CN101781284A - Method for purifying 2-[N-(2-methyl-5-nitrophenyl)amino]-4-(3-pyridyl)pyrimidine - Google Patents
Method for purifying 2-[N-(2-methyl-5-nitrophenyl)amino]-4-(3-pyridyl)pyrimidine Download PDFInfo
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- CN101781284A CN101781284A CN201010118251A CN201010118251A CN101781284A CN 101781284 A CN101781284 A CN 101781284A CN 201010118251 A CN201010118251 A CN 201010118251A CN 201010118251 A CN201010118251 A CN 201010118251A CN 101781284 A CN101781284 A CN 101781284A
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Abstract
A method for purifying 2-[N-(2-methyl-5-nitrophenyl)amino]-4-(3-pyridyl)pyrimidine is characterized by firstly reacting 2-[N-(2-methyl-5-nitrophenyl)amino]-4-(3-pyridyl)pyrimidine with protonic acid to generate salts, dissolving the salts into water, then adding an organic solvent, adding a decolorant into salt aqueous solution phase after extraction separation, carrying out decolorization while stirring at the temperature not less than 40 DEG C, neutralizing the decolorized salt aqueous solution phase with aqueous alkali to precipitate the 2-[N-(2-methyl-5-nitrophenyl)amino]-4-(3-pyridyl)pyrimidine, and obtaining the 2-[N-(2-methyl-5-nitrophenyl)amino]-4-(3-pyridyl)pyrimidine with purity being not less than 98% after separation, washing and drying. The method is simple in process, high in purity and yield and suitable for industrial production.
Description
One, technical field
The present invention relates to a kind of method of purification of medicine intermediate, exactly is a kind of intermediate 2-[N-(2-methyl-5-nitro phenyl) amino of antitumor drug imatinib]-purification process of 4-(3-pyridyl) pyrimidine.
Two, background technology
Imatinib intermediate 2-[N-(2-methyl-5-nitro phenyl) amino]-4-(3-pyridyl) pyrimidine, faint yellow solid, fusing point 194-198 ℃, its structural formula is as follows:
In the existing technology, U.S. Pat 5521184, " Chinese Pharmaceutical Journal " 2008,3 (43), 228-229 discloses a kind of 2-[N-(2-methyl-5-nitro phenyl) amino respectively]-purification process of 4-(3-pyridyl) pyrimidine is to use ethanol, recrystallizing methanol, this class purification process is for 2-[N-(2-methyl-5-nitro phenyl) amino]-it is effective that the higher crude product of 4-(3-pyridyl) pyrimidine content separates.And separate for the more reaction product of impurity is uneconomic, must just can reach the higher 2-[N-of purity (2-methyl-5-nitro phenyl) amino through recrystallization repeatedly]-4-(3-pyridyl) pyrimidine product, solvent load is very big, and yield also reduces with the number of times increase of recrystallization.
U.S. Pat 7507821B2 and " Organic Process Research﹠amp; Development " 2008,12, the 490-495 disclosed method is to 2-[N-(2-methyl-5-nitro phenyl) amino with eluent]-4-(3-pyridyl) pyrimidine crude product carries out purification by silica gel column chromatography, and this method mainly is suitable for laboratory scale preparation, and solvent load is big especially.
Three, summary of the invention
The present invention is directed to above-mentioned 2-[N-(2-methyl-5-nitro phenyl) amino]-deficiency of 4-(3-pyridyl) pyrimidine purification process, aim to provide a kind of new purification process and prepare highly purified 2-[N-(2-methyl-5-nitro phenyl) amino]-4-(3-pyridyl) pyrimidine, technical problem to be solved is that this purification process is applicable to suitability for industrialized production.
Technical scheme of the present invention comprises 2-[N-(2-methyl-5-nitro phenyl) amino]-dissolving of 4-(3-pyridyl) pyrimidine and separate out and extract, separate, decolouring, washing, dry each unit process, it is characterized in that described dissolving is 2-[N-(2-methyl-5-nitro phenyl) amino]-reaction of 4-(3-pyridyl) pyrimidine and protonic acid generates salt and is dissolved in the water, in solution, add organic solvent, add discoloring agent to the salt aqueous phase after the extracting and separating, ℃ stirring decolouring down in temperature 〉=40, salt water after decolouring makes 2-[N-(2-methyl-5-nitro phenyl) amino with alkaline solution neutralization]-4-(3-pyridyl) pyrimidine separates out, and the water washing after drying obtains highly purified 2-[N-(2-methyl-5-nitro phenyl) amino]-4-(3-pyridyl) pyrimidine.
Concrete operations are as follows:
With 2-[N-(2-methyl-5-nitro phenyl) amino]-4-(3-pyridyl) pyrimidine crude product and the dissolving of sour salify, add organic solvent extraction then, separate and remove water-insoluble organic impurity, salt solution is added to the decolouring of discoloring agent reflux, remove by filter discoloring agent, separate out with regeneration in the alkali, separate, the washing drying obtains highly purified 2-[N-(2-methyl-5-nitro phenyl) amino]-4-(3-pyridyl) pyrimidine.
Described protonic acid is selected from non-oxidizable acid materials such as dilute hydrochloric acid, dilute sulphuric acid or acetate, the amount that adds acid is no longer dissolved for making crude product, experiment shows, 2-[N-when pH value of solution transfers to 1～3 (2-methyl-5-nitro phenyl) amino]-4-(3-pyridyl) pyrimidine all dissolves.
Described organic solvent is selected from: organic solvents such as ethyl acetate, methylene dichloride or ether, solvent adding amount is 0.2～1.0 times (volume) of water.
Described discoloring agent is selected from nonmetalliferous ore soil powder sorptive materials such as gac, acid clay or diatomaceous earth.Decolouring is carried out under reflux temperature being not less than 40 ℃, time was controlled at 20～40 minutes, then, remove by filter discoloring agent, filtrate is faint yellow, the discoloring agent add-on is 2-[N-(2-methyl-5-nitro phenyl) amino]-0.015～0.1 times (weight) of 4-(3-pyridyl) pyrimidine crude product, fineness requirement 200～400 orders of discoloring agent.
Described neutralization is selected from alkaline solution: alkaline substance solutions such as sodium hydroxide, potassium hydroxide, ammoniacal liquor, salt of wormwood or sodium bicarbonate, the alkali add-on is not for separating out until there being precipitation, experiment shows, 2-[N-when solution PH transfers to 8～10 (2-methyl-5-nitro phenyl) amino]-4-(3-pyridyl) pyrimidine separates out fully.
2-[N-of the present invention (2-methyl-5-nitro phenyl) amino]-purifying process of 4-(3-pyridyl) pyrimidine compared with prior art advantage be: utilize 2-[N-(2-methyl-5-nitro phenyl) amino]-alkalescence of 4-(3-pyridyl) pyrimidine, adopt acid-base reaction, remove water-insoluble organic impurity by organic solvent, salt solution communicated in activated carbon decolorizing, the alkali and regeneration is separated out, technological process is simple, and operation control is easy, products obtained therefrom purity height, the yield height is applicable to suitability for industrialized production.
Four, embodiment
Embodiment 1
Outward appearance is 72.5% 2-[N-(2-methyl-5-nitro phenyl) amino for yellow, purity]-4-(3-pyridyl) pyrimidine crude product 15.0g, stir down and drip 1mol/L hydrochloric acid 100mL to it, the product dissolving adds ethyl acetate 25mL, stirs, leave standstill, tell water, add 1.0g350 purpose gac, 100 ℃ of heated and stirred backflow 20min, remove by filter gac, to the NaOH solution of filtrate dropping 1mol/L,, separate until no longer separating out precipitation, washing, drying gets faint yellow solid 9.4g, purity 〉=98%, fusing point 196.5-198 ℃, yield 86.8%.
Embodiment 2
Outward appearance is 72.5% 2-[N-(2-methyl-5-nitro phenyl) amino for yellow, purity]-4-(3-pyridyl) pyrimidine crude product 15.0g, stir down and drip 1mol/L sulfuric acid 85mL to it, the product dissolving adds ethyl acetate 25mL, stir, leave standstill, tell water, add 1.2g350 purpose gac, 100 ℃ of heated and stirred washings, dry 35min removes by filter gac, drips the solution of potassium carbonate of 1mol/L to filtrate, until no longer separating out precipitation, separate washing, drying, get faint yellow solid 8.7g, purity 〉=98%, fusing point 196-197 ℃, yield 80.0%.
Embodiment 3
Outward appearance is 72.5% 2-[N-(2-methyl-5-nitro phenyl) amino for yellow, purity]-4-(3-pyridyl) pyrimidine crude product 15.0g, stir down and drip 1mol/L acetate 120mL to it, the product dissolving, the 25mL that adds diethyl ether stirs, leave standstill, tell lower floor's water, add 1.5g250 purpose diatomite, 80 ℃ of heated and stirred 30min, remove by filter diatomite, to the ammonia soln of filtrate dropping 1mol/L,, separate until no longer separating out precipitation, washing, drying gets faint yellow solid 9.0g, purity 〉=98%, fusing point 196-198 ℃, yield 82.8%.
Embodiment 4
Outward appearance is 83.2% 2-[N-(2-methyl-5-nitro phenyl) amino for yellow, purity]-4-(3-pyridyl) pyrimidine crude product 20.0g, stir down and drip 1mol/L sulfuric acid 150mL to it, the product dissolving, the 30mL that adds methylene chloride stirs, leave standstill, tell water, add 1.5g200 purpose gac, 60 ℃ of heated and stirred 25min, remove by filter gac, to the NaOH solution of filtrate dropping 1mol/L,, separate until no longer separating out precipitation, washing, drying gets faint yellow solid 15.5g, purity 〉=98%, fusing point 196-197 ℃, yield 93.1%.
Embodiment 5
Outward appearance is 83.2% 2-[N-(2-methyl-5-nitro phenyl) amino for yellow, purity]-4-(3-pyridyl) pyrimidine crude product 20.0g, stir down and drip 1mol/L hydrochloric acid 180mL to it, the product dissolving, the 30mL that adds methylene chloride stirs, and leaves standstill, tell water, add 2.0g200 purpose gac, 75 ℃ of heated and stirred 30min remove by filter gac, drip the KOH solution of 1mol/L to filtrate, until no longer separating out precipitation, separate washing, the dry faint yellow solid 15.4g that gets, purity 〉=98%, fusing point 196-197.5 ℃, yield 92.3/%.
Embodiment 6
Outward appearance is 83.2% 2-[N-(2-methyl-5-nitro phenyl) amino for yellow, purity]-4-(3-pyridyl) pyrimidine crude product 20.0g, stir down and drip 1mol/L acetate 200mL to it, the product dissolving, add ethyl acetate 30mL, stir, leave standstill, tell water, add 2.0g 150 purpose acidic white earths, 80 ℃ of heated and stirred 30min remove by filter acidic white earth, drip the KOH solution of 1mol/L to filtrate, until no longer separating out precipitation, separate washing, the dry faint yellow solid 14.9g that gets, purity 〉=98%, fusing point 197-198 ℃, yield 89.5/%.
Claims (5)
1. a 2-[N-(2-methyl-5-nitro phenyl) amino]-4-(3-pyridyl) pyrimidine purification process, comprise 2-[N-(2-methyl-5-nitro phenyl) amino]-dissolving of 4-(3-pyridyl) pyrimidine and separate out and extract, separate, decolouring, washing, dry each unit process, it is characterized in that: described dissolving is 2-[N-(2-methyl-5-nitro phenyl) amino]-that the reaction of 4-(3-pyridyl) pyrimidine and protonic acid generates salt is soluble in water, in solution, add organic solvent, after the extracting and separating, add discoloring agent to the salt aqueous phase, stir decolouring down in temperature 〉=40 ℃, the salt water after decolouring makes 2-[N-(2-methyl-5-nitro phenyl) amino with the alkaline solution neutralization]-4-(3-pyridyl) pyrimidine separates out.
2. purification process according to claim 1 is characterized in that: described protonic acid is selected from dilute hydrochloric acid, dilute sulphuric acid or acetate.
3. purification process according to claim 1 is characterized in that: described organic solvent is selected from ethyl acetate, methylene dichloride or ether.
4. purification process according to claim 1 is characterized in that: described discoloring agent is selected from fineness 200～400 purpose gacs, acid clay or diatomaceous earth.
5. purification process according to claim 1 is characterized in that: described alkali is selected from sodium hydroxide, potassium hydroxide, ammoniacal liquor, salt of wormwood or sodium bicarbonate.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060014906A1 (en) * | 2002-10-24 | 2006-01-19 | Dow Corning Corporation | Siloxane based amide modified nylons |
| US20060149061A1 (en) * | 2004-12-30 | 2006-07-06 | Huang Anli | Novel process for preparing Imatinib |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060014906A1 (en) * | 2002-10-24 | 2006-01-19 | Dow Corning Corporation | Siloxane based amide modified nylons |
| US20060149061A1 (en) * | 2004-12-30 | 2006-07-06 | Huang Anli | Novel process for preparing Imatinib |
Non-Patent Citations (1)
| Title |
|---|
| 郁建平: "博落回生物碱酸水提取工艺及优化", 《2008年全国有机和精细化工中间体学术研讨会》, 31 December 2008 (2008-12-31), pages 84 - 90 * |
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Application publication date: 20100721 Assignee: Anhui easy agriculture limited-liability company of a specified duration Assignor: Hefei University of Technology Contract record no.: 2014340000189 Denomination of invention: Method for purifying 2-[N- (2- methyl -5- nitro phenyl) amino]-4- (3- pyridyl) pyrimidine Granted publication date: 20130403 License type: Exclusive License Record date: 20141225 |
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