CN1626515A - Method for preparing nitro indole-2-carboxylic acid - Google Patents
Method for preparing nitro indole-2-carboxylic acid Download PDFInfo
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- CN1626515A CN1626515A CN 200310109254 CN200310109254A CN1626515A CN 1626515 A CN1626515 A CN 1626515A CN 200310109254 CN200310109254 CN 200310109254 CN 200310109254 A CN200310109254 A CN 200310109254A CN 1626515 A CN1626515 A CN 1626515A
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- ethyl ester
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Abstract
A process for preparing 5-nitroindole-2-carboxylic acid includes condensation reaction between p-nitrophenylhydrazine hydrochloride and ethyl pyruvate to obtain hydrazone, cyclizing reaction on Fischer's indole in benzene solvent under existance of polyphosphoric acid as catalyst to obtain 5-nitroindole-2-ethyl carboxylate, alkaline hydrolyzing and acidifying by hydrochloric acid. Its advantages are high puritity and high output rate.
Description
Technical field
The present invention relates to the preparation method of a kind of 5-nitroindoline-2-carboxylic acid.
Background technology
5-nitroindoline-2-carboxylic acid is a kind of important medicine intermediate, especially can be used as the intermediate of preparation azidothymidine.Its structural formula is as follows:
Tetrahedron Letter 41 (2000) 2443-2446 disclose the method for a kind of 5-of preparation nitroindoline-2-carboxylic acid, adopt Jia Pu-crin graceful (Japp-Klingemann) reaction, diazonium salt solution and methyl-acetoacetic ester reaction with p-Nitroaniline generate hydrazone, obtain 5-nitroindoline-2-carboxylic acid through cyclization, hydrolysis again, methyl-acetoacetic ester costs an arm and a leg, the preparation cost height, the value of not applying.
J.Am.Chem.Soc.1958,80, the legal preparation of the Fei Sheer indole ring 5-nitroindoline-2-carboxylic acid of 4621-4622 report need not any solvent in the reaction process, and mixing effect is poor, complex operation; The reactant inequality of being heated, moment is emitted big calorimetric when reaching 90 ℃ of reflecting points, and difficult control of temperature lacks security, and industrial prospect is undesirable.
Summary of the invention
The technical problem that the present invention solves provides the preparation method of a kind of 5-nitroindoline-2-carboxylic acid, to overcome expensive raw material price in the prior art, cost height, complex operation, the shortcoming of shortage security.
Technical conceive of the present invention is such: with the paranitrophenylhydrazine hydrochloride is raw material, is condensed into hydrazone with Pyruvic Acid Ethyl ester; Hydrazone becomes 5-nitroindoline-2-carboxylic acid, ethyl ester with the Fei Sheer indole ring symphysis in benzene class reaction solvent of catalyzer polyphosphoric acid, and the salt acidifying is carried out in alkaline hydrolysis then, promptly obtains target product of the present invention.
Method of the present invention comprises the steps:
(1) synthetic Pyruvic Acid Ethyl ester-4-nitro phenylhydrazone: the aqueous solution of paranitrophenylhydrazine hydrochloride and the ethanolic soln of Pyruvic Acid Ethyl ester reacted 20-60 minute under 20 ℃-60 ℃ condition, collected intermediate product Pyruvic Acid Ethyl ester-4-nitro phenylhydrazone from reaction product;
(2) synthetic 5-nitroindoline-2-carboxylic acid: intermediate product that step (1) is obtained and catalyzer polyphosphoric acid are in benzene class reaction solvent, reaction is 20-60 minute under 85 ℃～115 ℃ the condition, obtain 5-nitroindoline-2-carboxylic acid, ethyl ester, alkaline hydrolysis, reaction is 5-8 hour under 20-30 ℃ condition, carry out the salt acidifying, from reaction product, collect purpose product 5-nitroindoline-2-carboxylic acid.
According to the present invention, the mol ratio of reactant paranitrophenylhydrazine hydrochloride and Pyruvic Acid Ethyl ester is 1.0: 1.0-1.1, the weightmeasurement ratio of the reactant paranitrophenylhydrazine hydrochloride and the aqueous solution is 1: 10-25, and Pyruvic Acid Ethyl ester and alcoholic acid weightmeasurement ratio are 1.0: 1.5-2.5;
Benzene class reaction solvent used in the present invention is a kind of in toluene, the dimethylbenzene, preferred toluene;
Ratio of components Pyruvic Acid Ethyl ester-4-nitro phenylhydrazone: catalyzer=1.0: 6.0-9.0 (weight ratio), Pyruvic Acid Ethyl ester-4-nitro phenylhydrazone: reaction solvent=1.0: 6.0-9.0 (weightmeasurement ratio);
The employed alkaline solution of alkaline hydrolysis of the present invention is the aqueous solution of potassium hydroxide, and the weightmeasurement ratio of potassium hydroxide and water is 1.0: 2.5-4.5;
The employed concentration of hydrochloric acid of salt acidifying of the present invention is the 3-6 equivalent, and control terminal point pH value is 1.
Collect target product 5-nitroindoline-2-carboxylic acid and can comprise the steps: that the solid crude product of separating out filters from reaction product, wash with water, drying obtains target product of the present invention.
5-nitroindoline-2-carboxylic acid the purity that obtains with preparation method of the present invention reaches (HPLC) more than 98%, and Fei Sheer indoles cyclization productive rate is more than 70% (literature value 57%), and productive rate is greatly improved, and identifies the structure of product with infrared spectra.
Reaction formula of the present invention is as follows:
The present invention compared with prior art, raw material is easy to get, cost is low, simple and safe operation, the yield height, constant product quality is suitable for suitability for industrialized production.
Embodiment
Below by embodiment the invention will be further described the present invention, but embodiment does not limit protection scope of the present invention.
Embodiment 1
The preparation of Pyruvic Acid Ethyl ester-4-nitro phenylhydrazone
In being housed, the 500ml four-hole boiling flask of agitator, thermometer, dropping funnel adds paranitrophenylhydrazine hydrochloride 19.0g (0.10mol), water 400ml, stir, keep 25-35 ℃ temperature, drip the solution of forming by Pyruvic Acid Ethyl ester 12.0g (0.104mol) and 20ml ethanol, generate yellow mercury oxide, continue to stir 30min, filtration, drying obtain Pyruvic Acid Ethyl ester-4-nitro phenylhydrazone 22.9g, productive rate 91.1%.The preparation of 5-nitroindoline-2-carboxylic acid
(1) in the 500ml four-hole boiling flask of agitator, reflux condensing tube, thermometer is housed, add hydrazone 17.5g (0.07mol), toluene 150ml, stir and slowly add polyphosphoric acid 150g down, stop when being heated to 85 ℃-90 ℃ heating up, with the generation of reaction heat, temperature rises, keep 105 ℃ of-115 ℃ of temperature backflow 30min, be cooled to 60 ℃, add the 150ml frozen water, continue to stir 30min, the polyphosphoric acid of hydrolysis surplus, filter, wash drying with water, obtain 5-nitroindoline-2-carboxylic acid, ethyl ester 11.7g, productive rate 71.4%.
(2) in being housed, the 500ml four-hole boiling flask of agitator, thermometer, dropping funnel adds the ester 9.7g (0.04mol) that step (1) obtains, dehydrated alcohol 75ml, slowly add the alkali lye that is made into by potassium hydroxide 7.5g (0.13mol) and water 18ml under the stirring at room, hydrolysis reaction 6 hours, filter, use the absolute ethanol washing filter cake, use the 350ml water dissolution, filter, filtrate uses the 4N hcl acidifying to PH=1, separate out the suspension solid, filter, drying obtains target product 7.5g, purity 98.5%, productive rate 87.4%.
Embodiment 2
The preparation of Pyruvic Acid Ethyl ester-4-nitro phenylhydrazone
In being housed, the 500ml four-hole boiling flask of agitator, thermometer, dropping funnel adds paranitrophenylhydrazine hydrochloride 19.0g (0.10mol), water 240ml, stir, keep 60 ℃ temperature, drip the solution of forming by Pyruvic Acid Ethyl ester 12.0g (0.104mol) and 20ml ethanol, generate yellow mercury oxide, continue to stir 30min, cooling, filtration, drying obtain Pyruvic Acid Ethyl ester-4-nitro phenylhydrazone 23.2g, productive rate 92.3%.
The preparation of 5-nitroindoline-2-carboxylic acid
(1) in the 500ml four-hole boiling flask of agitator, reflux condensing tube, thermometer is housed, add hydrazone 17.5g (0.07mol), toluene 120ml, stir and slowly add polyphosphoric acid 120g down, stop when being heated to 85 ℃-90 ℃ heating up, with the generation of reaction heat, temperature rises, keep 105 ℃ of-115 ℃ of temperature backflow 40min, be cooled to 60 ℃, add the 120ml frozen water, continue to stir 30min, the polyphosphoric acid of hydrolysis surplus, filter, wash drying with water, obtain 5-nitroindoline-2-carboxylic acid, ethyl ester 10.7g, productive rate 65.3%.
(2) in being housed, the 500ml four-hole boiling flask of agitator, thermometer, dropping funnel adds the ester 9.7g (0.04mol) that step (1) obtains, dehydrated alcohol 75ml, slowly add the alkali lye that is made into by potassium hydroxide 7.5g (0.13mol) and water 18ml under the stirring at room, hydrolysis reaction 6 hours, filter, use the absolute ethanol washing filter cake, use the 350ml water dissolution, filter, filtrate uses the 4N hcl acidifying to PH=1, separate out the suspension solid, filter, drying obtains target product 7.0g, purity 98.3%, productive rate 81.6%.
Claims (10)
1. the preparation method of 5-nitroindoline-2-carboxylic acid is characterized in that comprising the steps:
(1) with the aqueous solution of paranitrophenylhydrazine hydrochloride, reacted 20-60 minute under 20 ℃-60 ℃ condition with the ethanolic soln of Pyruvic Acid Ethyl ester, from reaction product, collect intermediate product Pyruvic Acid Ethyl ester-4-nitro phenylhydrazone;
(2) Pyruvic Acid Ethyl ester that step (1) is obtained-4-nitro phenylhydrazone and catalyzer polyphosphoric acid are in benzene class reaction solvent, reaction is 20-60 minute under 85 ℃～115 ℃ the condition, obtain 5-nitroindoline-2-carboxylic acid, ethyl ester, alkaline hydrolysis, reaction is 5-8 hour under 20-30 ℃ the condition, carry out the salt acidifying, from reaction product, collect 5-nitroindoline-2-carboxylic acid.
2. method according to claim 1 is characterized in that benzene class reaction solvent is a toluene, one or more in the dimethylbenzene.
3. method according to claim 2 is characterized in that benzene class reaction solvent is a toluene.
4. method according to claim 1, the concentration that it is characterized in that salt acidifying hydrochloric acid is the 3-6 equivalent.
5. method according to claim 1, the mol ratio that it is characterized in that reactant paranitrophenylhydrazine hydrochloride and Pyruvic Acid Ethyl ester is 1.0: 1.0-1.1.
6. method according to claim 1, the weightmeasurement ratio that it is characterized in that the reactant paranitrophenylhydrazine hydrochloride and the aqueous solution is 1: 10-25.
7. method according to claim 1 is characterized in that Pyruvic Acid Ethyl ester and alcoholic acid weightmeasurement ratio are 1.0: 1.5-2.5.
8. method according to claim 1 is characterized in that Pyruvic Acid Ethyl ester-4-nitro phenylhydrazone and catalyst consumption ratio are 1.0: 6.0-9.0 (weight ratio).
9. method according to claim 1 is characterized in that Pyruvic Acid Ethyl ester-4-nitro phenylhydrazone and reaction solvent weightmeasurement ratio are 1.0: 6.0-9.0.
10. method according to claim 1 is characterized in that employed alkaline solution is the aqueous solution of potassium hydroxide, and the weightmeasurement ratio of potassium hydroxide and water is 1.0: 2.5-4.5.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2003101092549A CN100491350C (en) | 2003-12-10 | 2003-12-10 | Method for preparing nitro indole-2-carboxylic acid |
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| CNB2003101092549A CN100491350C (en) | 2003-12-10 | 2003-12-10 | Method for preparing nitro indole-2-carboxylic acid |
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| CN1626515A true CN1626515A (en) | 2005-06-15 |
| CN100491350C CN100491350C (en) | 2009-05-27 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100387578C (en) * | 2006-01-24 | 2008-05-14 | 北京成宇化工有限公司 | Indole-3-formic acid purification process |
| CN102285968A (en) * | 2011-07-07 | 2011-12-21 | 河南农业大学 | Method for preparing 3-[4-(2,6-dichlorophenyl)-piperidine-1-methylene]-2,5-disubstituted indole |
| CN104370798A (en) * | 2014-11-11 | 2015-02-25 | 常州大学 | Synthesis method of 2-fluorobenzopyrrole |
| CN104402795A (en) * | 2014-12-04 | 2015-03-11 | 中国农业大学 | Synthetic method of substituted indol-2-formic acid |
| CN114605303A (en) * | 2022-03-14 | 2022-06-10 | 武汉工程大学 | Synthesis method of delavirdine and intermediate thereof |
-
2003
- 2003-12-10 CN CNB2003101092549A patent/CN100491350C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100387578C (en) * | 2006-01-24 | 2008-05-14 | 北京成宇化工有限公司 | Indole-3-formic acid purification process |
| CN102285968A (en) * | 2011-07-07 | 2011-12-21 | 河南农业大学 | Method for preparing 3-[4-(2,6-dichlorophenyl)-piperidine-1-methylene]-2,5-disubstituted indole |
| CN104370798A (en) * | 2014-11-11 | 2015-02-25 | 常州大学 | Synthesis method of 2-fluorobenzopyrrole |
| CN104402795A (en) * | 2014-12-04 | 2015-03-11 | 中国农业大学 | Synthetic method of substituted indol-2-formic acid |
| CN114605303A (en) * | 2022-03-14 | 2022-06-10 | 武汉工程大学 | Synthesis method of delavirdine and intermediate thereof |
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| CN100491350C (en) | 2009-05-27 |
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