CN103450107A - Method for preparing N-methyl isatoic anhydride - Google Patents
Method for preparing N-methyl isatoic anhydride Download PDFInfo
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- CN103450107A CN103450107A CN2013104193757A CN201310419375A CN103450107A CN 103450107 A CN103450107 A CN 103450107A CN 2013104193757 A CN2013104193757 A CN 2013104193757A CN 201310419375 A CN201310419375 A CN 201310419375A CN 103450107 A CN103450107 A CN 103450107A
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Abstract
The invention provides a method for preparing N-methyl isatoic anhydride. The method comprises simple steps, is simple and convenient to operate, and is suitable for industrial production, and the raw materials are cheap and are easily available. The method comprises following steps of firstly taking anhydrous potassium carbonate as acid-binding agent and copper powder as a catalyst, carrying out a condensation reaction on o-chlorobenzoic acid and methylamine so as to obtain N-methyl o-aminobenzoic acid, and carrying out cyclization through condensation by adopting triphosgene and N-methyl o-aminobenzoic acid, so as to prepare the N-methyl isatoic anhydride.
Description
Technical field
The invention belongs to organic chemistry filed, relate to a kind of preparation method of N-methyl-isatin acid anhydrides.
Background technology
The N-methyl-isatin acid anhydrides, English name N-Methylisatoic anhydride, chemical name, 1-methyl-2H-3,1-benzoxazine 2,4 (1H)-diketone, molecular formula: C9H7NO3CAS:10328-92-4.
The N-methyl-isatin acid anhydrides, raw material as medicine, agricultural chemicals, dyestuff, being the important intermediate of weedicide bentazone, is also the intermediate of urgent help with new drug laquinimod sheet (Laquinimod), is also the key intermediate of natural product evodiamine simultaneously.
About the preparation method of N-methyl-isatin acid anhydrides, the domestic literature report is few.
Carry out methylation reaction at methylating reagent under as methyl iodide or methyl-sulfate etc. with isatoic anhydride during conventional preparation method.Dong Guoqiang in 2012, Darras, the reports such as Fouda H. be take methyl iodide and are methylated as methylating reagent under DMF with isatoic anhydride, and patent WO201140338 has prepared the N-methyl-isatin acid anhydrides with the very short time under isatoic anhydride, methyl iodide, NaH condition.WO201070449 and US20129226 are methylated with methyl-sulfate under salt of wormwood catalysis with isatoic anhydride respectively.At first this method prepares the N-methyl-isatin acid anhydrides will use the raw material isatoic anhydride, and the relative product of isatoic anhydride, price is suitable, products obtained therefrom does not have price advantage, and methylating reagent is that methyl iodide or methyl-sulfate are all severe toxicity, the methyl iodide price is also high, and methyl-sulfate is carcinogenic by force, all is not suitable for suitability for industrialized production.
Patent CN201010265405 report, with raw material N-methyl anthranilic acid, refluxes and closes ring under Vinyl chloroformate, and the yield with 70% obtains the N-methyl-isatin acid anhydrides, yet, raw material N-methyl anthranilic acid is not easy to obtain on the market, and Vinyl chloroformate is also hypertoxic product, and yield is not high.
Summary of the invention:
The invention provides a kind of preparation method of N-methyl-isatin acid anhydrides, its route is simple, easy and simple to handle, and raw material cheaply is easy to get, and is adapted to suitability for industrialized production.
The N-methyl-isatin acid anhydrides preparation method's that the present invention proposes basic synthetic route is as follows:
General planning of the present invention is as follows:
The preparation method of N-methyl-isatin acid anhydrides, it is characterized in that: first adopt 0-chloro-benzoic acid and methylamine, take Anhydrous potassium carbonate as acid binding agent, copper powder be catalyzer, carry out condensation reaction and prepare N-methyl anthranilic acid, adopt again triphosgene and the condensation of N-methyl anthranilic acid to close ring, make the N-methyl-isatin acid anhydrides.
Based on above-mentioned general planning, the present invention also does following optimization and limits and improve:
The condensation reaction of carrying out at preparation N-methyl anthranilic acid, its reaction solvent is water or DMF; Encircle in triphosgene and N-methyl anthranilic acid condensation pass reacting of carrying out, its reaction solvent is methylene dichloride or toluene.
Further, the present invention provides a concrete operations scheme, comprises the following steps:
(1) preparation of intermediate N methyl anthranilic acid
Get 0-chloro-benzoic acid, Anhydrous potassium carbonate, aqueous methylamine solution and copper powder, wherein self concentration of aqueous methylamine solution is 25wt%, according to mol ratio 1:(1～3): (1.5～4): (0.2～1.0) feeds intake and carries out condensation reaction, reaction solvent is water or DMF, temperature of reaction is 20 ℃～110 ℃, reaction times is 10min～4h, makes N-methyl anthranilic acid;
(2) preparation of N-methyl-isatin acid anhydrides
Get N-methyl anthranilic acid and triphosgene, according to mol ratio 1:(0.4～1) feed intake, reacted, reaction solvent is methylene dichloride or toluene, and temperature of reaction is 0 ℃～20 ℃, and the reaction times is 1h～5h; Finally make the N-methyl-isatin acid anhydrides.
Can also do further to optimize to above-mentioned concrete operation step and limit and improve:
After in step (1), reaction 10min～4h finishes, be cooled to room temperature, then add the glacial acetic acid aqueous solution to regulate, putting PH is slightly acidic, places 2h; Filter, washing obtains N-methyl anthranilic acid.
In step (2), be that N-methyl anthranilic acid is placed in to reaction solvent, first be cooled to 0～5 ℃, then slowly add triphosgene, then be warming up to 0 ℃～20 ℃; After reaction completes, add water, separatory is got organic phase, is washed to neutrality, and decompression and solvent recovery obtains the N-methyl-isatin acid anhydrides.
The present invention has the following advantages:
The present invention prepares the technique of N-methyl-isatin acid anhydrides, and synthetic route is simple, easy and simple to handle, and raw material cheaply is easy to get; The whole process reaction time is short, and unit process completes thoroughly, and convenient post-treatment, be adapted to suitability for industrialized production.
For the preparation of intermediate N methyl anthranilic acid, the present invention adopts 0-chloro-benzoic acid and methylamine, take Anhydrous potassium carbonate as acid binding agent, a small amount of copper powder are catalyzer, carries out condensation reaction, and approximately 30min just can react thorough.And traditional scheme carries out methylated method to the raw material anthranilic acid, the easy poison processed of anthranilic acid at first, buy inconveniently, and secondly methylating reagent methyl-sulfate is carcinogenic by force.Therefore, compare to traditional scheme, it is higher that the present invention prepares intermediate N methyl anthranilic acid yield, and cost is lower.
For by intermediate N methyl anthranilic acid, preparing the N-methyl-isatin acid anhydrides, traditional method is taked to reflux in methyl-chloroformate and is closed ring, and the present invention adopts the triphosgene condensation to close ring, reaction times is short, yield reaches more than 90%, and triphosgene mole utilization ratio is high, and consumption is few, further reduced process costs.
Embodiment
Embodiment mono-:
1, the preparation of N-methyl anthranilic acid
The 0-chloro-benzoic acid 62.4g that feeds intake, methylamine solution 105g, Anhydrous potassium carbonate 28g, copper powder 3g, DMF40ml, stir, and is warming up to 110 ℃, reaction 1h, stopped reaction.Be cooled to room temperature, add the glacial acetic acid aqueous solution 100ml of 1:1, place 2h.Filter, washing obtains white solid 58g, is N-methyl anthranilic acid.Yield is 87.8%.
2, the preparation of N-methyl-isatin acid anhydrides
The N-methyl anthranilic acid 15g that feeds intake, methylene dichloride 60ml, lower the temperature 0～5 ℃, slowly adds triphosgene 14g, is warming up to 20 ℃, reaction 2h.Stopped reaction, add water 100ml, and separatory is got organic phase, is washed to neutrality, and decompression and solvent recovery obtains white solid, the refining elaboration 15.4g that obtains of ethanol.Yield is 96%.
Embodiment bis-:
1, the preparation of N-methyl anthranilic acid
The 0-chloro-benzoic acid 62.4g that feeds intake, methylamine solution 145g, Anhydrous potassium carbonate 36.4g, copper powder 3.2g, water 50ml, stir, and is warming up to 80 ℃, reaction 45min, stopped reaction.Be cooled to room temperature, add the glacial acetic acid aqueous solution 120ml of 1:1, place 3h.Filter, washing obtains white solid 52g, is N-methyl anthranilic acid.Yield is 78.9%.
2, the preparation of N-methyl-isatin acid anhydrides
The N-methyl anthranilic acid 15g that feeds intake, methylene dichloride 60ml, lower the temperature 0～5 ℃, slowly adds triphosgene 12.5g, is warming up to room temperature, reaction 2h.Stopped reaction, add water 100ml, and separatory is got organic phase, is washed to neutrality, and decompression and solvent recovery obtains white solid, the refining elaboration 15.5g that obtains of ethanol.Yield is 97%.
Embodiment tri-
1, the preparation of N-methyl anthranilic acid
The 0-chloro-benzoic acid 62.4g that feeds intake, methylamine solution 108g, Anhydrous potassium carbonate 30.84g, copper powder 3g, water 50ml, stir, and is warming up to 80 ℃, reaction 30min, stopped reaction.Be cooled to room temperature, add the glacial acetic acid aqueous solution 120ml of 1:1, place 2h.Filter, washing obtains white solid 49g.Yield is 74%.
2, the preparation of N-methyl-isatin acid anhydrides
The N-methyl anthranilic acid 15g that feeds intake, toluene 60ml, lower the temperature 0～5 ℃, slowly adds triphosgene 17.5g, is warming up to room temperature ℃, reaction 3.5h.Stopped reaction, add water 100ml, and separatory is got organic phase, is washed to neutrality, and decompression and solvent recovery obtains white solid, the refining elaboration 15.2 that obtains of ethanol.Yield is 95%.
Above each specific embodiment, chosen concrete processing parameter and be illustrated.Based on technological thought of the present invention and general planning, match other various concrete operations schemes in each process parameters range that those skilled in the art should determine in aforementioned schemes, these concrete operations schemes also all can reach more satisfied technique effect.
Claims (5)
1. the preparation method of a N-methyl-isatin acid anhydrides, it is characterized in that: first adopt 0-chloro-benzoic acid and methylamine, take Anhydrous potassium carbonate as acid binding agent, copper powder be catalyzer, carry out condensation reaction and prepare N-methyl anthranilic acid, adopt again triphosgene and the condensation of N-methyl anthranilic acid to close ring, make the N-methyl-isatin acid anhydrides.
2. the preparation method of N-methyl-isatin acid anhydrides according to claim 1 is characterized in that: the condensation reaction of carrying out at preparation N-methyl anthranilic acid, and its reaction solvent is water or DMF; Encircle in triphosgene and N-methyl anthranilic acid condensation pass reacting of carrying out, its reaction solvent is methylene dichloride or toluene.
3. the preparation method of N-methyl-isatin acid anhydrides according to claim 2 is characterized in that: specifically comprise the following steps:
(1) preparation of intermediate N methyl anthranilic acid
Get 0-chloro-benzoic acid, Anhydrous potassium carbonate, aqueous methylamine solution and copper powder, wherein self concentration of aqueous methylamine solution is 25wt%, according to mol ratio 1:(1～3): (1.5～4): (0.2～1.0) feeds intake and carries out condensation reaction, reaction solvent is water or DMF, temperature of reaction is 20 ℃～110 ℃, reaction times is 10min～4h, makes N-methyl anthranilic acid;
(2) preparation of N-methyl-isatin acid anhydrides
Get N-methyl anthranilic acid and triphosgene, according to mol ratio 1:(0.4～1) feed intake, reacted, reaction solvent is methylene dichloride or toluene, and temperature of reaction is 0 ℃～20 ℃, and the reaction times is 1h～5h; Finally make the N-methyl-isatin acid anhydrides.
4. the preparation method of N-methyl-isatin acid anhydrides according to claim 3 is characterized in that:
After in step (1), reaction 10min～4h finishes, be cooled to room temperature, then add the glacial acetic acid aqueous solution to regulate, putting PH is slightly acidic, places 2h; Filter, washing obtains N-methyl anthranilic acid.
5. the preparation method of N-methyl-isatin acid anhydrides according to claim 3 is characterized in that:
In step (2), be that N-methyl anthranilic acid is placed in to reaction solvent, first be cooled to 0～5 ℃, then slowly add triphosgene, then be warming up to 0 ℃～20 ℃; After reaction completes, add water, separatory is got organic phase, is washed to neutrality, and decompression and solvent recovery obtains the N-methyl-isatin acid anhydrides.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105037291A (en) * | 2015-06-11 | 2015-11-11 | 武汉大学 | Preparation method of isatoic anhydride derivative |
| CN114516855A (en) * | 2020-11-20 | 2022-05-20 | 湖南化工研究院有限公司 | Preparation of pyridylpyrazole amide compounds and intermediates therefor |
| CN114516854A (en) * | 2020-11-20 | 2022-05-20 | 湖南化工研究院有限公司 | Preparation method of 1-pyridyl pyrazole amide compound and intermediate thereof |
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| CN101973956A (en) * | 2010-09-26 | 2011-02-16 | 合肥星宇化学有限责任公司 | Methods for synthesizing isatoic anhydride and N-isopropyl-2-aminobenzamide |
| CN101973955A (en) * | 2010-09-07 | 2011-02-16 | 合肥星宇化学有限责任公司 | Method for synthesizing isatoic anhydride |
| CN102863399A (en) * | 2012-10-09 | 2013-01-09 | 西北大学 | Synthetic method for isatoic anhydride derivative |
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| CN1042906A (en) * | 1988-11-23 | 1990-06-13 | 美国辉瑞有限公司 | The method for preparing the Quinolonecar boxylic acid intermediate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105037291A (en) * | 2015-06-11 | 2015-11-11 | 武汉大学 | Preparation method of isatoic anhydride derivative |
| CN114516855A (en) * | 2020-11-20 | 2022-05-20 | 湖南化工研究院有限公司 | Preparation of pyridylpyrazole amide compounds and intermediates therefor |
| CN114516854A (en) * | 2020-11-20 | 2022-05-20 | 湖南化工研究院有限公司 | Preparation method of 1-pyridyl pyrazole amide compound and intermediate thereof |
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