CN103396367B - Containing the pyrazoles bisamide compounds of amygdalic acid group and preparation method and purposes - Google Patents
Containing the pyrazoles bisamide compounds of amygdalic acid group and preparation method and purposes Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 97
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical group OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 title claims abstract description 20
- -1 pyrazoles bisamide compounds Chemical class 0.000 title claims abstract description 14
- 150000001875 compounds Chemical group 0.000 claims abstract description 111
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims abstract description 40
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 27
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 27
- OEICGMPRFOJHKO-UHFFFAOYSA-N 2-(ethoxymethylidene)propanedinitrile Chemical class CCOC=C(C#N)C#N OEICGMPRFOJHKO-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229960002510 mandelic acid Drugs 0.000 claims abstract description 10
- 230000002507 anti-phytoviral effect Effects 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 6
- 150000004031 phenylhydrazines Chemical class 0.000 claims abstract description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 84
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 claims description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 31
- 239000007787 solid Substances 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 238000010992 reflux Methods 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 230000006837 decompression Effects 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 239000011630 iodine Substances 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 5
- 239000008346 aqueous phase Substances 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000010790 dilution Methods 0.000 claims description 3
- 239000012895 dilution Substances 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000011521 glass Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000006210 lotion Substances 0.000 claims description 3
- 238000005070 sampling Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 3
- 239000000284 extract Substances 0.000 claims description 2
- 238000004809 thin layer chromatography Methods 0.000 claims 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 3
- 241000723873 Tobacco mosaic virus Species 0.000 abstract description 16
- 230000000694 effects Effects 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract 1
- 239000000843 powder Substances 0.000 description 13
- WVZYRBAQDCYFCM-UHFFFAOYSA-N 2-n-(4-bromophenyl)-4-n-(furan-2-ylmethyl)quinazoline-2,4-diamine;hydrochloride Chemical compound Cl.C1=CC(Br)=CC=C1NC1=NC(NCC=2OC=CC=2)=C(C=CC=C2)C2=N1 WVZYRBAQDCYFCM-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- AMNAZJFEONUVTD-KEWDHRJRSA-N (2s,3s,4s,5r,6r)-6-(4-amino-2-oxopyrimidin-1-yl)-4,5-dihydroxy-3-[[(2s)-3-hydroxy-2-[[2-(methylamino)acetyl]amino]propanoyl]amino]oxane-2-carboxamide Chemical compound O1[C@H](C(N)=O)[C@@H](NC(=O)[C@H](CO)NC(=O)CNC)[C@H](O)[C@@H](O)[C@@H]1N1C(=O)N=C(N)C=C1 AMNAZJFEONUVTD-KEWDHRJRSA-N 0.000 description 2
- BWSFWXSSALIZAU-UHFFFAOYSA-N 2-(4-chlorophenyl)-2-hydroxyacetic acid Chemical compound OC(=O)C(O)C1=CC=C(Cl)C=C1 BWSFWXSSALIZAU-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- FEACDOXQOYCHKU-UHFFFAOYSA-N Gougerotin Natural products CNCC(=O)NC1=NC(=O)N(C=C1)C2OC(C(O)C(NC(=O)C(N)CO)C2O)C(=O)N FEACDOXQOYCHKU-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- FTQWRYSLUYAIRQ-UHFFFAOYSA-N n-[(octadecanoylamino)methyl]octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NCNC(=O)CCCCCCCCCCCCCCCCC FTQWRYSLUYAIRQ-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 2
- 229940067157 phenylhydrazine Drugs 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 150000003217 pyrazoles Chemical class 0.000 description 2
- 230000000452 restraining effect Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- PESJTQQZJJTNOC-UHFFFAOYSA-N (3-bromophenyl)hydrazine Chemical compound NNC1=CC=CC(Br)=C1 PESJTQQZJJTNOC-UHFFFAOYSA-N 0.000 description 1
- NRESDXFFSNBDGP-UHFFFAOYSA-N (4-bromophenyl)hydrazine Chemical compound NNC1=CC=C(Br)C=C1 NRESDXFFSNBDGP-UHFFFAOYSA-N 0.000 description 1
- RWOLDZZTBNYTMS-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-hydroxyacetic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1Cl RWOLDZZTBNYTMS-UHFFFAOYSA-N 0.000 description 1
- XXNOGQJZAOXWAQ-UHFFFAOYSA-N 4-chlorophenylhydrazine Chemical compound NNC1=CC=C(Cl)C=C1 XXNOGQJZAOXWAQ-UHFFFAOYSA-N 0.000 description 1
- 241000123650 Botrytis cinerea Species 0.000 description 1
- 240000008067 Cucumis sativus Species 0.000 description 1
- 235000010799 Cucumis sativus var sativus Nutrition 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 241001495644 Nicotiana glutinosa Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000003927 aminopyridines Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 244000053095 fungal pathogen Species 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- MAGPZHKLEZXLNU-UHFFFAOYSA-N mandelamide Chemical compound NC(=O)C(O)C1=CC=CC=C1 MAGPZHKLEZXLNU-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- HBMJWWWQQXIZIP-UHFFFAOYSA-N silicon carbide Chemical compound [Si+]#[C-] HBMJWWWQQXIZIP-UHFFFAOYSA-N 0.000 description 1
- 229910010271 silicon carbide Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 239000005723 virus inoculator Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a class containing the pyrazoles bisamide compounds of amygdalic acid group and preparation method and purposes, its compound structure is represented by following general formula (I).Invention describes substituted phenylhydrazines, 2-Ethoxy methylene malononitrile 99, replace the pyrazole amide compound that the series of new that be Material synthesis such as amygdalic acid, oxalyl chloride contains amygdalic acid, synthesized compound has good resisting tobacco mosaic virus effect, can be used for the medicine preparing Antiphytoviral.
Description
Technical field
The present invention relates to the pyrazoles bisamide compounds Preparation method and use of the amygdalic acid group with Antiphytoviral effect.
Background technology
Wu Yi etc. take parachloromandelic acid as raw material, through acetic anhydride protection hydroxyl, carboxyl chlorination, with aminopyridine condensation, then through deprotection obtain
n-pyridyl, to chlorine mandelamide type compound, is 17% ~ 63%(agricultural chemicals by mycelial growth rate method test compounds to the inhibiting rate of botrytis cinerea, 2012,51 (4), 246-250); Yao Hongwei etc. are with Vanillin and replace amygdalic acid for raw material, synthesized substituted benzene ethyl mandelic acidamide through polystep reaction, under Catalyzed by p-Toluenesulfonic Acid, and aldehyde dehydration ring closure.Obtain the 3-substituted benzene ethyl-5-aryl of series of novel uh azoles 4-ketone compounds and IV-mandeloyl tetrahydroisoquinolicompounds compounds. under 10 μ g/mL concentration; part of compounds is taken root to cucumber cotyledons and is had promoter action (SCI; 2009; 30 (5), 908-912).
Amides has the biological activity of good anti-plant pathogen, Antiphytoviral, the aspect such as anticancer, but there is no people at present about the pyrazoles bisamide containing amygdalic acid group to synthesize, and have no the research report about this compounds anti-plant pathogenic fungi and anti-phytoviral activity both at home and abroad.The present invention with substituted phenylhydrazines, 2-Ethoxy methylene malononitrile 99, replace amygdalic acid, oxalyl chloride etc. for raw material, the pyrazoles bisamide containing amygdalic acid group of series of novel is obtained through four-step reaction synthesis, find that this compounds has certain restraining effect to tobacco mosaic virus (TMV), can be used as the medicine preventing and treating tobacco mosaic disease.
Summary of the invention
The object of the invention is the pyrazoles bisamide compounds of the amygdalic acid group of a series of novel structure of design and synthesis, and has carried out synthetic method and anti-phytoviral activity research to this series compound.Compound structure general formula (
i) as follows:
(
I)
Wherein R
1for hydrogen, halogen atom, C1-4 alkyl, halogen atom can be fluorine, chlorine, bromine, iodine;
R
2for hydrogen, halogen atom, C1-4 alkyl and halogen atom, halogen atom can be fluorine, chlorine, bromine, iodine.
In content of the present invention, this compounds has good inhibit activities to tobacco mosaic virus disease, and its purposes is preparing the application in Antiphytoviral medicine.
General formula of the present invention (
i) preparation method of compound is substituted phenylhydrazines, 2-Ethoxy methylene malononitrile 99, to replace amygdalic acid, oxalyl chloride etc. be raw material, synthesize through four-step reaction, its synthetic route is:
Synthetic method is:
The first step: the preparation of 5-amino-1-substituted-phenyl-1H-pyrazoles-4-acetonitrile
Compound substituted phenylhydrazines (10 mmol) and compound 2-Ethoxy methylene malononitrile 99 (10 mmol) are dissolved in 50mL methyl alcohol, then triethylamine (15 mmol) is added above-mentioned vlil 2 hours, (TLC followed the tracks of by some plate, PE/EA=3/1). decompression remove portion methyl alcohol (about 2/3,30mL water is added 33mL), a large amount of solid is now had to separate out, filter, priority water, sherwood oil drip washing solid, obtains 5-amino-1-substituted-phenyl-1H-pyrazoles-4-acetonitrile (yield is greater than 90%) under decompression by solid drying.
Second step: the preparation of 5-amino-1-substituted-phenyl-1H-pyrazoles-4-methyl-formiate
Compound 5-amino-1-substituted-phenyl-1H-pyrazoles-4-acetonitrile (10 mmol) to be dissolved in 50mL methanolic HCl solution (5mol/L) reflux 16 hours, (TLC followed the tracks of by some plate, PE/EA=3/1). by the remove portion methyl alcohol (about 2/3 that reduces pressure after reacting liquid filtering, 30mL water is added 33mL), a large amount of solid is now had to separate out, filter, successively use water wash solid, under decompression, solid drying obtained 5-amino-1-substituted-phenyl-1H-pyrazoles-4-methyl-formiate (yield is greater than 80%).
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride list benzene methyl
(30 g) to be dissolved in 150 mL methylene dichloride and to add oxalyl chloride (5eq) reflux after 1 hour, slowly instills catalytic amount will to replace amygdalic acid 5
n,
n-dimethyl formamide (DMF); continue backflow 2 hours; point plate is followed the tracks of (sampling is put plate and followed the tracks of TLC, PE/EA=3/1 after adding methyl alcohol), and reaction solution underpressure distillation is obtained 2-chloroformyl-2-oxalyl chloride list benzene methyl except after desolventizing and oxalyl chloride.
4th step: the preparation of target product
5-amino-1-substituted-phenyl-1H-pyrazoles-4-methyl-formiate (500mg) and 2-chloroformyl-2-oxalyl chloride list benzene methyl (1.0g) is joined reaction flask (30mL glass reaction bottle), be heated to 140 rapidly
oc reacts 1 hour, (TLC followed the tracks of by some plate, PE/EA=3/1). add 2 mL aqueous methylamine solution temperature after cooling and stir after 14 hours, after adding water (2 mL) dilution, with methylene dichloride (5mL*2) extraction, regulate pH to about 2 (a large amount of white solid precipitations) aqueous phase 1mol/L HCl, filter, with the washing lotion drip washing solid respectively of PE and PE/EA=2/1, drying under reduced pressure obtains product (yield is greater than 50%).
This step be applicable to all above-mentioned target compound 1-substituted-phenyl-5-(2-substituted-phenyl-2-glycoloyl amido)-
nthe synthesis of-methyl isophthalic acid H-pyrazoles-4-acetyl methylamines.
Synthesize according to invention route and preparation method and proved that the compound of resisting tobacco mosaic virus effect is as follows.
Embodiment
Embodiment one, 1-(4-fluorophenyl)-5-(2-hydroxyl-2-phenylacetyl amido)-
n(compound number is-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
a) synthesis
The first step: 5-amino-1-replaces the preparation of-4-phenyl-1H-pyrazoles-4-acetonitrile
Compound 4-fluorine phenylhydrazine (10 mmol) and compound 2-Ethoxy methylene malononitrile 99 (10 mmol) are dissolved in 50mL methyl alcohol, then triethylamine (15 mmol) is added above-mentioned vlil 2 hours, (TLC followed the tracks of by some plate, PE/EA=3/1), decompression remove portion methyl alcohol (about 2/3,30mL water is added 33mL), a large amount of solid is had to separate out, filter, successively use water, sherwood oil drip washing solid, obtain compound (yield about 90%) by solid drying under decompression.
Second step: 5-amino-1-replaces the preparation of-4-phenyl-1H-pyrazoles-4-methyl-formiate
Compound 5-amino-1-substituted-phenyl-1H-pyrazoles-4-acetonitrile (10 mmol) is dissolved in (5mol/L) reflux in 50mL methanolic HCl solution, (TLC followed the tracks of by some plate, PE/EA=3/1), 16 hours by the remove portion methyl alcohol (about 2/3 that reduces pressure after reacting liquid filtering, 30mL water is added 33mL), a large amount of solid is now had to separate out, filter, successively use water wash solid, under decompression, solid drying is obtained compound (yield about 80%).
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride list benzene methyl
Amygdalic acid 5 (30g) to be dissolved in 150mL methylene dichloride and to add oxalyl chloride (5eq) reflux after 1 hour, slowly instilling catalytic amount
n,
n-dimethyl formamide (DMF), continues backflow 2 hours, and some plate is followed the tracks of (sampling is put plate and followed the tracks of TLC, PE/EA=3/1 after adding methyl alcohol), by reaction solution underpressure distillation except for subsequent use after desolventizing and oxalyl chloride.
4th step: the preparation of target product
The compound (1.0g) of the compound (500mg) synthesize second step and the synthesis of the 3rd step joins reaction flask (30mL glass reaction bottle), be heated to rapidly 140 DEG C of reactions 1 hour, (TLC followed the tracks of by some plate, PE/EA=3/1), adding 2 mL aqueous methylamine solution temperature after cooling stirs after 14 hours, after adding water (2 mL) dilution, extract with methylene dichloride (5mL*2), regulate pH to about 2 (a large amount of white solid precipitations) aqueous phase 1mol/L HCl, filter, with the washing lotion drip washing solid respectively of PE and PE/EA=2/1, drying under reduced pressure obtains product (yield about 50%).
Embodiment two, 1-(4-fluorophenyl)-5-(2-(2-chloro-phenyl-)-2-glycoloyl amido)-
n(compound number is-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
b) synthesis
The first step: 5-amino-1-replaces the preparation of-4-fluorophenyl-1H-pyrazoles-4-acetonitrile
Identical with embodiment one.
Second step: 5-amino-1-replaces the preparation of-4-fluorophenyl-1H-pyrazoles-4-methyl-formiate
Identical with embodiment one
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride-2-chlorobenzene methyl esters
Being dissolved in by 2-chloro mandelic acid 5 (30g) in 150mL methylene dichloride and adding oxalyl chloride (5eq) reflux after 1 hour, all the other are identical with embodiment one.
4th step: the preparation of target product
Identical with embodiment one.
Embodiment three, 1-(4-fluorophenyl)-5-(2-(4-chloro-phenyl-)-2-glycoloyl amido)-
n(compound number is-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
c) synthesis
The first step: 5-amino-1-replaces the preparation of-4-fluorophenyl-1H-pyrazoles-4-acetonitrile
Identical with embodiment one
Second step: 5-amino-1-replaces the preparation of-4-fluorophenyl-1H-pyrazoles-4-methyl-formiate
Identical with embodiment one
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride-4-chlorobenzene methyl esters
Being dissolved in by 4-chloro mandelic acid 5 (30g) in 150mL methylene dichloride and adding oxalyl chloride (5eq) reflux after 1 hour, all the other are identical with embodiment one.
4th step: the preparation of target product
Identical with embodiment one.
Embodiment four, 1-(4-fluorophenyl)-5-(2-(2-fluorophenyl)-2-glycoloyl amido)-
n(compound number is-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
d) synthesis
The first step: 5-amino-1-replaces the preparation of-4-fluorophenyl-1H-pyrazoles-4-acetonitrile
Identical with embodiment one
Second step: 5-amino-1-replaces the preparation of-4-fluorophenyl-1H-pyrazoles-4-methyl-formiate
Identical with embodiment one
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride-2-fluorobenzene methyl esters
Being dissolved in by 2-fluorine amygdalic acid 5 (30g) in 150mL methylene dichloride and adding oxalyl chloride (5eq) reflux after 1 hour, all the other are identical with embodiment one.
4th step: the preparation of target product
Identical with embodiment one.
Embodiment five, 1-(3-bromophenyl)-5-(2-(2-fluorophenyl)-2-glycoloyl amido)-
n(compound number is-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
e) synthesis
The first step: 5-amino-1-replaces the preparation of-3-bromophenyl-1H-pyrazoles-4-acetonitrile
Be dissolved in 50mL methyl alcohol by compound 3-bromophenyl-hydrazine (10 mmol) and compound 2-Ethoxy methylene malononitrile 99 (10 mmol), all the other operation stepss are identical with embodiment one, and yield is 92 %.
Second step: 5-amino-1-replaces the preparation of-3-bromophenyl-1H-pyrazoles-4-methyl-formiate
Compound 5-amino-1-is replaced-3-bromophenyl-1H-pyrazoles-4-acetonitrile (10 mmol) and is dissolved in (5mol/L) reflux in 50mL methanolic HCl solution, all the other operation stepss are identical with embodiment one, and yield is 90 %.
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride-2-fluorobenzene methyl esters
Identical with embodiment four.
4th step: the preparation of target product
Identical with embodiment one.
Embodiment six, 1-(3-bromophenyl)-5-(2-(4-chloro-phenyl-)-2-glycoloyl amido)-
n(compound number is-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
f) synthesis
The first step: 5-amino-1-replaces the preparation of-3-bromophenyl-1H-pyrazoles-4-acetonitrile
Identical with embodiment five.
Second step: 5-amino-1-replaces the preparation of-3-bromophenyl-1H-pyrazoles-4-methyl-formiate
Identical with embodiment five.
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride-4-chlorobenzene methyl esters
Identical with embodiment three.
4th step: the preparation of target product
Identical with embodiment one.
Embodiment seven, 1-(3-bromophenyl)-5-(2-(2-chloro-phenyl-)-2-glycoloyl amido)-
n(compound number is-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
g) synthesis
The first step: 5-amino-1-replaces the preparation of-3-bromophenyl-1H-pyrazoles-4-acetonitrile
Identical with embodiment five.
Second step: 5-amino-1-replaces the preparation of-3-bromophenyl-1H-pyrazoles-4-methyl-formiate
Identical with embodiment five.
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride-2-chlorobenzene methyl esters
Identical with embodiment two.
4th step: the preparation of target product
Identical with embodiment one.
Embodiment eight, 1-(3-bromophenyl)-5-(2-(2-hydroxyl)-2-phenylacetyl amido)-
n(compound number is-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
h) synthesis
The first step: 5-amino-1-replaces the preparation of-3-bromophenyl-1H-pyrazoles-4-acetonitrile
Identical with embodiment five.
Second step: 5-amino-1-replaces the preparation of-3-bromophenyl-1H-pyrazoles-4-methyl-formiate
Identical with embodiment five.
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride benzene methyl
Identical with embodiment one.
4th step: the preparation of target product
Identical with embodiment one.
Embodiment nine, 1-(4-bromophenyl)-5-(2-(2-hydroxyl)-2-phenylacetyl amido)-
n(compound number is synthesis i) to-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
The first step: 5-amino-1-replaces the preparation of-4-bromophenyl-1H-pyrazoles-4-acetonitrile
Be dissolved in 50mL methyl alcohol by compound 4-bromophenyl-hydrazine (10 mmol) and compound 2-Ethoxy methylene malononitrile 99 (10 mmol), all the other are identical with embodiment one, yield 90 %.
Second step: 5-amino-1-replaces the preparation of-4-bromophenyl-1H-pyrazoles-4-methyl-formiate
Compound 5-amino-1-is replaced-4-bromophenyl-1H-pyrazoles-4-acetonitrile (10 mmol) and is dissolved in (5mol/L) reflux in 50 mL methanolic HCl solution, all the other operation stepss are identical with embodiment one, and yield is 89 %.
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride benzene methyl
Identical with embodiment one.
4th step: the preparation of target product
Identical with embodiment one.
Embodiment ten, 1-(4-bromophenyl)-5-(2-(2-chloro-phenyl-)-2-glycoloyl amido)-
n(compound number is synthesis j) to-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
The first step: 5-amino-1-replaces the preparation of-4-bromophenyl-1H-pyrazoles-4-acetonitrile
Identical with embodiment nine.
Second step: 5-amino-1-replaces the preparation of-4-bromophenyl-1H-pyrazoles-4-methyl-formiate
Identical with embodiment nine.
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride-2-chlorobenzene methyl esters
Identical with embodiment two.
4th step: the preparation of target product
Identical with embodiment one.
Embodiment 11,1-(4-chloro-phenyl-)-5-(2-(2-hydroxyl)-2-phenylacetyl amido)-
n(compound number is-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
k) synthesis
The first step: 5-amino-1-replaces the preparation of-4-chloro-phenyl--1H-pyrazoles-4-acetonitrile
Be dissolved in 50mL methyl alcohol by compound 4-chloro phenylhydrazine (10 mmol) and compound 2-Ethoxy methylene malononitrile 99 (10 mmol), all the other are identical with embodiment one, yield 90 %
Second step: 5-amino-1-replaces the preparation of-4-chloro-phenyl--1H-pyrazoles-4-methyl-formiate
Compound 5-amino-1-is replaced-4-chloro-phenyl--1H-pyrazoles-4-acetonitrile (10 mmol) and is dissolved in (5mol/L) reflux in 50 mL methanolic HCl solution, all the other operation stepss are identical with embodiment one, and yield is 89 %.
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride list benzene methyl
Identical with embodiment one.
4th step: the preparation of target product
Identical with embodiment one.
Embodiment 12,1-(4-chloro-phenyl-)-5-(2-(2-hydroxyl)-2-phenylacetyl amido)-
n(compound number is-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
l) synthesis
The first step: 5-amino-1-replaces the preparation of-4-chloro-phenyl--1H-pyrazoles-4-acetonitrile
Identical with embodiment 11.
Second step: 5-amino-1-replaces the preparation of-4-chloro-phenyl--1H-pyrazoles-4-methyl-formiate
Identical with embodiment 11.
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride list benzene methyl
Identical with embodiment one.
4th step: the preparation of target product
Identical with embodiment one.
Embodiment 13,1-(4-chloro-phenyl-)-5-(2-(4-chloro-phenyl-)-2-glycoloyl amido)-
n(compound number is-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
m) synthesis
The first step: 5-amino-1-replaces the preparation of-4-chloro-phenyl--1H-pyrazoles-4-acetonitrile
Identical with embodiment 11.
Second step: 5-amino-1-replaces the preparation of-4-chloro-phenyl--1H-pyrazoles-4-methyl-formiate
Identical with embodiment 11.
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride-4-chlorobenzene methyl esters
Identical with embodiment three.
4th step: the preparation of target product
Identical with embodiment one.
Embodiment 14,1-(4-chloro-phenyl-)-5-(2-(2-fluorophenyl)-2-glycoloyl amido)-
n(compound number is-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
n) synthesis
The first step: 5-amino-1-replaces the preparation of-4-chloro-phenyl--1H-pyrazoles-4-acetonitrile
Identical with embodiment 11.
Second step: 5-amino-1-replaces the preparation of-4-chloro-phenyl--1H-pyrazoles-4-methyl-formiate
Identical with embodiment 11.
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride 2-fluorobenzene methyl esters
Identical with embodiment four.
4th step: the preparation of target product
Identical with embodiment one.
Embodiment 15,1-phenyl-5-(2-(4-chloro-phenyl-)-2-glycoloyl amido)-
n(compound number is-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
o) synthesis
The first step: the preparation of 5-amino-1-substituted-phenyl-1H-pyrazoles-4-acetonitrile
Be dissolved in 50mL methyl alcohol by compound phenylhydrazine (10 mmol) and compound 2-Ethoxy methylene malononitrile 99 (10 mmol), all the other are identical with embodiment one, yield 91 %.
Second step: the preparation of 5-amino-1-phenyl-1H-pyrazoles-4-methyl-formiate
Compound 5-amino-1-is replaced-4-chloro-phenyl--1H-pyrazoles-4-acetonitrile (10 mmol) and is dissolved in (5mol/L) reflux in 50mL methanolic HCl solution, all the other operation stepss are identical with embodiment one, and yield is 89 %.
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride-4-chlorobenzene methyl esters
Identical with embodiment three.
4th step: the preparation of target product
Identical with embodiment one.
Embodiment 16,1-phenyl-5-(2-(2-fluorophenyl)-2-glycoloyl amido)-
n(compound number is-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
p) synthesis
The first step: the preparation of 5-amino-1-substituted-phenyl-1H-pyrazoles-4-acetonitrile
Identical with embodiment 15.
Second step: the preparation of 5-amino-1-substituted-phenyl-1H-pyrazoles-4-methyl-formiate
Identical with embodiment 15.
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride-2-fluorobenzene methyl esters
Identical with embodiment four.
4th step: the preparation of target product
Identical with embodiment one.
Embodiment 17,1-phenyl-5-(2-hydroxyl-2-phenylacetyl amido)-
n(compound number is-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
q) synthesis
The first step: the preparation of 5-amino-1-substituted-phenyl-1H-pyrazoles-4-acetonitrile
Identical with embodiment 15.
Second step: the preparation of 5-amino-1-substituted-phenyl-1H-pyrazoles-4-methyl-formiate
Identical with embodiment 15.
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride list benzene methyl
Identical with embodiment one.
4th step: the preparation of target product
Identical with embodiment one.
Embodiment 18,1-(4-chloro-phenyl-)-5-(2-chloro-phenyl--2-glycoloyl amido)-
n(compound number is-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
r) synthesis
The first step: 5-amino-1-replaces the preparation of-4-chloro-phenyl--1H-pyrazoles-4-acetonitrile
Identical with embodiment 11
Second step: 5-amino-1-replaces the preparation of-4-chloro-phenyl--1H-pyrazoles-4-methyl-formiate
Identical with embodiment 11
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride-2-chlorobenzene methyl esters
Identical with embodiment two.
4th step: the preparation of target product
Identical with embodiment one.
Embodiment 19,1-(4-bromophenyl)-5-(2-(4-chloro-phenyl-)-2-glycoloyl amido)-
n(compound number is-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
s) synthesis
The first step: 5-amino-1-replaces the preparation of-4-bromophenyl-1H-pyrazoles-4-acetonitrile
Identical with embodiment nine.
Second step: 5-amino-1-replaces the preparation of-4-bromophenyl-1H-pyrazoles-4-methyl-formiate
Identical with embodiment nine.
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride-4-chlorobenzene methyl esters
Identical with embodiment three.
4th step: the preparation of target product
Identical with embodiment one.
Embodiment 20,1-(4-bromophenyl)-5-(2-(2-fluorophenyl)-2-glycoloyl amido)-
n(compound number is-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
t) synthesis
The first step: the preparation of 5-amino-1-substituted-phenyl-1H-pyrazoles-4-acetonitrile
Identical with embodiment nine.
Second step: the preparation of 5-amino-1-substituted-phenyl-1H-pyrazoles-4-methyl-formiate
Identical with embodiment nine.
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride list benzene methyl
Identical with embodiment four.
4th step: the preparation of target product
Identical with embodiment one.
Synthesized part of compounds structural formula is as follows:
Table
1composite part containing 1-substituted-phenyl-5-(2-substituted-phenyl-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine compounds structural formula
The part 1-substituted-phenyl-5-substituted-phenyl-2-glycoloyl amido synthesized-
nunder the spectral data institute of-methyl isophthalic acid H-pyrazoles-4-acetyl methylamines:
1-(4-fluorophenyl)-5-(2-hydroxyl-2-phenylacetyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine (compound a):
White powder, yield 48%, fusing point: 218-219 DEG C;
1h NMR (500 MHz, CDCl
3)
δ: 10.17 (s, 1H, NH), 8.08 (s, 1H, Py-H), 7.49 (s, 1H, NH), 7.47 (s, 1H, Ph-H), 7.33-7.27 (m, 8H, Ph-H), 6.59 (s, 1H, OH), 5.00 (s, 1H, CH), 3.61 (s, 3H, NCH
3);
13c NMR (125 MHz, CDCl
3)
δ: 172.4,162.5,162.4,160.4,140.7,139.6,135.6,128.5,128.1,127.3,125.9,125.8,116.1,115.9,112.3,74.1,40.5,26.0. IR (KBr)
ν: 3365,3304,3267,1714,1624,1593,1514,1487,1458,1398,1377,1276,1224,1186,1157,1089,1060,968,848,837,719. Anal. calcd for C
19h
17fN
4o
3: C, 61.95; H, 4.65; N, 15.21; Found C, 61.47; H, 4.10; N, 15.01.
1-(4-fluorophenyl)-5-(2-(2-chloro-phenyl-)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
(compound b):
White powder, yield 50%, fusing point: 227-228 DEG C;
1h NMR (500 MHz, CDCl
3)
δ: 10.23 (s, 1H, NH), 8.12 (s, 1H, Py-H), 7.52 (d,
j=8.6 Hz, 2H, Ph-H), 7.38 (d,
j=3.5 Hz, 4H, Ph-H), 7.32 (d,
j=8.6 Hz, 2H, Ph-H), 6.82 (s, 1H, OH), 5.07 (s, 1H, CH), 3.67 (s, 3H, OCH
3);
13c NMR (125 MHz, CDCl
3)
δ: 171.7,162.6,160.7,139.5,133.1,130.1,129.8,129.7,127.6,126.5,126.4,116.4,116.2,70.9,40.5,26.1. IR (KBr)
ν: 3365,3263,1716,1624,1591,1514,1489,1456,1396,1377,1222,1155,1082,1035,968,840,746. Anal. calcd for C
19h
16clFN
4o
3: C, 56.65; H, 4.00; N, 13.91; Found C, 56.47; H, 3.87; N, 13.97.
1-(4-fluorophenyl)-5-(2-(4-chloro-phenyl-)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
(compound c):
White powder, yield 49%, fusing point: 217-219 DEG C;
1h NMR (500 MHz, CDCl
3)
δ: 10.24 (s, 1H, NH), 8.06 (s, 1H, Py-H), 7.94 (d,
j=4.6 Hz, 1H, NH), 7.42-7.31 (m, 6H, Ph-H), 7.07 (t,
j=8.9 Hz, 2H, Ph-H), 6.71 (d,
j=4.6 Hz, 1H, OH), 5.03 (t, 1H, CH), 3.38 (s, 3H, OCH
3);
13c NMR (125 MHz, CDCl
3)
δ: 172.1,162.5,162.4,160.5,139.5,136.7,129.0,128.5,126.2,126.1,116.1,116.0,112.6,73.3,26.0. IR (KBr)
ν: 3363,1707,1616,1577,1489,1458,1398,1278,1224,1070,1014. Anal. calcd for C
19h
16clFN
4o
3: C, 56.65; H, 4.00; N, 13.91; Found C, 56.34; H, 3.70; N, 14.14.
1-(4-fluorophenyl)-5-(2-(2-fluorophenyl)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
(compound d):
Yellow powder, yield 52%, fusing point: 222-224 DEG C;
1h NMR (500 MHz, CDCl
3)
δ: 10.28 (s, 1H, NH), 8.06 (s, 1H, Py-H), 7.45 (q,
j=4.4 Hz, 2H, Ph-H), 7.32 (d,
j=7.5 Hz, 2H, Ph-H), 7.20 (t,
j=8.6 Hz, 2H, Ph-H), 7.14 (t, J=6.3 Hz, 2H, Ph-H), 6.77 (s, 1H, OH), 5.22 (d,
j=5.2 Hz, 1H, CH), 2.74 (d,
j=4.6 Hz, 3H, NCH
3);
13c NMR (125 MHz, CDCl
3)
δ: 171.8,160.6,160.0,159.3,139.5,136.8,130.4,129.7,126.3,126.2,124.7,116.3,112.5,68.0,27.0. IR (KBr)
ν: 3365,3304,3265,1716,1624,1593,1516,1489,1458,1398,1224,840,758. Anal. calcd for C
19h
16f
2n
4o
3: C, 59.07; H, 4.17; N, 14.50; Found C, 58.78; H, 3.92; N, 14.22.
1-(3-bromophenyl)-5-(2-(2-fluorophenyl)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine (Verbindung):
White solid, yield 51%, fusing point: 205-207 DEG C;
1h NMR (500 MHz, CDCl
3)
δ: 10.42 (s, 1H, NH), 8.12 (s, 1H, Py-H), 8.05 (d,
j=4.6 Hz, 1H, NH), 7.70 (s, 1H, Ph-H), 7.56 (d,
j=8.0 Hz, 1H, Ph-H), 7.46 (d,
j=9.2 Hz, 1H, Ph-H), 7.39-7.30 (m, 3H, Ph-H), 7.16 (q,
j=8.0 Hz, 2H, Ph-H), 6.86 (d,
j=5.2 Hz, 1H, OH), 5.27 (s, 1H, CH), 2.76 (s, 3H, NCH
3);
13c NMR (125 MHz, CDCl
3)
δ: 171.8,162.3,161.3,159.3,140.5,139.9,137.1,131.4,131.1,130.5,130.4,129.7,128.1,126.5,124.9,122.8,121.9,115.8,112.4,68.0,26.1.IR (KBr)
ν: 3232,3296,1714,1616,1593,1506,1485,1456,1398,1375,1273,1222,1147,1101,1068,970,869,752. Anal. calcd for C
19h
16brFN
4o
3: C, 51.02; H, 3.61; N, 12.53; Found C, 50.84; H, 3.45; N, 12.71.
1-(3-bromophenyl)-5-(2-(4-chloro-phenyl-)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine (compound f):
White solid, yield 52%, fusing point: 233-235 DEG C;
1h NMR (500 MHz, CDCl
3)
δ: 10.33 (s, 1H, NH), 8.07 (s, 1H, Py-H), 7.98 (d,
j=4.6 Hz, 1H, NH), 7.57 (s, 1H, Ph-H), 7.48 (d,
j=8.0 Hz, 1H, Ph-H), 7.32-7.29 (m, 5H, Ph-H), 7.18 (t,
j=8.0 Hz, 1H, Ph-H), 6.76 (s, 1H, OH), 5.01 (s, 1H, CH), 2.70 (s, 3H, NCH
3);
13c NMR (125 MHz, CDCl
3)
δ: 172.1,162.3,140.4,139.8,139.5,137.1,132.9,131.2,131.0,129.1,128.6,126.5,122.7,121.9,112.4,73.3,26.0.IR (KBr)
ν: 3321,3292,1705,1616,1593,1577,1485,1458,1400,1186,1138,1080,1014,970,954,867,794,761,636. Anal. calcd for C
19h
16brClN
4o
3: C, 49.21; H, 3.48; N, 12.08; Found C, 48.85; H, 3.37; N, 12.42.
1-(3-bromophenyl)-5-(2-(2-chloro-phenyl-)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine (compound g):
Brown ceramic powder, yield 46%, fusing point: 197-199 DEG C;
1h NMR (500 MHz, CDCl
3)
δ: 10.44 (s, 1H, NH), 8.12 (s, 1H, Py-H), 8.07 (s, 1H, NH), 7.73 (s, 1H, Ph-H), 7.58 (d,
j=8.0 Hz, 1H, Ph-H), 7.50 (d,
j=9.2 Hz, 2H, Ph-H), 7.48-7.29 (m, 4H, Ph-H), 5.40 (s, 1H, OH), 5.28 (s, 1H, CH), 2.75 (s, 3H, NCH
3);
13c NMR (125 MHz, CDCl
3)
δ: 173.6,171.7,162.3,131.5,131.1,130.1,129.7,129.6,127.7,126.6,123.0,70.9,26.1.IR (KBr)
ν: 3381,3362,3342,1699,1653,1627,1591,1575,1558,1475,1386,1280,1253,1087,1033,947,875,754. Anal. calcd for C
19h
16brClN
4o
3c, 49.21; H, 3.48; N, 12.08; Found C, 49.05; H, 3.50; N, 12.02.
1-(3-bromophenyl)-5-(2-(2-hydroxyl)-2-phenylacetyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine (compound h):
Gray solid, yield 51%, fusing point: 203-205 DEG C;
1h NMR (500 MHz, CDCl
3)
δ: 10.39 (s, 1H, NH), 8.12 (s, 1H, Py-H), 7.66 (s, 1H, NH), 7.52 (d,
j=8.6 Hz, 1H, Ph-H), 7.38 (d,
j=3.5 Hz, 2H, Ph-H), 7.33-7.25 (m, 7H, Ph-H), 6.72 (s, 1H, OH), 5.01 (s, 1H, CH), 2.50 (s, 3H, NCH
3);
13c NMR (125 MHz, CDCl
3)
δ: 173.1,172.5,162.3,140.1,131.2,130.9,128.6,128.4,128.2,127.8,127.0,126.4,122.5,74.0,26.1. IR (KBr)
ν: 3323,3280,1701,1622,1593,1575,1558,1479,1456,1408,1315,1274,1186,1151,1093,1058,750,717,696. Anal. calcd for C
19h
17brN
4o
3: C, 53.16; H, 3.99; N, 13.05; Found C, 52.75; H, 3.90; N, 12.87.
1-(4-bromophenyl)-5-(2-(2-hydroxyl)-2-phenylacetyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine (compound i):
White crystal, yield 51%, fusing point: 183-185 DEG C;
1h NMR (500 MHz, CDCl
3)
δ: 10.33 (s, 1H, NH), 8.05 (s, 1H, Py-H), 7.36 (s, 1H, NH), 7.34 (s, 1H, Ph-H), 7.29-7.27 (m, 6H, Ph-H), 7.23 (s, 1H, Ph-H), 7.21 (s, 1H, OH), 4.98 (s, 1H, CH), 2.47 (s, 3H, NCH
3);
13c NMR (125 MHz, CDCl
3)
δ: 172.7,172.4,162.4,140.0,136.6,132.7,132.2,128.5,128.2,127.3,125.6,112.7,74.0,52.5,39.8,24.8. IR (KBr)
ν: 3444,3347,3327,1716,1670,1624,1600,1577,1558,1483,1456,1394,1273,1060,966,827,715. Anal. calcd for C
19h
17brN
4o
3: C, 53.16; H, 3.99; N, 13.05; Found C, 53.44; H, 4.03; N, 12.97.
1-(4-bromophenyl)-5-(2-(2-chloro-phenyl-)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
(compound j):
White powder, yield 52%, fusing point: 203-205 DEG C;
1h NMR (500 MHz, CDCl
3)
δ: 10.32 (s, 1H, NH), 8.06 (s, 1H, Py-H), 7.55 (d,
j=8.6 Hz, 2H, Ph-H+NH), 7.38-7.36 (m, 5H, Ph-H), 7.28 (t,
j=5.2 Hz, 2H, Ph-H), 6.82 (s, 1H, OH), 5.35 (s, 1H, CH), 2.72 (s, 3H, NCH
3);
13c NMR (125 MHz, CDCl
3)
δ: 171.6,162.4,139.8,138.5,133.1,132.6,132.4,130.1,129.8,129.7,127.6,126.0,121.1,112.6,70.9,26.1. IR (KBr)
ν: 3342,3165,1697,1625,1593,1573,1492,1471,1458,1408,1390,1296,1265,1188,1083,1070,1031,1006,958,827,754. Anal. calcd for C
19h
16brClN
4o
3: C, 49.21; H, 3.48; N, 12.08; Found C, 49.30; H, 3.23; N, 11.84.
1-(4-chloro-phenyl-)-5-(2-(2-chloro-phenyl-)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine (compound k):
White powder, yield 47%, fusing point: 210-212 DEG C;
1h NMR (500 MHz, CDCl
3)
δ: 10.35 (s, 1H, NH), 8.12 (s, 1H, Py-H), 10.35 (s, 1H, NH), 7.52 (d,
j=8.6 Hz, 2H, Ph-H), 7.38 (d,
j=3.5 Hz, 4H, Ph-H), 7.32 (d,
j=8.6 Hz, 2H, Ph-H), 6.82 (s, 1H, OH), 5.07 (s, 1H, CH), 3.67 (s, 3H, NCH
3);
13c NMR (125 MHz, CDCl
3)
δ: 171.7,162.4,139.9,130.1,129.8,129.7,129.5,127.6,125.8,112.7,70.9,40.2,26.1. IR (KBr)
ν: 3365,3278,1718,1624,1600,1579,1500,1485,1454,1411,1394,1377,1273,1182,1082,1035,966,835,752. Anal. calcd for C
19h
16c
l2n
4o
3: C, 54.43; H, 3.85; N, 13.36; Found C, 54.29; H, 3.73; N, 13.25
1-(4-chloro-phenyl-)-5-(2-(2-hydroxyl)-2-phenylacetyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine (compound l):
White powder, yield 48%, fusing point: 83-85 DEG C;
1h NMR (500 MHz, CDCl
3)
δ: 10.30 (s, 1H, NH), 8.04 (s, 1H, Py-H), 7.95 (d,
j=4.6 Hz, 1H, NH), 7.34-7.22 (m, 9H, Ph-H), 6.63 (s, 1H, OH), 4.98 (s, 1H, CH), 2.69 (d, J=4.6 Hz, 3H, NCH
3);
13c NMR (125 MHz, CDCl
3)
δ: 172.3,162.4,140.4,139.8,138.0,136.8,129.3,128.5,128.2,127.3,125.3,112.5,74.0,40.1,39.9,26.1. IR (KBr)
ν: 3361,3269,1707,1625,1581,1500,1485,1456,1411,1394,1377,1313,1273,1188,1089,1060,966,831,717,692. Anal. calcd for C
19h
17clN
4o
3: C, 59.30; H, 4.45; N, 14.56; Found C, 59.09; H, 4.28; N, 14.32.
1-(4-chloro-phenyl-)-5-(2-(4-chloro-phenyl-)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine (compound m):
Pink colour crystal, yield 53%, fusing point: 83-85 DEG C;
1h NMR (500 MHz, CDCl
3)
δ: 10.29 (s, 1H, NH), 8.07 (s, 1H, Py-H), 7.99 (d,
j=4.6 Hz, 1H, NH), 7.38 (q,
j=8.6,8.6 Hz, 4H, Ph-H), 7.32 (q,
j=9.2,9.2 Hz, 4H, Ph-H), 6.73 (d,
j=4.6 Hz, 1H, OH), 5.03 (d,
j=4.6 Hz, 1H, CH), 2.73 (d,
j=4.6 Hz, 3H, NCH
3);
13c NMR (125 MHz, CDCl
3)
δ: 172.0,139.7,139.3,137.8,136.3,132.6,130.0,129.2,129.0,128.5,127.0,125.4,112.7,73.2,40.0. IR (KBr)
ν: 3363,3269,1714,1622,1600,1579,1456,1396,1273,1091,1014,833,758. Anal. calcd for C
19h
16cl
2n
4o
3: C, 54.43; H, 3.85; N, 13.36; Found C, 54.32; H, 3.61; N, 13.88.
1-(4-chloro-phenyl-)-5-(2-(2-fluorophenyl)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine (compound n):
Yellow crystals, yield 50%, fusing point: 229-231 DEG C;
1h NMR (500 MHz, CDCl
3)
δ: 10.31 (s, 1H, NH), 8.07 (s, 1H, Py-H), 7.99 (s, 1H, Ph-H), 7.42-7.32 (m, 6H, Ph-H), 7.12 (q,
j=8.9 Hz, 2H, Ph-H), 6.79 (s, 1H, OH), 5.22 (d,
j=4.6 Hz, 1H, CH), 2.72 (d,
j=4.6 Hz, 3H, NCH
3);
13c NMR (125 MHz, CDCl
3)
δ: 171.7,162.4,161.2,159.3,139.8,138.1,136.9,132.6,129.7,129.4,125.6,124.8,115.9,112.5,68.0,40.5,26.1. IR (KBr)
ν: 3361,3267,1714,1627,1600,1581,1500,1487,1456,1411,1396,1377,1273,1230,1091,1068,968,835,754. Anal. calcd for C
19h
16clFN
4o
3: C, 56.65; H, 4.00; N, 13.91; Found C, 56.19; H, 3.91; N, 14.17.
1-phenyl-5-(2-(4-chloro-phenyl-)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine (compound o):
White powder, yield 56%, fusing point: 83-85 DEG C;
1h NMR (500 MHz, CDCl
3)
δ: 10.22 (s, 1H, NH), 8.03 (s, 1H, Py-H), 10.22 (s, 1H, NH), 7.31-7.25 (m, 9H, Ph-H), 6.67 (d,
j=5.2 Hz, 1H, OH), 5.00 (d,
j=4.6 Hz, 1H, CH), 2.69 (d,
j=4.6 Hz, 3H, NCH
3);
13c NMR (125 MHz, CDCl
3)
δ: 172.1,162.4,139.5,139.2,136.5,132.8,129.3,129.1,128.5,128.1,123.7,112.7,73.3,40.0.IR (KBr)
ν: 3375,3263,1701,1616,1579,1558,1506,1456,1398,1276,1138,1076,1014,954,848,763,694. Anal. calcd for C
19h
17clN
4o
3: C, 59.30; H, 4.45; N, 14.56; Found C, 59.02; H, 4.56; N, 14.70.
1-phenyl-5-(2-(2-fluorophenyl)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine (compound p):
White powder, yield 49%, fusing point: 213-215 DEG C;
1h NMR (500 MHz, CDCl
3)
δ: 10.30 (s, 1H, NH), 8.08 (s, 1H, Py-H), 7.95 (d,
j=4.6 Hz, 1H, NH), 7.44-7.42 (m, 2H, Ph-H), 7.39-7.32 (m, 5H, Ph-H), 7.16-7.12 (m, 2H, Ph-H), 6.78 (d,
j=5.2 Hz, 1H, OH), 5.24 (s, 1H, CH), 2.74 (s, 3H, NCH
3);
13c NMR (125 MHz, CDCl
3)
δ: 171.8,162.4,139.5,136.5,129.7,129.4,128.2,124.8,123.9,112.7,68.0,40.0. IR (KBr)
ν: 3363,3304,3269,1716,1624,1600,1587,1487,2462,1448,1396,1276,1068,966,756,694. Anal. calcd for C
19h
17fN
4o
3: C, 61.95; H, 4.65; N, 15.21; Found C, 61.89; H, 4.47; N, 15.47.
1-phenyl-5-(2-hydroxyl-2-phenylacetyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine (compound q):
White crystal, yield 50%, fusing point: 83-85 DEG C;
1h NMR (500 MHz, CDCl
3)
δ: 10.34 (s, 1H, NH), 8.08 (s, 1H, Py-H), 7.97 (d,
j=4.6 Hz, 1H, NH), 7.35-7.33 (m, 5H, Ph-H), 7.30-7.27 (m, 5H, Ph-H), 6.68 (s, 1H, OH), 5.01 (s, 1H, CH), 2.72 (d,
j=4.6 Hz, 3H, NCH
3);
13c NMR (125 MHz, CDCl
3)
δ: 172.5,162.5,139.7,129.3,128.6,128.2,127.4,123.6,112.8,74.1,40.1,26.1.IR (KBr)
ν: 3360,3305,3273,1705,1624,1600,1587,1489,1462,1448,1375,1276,1186,1149,1060,754,721,692. Anal. calcd for C
19h
18n
4o
3: C, 65.13; H, 5.18; N, 15.99; Found C, 64.87; H, 5.51; N, 15.60.
1-(4-chloro-phenyl-)-5-(2-(2-chloro-phenyl-)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine (compound r):
White powder, yield 51%, fusing point: 200-202 DEG C;
1h NMR (500 MHz, CDCl
3)
δ: 10.28 (s, 1H, NH), 8.05 (s, 1H, Py-H), 7.95 (d,
j=4.6 Hz, 1H, Ph-H), 7.44-7.25 (m, 9H, Ph-H), 6.79 (s, 1H, OH), 5.34 (s, 1H, CH), 2.72 (d,
j=4.6 Hz, 3H, NCH
3);
13c NMR (125 MHz, CDCl
3)
δ: 171.7,162.3,139.5,138.6,133.2,130.1,129.9,129.6,129.5,128.3,127.6,124.1,70.6,26.4. IR (KBr)
ν: 3363,3269,3064,1716,1624,1600,1587,1558,1506,1487,1462,1446,1396,1311,1274,1176,1083,1033,966,748,686. Anal. calcd for C
19h
17clN
4o
3: C, 59.30; H, 4.45; N, 14.56; Found C, 58.97; H, 4.18; N, 14.27.
1-(4-bromophenyl)-5-(2-(4-chloro-phenyl-)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine (compound s):
White powder, yield 51%, fusing point: 83-85 DEG C;
1h NMR (500 MHz, CDCl
3)
δ: 10.29 (s, 1H, NH), 8.08 (s, 1H, NH), 8.00 (d,
j=4.6 Hz, 1H, Py-H), 7.40 (d,
j=8.6 Hz, 2H, Ph-H), 7.36 (d,
j=3.5 Hz, 4H, Ph-H), 7.24 (d,
j=8.6 Hz, 2H, Ph-H), 6.72 (d,
j=4.6 Hz, 1H, OH), 5.04 (s, 1H, CH), 2.73 (s, 3H, NCH
3);
13c NMR (125 MHz, CDCl
3)
δ: 171.9,162.3,139.7,139.3,132.9,132.2,129.0,128.5,125.6,112.7,110.1,73.2,26.1. IR (KBr)
ν: 3369,3265,1707,1620,1598,1577,1485,1450,1394,1375,1315,1273,1188,1151,1082,1014,968,829,771,756. Anal. calcd for C
19h
16brClN
4o
3: C, 49.21; H, 3.48; N, 12.08; Found C, 49.08; H, 3.30; N, 12.25.
1-(4-bromophenyl)-5-(2-(2-fluorophenyl)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
(compound t):
White powder, yield 52%, fusing point: 202-204 DEG C;
1h NMR (500 MHz, CDCl
3)
δ: 10.37 (s, 1H, NH), 8.10 (s, 1H, NH), 8.01 (s, 1H, Py-H), 7.54 (d,
j=9.2 Hz, 2H, Ph-H), 7.39 (d,
j=8.6 Hz, 4H, Ph-H), 7.20-7.13 (m, 2H, Ph-H), 6.82 (s, 1H, OH), 5.26 (d,
j=14.9 Hz, 1H, CH), 2.74 (s, 3H, NCH
3);
13c NMR (125 MHz, CDCl
3)
δ: 171.7,162.3,159.3,139.8,136.9,132.4,125.8,124.8,115.9,115.7,112.5,68.0,26.3. IR (KBr)
ν: 3361,3265,1718,1625,1598,1577,1487,1458,1409,1394,1375,1313,1228,1151,1068,1006,966,852,833,817,752,698. Anal. calcd for C
19h
16brFN
4o
3: C, 51.02; H, 3.61; N, 12.53; Found C, 50.90; H, 3.49; N, 12.11
The inhibit activities test test method that embodiment 21, compound are sick to tobacco mosaic virus (TMV) (TMV)
Select the Nicotiana glutinosa that growing way is consistent, with phosphoric acid buffer, TMV crude extract is diluted to suitable concentration, with the artificial frictional inoculation of writing brush in sprinkled with (full leaf virus inoculation on the of the right age blade of silicon carbide, every blade manually smears virus once gently, left and right half leaf dynamics of smearing is accomplished evenly as far as possible), rinse with clear water after inoculation.After blade is dry, (be generally 2 h), spread compound solution at Zuo Banye, the solvent that right half leaf spreads matched doses compares.In illumination box, moisturizing is cultivated subsequently, and control temperature 23 ± 1 ° of C, illumination 10000 Lux, observe after 3 ~ 4 d and record the number producing withered spot.Every chemicals treatment establishes 3 strains, every strain 3 ~ 4 leaves.Every medicament carries out 3 repetitions as stated above.
On half leaf of blank, present obvious withered spot, just can investigate after test 3-4 d, record the withered spot number of left and right half leaf of every sheet leaf respectively, be calculated as follows out the inhibiting rate of test compound to plant virus, i.e. relative efficacy.
Representation: Y=(C-A)/C × 100
Wherein: Y is the inhibiting rate of compound to plant virus,
C is control group (right half leaf) withered spot number, unit: individual
A is compound treatment group (Zuo Banye) withered spot number, unit: individual
Wherein control group (right half leaf) withered spot number and compound treatment group (Zuo Banye) withered spot number can join the withered spot sum of mean number or each group repetition repeated with each group.Each process be with oneself second half in contrast, then the process arranging one group of commodity Ningnanmycin is as a comparison.
Test the live body therapeutic activity of target compound to tobacco mosaic virus (TMV), the results are shown in
table 2.Result shows compound under 500 μ g/mL concentration
a,
b, h,
kshow higher resisting tobacco mosaic virus inhibit activities.
table 2target compound is to the inhibit activities of tobacco mosaic virus (TMV)
From table, under the concentration of 500 μ g/mL, part of compounds has certain restraining effect to tobacco mosaic virus (TMV), and medicament Ningnanmycin is suitable with contrasting.
The embodiment of the present invention is aided with explanation technical scheme of the present invention, but the content of embodiment is not limited thereto.
Claims (5)
1., containing the pyrazoles bisamide compounds of amygdalic acid group, its compound structure general formula is as follows:
(
I)
Wherein R
1for hydrogen, halogen atom, C1-4 alkyl, halogen atom can be fluorine, chlorine, bromine, iodine;
R
2for hydrogen, halogen atom, C1-4 alkyl, halogen atom can be fluorine, chlorine, bromine, iodine.
2. compound according to claim 1, is characterized in that described compound is as follows:
Compound a:
1-(4-fluorophenyl)-5-(2-hydroxyl-2-phenylacetyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
Compound b:
1-(4-fluorophenyl)-5-(2-(2-chloro-phenyl-)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
Compound c:
1-(4-fluorophenyl)-5-(2-(4-chloro-phenyl-)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
Compound d:
1-(4-fluorophenyl)-5-(2-(2-fluorophenyl)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
Verbindung:
1-(3-bromophenyl)-5-(2-(2-fluorophenyl)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
Compound f:
1-(3-bromophenyl)-5-(2-(4-chloro-phenyl-)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
Compound g:
1-(3-bromophenyl)-5-(2-(2-chloro-phenyl-)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
Compound h:
1-(3-bromophenyl)-5-(2-(2-hydroxyl)-2-phenylacetyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
Compound i:
1-(4-bromophenyl)-5-(2-(2-hydroxyl)-2-phenylacetyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
Compound j:
1-(4-bromophenyl)-5-(2-(2-chloro-phenyl-)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
Compound k:
1-(4-chloro-phenyl-)-5-(2-(2-chloro-phenyl-)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
Compound l:
1-(4-chloro-phenyl-)-5-(2-(2-hydroxyl)-2-phenylacetyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
Compound m:
1-(4-chloro-phenyl-)-5-(2-(4-chloro-phenyl-)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
Compound n:
1-(4-chloro-phenyl-)-5-(2-(2-fluorophenyl)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
Compound o:
1-phenyl-5-(2-(4-chloro-phenyl-)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
Compound p:
1-phenyl-5-(2-(2-fluorophenyl)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
Compound q:
1-phenyl-5-(2-hydroxyl-2-phenylacetyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
Compound s:
1-(4-bromophenyl)-5-(2-(4-chloro-phenyl-)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine
Compound t:
1-(4-bromophenyl)-5-(2-(2-fluorophenyl)-2-glycoloyl amido)-
n-methyl isophthalic acid H-pyrazoles-4-acetyl methylamine.
3. compound according to claim 1 and 2 is preparing the application in Antiphytoviral medicine.
4. according to claim 1 containing the preparation method of pyrazoles bisamide compounds of amygdalic acid group, it is characterized in that general formula (
i) preparation method of compound is with substituted phenylhydrazines, 2-Ethoxy methylene malononitrile 99, replaces amygdalic acid, oxalyl chloride etc. for raw material, through four-step reaction synthesis, its synthetic route is as follows:
Wherein R
1for hydrogen, halogen atom, C1-4 alkyl, halogen atom can be fluorine, chlorine, bromine, iodine;
R
2for hydrogen, halogen atom, C1-4 alkyl, halogen atom can be fluorine, chlorine, bromine, iodine.
5. the preparation method of the pyrazoles bisamide compounds of amygdalic acid group according to claim 4, it is characterized in that four step synthesis, synthetic method is:
The first step: the preparation of 5-amino-1-substituted-phenyl-1H-pyrazoles-4-acetonitrile
Compound substituted phenylhydrazines 10 mmol and compound 2-Ethoxy methylene malononitrile 99 10 mmol is dissolved in 50mL methyl alcohol, then triethylamine 15 mmol is added above-mentioned vlil 2 hours, point plate is followed the tracks of, thin-layer chromatography TLC, sherwood oil PE and ethyl acetate EA=3/1, decompression remove portion methyl alcohol about 2/3,30mL water is added after 33mL, a large amount of solid is had to separate out, filter, successively use water, sherwood oil drip washing solid, obtain 5-amino-1-substituted-phenyl-1H-pyrazoles-4-acetonitrile, yield about 90% by solid drying under decompression;
Second step: the preparation of 5-amino-1-substituted-phenyl-1H-pyrazoles-4-methyl-formiate
Compound 5-amino-1-substituted-phenyl-1H-pyrazoles-4-acetonitrile 10 mmol is dissolved in 5mol/L reflux in 50mL methanolic HCl solution, point plate is followed the tracks of, TLC, PE/EA=3/1,16 hours by the remove portion methyl alcohol about 2/3 that reduces pressure after reacting liquid filtering, 30mL water is added after 33mL, now there is a large amount of solid to separate out, filter, successively use water wash solid, under decompression, solid drying is obtained 5-amino-1-substituted-phenyl-1H-pyrazoles-4-methyl-formiate, yield about 80%;
3rd step: the preparation of 2-chloroformyl-2-oxalyl chloride list benzene methyl
Replacement amygdalic acid 30g to be dissolved in 150mL methylene dichloride and to add oxalyl chloride 5eq reflux after 1 hour, slowly instill the N of catalytic amount, dinethylformamide DMF, continue backflow 2 hours, point plate is followed the tracks of, put plate after sampling adds methyl alcohol and follow the tracks of TLC, PE/EA=3/1, reaction solution underpressure distillation is obtained 2-chloroformyl-2-oxalyl chloride list benzene methyl except after desolventizing and oxalyl chloride;
4th step: the preparation of target product
5-amino-1-substituted-phenyl-1H-pyrazoles-4-methyl-formiate 500mg and 2-chloroformyl-2-oxalyl chloride list benzene methyl 1.0g is joined reaction flask 30 mL glass reaction bottle, be heated to rapidly 140 DEG C of reactions 1 hour, point plate is followed the tracks of, TLC, PE/EA=3/1, adding 2 mL aqueous methylamine solution temperature after cooling stirs after 14 hours, after adding water 2 mL dilution, extract with methylene dichloride 5mL Χ 2, regulate pH to about 2 aqueous phase 1mol/L HCl, a large amount of white solid is separated out, filter, with the washing lotion drip washing solid respectively of PE and PE/EA=2/1, drying under reduced pressure obtains product, yield about 50%.
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| CN102267986A (en) * | 2011-09-01 | 2011-12-07 | 中国农业大学 | Pyrazole bisamide compounds as well as synthesis method and application thereof |
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| JPS63310885A (en) * | 1987-06-13 | 1988-12-19 | Nissan Chem Ind Ltd | Pyrazolesulfonylurea derivative and herbicide containing said derivative |
| US5486618A (en) * | 1990-12-13 | 1996-01-23 | Basf Aktiengesellschaft | Substituted 5-aminopyrazoles |
| CN102285979A (en) * | 2011-07-26 | 2011-12-21 | 贵州大学 | N-(2-(substituted benzothiazol-2-aminobenzoyl)-phenyl)-substituted pyrazolecarboxamide compounds and preparation method and use thereof |
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Application publication date: 20131120 Assignee: Hechi Product Quality Inspection Institute Assignor: Hechi Yizhou District Food Inspection and Testing Center Contract record no.: X2023980045469 Denomination of invention: Pyrazole bisamide compounds containing mandelic acid groups, preparation methods and applications Granted publication date: 20150909 License type: Common License Record date: 20231103 |