CN103288816A - Mannich alkali compounds containing phenothiazine group and 1,3,4-thiadiazole group as well as preparation method and application thereof - Google Patents
Mannich alkali compounds containing phenothiazine group and 1,3,4-thiadiazole group as well as preparation method and application thereof Download PDFInfo
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- CN103288816A CN103288816A CN2013102028632A CN201310202863A CN103288816A CN 103288816 A CN103288816 A CN 103288816A CN 2013102028632 A CN2013102028632 A CN 2013102028632A CN 201310202863 A CN201310202863 A CN 201310202863A CN 103288816 A CN103288816 A CN 103288816A
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- phenothiazine
- thiadiazolyl
- ethanol
- thiadiazole
- amino
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- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 title abstract description 11
- 239000003513 alkali Substances 0.000 title description 14
- MBIZXFATKUQOOA-UHFFFAOYSA-N 1,3,4-thiadiazole Chemical group C1=NN=CS1 MBIZXFATKUQOOA-UHFFFAOYSA-N 0.000 title 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 65
- 238000006243 chemical reaction Methods 0.000 claims abstract description 52
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 claims abstract description 48
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 37
- 239000012043 crude product Substances 0.000 claims abstract description 32
- -1 1,3,4- Thiadiazolyl Mannich bases Chemical compound 0.000 claims abstract description 29
- 239000008098 formaldehyde solution Substances 0.000 claims abstract description 25
- 239000002904 solvent Substances 0.000 claims abstract description 20
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 claims abstract description 19
- 239000002994 raw material Substances 0.000 claims abstract description 17
- 150000004869 1,3,4-thiadiazoles Chemical class 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 11
- 241000894006 Bacteria Species 0.000 claims abstract description 10
- 229950000688 phenothiazine Drugs 0.000 claims abstract 11
- 229940079593 drug Drugs 0.000 claims abstract 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 90
- 238000000034 method Methods 0.000 claims description 22
- 238000001953 recrystallisation Methods 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 15
- 241000191967 Staphylococcus aureus Species 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- RREANTFLPGEWEN-MBLPBCRHSA-N 7-[4-[[(3z)-3-[4-amino-5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidin-2-yl]imino-5-fluoro-2-oxoindol-1-yl]methyl]piperazin-1-yl]-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(\N=C/3C4=CC(F)=CC=C4N(CN4CCN(CC4)C=4C(=CC=5C(=O)C(C(O)=O)=CN(C=5C=4)C4CC4)F)C\3=O)=NC=2)N)=C1 RREANTFLPGEWEN-MBLPBCRHSA-N 0.000 claims description 4
- 244000063299 Bacillus subtilis Species 0.000 claims description 4
- QUKGLNCXGVWCJX-UHFFFAOYSA-N 1,3,4-thiadiazol-2-amine Chemical group NC1=NN=CS1 QUKGLNCXGVWCJX-UHFFFAOYSA-N 0.000 claims description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 4
- 239000003208 petroleum Substances 0.000 claims 2
- 235000014469 Bacillus subtilis Nutrition 0.000 claims 1
- 241000588724 Escherichia coli Species 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 150000004867 thiadiazoles Chemical class 0.000 claims 1
- 229960004756 ethanol Drugs 0.000 description 19
- 239000000126 substance Substances 0.000 description 16
- 239000003795 chemical substances by application Substances 0.000 description 14
- 229960000935 dehydrated alcohol Drugs 0.000 description 14
- 238000001035 drying Methods 0.000 description 14
- 230000008034 disappearance Effects 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 11
- 239000000843 powder Substances 0.000 description 11
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 239000001301 oxygen Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 230000003385 bacteriostatic effect Effects 0.000 description 4
- 230000000968 intestinal effect Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000006683 Mannich reaction Methods 0.000 description 3
- CEDZFAONRDZJKJ-UHFFFAOYSA-N [O].ClC1=CC=CC(=C1)Cl Chemical compound [O].ClC1=CC=CC(=C1)Cl CEDZFAONRDZJKJ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YAVVGPBYBUYPSR-UHFFFAOYSA-N benzene;oxygen Chemical compound [O].C1=CC=CC=C1 YAVVGPBYBUYPSR-UHFFFAOYSA-N 0.000 description 3
- LOGVJDSEHISUDU-UHFFFAOYSA-N 2-amino-5-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=CC(C(O)=O)=C(N)C(C(O)=O)=C1 LOGVJDSEHISUDU-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 238000002791 soaking Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XFDSCEVGRGOSAF-UHFFFAOYSA-N 5-naphthalen-2-yl-1,3,4-thiadiazol-2-amine Chemical class S1C(N)=NN=C1C1=CC=C(C=CC=C2)C2=C1 XFDSCEVGRGOSAF-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000004705 aldimines Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000002082 anti-convulsion Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000006916 nutrient agar Substances 0.000 description 1
- 210000004681 ovum Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
Images
Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
含吩噻嗪基及1,3,4-噻二唑基Mannich碱类化合物及其制备方法和应用，以吩噻嗪、甲醛溶液、1,3,4-噻二唑衍生物为原料，以乙醇为溶剂在室温下搅拌反应，然后将得到的反应液中的溶剂蒸出，反应器中的剩余物即为粗品，将粗品重结晶，即得含吩噻嗪基及1,3,4-噻二唑基Mannich碱。本发明操作步骤简单、后处理方便，产率高，且该化合物能够在制备抗革兰氏菌药物中的应用。Mannich base compound containing phenothiazine group and 1,3,4-thiadiazolyl group and its preparation method and application, using phenothiazine, formaldehyde solution and 1,3,4-thiadiazole derivative as raw materials, and Ethanol is used as a solvent, and the reaction is stirred at room temperature, and then the solvent in the obtained reaction solution is distilled off, and the residue in the reactor is the crude product. The crude product is recrystallized to obtain phenothiazinyl and 1,3,4- Thiadiazolyl Mannich bases. The invention has simple operation steps, convenient post-treatment and high yield, and the compound can be used in the preparation of anti-gram bacteria drugs.
Description
Technical field
The invention belongs to the field of chemical synthesis, be specifically related to contain phenothiazinyl and 1,3,4-thiadiazolyl group Mannich bases compound and its preparation method and application.
Background technology
The phenothiazines compound is the heterogeneous ring compound that contains N, S atom, and having wide range of applications of it can be used for the fields such as oxidation inhibitor, conductive polymeric material and dyestuff in biological medicine, stopper, the lubricant.Wherein, because thiodiphenylamine and derivative thereof have very high pharmacologically active and biological activity, therefore, the medicinal application of phenothiazines compound becomes the research focus of researcher.
1,3,4-thiadiazole compound is the important heterogeneous ring compound of a class, industry, agricultural and medical aspect all have widely and to use.Aspect medical, it have antibiotic, anticonvulsion, prevent depression, suppress nervous, bring high blood pressure down and anticancer isoreactivity that all the time, the synthetic and activity research of relevant 1,3,4-thiadiazole compound is the hot subject on current chemical boundary.
Mannich reaction is that the compound that contains reactive hydrogen carries out dehydrating condensation with aldehyde and amine (ammonia), the organic chemical reactions of generation beta-amino (carbonyl) compound.The reaction of general aldimine and alpha-methylene carbonyl compound is also regarded as the Mannich reaction.Reaction product is called Mannich alkali, and it is not only the important intermediate of synthesis of natural its lytic activity molecule, and is widely used, and can be used for aspects such as medicine, dyestuff, agricultural chemicals, coating, explosive.In recent years, relevant Mannich alkali document synthetic and application facet is reported in succession.
Yet, learn that according to existing literature the Mannich reaction exists long reaction time mostly, productive rate is low, adopt defectives such as complicated catalyzer, in order to overcome above-mentioned drawback, my seminar is through exploring repeatedly, testing, and it is shorter finally to have drawn a kind of reaction times, productive rate is higher and do not adopt the method for the synthetic Mannich alkali of any catalyzer, at last these a series of novel cpds have been carried out the research of bacteriostatic experiment, the result shows that this compounds has the physiologically active that suppresses the gram-bacteria growth.
Summary of the invention
The object of the present invention is to provide and contain phenothiazinyl and 1,3,4-thiadiazolyl group Mannich bases compound and its preparation method and application, the inventive method operation steps is simple, convenient post-treatment, the productive rate height, and this compound can be used in the anti-gram-bacteria medicine of preparation.
In order to achieve the above object, phenothiazinyl and 1,3, the 4-thiadiazolyl group Mannich alkali of containing of the present invention, its general structure is as follows:
Wherein, R=H, methyl, ethyl, propyl group, phenyl, Alpha-Naphthyl, betanaphthyl, benzene oxygen methylene radical, 2,4 dichloro benzene oxygen methylene radical, alpha-naphthoxy methylene radical or β-naphthalene oxygen methylene radical.
This contains the method for phenothiazinyl and 1,3,4-thiadiazolyl group Mannich alkali a kind of preparation, may further comprise the steps:
1) in reactor, add thiodiphenylamine, formaldehyde solution, 1,3,4-thiadiazoles derivative and ethanol, stirring reaction under room temperature, the raw material point that monitors thiodiphenylamine up to TLC disappears, and gets reaction solution; Wherein, the mol ratio of the formaldehyde in described thiodiphenylamine, the formaldehyde solution and 1,3,4-thiadiazoles derivative is 1:(2～4): (1～2); And 1,3,4-thiadiazoles derivative is 2-amino-1,3,4-thiadiazoles or 2-amino-5-substituting group-1,3,4-thiadiazoles;
2) solvent in the reaction solution is steamed, the residuum in the reactor is crude product, with the crude product recrystallization, namely gets and contains phenothiazinyl and 1,3,4-thiadiazolyl group Mannich alkali.
The mass concentration of described step 1) formaldehyde solution is 37%～40%.
2-amino-5-substituting group-1,3 in the described step 1), the substituting group in the 4-thiadiazoles are methyl, ethyl, propyl group, phenyl, Alpha-Naphthyl, betanaphthyl, benzene oxygen methylene radical, 2,4 dichloro benzene oxygen methylene radical, alpha-naphthoxy methylene radical or β-naphthalene oxygen methylene radical.
The mass concentration of ethanol is 95% in the described step 1), in reactor, adding thiodiphenylamine, formaldehyde solution, 1,3, when 4-thiadiazoles derivative and ethanol, add thiodiphenylamine, formaldehyde solution, 1,3,4-thiadiazoles derivative earlier, add ethanol then, and the ethanol of every mole of thiodiphenylamine adding 10000～15000mL.
The described step 1) reaction times is 5～7 hours, and the developping agent of TLC is mixed by ethyl acetate and sherwood oil, and the volume ratio of ethyl acetate and sherwood oil is 1:5.
Described step 2) recrystallization solvent in is dehydrated alcohol.
This contains phenothiazinyl and the application of 1,3,4-thiadiazolyl group Mannich alkali in the anti-gram-bacteria medicine of preparation.
Described gram-bacteria is streptococcus aureus, intestinal bacteria or subtilis.
Further, described gram-bacteria is gram-positive microorganism or Gram-negative bacteria, and further, described gram-positive microorganism is streptococcus aureus or Bacillus subtillis, and Gram-negative bacteria is intestinal bacteria.
Preferably, in the described step 1) reactor through drying treatment.
Compared with prior art, beneficial effect of the present invention is: the present invention is that feedstock production has gone out a series of phenothiazinyl and 1,3,4-thiadiazolyl group Mannich alkali of containing with thiodiphenylamine, formaldehyde and 1,3,4-thiadiazoles derivative.This method experimental procedure is easy, and aftertreatment is simple, and the productive rate height meets industrial needs.In addition, this compounds is carried out Research on antibacterial, find that this compounds can suppress the growth of gram-bacteria, has certain physiologically active, can be expected to be applied to fields such as medicine, agricultural chemicals as anti-gram-bacteria medicine or the application in the anti-gram-bacteria medicine of preparation.
Further, the present invention's reaction only needs 5～7 hours, and the raw material point that TLC namely monitors thiodiphenylamine disappears, and reaction finishes, and therefore, the reaction times of the present invention is short.
Description of drawings
Fig. 1 is reaction scheme figure of the present invention.
Embodiment
Referring to Fig. 1, add thiodiphenylamine, mass concentration in the there-necked flask of drying and be 37%～40% formaldehyde solution, 1,3, the 4-thiadiazoles derivative, add mass concentration again and be 95% ethanol, stirring reaction is 5～7 hours under room temperature, when this moment, TLC monitored the raw material point disappearance of thiodiphenylamine, gets reaction solution; Wherein, the mol ratio of the formaldehyde in thiodiphenylamine, the formaldehyde solution and 1,3,4-thiadiazoles derivative is 1:(2～4): (1～2); Every mole of thiodiphenylamine adds the ethanol of 10000～15000mL, and the developping agent of TLC is mixed by ethyl acetate and sherwood oil, and the volume ratio of ethyl acetate and sherwood oil is 1:5;
1,3 of the present invention's employing, the 4-thiadiazoles derivative is 2-amino-1,3,4-thiadiazoles, 2-amino-5-methyl isophthalic acid, 3, the 4-thiadiazoles, 2-amino-5-ethyl-1,3, the 4-thiadiazoles, 2-amino-5-propyl group-1,3,4-thiadiazoles, 2-amino-5-phenyl-1,3, the 4-thiadiazoles, 2-amino-5-(Alpha-Naphthyl)-1,3, the 4-thiadiazoles, 2-amino-5-(betanaphthyl)-1,3,4-thiadiazoles, 2-amino-5-benzene oxygen methylene radical-1,3, the 4-thiadiazoles, 2-amino-5-(2,4-Dichlorophenoxy methylene radical)-1,3, the 4-thiadiazoles, 2-amino-5-(alpha-naphthoxy methylene radical)-1,3,4-thiadiazoles or 2-amino-5-(β-naphthalene oxygen methylene radical)-1,3, the 4-thiadiazoles.
2) solvent in the reaction solution is steamed, the residuum in the there-necked flask is crude product, crude product dehydrated alcohol recrystallization, and what namely get white powder contains phenothiazinyl and 1,3,4-thiadiazolyl group Mannich alkali.Its general structure is:
R=H, methyl, ethyl, propyl group, phenyl, Alpha-Naphthyl, betanaphthyl, benzene oxygen methylene radical, 2,4 dichloro benzene oxygen methylene radical, alpha-naphthoxy methylene radical or β-naphthalene oxygen methylene radical.
Table 1 has provided a series of chemical structural formula and corresponding chemical names that contain phenothiazinyl and 1,3,4-thiadiazolyl group Mannich alkali that the present invention prepares.
Table 1 contains chemical structural formula and the corresponding chemistry of phenothiazinyl and 1,3,4-thiadiazolyl group Mannich alkali
Name
1, the preparation method who contains phenothiazinyl and 1,3,4-thiadiazolyl group Mannich bases compound below in conjunction with the present invention of embodiment is elaborated.
Embodiment 1:
Tianjin chemical industry all generations company limited) and the 2-amino-1 of 0.001mol 1) thiodiphenylamine, the 0.002mol mass concentration that adds 0.001mol in the there-necked flask of drying is 37%～40% formaldehyde solution (manufacturer:, 3, the 4-thiadiazoles, add the 10mL mass concentration again and be 95% ethanol, stirring reaction is 5 hours under room temperature, at this moment, when TLC monitors the raw material point disappearance of thiodiphenylamine, get reaction solution; Wherein, the developping agent of TLC is mixed by ethyl acetate and sherwood oil, and the volume ratio of ethyl acetate and sherwood oil is 1:5;
2) solvent in the reaction solution is steamed, the residuum in the there-necked flask is crude product, crude product dehydrated alcohol recrystallization, and it is amino-1,3 namely to get the 2-(N-methyl thiodiphenylamine) of white powder, and 4-thiadiazoles, productive rate are 76%.
The IR(KBr pressed disc method, ν/cm
-1): 3487,3088,1648,1601,1447,1327,763.
1H NMR (CDCl
3, mark in the 400M, TMS, δ: ppm): 6.93～7.25(8H, Ar-H), 4.85 (2H, N-CH
2-N), 4.6 (1H, NH-Ar), 9.3(1H, N=CH-S).
Embodiment 2:
Tianjin chemical industry all generations company limited) and 2-amino-5-methyl isophthalic acid of 0.001mol 1) thiodiphenylamine, the 0.003mol mass concentration that adds 0.001mol in the there-necked flask of drying is 37%～40% formaldehyde solution (manufacturer:, 3, the 4-thiadiazoles, add the 10mL mass concentration again and be 95% ethanol, stirring reaction is 6 hours under room temperature, at this moment, when TLC monitors the raw material point disappearance of thiodiphenylamine, get reaction solution; Wherein, the developping agent of TLC is mixed by ethyl acetate and sherwood oil, and the volume ratio of ethyl acetate and sherwood oil is 1:5;
2) solvent in the reaction solution is steamed, the residuum in the there-necked flask is crude product, crude product dehydrated alcohol recrystallization, and it is amino-1,3 namely to get the 2-methyl-5-(N-methyl thiodiphenylamine) of white powder, and 4-thiadiazoles, productive rate are 90%.
The IR(KBr pressed disc method, ν/cm
-1): 3487,3085,2972,2871,1650,1602,1449,1333,768.
1H NMR (CDCl
3, mark in the 400M, TMS, δ: ppm): 6.93～7.25(8H, Ar-H), 4.83 (2H, N-CH
2-N), 4.5 (1H, NH-Ar), 2.65(1H, N=C-CH
3).
Embodiment 3
Tianjin chemical industry all generations company limited) and 2-amino-5-ethyl-1 of 0.002mol 1) thiodiphenylamine, the 0.003mol mass concentration that adds 0.001mol in the there-necked flask of drying is 37%～40% formaldehyde solution (manufacturer:, 3, the 4-thiadiazoles, add the 11mL massfraction again and be 95% ethanol, stirring reaction is 6 hours under room temperature, at this moment, when TLC monitors the raw material point disappearance of thiodiphenylamine, get reaction solution; Wherein, the developping agent of TLC is mixed by ethyl acetate and sherwood oil, and the volume ratio of ethyl acetate and sherwood oil is 1:5;
2) solvent in the reaction solution is steamed, the residuum in the there-necked flask is crude product, crude product dehydrated alcohol recrystallization, and it is amino-1,3 namely to get the 2-ethyl-5-(N-methyl thiodiphenylamine) of white powder, and 4-thiadiazoles, productive rate are 80%.
The IR(KBr pressed disc method, ν/cm
-1): 3489,3090,2970,2928,2873,2855,1650,1603,1449,1330,766.
1H NMR (CDCl
3, mark in the 400M, TMS, δ: ppm): 6.93～7.25(8H, Ar-H), 4.84 (2H, N-CH
2-N), 4.2 (1H, NH-Ar), 1.28～3.07(5H ,-C
2H
5).
Embodiment 4
Tianjin chemical industry all generations company limited) and 2-amino-5-propyl group-1 of 0.001mol 1) thiodiphenylamine, the 0.002mol mass concentration that adds 0.001mol in the there-necked flask of drying is 37%～40% formaldehyde solution (manufacturer:, 3, the 4-thiadiazoles, add the 12mL mass concentration again and be 95% ethanol, stirring reaction is 6 hours under room temperature, at this moment, when TLC monitors the raw material point disappearance of thiodiphenylamine, get reaction solution; Wherein, the developping agent of TLC is mixed by ethyl acetate and sherwood oil, and the volume ratio of ethyl acetate and sherwood oil is 1:5;
2) solvent in the reaction solution is steamed, the residuum in the there-necked flask is crude product, crude product dehydrated alcohol recrystallization, and it is amino-1,3 namely to get the 2-propyl group-5-(N-methyl thiodiphenylamine) of white powder, and 4-thiadiazoles, productive rate are 79%.
The IR(KBr pressed disc method, ν/cm
-1): 3487,3088,2967,2875,1648,1601,1447,1327,763,739.
1H NMR (CDCl
3, mark in the 400M, TMS, δ: ppm): 6.93～7.25(8H, Ar-H), 4.86 (2H, N-CH
2-N), 4.3 (1H, NH-Ar), 0.80～2.89(7H ,-C
3H
7).
Embodiment 5:
Tianjin chemical industry all generations company limited) and the 2-amino-5-phenyl-1 of 0.002mol 1) thiodiphenylamine, the 0.004mol mass concentration that adds 0.001mol in the there-necked flask of drying is 37%～40% formaldehyde solution (manufacturer:, 3, the 4-thiadiazoles, add the 12mL mass concentration again and be 95% ethanol, stirring reaction is 5 hours under room temperature, at this moment, when TLC monitors the raw material point disappearance of thiodiphenylamine, get reaction solution; Wherein, the developping agent of TLC is mixed by ethyl acetate and sherwood oil, and the volume ratio of ethyl acetate and sherwood oil is 1:5;
2) solvent in the reaction solution is steamed, the residuum in the there-necked flask is crude product, crude product dehydrated alcohol recrystallization, and it is amino-1,3 namely to get the 2-phenyl-5-(N-methyl thiodiphenylamine) of white powder, and 4-thiadiazoles, productive rate are 77%.
The IR(KBr pressed disc method, ν/cm
-1): 3480,3082,1647,1605,1447,1327,1265,1057,763,758,699.
1H NMR (CDCl
3, mark in the 400M, TMS, δ: ppm): 6.93～7.25(8H, Ar-H), 4.83 (2H, N-CH
2-N), 4.1 (1H, NH-Ar), 7.4～8.1(5H ,-C
6H
5).
Embodiment 6
Tianjin chemical industry all generations company limited) and 0.002mol2-amino-5-(Alpha-Naphthyl)-1 1) thiodiphenylamine, the 0.003mol mass concentration that adds 0.001mol in the there-necked flask of drying is 37%～40% formaldehyde solution (manufacturer:, 3, the 4-thiadiazoles, add the 13mL mass concentration again and be 95% ethanol, stirring reaction is 5 hours under room temperature, at this moment, when TLC monitors the raw material point disappearance of thiodiphenylamine, get reaction solution; Wherein, the developping agent of TLC is mixed by ethyl acetate and sherwood oil, and the volume ratio of ethyl acetate and sherwood oil is 1:5;
2) solvent in the reaction solution is steamed, the residuum in the there-necked flask is crude product, crude product dehydrated alcohol recrystallization, and it is amino-1,3 namely to get 2-(the Alpha-Naphthyl)-5-(N-methyl thiodiphenylamine) of white powder, and 4-thiadiazoles, productive rate are 81%.
The IR(KBr pressed disc method, ν/cm
-1): 3488,3077,3046,1647,1605,1447,1327,1265,1057,787,768,710.
1H NMR (CDCl
3, mark in the 400M, TMS, δ: ppm): 6.95～7.21(8H, Ar-H), 4.83 (2H, N-CH
2-N), 4.0 (1H, NH-Ar), 7.55～8.55(7H ,-C
10H
7).
Embodiment 7
Tianjin chemical industry all generations company limited) and 0.001mol2-amino-5-(betanaphthyl)-1 1) thiodiphenylamine, the 0.004mol mass concentration that adds 0.001mol in the there-necked flask of drying is 37%～40% formaldehyde solution (manufacturer:, 3, the 4-thiadiazoles, add the 13mL mass concentration again and be 95% ethanol, stirring reaction is 6 hours under room temperature, at this moment, when TLC monitors the raw material point disappearance of thiodiphenylamine, get reaction solution; Wherein, the developping agent of TLC is mixed by ethyl acetate and sherwood oil, and the volume ratio of ethyl acetate and sherwood oil is 1:5;
2) solvent in the reaction solution is steamed, the residuum in the there-necked flask is crude product, crude product dehydrated alcohol recrystallization, and it is amino-1,3 namely to get 2-(the betanaphthyl)-5-(N-methyl thiodiphenylamine) of white powder, and 4-thiadiazoles, productive rate are 83%.
The IR(KBr pressed disc method, ν/cm
-1): 3489,3078,3046,1647,1605,1447,1327,1265,1057,787,768,707.
1H NMR (CDCl
3, mark in the 400M, TMS, δ: ppm): 6.95～7.21(8H, Ar-H), 4.83 (2H, N-CH
2-N), 4.0 (1H, NH-Ar), 5.21(2H, CH
2-OAr) 6.98～7.35(7H ,-C
10H
7).
Embodiment 8
Tianjin chemical industry all generations company limited) and 0.002mol2-amino-5-benzene oxygen methylene radical-1 1) thiodiphenylamine, the 0.003mol mass concentration that adds 0.001mol in the there-necked flask of drying is 37%～40% formaldehyde solution (manufacturer:, 3, the 4-thiadiazoles, add the 14mL mass concentration again and be 95% ethanol, stirring reaction is 6 hours under room temperature, at this moment, when TLC monitors the raw material point disappearance of thiodiphenylamine, get reaction solution; Wherein, the developping agent of TLC is mixed by ethyl acetate and sherwood oil, and the volume ratio of ethyl acetate and sherwood oil is 1:5;
2) solvent in the reaction solution is steamed, the residuum in the there-necked flask is crude product, crude product dehydrated alcohol recrystallization, and it is amino-1,3 namely to get the 2-benzene oxygen methylene radical-5-(N-methyl thiodiphenylamine) of white powder, and 4-thiadiazoles, productive rate are 80%.
The IR(KBr pressed disc method, ν/cm
-1): 3484,3067,3045,2928,2851,1648,1606,1473,1328,1266,1058,769,725.
1H NMR (CDCl
3, mark in the 400M, TMS, δ: ppm): 6.95～7.21(8H, Ar-H), 4.83 (2H, N-CH
2-N), 4.0 (1H, NH-Ar), 5.20 (2H, CH
2-O-Ar), 6.99～7.34 (5H ,-O-C
6H
5).
Embodiment 9
Tianjin chemical industry all generations company limited) and 0.002mol2-amino-5-(2 1) thiodiphenylamine, the 0.003mol mass concentration that adds 0.001mol in the there-necked flask of drying is 37%～40% formaldehyde solution (manufacturer:, 4-Dichlorophenoxy methylene radical)-1,3, the 4-thiadiazoles, add the 14mL mass concentration again and be 95% ethanol, stirring reaction is 7 hours under room temperature, at this moment, when TLC monitors the raw material point disappearance of thiodiphenylamine, get reaction solution; Wherein, the developping agent of TLC is mixed by ethyl acetate and sherwood oil, and the volume ratio of ethyl acetate and sherwood oil is 1:5;
2) solvent in the reaction solution is steamed, the residuum in the there-necked flask is crude product, crude product dehydrated alcohol recrystallization, and it is amino-1,3 namely to get the 2-(2,4 dichloro benzene oxygen methylene radical) of white powder-5-(N-methyl thiodiphenylamine), and 4-thiadiazoles, productive rate are 85%.
The IR(KBr pressed disc method, ν/cm
-1): 3484,3067,3045,2928,2851,1648,1606,1473,1328,1266,1058,769,725,711.
1H NMR (CDCl
3, mark in the 400M, TMS, δ: ppm): 6.95～7.21(8H, Ar-H), 4.83 (2H, N-CH
2-N), 4.0 (1H, NH-Ar), 5.20 (2H, CH
2-O-Ar), 7.25～7.58 (3H ,-O-C
6H
3Cl
2).
Embodiment 10
Tianjin chemical industry all generations company limited) and 0.002mol2-amino-5-(alpha-naphthoxy methylene radical)-1 1) thiodiphenylamine, the 0.004mol mass concentration that adds 0.001mol in the there-necked flask of drying is 37%～40% formaldehyde solution (manufacturer:, 3, the 4-thiadiazoles, add the 15mL mass concentration again and be 95% ethanol, stirring reaction is 7 hours under room temperature, at this moment, when TLC monitors the raw material point disappearance of thiodiphenylamine, get reaction solution; Wherein, the developping agent of TLC is mixed by ethyl acetate and sherwood oil, and the volume ratio of ethyl acetate and sherwood oil is 1:5;
2) solvent in the reaction solution is steamed, the residuum in the there-necked flask is crude product, crude product dehydrated alcohol recrystallization, and it is amino-1,3 namely to get 2-(alpha-naphthoxy the methylene radical)-5-(N-methyl thiodiphenylamine) of white powder, and 4-thiadiazoles, productive rate are 77%.
The IR(KBr pressed disc method, ν/cm
-1): 3485,3065,3040,2928,2852,1649,1607,1472,1329,1267,1060,768,726.
1H NMR (CDCl
3, mark in the 400M, TMS, δ: ppm): 6.95～7.21(8H, Ar-H), 4.83 (2H, N-CH
2-N), 4.0 (1H, NH-Ar), 5.20 (2H, CH
2-O-Ar), 6.65～8.31 (7H ,-O-C
10H
7).
Embodiment 11
Tianjin chemical industry all generations company limited) and 0.002mol2-amino-5-(β-naphthalene oxygen methylene radical)-1 1) thiodiphenylamine, the 0.003mol mass concentration that adds 0.001mol in the there-necked flask of drying is 37%～40% formaldehyde solution (manufacturer:, 3, the 4-thiadiazoles, add the 15mL mass concentration again and be 95% ethanol, stirring reaction is 7 hours under room temperature, at this moment, when TLC monitors the raw material point disappearance of thiodiphenylamine, get reaction solution; Wherein, the developping agent of TLC is mixed by ethyl acetate and sherwood oil, and the volume ratio of ethyl acetate and sherwood oil is 1:5;
2) solvent in the reaction solution is steamed, the residuum in the there-necked flask is crude product, crude product dehydrated alcohol recrystallization, and it is amino-1,3 namely to get the 2-(β-naphthalene oxygen methylene radical) of white powder-5-(N-methyl thiodiphenylamine), and 4-thiadiazoles, productive rate are 80%.
The IR(KBr pressed disc method, ν/cm
-1): 3487,3066,3042,2924,2853,1646,1605,1473,1328,1266,1061,766,727.
1H NMR (CDCl
3, mark in the 400M, TMS, δ: ppm): 6.95～7.21(8H, Ar-H), 4.83 (2H, N-CH
2-N), 4.0 (1H, NH-Ar), 5.30 (2H, CH
2-O-Ar), 7.23～7.97 (7H ,-O-C
10H
7).
Embodiment 12:
Tianjin chemical industry all generations company limited) and 0.0015mol2-amino-5-(alpha-naphthoxy methylene radical)-1 1) thiodiphenylamine, the 0.004mol mass concentration that adds 0.001mol in the there-necked flask of drying is 37%～40% formaldehyde solution (manufacturer:, 3, the 4-thiadiazoles, add the 15mL mass concentration again and be 95% ethanol, stirring reaction is 7 hours under room temperature, at this moment, when TLC monitors the raw material point disappearance of thiodiphenylamine, get reaction solution; Wherein, the developping agent of TLC is mixed by ethyl acetate and sherwood oil, and the volume ratio of ethyl acetate and sherwood oil is 1:5;
2) solvent in the reaction solution is steamed, the residuum in the there-necked flask is crude product, crude product dehydrated alcohol recrystallization, and it is amino-1,3 namely to get 2-(alpha-naphthoxy the methylene radical)-5-(N-methyl thiodiphenylamine) of white powder, the 4-thiadiazoles.
2, bacteriostatic test research
Selecting streptococcus aureus, intestinal bacteria and Bacillus subtillis for use is that bacterial classification carries out bacteriostatic test research, and substratum is nutrient agar.
Experimentation:
1) be solvent the preparation of experimental subjects solution: with the DMSO(dimethyl sulfoxide (DMSO)), respectively 11 kinds of Mannich bases compounds that contain phenothiazinyl and 1,3,4-thiadiazolyl group be mixed with the solution that concentration is 1.0mmol/L, standby.
2) with the aseptic inoculation ring fresh bacterium liquid that ovum educates 16～18h of learning from else's experience, being seeded in agar respectively with close method of scoring is on the thick plate of 4mm, be that the sterilized filter paper sheet of 24mm is put into the solution of getting ready with diameter, after soaking 12h, plate is put in taking-up, in 37 ℃ incubator, cultivate 24h, take out the size that inhibition zone was observed and recorded to culture dish again.
3) blank test: be that the sterilized filter paper sheet of 24mm is put into the solution that fills DMSO with diameter, after soaking 12h, take out and put into the plate of inoculated bacteria, in 37 ℃ of incubators, cultivate 24h after, take out culture dish and observe and record the size of inhibition zone, the result is as shown in table 1.
Table 1 bacteriostatic activity experimental result table
By table 1 result as can be seen, the present invention prepares a series of phenothiazinyl and 1 of containing, 3,4-thiadiazolyl group Mannich alkali all has good antibacterial properties to streptococcus aureus, intestinal bacteria and Bacillus subtillis, therefore, the present invention contains phenothiazinyl and 1,3,4-thiadiazolyl group Mannich alkali can be used in the anti-gram-bacteria medicine of preparation.
Claims (9)
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Cited By (3)
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| CN104356123A (en) * | 2014-11-19 | 2015-02-18 | 南开大学 | 1,2,4-triazole Mannich base derivatives containing substituted piperazidine, and preparation method and application thereof |
| CN105330651A (en) * | 2015-09-17 | 2016-02-17 | 南开大学 | 1,2,4-Triazolethione derivative containing (hetero)aryl group and piperazine, and preparation method and application thereof |
| CN111217805A (en) * | 2020-02-26 | 2020-06-02 | 陕西科技大学 | (E) 2-(2-(9-Alkyl)carbazole-3-)vinyl-5-amino-1,3,4-thiadiazole |
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| CN102276555A (en) * | 2011-08-09 | 2011-12-14 | 陕西科技大学 | Thiadiazole Mannich alkali as well as preparation method and application thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104356123A (en) * | 2014-11-19 | 2015-02-18 | 南开大学 | 1,2,4-triazole Mannich base derivatives containing substituted piperazidine, and preparation method and application thereof |
| CN105330651A (en) * | 2015-09-17 | 2016-02-17 | 南开大学 | 1,2,4-Triazolethione derivative containing (hetero)aryl group and piperazine, and preparation method and application thereof |
| CN105330651B (en) * | 2015-09-17 | 2018-05-01 | 南开大学 | 1 containing (miscellaneous) aryl and piperazine, 2,4- triazolinthione derivatives and preparation method and application |
| CN111217805A (en) * | 2020-02-26 | 2020-06-02 | 陕西科技大学 | (E) 2-(2-(9-Alkyl)carbazole-3-)vinyl-5-amino-1,3,4-thiadiazole |
| CN111217805B (en) * | 2020-02-26 | 2021-10-19 | 陕西科技大学 | (E)2- (2- (9-alkyl) carbazole-3-) vinyl-5-amino-1, 3, 4-thiadiazole |
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