CN113336745A - Method for synthesizing benzothiadiazine dioxide acetanilide derivatives by one-pot method - Google Patents
Method for synthesizing benzothiadiazine dioxide acetanilide derivatives by one-pot method Download PDFInfo
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- -1 benzothiadiazine dioxide acetanilide derivatives Chemical class 0.000 title claims abstract description 63
- 238000000034 method Methods 0.000 title claims abstract description 49
- 238000005580 one pot reaction Methods 0.000 title claims abstract description 18
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 12
- 230000008569 process Effects 0.000 claims abstract description 17
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims abstract description 16
- AVLSDPRGRUUKBD-UHFFFAOYSA-N 5-tert-butyl-2-(2-ethylhexylsulfanyl)aniline Chemical compound CCCCC(CC)CSC1=CC=C(C(C)(C)C)C=C1N AVLSDPRGRUUKBD-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000007788 liquid Substances 0.000 claims abstract description 14
- 238000005893 bromination reaction Methods 0.000 claims abstract description 13
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 238000002156 mixing Methods 0.000 claims abstract description 11
- 150000001412 amines Chemical class 0.000 claims abstract description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 8
- 238000005809 transesterification reaction Methods 0.000 claims abstract description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 230000031709 bromination Effects 0.000 claims abstract description 5
- 238000005406 washing Methods 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- JYJFNDQBESEHJQ-UHFFFAOYSA-N 5,5-dimethyloxazolidine-2,4-dione Chemical compound CC1(C)OC(=O)NC1=O JYJFNDQBESEHJQ-UHFFFAOYSA-N 0.000 claims description 17
- 239000012074 organic phase Substances 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 239000002585 base Substances 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 239000000376 reactant Substances 0.000 claims description 11
- 238000007710 freezing Methods 0.000 claims description 9
- 230000008014 freezing Effects 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 claims description 8
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 8
- 230000007935 neutral effect Effects 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 4
- 238000009776 industrial production Methods 0.000 abstract description 12
- 239000002699 waste material Substances 0.000 abstract description 9
- 230000008901 benefit Effects 0.000 abstract description 7
- 239000002351 wastewater Substances 0.000 abstract description 6
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 239000003960 organic solvent Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 60
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 31
- 239000000047 product Substances 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 10
- 230000007613 environmental effect Effects 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 230000035484 reaction time Effects 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 6
- 238000011403 purification operation Methods 0.000 description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000008096 xylene Substances 0.000 description 5
- 230000006837 decompression Effects 0.000 description 4
- 238000007599 discharging Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 208000012839 conversion disease Diseases 0.000 description 3
- 238000005265 energy consumption Methods 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- WRDWWAVNELMWAM-UHFFFAOYSA-N 4-tert-butylaniline Chemical class CC(C)(C)C1=CC=C(N)C=C1 WRDWWAVNELMWAM-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
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- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003568 thioethers Chemical group 0.000 description 1
Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a method for synthesizing benzothiadiazine dioxide acetanilide derivatives by a one-pot method, which comprises the following steps: (1) mixing ethyl [2- (3-butoxypropyl) -1, 1-dioxide-2H-1, 2, 4-benzothiadiazin-3-yl ] acetate, 3-tert-butyl-6- [ (2-ethylhexyl) thio ] aniline and a catalyst to perform amine transesterification; (2) mixing the amine ester exchange product obtained in the step (1) with 1, 3-dibromo-5, 5-dimethylhydantoin to perform alpha bromination reaction of carbonyl; (3) and (3) mixing the bromination product obtained in the step (2) with 5, 5-dimethyl oxazolidine-2, 4-diketone and alkali to perform nucleophilic substitution reaction. The synthesis method has the advantages of low requirement on equipment, simple operation process, low organic solvent consumption and low waste water and waste liquid discharge, and is very suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of chemical intermediate synthesis, in particular to a method for synthesizing benzothiadiazine dioxide acetanilide derivatives by a one-pot method.
Background
The benzothiadiazine compound and the derivative thereof have excellent performance in the aspect of medicine. The benzothiadiazine dioxide acetanilide derivative has wide biological and pharmacological activity, and among a plurality of derivatives, the benzothiadiazine dioxide acetanilide derivative also has wide application in the photosensitive industry. Because of the characteristics of excellent humidity and heat stability, high extinction coefficient (the dosage of the color former and silver can be reduced, the coating thickness can be effectively reduced), perfect absorption curve (less harmful absorption) and the like, the benzothiadiazine dioxide acetanilide compound is often used as the color former of the color photosensitive material, and obtains more ideal application effect.
At present, few reports are reported about the synthesis of benzothiadiazine dioxide acetanilide compounds, the structure is mainly generated by amine ester exchange of thioether substituted p-tert-butyl aniline with low reaction activity and a benzothiadiazine dioxide ethyl acetate derivative, the amine ester exchange reaction generally needs high temperature and a catalyst, and the process reaction conditions are not easy to control. Meanwhile, the structure needs to give consideration to the requirements of reaction effect and environmental protection policy in the aspect of selecting subsequent bromization reagent, and the whole process needs to have good economic and environmental protection benefits to be suitable for industrial production. In patent CN200310110359.6, the application of this kind of material as a yellow color former is described in detail by fuji corporation, and a brief description is given to the synthetic route, wherein the route relates to the synthesis of benzothiadiazine dioxide acetanilide compound from benzothiadiazine dioxide ethyl acetate compound, each step of the route requires post-treatment and discharging operation, partial reaction also requires pressure reduction condition, and the charging sequence of the subsequent reaction also has great inconvenience, which increases the complexity of the process operation and the discharge amount of waste water and waste liquid, and increases the labor cost and environmental cost.
Therefore, the existing synthesis method of benzothiadiazine dioxide acetanilide derivatives is still in need of improvement.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, one object of the present invention is to provide a one-pot method for synthesizing benzothiadiazine dioxide acetanilide derivatives, which has the following advantages: (1) the benzothiadiazine dioxide acetanilide compound is prepared through three steps of one-pot reaction, and purification and discharging operations are not required among the three steps of reaction; (2) the whole reaction is carried out under normal pressure, the operation is simple and convenient, and the requirement on equipment is reduced; (3) the charging sequence of nucleophilic substitution reaction is optimized, so that the process flow better meets the requirements of industrial production, and manual operation is effectively reduced; (4) the discharge of waste water and waste liquid brought by purification and discharge is reduced, and the environmental protection pressure of industrial production is reduced.
In one aspect of the invention, the invention provides a method for synthesizing benzothiadiazine dioxide acetanilide derivatives by a one-pot method. According to an embodiment of the invention, the method comprises:
(1) mixing ethyl [2- (3-butoxypropyl) -1, 1-dioxide-2H-1, 2, 4-benzothiadiazin-3-yl ] acetate, 3-tert-butyl-6- [ (2-ethylhexyl) thio ] aniline and a catalyst to perform amine transesterification;
(2) mixing the amine ester exchange product obtained in the step (1) with 1, 3-dibromo-5, 5-dimethylhydantoin to perform alpha bromination reaction of carbonyl;
(3) and (3) mixing the bromination product obtained in the step (2) with 5, 5-dimethyl oxazolidine-2, 4-diketone and alkali to perform nucleophilic substitution reaction so as to obtain a reactant containing benzothiadiazine dioxide acetanilide derivatives.
According to the one-pot synthesis method of benzothiadiazine dioxide acetanilide derivatives of the embodiment of the invention, firstly, the [2- (3-butoxypropyl) -1, 1-dioxide-2H-1, 2, 4-benzothiadiazin-3-yl ] ethyl acetate and the 3-tert-butyl-6- [ (2-ethylhexyl) thio ] aniline are used as starting materials to carry out amine transesterification reaction under the action of a catalyst, the [2- (3-butoxypropyl) -1, 1-dioxide-2H-1, 2, 4-benzothiadiazin-3-yl ] ethyl acetate has high reaction activity and can react with the amino group of the 3-tert-butyl-6- [ (2-ethylhexyl) thio ] aniline, thus obtaining amine ester exchange products, wherein the step does not need decompression condition and purification operation, the process condition is easy to control, and the use of reagents and the manual operation cost are reduced; the obtained amine ester exchange product directly reacts with 1, 3-dibromo-5, 5-dimethylhydantoin to generate alpha bromination of carbonyl, so as to obtain a bromo-product, and the bromo-reagent is selected without considering both the reaction effect requirement and the environmental policy requirement and without purification operation, thereby further reducing the use cost of the reagent and the manual operation cost; the obtained brominated product directly reacts with 5, 5-dimethyl oxazolidine-2, 4-diketone and alkali to generate nucleophilic substitution reaction, so that a reactant containing benzothiadiazine dioxide acetanilide derivatives is obtained, the charging sequence of the nucleophilic substitution reaction is optimized, the process flow better meets the requirements of industrial production, and manual operation is effectively reduced. Thus, the method has the following advantages: (1) the benzothiadiazine dioxide acetanilide compound is prepared through three steps of one-pot reaction, and purification and discharging operations are not required among the three steps of reaction; (2) the whole reaction is carried out under normal pressure, the operation is simple and convenient, and the requirement on equipment is reduced; (3) the charging sequence of nucleophilic substitution reaction is optimized, so that the process flow better meets the requirements of industrial production, and manual operation is effectively reduced; (4) the discharge of waste water and waste liquid brought by purification and discharge is reduced, and the environmental protection pressure of industrial production is reduced.
In addition, the method for synthesizing benzothiadiazine dioxide acetanilide derivatives by the one-pot method according to the above embodiments of the present invention may further have the following additional technical features:
in some embodiments of the invention, the molar ratio of the ethyl [2- (3-butoxypropyl) -1, 1-dioxide-2H-1, 2, 4-benzothiadiazin-3-yl ] acetate, the 3-tert-butyl-6- [ (2-ethylhexyl) thio ] aniline, the 1, 3-dibromo-5, 5-dimethylhydantoin, and the 5, 5-dimethyloxazolidine-2, 4-dione is 1: (1-1.3): (0.5-0.7): (1 to 1.5), preferably 1: (1-1.15): (0.5-0.6): (1-1.3). Thus, the atom economy is better, the yield is improved and the cost is reduced.
In some embodiments of the invention, in step (1), the temperature of the amine transesterification reaction is from 140 ℃ to 175 ℃, preferably from 150 ℃ to 170 ℃. Thus, the yield of the reaction can be improved and the cost can be reduced.
In some embodiments of the invention, in step (1), the catalyst comprises at least one of aluminum isopropoxide, aluminum chloride, and titanium chloride. Thereby, the yield of the reaction can be improved.
In some embodiments of the present invention, in step (2), the temperature of the bromination reaction is 0 ℃ to 50 ℃, preferably 5 ℃ to 30 ℃. Thus, the yield of the reaction can be improved and the cost can be reduced.
In some embodiments of the present invention, in step (3), the molar ratio of the 5, 5-dimethyloxazolidine-2, 4-dione to the base is 1 (1:1) to 1.5, preferably (1:1) to (1: 1.3). Thus, the reaction conversion rate can be improved and the cost can be reduced.
In some embodiments of the invention, in step (3), the base comprises K2CO3、Na2CO3And NaHCO3At least one of (a). Thereby, the yield of the reaction can be improved.
In some embodiments of the invention, in step (3), the 5, 5-dimethyloxazolidine-2, 4-dione is added to the brominated product from step (2), followed by a further addition of the base in portions. Thus, the yield of the reaction can be improved and the cost can be reduced.
In some embodiments of the invention, the method further comprises: (4) extracting the reactant containing the benzothiadiazine dioxide acetanilide derivative by using an extraction liquid, then carrying out acid washing on an organic phase, washing the organic phase to be neutral, and finally carrying out reduced pressure concentration, solvent addition and freezing to separate out the benzothiadiazine dioxide acetanilide derivative. Therefore, the purification steps can be simplified, and manual operation is effectively reduced.
In some embodiments of the invention, in step (4), the eluting solvent comprises at least one of methanol, ethanol, and acetonitrile. Therefore, the purification steps can be simplified, and manual operation is effectively reduced.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:
FIG. 1 is a flow diagram of a one-pot method for synthesizing benzothiadiazine dioxide acetanilide derivatives in accordance with one embodiment of the present invention;
FIG. 2 is a flow diagram of a one-pot method for synthesizing benzothiadiazine dioxide acetanilide derivatives in accordance with yet another embodiment of the present invention;
FIG. 3 is a nuclear magnetic representation of benzothiadiazine dioxide acetanilide derivatives obtained according to examples and comparative examples.
Detailed Description
The embodiments described below with reference to the drawings are illustrative and intended to be illustrative of the invention and are not to be construed as limiting the invention.
In one aspect of the present invention, the present invention provides a method for synthesizing benzothiadiazine dioxide acetanilide derivatives by a one-pot method, which comprises the following steps:
s100: mixing ethyl [2- (3-butoxypropyl) -1, 1-dioxide-2H-1, 2, 4-benzothiadiazin-3-yl ] acetate, 3-tert-butyl-6- [ (2-ethylhexyl) thio ] aniline and catalyst to produce amine ester exchange reaction
In this step, [2- (3-butoxypropyl) -1, 1-dioxide-2H-1, 2, 4-benzothiadiazin-3-yl ] acetic acid ethyl ester, 3-tert-butyl-6- [ (2-ethylhexyl) thio ] aniline and a catalyst were mixed to carry out an amine transesterification. The method does not need decompression and purification operation, the process conditions are easy to control, and the use cost and the manual operation cost of the reagent are reduced. The reaction process of this step is as follows:
specifically, the N atom on 3-tert-butyl-6- [ (2-ethylhexyl) thio ] aniline attacks the carbonyl carbon of ethyl [2- (3-butoxypropyl) -1, 1-dioxide-2H-1, 2, 4-benzothiadiazin-3-yl ] acetate, and then one molecule of ethanol is removed to form an amide. The temperature of the amine ester exchange reaction is 140-175 ℃, the preferable temperature is 150-170 ℃, and the reaction time is 5-10 h. The inventor finds that the reaction temperature is too low and the reaction time is too short, so that the reaction is not completely carried out and the yield of the product is reduced; too high reaction temperature and too long reaction time can lead to increased side reactions, reduced product content, increased energy consumption and increased production cost. Thus, with the reaction temperature and time of the present application, product yield can be increased and cost can be reduced.
It should be noted that the type of the catalyst is not particularly limited, and may be selected by those skilled in the art according to actual needs, for example, the catalyst includes at least one of aluminum isopropoxide, aluminum chloride, and titanium chloride.
S200: mixing the amine ester exchange product obtained in the step S100 with 1, 3-dibromo-5, 5-dimethylhydantoin to perform alpha bromination reaction of carbonyl
In this step, the amine ester exchange product obtained in step S100 is mixed with 1, 3-dibromo-5, 5-dimethylhydantoin to perform a bromination reaction at the α -position of the carbonyl group. The bromine generation reagent is selected without considering the reaction effect requirement and the environmental protection policy requirement, and the purification operation is not needed, so that the use cost and the manual operation cost of the reagent are further reduced. The reaction process of this step is as follows:
specifically, the temperature of the bromination reaction is 0-50 ℃, preferably 5-30 ℃, and the reaction time is 1-3 h. The inventor finds that the reaction is not completely performed due to the excessively low reaction temperature and the excessively short reaction time, the yield of the product is reduced, and meanwhile, the low-temperature condition can increase the reaction energy consumption and the reaction cost; too high a reaction temperature and too long a reaction time may result in increased side reactions and reduced product content. Thus, with the reaction temperature and time of the present application, product yield can be increased and cost can be reduced.
S300: the bromo product obtained in step S200 is mixed with 5, 5-dimethyloxazolidine-2, 4-diketone and alkali to carry out nucleophilic substitution reaction
In this step, 5-dimethyloxazolidine-2, 4-dione is added to the brominated product obtained in step S200, and then the base is added in portions, so as to obtain a reaction product containing benzothiadiazine dioxide acetanilide derivatives. The step optimizes the feeding sequence of nucleophilic substitution reaction, so that the process flow better meets the requirements of industrial production, and the manual operation is effectively reduced.
The reaction process of this step is as follows:
specifically, 5, 5-dimethyloxazolidine-2, 4-dione is added to the brominated product obtained in step S200, and then a base is added in portions, and further, the molar ratio of 5, 5-dimethyloxazolidine-2, 4-dione to base is 1 (1-1.5), preferably (1:1) - (1: 1.3). The inventors found that when the molar ratio of 5, 5-dimethyloxazolidine-2, 4-dione to base is too high, N anion is not sufficiently generated, resulting in a decrease in the reaction conversion rate; too low a molar ratio of 5, 5-dimethyloxazolidine-2, 4-dione to base wastes the base reagent, thereby increasing the reaction cost. Therefore, the reaction conversion rate can be improved and the cost can be reduced by adopting the reactants with the molar ratio.
Furthermore, the temperature of the nucleophilic substitution reaction is 30-80 ℃, and the reaction time is 3-6 h. The inventor finds that the reaction temperature is too low and the reaction time is too short, so that the reaction is not completely carried out and the yield of the product is reduced; too high reaction temperature and too long reaction time can result in increased side reactions, reduced product content, waste of energy consumption and increased reaction cost. Thus, with the reaction temperature and time of the present application, product yield can be increased and cost can be reduced.
It should be noted that the type of the base is not particularly limited, and can be selected by those skilled in the art according to actual needs, for example, the base includes K2CO3、Na2CO3And NaHCO3At least one of (a).
According to one embodiment of the invention, the molar ratio of [2- (3-butoxypropyl) -1, 1-dioxide-2H-1, 2, 4-benzothiadiazin-3-yl ] acetic acid ethyl ester, 3-tert-butyl-6- [ (2-ethylhexyl) thio ] aniline, 1, 3-dibromo-5, 5-dimethylhydantoin and the 5, 5-dimethyloxazolidine-2, 4-dione is 1: (1-1.3): (0.5-0.7): (1 to 1.5), preferably 1: (1-1.15): (0.5-0.6): (1-1.3). The inventors have found that the molar ratio of the reactants is within the defined range, the reaction is carried out sufficiently and the atom economy is good, and that exceeding the defined range causes waste of raw materials and increases the cost, and that excessive amounts of reactants may remain in the product to reduce the content of the product. Therefore, the reactants with the molar ratio are adopted, the atom economy is better, the yield is improved, and the cost is reduced.
According to the one-pot synthesis method of benzothiadiazine dioxide acetanilide derivatives of the embodiment of the invention, firstly, the [2- (3-butoxypropyl) -1, 1-dioxide-2H-1, 2, 4-benzothiadiazin-3-yl ] ethyl acetate and the 3-tert-butyl-6- [ (2-ethylhexyl) thio ] aniline are used as starting materials to carry out amine transesterification reaction under the action of a catalyst, the [2- (3-butoxypropyl) -1, 1-dioxide-2H-1, 2, 4-benzothiadiazin-3-yl ] ethyl acetate has high reaction activity and can react with the amino group of the 3-tert-butyl-6- [ (2-ethylhexyl) thio ] aniline, thus obtaining amine ester exchange products, wherein the step does not need decompression condition and purification operation, the process condition is easy to control, and the use of reagents and the manual operation cost are reduced; the obtained amine ester exchange product directly reacts with 1, 3-dibromo-5, 5-dimethylhydantoin to generate alpha bromination of carbonyl, so as to obtain a bromo-product, and the bromo-reagent is selected without considering both the reaction effect requirement and the environmental policy requirement and without purification operation, thereby further reducing the use cost of the reagent and the manual operation cost; the obtained brominated product directly reacts with 5, 5-dimethyl oxazolidine-2, 4-diketone and alkali to generate nucleophilic substitution reaction, so that a reactant containing benzothiadiazine dioxide acetanilide derivatives is obtained, the charging sequence of the nucleophilic substitution reaction is optimized, the process flow better meets the requirements of industrial production, and manual operation is effectively reduced. Thus, the method has the following advantages: (1) the benzothiadiazine dioxide acetanilide compound is prepared through three steps of one-pot reaction, and purification and discharging operations are not required among the three steps of reaction; (2) the whole reaction is carried out under normal pressure, the operation is simple and convenient, and the requirement on equipment is reduced; (3) the charging sequence of nucleophilic substitution reaction is optimized, so that the process flow better meets the requirements of industrial production, and manual operation is effectively reduced; (4) the discharge of waste water and waste liquid brought by purification and discharge is reduced, and the environmental protection pressure of industrial production is reduced.
Further, referring to fig. 2, the method for synthesizing benzothiadiazine dioxide acetanilide derivatives by the above one-pot method of the present invention further comprises:
s400: extracting the reaction product containing benzothiadiazine dioxide acetanilide derivative with the extract, acid-washing the organic phase, water-washing to neutrality, vacuum concentrating, adding solvent, and freezing
In the step, the reactant containing the benzothiadiazine dioxide acetanilide derivative is extracted by using an extraction liquid, then an organic phase is subjected to acid washing and water washing to be neutral, and finally the benzothiadiazine dioxide acetanilide derivative is separated out by decompression, concentration and solvent adding and freezing. It is to be noted that the type of the eluting solvent is not particularly limited, and may be selected by those skilled in the art as needed, and includes at least one of methanol, ethanol, and acetonitrile. The invention can obtain the final product only by simple purification steps of extraction, water washing, recrystallization and the like for the mixed system obtained by the one-pot reaction, does not need further column chromatography or chromatographic purification operation, effectively reduces manual operation, and reduces the use of reagents, thereby reducing the discharge of waste water and waste liquid brought by purification and discharge and lightening the environmental protection pressure of industrial production.
The invention will now be described with reference to specific examples, which are intended to be illustrative only and not to be limiting in any way.
Example 1
500mL three-necked flask equipped with a water separator was charged with 3-tert-butyl-6- [ (2-ethylhexyl) thio group]Aniline 14.67g, [2- (3-butoxypropyl) -1, 1-dioxide-2H-1, 2, 4-benzothiadiazin-3-yl]19.10g of ethyl acetate, 4.08g of aluminum isopropoxide, 0.67g of anhydrous aluminum trichloride and 30mL of xylene, reacting at 150 ℃ for 2 hours, and then heatingAfter 5 hours of reaction at 160 ℃ toluene 100mL was added, 7.15g of 1, 3-dibromo-5, 5-dimethylhydantoin were added in portions at 5 ℃ and after 1.5 hours of reaction 16.45g of 5, 5-dimethyloxazolidine-2, 4-dione, K2CO36.9g, reacting for 2h at 60 ℃, adding toluene and water for extracting and separating liquid after the reaction is finished, washing an organic phase for 1 time by using dilute acid, washing the organic phase to be neutral by using water, concentrating under reduced pressure, adding methanol, and freezing to separate out 28.61g of solid. The nuclear magnetic representation of the final compound is shown in figure 3.
Example 2
500mL three-necked flask equipped with a water separator was charged with 3-tert-butyl-6- [ (2-ethylhexyl) thio group]Aniline 16.87g, [2- (3-butoxypropyl) -1, 1-dioxide-2H-1, 2, 4-benzothiadiazin-3-yl]19.10g of ethyl acetate, 4.08g of aluminum isopropoxide, 0.95g of titanium chloride and 30mL of xylene, the temperature is raised to 165 ℃ after 2 hours of reaction at 155 ℃, 100mL of toluene is added after 5 hours of reaction, 8.58g of 1, 3-dibromo-5, 5-dimethylhydantoin is added in portions at 15 ℃, 8.38g of 5, 5-dimethyloxazolidine-2, 4-dione and Na are added after 1.5 hours of reaction2CO38.96g, reacting for 2h at 60 ℃, adding toluene and water for extracting and separating liquid after the reaction is finished, washing an organic phase for 1 time by using dilute acid, washing the organic phase to be neutral by using water, concentrating under reduced pressure, adding ethanol, and freezing to separate out 29.67g of solid. The nuclear magnetic representation of the final compound is shown in figure 3.
Example 3
500mL three-necked flask equipped with a water separator was charged with 3-tert-butyl-6- [ (2-ethylhexyl) thio group]Aniline 16.14g, [2- (3-butoxypropyl) -1, 1-dioxide-2H-1, 2, 4-benzothiadiazin-3-yl]19.10g of ethyl acetate, 4.08g of aluminum isopropoxide and 30mL of xylene, reacting at 150 ℃ for 2 hours, heating to 165 ℃, reacting at 5 hours, adding 100mL of toluene, adding 7.86g of 1, 3-dibromo-5, 5-dimethylhydantoin in batches at 25 ℃, reacting for 1.5 hours, adding 7.74g of 5, 5-dimethyloxazolidine-2, 4-dione and NaHCO36.05g, reacting for 2h at 60 ℃, adding toluene and water for extracting and separating liquid after the reaction is finished, washing an organic phase for 1 time by using dilute acid, washing the organic phase to be neutral by using water, concentrating under reduced pressure, adding acetonitrile, and freezing to separate out 28.92g of solid. The nuclear magnetic representation of the final compound is shown in figure 3.
Example 4
500mL three-necked flask equipped with a water separator was charged with 3-t-butyl-6- [ (2-ethylhexyl) thio group]Aniline 14.67g, [2- (3-butoxypropyl) -1, 1-dioxide-2H-1, 2, 4-benzothiadiazin-3-yl]19.10g of ethyl acetate, 4.08g of aluminum isopropoxide, 0.67g of anhydrous aluminum trichloride and 30mL of xylene, wherein after 2 hours of reaction at 155 ℃, the temperature is raised to 170 ℃, 100mL of toluene is added after 5 hours of reaction, 8.58g of 1, 3-dibromo-5, 5-dimethylhydantoin is added in batches at 25 ℃, 7.09g of 5, 5-dimethyloxazolidine-2, 4-dione and K are added after 1.5 hours of reaction2CO38.35g, reacting for 2h at 60 ℃, adding toluene and water for extracting and separating liquid after the reaction is finished, washing an organic phase for 1 time by using dilute acid, washing the organic phase to be neutral, concentrating under reduced pressure, adding ethanol, and freezing to separate out 29.56g of solid. The nuclear magnetic representation of the final compound is shown in figure 3.
Example 5
500mL three-necked flask equipped with a water separator was charged with 3-tert-butyl-6- [ (2-ethylhexyl) thio group]Aniline 15.41g, [2- (3-butoxypropyl) -1, 1-dioxide-2H-1, 2, 4-benzothiadiazin-3-yl]19.10g of ethyl acetate, 4.08g of aluminum isopropoxide and 30mL of xylene, reacting at 155 ℃ for 2 hours, heating to 165 ℃, reacting for 5 hours, adding 100mL of toluene, adding 8.58g of 1, 3-dibromo-5, 5-dimethylhydantoin in portions at 30 ℃, reacting for 1.5 hours, adding 8.39g of 5, 5-dimethyloxazolidine-2, 4-dione and Na2CO38.27g, reacting for 2h at 60 ℃, adding toluene and water for extracting and separating liquid after the reaction is finished, washing an organic phase for 1 time by using dilute acid, washing the organic phase to be neutral by using water, concentrating under reduced pressure, adding methanol, and freezing to separate out 29.33g of solid. The nuclear magnetic representation of the final compound is shown in figure 3.
Comparative example
Under reduced pressure, a mixture of 110g of ethyl [2- (3-butoxypropyl) -1, 1-dioxide-2H-1, 2, 4-benzothiadiazin-3-yl ] acetate and 84.5g of 3-tert-butyl-6- [ (2-ethylhexyl) thio ] aniline was heated and stirred at 150 ℃ for 6 hours, 750mL of toluene was added after the reaction was completed, 41.2g of 1, 3-dibromo-5, 5-dimethylhydantoin was added thereto under ice-cooling for 15 minutes, water was added after the reaction at room temperature for 1 hour to conduct extraction separation, and the separated organic layer was washed with water several times to obtain an intermediate solution.
The intermediate reaction product obtained previously was added dropwise to a mixed solution of 39.0g of 5, 5-dimethyloxazolidine-2, 4-dione, 41.8g of potassium carbonate and 150mL of N, N-dimethylacetamide at room temperature, and the reaction was stirred at 50 ℃ for 2 hours. After the extractive separation, the organic phase is washed with a standard aqueous solution of potassium hydroxide, dilute hydrochloric acid and saturated brine. The mixture was concentrated under reduced pressure and recrystallized from methanol to yield 171.6g of a product. The nuclear magnetic representation of the final compound is shown in figure 3.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. A method for synthesizing benzothiadiazine dioxide acetanilide derivatives by a one-pot method is characterized by comprising the following steps:
(1) mixing ethyl [2- (3-butoxypropyl) -1, 1-dioxide-2H-1, 2, 4-benzothiadiazin-3-yl ] acetate, 3-tert-butyl-6- [ (2-ethylhexyl) thio ] aniline and a catalyst to perform amine transesterification;
(2) mixing the amine ester exchange product obtained in the step (1) with 1, 3-dibromo-5, 5-dimethylhydantoin to perform alpha bromination reaction of carbonyl;
(3) and (3) mixing the bromination product obtained in the step (2) with 5, 5-dimethyl oxazolidine-2, 4-diketone and alkali to perform nucleophilic substitution reaction so as to obtain a reactant containing benzothiadiazine dioxide acetanilide derivatives.
2. The process according to claim 1, wherein the molar ratio of ethyl [2- (3-butoxypropyl) -1, 1-dioxide-2H-1, 2, 4-benzothiadiazin-3-yl ] acetate, 3-tert-butyl-6- [ (2-ethylhexyl) thio ] aniline, 1, 3-dibromo-5, 5-dimethylhydantoin and 5, 5-dimethyloxazolidine-2, 4-dione is 1: (1-1.3): (0.5-0.7): (1 to 1.5), preferably 1: (1-1.15): (0.5-0.6): (1-1.3).
3. The process according to claim 1, characterized in that in step (1) the temperature of the amine transesterification reaction is between 140 ℃ and 175 ℃, preferably between 150 ℃ and 170 ℃.
4. The method of claim 1 or 3, wherein in step (1), the catalyst comprises at least one of aluminum isopropoxide, aluminum chloride, and titanium chloride.
5. The process according to claim 1, wherein in step (2), the temperature of the bromination reaction is from 0 ℃ to 50 ℃, preferably from 5 ℃ to 30 ℃.
6. The process according to claim 1, wherein in step (3), the molar ratio of the 5, 5-dimethyloxazolidine-2, 4-dione to the base is 1 (1:1) to 1.5, preferably (1:1) to (1: 1.3).
7. The method of claim 1 or 6, wherein in step (3), the base comprises K2CO3、Na2CO3And NaHCO3At least one of (a).
8. The process according to claim 1, wherein in step (3), the 5, 5-dimethyloxazolidine-2, 4-dione is added to the brominated product obtained in step (2), and then the base is added in portions.
9. The method of claim 1, further comprising:
(4) extracting the reactant containing the benzothiadiazine dioxide acetanilide derivative by using an extraction liquid, then carrying out acid washing on an organic phase, washing the organic phase to be neutral, and finally carrying out reduced pressure concentration, solvent addition and freezing to separate out the benzothiadiazine dioxide acetanilide derivative.
10. The method of claim 9, wherein in step (4), the eluting solvent comprises at least one of methanol, ethanol, and acetonitrile.
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