CN103288774B - Method for preparing 2-(carbonyl-N-phenothizainyl)-benzoic acid - Google Patents
Method for preparing 2-(carbonyl-N-phenothizainyl)-benzoic acid Download PDFInfo
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- CN103288774B CN103288774B CN201310188968.7A CN201310188968A CN103288774B CN 103288774 B CN103288774 B CN 103288774B CN 201310188968 A CN201310188968 A CN 201310188968A CN 103288774 B CN103288774 B CN 103288774B
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Abstract
The invention discloses a method for preparing 2-(carbonyl-N-phenothizainyl)-benzoic acid. The method comprises steps of: adding A mol phenothiazine and B mol phthalic anhydride into a reaction container, and then adding acetonitrile; dropwise adding concentrated hydrochloric acid into the reaction container while stirring so as to obtain a reaction liquid, heating the reaction liquid from a room temperature to 45-85 DEG C and stirring to react for 1-3h so as to obtain a mixed liquid, wherein A:B=2.5:(2.5-3.3); reducing the pressure of the mixed liquid to evaporate the acetonitrile, wherein the volume of the acetonitrile in a concentrated solution accounts for 10-15% of the volume of the acetonitrile in the mixed liquid; and cooling the concentrated solution to room temperature, adding water into the concentrated solution, stirring uniformly and then filtering, washing and drying a filter cake so as to obtain the 2-(carbonyl-N-phenothizainyl)-benzoic acid. The acetonitrile is served as a solvent and the concentrated hydrochloric acid is utilized as a catalyst, so that the method has the advantages of convenience in operation, short reaction time, moderate conditions, simple aftertreatment, easily available raw materials and high yield.
Description
Technical field
The invention belongs to the field of chemical synthesis, particularly one prepares 2-(carbonyl-N-phenothiazinyl)-benzoic method.
Background technology
Thiodiphenylamine is a kind of heterogeneous ring compound of nitrogenous, sulphur, and also known as sulphur naphthazin(e) or phenothiazine, this compounds is just found to have a series of pharmacologically active at the beginning of synthesis.In recent years, oxidation inhibitor, biological medicine and dyestuff etc. that phenothiazine compound is widely used in stopper, lubricant are industrial, in addition, also can be used for synthesizing the aspect such as fruit tree insecticide, electroluminescent organic material.Along with the continuous exploration discovery of researcher, phenothiazines is applicable to treat acute and chronic schizophrenia, mania and other severe psychosis.Therefore, the research for phenothiazine compound is very meaningful.
Philip S.Winnek etc. mentions in US Patent No. 2461460: mixed with succinyl oxide by thiodiphenylamine, oil bath backflow 16h at 150 DEG C, products therefrom under agitation adds ammonium hydroxide, after filtration, filtrate uses 10% hcl acidifying, solid 75% ethyl alcohol recrystallization.And claim aforesaid method to be applicable to too using Pyroglutaric acid, pimelic acid acid anhydride, sebacic anhydride, butyl-malonic anhydride, methylmalonic acid acid anhydride and Tetra hydro Phthalic anhydride as acylating agent to synthesize different acylates.The method temperature of reaction is high and the time is longer, and aftertreatment also bothers relatively.
Summary of the invention
The object of the present invention is to provide that a kind of reaction conditions is gentle, easy and simple to handle, the reaction times is short, aftertreatment is simple and the preparation 2-that productive rate is high (carbonyl-N-phenothiazinyl)-benzoic method.
To achieve these goals, technical scheme of the present invention comprises the following steps:
The first step, adds A mol thiodiphenylamine and B mol Tetra hydro Phthalic anhydride, then adds acetonitrile in reaction vessel; Stir in downhill reaction container and drip concentrated hydrochloric acid, obtain reaction solution, by reaction solution from room temperature to 45 ~ 85 DEG C and stirring reaction 1 ~ 3h, obtain mixed solution, wherein A:B=2.5:(2.5 ~ 3.3);
Second step, mixed solution decompression is steamed acetonitrile, and obtain concentrated solution, wherein in concentrated solution, the volume of acetonitrile is 10 ~ 15% of acetonitrile volume in mixed solution; Solution to be concentrated adds water after being cooled to room temperature wherein, suction filtration after stirring, and by filter cake washing, drying, obtains 2-(carbonyl-N-phenothiazinyl)-phenylformic acid.
The consumption of described acetonitrile is C mL, C=(2000 ~ 6000) A.
The mass concentration of described concentrated hydrochloric acid is 36 ~ 38%, and consumption is D mL, D=(40 ~ 80) A.
Stir speed (S.S.) in the described the first step is 2000 ~ 3000r/min.
Heat-up rate in the described the first step is 4 ~ 5 DEG C/min.
In described second step, solution to be concentrated adds X mL water wherein after being cooled to room temperature, X=(6000 ~ 10000) A.
Required time that stirs in described second step is 5 ~ 10min.
Drying in described second step is that room temperature is dried.
Described A:B=2.5:(2.75 ~ 3.25), temperature of reaction is 55 ~ 75 DEG C.
Described A:B=2.5:3.0, temperature of reaction is 65 DEG C, and the reaction times is 1.5h.
Compared with prior art, the present invention has following beneficial effect:
The invention provides a kind of 2-(carbonyl-N-phenothiazinyl)-benzoic preparation method, the method with thiodiphenylamine and MALEIC ANHYDRIDE for raw material, acetonitrile is solvent, concentrated hydrochloric acid is catalyzer, namely prepares 2-(carbonyl-N-phenothiazinyl)-phenylformic acid in 45 ~ 85 DEG C of reactions.Cheap and easy to get and the excellent catalytic effect of concentrated hydrochloric acid that the present invention uses, raw material of the present invention is easy to get, easy and simple to handle, reaction is easy to control, reaction conditions is gentle and the reaction times is shorter, equipment requirements is low, and aftertreatment is simple and productive rate is high, is a kind of simple, economic preparation 2-(carbonyl-N-phenothiazinyl)-benzoic method.
Embodiment
The present invention is using acetonitrile as solvent, and concentrated hydrochloric acid is catalyzer, reaction solution is reacted at 45 ~ 85 DEG C generate 2-(carbonyl-N-phenothiazinyl)-phenylformic acid, its reaction formula as the formula (1):
Below in conjunction with the present invention preferably specific embodiment the present invention is described in further detail.
Embodiment 1
The first step, 0.0025mol thiodiphenylamine and 0.0025mol Tetra hydro Phthalic anhydride is added in the there-necked flask of drying, add 5mL acetonitrile again, the concentrated hydrochloric acid that 0.15mL mass concentration is 36 ~ 38% is slowly dripped in the stirring velocity downhill reaction container of 2200r/min, obtain reaction solution, reaction solution is warming up to 45 DEG C from room temperature with the speed of 4 DEG C/min, and with the speed stirring reaction 3h of 2200r/min, obtains mixed solution;
Second step, mixed solution decompression is steamed acetonitrile, obtain concentrated solution, in concentrated solution, the volume of acetonitrile is 12% of acetonitrile volume in mixed solution, solution to be concentrated adds 15mL water after being cooled to room temperature wherein, suction filtration after stirring 5min, filter cake washing, room temperature are dried, the white powder obtained is 2-(carbonyl-N-phenothiazinyl)-phenylformic acid; Productive rate is 88%.
1H-NMR(DMSO，400MHZ)δppm：7.49～7.76(m,8H,ArH),7.66～8.32(m,4H,ArH),12.05(s,1H,COOH)。
Embodiment 2
The first step, 0.00250mol thiodiphenylamine and 0.00275mol Tetra hydro Phthalic anhydride is added in the there-necked flask of drying, add 8mL acetonitrile again, the concentrated hydrochloric acid that 0.2mL mass concentration is 36 ~ 38% is slowly dripped in the stirring velocity downhill reaction container of 2000r/min, obtain reaction solution, reaction solution is warming up to 55 DEG C from room temperature with the speed of 5 DEG C/min, and with the speed stirring reaction 2.5h of 2000r/min, obtains mixed solution;
Second step, mixed solution decompression is steamed acetonitrile, obtain concentrated solution, in concentrated solution, the volume of acetonitrile is 10% of acetonitrile volume in mixed solution, solution to be concentrated adds 15mL water after being cooled to room temperature wherein, suction filtration after stirring 8min, filter cake washing, room temperature are dried, the white powder obtained is 2-(carbonyl-N-phenothiazinyl)-phenylformic acid; Productive rate is 92%.
Embodiment 3
The first step, 0.0025mol thiodiphenylamine and 0.0030mol Tetra hydro Phthalic anhydride is added in the there-necked flask of drying, add 12mL acetonitrile again, the concentrated hydrochloric acid that 0.1mL mass concentration is 36 ~ 38% is slowly dripped in the stirring velocity downhill reaction container of 2500r/min, obtain reaction solution, reaction solution is warming up to 65 DEG C from room temperature with the speed of 5 DEG C/min, and with the speed stirring reaction 1.5h of 2500r/min, obtains mixed solution;
Second step, mixed solution decompression is steamed acetonitrile, obtain concentrated solution, in concentrated solution, the volume of acetonitrile is 10% of acetonitrile volume in mixed solution, solution to be concentrated adds 20mL water after being cooled to room temperature wherein, suction filtration after stirring 5min, filter cake washing, room temperature are dried, the white powder obtained is 2-(carbonyl-N-phenothiazinyl)-phenylformic acid; Productive rate is 94%.
Embodiment 4
The first step, 0.00250mol thiodiphenylamine and 0.00325mol Tetra hydro Phthalic anhydride is added in the there-necked flask of drying, add 15mL acetonitrile again, the concentrated hydrochloric acid that 0.15mL mass concentration is 36 ~ 38% is slowly dripped in the stirring velocity downhill reaction container of 3000r/min, obtain reaction solution, reaction solution is warming up to 75 DEG C from room temperature with the speed of 4 DEG C/min, and with the speed stirring reaction 1.5h of 3000r/min, obtains mixed solution;
Second step, mixed solution decompression is steamed acetonitrile, obtain concentrated solution, in concentrated solution, the volume of acetonitrile is 13% of acetonitrile volume in mixed solution, solution to be concentrated adds 20mL water after being cooled to room temperature wherein, suction filtration after stirring 10min, filter cake washing, room temperature are dried, the white powder obtained is 2-(carbonyl-N-phenothiazinyl)-phenylformic acid; Productive rate is 93%.
Embodiment 5
The first step, 0.0025mol thiodiphenylamine and 0.0033mol Tetra hydro Phthalic anhydride is added in the there-necked flask of drying, add 15mL acetonitrile again, the concentrated hydrochloric acid that 0.15mL mass concentration is 36 ~ 38% is slowly dripped in the stirring velocity downhill reaction container of 2800r/min, obtain reaction solution, reaction solution is warming up to 85 DEG C from room temperature with the speed of 5 DEG C/min, and with the speed stirring reaction 1h of 2800r/min, obtains mixed solution;
Second step, mixed solution decompression is steamed acetonitrile, obtain concentrated solution, in concentrated solution, the volume of acetonitrile is 15% of acetonitrile volume in mixed solution, solution to be concentrated adds 25mL water after being cooled to room temperature wherein, suction filtration after stirring 7min, filter cake washing, room temperature are dried, the white powder obtained is 2-(carbonyl-N-phenothiazinyl)-phenylformic acid; Productive rate is 90%.
A kind of 2-provided by the invention (carbonyl-N-phenothiazinyl)-benzoic preparation method, have employed concentrated hydrochloric acid cheap and easy to get as reaction catalyzer and catalytic effect is splendid, be solvent with acetonitrile and in aftertreatment, most of solvent reclaimed, reaction conditions is gentle and the time is short, does not need recrystallization can obtain productive rate and all higher target compound of purity.Can yet be regarded as a kind of easy, economic 2-(carbonyl-N-phenothiazinyl)-benzoic preparation method.
Claims (8)
1. prepare 2-(carbonyl-N-phenothiazinyl)-benzoic method, it is characterized in that, comprise the following steps:
The first step, adds A mol thiodiphenylamine and B mol Tetra hydro Phthalic anhydride, then adds C mL acetonitrile in reaction vessel; Stirring and dripping D mL mass concentration in downhill reaction container is the concentrated hydrochloric acid of 36 ~ 38%, obtain reaction solution, by reaction solution from room temperature to 45 ~ 85 DEG C and stirring reaction 1 ~ 3h, obtain mixed solution, wherein A:B=2.5:(2.5 ~ 3.3), A:C=1:(2000 ~ 6000), A:D=1:(40 ~ 80);
Second step, mixed solution decompression is steamed acetonitrile, and obtain concentrated solution, wherein in concentrated solution, the volume of acetonitrile is 10 ~ 15% of acetonitrile volume in mixed solution; Solution to be concentrated adds water after being cooled to room temperature wherein, suction filtration after stirring, and by filter cake washing, drying, obtains 2-(carbonyl-N-phenothiazinyl)-phenylformic acid.
2. preparation 2-according to claim 1 (carbonyl-N-phenothiazinyl)-benzoic method, is characterized in that: the stir speed (S.S.) in the described the first step is 2000 ~ 3000r/min.
3. preparation 2-according to claim 1 (carbonyl-N-phenothiazinyl)-benzoic method, is characterized in that: the heat-up rate in the described the first step is 4 ~ 5 DEG C/min.
4. preparation 2-according to claim 1 (carbonyl-N-phenothiazinyl)-benzoic method, is characterized in that: in described second step, solution to be concentrated adds X mL water wherein after being cooled to room temperature, X=(6000 ~ 10000) A.
5. preparation 2-according to claim 1 (carbonyl-N-phenothiazinyl)-benzoic method, is characterized in that: the required time that stirs in described second step is 5 ~ 10min.
6. preparation 2-according to claim 1 (carbonyl-N-phenothiazinyl)-benzoic method, is characterized in that: the drying in described second step is that room temperature is dried.
7. preparation 2-according to claim 1 (carbonyl-N-phenothiazinyl)-benzoic method, is characterized in that: described A:B=2.5:(2.75 ~ 3.25), temperature of reaction is 55 ~ 75 DEG C.
8. preparation 2-according to claim 1 (carbonyl-N-phenothiazinyl)-benzoic method, it is characterized in that: described A:B=2.5:3.0, temperature of reaction is 65 DEG C, and the reaction times is 1.5h.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2461460A (en) * | 1949-02-08 | N-acixphenothiazines | ||
| CN1086825A (en) * | 1992-08-31 | 1994-05-18 | 弗·哈夫曼-拉罗切有限公司 | Three ring and tetracyclic compounds |
| WO2011153331A2 (en) * | 2010-06-02 | 2011-12-08 | The General Hospital Corporation | Optical sensor conjugates for detecting reactive oxygen and/or reactive nitrogen species in vivo |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2461460A (en) * | 1949-02-08 | N-acixphenothiazines | ||
| CN1086825A (en) * | 1992-08-31 | 1994-05-18 | 弗·哈夫曼-拉罗切有限公司 | Three ring and tetracyclic compounds |
| WO2011153331A2 (en) * | 2010-06-02 | 2011-12-08 | The General Hospital Corporation | Optical sensor conjugates for detecting reactive oxygen and/or reactive nitrogen species in vivo |
Non-Patent Citations (2)
| Title |
|---|
| Phenothiazine Inhibitors of Trypanothione Reductase as Potential Antitrypanosomal and Antileishmanial Drugs†;Cecil Chan et al.;《J.Med.Chem》;19980115;第41卷(第2期);第148-156页 * |
| 闻韧.药物合成反应.《药物合成反应》.化学工业出版社,2003,(第2版),第134-141页. * |
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