H), 7.14 (d, J=6.39Hz, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H) .MS (ESI): 536.04 ([M+H] +) .Anal.calc.for C 22h 22brN 3o 6s:C, 49.26; H, 4.13; N, 7.83%; Found:C, 49.27; H, 4.12; N, 7.82%.
Embodiment five: (E) preparation of N-(5-(2-bromo-3,4,5-trimethoxy styryl)-1,3,4-thiadiazoles-2-yl)-3-methoxy benzamide
Preparation method is with embodiment mono-, with 3-methoxybenzoic acid, replaces 2-bromo-3,4, and 5-trimethoxybenzoic acid, obtains white powder target compound.Productive rate 53.2%.m.p226～227 ℃. 1h NMR (DMSO-d 6, 300MHz) δ: 13.17 (s, 1H), 7.71 (s, 2H), 7.67 (d, J=1.53Hz, 2H), 7.49 (t, J=6.12Hz, 1H), 7.43 (s, 1H), 7.24 (d, J=7.47Hz, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H) .MS (ESI): 506.03 ([M+H] +) .Anal.calc.for C 21h 20brN 3o 5s:C, 49.81; H, 3.98; N, 8.30%; Found:C, 49.80; H, 3.97; N, 8.31%.
Embodiment six: the preparation of (E)-N-(5-(2-bromo-3,4,5-trimethoxy styryl)-1,3,4-thiadiazoles-2-yl)-4-methoxy benzamide
Figure BSA0000097152480000062
Preparation method is with embodiment mono-, with 4-methoxybenzoic acid, replaces 2-bromo-3,4, and 5-trimethoxybenzoic acid, obtains white powder target compound.Productive rate 57.5%.m.p243～244 ℃. 1h NMR (DMSO-d 6, 300MHz) δ: 12.98 (s, 1H), 8.16 (s, 1H), 8.14 (s, 1H), 7.65 (d, J=2.07Hz, 2H), 7.42 (s, 1H), 7.12 (s, 1H), 7.10 (s, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H) .MS (ESI): 506.03 ([M+H] +) .Anal.calc.for C 21h 20brN 3o 5s:C, 49.81; H, 3.98; N, 8.30%; Found:C, 49.82; H, 3.97; N, 8.31%.
Embodiment seven: the preparation of the bromo-N-of (E)-2-(5-(2-bromo-3,4,5-trimethoxy styryl)-1,3,4-thiadiazoles-2-yl)-benzamide
Figure BSA0000097152480000071
Preparation method is with embodiment mono-, with 2-bromo-benzoic acid, replaces 2-bromo-3,4, and 5-trimethoxybenzoic acid, obtains white powder target compound.Productive rate 40.2%.m.p218～219 ℃. 1h NMR (DMSO-d 6, 300MHz) δ: 13.30 (s, 1H), 7.80 (d, J=6.42Hz, 1H), 7.70 (s, 1H), 7.67 (s, 1H), 7.48～7.57 (m, 2H), 7.45 (s, 1H), 3.94 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H) .MS (ESI): 553.93 ([M+H] +) .Anal.calc.for C 20h 17br 2n 3o 4s:C, 43.26; H, 3.09; N, 7.57%; Found:C, 43.25; H, 3.10; N, 7.56%.
Embodiment eight: the preparation of the bromo-N-of (E)-3-(5-(2-bromo-3,4,5-trimethoxy styryl)-1,3,4-thiadiazoles-2-yl)-benzamide
Figure BSA0000097152480000072
Preparation method is with embodiment mono-, with 3-bromo-benzoic acid, replaces 2-bromo-3,4, and 5-trimethoxybenzoic acid, obtains white powder target compound.Productive rate 47.2%.m.p279～280 ℃. 1h NMR (DMSO-d 6, 300MHz) δ: 13.29 (s, 1H), 8.34 (s, 1H), 8.12 (d, J=5.94Hz, 1H), 7.89 (d, J=5.97Hz, 1H), 7.67 (d, J=2.16Hz, 2H), 7.55 (t, J=5.91Hz, 1H), 7.43 (s, 1H), 3.93 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H) .MS (ESI): 553.93 ([M+H] +) .Anal.calc.for C 20h 17br 2n 3o 4s:C, 43.26; H, 3.09; N, 7.57%; Found:C, 43.27; H, 3.10; N, 7.56%.
Embodiment nine: the preparation of the bromo-N-of (E)-4-(5-(2-bromo-3,4,5-trimethoxy styryl)-1,3,4-thiadiazoles-2-yl)-benzamide
Figure BSA0000097152480000081
Preparation method is with embodiment mono-, with 4-bromo-benzoic acid, replaces 2-bromo-3,4, and 5-trimethoxybenzoic acid, obtains white powder target compound.Productive rate 50.2%.m.p295～296 ℃. 1h NMR (DMSO-d 6, 300MHz) δ: 13.28 (s, 1H), 8.08 (s, 1H), 8.06 (s, 1H), 7.81 (s, 1H), 7.79 (s, 1H), 7.66 (d, J=1.62Hz, 2H), 7.42 (s, 1H), 3.93 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H) .MS (ESI): 553.93 ([M+H] +) .Anal.calc.for C 20h 17br 2n 3o 4s:C, 43.26; H, 3.09; N, 7.57%; Found:C, 43.27; H, 3.08N, 7.56%.
Embodiment ten: the preparation of (E)-N-(5-(2-bromo-3,4,5-trimethoxy styryl)-1,3,4-thiadiazoles-2-yl)-3-chlorobenzamide
Figure BSA0000097152480000082
Preparation method is with embodiment mono-, with 3-chloro-benzoic acid, replaces 2-bromo-3,4, and 5-trimethoxybenzoic acid, obtains white powder target compound.Productive rate 59.2%.m.p293～294 ℃. 1h NMR (DMSO-d 6, 300MHz) δ: 13.28 (s, 1H), 8.20 (s, 1H), 8.08 (d, J=5.88Hz, 1H), 7.76 (d, J=5.94Hz, 1H), 7.68 (d, J=2.04Hz, 2H), 7.62 (t, J=5.94Hz, 1H), 7.44 (s, 1H), 3.93 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H) .MS (ESI): 509.98 ([M+H] +) .Anal.calc.forC 20h 17brClN 3o 4s:C, 47.03; H, 3.35; N, 8.23%; Found:C, 47.02; H, 3.34; N, 8.24%.
Embodiment 11: the preparation of (E)-N-(5-(2-bromo-3,4,5-trimethoxy styryl)-1,3,4-thiadiazoles-2-yl)-4-chlorobenzamide
Figure BSA0000097152480000091
Preparation method is with embodiment mono-, with 4-chloro-benzoic acid, replaces 2-bromo-3,4, and 5-trimethoxybenzoic acid, obtains white powder target compound.Productive rate 44.5%.m.p285～286 ℃. 1h NMR (DMSO-d 6, 300MHz) δ: 13.26 (s, 1H), 8.16 (s, 1H), 8.14 (s, 1H), 7.62～7.7l (m, 4H), 7.43 (s, 1H), 3.93 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H) .MS (ESI): 509.98 ([M+H] +) .Anal.calc.for C 20h 17brClN 3o 4s:C, 47.03; H, 3.35; N, 8.23%; Found:C, 47.04; H, 3.34; N, 8.24%.
Embodiment 12: the preparation of (E)-N-(5-(2-bromo-3,4,5-trimethoxy styryl)-1,3,4-thiadiazoles-2-yl)-3-fluorobenzamide
Figure BSA0000097152480000092
Preparation method is with embodiment mono-, with 3-fluorobenzoic acid, replaces 2-bromo-3,4, and 5-trimethoxybenzoic acid, obtains white powder target compound.Productive rate 48.2%.m.p273～274 ℃. 1h NMR (DMSO-d 6, 300MHz) δ: 13.28 (s, 1H), 7.98 (t, J=6.0Hz, 2H), 7.67 (d, J=1.59Hz, 3H), 7.53～7.57 (m, 1H), 7.43 (s, 1H), 3.93 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H) .MS (ESI): 494.01 ([M+H] +) .Anal.calc.for C 20h 17brFN 3o 4s:C, 48.59; H, 3.47; N, 8.50%; Found:C, 48.58; H, 3.48; N, 8.51%.
Embodiment 13: the preparation of (E)-N-(5-(2-bromo-3,4,5-trimethoxy styryl)-1,3,4-thiadiazoles-2-yl)-4-fluorobenzamide
Figure BSA0000097152480000101
Preparation method is with embodiment mono-, with 4-fluorobenzoic acid, replaces 2-bromo-3,4, and 5-trimethoxybenzoic acid, obtains white powder target compound.Productive rate 46.8%.m.p277～278 ℃. 1h NMR (DMSO-d 6, 300MHz) δ: 13.19 (s, 1H), 8.21～8.24 (m, 2H), 7.66 (d, J=1.77Hz, 2H), 7.43 (t, J=6.66Hz, 3H), 3.93 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H) .MS (ESI): 494.01 ([M+H] +) .Anal.calc.for C 20h 17brFN 3o 4s:C, 48.59; H, 3.47; N, 8.50%; Found:C, 48.60; H, 3.48; N, 8.51%.
Embodiment 14: the preparation of (E)-N-(5-(2-bromo-3,4,5-trimethoxy styryl)-1,3,4-thiadiazoles-2-yl)-3-hydroxybenzamide
Figure BSA0000097152480000102
Preparation method is with embodiment mono-, with 3-hydroxy-benzoic acid, replaces 2-bromo-3,4, and 5-trimethoxybenzoic acid, obtains white powder target compound.Productive rate 69.5%.m.p312～313 ℃. 1h NMR (DMSO-d 6, 300MHz) δ: 13.06 (s, 1H), 9.90 (s, 1H), 7.65 (d, J=2.82Hz, 2H), 7.60 (d, J=6.15Hz, 1H), 7.49 (s, 1H), 7.42 (s, 1H), 7.37 (t, J=5.94Hz, 1H), 7.06 (d, J=7.44Hz, 1H), 3.93 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H) .MS (ESI): 492.02 ([M+H] +) .Anal.calc.for C 20h 18brN 3o 5s:C, 48.79; H, 3.69; N, 8.53%; Found:C, 48.80; H, 3.68; N, 8.54%.
Embodiment 15: (E)-3, the preparation of 4-dimethoxy-N-(5-(3,4,5-trimethoxy styryl)-1,3,4-thiadiazoles-2-yl)-benzamide
Figure BSA0000097152480000111
Get 3,4,5-trimethoxy cinnamic acid (1.5g, 6.30mmoL) and join in 100mL single necked round bottom flask, add the thiosemicarbazide of 0.57g, in stink cupboard to the POCl that adds 15mL in flask 3, react after about 1h at 75 ℃, standingly treat that it is cooling, then with about 20mL frozen water, carry out cancellation, and then reactant is poured in 200mL frozen water, the KOH with 50% regulates pH value to 8-9, and the solid filtering of separating out is used anhydrous alcohol solution recrystallization after drying.Get the solid (150mg that above-mentioned recrystallization obtains, 0.5mmol), join in 50mL single necked round bottom flask, 3 of the amount such as add, 4-dimethoxybenzoic acid (93.15mg, 0.5mmol), EDCI (1-ethyl-3-(3-dimethylamine propyl) carbodiimide) (98.03mg, 0.5mmol), HoBt (I-hydroxybenzotriazole) (60.10mg, 0.5mmol), be dissolved in 20mL methylene dichloride, 50 ℃ of heating reflux reactions spend the night.Reactant is washed (5mL) with 1M HCl, buck is washed (3 * 5mL), and salt washing (5mL), dewaters by anhydrous sodium sulphate, after underpressure distillation, obtain crude product, crude product is through column chromatography [elutriant: V (methylene dichloride): V (ethyl acetate)=5:1] white solid of purifying to obtain.Productive rate 40.9%.m.p234～235 ℃. 1h NMR (DMSO-d 6, 300MHz) δ: 12.93 (s, 1H), 7.80 (t, J=74.7Hz, 2H), 7.58 (d, J=12.3Hz, 1H), 7.44 (d, J=12.27Hz, 1H), 7.14 (d, J=6.42Hz, 1H), 7.10 (s, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.86 (s, 6H), 3.70 (s, 3H) .MS (ESI): 458.13 ([M+H] +) .Anal.calc.for C 22h 23n 3o 6s:C, 57.76; H, 5.07; N, 9.18%; Found:C, 57.77; H, 5.06; N, 9.19%.
Embodiment 16: (E)-3,4, the preparation of 5-trimethoxy-N-(5-(3,4,5-trimethoxy styryl)-1,3,4-thiadiazoles-2-yl)-benzamide
Figure BSA0000097152480000112
Preparation method, with embodiment 15, replaces 3,4-dimethoxybenzoic acid with 3,4,5-trimethoxybenzoic acid, obtains white powder target compound.Productive rate 39.5%.m.p205～206 ℃. 1h NMR (DMSO-d 6, 300MHz) δ: 13.05 (s, 1H), 7.57 (d, J=12.3Hz, 1H), 7.51 (s, 2H), 7.43 (d, J=9.3Hz, 1H), 7.09 (s, 2H), 3.89 (s, 6H), 3.84 (s, 6H), 3.76 (s, 3H), 3.69 (s, 3H) .MS (ESI): 488.14 ([M+H] +) .Anal.calc.for C 23h 25n 3o 7s:C, 56.66; H, 5.17; N, 8.62%; Found:C, 56.65; H, 5.16; N, 8.63%.
Embodiment 17: the preparation of (E)-3-methoxyl group-N-(5-(3,4,5-trimethoxy styryl)-1,3,4-thiadiazoles-2-yl)-benzamide
Figure BSA0000097152480000121
Preparation method, with embodiment 15, replaces 3,4-dimethoxybenzoic acid with 3-methoxybenzoic acid, obtains white powder target compound.Productive rate 49.5%.m.p190～191 ℃. 1h NMR (DMSO-d 6, 300MHz) δ: 13.08 (s, 1H), 7.71 (s, 2H), 7.59 (d, J=12.3Hz, 1H), 7.43～7.51 (m, 2H), 7.24 (d, J=6.27Hz, 1H), 7.10 (s, 2H), 3.87 (s, 3H), 3.85 (s, 6H), 3.70 (s, 3H) .MS (ESI): 428.12 ([M+H] +) .Anal.calc.for C 21h 21n 3o 5s:C, 59.00; H, 4.95; N, 9.83%; Fourd:C, 59.01; H, 4.94; N, 9.82%.
Embodiment 18: the preparation of (E)-N-(5-(3,4,5-trimethoxy styryl)-1,3,4-thiadiazoles-2-yl)-3-hydroxybenzamide
Figure BSA0000097152480000122
Preparation method, with embodiment 15, replaces 3,4-dimethoxybenzoic acid with 3-hydroxy-benzoic acid, obtains white powder target compound.Productive rate 45.5%.m.p281～282 ℃. 1h NMR (DMSO-d 6, 300MHz) δ: 12.98 (s, 1H), 9.89 (s, 1H), 7.58 (t, J=7.11Hz, 2H), 7.47 (d, J=3.57Hz, 2H), 7.37 (t, J=5.94Hz, 1H), 7.10 (s, 2H), 7.06 (d, J=7.50Hz, 1H), 3.95 (s, 6H), 3.70 (s, 3H) .MS (ESI): 414.10 ([M+H] +) .Anal.calc.for C 20h 19n 3o 5s:C, 58.10; H, 4.63; N, 10.16%; Found:C, 58.11; H, 4.64; N, 10.15%.
Embodiment 19: (E)-N-(5-(3,4-dimethoxy-styryl)-1,3,4-thiadiazoles-2-yl)-3,4, the preparation of 5-trimethoxy-benzamide
Figure BSA0000097152480000131
Get 3,4-dimethoxy-cinnamic acid (1.5g, 7.20mmoL) and join in 100mL single necked round bottom flask, add the thiosemicarbazide of 0.66g, in stink cupboard to the POCl that adds 15mL in flask 3, react after about 1h at 75 ℃, standingly treat that it is cooling, then with about 20mL frozen water, carry out cancellation, and then reactant is poured in 200mL frozen water, the KOH with 50% regulates pH value to 8-9, and the solid filtering of separating out is used anhydrous alcohol solution recrystallization after drying.Get the solid (200mg, 0.76mmol) that above-mentioned recrystallization obtains, join in 50mL single necked round bottom flask, 3 of the amount such as add, 4,5-trimethoxybenzoic acid (161.17mg, 0.76mmol), EDCI (1-ethyl-3-(3-dimethylamine propyl) carbodiimide) (145.60mg, 0.76mmol), HoBt (I-hydroxybenzotriazole) (102.64mg, 0.76mmol), be dissolved in 20mL methylene dichloride, 50 ℃ of heating reflux reactions spend the night.Reactant is washed (5mL) with 1M HCl, buck is washed (3 * 5mL), and salt washing (5mL), dewaters by anhydrous sodium sulphate, after underpressure distillation, obtain crude product, crude product is through column chromatography [elutriant: V (methylene dichloride): V (ethyl acetate)=5:1] white solid of purifying to obtain.Productive rate 40.6%.m.p203～204 ℃. 1h NMR (DMSO-d 6, 300MHz) δ: 13.02 (s, 1H), 7.52 (s, 2H), 7.46 (s, 1H), 7.44 (s, 1H), 7.39 (d, J=1.23Hz, 1H), 7.24～7.26 (m, 1H), 7.00 (d, J=6.3Hz, 1H), 3.90 (s, 6H), 3.85 (s, 3H), 3.81 (s, 3H), 3.77 (s, 3H) .MS (ESI): 458.13 ([M+H] +) .Anal.calc.for C 22h 23n 3o 6s:C, 57.76; H, 5.07; N, 9.18%; Found:C, 57.75; H, 5.06; N, 9.19%.
Embodiment 20: (E) preparation of N-(5-(3,4-dimethoxy-styryl)-1,3,4-thiadiazoles-2-yl)-2-methoxy benzamide
Figure BSA0000097152480000141
Preparation method, with embodiment 19, replaces 3,4,5-trimethoxybenzoic acid with O-Anisic Acid, obtains white powder target compound.Productive rate 42.5%.m.p207～208 ℃. 1h NMR (DMSO-d 6, 300MHz) δ: 12.31 (s, 1H), 7.70～7.73 (m, 1H), 7.60 (t, J=6.57Hz, 1H), 7.47 (s, 1H), 7.45 (s, 1H), 7.40 (d, J=1.53Hz, 1H), 7.23～7.27 (m, 2H), 7.12 (t, J=5.55Hz, 1H), 7.00 (d, J=6.30Hz, 1H), 3.94 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H) .MS (ESI): 398.11 ([M+H] +) .Anal.calc.for C 20h 19n 3o 4s:C, 60.44; H, 4.82; N, 10.57%; Found:C, 60.43; H, 4.83; N, 10.56%.
Embodiment 21: (E)-2-bromine N-(5-(4-methoxyl-styrene)-1,3,4-thiadiazoles-2-yl)-3,4, the preparation of 5-trimethoxy-benzamide
Figure BSA0000097152480000142
Get 4-methoxy cinnamic acid (1.5g, 8.42mmoL) and join in 100mL single necked round bottom flask, add the thiosemicarbazide of 0.77g, in stink cupboard to the POCl that adds 15mL in flask 3, react after about 1h at 75 ℃, standingly treat that it is cooling, then with about 20mL frozen water, carry out cancellation, and then reactant is poured in 200mL frozen water, the KOH with 50% regulates pH value to 8-9, and the solid filtering of separating out is used anhydrous alcohol solution recrystallization after drying.Get the solid (200mg, 0.86mmol) that above-mentioned recrystallization obtains, join in 50mL single necked round bottom flask, the 2-bromo-3 that the amount such as adds, 4,5-trimethoxybenzoic acid (249.56mg, 0.86mmol), EDCI (1-ethyl-3-(3-dimethylamine propyl) carbodiimide) (164.34mg, 0.86mmol), HoBt (I-hydroxybenzotriazole) (115.85mg, 0.86mmol), be dissolved in 20mL methylene dichloride, 50 ℃ of heating reflux reactions spend the night.Reactant is washed (5mL) with 1M HCl, buck is washed (3 * 5mL), and salt washing (5mL), dewaters by anhydrous sodium sulphate, after underpressure distillation, obtain crude product, crude product is through column chromatography [elutriant: V (methylene dichloride): V (ethyl acetate)=5:1] white solid of purifying to obtain.Productive rate 44.5%.m.p256～257 ℃. 1h NMR (DMSO-d 6, 300MHz) δ: 13.06 (s, 1H), 7.70 (s, 1H), 7.68 (s, 1H), 7.48 (d, J=12.33Hz, 1H), 7.41 (d, J=12.33Hz, 1H), 7.23 (s, 1H), 7.01 (s, 1H), 6.99 (s, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H) .MS (ESI): 506.03 ([M+H] +) .Anal.calc.for C 21h 20brN 3o 5s:C, 49.81; H, 3.98; N, 8.30%; Found:C, 49.80; H, 3.97; N, 8.31%.
Embodiment 22: the bromo-N-of (E)-2-(5-(3-methoxyl-styrene)-1,3,4-thiadiazoles-2-yl)-3,4, the preparation of 5-trimethoxy-benzamide
Figure BSA0000097152480000151
Preparation method, with embodiment 21, replaces 4-methoxy cinnamic acid with 3-methoxy cinnamic acid, obtains white powder target compound.Productive rate 39.5%.m.p194～195 ℃. 1h NMR (DMSO-d 6, 300MHz) δ: 13.11 (s, 1H), 7.59 (s, 1H), 7.52 (s, 1H), 7.30～7.36 (m, 3H), 7.24 (s, 1H), 6.95 (d, J=5.97Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H) .MS (ESI): 506.03 ([M+H] +) .Anal.calc.for C 21h 20brN 3o 5s:C, 49.81; H, 3.98; N, 8.30%; Found:C, 49.82; H, 3.97; N, 8.31%.

Claims (2)

1. a class 3,4-thiadiazoles-2-amide derivatives, is characterized in that they have following general formula:
Figure FSA0000097152470000011
In formula, R 1, R 2, R 3be selected from hydrogen, methoxyl group; R 4be selected from hydrogen, bromine;
R 5, R 6, R 7be selected from hydrogen, methoxyl group, halogen; R 8be selected from hydrogen, bromine.
2. prepare a class 1,3 claimed in claim 1 for one kind, 4-thiadiazoles-2-amide derivatives method for making, they are become by the following step:
Figure FSA0000097152470000012
Step 1. is in stink cupboard, the mixture that adds compound 1 and NBS (N-bromo-succinimide) in flask, be dissolved in appropriate organic solvent, heated and stirred for some time, TLC follows the tracks of reaction, after reacting completely, solution with water is washed multipass, use anhydrous desiccant dryness, pressure reducing and steaming organic solvent obtains crude product, and crude product obtains yellow crystals 2 after recrystallization.
Step 2., in stink cupboard, is mixed compound 2 obtained above and propanedioic acid, adds a certain amount of organic solvent dissolution, drip appropriate piperidines, heated and stirred for some time, TLC follows the tracks of reaction, after question response is complete, pressure reducing and steaming organic solvent, a small amount of dissolving without good solvent for remaining mixture, then pour a large amount of saturated aqueous common salts into it, by sedimentation and filtration out, with low polar solvent, wash twice again, final drying, obtains white powder 3.
Step 3., in stink cupboard, adds a certain amount of compound 3, thiosemicarbazide and POCl in flask 3mixture, heated and stirred is (TLC follows the tracks of reaction) after for some time, reaction system is cooled to room temperature, with a certain amount of frozen water cancellation, be poured in the frozen water of a large amount of volumes again, with alkali, regulate pH value to 5-10, decompress filter obtains yellow solid, dry, the method by column chromatography or recrystallization obtains white powder 4 to its purifying.Step 4. is in stink cupboard, by synthetic compound 4, containing various substituent phenylformic acid, HoBt (I-hydroxybenzotriazole), EDCI (1-ethyl-3-(3-dimethylamine propyl) carbodiimide) is appropriate, is dissolved in appropriate organic solvent reacting by heating for some time.Reactant is washed by acid solution, and alkali lye is washed, and inorganic salt solution is washed, and uses anhydrous desiccant dryness, boils off organic solvent and obtains crude product.Finally the method by column chromatography obtains target compound 5 to its purifying.
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