CN102757425B - Novel lipoic octanoylhydrazide derivative, preparation method and application thereof - Google Patents
Novel lipoic octanoylhydrazide derivative, preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a novel lipoic octanoylhydrazide derivative, a preparation method and an application thereof, belongs to the technical field of pharmaceutical synthesis and medicine technology, and aims to solve the problem that the effect of the lipoic octanoylhydrazide derivative on an anti-tumor activity is not reported in the prior art. The compound is obtained through a hydrazone reaction of the lipoic octanoylhydrazide which serves as a raw material with a compound aldehyde presented in formula IV. The lipoic octanoylhydrazide compound has the advantages of being novel in structure, high in biological activity, provided with an inhabitation effect on tumors, and capable of being applied to food or pharmaceutical preparations for preventing or curing tumor diseases. The preparation method has the advantages of being short in process route, easy to operate and low in cost; and obtained products are high in yield and purity.
Description
Technical field
The present invention relates to a kind of sulphur decoyl hydrazine derivative, particularly relate to a kind of sulphur decoyl hydrazine derivative itself and preparation method and application, belong to pharmaceutical synthesis and medical art.
Background technology
Thioctic Acid has a lot of unique physiologically active, as diabetes, apoplexy, cardiovascular disorder, hepatopathy, skin carcinoma etc., thus quite pay close attention to by investigator, and lipoic acid derivatives often can strengthen the high-efficiency low-toxicity of Thioctic Acid as medicine, thus become study hotspot in recent years.As international patent application (publication number: WO2008/131117A1; publication date: on October 30th, 2008) disclose a kind of lipoic acid derivatives, specifically disclose di-acetyl sulfydryl Thioctic Acid, two benzoyl sulfydryl Thioctic Acid and other similar single, double mercapto acylated derivatives etc. and all to cancer cells, there is certain restraining effect.And for example Chinese patent application (publication number: CN101787013A, publication date: on 07 28th, 2010) also disclose a kind of Thioctamide analog derivative and preparation method thereof, and disclose the effect that this compounds has the low and good anti-tumor activity of acute toxicity, can be applicable to functional food or the medicine of preparing prevention or treatment tumor disease, it all has good restraining effect to people lung cancer NCI-460, human ovarian cancer HO-8910, people's squamous cell carcinoma KB and Human hepatocarcinoma cell line SMMC-7721.But, report over cure decoyl hydrazine derivative compound and preparation method thereof is seldom had in existing document, its report in anti-tumor activity is not reported yet, particularly sulphur decoyl hydrazine hydrazone analog derivative compound was not also in the news and synthetic method and the report in anti-tumor activity so far, made the blank studied in anti-tumor activity at sulphur decoyl hydrazine derivative compound.
Summary of the invention
The present invention is directed to exist in above prior art not to the problem that the anti-tumor activity aspect of sulphur decoyl hydrazine derivative is reported, propose a kind ofly to have compared with high biological activity, to the inhibited sulphur decoyl hydrazine derivative compound of tumour.
Second object of the present invention is to provide the preparation method of the sulphur decoyl hydrazine derivative that a kind of raw material is easy to get, operational path is short, and the method can obtain sulphur decoyl hydrazine derivative.
3rd object of the present invention is to provide the application of a kind of sulphur decoyl hydrazine derivative in the functional food preparing prevention or treatment tumour or medicine.
An object of the present invention is achieved by the following technical programs, a kind of sulphur decoyl hydrazine derivative type I compound, and the general formula of this compound is:
R wherein described in type I compound is selected from substituted-phenyl, furyl
in one.
Above-mentioned a kind of sulphur decoyl hydrazine derivative of the present invention is a kind of new compound, due to the beneficial effect of Thioctic Acid compound in anti-tumor activity, is conducive to making major contribution in treatment tumor disease.The present invention is by providing a kind of sulphur decoyl hydrazine derivative to the improvement of Thioctic Acid structure, there is the feature of novel structure, find that it has higher biological activity by analysis and research, to tumour cell, there is good restraining effect, with the restraining effect (IC of cis-platinum to tumour cell
50: μ g/mL) to compare, sulphur decoyl hydrazine derivative compound of the present invention can realize the restraining effect to tumour cell, and the restraining effect of some sulphur decoyl hydrazine derivative compound on tumor cells can reach and the restraining effect (IC of cis-platinum to tumour cell
50: μ g/mL) suitable intensity.So sulphur decoyl hydrazine derivative of the present invention is expected to the food and the pharmaceutical preparation that are applied in prevention and therapy tumour aspect, described pharmaceutical preparation can be pharmaceutically acceptable any formulation, as tablet, capsule, liquid preparation etc.
In above-mentioned sulphur decoyl hydrazine derivative type I compound, described substituted-phenyl is
described R
1be selected from the one in hydrogen, halogen; Described R
2be selected from the one in hydrogen, hydroxyl, alkoxyl group, halogen; Described R
3be selected from the one in hydrogen, hydroxyl, dimethylamino, halogen, alkoxyl group, nitro; Described furyl
be selected from the one in furans-2-base, furans-3-base.
As preferably, in above-mentioned sulphur decoyl hydrazine derivative type I compound, wherein R
1, R
2and R
3described in halogen be selected from one in chlorine, fluorine; Wherein R
2and R
3described in alkoxyl group be selected from one in methoxyl group, oxyethyl group, propoxy-.Because methoxyl group, oxyethyl group, propoxy-are all similar substituted radicals, substantially similar effect can both be reached.
Second object of the present invention is achieved by the following technical programs, a kind of preparation method of sulphur decoyl hydrazine derivative type I compound, and the method comprises the following steps:
Under organic solvent existent condition, formula III compound sulphur decoyl hydrazine and formula IV compound are carried out hydrazone and are obtained by reacting type I compound:
Wherein, the R described in formula IV compound is selected from substituted-phenyl, furyl
in one.Wherein, the R described in type I compound is corresponding with the R described in formula IV compound.
In the preparation method of above-mentioned sulphur decoyl hydrazine derivative type I compound, the reaction equation of the preparation method of described sulphur decoyl hydrazine derivative is as follows:
In the preparation method of above-mentioned sulphur decoyl hydrazine derivative type I compound, the preparation method of described formula III compound sulphur decoyl hydrazine comprises the following steps:
Under alcoholic solvent and catalyzer existent condition, formula II compound Thioctic Acid and hydrazine hydrate are carried out hydrazine and are obtained by reacting formula III compound sulphur decoyl hydrazine:
In the preparation method of above-mentioned sulphur decoyl hydrazine derivative type I compound, the reaction equation of the preparation method of described formula III compound Thioctic Acid hydrazides is as follows:
In the preparation method of above-mentioned sulphur decoyl hydrazine derivative type I compound, described organic solvent is selected from one or more in alcohols, ester class, ethers, halogenated hydrocarbon.These solvents can effectively make the raw material of reaction and product dissolve, and make the carrying out being conducive to reacting, and add above-mentioned organic solvent simultaneously and reaction conditions can also be made gentle, reduce by product, improve the quality of products.As preferably, described alcohols is selected from C
1~ C
5lower alcohol, as methyl alcohol, ethanol, propyl alcohol, Virahol etc.; Described ester class is selected from ethyl acetate, ethyl ester propyl etc.; Described halogenated hydrocarbon is selected from methylene dichloride, trichloromethane etc.; Described ethers is selected from tetrahydrofuran (THF) etc.As further preferred, described organic solvent is selected from one or more in methyl alcohol, propyl alcohol, ethanol, ethyl acetate, methylene dichloride, trichloromethane, tetrahydrofuran (THF).
In the preparation method of above-mentioned sulphur decoyl hydrazine derivative type I compound, described formula III compound sulphur decoyl hydrazine and the mol ratio of formula IV compound are 1:1 ~ 2.0.In this molar ratio range, can the waste of more effective minimizing raw material, reduce production cost, can make that reaction is more effective to be carried out, improve reaction efficiency and yield, can improve the quality of products.As preferably, described formula III compound sulphur decoyl hydrazine and the mol ratio of formula IV compound are 1:1 ~ 1.2.
In the preparation method of above-mentioned sulphur decoyl hydrazine derivative type I compound, the temperature of described hydrazoneization reaction is-10 DEG C ~ 30 DEG C, and the described hydrazone reaction times is 0.5 ~ 5.0 hour.Under the condition of above-mentioned hydrazoneization reaction, the efficiency of reaction can be improved, be conducive to production operation, and can also improve the quality of products.As preferably, the temperature of described hydrazoneization reaction is-5.0 DEG C ~ 10 DEG C, and the described hydrazone reaction times is 1.0 ~ 3.0 hours.
In the preparation method of above-mentioned sulphur decoyl hydrazine derivative type I compound, also comprise aftertreatment after described hydrazoneization reaction terminates, described aftertreatment comprises the following steps:
Reaction solution distillation after hydrazoneization reaction being terminated, except desolventizing, obtains residuum, then residuum purifying is obtained type I compound.The purity of product further can be improved by aftertreatment purifying.
In the preparation method of above-mentioned sulphur decoyl hydrazine derivative type I compound, the purifying described in aftertreatment comprises column chromatography purification or recrystallization purifying.
In the preparation method of above-mentioned sulphur decoyl hydrazine derivative type I compound, the alcoholic solvent in the preparation method of described formula III compound sulphur decoyl hydrazine is selected from C
1~ C
5lower alcohol.Adopt lower alcohol to be conducive to the carrying out reacted, the efficiency of follow-up solvent recuperation process can also be ensured, enhance productivity.As preferably, described alcoholic solvent is dehydrated alcohol.Dehydrated alcohol is adopted also to have the effect of low toxicity.
In the preparation method of above-mentioned sulphur decoyl hydrazine derivative type I compound, the add-on of described catalyzer is 1.0% ~ 5.0% of the weight of formula II compound Thioctic Acid.Adding catalyzer makes reaction carry out to positive dirction, reduces the generation of impurity, improves the quality of products.As preferably, described catalyzer is alkane acyl chlorides.Above-mentioned alkane acyl chlorides is C
1~ C
5alkane acyl chlorides, as Acetyl Chloride 98Min., propionyl chloride, butyryl chloride, valeryl chloride etc.As further preferred, described catalyzer is selected from the one in Acetyl Chloride 98Min., propionyl chloride.Carboxylate is reacted into first adopting thionyl chloride, ethanol and Thioctic Acid in prior art, again carboxylate and hydrazine hydrate are obtained by reacting compared with sulphur decoyl hydrazine, the present invention selects alkane acyl chlorides as catalyzer, do not need stepwise synthesis, adopt " one kettle way " reaction can be obtained by reacting sulphur decoyl hydrazine, decrease the process of pilot process to a great extent, more be conducive to suitability for industrialized production, and after adopting above-mentioned catalyzer of the present invention, consumption is few, in reaction process, side reaction is few, reduces the generation of impurity, is more conducive to the quality and the yield that ensure product.
In the preparation method of above-mentioned sulphur decoyl hydrazine derivative type I compound, described formula II compound Thioctic Acid and the mol ratio of hydrazine hydrate are 1:1.0 ~ 1.5.Reduce wastage of material, the generation of by product can also be reduced, improve the quality of products, reduce the difficulty of aftertreatment, can enhance productivity equally.As preferably, described formula II compound Thioctic Acid and the mol ratio of hydrazine hydrate are 1:1.0 ~ 1.2.
In the preparation method of above-mentioned sulphur decoyl hydrazine derivative type I compound, the temperature of the reaction of the hydrazineization described in preparation method of described formula III compound sulphur decoyl hydrazine is 10 DEG C ~ 80 DEG C, and the time of described hydrazineization reaction is 3 ~ 24 hours.As preferably, the temperature of described hydrazineization reaction is 20 DEG C ~ 60 DEG C, and the time of described hydrazineization reaction is 4 ~ 20 hours.Further preferred, the temperature of described hydrazineization reaction is 30 DEG C ~ 40 DEG C, and the time of described hydrazineization reaction is 5 ~ 10 hours.
In the preparation method of above-mentioned sulphur decoyl hydrazine derivative type I compound, also comprise extraction, drying, distillation after the reaction described in preparation method of described formula III compound sulphur decoyl hydrazine terminates, obtain formula III compound sulphur decoyl hydrazine.In particular, add water and extraction agent extracts to reaction in the reaction solution after terminating, add siccative and carry out drying treatment, collecting by filtration filtrate in the organic phase that extraction obtains, distillation, except desolventizing, obtains formula III compound sulphur decoyl hydrazine.The sulphur decoyl hydrazine obtained does not need to be further purified, and can be directly used in next step Reactive Synthesis sulphur decoyl hydrazine derivative type I compound.Described extraction agent is the insoluble or slightly soluble of water, and has better deliquescent organic solvent to sulphur decoyl hydrazine.Enabling to realize being separated preferably with aqueous phase when extracting, can be good at again product to extract in organic phase.As preferably, described extraction agent is selected from the one in ethyl acetate, chloroform, methylene dichloride; Described siccative is selected from anhydrous sodium sulphate, anhydrous sodium carbonate etc.
3rd object of the present invention is achieved by the following technical programs, a kind of application of sulphur decoyl hydrazine derivative, the application of described sulphur decoyl hydrazine derivative in the functional food preparing prevention or treatment tumour or pharmaceutical preparation.Because sulphur decoyl hydrazine derivative of the present invention has higher biological activity, and to tumour, there is good restraining effect.Therefore, it is possible to for the preparation of prevention or functional food or the pharmaceutical preparation for the treatment of tumour.
In the application of above-mentioned sulphur decoyl hydrazine derivative, described tumour comprises fibrosarcoma, human breast carcinoma, people's lung cancer, human colon carcinoma, human leukemia, people's liver cancer, human ovarian cancer, human prostata cancer, human cervical carcinoma, people's kidney, people's cancer of the stomach.
In sum, the present invention compared with prior art, has the following advantages:
1. sulphur decoyl hydrazine derivative of the present invention, there is the feature of novel structure, have comparatively high biological activity, to tumour cell, there is certain restraining effect, and there is the low advantage of toxicity, very low to the acute toxicity of mouse, there is good application prospect, especially in the food for preventing or treat in tumor disease or pharmaceutical preparation, can coordinate to pharmaceutically acceptable auxiliary material and make corresponding pharmaceutical preparation, as tablet, capsule or liquid preparation etc.
2. to have synthetic route short for the preparation method of sulphur decoyl hydrazine derivative of the present invention, and be easier to operation, raw material is easy to get, and production cost is lower, and practicality is high, is conducive to industrial applications.
3. the preparation method of sulphur decoyl hydrazine derivative of the present invention, the synthesis technique of raw material sulphur decoyl hydrazine used adopts " one kettle way " reaction, not only easy handling, and the product sulfur decoyl hydrazine yield obtained is high, the molar yield of sulphur decoyl hydrazine can reach more than 85%, and purity is high.Be reacted into carboxylate with first adopting thionyl chloride, ethanol and Thioctic Acid in prior art, then carboxylate and hydrazine hydrate be obtained by reacting compared with sulphur decoyl hydrazine, substantially increase quality product and yield, the product yield finally obtained and purity are all higher.
Accompanying drawing explanation
Fig. 1 is N '-2-chlorobenzene methylene radical-5-of the present invention (1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-7)
1h-NMR spectrogram;
Fig. 2 is N ' of the present invention-(3-methoxyl group-4-hydroxyl) α-tolylene-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-8)
1h-NMR spectrogram.
Embodiment
Below by specific embodiment, technical scheme of the present invention is described in further detail, but the present invention is not limited to these embodiments.
Embodiment 1
The preparation of sulphur decoyl hydrazine
40mL anhydrous ethanol solvent is added in the four-hole bottle of 100mL, add catalyst acetyl chloride again, the add-on of Acetyl Chloride 98Min. is 5.0% of Thioctic Acid weight, namely Acetyl Chloride 98Min. 0.1g is added, under alcoholic solvent dehydrated alcohol and catalyst acetyl chloride existent condition, add Thioctic Acid 2.06g (10mmol), stir 15 minutes under room temperature condition, then, at ambient temperature, slowly add the hydrazine hydrate aqueous solution that mass concentration is 80%, the add-on of hydrazine hydrate is make the mol ratio of Thioctic Acid and hydrazine hydrate be 1:1, then 80 DEG C are warming up under agitation, control temperature is under the condition of 80 DEG C, stir hydrazine and react 3 hours, after hydrazineization reaction terminates, add 10mL water, and then add 40mL ethyl acetate solvent and extract, stir 30 minutes, leave standstill 30 minutes, organic phase is collected in layering, in organic phase, add 0.5g anhydrous magnesium sulfate again carry out drying, stir 30 minutes, filter, collect filtrate, the filtrate obtained is joined in another four-hole bottle, under stirring, control vacuum distillation temperature within 35 DEG C, carry out underpressure distillation, remove solvent, be distilled to dry, obtain solid residue sulphur decoyl hydrazine 2.0g, molar yield is 91%, HPLC detects, purity is 95%, the product obtained is directly used in next step reaction.
Embodiment 2
The preparation of sulphur decoyl hydrazine
40mL methanol solvate is added in the four-hole bottle of 100mL, add catalyzer propionyl chloride again, the add-on of propionyl chloride is 3.0% of Thioctic Acid weight, namely propionyl chloride 0.06g is added, under alcoholic solvent methyl alcohol and catalyzer propionyl chloride existent condition, add Thioctic Acid 2.06g (10mmol), stir 30 minutes under room temperature condition, then, at ambient temperature, slowly add the hydrazine hydrate aqueous solution that mass concentration is 80%, the add-on of hydrazine hydrate is make the mol ratio of Thioctic Acid and hydrazine hydrate be 1:1.2, then 60 DEG C are warming up under agitation, control temperature is under the condition of 60 DEG C, stir hydrazine and react 5 hours, after hydrazineization reaction terminates, add 10mL water, and then add 40mL ethyl acetate solvent and extract, stir 30 minutes, leave standstill 30 minutes, organic phase is collected in layering, aqueous phase ethyl acetate extracts 1 ~ 2 time again, collect organic phase, merge all organic phases, in organic phase, add 0.5g anhydrous sodium sulphate again carry out drying, stir 30 minutes, filter, collect filtrate, the filtrate obtained is joined in another four-hole bottle, under stirring, control vacuum distillation temperature within 35 DEG C, carry out underpressure distillation, remove solvent, be distilled to dry, obtain solid residue sulphur decoyl hydrazine 1.95g, molar yield is 85%, HPLC detects, purity is 95.5%, the product sulfur decoyl hydrazine obtained is directly used in next step reaction.
Embodiment 3
The preparation of sulphur decoyl hydrazine
40mL isopropanol solvent is added in the four-hole bottle of 100mL, add catalyst acetyl chloride again, the add-on of Acetyl Chloride 98Min. is 1.0% of Thioctic Acid weight, namely Acetyl Chloride 98Min. 0.02g is added, under alcoholic solvent Virahol and catalyst acetyl chloride existent condition, add Thioctic Acid 2.06g (10mmol), stir 30 minutes under room temperature condition, then, at ambient temperature, slowly add the hydrazine hydrate aqueous solution that mass concentration is 80%, the add-on of hydrazine hydrate is make the mol ratio of Thioctic Acid and hydrazine hydrate be 1:1.5, then under agitation, control temperature is under the condition of 20 DEG C, stir hydrazine and react 20 hours, after hydrazineization reaction terminates, add 10mL water, and then add 40mL chloroform solvent and extract, stir 30 minutes, leave standstill 30 minutes, organic phase is collected in layering, in organic phase, add 0.5g anhydrous magnesium sulfate again carry out drying, stir 30 minutes, the filtrate obtained is joined in another four-hole bottle, under stirring, control vacuum distillation temperature below 30 DEG C, carry out underpressure distillation, remove solvent, be distilled to dry, obtain solid residue sulphur decoyl hydrazine 1.97g, molar yield is 89.4%, HPLC detects, purity is 95.2%, the product sulfur decoyl hydrazine obtained is directly used in next step reaction.
Embodiment 4
The preparation of sulphur decoyl hydrazine
40mL anhydrous ethanol solvent is added in the four-hole bottle of 100mL, add catalyzer butyryl chloride again, the add-on of butyryl chloride is 2.5% of Thioctic Acid weight, namely butyryl chloride 0.05g is added, under alcoholic solvent dehydrated alcohol and catalyzer butyryl chloride existent condition, add Thioctic Acid 2.06g (10mmol), stir 1 hour under room temperature condition, then, at ambient temperature, slowly add the hydrazine hydrate aqueous solution that mass concentration is 80%, the add-on of hydrazine hydrate is make the mol ratio of Thioctic Acid and hydrazine hydrate be 1:1.05, then under agitation, control temperature is under the condition of 10 DEG C, stir hydrazine and react 24 hours, after hydrazineization reaction terminates, add 10mL water, and then add 40mL chloroform solvent and extract, stir 30 minutes, leave standstill 30 minutes, organic phase is collected in layering, aqueous phase chloroform extracts 1 ~ 2 time again, collect organic phase, merge all organic phases of collecting, the all organic phases obtained are joined in another four-hole bottle, in organic phase, add 0.5g anhydrous sodium sulphate again carry out drying, stir 30 minutes, filter, collect filtrate, the filtrate obtained is joined in another four-hole bottle, under stirring, control vacuum distillation temperature within 30 DEG C, carry out underpressure distillation, remove solvent, be distilled to dry, obtain solid residue sulphur decoyl hydrazine 1.95g, molar yield is 88.5%, HPLC detects, purity is 95.1%, the product sulfur decoyl hydrazine obtained is directly used in next step reaction.
Embodiment 5
The preparation of N '-to chlorobenzene methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-1)
30mL dehydrated alcohol is added in the four-hole bottle of 100mL, under anhydrous ethanol solvent existent condition, add 4-chloro-benzaldehyde 0.70g (5mmol) again, under agitation condition, be cooled to 0 DEG C, add sulphur decoyl hydrazine 1.10g (5mmol) again, then, control temperature is under the condition of 0 DEG C, under agitation condition, make 4-chloro-benzaldehyde and sulphur decoyl hydrazine carry out hydrazone and react 1 hour, after reaction terminates, for improving product purity further, carry out aftertreatment, namely the reaction solution after adopting Rotary Evaporators above-mentioned reaction to be terminated carries out the solvent in underpressure distillation removal system, control vacuum distillation temperature below 35 DEG C, be distilled to dry residuum, column chromatography is adopted by residuum to carry out purifying, column chromatography eluent used is CH
2cl
2: PE=1:1, above-mentioned PE is sherwood oil, column chromatography sorbent material used is silica gel, is adopted to rotate by the elutriant being rich in final product obtained and steams instrument underpressure distillation, control vacuum distillation temperature below 35 DEG C after column chromatography, be distilled to dry, obtain final product 1.28g faint yellow solid N '-to chlorobenzene methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine, molar yield is 75.0%, HPLC detects, and purity is 98.5%.To the product N ' obtained-analyze chlorobenzene methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine, concrete analysis result is as follows:
Fusing point (m.p.): 115 DEG C ~ 117 DEG C; MS (m/z, %): 343.1 (M+H
+);
1H-NMR(CDCl
3,500MHz)δ：8.66(s,1H,CH＝N),8.55(d,2H,J＝8.6Hz),7.64(d,2H,J＝8.6Hz),3.59(m,1H,-S-CH-),3.20-3.09(m,2H,-S-CH
2-),2.47(t,2H,-CH
2-CO-),1.96-1.50(m,8H,-CH
2-CH-CH
2-CH
2-CH
2-)；
IR(KBr)ν：3172cm
-1,3080cm
-1,2929cm
-1,2845cm
-1,1667cm
-1,1400cm
-1,1346cm
-1,1080cm
-1；
Anal.calcd?for?C
15H
19N
3O
3S
2：C，52.54；H，5.58；N，8.17；O，4.67；Found：C，52.41；H，5.49；N，8.43；O，4.55。
Embodiment 6
The preparation of N '-to chlorobenzene methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-1)
First prepare sulphur decoyl hydrazine according to the method for embodiment 1, the sulphur decoyl hydrazine obtained does not need to be further purified, and is directly used in synthesis N '-to chlorobenzene methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-1);
Namely in the four-hole bottle of 100mL, 40mL dehydrated alcohol is added, under anhydrous ethanol solvent existent condition, add 4-chloro-benzaldehyde 0.84g (6mmol) again, under agitation condition, be cooled to-10 DEG C, add above-mentioned sulphur decoyl hydrazine 1.10g (5mmol) prepared again, then, under stirring, control temperature is under the condition of-10 DEG C, make 4-chloro-benzaldehyde and sulphur decoyl hydrazine carry out hydrazone and react 3 hours, after reaction terminates, for improving product purity further, carry out aftertreatment, namely the reaction solution after adopting Rotary Evaporators above-mentioned reaction to be terminated carries out the solvent in underpressure distillation removal system, control vacuum distillation temperature within 35 DEG C, be distilled to and dryly obtain residuum, the residuum obtained is carried out recrystallization, add in 20mL dehydrated alcohol by residuum, under stirring, be warming up to backflow molten clear after, stir 30 minutes, then, slow cooling to 0 DEG C ~ 5 DEG C, control temperature, stirred crystallization 30 minutes, filter, obtain final product 1.35g faint yellow solid N '-to chlorobenzene methylene radical-5-(1, 2-dithio pentamethylene-3-base) valeryl hydrazine, molar yield is 78.7%, HPLC detects, purity is 98.6%.
Embodiment 7
The preparation of N '-p-nitrophenyl methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-2)
30mL dehydrated alcohol is added in 100mL four-hole bottle, under anhydrous ethanol solvent existent condition, add paranitrobenzaldehyde 0.75g (5mmol) again, under agitation condition, be cooled to 0 DEG C, add sulphur decoyl hydrazine 1.10g (5mmol) again, then, control temperature is under the condition of 0 DEG C, under agitation condition, make paranitrobenzaldehyde and sulphur decoyl hydrazine carry out hydrazone and react 0.5 hour, after reaction terminates, for improving product purity further, carry out aftertreatment, namely the reaction solution after adopting Rotary Evaporators above-mentioned reaction to be terminated carries out the solvent in underpressure distillation removal system, control vacuum distillation temperature below 40 DEG C, be distilled to dry residuum, column chromatography is adopted by residuum to carry out purifying, column chromatography eluent used is CH
2cl
2: PE=1:1, above-mentioned PE is sherwood oil, column chromatography sorbent material used is silica gel, is adopted to rotate by the elutriant being rich in final product obtained and steams instrument underpressure distillation, control vacuum distillation temperature below 40 DEG C after column chromatography, be distilled to dry, obtain final product 1.37g faint yellow solid N '-p-nitrophenyl methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine, molar yield is 78.0%, HPLC detects, and purity is 99.0%.Analyze the product N ' obtained-p-nitrophenyl methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine, concrete analysis result is as follows:
Fusing point (m.p.): 135 DEG C ~ 137 DEG C; MS (m/z, %): 354.1 (M+H
+);
1H-NMR(CDCl
3,500MHz)δ：8.62(s,1H,CH＝N),8.20(d,2H,J＝8.8Hz),7.68(d,2H,J＝8.8Hz),3.59(m,1H,-S-CH-),3.21-3.09(m,2H,-S-CH
2-),2.45(t,2H,-CH
2-CO-),1.98-1.51(m,8H,-CH
2-CH-CH
2-CH
2-CH
2-)；
IR(KBr)ν：3103cm
-1，2928cm
-1,2845cm
-1,2376cm
-1,1697cm
-1,1525cm
-1,1342cm
-1,1190cm
-1；
Anal.calcd?for?C
15H
19N
3O
3S
2：C,50.97；H,5.42；N,11.89；O,13.58；Found：C，51.08；H，5.36；N，12.01；O，13.44。
Embodiment 8
The preparation of N '-p-nitrophenyl methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-2)
First prepare sulphur decoyl hydrazine according to the method for embodiment 3, the sulphur decoyl hydrazine obtained does not need to be further purified, and is directly used in synthesis N '-p-nitrophenyl methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-2);
40mL Virahol is added in 100mL four-hole bottle, under isopropanol solvent existent condition, add paranitrobenzaldehyde 1.12g (7.5mmol) again, under agitation condition, be cooled to-5 DEG C, add sulphur decoyl hydrazine 1.10g (5.0mmol) again, then, control temperature is under the condition of-5 DEG C, under agitation condition, make paranitrobenzaldehyde and sulphur decoyl hydrazine carry out hydrazone and react 3.5 hours, after reaction terminates, for improving product purity further, carry out aftertreatment, namely the reaction solution after adopting Rotary Evaporators above-mentioned reaction to be terminated carries out the solvent in underpressure distillation removal system, control vacuum distillation temperature within 35 DEG C, be distilled to dry residuum, column chromatography is adopted by residuum to carry out purifying, column chromatography eluent used is CH
2cl
2: PE=1:1, above-mentioned PE is sherwood oil, column chromatography sorbent material used is silica gel, is adopted to rotate by the elutriant being rich in final product obtained and steams instrument underpressure distillation, control vacuum distillation temperature below 35 DEG C after column chromatography, be distilled to dry, obtain final product 1.42g faint yellow solid N '-p-nitrophenyl methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine, molar yield is 80%, HPLC detects, and purity is 98.7%.
Embodiment 9
The preparation of N '-to fluorobenzylidene-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-3)
30mL methanol solvate is added in the four-hole bottle of 100mL, under methanol solvate existent condition, add p-Fluorobenzenecarboxaldehyde 0.62g (5mmol) again, under agitation condition, be cooled to 0 DEG C, add sulphur decoyl hydrazine 1.10g (5mmol) again, then, control temperature is under the condition of 0 DEG C, under agitation condition, make p-Fluorobenzenecarboxaldehyde and sulphur decoyl hydrazine carry out hydrazone and react 1 hour, after reaction terminates, for improving product purity further, carry out aftertreatment, namely the reaction solution after adopting Rotary Evaporators above-mentioned reaction to be terminated carries out the solvent in underpressure distillation removal system, control vacuum distillation temperature below 30 DEG C, be distilled to dry residuum, residuum is carried out purifying through column chromatography, column chromatography eluent used is CH
2cl
2: PE=1:1, above-mentioned PE is sherwood oil, the elutriant being rich in final product obtained after column chromatography is adopted to rotate and steams instrument underpressure distillation, control vacuum distillation temperature below 35 DEG C, be distilled to dry, obtain final product 1.32g faint yellow solid N '-to fluorobenzylidene-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine, productive rate is that 81%, HPLC detects, and purity is 98.6%.To the product N ' obtained-analyze fluorobenzylidene-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine, concrete analysis result is as follows:
Fusing point (m.p.): 108 ~ 110 DEG C; MS. (m/z, %) .327.1 (M+H
+);
1H-NMR(CDCl
3,500MHz)δ：8.64(s,1H,CH＝N),7.85(q,2H,
3J
FH＝8.6Hz,
4J
FH＝5.5Hz),7.16(t,2H,J＝8.6Hz),3.60(m,1H,-S-CH-),3.22-3.10(m,2H,-S-CH
2-),2.48(t,2H,J＝6.3Hz,-CH
2-CO-),1.96-1.56(m,8H,-CH
2-CH-CH
2-CH
2-CH
2-)；
IR(KBr)ν：3058cm
-1，2921cm
-1，2845cm
-1，1636cm
-1，1598cm
-1，1502cm
-1,1411cm
-1,1245cm
-1,1156cm
-1,1091cm
-1；
Anal.calcd?for?C
15H
19FN
2OS
2：C，55.19；H，5.87；F，5.82；N，8.58；Found：C，55.28；H，6.05；F，5.66；N，8.59。
Embodiment 10
The preparation of N '-to fluorobenzylidene-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-3)
First prepare sulphur decoyl hydrazine according to the method for embodiment 3, the sulphur decoyl hydrazine obtained does not need to be further purified, and is directly used in synthesis N '-to fluorobenzylidene-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-3);
30mL tetrahydrofuran solvent is added in the four-hole bottle of 100mL, under tetrahydrofuran solvent existent condition, add p-Fluorobenzenecarboxaldehyde 1.24g (10mmol) again, under agitation condition, be cooled to 10 DEG C, add sulphur decoyl hydrazine 1.10g (5mmol) again, then, under agitation condition, control temperature is under the condition of 10 DEG C, make p-Fluorobenzenecarboxaldehyde and sulphur decoyl hydrazine carry out hydrazone and react 2.0 hours, after reaction terminates, for improving product purity further, carry out aftertreatment, reaction solution after namely described aftertreatment adopts Rotary Evaporators above-mentioned reaction to be terminated carries out the solvent in underpressure distillation removal system, control vacuum distillation temperature within 30 DEG C, be distilled to dry residuum, the residuum obtained is carried out recrystallization, namely in residuum, 20mL Virahol is added, under stirring, be warming up to backflow molten clear after, stir 30 minutes, then, slow cooling to 0 DEG C ~ 5 DEG C, control temperature, stirred crystallization 30 minutes, filter, obtain 1.26g faint yellow solid N '-to fluorobenzylidene-5-(1, 2-dithio pentamethylene-3-base) valeryl hydrazine, molar yield is 77%, HPLC detects, purity is 98.5%.
Embodiment 11
The preparation of N '-2,4 dichloro benzene methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-4)
30mL tetrahydrofuran (THF) is added in the four-hole bottle of 100mL, under tetrahydrofuran solvent existent condition, add 2 again, 4-dichlorobenzaldehyde 0.88g (5mmol), under agitation condition, be cooled to 0 DEG C, add sulphur decoyl hydrazine 1.10g (5mmol) again, then, control temperature is under the condition of 0 DEG C, under agitation condition, make 2, 4-dichlorobenzaldehyde and sulphur decoyl hydrazine carry out hydrazone and react 1 hour, after reaction terminates, for improving product purity further, carry out aftertreatment, namely the reaction solution after adopting Rotary Evaporators above-mentioned reaction to be terminated carries out the solvent in underpressure distillation removal system, control vacuum distillation temperature within 35 DEG C, be distilled to dry residuum, residuum is carried out purifying through column chromatography, column chromatography eluent used is CH
2cl
2: PE=1:1, above-mentioned PE is sherwood oil, and column chromatography sorbent material used is silica gel, is adopted to rotate by the elutriant being rich in final product obtained and steam instrument underpressure distillation after column chromatography, control vacuum distillation temperature below 35 DEG C, be distilled to dry, obtain final product 1.59g faint yellow solid N '-2,4 dichloro benzene methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine, productive rate is that 84%, HPLC detects, and purity is 98.6%.Analyze the product N ' obtained-2,4 dichloro benzene methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine, concrete analysis result is as follows:
Fusing point (m.p.) 135 DEG C ~ 137 DEG C; MS (m/z, %): 377.0 (M+H
+);
1H-NMR(CDCl
3,500MHz)δ：8.69(s,1H,CH＝N),8.07(d,1H,J＝8.6Hz),7.75(s,1H),7.55(d,1H,J＝8.6Hz),3.59(m,1H,-S-CH-),3.19-3.08(m,2H,-S-CH
2-),2.45(t,2H,-CH
2-CO-),1.98-1.53(m,8H,-CH
2-CH-CH
2-CH
2-CH
2-)；
IR(KBr)ν：3185cm
-1，3083cm
-1，2939cm
-1，2855cm
-1，1667cm
-1，1599cm
-1，1463cm
-1，1401cm
-1，1095cm
-1；
Anal.calcd?for?C
15H
18Cl
2N
2OS
2：C，47.74；H，4.81；N，7.42；O，4.24；Found：C，47.89；H,5.06；N，7.66；O，4.08。
Embodiment 12
The preparation of N '-2,4 dichloro benzene methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-4)
First prepare sulphur decoyl hydrazine according to the method for embodiment 5, the sulphur decoyl hydrazine obtained does not need to be further purified, and is directly used in synthesis N '-2,4 dichloro benzene methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-4);
30mL methylene dichloride is added in the four-hole bottle of 100mL, under dichloromethane solvent existent condition, add 2 again, 4-dichlorobenzaldehyde 0.97g (5.5mmol), under agitation condition, be cooled to-10 DEG C, add sulphur decoyl hydrazine 1.10g (5mmol) prepared according to the method described above again, then, under agitation condition, control temperature is under the condition of-10 DEG C ~-5 DEG C, make 2, 4-dichlorobenzaldehyde and sulphur decoyl hydrazine carry out hydrazone and react 2.5 hours, after reaction terminates, for improving product purity further, carry out aftertreatment, reaction solution after namely described aftertreatment adopts Rotary Evaporators above-mentioned reaction to be terminated carries out the solvent in underpressure distillation removal system, control vacuum distillation temperature below 25 DEG C, be distilled to and dryly obtain residuum, the residuum obtained is carried out recrystallization, namely add in residuum in 20mL dehydrated alcohol, under stirring, be warming up to backflow molten clear after, stir 30 minutes, then, slow cooling to 0 DEG C ~ 5 DEG C, control temperature, stirred crystallization 30 minutes, filter, obtain 1.61g faint yellow solid N '-2, 4-dichlorobenzene methylene radical-5-(1, 2-dithio pentamethylene-3-base) valeryl hydrazine, molar yield is 86%, HPLC detects, purity is 98.7%.
Embodiment 13
The preparation of N '-4-(N, N-dimethylamino) α-tolylene-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-5)
30mL dehydrated alcohol is added in the four-hole bottle of 100mL, under anhydrous ethanol solvent existent condition, add 4-(N again, N-dimethylamino) phenyl aldehyde 0.75g (5mmol), under agitation condition, under room temperature condition, add sulphur decoyl hydrazine 1.10g (5mmol) again, control temperature of reaction under the condition of 25 DEG C, make 4-(N, N-dimethylamino) phenyl aldehyde and sulphur decoyl hydrazine carry out hydrazone and react 1 hour, after reaction terminates, for improving product purity further, carry out aftertreatment, namely the reaction solution after adopting Rotary Evaporators reaction to be terminated carries out the solvent in underpressure distillation removal system, control vacuum distillation temperature below 40 DEG C, be distilled to dry residuum, column chromatography is adopted by residuum to carry out purifying, column chromatography eluent used is CH
2cl
2: PE=1:1, above-mentioned PE are sherwood oil, and column chromatography sorbent material used is silica gel, the elutriant being rich in final product obtained after column chromatography is adopted to rotate and steams instrument underpressure distillation, control vacuum distillation temperature below 35 DEG C, be distilled to dry, obtain final product 0.97
gyellow solid N '-4-(N, N-dimethylamino) α-tolylene-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine, productive rate is 55%, HPLC detection, and purity is 98.1%.Analyze product N '-4-(N, the N-dimethylamino) α-tolylene-5-obtained (1,2-dithio pentamethylene-3-base) valeryl hydrazine, concrete analysis result is as follows:
Fusing point (m.p.): 145 DEG C ~ 147 DEG C (Dec); MS (m/z, %): 352.1 (M+H
+);
1H-NMR(CDCl
3,500MHz)δ：8.59(s,1H,CH＝N),7.72(d,2H,J＝8.8Hz),6.73(d,2H,J＝8.8Hz),3.60(m,1H,-S-CH-),3.22-3.10(m,2H,-S-CH
2-),3.05(s,6H,2CH
3),2.48(t,2H,J＝6.3Hz,-CH
2-CO-),1.98-1.51(m,8H,-CH
2-CH-CH
2-CH
2-CH
2-)；
IR(KBr)ν：3202cm
-1,3035cm
-1,2928cm
-1,2853cm
-1,1655cm
-1,1602cm
-1,1525cm
-1,1358cm
-1,1182cm
-1；
Anal.calcd?for?C
17H
25N
3OS
2：C，58.08；H，7.17；N，11.95；O，4.55；Found：C，58.23；H，7.06；N，12.12；O，4.67。
Embodiment 14
The preparation of N '-4-phenol methylene-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-6)
30mL tetrahydrofuran (THF) is added in the four-hole bottle of 100mL, under tetrahydrofuran solvent existent condition, add 4-hydroxy benzaldehyde 0.61g (5mmol) again, under agitation condition, at room temperature, add sulphur decoyl hydrazine 1.10g (5mmol) again, then, control temperature of reaction under the condition of 35 DEG C, under stirring, make 4-hydroxy benzaldehyde and sulphur decoyl hydrazine carry out hydrazone and react 4 hours, after reaction terminates, for improving product purity further, carry out aftertreatment, namely the reaction solution after adopting Rotary Evaporators above-mentioned reaction to be terminated carries out the solvent in underpressure distillation removal system, control vacuum distillation temperature within 30 DEG C, be distilled to dry residuum, column chromatography is adopted by residuum to carry out purifying, column chromatography eluent used is CH
2cl
2: PE=1:1, above-mentioned PE is sherwood oil, column chromatography sorbent material used is silica gel, is adopted to rotate by the elutriant being rich in final product obtained and steams instrument underpressure distillation, control vacuum distillation temperature below 35 DEG C after column chromatography, be distilled to dry, obtain final product 0.73g yellow solid N '-4-phenol methylene--5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine, productive rate is 45%, HPLC detects, and purity is 98.6%.To product the N '-4-phenol methylene obtained--5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine is analyzed, and concrete analysis result is as follows:
Fusing point (m.p.): 159 DEG C ~ 161 DEG C; MS (m/z, %): 325.1 (M+H
+);
1H-NMR(CDCl
3,500MHz)δ：8.60(s,1H,CH＝N),7.45(d,2H,J＝8.6Hz),6.83(d,2H,J＝8.6Hz),5.42(brs,1H,OH),3.59(m,1H,-S-CH-),3.22-3.10(m,2H,-S-CH
2-),2.47(t,2H,-CH
2-CO-),1.95-1.49(m,8H,-CH
2-CH-CH
2-CH
2-CH
2-)；
IR(KBr)ν：3301cm
-1，3164cm
-1，3058cm
-1，2906cm
-1，2800cm
-1，1606cm
-1，1510cm
-1，1441cm
-1，1274cm
-1，1160cm
-1，1091cm
-1；
Anal.calcd?for?C
15H
20N
2O
2S
2：C，55.53；H，6.21；N，8.63；O，9.86；Found：C，55.68；H，6.25；N，8.59；O，9.62。
Embodiment 15
The preparation of N '-2-chlorobenzene methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-7)
30mL dehydrated alcohol is added in the four-hole bottle of 100mL, under anhydrous ethanol solvent existent condition, add 2-chlorobenzaldehyde 0.70g (5mmol) again, under agitation condition, be cooled to 0 DEG C, add sulphur decoyl hydrazine 1.10g (5mmol) again, then, control temperature is under the condition of 0 DEG C, under agitation condition, make 2-chlorobenzaldehyde and sulphur decoyl hydrazine carry out hydrazone and react 2 hours, after reaction terminates, for improving product purity further, carry out aftertreatment, namely the reaction solution after adopting Rotary Evaporators above-mentioned reaction to be terminated carries out the solvent in underpressure distillation removal system, control vacuum distillation temperature within 35 DEG C, be distilled to dry residuum, column chromatography is adopted by residuum to carry out purifying, column chromatography eluent used is CH
2cl
2: PE=1:1, above-mentioned PE is sherwood oil, column chromatography sorbent material used is silica gel, and the elutriant being rich in final product obtained after column chromatography is adopted Rotary Evaporators underpressure distillation, controls vacuum distillation temperature below 35 DEG C, be distilled to dry, obtain final product 1.28g faint yellow solid N '-2-chlorobenzene methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine, productive rate is 75%, HPLC detects, and purity is 98.6%.Analyze product N '-2-chlorobenzene methylene radical-5-(1,2-dithio pentamethylene-3-base) the valeryl hydrazine obtained, concrete analysis result is as follows:
Fusing point (m.p.): 159 DEG C ~ 161 DEG C;
MS(m/z,％)：343.5(M+H
+),382.2(M+K)
+；
1H-NMR(CDCl
3，500MHz)δ:9.34(s，1H，CH＝N)，8.20(s，1H，NH)，7.98(d，1H，J＝9.5Hz)，7.40(d，1H，J＝9.5Hz)，7.33(t，2H，J＝9.5Hz)，3.59-3.62(m，1H，-S-CH-)，3.09-3.21(m，2H，-S-CH2-)，2.79(t，J＝7.5Hz，2H，-CH2-CO-)，2.48(m，1H，-S-CH
2-CH-CH-S-)，1.93(m，1H，-S-CH
2-CH-CH-S-)，1.54-1.81(m，6H，-CH
2-CH
2-CH
2-)；
IR(KBr)v:3301cm
-1，3164cm
-1，3058cm
-1，2906cm
-1，2800cm
-1，1606cm
-1，1510cm
-1，1441cm
-1，1274cm
-1，1160cm
-1，1091cm
-1；
Anal.calcdforC
15H
19N
2OS
2:C，52.54；H，5.58；Cl，10.34；N，8.17；0，4.67；Found:C，52.64；H，5.60；Cl，10.27；N，8.14；0，4.71。
Embodiment 16
The preparation of N '-(3-methoxyl group-4-hydroxyl) α-tolylene-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-8)
30mL ethyl acetate is added in the four-hole bottle of 100mL, under ethyl acetate solvent existent condition, add Vanillin 0.76g (5mmol) again, at ambient temperature, add sulphur decoyl hydrazine 1.10g (5mmol), then, control temperature is under the condition of 30 DEG C, under agitation condition, make Vanillin and sulphur decoyl hydrazine carry out hydrazone and react 2 hours, after reaction terminates, for improving product purity further, carry out aftertreatment, namely the reaction solution after adopting Rotary Evaporators above-mentioned reaction to be terminated carries out the solvent in underpressure distillation removal system, control vacuum distillation temperature within 35 DEG C, be distilled to dry residuum, column chromatography is adopted by residuum to carry out purifying, column chromatography eluent used is CH
2cl
2: PE=1:1, above-mentioned PE is sherwood oil, column chromatography sorbent material used is silica gel, and the elutriant being rich in final product obtained after column chromatography is adopted Rotary Evaporators underpressure distillation, controls vacuum distillation temperature below 35 DEG C, be distilled to dry, obtain 1.35g faint yellow solid N '-(3-methoxyl group-4-hydroxyl) α-tolylene-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine, productive rate is 76%, HPLC detects, and purity is 98.5%.Analyze the product N ' obtained-(3-methoxyl group-4-hydroxyl) α-tolylene-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine, concrete analysis result is as follows:
Fusing point (m.p.): 96 DEG C ~ 98 DEG C;
MS(m/z,％)：355.4(M+H
+),377.3(M+Na)
+；
1H-NMR(CDCl
3,500MHz)δ：9.09(s,1H,CH＝N)，7.68(s,1H,NH)，7.27(s,1H,Ar),7.10(d,1H,J＝8.1Hz),6.94(t,2H,J＝9.5Hz)，5.93(brs,1H,OH),3.59-3.62(m,1H,-S-CH-),3.09-3.21(m,2H,-S-CH
2-),2.79(t,J＝7.5Hz,2H,-CH
2-CO-),2.48(m,1H,-S-CH
2-CH-CH-S-),1.93(m,1H,-S-CH
2-CH-CH-S-),1.54-1.81(m,6H,-CH
2-CH
2-CH
2-)；
IR(KBr)ν：3301cm
-1，3164cm
-1，3058cm
-1，2906cm
-1，2800cm
-1，1606cm
-1，1510cm
-1，1441cm
-1，1274cm
-1，1160cm
-1，1091cm
-1；
Anal.calcd?for?C
15H
19N
2OS
2：C，52.54；H，5.58；Cl，10.34；N，8.17；O，4.67；Found：C，52.64；H，5.60；Cl，10.27；N，8.14；O，4.71。
Embodiment 17
The preparation of N '-(furans-2-base) methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-9)
30mL ethyl acetate is added in the four-hole bottle of 100mL, under ethyl acetate solvent existent condition, add furans-2-formaldehyde 0.48g (5mmol) again, add sulphur decoyl hydrazine 1.10g (5mmol) again, then, control temperature of reaction under the condition of 10 DEG C, under agitation condition, make furans-2-formaldehyde and sulphur decoyl hydrazine carry out hydrazone and react 1.5 hours, after reaction terminates, for improving product purity further, carry out aftertreatment, namely the reaction solution after adopting Rotary Evaporators above-mentioned reaction to be terminated carries out the solvent in underpressure distillation removal system, control vacuum distillation temperature below 30 DEG C, be distilled to dry residuum, column chromatography is adopted by residuum to carry out purifying, column chromatography eluent used is CH
2cl
2column chromatography sorbent material used is silica gel, the elutriant being rich in final product obtained after column chromatography is adopted to rotate and steams instrument underpressure distillation, control vacuum distillation temperature below 35 DEG C, be distilled to dry, obtain final product 1.05g faint yellow solid N '-(furans-2-base) methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine, productive rate is that 71%, HPLC detects, and purity is 98.7%.Analyze the product N ' obtained-(furans-2-base) methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine, concrete analysis result is as follows:
Fusing point (m.p.): 159 DEG C ~ 161 DEG C;
MS(m/z,％)：299.3(M+H)
+，382.2(M+K)
+；
1H-NMR(CDCl
3,500MHz)δ：9.32(s,1H,CH＝N),7.64(s,0.65H,NH),7.61(s,0.35H,NH),7.53(s,0.65H,O-CH＝CH-CH＝C),7.02(s,0.35H,O-CH＝CH-CH＝C),6.68-6.71(m,1H,O-CH＝CH-CH＝C),6.50-6.56(m,1H,O-CH＝CH-CH＝C),3.59-3.62(m,1H,-S-CH-),3.11-3.19(m,2H,-S-CH
2-),2.71-2.78(m,2H,-CH
2-CO-),2.46-2.50(m,1H,-S-CH
2-CH-CH-S-),1.93(m,1H,-S-CH
2-CH-CH-S-),1.53-1.79(m,6H,-CH
2-CH
2-CH
2-)；
IR(KBr)ν：3301cm
-1，3164cm
-1,3058cm
-1，2906cm
-1，2800cm
-1，1606cm
-1，1510cm
-1，1441cm
-1，1274cm
-1，1160cm
-1，1091cm
-1；
Anal.calcd?for?C
13H
18N
2O
2S
2：C，52.32；H，6.08；N，9.39；O，10.72；Found：C，52.44；H，6.04；N，9.32；O，10.91。
Embodiment 18
The preparation of N '-(3,4-dimethoxy) α-tolylene-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-10)
30mL methylene dichloride is added in the four-hole bottle of 100mL, under dichloromethane solvent existent condition, add 3, 4-dimethoxy benzaldehyde 0.83g (5mmol), add sulphur decoyl hydrazine 1.10g (5mmol) again, then temperature of reaction is controlled under the condition of 30 DEG C, under agitation condition, make 3, 4-dimethoxy benzaldehyde and sulphur decoyl hydrazine carry out hydrazone and react 1.5 hours, after reaction terminates, for improving product purity further, carry out aftertreatment, namely the reaction solution after adopting Rotary Evaporators above-mentioned reaction to be terminated carries out the solvent in underpressure distillation removal system, control vacuum distillation temperature within 25 DEG C, be distilled to dry residuum, column chromatography is adopted by residuum to carry out purifying, column chromatography eluent used is CH
2cl
2: PE=1:1, above-mentioned PE is sherwood oil, and column chromatography sorbent material used is silica gel, and the elutriant being rich in final product obtained after column chromatography is adopted Rotary Evaporators underpressure distillation, control vacuum distillation temperature below 35 DEG C, be distilled to dry, obtain final product 1.23g faint yellow solid N '-(3,4-dimethoxy) α-tolylene-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine, productive rate is that 67%, HPLC detects, and purity is 98.4%.Analyze the N ' obtained-(3,4-dimethoxy) α-tolylene-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine, concrete analysis result is as follows:
Fusing point (m.p.): 65 DEG C ~ 67 DEG C; MS (m/z, %): 369.9 (M+H)
+;
1H-NMR(CDCl
3,500MHz)δ：9.02(s,1H,CH＝N)，8.11(s,0.65H，NH)，7.61(s,0.35H,NH)，7.48(s,1H,Ar)，7.10(t,1H,J＝8.0Hz,Ar)，6.95(d,1H,J＝8.0Hz,Ar)，3.89(s,3H,-OMe),3.88(s,3H,-OMe)，3.58-3.64(m,1H,-S-CH-),3.09-3.21(m,2H,-S-CH
2-),2.78(t,2H,J＝7.5Hz,-CH
2-CO-)，2.45-2.49(m,1H,-S-CH
2-CH-CH-S-)，1.91-1.95(m,1H,-S-CH
2-CH-CH-S-)，1.53-1.80(m,6H,-CH
2-CH
2-CH
2-)；
IR(KBr)ν：3301cm
-1，3164cm
-1，3058cm
-1，2906cm
-1，2800cm
-1，1606cm
-1，1510cm
-1，1441cm
-1，1274cm
-1，1160cm
-1，1091cm
-1；
Anal.calcd?for?C
17H
24N
2O
3S
2：C，55.41；H，6.56；N，7.60；O，13.02；Found：C，55.29；H，6.50；N，7.62；O，13.21。
Embodiment 19
The preparation of N '-(3,4-dihydroxyl) α-tolylene-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-11)
30mL trichloromethane is added in the four-hole bottle of 100mL, under trichloromethane solvent existent condition, add 3, 4-Dihydroxy benzaldehyde 0.69g (5mmol), add sulphur decoyl hydrazine 1.10g (5mmol) again, then, control temperature is under the condition of 30 DEG C, under agitation condition, make 3, 4-Dihydroxy benzaldehyde and sulphur decoyl hydrazine carry out hydrazone and react 5 hours, after reaction terminates, for improving product purity further, carry out aftertreatment, namely the reaction solution after adopting Rotary Evaporators above-mentioned reaction to be terminated carries out the solvent in underpressure distillation removal system, control vacuum distillation temperature below 30 DEG C, be distilled to dry residuum, column chromatography is adopted by residuum to carry out purifying, column chromatography eluent used is EtOAc:PE=1:1, above-mentioned EtOAc is vinyl acetic monomer, above-mentioned PE is sherwood oil, column chromatography sorbent material used is silica gel, the elutriant being rich in final product obtained after column chromatography is adopted Rotary Evaporators underpressure distillation, control vacuum distillation temperature below 60 DEG C, be distilled to dry, obtain 0.92g faint yellow solid N '-(3, 4-dihydroxyl) α-tolylene-5-(1, 2-dithio pentamethylene-3-base) valeryl hydrazine, productive rate is 54%, HPLC detects, purity is 98.4%.Analyze the product N ' obtained-(3,4-dihydroxyl) α-tolylene-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine, concrete analysis result is as follows:
Fusing point (m.p.): 141 DEG C ~ 143 DEG C;
MS(m/z,％)：341.4(M+H)
+，363.2(M+Na)
+；
1H-NMR(CDCl
3,500MHz)δ：10.10(s,1H,-OH),9.55(s,1H,-OH),9.15(s,1H,CH＝N),7.77(s,1H,NH),7.26(s,1H,Ar),7.10(m,1H,Ar),6.95(m,1H,Ar),3.60-3.63(m,1H,-S-CH-),3.11-3.19(m,2H,-S-CH
2-),2.78(t,2H,J＝7.5Hz,-CH
2-CO-),2.46-2.49(m,1H,-S-CH
2-CH-CH-S-),1.91-1.95(m,1H,-S-CH
2-CH-CH-S-),1.55-1.79(m,6H,-CH
2-CH
2-CH
2-)；
IR(KBr)ν：3301cm
-1,3164cm
-1,3058cm
-1,2906cm
-1,2800cm
-1,1606cm
-1,1510cm
-1,1441cm
-1,1274cm
-1,1160cm
-1,1091cm
-1；
Anal.calcd?for?C
15H
20N
2O
3S
2：C，52.92；H，5.92；N，8.23；O，14.10；Found：C，53.01；H，5.90；N，8.11；O，14.19。
Embodiment 20
The preparation of N '-3-chlorobenzene methylene radical-5-(1,2-dithio pentamethylene-3-base) valeryl hydrazine (I-11)
30mL dehydrated alcohol is added in the four-hole bottle of 100mL, under anhydrous ethanol solvent existent condition, add 3-chlorobenzaldehyde 0.70g (5mmol), add sulphur decoyl hydrazine 1.10g (5mmol) again, then, control temperature is under the condition of 30 DEG C, under agitation condition, make 3-chlorobenzaldehyde and sulphur decoyl hydrazine carry out hydrazone and react 3 hours, after reaction terminates, for improving product purity further, carry out aftertreatment, namely the reaction solution after adopting Rotary Evaporators above-mentioned reaction to be terminated carries out the solvent in underpressure distillation removal system, control vacuum distillation temperature within 30 DEG C, be distilled to dry residuum, residuum is carried out recrystallization purifying, namely in residuum, 20mL dehydrated alcohol is added, under stirring, be warming up to backflow molten clear after, stir 30 minutes, then, slow cooling to 0 DEG C ~ 5 DEG C, control temperature, stirred crystallization 30 minutes, filter, obtain 1.10g faint yellow solid N '-3-chlorobenzene methylene radical-5-(1, 2-dithio pentamethylene-3-base) valeryl hydrazine, productive rate is 64%, HPLC detects, purity is 98.3%.Analyze product N '-3-chlorobenzene methylene radical-5-(1,2-dithio pentamethylene-3-base) the valeryl hydrazine obtained, concrete analysis result is as follows:
Fusing point (m.p.): 89 DEG C ~ 90 DEG C;
MS(m/z,％)：343.1(M+H)
+，365.1(M+Na)
+；
1H-NMR(CDCl
3,500MHz)δ:9.32(s,1H,CH＝N),8.18(s,1H,NH),7.96(s,1H),7.70(d,1H,J＝9.5Hz),7.45-7.52(m,2H,Ar),3.57-3.61(m,1H,-S-CH-),3.08-3.20(m,2H,-S-CH
2-),2.78(t,J＝7.5Hz,2H,-CH
2-CO-),2.48(m,1H,-S-CH
2-CH-CH-S-),1.93(m,1H,-S-CH
2-CH-CH-S-),1.54-1.81(m,6H,-CH
2-CH
2-CH
2-)；
IR(KBr)ν：3305cm
-1,3168cm
-1,3062cm
-1,2916cm
-1,1621cm
-1,1521cm
-1,1439cm
-1,1275cm
-1,1162cm
-1,1095cm
-1；
Anal.calcd?for?C
15H
19ClN
2OS
2：C，52.54；H,5.58；Cl,10.34；N,8.17；O，4.67；Found：C，52.66；H，5.65；Cl,10.21；N,8.15；O，4.47。
The corresponding sulphur decoyl hydrazine derivative compound obtained in random selecting above-described embodiment carries out the vitro test of antitumour activity, testing method adopts tetrazolium reduction method (mtt assay), select human cervical carcinoma cell strain Hela, human lung carcinoma cell line A549, MCF-7 cell strainHJ2mm, human leukemia HL-60, select above-mentioned four kinds of JEG-3, action time is 72 hours.Test result, as table 1, is with I-1 to I-12 for drugs with function with the data in following table 1, to the restraining effect (IC of the corresponding cancer cell in vitro strain of the cell strain selected
50: μ g/mL) test result, with cis-platinum to the restraining effect of corresponding JEG-3 in contrast.
Table 1:
" > 100 " described in above-mentioned table 1 represents under this drug level, does not detect the antitumour activity to corresponding JEG-3.
Data in above-mentioned table 1 are that chemical compounds I-1 ~ I-12 of the present invention and reference substance cis-platinum (Cisplatin) are to the restraining effect (IC of external corresponding JEG-3
50: μ g/mL) effect, the data as can be seen from table 1, cis-platinum all has stronger restraining effect to the JEG-3 of HL-60, A549, MCF-7, Hela, its IC
50be respectively 6.65 μ g/mL, 2.62 μ g/mL, 6.38 μ g/mL, 0.58 μ g/mL.And relative to the restraining effect of cis-platinum to above-mentioned corresponding JEG-3, sulphur decoyl hydrazine derivative compound of the present invention also has good restraining effect (IC to corresponding JEG-3
50: μ g/mL), anticancer bioactive is higher, and what have can reach the suitable level of the restraining effect of cis-platinum to corresponding cancer cells.Therefore, sulphur decoyl hydrazine derivative compound of the present invention has good antitumour activity, is expected in cancer therapy drug, realize application preferably.
Specific embodiment described in the present invention is only to the explanation for example of the present invention's spirit.Those skilled in the art can make various amendment or supplement or adopt similar mode to substitute to described specific embodiment, but can't depart from spirit of the present invention or surmount the scope that appended claims defines.
Although made a detailed description the present invention and quoted some specific embodiments as proof, to those skilled in the art, only otherwise it is obvious for leaving that the spirit and scope of the present invention can make various changes or revise.
Claims (8)
1. a sulphur decoyl hydrazine derivative type I compound, is characterized in that, the general formula of this compound is:
R wherein described in type I compound is selected from substituted-phenyl, furyl
in one; Described substituted-phenyl is
described R
1be selected from the one in hydrogen, halogen; Described R
2be selected from the one in hydrogen, hydroxyl, alkoxyl group, halogen; Described R
3be selected from the one in hydrogen, hydroxyl, dimethylamino, halogen, alkoxyl group, nitro; Described furyl
be selected from the one in furans-2-base, furans-3-base; Wherein R
1, R
2and R
3described in halogen be selected from one in chlorine, fluorine; Wherein R
2and R
3described in alkoxyl group be selected from one in methoxyl group, oxyethyl group, propoxy-.
2. a preparation method for sulphur decoyl hydrazine derivative type I compound, it is characterized in that, the method comprises the following steps:
Under organic solvent existent condition, described organic solvent is selected from one or more in alcohols, ester class, ethers or halogenated alkane, formula III compound sulphur decoyl hydrazine and formula IV compound is carried out hydrazone and is obtained by reacting type I compound;
Described alcohols is selected from C
1~ C
5lower alcohol; Described ester class is selected from ethyl acetate or propyl acetate; Described ethers is selected from tetrahydrofuran (THF); Described halogenated alkane is selected from methylene dichloride or trichloromethane;
Its R described in Chinese style IV compound is selected from substituted-phenyl, furyl
in one; Described substituted-phenyl is
described R
1be selected from the one in hydrogen, halogen; Described R
2be selected from the one in hydrogen, hydroxyl, alkoxyl group, halogen; Described R
3be selected from the one in hydrogen, hydroxyl, dimethylamino, halogen, alkoxyl group, nitro; Described furyl
be selected from the one in furans-2-base, furans-3-base; Wherein R
1, R
2and R
3described in halogen be selected from one in chlorine, fluorine; Wherein R
2and R
3described in alkoxyl group be selected from one in methoxyl group, oxyethyl group, propoxy-.
3. the preparation method of sulphur decoyl hydrazine derivative type I compound according to claim 2, it is characterized in that, the preparation method of described formula III compound Thioctic Acid hydrazides comprises the following steps:
At C
1~ C
5lower alcohol solvent and catalyzer alkane acyl chlorides existent condition under, formula II compound Thioctic Acid and hydrazine hydrate are carried out hydrazine and are obtained by reacting formula III compound Thioctic Acid hydrazides:
4. the preparation method of sulphur decoyl hydrazine derivative type I compound according to claim 2, it is characterized in that, described organic solvent is selected from one or more in methyl alcohol, propyl alcohol, ethanol, ethyl acetate, methylene dichloride, trichloromethane, tetrahydrofuran (THF).
5., according to the preparation method of sulphur decoyl hydrazine derivative type I compound described in any one in claim 2-4, it is characterized in that, described hydrazone temperature of reaction is-10 DEG C ~ 30 DEG C, and the described hydrazone reaction times is 0.5 ~ 5.0 hour.
6. the preparation method of sulphur decoyl hydrazine derivative type I compound according to claim 3, it is characterized in that, described catalyzer alkane acyl chlorides is selected from the one in Acetyl Chloride 98Min., propionyl chloride.
7. according to the preparation method of the decoyl of sulphur described in claim 3 or 6 hydrazine derivative type I compound, it is characterized in that, described hydrazine temperature of reaction is 10 DEG C ~ 80 DEG C, and the described hydrazine reaction times is 3 ~ 24 hours.
8. the application of sulphur decoyl hydrazine derivative type I compound according to claim 1, is characterized in that, the application of described type I compound in the functional food or medicine of preparation prevention or treatment tumour.
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| WO2003079403A2 (en) * | 2001-09-05 | 2003-09-25 | Nelson Deanna J | Oligo(ethylene glycol)-terminated 1,2-dithiolanes and their conjugates useful for preparing self-assembled monolayers |
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| WO2003079403A2 (en) * | 2001-09-05 | 2003-09-25 | Nelson Deanna J | Oligo(ethylene glycol)-terminated 1,2-dithiolanes and their conjugates useful for preparing self-assembled monolayers |
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| Title |
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| Maria Koufaki,等.Design and synthesis of 1,2-dithiolane derivatives and evaluation of their neuroprotective activity.《Bioorganic & * |
| Maria Koufaki,等.Design and synthesis of novel neuroprotective 1,2-dithiolane/chroman hybrids.《Bioorganic & * |
| Medicinal Chemistry Letters》.2007,第17卷(第15期),第4223-4227页. * |
| Medicinal Chemistry》.2009,第17卷(第17期),第6431-6441页. * |
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