CN108033904B - A kind of synthetic method of medicine intermediate semicarbazones - Google Patents
A kind of synthetic method of medicine intermediate semicarbazones Download PDFInfo
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- CN108033904B CN108033904B CN201711494340.4A CN201711494340A CN108033904B CN 108033904 B CN108033904 B CN 108033904B CN 201711494340 A CN201711494340 A CN 201711494340A CN 108033904 B CN108033904 B CN 108033904B
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- 150000007659 semicarbazones Chemical class 0.000 title claims abstract description 40
- 238000010189 synthetic method Methods 0.000 title claims abstract description 9
- 239000003814 drug Substances 0.000 title claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 11
- VIUDTWATMPPKEL-UHFFFAOYSA-N 3-(trifluoromethyl)aniline Chemical compound NC1=CC=CC(C(F)(F)F)=C1 VIUDTWATMPPKEL-UHFFFAOYSA-N 0.000 claims abstract description 9
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 8
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 7
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 150000002148 esters Chemical class 0.000 claims abstract description 6
- 238000012986 modification Methods 0.000 claims abstract description 6
- 150000002527 isonitriles Chemical class 0.000 claims abstract description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims abstract description 4
- 230000004048 modification Effects 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 48
- 235000019441 ethanol Nutrition 0.000 claims description 24
- 238000001291 vacuum drying Methods 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 239000012065 filter cake Substances 0.000 claims description 15
- 238000010992 reflux Methods 0.000 claims description 13
- 244000144992 flock Species 0.000 claims description 12
- 238000009413 insulation Methods 0.000 claims description 12
- 238000001953 recrystallisation Methods 0.000 claims description 12
- 230000000630 rising effect Effects 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- 238000005119 centrifugation Methods 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 8
- 239000011973 solid acid Substances 0.000 claims description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 150000002825 nitriles Chemical class 0.000 claims description 5
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002808 molecular sieve Substances 0.000 claims description 4
- 229910052710 silicon Inorganic materials 0.000 claims description 4
- 239000010703 silicon Substances 0.000 claims description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 238000010792 warming Methods 0.000 claims description 4
- 239000002826 coolant Substances 0.000 claims description 3
- 239000008367 deionised water Substances 0.000 claims description 3
- 229910021641 deionized water Inorganic materials 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 238000004321 preservation Methods 0.000 claims description 3
- 239000012265 solid product Substances 0.000 claims description 3
- 238000005292 vacuum distillation Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- -1 Phenyl ester Chemical class 0.000 claims description 2
- 229910006069 SO3H Inorganic materials 0.000 claims 2
- 238000001914 filtration Methods 0.000 claims 1
- 238000002386 leaching Methods 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 230000003197 catalytic effect Effects 0.000 abstract description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 abstract description 4
- WHLUQAYNVOGZST-UHFFFAOYSA-N tifenamil Chemical group C=1C=CC=CC=1C(C(=O)SCCN(CC)CC)C1=CC=CC=C1 WHLUQAYNVOGZST-UHFFFAOYSA-N 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 229930192474 thiophene Natural products 0.000 abstract description 2
- 238000004064 recycling Methods 0.000 abstract 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 11
- 229910021529 ammonia Inorganic materials 0.000 description 11
- 239000004202 carbamide Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 5
- 230000003115 biocidal effect Effects 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 238000007654 immersion Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- CDYIVTJODJNCNP-UHFFFAOYSA-N benzaldehyde hydrazine hydrate Chemical compound C(C1=CC=CC=C1)=O.O.NN CDYIVTJODJNCNP-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000000696 magnetic material Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 201000009032 substance abuse Diseases 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C337/00—Derivatives of thiocarbonic acids containing functional groups covered by groups C07C333/00 or C07C335/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
- C07C337/06—Compounds containing any of the groups, e.g. thiosemicarbazides
- C07C337/08—Compounds containing any of the groups, e.g. thiosemicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. thiosemicarbazones
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J29/00—Catalysts comprising molecular sieves
- B01J29/03—Catalysts comprising molecular sieves not having base-exchange properties
- B01J29/0308—Mesoporous materials not having base exchange properties, e.g. Si-MCM-41
-
- B01J35/61—
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C263/00—Preparation of derivatives of isocyanic acid
- C07C263/10—Preparation of derivatives of isocyanic acid by reaction of amines with carbonyl halides, e.g. with phosgene
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
- C07C281/06—Compounds containing any of the groups, e.g. semicarbazides
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2229/00—Aspects of molecular sieve catalysts not covered by B01J29/00
- B01J2229/10—After treatment, characterised by the effect to be obtained
- B01J2229/18—After treatment, characterised by the effect to be obtained to introduce other elements into or onto the molecular sieve itself
Abstract
The invention discloses a kind of synthetic methods of medicine intermediate semicarbazones, dichloroethanes, triphosgene, 3-Aminotrifluorotoluene, isonitrile acid phenenyl ester, hydrazine hydrate, N-(3- trifluoromethyl)-semicarbazides and thiophene -2-formaldehyde be primary raw material, utilize N-(3- trifluoromethyl)-semicarbazides synthesis semicarbazones method, be added sulfonic group modification SZ@SBA-15-SO3After H catalyst, thiophene -2-formaldehyde is added to precipitate at once, thiphene ring is that five atoms, six electronics grips structure altogether, after generating thiophene -2-formaldehyde-N (4)-m-trifluoromethylphenyl semicarbazones under catalytic action, it is conjugated since-CN and thiphene ring are formed, electronics is caused more to disperse, thus more stable；Semicarbazones preparation method has simple and easy, the features such as short preparation period, technical process is raw materials used and catalyst efficiency is high, simple and convenient, and easily recycling, renewable, polar ring are protected, have a wide range of application, and have excellent catalytic effect to semicarbazones synthetic reaction.
Description
Technical field
The present invention relates to a kind of synthetic methods of medicine intermediate semicarbazones, belong to catalysis technical field.
Background technique
In in the past few decades, it has been found that the resistance of bacterial antibiotic occurs rapidly.It is widely used and abuses and is anti-
Raw element provides powerful strength to the selection of microorganism and makes them carry out mutation generation resistance or enhance it to antibiotic
Resistance.Mutant bacteria obtains new gene to generate new mechanism to overcome the effect of existing antibiotic.In recent years, many new
Antibody-resistant bacterium oneself separated from global patient body.Therefore, the new compound with antibacterial action is needed into one
The research and development of step come out, to resist bacterium to the resistance of existing antibiotic/antibacterials.Semicarbazones is called semicarbazone, is
The product of aldehyde and ketone compounds and semicarbazide condensation reaction containing carbonyl has been found to have good with its metal complex
Anti-spasm, anticancer, antibacterial activity, and to the thio contracting amino pulse-phase ratio of similar structure, toxicity is smaller, and receives biggish
Concern.Simultaneously its magnetic material, molecular recognition, optical material, in terms of also there is actual application prospect.
Summary of the invention
The purpose of the present invention is to provide a kind of synthetic method of medicine intermediate semicarbazones, this method can be in low temperature item
Semicarbazones synthetic reaction, product yield with higher are catalyzed under part.
A kind of N-(3- trifluoromethyl)-semicarbazides semicarbazones synthetic method, method includes the following steps:
Dichloroethanes 80ml is added in step 1 in the three-necked flask of 150ml, is put into -5 DEG C of low-temperature coolant circulating machine
In, the triphosgene of 11.88g, stirring and dissolving is added；20 DEG C are warming up to, 9.66g 3-Aminotrifluorotoluene is added dropwise, is added dropwise, is risen
Temperature to flowing back, clarify by heat preservation to solution, and revolving removes solvent, and vacuum distillation is collected 54-55 DEG C of fraction at 1.5kPa, obtained different
Nitrile acid phenenyl ester colourless liquid；
Nitrile 80ml is added in step 2 in the three-necked flask of 150ml, and the above-mentioned isonitrile acid phenenyl ester of 11.24g is added, and is added
4.7g85% hydrazine hydrate is added a small amount of water to solution and is clarified.Ultrasonic 4h, obtains red reaction solution, and revolving removes solvent, thereto plus
Enter 30mL methylene chloride, 2h is placed at 0 DEG C, filter, filter cake is washed with a small amount of methylene chloride to white, 60 DEG C of vacuum drying
6h obtains N-(3- trifluoromethyl)-semicarbazides white solid；
Ethyl alcohol 80ml is added in step 3 in the three-necked flask of 150ml, and 8.76gN-(3- trifluoromethyl is added)-ammonia
2.19g thiophene -2-formaldehyde is added in base urea, temperature rising reflux, and catalyst 0.8g insulation reaction 12h is added, is cooled to room temperature, filters,
Filter cake ethyl alcohol recrystallization, 60 DEG C of vacuum drying 6h, obtains the semicarbazones of white flock.
The method for preparing catalyst is as follows:
Step 1 weighs the silicon-based mesoporous molecular sieve SBA-15 of 0.2g after drying and is dispersed in 10mL n-hexane, is stirring
Under conditions of, the zirconium-n-propylate of 0.6g is added dropwise into mixed system；After hydrolyzing 6h at 50 DEG C, gained produces reaction system
Object through distillation water washing 3-5 times, be collected by centrifugation and obtain ZrO with 40 DEG C of vacuum drying2@SBA-15;
Step 2, by the resulting ZrO of 0.2g above-mentioned steps2@SBA-15 is immersed in the sulfuric acid solution of 10ml0.005mo1/L
In, the collected product of centrifugation is placed in Muffle furnace at 400 DEG C through 60 DEG C of vacuum drying after immersion 4h keeps 1h, obtains SBA-15
The ZrO of load2/SO4 2-Type solid acid；
The resulting solid acid of 0.5g above-mentioned steps is added in the mixed solution of 0.5mlMPTMS and 2ml toluene step 3,
?
Back flow reaction is carried out at 100 DEG C, is then centrifuged gains, and the solid product after centrifugation is added to
In the mixed solution of the hydrogen peroxide of 10ml30%, 2mL deionized water and 5mL methanol, 5h is stirred at 30 DEG C, it is then, centrifugation, true
Sky is dried to obtain the SZ@SBA-15-SO of sulfonic group modification3H catalyst.
The utility model has the advantages that the present invention provides a kind of N-(3- trifluoromethyls) the synthesis side of-semicarbazides semicarbazones
Method utilizes N-(3- trifluoromethyl)-semicarbazides synthesis semicarbazones method, be added sulfonic group modification SZ@SBA-
15-SO3After H catalyst, thiophene -2-formaldehyde is added and precipitates at once, thiphene ring is that five atoms, six electronics grips knot altogether
Structure, after generating thiophene -2-formaldehyde-N (4)-m-trifluoromethylphenyl semicarbazones under catalytic action, due to-CN and thiphene ring
Conjugation is formed, causes electronics more to disperse, thus more stable;- the SO that solid acid passes through silane coupled reactive grafting acidity3H
- the NH of group and alkalinity2Group obtains the difunctional solid of soda acid simultaneously for ZrO2/S04 2-Type solid acid, sulfonic group and amino
It is supported on silicon-based mesoporous molecular sieve SBA-15, not only increases the specific surface area of catalyst, while enhancing the heat of catalyst
Stability, catalyst regeneration performance are significantly improved, and have excellent catalytic effect to the synthetic reaction of semicarbazones.
Specific embodiment
Embodiment 1
A kind of synthetic method of medicine intermediate semicarbazones, method includes the following steps:
Dichloroethanes 80ml is added in step 1 in the three-necked flask of 150ml, is put into -5 DEG C of low-temperature coolant circulating machine
In, the triphosgene of 11.88g, stirring and dissolving is added；20 DEG C are warming up to, 9.66g 3-Aminotrifluorotoluene is added dropwise, is added dropwise, is risen
Temperature to flowing back, clarify by heat preservation to solution, and revolving removes solvent, and vacuum distillation is collected 54-55 DEG C of fraction at 1.5kPa, obtained different
Nitrile acid phenenyl ester colourless liquid；
Nitrile 80ml is added in step 2 in the three-necked flask of 150ml, and the above-mentioned isonitrile acid phenenyl ester of 11.24g is added, and is added
4.7g85% hydrazine hydrate is added a small amount of water to solution and is clarified.Ultrasonic 4h, obtains red reaction solution, and revolving removes solvent, thereto plus
Enter 30mL methylene chloride, 2h is placed at 0 DEG C, filter, filter cake is washed with a small amount of methylene chloride to white, 60 DEG C of vacuum drying
6h obtains N-(3- trifluoromethyl)-semicarbazides white solid；
Ethyl alcohol 80ml is added in step 3 in the three-necked flask of 150ml, and 8.76gN-(3- trifluoromethyl is added)-ammonia
2.19g thiophene -2-formaldehyde is added in base urea, temperature rising reflux, and catalyst 0.8g insulation reaction 12h is added, is cooled to room temperature, filters,
Filter cake ethyl alcohol recrystallization, 60 DEG C of vacuum drying 6h, obtains the semicarbazones of white flock.
The method for preparing catalyst is as follows:
Step 1 weighs the silicon-based mesoporous molecular sieve SBA-15 of 0.2g after drying and is dispersed in 10mL n-hexane, is stirring
Under conditions of, the zirconium-n-propylate of 0.6g is added dropwise into mixed system；After hydrolyzing 6h at 50 DEG C, gained produces reaction system
Object through distillation water washing 3-5 times, be collected by centrifugation and obtain ZrO with 40 DEG C of vacuum drying2@SBA-15;
Step 2, by the resulting ZrO of 0.2g above-mentioned steps2@SBA-15 is immersed in the sulfuric acid solution of 10ml0.005mo1/L
In, the collected product of centrifugation is placed in Muffle furnace at 400 DEG C through 60 DEG C of vacuum drying after immersion 4h keeps 1h, obtains SBA-15
The ZrO of load2/SO4 2-Type solid acid；
The resulting solid acid of 0.5g above-mentioned steps is added in the mixed solution of 0.5mlMPTMS and 2ml toluene step 3,
?
Back flow reaction is carried out at 100 DEG C, is then centrifuged gains, and the solid product after centrifugation is added to
In the mixed solution of the hydrogen peroxide of 10ml30%, 2mL deionized water and 5mL methanol, 5h is stirred at 30 DEG C, it is then, centrifugation, true
Sky is dried to obtain the SZ@SBA-15-SO of sulfonic group modification3H catalyst.
Embodiment 2
Ethyl alcohol 80ml is added in step 3 in the three-necked flask of 150ml, and 4.38gN-(3- trifluoromethyl is added)-ammonia
2.19g thiophene -2-formaldehyde is added in base urea, temperature rising reflux, and catalyst 0.8g insulation reaction 12h is added, is cooled to room temperature, filters,
Filter cake ethyl alcohol recrystallization, 60 DEG C of vacuum drying 6h, obtains the semicarbazones of white flock.Remaining step is the same as embodiment 1.
Embodiment 3
Ethyl alcohol 80ml is added in step 3 in the three-necked flask of 150ml, and 2.19gN-(3- trifluoromethyl is added)-ammonia
2.19g thiophene -2-formaldehyde is added in base urea, temperature rising reflux, and catalyst 0.8g insulation reaction 12h is added, is cooled to room temperature, filters,
Filter cake ethyl alcohol recrystallization, 60 DEG C of vacuum drying 6h, obtains the semicarbazones of white flock.Remaining step is the same as embodiment 1.
Embodiment 4
Ethyl alcohol 80ml is added in step 3 in the three-necked flask of 150ml, and 1.01gN-(3- trifluoromethyl is added)-ammonia
2.19g thiophene -2-formaldehyde is added in base urea, temperature rising reflux, and catalyst 0.8g insulation reaction 12h is added, is cooled to room temperature, filters,
Filter cake ethyl alcohol recrystallization, 60 DEG C of vacuum drying 6h, obtains the semicarbazones of white flock.Remaining step is the same as embodiment 1.
Embodiment 5
Ethyl alcohol 80ml is added in step 3 in the three-necked flask of 150ml, and 0.55gN-(3- trifluoromethyl is added)-ammonia
2.19g thiophene -2-formaldehyde is added in base urea, temperature rising reflux, and catalyst 0.8g insulation reaction 12h is added, is cooled to room temperature, filters,
Filter cake ethyl alcohol recrystallization, 60 DEG C of vacuum drying 6h, obtains the semicarbazones of white flock.Remaining step is the same as embodiment 1.
Embodiment 6
Ethyl alcohol 80ml is added in step 3 in the three-necked flask of 150ml, and 0.11gN-(3- trifluoromethyl is added)-ammonia
2.19g thiophene -2-formaldehyde is added in base urea, temperature rising reflux, and catalyst 0.8g insulation reaction 12h is added, is cooled to room temperature, filters,
Filter cake ethyl alcohol recrystallization, 60 DEG C of vacuum drying 6h, obtains the semicarbazones of white flock.Remaining step is the same as embodiment 1.
Embodiment 7
Ethyl alcohol 80ml is added in step 3 in the three-necked flask of 150ml, and 5.25gN-(3- trifluoromethyl is added)-ammonia
2.19g thiophene -2-formaldehyde is added in base urea, temperature rising reflux, and catalyst 0.8g insulation reaction 12h is added, is cooled to room temperature, filters,
Filter cake ethyl alcohol recrystallization, 60 DEG C of vacuum drying 6h, obtains the semicarbazones of white flock.Remaining step is the same as embodiment 1.
Embodiment 8
Ethyl alcohol 80ml is added in step 3 in the three-necked flask of 150ml, and 15.76gN-(3- trifluoromethyl is added)-ammonia
2.19g thiophene -2-formaldehyde is added in base urea, temperature rising reflux, and catalyst 0.8g insulation reaction 12h is added, is cooled to room temperature, filters,
Filter cake ethyl alcohol recrystallization, 60 DEG C of vacuum drying 6h, obtains the semicarbazones of white flock.Remaining step is the same as embodiment 1.
Embodiment 9
Ethyl alcohol 80ml is added in step 3 in the three-necked flask of 150ml, and 21.06gN-(3- trifluoromethyl is added)-ammonia
2.19g thiophene -2-formaldehyde is added in base urea, temperature rising reflux, and catalyst 0.8g insulation reaction 12h is added, is cooled to room temperature, filters,
Filter cake ethyl alcohol recrystallization, 60 DEG C of vacuum drying 6h, obtains the semicarbazones of white flock.Remaining step is the same as embodiment 1.
Embodiment 10
Ethyl alcohol 80ml is added in step 3 in the three-necked flask of 150ml, and 28.04gN-(3- trifluoromethyl is added)-ammonia
2.19g thiophene -2-formaldehyde is added in base urea, temperature rising reflux, and catalyst 0.8g insulation reaction 12h is added, is cooled to room temperature, filters,
Filter cake ethyl alcohol recrystallization, 60 DEG C of vacuum drying 6h, obtains the semicarbazones of white flock.Remaining step is the same as embodiment 1.
Reference examples 1
Be with 1 difference of embodiment: in the step 1 of the synthesis of semicarbazones, not adding triphosgene, remaining step with
Embodiment 1 is identical.
Reference examples 2
It is with 1 difference of embodiment: in the step 1 of the synthesis of semicarbazones, does not add 3-Aminotrifluorotoluene,
Remaining step is identical with embodiment 1.
Reference examples 3
It is with 1 difference of embodiment: in the step 1 of the synthesis of semicarbazones, triphosgene and 3-Aminotrifluorotoluene matter
Amount ratio is 1:7, remaining step is identical with embodiment 1.
Reference examples 4
It is with 1 difference of embodiment: in the step 1 of the synthesis of semicarbazones, triphosgene and 3-Aminotrifluorotoluene matter
Amount ratio is 7:1, remaining step is identical with embodiment 1.
Reference examples 5
Be with 1 difference of embodiment: in the step 2 of the synthesis of semicarbazones, not adding hydrazine hydrate, remaining step with
Embodiment 1 is identical.
Reference examples 6
It is with 1 difference of embodiment: in the step 2 of the synthesis of semicarbazones, replaces hydrazine hydrate dosage not with benzaldehyde
Become, remaining step is identical with embodiment 1.
Reference examples 7
It is with 1 difference of embodiment: in catalyst preparation step 1, does not add zirconium-n-propylate, remaining step and implementation
Example 1 is identical.
Reference examples 8
It is with 1 difference of embodiment: in catalyst preparation step 1, replaces zirconium-n-propylate dosage constant with aluminium isopropoxide,
Remaining step is identical with embodiment 1.
Reference examples 9
Be with 1 difference of embodiment: in catalyst preparation step 3, MPTMS and volume of toluene ratio are 3:1, remaining step
It is identical with embodiment 1.
Reference examples 10
Be with 1 difference of embodiment: in catalyst preparation step 3, MPTMS and volume of toluene ratio are 1:3, remaining step
It is identical with embodiment 1.
It is as shown in the table for reaction result under embodiment and reference examples different condition
The experimental results showed that catalyst has good catalytic effect to the synthetic reaction of semicarbazones, in reaction condition one
Periodically, semicarbazones yield is higher, and catalytic performance is better, otherwise poorer；In N-(3- trifluoromethyl)-semicarbazides, thiophene-
When the mass ratio of 2- formaldehyde is 4:1, other ingredients are fixed, and synthetic effect is best, with embodiment 1 the difference lies in that embodiment 2
Change primary raw material N-(3- trifluoromethyl respectively to embodiment 10)-semicarbazides, thiophene -2-formaldehyde dosage and proportion,
There is different influences to the yield of synthetic product；Reference examples 1 to reference examples 4 do not add triphosgene and 3-Aminotrifluorotoluene simultaneously
The proportion of the two, other steps are identical, cause the yield of semicarbazones to be substantially reduced, illustrate triphosgene and m-trifluoromethyl
Aniline mass ratio has an important influence on reaction；Reference examples 5 to reference examples 6 do not add hydrazine hydrate benzaldehyde and replace water
Conjunction hydrazine dosage is constant, so that the yield of product reduces, reaction effect is obviously deteriorated, and illustrates the addition of hydrazine hydrate to reaction to Guan Chong
It wants；Reference examples 7 to reference examples 8 do not add zirconium-n-propylate and replace zirconium-n-propylate dosage constant with aluminium isopropoxide, and effect is still
It is bad, illustrate that zirconium-n-propylate is very big on the modified influence of catalyst；Reference examples 9 are to reference examples 10 by MPTMS and volume of toluene ratio
Change, the activity of catalyst changes, and catalytic effect is obviously deteriorated, and the yield of semicarbazones is not still high；Therefore this is used
The synthetic method of invention has excellent catalytic effect to the synthetic reaction of semicarbazones.
Claims (1)
1. a kind of synthetic method of medicine intermediate semicarbazones, it is characterised in that method includes the following steps:
Dichloroethanes 80ml is added in step 1 in the three-necked flask of 150ml, is put into -5 DEG C of low-temperature coolant circulating machine, adds
Enter the triphosgene of 11.88g, stirring and dissolving；20 DEG C are warming up to, 9.66g 3-Aminotrifluorotoluene is added dropwise, is added dropwise, is warming up to
Reflux, heat preservation to solution are clarified, and revolving removes solvent, and 54-55 DEG C of fraction is collected in vacuum distillation at 1.5kPa, obtain isonitrile acid
Phenyl ester colourless liquid；
Nitrile 80ml is added in step 2 in the three-necked flask of 150ml, and the above-mentioned isonitrile acid phenenyl ester of 11.24g is added, and 4.7g85% is added
Hydrazine hydrate is added a small amount of water to solution and is clarified；Ultrasonic 4h, obtains red reaction solution, and revolving removes solvent, 30mL is added thereto
Methylene chloride places 2h at 0 DEG C, and filtering, filter cake is washed with a small amount of methylene chloride to white, and 60 DEG C of vacuum drying 6h obtain N-
(3- trifluoromethyl)-semicarbazides white solid；
Ethyl alcohol 80ml is added in step 3 in the three-necked flask of 150ml, and 8.76gN-(3- trifluoromethyl is added)-semicarbazides,
2.19g thiophene -2-formaldehyde is added in temperature rising reflux, and catalyst 0.8g insulation reaction 12h is added, is cooled to room temperature, filters, filter cake
With ethyl alcohol recrystallization, 60 DEG C of vacuum drying 6h obtain the semicarbazones of white flock；
The catalyst is the SZ@SBA-15-SO3H catalyst of sulfonic group modification, the preparation method is as follows:
Step 1 weighs the silicon-based mesoporous molecular sieve SBA-15 of 0.2g after drying and is dispersed in 10mL n-hexane, in the item of stirring
Under part, the zirconium-n-propylate of 0.6g is added dropwise into mixed system；Reaction system is after hydrolyzing 6h at 50 DEG C, products therefrom warp
Distillation water washing 3-5 times is collected by centrifugation and obtains ZrO2 SBA-15 with 40 DEG C of vacuum drying;
The resulting ZrO2@SBA-15 of 0.2g above-mentioned steps is immersed in the sulfuric acid solution of 10ml0.005mo1/L by step 2, leaching
Product collected by being centrifuged after bubble 4h is placed in Muffle furnace at 400 DEG C through 60 DEG C of vacuum drying and keeps 1h, obtains SBA-15 load
ZrO2/SO42- type solid acid；
The resulting solid acid of 0.5g above-mentioned steps is added in the mixed solution of 0.5mlMPTMS and 2ml toluene step 3,
Back flow reaction is carried out at 100 DEG C, is then centrifuged gains, and the solid product after centrifugation is added to 10ml30%'s
In the mixed solution of hydrogen peroxide, 2mL deionized water and 5mL methanol, 5h is stirred at 30 DEG C, then, centrifugation, vacuum drying obtain
The SZ@SBA-15-SO3H catalyst of sulfonic group modification.
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|---|---|---|---|---|
| CN103709077A (en) * | 2014-01-20 | 2014-04-09 | 桂林理工大学 | Benzaldehyde semicarbazide derivative and application thereof |
| CN105367543A (en) * | 2015-12-07 | 2016-03-02 | 西华大学 | Thiophene chalcone semicarbazone Schiff base compounds, and preparation method and applications thereof |
| CN106540746A (en) * | 2016-10-19 | 2017-03-29 | 天津大学 | A kind of preparation method and applications of the organic silica nanotube of sulfonic functional |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103709077A (en) * | 2014-01-20 | 2014-04-09 | 桂林理工大学 | Benzaldehyde semicarbazide derivative and application thereof |
| CN105367543A (en) * | 2015-12-07 | 2016-03-02 | 西华大学 | Thiophene chalcone semicarbazone Schiff base compounds, and preparation method and applications thereof |
| CN106540746A (en) * | 2016-10-19 | 2017-03-29 | 天津大学 | A kind of preparation method and applications of the organic silica nanotube of sulfonic functional |
Non-Patent Citations (1)
| Title |
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| Synthesis, characterization and physicochemical properties of copper(II) complexes containing salicylaldehyde semicarbazone;Peng Foo Lee等;《Polyhedron》;20031231;第22卷;P2781-2786 |
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