CN108003090A - The method that one kind prepares 4- [2- (5- ethyl -2- pyridine radicals) ethyoxyl] nitrobenzene - Google Patents
The method that one kind prepares 4- [2- (5- ethyl -2- pyridine radicals) ethyoxyl] nitrobenzene Download PDFInfo
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- CN108003090A CN108003090A CN201810009306.1A CN201810009306A CN108003090A CN 108003090 A CN108003090 A CN 108003090A CN 201810009306 A CN201810009306 A CN 201810009306A CN 108003090 A CN108003090 A CN 108003090A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- Pyridine Compounds (AREA)
Abstract
The present invention relates to the method that one kind prepares 4 [2 (5 ethyl, 2 pyridine radicals) ethyoxyl] nitrobenzenes, it is characterised in that：By 2（5 ethyl, 2 pyridine radicals）Ethanol is dissolved in halogenated hydrocarbons, inorganic base and phase transfer catalyst are added, adds p-fluoronitrobenzene, reaction temperature control is 0 50 DEG C, when reaction time control is 4 small, 4 [2 (5 ethyl, 2 pyridine radicals) ethyoxyl] nitrobenzenes are obtained after isolating and purifying.The present invention replaces the sodium hydride of document report with inorganic bases such as safe sodium hydroxides, and solvent is done with halogenated hydrocarbons such as dichloromethane, phase transfer method synthesizes 4 [2 (5 ethyl, 2 pyridine radicals) ethyoxyl] nitrobenzenes of high quality, substantially increase production security, reduce pollution of the DMF equal solvents to environment, reduce production cost.
Description
Technical field
The invention belongs to medicine intermediate field, more particularly to one kind prepares 4- [2- (5- ethyl -2- pyridine radicals) ethoxies
Base] nitrobenzene method.
Background technology
PIOGITAZONE HYDROCHLORIDE indication II diabetics, document report a variety of synthetic methods, mainstream synthetic route have
Two：
First, EP 257 78 1, Chem. Pharm. Bull. 39 (6) 1,440 1445 (1991), EP 506 273, WO
93/13095 and EP 816 340 is reported is made PIOGITAZONE HYDROCHLORIDE by alkene reduction route, and specific reaction equation is as follows：
The method final step needs to be catalyzed reduction with substantial amounts of Pd/C or with cobalt chloride when reducing.Substantial amounts of palladium carbon causes product
It is with high costs, it can not industrialize.When being catalyzed reduction with cobalt chloride, the bad removing of heavy metal cobalt remaining, has human body certain danger
Evil.
2nd, the pyrrole lattice imines hydrolysis of the document report such as US7009057 prepares the route of PIOGITAZONE HYDROCHLORIDE, specific reaction equation
It is as follows：
The raw material of the method selection is relatively easy to be easy to get, and operation is simple, compares easy to industrialized production.
In pyrrole lattice imines route technique, 4- [2- (5- ethyl -2- pyridine radicals) ethyoxyl] nitrobenzene is one crucial
Intermediate, its purity and price directly determine the production cost of this route PIOGITAZONE HYDROCHLORIDE.Document to its study on the synthesis compared with
Few, main method does alkali with sodium hydride in DMF and 4- [2- is made for 2- (5- ethyl -2- pyridine radicals) ethanol and p-fluoronitrobenzene
(5- ethyl -2- pyridine radicals) ethyoxyl] nitrobenzene, see document US7009057.Sodium hydride is dangerous when being used in industrial production
Too high, explosive reaction can be occurred by meeting water, meanwhile, using the hydrogen that a large amount of uncontrollable discharges can be produced during sodium hydride, easily send out
Raw security incident.Therefore, our productions to 4- [2- (5- ethyl -2- pyridine radicals) ethyoxyl] nitrobenzene, which have been done, largely grinds
Study carefully, it was found that a kind of simple and practicable method for preparing 4- [2- (5- ethyl -2- pyridine radicals) ethyoxyl] nitrobenzene.
The content of the invention
It is an object of the invention to avoid the deficiencies in the prior art, there is provided one kind prepares 4- [2- (5- ethyl -2- pyridine radicals)
Ethyoxyl] nitrobenzene method.
To achieve the above object, the technical solution taken of the present invention is：One kind prepares 4- [2- (5- ethyl -2- pyridine radicals)
Ethyoxyl] nitrobenzene method, it is characterised in that：By 2-（5- ethyl -2- pyridine radicals）Ethanol is dissolved in halogenated hydrocarbons, adds nothing
Machine alkali and phase transfer catalyst, it is 0-50 DEG C to add the control of p-fluoronitrobenzene reaction temperature, when reaction time control is 4 small,
4- [2- (5- ethyl -2- pyridine radicals) ethyoxyl] nitrobenzene is obtained after isolating and purifying.
The halogenated hydrocarbons is appointed for the halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethanes and chlorobenzene
Meaning is a kind of, preferably dichloromethane.
The inorganic base is potassium carbonate, potassium hydroxide, sodium hydroxide any one, preferred sodium hydroxide.
The phase transfer catalyst be tetrabutylammonium bromide, TEBA, tri-n-octyl methyl ammonium chloride any one, preferably three
Octylmethylammonium chloride.
Preferred 0-5 DEG C of the reaction temperature.
2-（5- ethyl -2- pyridine radicals）The molar ratio of ethanol and p-fluoronitrobenzene is 1：1.07
The beneficial effects of the invention are as follows：The present invention replaces the hydrogenation of document report with inorganic bases such as safe sodium hydroxides
Sodium, and solvent is done with halogenated hydrocarbons such as dichloromethane, phase transfer method synthesizes 4- [2- (5- ethyl -2- pyridine radicals) ethoxies of high quality
Base] nitrobenzene, production security is substantially increased, reduces pollution of the DMF equal solvents to environment, reduces production cost, from
And reduce the production cost of PIOGITAZONE HYDROCHLORIDE.
Embodiment
The principles and features of the present invention are described below, and the given examples are served only to explain the present invention, is not intended to limit
Determine the scope of the present invention.
Embodiment 1
By 150g 2-（5- ethyl -2- pyridine radicals）Ethanol is dissolved in 450g dichloromethane, adds 150g solid sodium hydroxides
（96%）With the tri-n-octyl methyl ammonium chloride of 7.5g 75%, 0-5 DEG C of temperature control, it is molten to be added dropwise 150g p-fluoronitrobenzenes/150g dichloromethane
Liquid, when 0-5 DEG C of reaction 4 of insulation is small after adding, reaction terminates, and 0-5 DEG C of dropwise addition 300g water of temperature control, is stirred 5 minutes, stratification,
Organic layer is washed three times with 200g*3, and saturated brine 100g is washed once, is added the drying of 10g anhydrous magnesium sulfates, is added 5g activated carbons
Decoloration, filtering, filtrate decompression are concentrated to dryness, when the 0-5 DEG C of insulation 2 of addition 300g petroleum ethers is small, filtering, and 30-40 DEG C of air blast drying,
Obtain 4- [2- (5- ethyl -2- pyridine radicals) ethyoxyl] nitrobenzene 254g, yield：94.0%, HPLC purity：99.2%.
Embodiment 2
By 150g solid sodium hydroxides in embodiment 1（96%）150g90% solid potassium hydroxides are changed to, other operations are identical, obtain 4-
[2- (5- ethyl -2- pyridine radicals) ethyoxyl] nitrobenzene 249g, yield：92.2%, HPLC purity：99.1%.
Embodiment 3
By 150g solid sodium hydroxides in embodiment 1（96%）It is changed to 150g solid carbonic acid potassiums, column chromatography for separation, other operation phases
Together, 4- [2- (5- ethyl -2- pyridine radicals) ethyoxyl] nitrobenzene 63g, yield are obtained：23.3%, HPLC purity：99.7%.
Embodiment 4
By 150g solid sodium hydroxides in embodiment 1（96%）150g sodium hydroxides/150g water is changed to, other operations are identical, obtain 4-
[2- (5- ethyl -2- pyridine radicals) ethyoxyl] nitrobenzene 247g, yield：91.4%, HPLC purity：98.3%.
Embodiment 5
Dichloromethane in embodiment 1 is changed to chloroform, other operations are identical, obtain 4- [2- (5- ethyl -2- pyridine radicals) ethyoxyl]
Nitrobenzene 249g, yield：92.2%, HPLC purity：97.3%.
Embodiment 6
Dichloromethane in embodiment 1 is changed to 1,2- dichloroethanes, other operations are identical, obtain 4- [2- (5- ethyl -2- pyridine radicals)
Ethyoxyl] nitrobenzene 255g, yield：94.4%, HPLC purity：99.3%.
Embodiment 7
Tri-n-octyl methyl ammonium chloride in embodiment 1 is changed to TEBA, other operations are identical, obtain 4- [2- (5- ethyl -2- pyridine radicals)
Ethyoxyl] nitrobenzene 248g, yield：91.8%, HPLC purity：98.9%.
Embodiment 8
Tri-n-octyl methyl ammonium chloride in embodiment 1 is changed to tetrabutylammonium bromide, other operations are identical, obtain 4- [2- (5- ethyls-
2- pyridine radicals) ethyoxyl] nitrobenzene 248g, yield：91.8%, HPLC purity：98.7%.
Embodiment 9
Reaction temperature in embodiment 1 is changed to 5-10 DEG C, other operations are identical, obtain 4- [2- (5- ethyl -2- pyridine radicals) ethoxies
Base] nitrobenzene 235g, yield：87.0%, HPLC purity：98.5%.
Embodiment 10
Reaction temperature in embodiment 1 is changed to 20-25 DEG C, other operations are identical, obtain 4- [2- (5- ethyl -2- pyridine radicals) ethoxies
Base] nitrobenzene 212g, yield：78.5%, HPLC purity：97.5%.
Embodiment 11
By 12g2- under nitrogen protection（5- ethyl -2- pyridine radicals）Ethanol and 11.2g p-fluoronitrobenzenes are dissolved in 80gDMF, cold
But 0-5 DEG C is arrived, 3.9g sodium hydrides are added portionwise（60%）, when insulation 4 is small after adding, system is punched into 240g water, uses dichloro
Methane extracts twice, merges organic phase, is washed with water 1 time, and anhydrous magnesium sulfate drying, filtering, is concentrated to dryness, and adds 50g petroleum ethers
Product yellow solid 17.8g, purity 97.3% are dried to obtain in crystallization, filtering, room temperature air blast.
Embodiment 12
By 150kg 2-（5- ethyl -2- pyridine radicals）Ethanol is dissolved in 450kg dichloromethane, adds 150kg solid hydroxides
Sodium（96%）With the tri-n-octyl methyl ammonium chloride of 7.5kg 75%, 0-5 DEG C of temperature control, is added dropwise 150kg p-fluoronitrobenzenes/150kg dichloros
Dichloromethane, when 0-5 DEG C of reaction 4 of insulation is small after adding, reaction terminates, and 0-5 DEG C of dropwise addition 300kg water of temperature control, is stirred 5 minutes, quiet
Layering is put, organic layer is washed three times with 200kg*3, and saturated brine 100kg is washed once, is added the drying of 10kg anhydrous magnesium sulfates, is added
Entering 5kg activated carbon decolorizings, filter, filtrate decompression is concentrated to dryness, and when the 0-5 DEG C of insulation 2 of addition 300kg petroleum ethers is small, is centrifuged,
30-40 DEG C of air blast drying, obtains 4- [2- (5- ethyl -2- pyridine radicals) ethyoxyl] nitrobenzene 253g, yield：93.6%, HPLC are pure
Degree：99.4%.
The foregoing is merely presently preferred embodiments of the present invention, is not intended to limit the invention, it is all the present invention spirit and
Any modification, equivalent replacement, improvement and so within principle, should all be included in the protection scope of the present invention.
Claims (6)
1. the method that one kind prepares 4- [2- (5- ethyl -2- pyridine radicals) ethyoxyl] nitrobenzene, it is characterised in that：By 2-（5- second
Base -2- pyridine radicals）Ethanol is dissolved in halogenated hydrocarbons, is added inorganic base and phase transfer catalyst, is added p-fluoronitrobenzene, is reacted
Temperature control is 0-50 DEG C, and when reaction time control is 4 small, 4- [2- (5- ethyl -2- pyridine radicals) are obtained after isolating and purifying
Ethyoxyl] nitrobenzene.
2. the method that one kind as claimed in claim 1 prepares 4- [2- (5- ethyl -2- pyridine radicals) ethyoxyl] nitrobenzene, it is special
Sign is：The halogenated hydrocarbons for dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethanes, chlorobenzene halogenated hydrocarbons it is any one
Kind.
3. the method that one kind as claimed in claim 1 prepares 4- [2- (5- ethyl -2- pyridine radicals) ethyoxyl] nitrobenzene, it is special
Sign is：The inorganic base is any one of potassium carbonate, potassium hydroxide, sodium hydroxide.
4. the method that one kind as claimed in claim 1 prepares 4- [2- (5- ethyl -2- pyridine radicals) ethyoxyl] nitrobenzene, it is special
Sign is：The phase transfer catalyst is any one of tetrabutylammonium bromide, TEBA, tri-n-octyl methyl ammonium chloride.
5. the method that one kind as claimed in claim 1 prepares 4- [2- (5- ethyl -2- pyridine radicals) ethyoxyl] nitrobenzene, it is special
Sign is：The reaction temperature is 0-5 DEG C.
6. the method that one kind as claimed in claim 1 prepares 4- [2- (5- ethyl -2- pyridine radicals) ethyoxyl] nitrobenzene, it is special
Sign is：2-（5- ethyl -2- pyridine radicals）The molar ratio of ethanol and p-fluoronitrobenzene is 1：1.07.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59110673A (en) * | 1982-12-15 | 1984-06-26 | Takeda Chem Ind Ltd | 2-(substituted pyridyl)ethylphenyl ether derivative and its preparation |
| JPS62185063A (en) * | 1986-02-06 | 1987-08-13 | Takeda Chem Ind Ltd | Urea derivative |
| WO2002088120A1 (en) * | 2001-04-26 | 2002-11-07 | Léciva, a.s. | Method for obtaining pioglitazone as an antidiabetic agent |
| WO2006035459A1 (en) * | 2004-09-28 | 2006-04-06 | Morepen Laboratories Limited | An improved process for the production of derivatives of thiozolidinediones and their precursors |
| CN101228128A (en) * | 2005-07-27 | 2008-07-23 | 桑多斯股份公司 | A process for the preparation of substituted phenyl ether compounds and rosiglitazone |
| JP2013203685A (en) * | 2012-03-28 | 2013-10-07 | Tokuyama Corp | Method of producing 4-[2-(5-ethyl-2-pyridyl)ethoxy]nitrobenzene or salt thereof |
-
2018
- 2018-01-05 CN CN201810009306.1A patent/CN108003090A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59110673A (en) * | 1982-12-15 | 1984-06-26 | Takeda Chem Ind Ltd | 2-(substituted pyridyl)ethylphenyl ether derivative and its preparation |
| JPS62185063A (en) * | 1986-02-06 | 1987-08-13 | Takeda Chem Ind Ltd | Urea derivative |
| WO2002088120A1 (en) * | 2001-04-26 | 2002-11-07 | Léciva, a.s. | Method for obtaining pioglitazone as an antidiabetic agent |
| WO2006035459A1 (en) * | 2004-09-28 | 2006-04-06 | Morepen Laboratories Limited | An improved process for the production of derivatives of thiozolidinediones and their precursors |
| CN101228128A (en) * | 2005-07-27 | 2008-07-23 | 桑多斯股份公司 | A process for the preparation of substituted phenyl ether compounds and rosiglitazone |
| JP2013203685A (en) * | 2012-03-28 | 2013-10-07 | Tokuyama Corp | Method of producing 4-[2-(5-ethyl-2-pyridyl)ethoxy]nitrobenzene or salt thereof |
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Application publication date: 20180508 |