CN106380439A - A Pd/C reduction method adopting water as a solvent for preparing indole-2-carboxylic acid - Google Patents
A Pd/C reduction method adopting water as a solvent for preparing indole-2-carboxylic acid Download PDFInfo
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- CN106380439A CN106380439A CN201610701516.8A CN201610701516A CN106380439A CN 106380439 A CN106380439 A CN 106380439A CN 201610701516 A CN201610701516 A CN 201610701516A CN 106380439 A CN106380439 A CN 106380439A
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- carboxylic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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Abstract
The invention relates to a Pd/C reduction method adopting water as a solvent for preparing indole-2-carboxylic acid. Ethyl 2-nitrophenyl pyruvate is subjected to hydrogenation reduction cyclization in a high-pressure reaction kettle by adopting water as the solvent and adopting Pd/C as a catalyst, the Pd/C is recovered by filtering, and a filtrate is subjected to distillation, acidity adjustment and crystallization to obtain the indole-2-carboxylic acid. The catalyst is easily available and low in cost and can be repeatedly used. According to the method, the raw material can be easily recovered, post-treatment operation is simple, environment pollution is low, reaction operation safety is high, a reaction yield is high, and product quality is good, thus facilitating industrialization.
Description
Technical field
The invention belongs to the synthetically prepared field of medicine intermediate is and in particular to a kind of water does the preparation of solvent palladium charcoal reduction method
Indole-2-carboxylic acid.
Background technology
Indole-2-carboxylic acid is a kind of white crystal of colorless and odorless, can be dissolved in ethanol, acetone and other organic solvent, is a kind of
For preparing the important industrial chemicals of the products such as medicine, fuel.In recent years, the derivant of indole-2-carboxylic acid, hydrogenation products etc. are wide
The general medicine having treatment and health function for hypertension therapeutic medicine or to cardiovascular disease.Structural formula is as follows：
The synthesis of indole-2-carboxylic acid has more document, the Fischer indole with ortho-methylnitrobenzene and ethyl oxalate as raw material
Synthetic method has certain industrial advantages, but needs the high catalyst of activity.J Org Chem,1974,39：731《
Stereospecific synthesis of 1-substituted pyrolizidines》Use zinc powder reduction method, this method
High cost, environmental pollution is serious, and consuming man-hour is many, and post processing behaviour does loaded down with trivial details it is difficult to form large-scale production；Have document introduction with
Platinum oxide, as catalyst, in acid flux material medium, is obtained with hydrogen reducing, but because catalyst is relatively costly, should not be in work
Use in a large number in industry；《Fine chemistry industry》The 6th phase of volume 24 in 2007《Synthesis of Indole-2-carboxylic Acid by Raney Ni Catalytic Hydrogenation》In carry
To with ortho-methylnitrobenzene and ethyl oxalate as initiation material, after preparing ortho-nitrophenyl ethyl pyruvate ethanol solution, in alkalescence
Under the conditions of, directly make catalyst with Raney's nickel, with method for hydrogenation synthesis of indole -2- formic acid, but this method Raney's nickel price is high,
And inflammable, behaviour does danger.
These are unfavorable for industrialized production and improve product quality, need to develop a kind of catalyst and are easy to get, low cost, raw material
Easy recovery, post processing behaviour do simply, and environmental pollution is little, and reaction behaviour does safe, reaction yield height, good product quality, is beneficial to
The preparation method of industrialized indole-2-carboxylic acid.
Content of the invention
It is an object of the invention to provide a kind of water does solvent palladium charcoal reduction method prepares indole-2-carboxylic acid.
Based on above-mentioned purpose, this invention takes following technical scheme：
A kind of water does solvent palladium charcoal reduction method and prepares indole-2-carboxylic acid, with ortho-methylnitrobenzene and ethyl oxalate as reaction raw materials,
There is condensation reaction, through hydrolysis, distillation, extraction, obtain ortho-nitrophenyl ethyl pyruvate aqueous solution, reclaim ortho-methylnitrobenzene；Adjacent
Nitrobenzol ethyl pyruvate aqueous solution, in autoclave, carries out hydrogenating reduction cyclisation with palladium charcoal for catalyst, is recovered by filtration
Catalyst, filtrate, through distillation, acid adjustment, crystallize, obtains indole-2-carboxylic acid；
Above-mentioned ortho-nitrophenyl ethyl pyruvate aqueous solution, in autoclave, carries out hydrogenating reduction ring with palladium charcoal for catalyst
Change reaction, reaction temperature is 60～80 DEG C；Reaction pressure is 0.3～0.7Mpa；Response time is 8～10h；
The post-reaction treatment that water does solvent palladium charcoal reduction method is that catalyst is recovered by filtration, and filtrate, through distillation, acid adjustment, crystallize, obtains
Indole-2-carboxylic acid.
Reclaim palladium carbon catalyst, scrubbed, activation, dry after reusable.
Water of the present invention makees solvent, palladium charcoal hydrogenating reduction ortho-nitrophenyl ethyl pyruvate aqueous solution, palladium carbon catalyst activity is high,
It is easy to get, catalyst can be reused, raw material ortho-methylnitrobenzene easily reclaims, post processing behaviour do simply, and environmental pollution is little, reaction behaviour
Do safe, reaction yield is high, good product quality, and low cost, beneficial to industrialization.
Specific embodiment
Below by way of specific embodiment, technical scheme is described in further detail, but the protection model of the present invention
Enclose and be not limited thereto.
Embodiment 1
A kind of water does solvent palladium charcoal reduction method and prepares indole-2-carboxylic acid,
Comprise the following steps that：
To with stirring, thermometer, addition funnel, reflux condenser（Band calcium oxide drying tube）Four-hole bottle in sequentially add
27g（0.5mol）Solid sodium methylate, 100mL oxolane, stir, successively Deca 73.1g（0.5mol）Ethyl oxalate
And 68.6g（0.5mol）Ortho-methylnitrobenzene, is heated to flowing back, reacts 1h；Then lower the temperature, Deca water 200 g hydrolyzes.Air-distillation
Go out oxolane, be cooled to room temperature, extracted 2 times with dichloromethane 100mL, layering, water layer distills out residual dichloromethane, obtains final product
Ortho-nitrophenyl ethyl pyruvate aqueous solution；The complete ortho-methylnitrobenzene of organic layer merging, distillation, recovery dichloromethane and unreacted.
By ortho-nitrophenyl ethyl pyruvate aqueous solution, palladium charcoal（5% content）In mass ratio 1：0.5% input autoclave
In, with nitrogen displacement air 3 times, logical hydrogen, at 60 DEG C, under 0.4 Mpa pressure, react 8h.After reactant liquor reaction completely, take out
Filter, filter cake palladium carbon catalyst is scrubbed, activation, dry after reusable.After filtrate distills out low boiling organic impuritiess, use
Hydrochloric acid adjusts pH acidifying, obtains indole-2-carboxylic acid crude product.Crude product crystallize stage by stage, to pH value 2～3, has a large amount of white crystal analysis
Go out, filter, filter cake is rinsed 2 times with water, vacuum drying, obtain final product indole-2-carboxylic acid 52.4g.Yield 65%, content 98.85%.
Embodiment 2
A kind of water does solvent palladium charcoal reduction method and prepares indole-2-carboxylic acid,
Comprise the following steps that：
To with stirring, thermometer, addition funnel, reflux condenser（Band calcium oxide drying tube）Four-hole bottle in sequentially add
27g（0.5mol）Solid sodium methylate, 100mL oxolane, stir, successively Deca 73.1g（0.5mol）Ethyl oxalate
And 82.3g（0.6mol）Ortho-methylnitrobenzene, is heated to flowing back, reacts 1h；Then lower the temperature, Deca water 200 g hydrolyzes.Air-distillation
Go out oxolane, be cooled to room temperature, extracted 2 times with dichloromethane 100mL, layering, water layer distills out residual dichloromethane, obtains final product
Ortho-nitrophenyl ethyl pyruvate aqueous solution；The complete ortho-methylnitrobenzene of organic layer merging, distillation, recovery dichloromethane and unreacted.
By ortho-nitrophenyl ethyl pyruvate aqueous solution, palladium charcoal（5% content）In mass ratio 1：0.5% input autoclave
In, with nitrogen displacement air 3 times, logical hydrogen, at 70 DEG C, under 0.4Mpa pressure, react 8h.After reactant liquor reaction completely, take out anti-
Answer liquid to filter, filter cake palladium carbon catalyst is scrubbed, activation, dry after reusable.Filtrate distills out low boiling organic impuritiess
Afterwards, adjust pH acidifying with hydrochloric acid, obtain indole-2-carboxylic acid crude product.Crude product crystallize stage by stage, to pH value 2～3, has white in a large number brilliant
Body separates out, and filters, and filter cake is rinsed 2 times with water, and vacuum drying obtains final product indole-2-carboxylic acid 56.4g.Yield 70%, content 99.05%.
Embodiment 3
A kind of water does solvent palladium charcoal reduction method and prepares indole-2-carboxylic acid,
Comprise the following steps that：
To with stirring, thermometer, addition funnel, reflux condenser（Band calcium oxide drying tube）Four-hole bottle in sequentially add
27g（0.5mol）Solid sodium methylate, 100mL oxolane, stir, successively Deca 73.1g（0.5mol）Ethyl oxalate
And 82.3g（0.6mol）Ortho-methylnitrobenzene, is heated to flowing back, reacts 1h；Then lower the temperature, Deca water 200 g hydrolyzes.Air-distillation
Go out oxolane, be cooled to room temperature, extracted 2 times with dichloromethane 100mL, layering, water layer distills out residual dichloromethane, obtains final product
Ortho-nitrophenyl ethyl pyruvate aqueous solution；The complete ortho-methylnitrobenzene of organic layer merging, distillation, recovery dichloromethane and unreacted.
By ortho-nitrophenyl ethyl pyruvate aqueous solution, palladium charcoal（5% content）In mass ratio 1：0.5% input autoclave
In, with nitrogen displacement air 3 times, logical hydrogen, at 80 DEG C, under 0.4 Mpa pressure, react 8h.After reactant liquor reaction completely, take out
Reacting liquid filtering, filter cake palladium carbon catalyst is scrubbed, activation, dry after reusable.It is organic miscellaneous that filtrate distills out low boiling
After matter, adjust pH acidifying with hydrochloric acid, obtain indole-2-carboxylic acid crude product.Crude product crystallize stage by stage, to pH value 2～3, has a large amount of whites
Crystal separates out, and filters, and filter cake is rinsed 2 times with water, and vacuum drying obtains final product indole-2-carboxylic acid 54g.Yield 67%, content 99.13%.
Embodiment 4
A kind of water does solvent palladium charcoal reduction method and prepares indole-2-carboxylic acid,
Comprise the following steps that：
To with stirring, thermometer, addition funnel, reflux condenser（Band calcium oxide drying tube）Four-hole bottle in sequentially add
27g（0.5mol）Solid sodium methylate, 100mL oxolane, stir, successively Deca 73.1g（0.5mol）Ethyl oxalate
And 82.3g（0.6mol）Ortho-methylnitrobenzene, is heated to flowing back, reacts 1h；Then lower the temperature, Deca water 200 g hydrolyzes.Air-distillation
Go out oxolane, be cooled to room temperature, extracted 2 times with dichloromethane 100mL, layering, water layer distills out residual dichloromethane, obtains final product
Ortho-nitrophenyl ethyl pyruvate aqueous solution；The complete ortho-methylnitrobenzene of organic layer merging, distillation, recovery dichloromethane and unreacted.
By ortho-nitrophenyl ethyl pyruvate aqueous solution, palladium charcoal（5% content）In mass ratio 1：0.5% input autoclave
In, with nitrogen displacement air 3 times, logical hydrogen, at 70 DEG C, under 0.5 Mpa pressure, react 8h.After reactant liquor reaction completely, take out
Reacting liquid filtering, filter cake palladium carbon catalyst is scrubbed, activation, dry after reusable.It is organic miscellaneous that filtrate distills out low boiling
After matter, adjust pH acidifying with hydrochloric acid, obtain indole-2-carboxylic acid crude product.Crude product crystallize stage by stage, to pH value 2～3, has a large amount of whites
Crystal separates out, and filters, and filter cake is rinsed 2 times with water, and vacuum drying obtains final product indole-2-carboxylic acid 55.6g.Yield 69%, content
99.23%.
Claims (5)
1. a kind of water does solvent palladium charcoal reduction method and prepares indole-2-carboxylic acid it is characterised in that ortho-nitrophenyl ethyl pyruvate is with water
Make solvent in autoclave, hydrogenating reduction cyclisation is carried out for catalyst with palladium charcoal, catalyst filtration reclaims, filtrate is through steaming
Evaporate, acid adjustment, crystallize, obtain indole-2-carboxylic acid；Reaction equation is as follows：
.
2. a kind of water according to claim 1 do solvent palladium charcoal reduction method prepare indole-2-carboxylic acid it is characterised in that reaction
Temperature is 60 ~ 80 DEG C.
3. a kind of water according to claim 1 do solvent palladium charcoal reduction method prepare indole-2-carboxylic acid it is characterised in that reaction
Pressure is 0.3 ~ 0.7Mpa.
4. a kind of water according to claim 1 do solvent palladium charcoal reduction method prepare indole-2-carboxylic acid it is characterised in that reaction
Time is 8 ~ 10h.
5. a kind of water according to claim 1 do solvent palladium charcoal reduction method prepare indole-2-carboxylic acid it is characterised in that reaction
Post processing is that catalyst is recovered by filtration, and filtrate, through distillation, acid adjustment, crystallize, obtains indole-2-carboxylic acid.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111087315A (en) * | 2018-10-24 | 2020-05-01 | 武汉武药科技有限公司 | Synthetic method of eltrombopag intermediate and synthetic method of eltrombopag |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102060745A (en) * | 2010-11-23 | 2011-05-18 | 安徽世华化工有限公司 | Preparation method of (S)-indoline-2-carboxylic acid |
| CN105732473A (en) * | 2016-04-19 | 2016-07-06 | 杭州师范大学 | Preparation method of novel catalyzed and synthesized benzpyrole-2-formic acid |
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- 2016-08-23 CN CN201610701516.8A patent/CN106380439A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102060745A (en) * | 2010-11-23 | 2011-05-18 | 安徽世华化工有限公司 | Preparation method of (S)-indoline-2-carboxylic acid |
| CN105732473A (en) * | 2016-04-19 | 2016-07-06 | 杭州师范大学 | Preparation method of novel catalyzed and synthesized benzpyrole-2-formic acid |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111087315A (en) * | 2018-10-24 | 2020-05-01 | 武汉武药科技有限公司 | Synthetic method of eltrombopag intermediate and synthetic method of eltrombopag |
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Application publication date: 20170208 |