CN100387577C - Process for preparing 4-bromo-7-methyl indole-2-carboxylic acid - Google Patents
Process for preparing 4-bromo-7-methyl indole-2-carboxylic acid Download PDFInfo
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- CN100387577C CN100387577C CNB2004100528894A CN200410052889A CN100387577C CN 100387577 C CN100387577 C CN 100387577C CN B2004100528894 A CNB2004100528894 A CN B2004100528894A CN 200410052889 A CN200410052889 A CN 200410052889A CN 100387577 C CN100387577 C CN 100387577C
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Abstract
The present invention discloses a preparation method for 4-bromo-7-methyl indole-2-carboxylic acid. 5-bromo-2-methyl phenylhydrazine hydrochloride is taken as a raw material to carry out the condensation reaction with ethyl pyruvate in an alcohol reaction solvent; a condensation product is cyclized under appearance of a dihydric alcohol reaction solvent and a catalyst; the target product of the present invention is obtained by alkaline hydrolysis and post treatment. The purity of the 4-bromo-7-methyl indole-2-carboxylic acid obtained by the method of the present invention reaches more than 98%, and the melting point is from 196 to 198 DEG C. Compared with the prior art, the present invention has the advantages of easy acquirement of raw materials, low cost, safe and convenient operation and stable product quality and is suitable for industrial process.
Description
Technical field
The present invention relates to the preparation method of a kind of 4-bromo-7-skatole-2-carboxylic acid.
Background technology
4-bromo-7-skatole-the 2-carboxylic acid is a kind of intermediate of organic synthesis, can be used as the intermediate of synthetic drugs, aspect the treatment cancer wider application prospect is being arranged, and its structural formula is as follows:
The do not appear in the newspapers preparation method of 4-bromo-7-skatole-2-carboxylic acid of prior art.Tetrahedron Letters41 (2000) 2443-2446 has reported the proximate preparation method of Indoline-2-carboxylic acid compounds, is raw material with the methyl-acetoacetic ester, prepares the Indoline-2-carboxylic acid compounds of different substituents.Because reaction raw materials is difficult to obtain, cost an arm and a leg, the reaction process complex operation, industrial prospect is undesirable.
Summary of the invention
The purpose of this invention is to provide the preparation method of a kind of 4-bromo-7-skatole-2-carboxylic acid, raw material is difficult to obtain in the prior art to overcome, and costs an arm and a leg the weak point of complex operation.
Technical conceive of the present invention is such: with 5-bromo-2-procarbazine hydrochloride is raw material, makes reaction solvent with alcohols, carries out condensation reaction with Pyruvic Acid Ethyl ester, gets condensation product.Above-mentioned condensation product is made reaction solvent with dibasic alcohol, carries out cyclization in the presence of catalyzer; Through alkaline hydrolysis, aftertreatment promptly obtains target product of the present invention.
Reaction formula of the present invention is as follows:
Method of the present invention comprises the steps:
(1) Pyruvic Acid Ethyl ester-5-bromo-2-methyl phenylhydrazone is synthetic: 5-bromo-2-procarbazine hydrochloride is that starting raw material, Pyruvic Acid Ethyl ester, ethanol synthesis solvent reacted 0.5-1.0 hour under 30 ℃-50 ℃ condition, backflow 5-15 minute, from reaction product, collect Pyruvic Acid Ethyl ester-5-bromo-2-methyl phenylhydrazone;
According to the present invention, the ratio of components of step (1) is a 5-bromo-2-procarbazine hydrochloride: Pyruvic Acid Ethyl ester=1.0: 1.0-1.1, mol ratio; The consumption of alcohol solvent is a 5-bromo-2-procarbazine hydrochloride: ethanol=1.0: 6.0-10.0, mass ratio;
(2) 4-bromo-7-skatole-2-carboxylic acid, ethyl ester is synthetic: Pyruvic Acid Ethyl ester-5-bromo-2-methyl phenylhydrazone, catalyzer Zinc Chloride Anhydrous, ethylene glycol solvent that step (1) is collected, in nitrogen protection, reaction is 2.0-4.5 hour under 150 ℃-170 ℃ the condition, collects 4-bromo-7-skatole-2-carboxylic acid, ethyl ester from reaction product;
According to the present invention, the ratio of components of step (2) is Pyruvic Acid Ethyl ester-5-bromo-2-methyl phenylhydrazone: Zinc Chloride Anhydrous=1.0: 1.8-2.2, mol ratio; The consumption of ethylene glycol is Pyruvic Acid Ethyl ester-5-bromo-2-methyl phenylhydrazone: ethylene glycol=1.0: 5.0-10.0, mass ratio;
(3) alkaline hydrolysis: 4-bromo-7-skatole-2-carboxylic acid, ethyl ester, ethanol synthesis solvent, potassium hydroxide that step (2) is collected are hydrolyzed at ambient temperature, and the hydrolysate aftertreatment is 4-bromo-7-skatole-2-carboxylic acid.
According to the present invention, the ratio of components of step (3) is 4-bromo-7-skatole-2-carboxylic acid, ethyl ester: potassium hydroxide=1.0: 2.0-2.5, mol ratio; Consumption of ethanol is 4-bromo-7-skatole-2-carboxylic acid, ethyl ester: ethanol=1.0: 5.0-10.0, mass ratio;
Step (3) hydrolysate aftertreatment comprises the steps: to use activated carbon decolorizing, hcl acidifying, and crystallization is filtered, and drying obtains target product of the present invention.
Ethanol in above-mentioned steps (1), (3) also can be changed to: one or more in methyl alcohol, propyl alcohol, Virahol, the butanols.
Said ethylene glycol solvent also can be changed to 1 in the above-mentioned steps (2), ammediol, 1, one or more in the 2-propylene glycol;
Said potassium hydroxide also can be changed to sodium hydroxide in the above-mentioned steps (3).
With 4-bromo-7-skatole-2-carboxylic acid that preparation method of the present invention obtains, more than the purity 98% (HPLC), fusing point is 196～198 ℃, identifies the structure of product with nucleus magnetic resonance.
Raw material 5-bromo-2-procarbazine hydrochloride used in the present invention can be according to U.S.5, and 830,911 reported method prepare.
The present invention compared with prior art, raw material is easy to get, and is with low cost, simple and safe operation, constant product quality is suitable for suitability for industrialized production.
Specific implementation method
The invention will be further described below by embodiment, but embodiment does not limit protection scope of the present invention.
Embodiment 1
In the reactor that has stirring, thermometer, reflux condensing tube, add 250ml ethanol, stir adding 31.7g (0.133mol) 5-bromo-2-procarbazine hydrochloride down, heating for dissolving slowly adds 15.5g (0.133mol) Pyruvic Acid Ethyl ester, continue to be warming up to backflow, be incubated 15 minutes.Be cooled to room temperature, separate out faint yellow needle-like crystal.Filter, drying obtains condensation product Pyruvic Acid Ethyl ester-5-bromo-2-methyl phenylhydrazone 35.4g, productive rate 88.7%, analytical results: purity 98.5% (HPLC), 93.5～94.6 ℃ of fusing points;
Having stirring, thermometer, add 250ml ethylene glycol (bp196-198 ℃) in the reactor of airway, stir and add 43.0g (0.144mol) Pyruvic Acid Ethyl ester-5-bromo-2-methyl phenylhydrazone down respectively, 39.2g (0.288mol) Zinc Chloride Anhydrous, import nitrogen, under nitrogen atmosphere, be stirred and heated to 160 ± 5 ℃, reacted 2.5 hours, cool to room temperature, reaction solution is used the 450ml ethyl acetate extraction with 30ml 36% hcl acidifying, dry, steam to remove ethyl acetate, steam and add 50ml mixed solvent (ethanol and normal hexane with volume ratio 1: 1 formulated) crystallization in the excess, the solid of separating out carries out drying, the cyclization product 4-bromo-7-skatole-2-carboxylic acid, ethyl ester 24.3g that obtains, productive rate 59.9%, analytical results: purity 98.3% (HPLC), 129～131 ℃ of fusing points;
Add 200ml ethanol in reactor, room temperature stirs adding 24.0g (0.085mol) 4-bromo-7-skatole-2-carboxylic acid, ethyl ester down, and 80g 10% sodium hydroxide solution is hydrolyzed, and separates out white solid product, standing over night; Hydrolysate filters, solid product is water-soluble, add the gac reflux decolour, filter, use 10% hcl acidifying, the white solid of separating out filters, drying obtains purpose product 4-bromo-7-skatole-2-carboxylic acid 16.4g, productive rate 76.0%, analytical results: purity 98.6% (HPLC), 196～198 ℃ of fusing points.Nucleus magnetic resonance carries out structure to be identified:
1H?NMR([D
6]acetome)
δ：11.12(s，1H，OH) δ：8.75(m，1H，NH)
δ：7.5(m，3H，arom，H) δ：2.28(s，3H，Ar-CH
3)
Embodiment 2
In the reactor that has stirring, thermometer, reflux condensing tube, add 250ml ethanol, stir adding 31.7g (0.133mol) 5-bromo-2-procarbazine hydrochloride down, heating for dissolving slowly adds 17.1g (0.146mol) Pyruvic Acid Ethyl ester, continue to be warming up to backflow, be incubated 5 minutes.Be cooled to room temperature, separate out faint yellow needle-like crystal.Filter, drying obtains condensation product Pyruvic Acid Ethyl ester-5-bromo-2-methyl phenylhydrazone 37.2g, productive rate 93.1%, analytical results: purity 98.8% (HPLC), 93.7～94.5 ℃ of fusing points;
Having stirring, thermometer, add 250ml ethylene glycol (bp196-198 ℃) in the reactor of airway, stir and add 43.0g (0.144mol) Pyruvic Acid Ethyl ester-5-bromo-2-methyl phenylhydrazone down respectively, 43.1g (0.317mol) Zinc Chloride Anhydrous, import nitrogen, under nitrogen atmosphere, be stirred and heated to 160 ± 5 ℃, reacted 4.0 hours, cool to room temperature, reaction solution is used the 450ml ethyl acetate extraction with 40ml 36% hcl acidifying, dry, steam to remove ethyl acetate, steam and add 50ml mixed solvent (ethanol and normal hexane with volume ratio 1: 1 formulated) crystallization in the excess, the solid of separating out carries out drying, the cyclization product 4-bromo-7-skatole-2-carboxylic acid, ethyl ester 26.8g that obtains, productive rate 66.1%, analytical results: purity 98.8% (HPLC), 130～131 ℃ of fusing points;
Add 200ml ethanol in reactor, room temperature stirs adding 24.0g (0.085mol) 4-bromo-7-skatole-2-carboxylic acid, ethyl ester down, and 112g 10% potassium hydroxide solution is hydrolyzed, and separates out white solid product, standing over night; Hydrolysate filters, solid product is water-soluble, add the gac reflux decolour, filter, use 10% hcl acidifying, the white solid of separating out filters, drying obtains purpose product 4-bromo-7-skatole-2-carboxylic acid 16.1g, productive rate 74.6%, analytical results: purity 98.4% (HPLC), 196～198 ℃ of fusing points.
Claims (5)
1. the preparation method of 4-bromo-7-skatole-2-carboxylic acid comprises the steps:
(1) Pyruvic Acid Ethyl ester-5-bromo-2-methyl phenylhydrazone is synthetic: 5-bromo-2-procarbazine hydrochloride, Pyruvic Acid Ethyl ester, ethanol synthesis solvent reacted 0.5-1.0 hour under 30-50 ℃ condition, backflow 5-15 minute, from reaction product, collect Pyruvic Acid Ethyl ester-5-bromo-2-methyl phenylhydrazone;
(2) 4-bromo-7-skatole-2-carboxylic acid, ethyl ester is synthetic: Pyruvic Acid Ethyl ester-5-bromo-2-methyl phenylhydrazone, catalyzer Zinc Chloride Anhydrous, ethylene glycol solvent that step (1) is collected, in nitrogen protection, reaction is 2.0-4.5 hour under 150-170 ℃ the condition, collects 4-bromo-7-skatole-2-carboxylic acid, ethyl ester from reaction product;
(3) alkaline hydrolysis: 4-bromo-7-skatole-2-carboxylic acid, ethyl ester, ethanol synthesis solvent, potassium hydroxide that step (2) is collected are hydrolyzed at ambient temperature, and the hydrolysate aftertreatment gets 4-bromo-7-skatole-2-carboxylic acid.
2. the preparation method of 4-bromo-7-skatole according to claim 1-2-carboxylic acid is characterized in that, the ratio of components of step (1) is a 5-bromo-2-procarbazine hydrochloride: Pyruvic Acid Ethyl ester=1.0: 1.0-1.1, mol ratio; Consumption of ethanol is a 5-bromo-2-procarbazine hydrochloride: ethanol=1.0: 6.0-10.0, mass ratio.
3. the preparation method of 4-bromo-7-skatole according to claim 1-2-carboxylic acid is characterized in that, the ratio of components of step (2) is Pyruvic Acid Ethyl ester-5-bromo-2-methyl phenylhydrazone: Zinc Chloride Anhydrous=1.0: 1.8-2.2, mol ratio; The consumption of ethylene glycol is Pyruvic Acid Ethyl ester-5-bromo-2-methyl phenylhydrazone: ethylene glycol=1.0: 5.0-10.0, mass ratio.
4. the preparation method of 4-bromo-7-skatole according to claim 1-2-carboxylic acid is characterized in that, the ratio of components of step (3) is 4-bromo-7-skatole-2-carboxylic acid, ethyl ester: potassium hydroxide=1.0: 2.0-2.5, mol ratio; Consumption of ethanol is 4-bromo-7-skatole-2-carboxylic acid, ethyl ester: ethanol=1.0: 5.0-10.0, mass ratio.
5. the preparation method of 4-bromo-7-skatole according to claim 1-2-carboxylic acid is characterized in that step (3) hydrolysate aftertreatment comprises the steps: to use activated carbon decolorizing, hcl acidifying, and crystallization is filtered, and drying obtains target product.
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| CNB2004100528894A CN100387577C (en) | 2004-07-15 | 2004-07-15 | Process for preparing 4-bromo-7-methyl indole-2-carboxylic acid |
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| CN100387577C true CN100387577C (en) | 2008-05-14 |
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| CN102020600B (en) * | 2010-11-23 | 2012-11-28 | 安徽世华化工有限公司 | Synthetic method of indole-2-carboxylic acid |
| CN104370798A (en) * | 2014-11-11 | 2015-02-25 | 常州大学 | Synthesis method of 2-fluorobenzopyrrole |
| CN113087652A (en) * | 2021-04-06 | 2021-07-09 | 宣城美诺华药业有限公司 | Improved preparation method of perindopril starting material indole-2-formic acid |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1265649A (en) * | 1997-08-07 | 2000-09-06 | 曾尼卡有限公司 | Indole derivatives as MCP-1 receptor antagonists |
| CN1276790A (en) * | 1997-09-19 | 2000-12-13 | 萨诺费合成实验室 | Carboxamidothiazole derivs., preparation, pharmaceutical composition contg. them |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1265649A (en) * | 1997-08-07 | 2000-09-06 | 曾尼卡有限公司 | Indole derivatives as MCP-1 receptor antagonists |
| CN1276790A (en) * | 1997-09-19 | 2000-12-13 | 萨诺费合成实验室 | Carboxamidothiazole derivs., preparation, pharmaceutical composition contg. them |
Non-Patent Citations (2)
| Title |
|---|
| Fisther Indolisation and Related Compounds.Part21.Drectionon the Cyclisation in the Fischer Indolisation ofEthyl Pyruvare2-(p- or m- SubstitutedPhenyl)phenylhydrazones.. Hisashi Ishii ,et al.J.CHEM.SOC.PERKIN TRANS 1. 1989 |
| Fisther Indolisation and Related Compounds.Part21.Drectionon the Cyclisation in the Fischer Indolisation ofEthyl Pyruvare2-(p- or m- SubstitutedPhenyl)phenylhydrazones.. Hisashi Ishii ,et al.J.CHEM.SOC.PERKIN TRANS 1. 1989 * |
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