CN105622304B - The sweep-out method of primary aromatic amine class impurity in drug or pharmaceutical intermediate - Google Patents
The sweep-out method of primary aromatic amine class impurity in drug or pharmaceutical intermediate Download PDFInfo
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Abstract
The present invention provides a kind of sweep-out methods of primary aromatic amine class impurity in drug or pharmaceutical intermediate, it is to add in the drug containing primary aromatic amine class impurity or intermediate, acid anhydrides, inorganic alkaline or organic basic compound, solvent into reaction kettle, stirring, maintain temperature, it reacts 0.5 24 hours, stop reaction, post-treated crystallization filters out solid and obtains sterling.By the present invention in that it is reacted with anhydride compound with primary aromatic amine class impurity, fundamentally reduce the content of primary aromatic amine class impurity, and obtained derivative products and product property are widely different, easily remove, there is no reversible risks, the drug or intermediate that are no more than 2ppm containing phenyl amines impurity can be obtained, the method can effectively remove drug or the primary aromatic amine class impurity contained by intermediate, be more suitable for large-scale industrial production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, suitable for production process use to or generated primary aromatic amine class
The medicine or medicine intermediate of compound remove its contained primary aromatic amine class impurity.More specifically a kind of drug or drug
The sweep-out method of primary aromatic amine class impurity in intermediate.
Background technology
Primary aromatic amine class compound is widely used in as raw material or medicine intermediate in medicine production（It is shown in Table I）.So
And most primary aromatic amine class compound has stronger genotoxicity, in recent years, with going deep into for research, people couple
Genotoxicity substance is more and more careful, shows drug development and production aspect, is exactly to the control with Genotoxic
It is increasingly stringenter.At present, for long-term administration（More than December）, the acceptable intake of general recommendations genotoxicity substance is every
Its 1.5 microgram, the control of genotoxicity substance difference different according to the dosage of drug, daily 1 gram such as dosage, control
To be no more than 1.5ppm, daily 0.1 gram of dosage, control be no more than 15ppm, such as：Telmisartan, maximum dose are
80mg/ days, genotoxicity Control of Impurities was no more than 20 ppm；Imatinib, maximum dose are 800mg/ days, and genotoxicity is miscellaneous
Quality Control is made as being no more than 2 ppm.Therefore, for using or generating the medicine of primary aromatic amine class compound in production process
Or medicine intermediate, finding a kind of efficient process for purification for removing primary aromatic amine class compound impurities just seems unusual
It is important.
At present, the conventional method for removing primary aromatic amine class compound has 3 kinds, one：It refines repeatedly, secondly：Aldehyde radical tree
Fat adsorbs, activated carbon adsorption etc., third, evading primary aromatic amine class compound in highway route design.These types of method has respectively
The shortcomings that.First, refining repeatedly will necessarily cause product yield significantly to reduce, and improve cost, expand energy consumption, both unrestrained
The burden that resource has aggravated patient again is taken, this method is very undesirable；Second, formaldehyde-based resin absorption, this method has very big
Limitation, formaldehyde-based resin is expensive, and cost is too high, and easily aoxidizes, and hydraulic performance decline is obvious after regeneration, most important
It is difficult to be scavenged into below 2ppm to be；Third evades primary aromatic amine class compound in highway route design, and this method has many limitations
Property, reaction step can be extended in most cases by the one hand evading primary aromatic amine class compound, increase operation difficulty, reduce production
Product yield improves cost, and on the other hand many primary aromatic amine class compounds are that can not evade at all, such as amides chemical combination
Hydrolysis, degradation of object etc..Therefore, current method can not reach effective removing primary aromatic amine class compound well
It is required that.
Invention content
The purpose of the present invention is to provide a kind of removing process for purification for primary aromatic amine class compound impurities, this hairs
The bright initiative method by derivatization is applied to the removing of primary aromatic amine class compound impurities, makes suitable for production process
The medicine or medicine intermediate of primary aromatic amine class compound are used or generated, removes its contained primary aromatic amine class impurity.
The medicine or medicine intermediate that are no more than 2ppm containing primary aromatic amine class impurity content can be obtained using the process for purification.
To achieve the above object, the present invention provides following technical solution：
The sweep-out method of primary aromatic amine class impurity in a kind of drug or pharmaceutical intermediate, it is characterised in that fragrance will be contained
Drug or intermediate, anhydride compound, acid binding agent, the solvent of the primary amine impurities of race are added in into reaction kettle, stirring, 20-100
DEG C temperature is maintained, react 0.5-24 hour, stop reacting, post-treated crystallization filters out solid and obtain sterling.Acid anhydrides of the present invention
Class compound is 30-150 with having the drug of primary aromatic amine class impurity or intermediate molar ratio:1, preferred molar ratio is 50-
100:1。
Post processing of the present invention refers to：Alkaline aqueous solution, stirring are added in, liquid separation, organic layer is washed with water, and adds in
Acidic aqueous solution extracts, and water layer is adjusted to alkalinity, crystallization, filters out solid, dry.Alkaline aqueous solution therein refers to hydroxide
Sodium water solution；Acidic aqueous solution refers to dilute hydrochloric acid.
Anhydride compound of the present invention is acetic anhydride, propionic andydride, butyric anhydride, benzoyl oxide, succinic anhydride, penta 2
Acid anhydrides, maleic anhydride or phthalic anhydride, preferably succinic anhydride or phthalic anhydride.Acid binding agent is inorganic or organic base is alkaline
Compound, such as：Sodium carbonate, potassium carbonate, triethylamine or pyridine.The solvent is halogenated alkanes, ethers, acetonitrile, tetrahydrochysene furan
It mutters, DMF or toluene, the w/v of volume and institute's refined substance is 5-50:1, preferred w/v is 10-30:1.
More detailed description of the present invention is as follows：
Medicine or medicine intermediate in order to obtain containing primary aromatic amine class impurity, we are with the following method：It takes and treats
The compound of research adds in suitable primary aromatic amine class compound, and the content for making wherein primary aromatic amine class compound is x%,
Sample is used to test in next step.This method is：By medicine or medicine intermediate containing primary aromatic amine class impurity, acid anhydrides, nothing
Machine alkali compounds or（With）Organic base, solvent are added in into reaction kettle, and stirring maintains temperature, reacts 0.5-24 hours, stops
Reaction adds in alkaline aqueous solution, stirring, liquid separation（Water-soluble solvent directly filters, and washing obtains product）, organic layer is washed with water
It washs, adds in acidic aqueous solution extraction, water layer is adjusted to alkalinity, crystallization, filters out solid, dry.
The sample that upper step is obtained, acid anhydrides, inorganic alkaline compound or（With）Organic base, solvent are added in into reaction kettle,
Stirring maintains temperature, reacts 0.5-24 hours, stops reaction, adds in alkaline aqueous solution, stirring, liquid separation（Water-soluble solvent is straight
Filter is taken over, washing obtains product）, organic layer is washed with water, and adds in acidic aqueous solution extraction, and water layer is adjusted to alkalinity, crystallization, filter
Go out solid, it is dry.
Typically by taking Imatinib as an example, in the refined research of Imatinib, in order to remove gene poison contained therein
Property impurity N- (2- methyl -5- aminocarbonyl phenyls) -4-（3- pyridyl groups）- 2- pyrilamines, We conducted a large amount of experimental studies.I
Find, suitable anhydride compound is added in when refined, neither influences the quality of Imatinib, but can make N- (2- methyl-
5- aminocarbonyl phenyls) -4-（3- pyridyl groups）The elimination efficiency of -2- pyrilamines nearly reaches 100%.On this basis, it has been found that acyl
Halogen class compound can also obtain similar result.We advanced optimize this method, and using other drugs from it is different
Primary aromatic amine class compound carries out comparative study, and discovery is attained by very outstanding effect.We are aware that this is a kind of
The splendid method of primary aromatic amine class compound is removed, the aromatic series primary removed and contained in medicine or medicine intermediate can be become
The technology platform of aminated compounds.This method is anti-by using the anhydride compound and primary aromatic amine class impurity of hypotoxicity
It answers, fundamentally reduces the content of primary aromatic amine class impurity, moreover, obtained derivative products and product property are widely different,
It easily removes, there is no reversible risks, can obtain the medicine or medicine intermediate that are no more than 2ppm containing phenyl amines impurity.
In order to prove the removing process for purification and existing method disclosed in this invention for primary aromatic amine class compound
Difference, the present invention using Imatinib has been contrast experiment, has been listed as follows：
Conclusion：The method yield higher of the present invention, refining effect are more preferable.
The sweep-out method of primary aromatic amine class impurity disclosed by the invention possessed good effect compared with prior art
It is：
（1）The process for purification of the present invention has at low cost, efficient, low toxic and environment-friendly, easy to operate, is suitble to industry metaplasia
Production, can bring huge economic and social benefit.
（2）The process for purification of the present invention high income, efficient, low toxic and environment-friendly compared with refining repeatedly.It is inhaled with formaldehyde-based resin
It is attached compared at low cost, efficient.It is easy to operate compared with evading in highway route design, at low cost, it is suitble to industrialized production.
Specific embodiment：
In order to more fully explain the implementation of the present invention, provide in removing medicine or medicine intermediate and contain phenyl amines impurity
Process for purification embodiment.These embodiments are only to explain rather than limit the scope of the invention.Wherein use
Raw material is prepared by bibliography.
Embodiment 1
By Torasemide（It is prepared using US2004/138469 A1 methods, methylaniline containing 3- 1%）90g is added in 3L's
In four-neck flask, chloroform 900ml, potassium carbonate 27g, succinic anhydride 13.5g are added in, stirring is heated to 60-63 DEG C, reflux 2
Hour, 20-25 DEG C is cooled to, adds in 1% sodium hydrate aqueous solution 900ml, is stirred 30 minutes, liquid separation, organic layer is washed to pH
For 7-8, water 1800ml is added in into organic layer, is 3-4 with salt acid for adjusting pH, separates organic layer, water layer chloroform 900ml
It washed once, liquid separation.PH to 10 is adjusted with ammonium hydroxide, white solid is precipitated in stirring, filters, dry, obtains product 76.5g, yield is
85%, HPLC-Ms are measured：3- methylanilines content is less than 2ppm.
Embodiment 2
By Torasemide（Methylaniline containing 3- 1.5%）90g is added in into the four-neck flask of 3L, adds in toluene 900ml, carbon
Sour potassium 27g, succinic anhydride 13.5g, stirring are heated to 60-63 DEG C, flow back 2 hours, are cooled to 20-25 DEG C, add in 1% hydrogen-oxygen
Change sodium water solution 900ml, stir 30 minutes, liquid separation, organic layer is washed to pH as 7-8, and water 1800ml is added in into organic layer, uses
Salt acid for adjusting pH is 3-4, separates organic layer, water layer washed once with toluene 900ml, liquid separation.PH to 10, stirring are adjusted with ammonium hydroxide
White solid is precipitated, filters, it is dry, product 76.5g, yield 85% are obtained, HPLC-Ms is measured：3- methylaniline contents are less than
2ppm。
Embodiment 3
By Torasemide（Methylaniline containing 3- 3%）90g is added in into the four-neck flask of 3L, adds in isopropyl ether 900ml, carbon
Sour potassium 27g, succinic anhydride 13.5g, stirring are heated to 60-63 DEG C, flow back 2 hours, are cooled to 20-25 DEG C, add in 1% hydrogen-oxygen
Change sodium water solution 900ml, stir 30 minutes, liquid separation, organic layer is washed to pH as 7-8, and water 1800ml is added in into organic layer, uses
Salt acid for adjusting pH is 3-4, separates organic layer, water layer washed once with isopropyl ether 900ml, liquid separation.PH to 10 is adjusted with ammonium hydroxide, is stirred
Precipitation white solid is mixed, is filtered, it is dry, product 76.5g, yield 85% are obtained, HPLC-Ms is measured：3- methylaniline contents are less than
2ppm。
Embodiment 4
By Telmisartan（It is prepared using WO2007/10558 A methods, containing 1,2- phenylenediamines 1%）90g is added in the four of 3L
In neck flask, chloroform 1800ml, potassium carbonate 27g, succinic anhydride 13.5g are added in, stirring is heated to 60-63 DEG C, reflux 2
Hour, 20-25 DEG C is cooled to, adds in 1% sodium hydrate aqueous solution 900ml, is stirred 30 minutes, liquid separation, organic layer is washed to pH
For 7-8, water 1800ml is added in into organic layer, is 3-4 with salt acid for adjusting pH, separates organic layer, water layer chloroform 900ml
It washed once, liquid separation.PH to 10 is adjusted with ammonium hydroxide, white solid is precipitated in stirring, filters, dry, obtains product 76.5g, yield is
85%, HPLC-Ms are measured：1,2- phenylenediamine content is less than 2ppm.
Embodiment 5
By Telmisartan（Containing 1,2- phenylenediamines 2%）90g is added in into the four-neck flask of 3L, adds in toluene 1800ml, carbonic acid
Potassium 27g, succinic anhydride 13.5g, stirring are heated to 60-63 DEG C, flow back 2 hours, are cooled to 20-25 DEG C, add in 1% hydroxide
Sodium water solution 900ml is stirred 30 minutes, liquid separation, and organic layer is washed to pH as 7-8, and water 1800ml is added in into organic layer, uses salt
Acid for adjusting pH is 3-4, separates organic layer, and water layer washed once with toluene 900ml, liquid separation.PH to 10, stirring analysis are adjusted with ammonium hydroxide
Go out white solid, filter, it is dry, product 76.5g, yield 85% are obtained, HPLC-Ms is measured：1,2- phenylenediamine content is less than
2ppm。
Embodiment 6
By Telmisartan（Containing 1,2- phenylenediamines 3%）90g is added in into the four-neck flask of 3L, adds in isopropyl ether 1800ml, carbon
Sour potassium 27g, succinic anhydride 13.5g, stirring are heated to 60-63 DEG C, flow back 2 hours, are cooled to 20-25 DEG C, add in 1% hydrogen-oxygen
Change sodium water solution 900ml, stir 30 minutes, liquid separation, organic layer is washed to pH as 7-8, and water 1800ml is added in into organic layer, uses
Salt acid for adjusting pH is 3-4, separates organic layer, water layer washed once with isopropyl ether 900ml, liquid separation.PH to 10 is adjusted with ammonium hydroxide, is stirred
Precipitation white solid is mixed, is filtered, it is dry, product 76.5g, yield 85% are obtained, HPLC-Ms is measured：1,2- phenylenediamine content is less than
2ppm。
Embodiment 7
By Torasemide（Methylaniline containing 3- 1%）90g is added in into the four-neck flask of 3L, adds in chloroform 1800ml,
Pyridine 16g, phthalic anhydride 20g, stirring are heated to 60-63 DEG C, flow back 2 hours, are cooled to 20-25 DEG C, add in 1% hydrogen
Aqueous solution of sodium oxide 900ml is stirred 30 minutes, liquid separation, and organic layer is washed to pH as 7-8, and water 1800ml is added in into organic layer,
It is 3-4 with salt acid for adjusting pH, separates organic layer, water layer washed once with chloroform 900ml, liquid separation.With ammonium hydroxide adjust pH to
10, white solid is precipitated in stirring, filters, dry, obtains product 76.5g, yield 85%, and HPLC-Ms is measured：3- methylanilines contain
Amount is less than 2ppm.
Embodiment 8
By Torasemide（Methylaniline containing 3- 1.5%）90g is added in into the four-neck flask of 3L, adds in dichloromethane
2700ml, pyridine 16g, phthalic anhydride 20g, stirring are heated to 60-63 DEG C, flow back 2 hours, are cooled to 20-25 DEG C, add
Enter 1% sodium hydrate aqueous solution 900ml, stir 30 minutes, liquid separation, organic layer is washed to pH as 7-8, is added in into organic layer
Water 1800ml is 3-4 with salt acid for adjusting pH, separates organic layer, and water layer washed once with dichloromethane 900ml, liquid separation.Use ammonium hydroxide
PH to 10 is adjusted, white solid is precipitated in stirring, filters, dry, obtains product 76.5g, yield 85%, and HPLC-Ms is measured：3- first
Base aniline content is less than 2ppm.
Embodiment 9
By Torasemide（Methylaniline containing 3- 3%）90g is added in into the four-neck flask of 3L, adds in dichloromethane 2700ml,
Pyridine 16g, phthalic anhydride 20g, stirring are heated to 60-63 DEG C, flow back 2 hours, are cooled to 20-25 DEG C, add in 1% hydrogen
Aqueous solution of sodium oxide 900ml is stirred 30 minutes, liquid separation, and organic layer is washed to pH as 7-8, and water 1800ml is added in into organic layer,
It is 3-4 with salt acid for adjusting pH, separates organic layer, water layer washed once with dichloromethane 900ml, liquid separation.With ammonium hydroxide adjust pH to
10, white solid is precipitated in stirring, filters, dry, obtains product 76.5g, yield 85%, and HPLC-Ms is measured：3- methylanilines contain
Amount is less than 2ppm.
Embodiment 10
By Telmisartan（Containing 1,2- phenylenediamines 1%）90g is added in into the four-neck flask of 3L, adds in dichloromethane 2700ml,
Pyridine 16g, phthalic anhydride 20g, stirring are heated to 60-63 DEG C, flow back 2 hours, are cooled to 20-25 DEG C, add in 1% hydrogen
Aqueous solution of sodium oxide 900ml is stirred 30 minutes, liquid separation, and organic layer is washed to pH as 7-8, and water 1800ml is added in into organic layer,
It is 3-4 with salt acid for adjusting pH, separates organic layer, water layer washed once with dichloromethane 900ml, liquid separation.With ammonium hydroxide adjust pH to
10, white solid is precipitated in stirring, filters, dry, obtains product 76.5g, yield 85%, and HPLC-Ms is measured：1,2 phenylenediamine content
Less than 2ppm.
Embodiment 11
By Telmisartan（Containing 1,2- phenylenediamines 2%）90g is added in into the four-neck flask of 3L, adds in dichloromethane 2700ml,
Pyridine 16g, phthalic anhydride 20g, stirring are heated to 60-63 DEG C, flow back 2 hours, are cooled to 20-25 DEG C, add in 1% hydrogen
Aqueous solution of sodium oxide 900ml is stirred 30 minutes, liquid separation, and organic layer is washed to pH as 7-8, and water 1800ml is added in into organic layer,
It is 3-4 with salt acid for adjusting pH, separates organic layer, water layer washed once with dichloromethane 900ml, liquid separation.With ammonium hydroxide adjust pH to
10, white solid is precipitated in stirring, filters, dry, obtains product 76.5g, yield 85%, and HPLC-Ms is measured：1,2 phenylenediamine content
Less than 2ppm.
Embodiment 12
By Telmisartan（Containing 1,2- phenylenediamines 3%）90g is added in into the four-neck flask of 3L, adds in chloroform 1800ml,
Pyridine 16g, phthalic anhydride 20g, stirring are heated to 60-63 DEG C, flow back 2 hours, are cooled to 20-25 DEG C, add in 1% hydrogen
Aqueous solution of sodium oxide 900ml is stirred 30 minutes, liquid separation, and organic layer is washed to pH as 7-8, and water 1800ml is added in into organic layer,
It is 3-4 with salt acid for adjusting pH, separates organic layer, water layer washed once with chloroform 900ml, liquid separation.With ammonium hydroxide adjust pH to
10, white solid is precipitated in stirring, filters, dry, obtains product 76.5g, yield 85%, and HPLC-Ms is measured：1,2 phenylenediamine content
Less than 2ppm.
Embodiment 13
By 4- [(4- methyl-1s-piperazinyl) methyl]-N- [4- methyl -3- [4- (3- pyridyl groups) -2- pyrimidine radicals] amino]
Phenyl] benzamide（It is prepared using the method for WO2008117298）Crude product 90g（HPLC is measured, impure N-（2- methyl -5-
Aminocarbonyl phenyl）-4-（3- pyridyl groups）- 2- pyrilamines 0.8%）It adds in into the four-neck flask of 3L, adds in chloroform 1800ml,
Potassium carbonate 27g, succinic anhydride 13.5g, stirring are heated to 60-63 DEG C, flow back 2 hours, are cooled to 20-25 DEG C, add in 1% hydrogen
Aqueous solution of sodium oxide 900ml is stirred 30 minutes, liquid separation, and organic layer is washed to pH as 7-8, and water 1800ml is added in into organic layer,
It is 3-4 with salt acid for adjusting pH, separates organic layer, water layer washed once with chloroform 900ml, liquid separation.With ammonium hydroxide adjust pH to
10, white solid is precipitated in stirring, filters, dry, obtains product 76.5g, yield 85%, and HPLC-Ms is measured：Impurity N-（2- first
Base -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）- 2- pyrimidines amine content is less than 2ppm.
Embodiment 14
By 4- [(4- methyl-1s-piperazinyl) methyl]-N- [4- methyl -3- [4- (3- pyridyl groups) -2- pyrimidine radicals] amino]
Phenyl] benzamide crude product 90g（HPLC is measured, impure N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）- 2- pyrimidines
Amine 0.6%）It adds in into the four-neck flask of 3L, adds in dichloromethane 2700ml, potassium carbonate 27g, maleic anhydride 13.5g, stir,
60-63 DEG C is heated to, flows back 2 hours, is cooled to 20-25 DEG C, adds in 1% sodium hydrate aqueous solution 900ml, is stirred 30 minutes,
Liquid separation, organic layer are washed to pH as 7-8, water 1800ml are added in into organic layer, is 3-4 with salt acid for adjusting pH, separates organic layer,
Water layer washed once with dichloromethane 900ml, liquid separation.PH to 10 is adjusted with ammonium hydroxide, white solid is precipitated in stirring, filters, dry,
Product 76.5g, yield 85% are obtained, HPLC-Ms is measured：Impurity N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）- 2- is phonetic
Pyridine amine content is less than 2ppm.
Embodiment 15
By 4- [(4- methyl-1s-piperazinyl) methyl]-N- [4- methyl -3- [4- (3- pyridyl groups) -2- pyrimidine radicals] amino]
Phenyl] benzamide crude product 90g（HPLC is measured, impure N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）- 2- pyrimidines
Amine 0.5%）It adds in into the four-neck flask of 3L, adds in chloroform 1800ml, potassium carbonate 27g, phthalic anhydride 18.9g are stirred
It mixes, is heated to 60-63 DEG C, flow back 2 hours, be cooled to 20-25 DEG C, add in 1% sodium hydrate aqueous solution 900ml, stir 30 points
Clock, liquid separation, organic layer are washed to pH as 7-8, water 1800ml are added in into organic layer, is 3-4 with salt acid for adjusting pH, separates organic
Layer, water layer washed once with chloroform 900ml, liquid separation.PH to 10 is adjusted with ammonium hydroxide, white solid is precipitated in stirring, filters, and does
It is dry, product 76.5g, yield 85% are obtained, HPLC-Ms is measured：Impurity N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）-
2- pyrimidines amine content is less than 2ppm.
Embodiment 16
By 4- [(4- methyl-1s-piperazinyl) methyl]-N- [4- methyl -3- [4- (3- pyridyl groups) -2- pyrimidine radicals] amino]
Phenyl] benzamide crude product 90g（HPLC is measured, impure N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）- 2- pyrimidines
Amine 0.7%）It adds in into the four-neck flask of 3L, adds in dichloromethane 2700ml, potassium carbonate 27g, phthalic anhydride 18.9g are stirred
It mixes, is heated to 60-63 DEG C, flow back 2 hours, be cooled to 20-25 DEG C, add in 1% sodium hydrate aqueous solution 900ml, stir 30 points
Clock, liquid separation, organic layer are washed to pH as 7-8, water 1800ml are added in into organic layer, is 3-4 with salt acid for adjusting pH, separates organic
Layer, water layer washed once with dichloromethane 900ml, liquid separation.PH to 10 is adjusted with ammonium hydroxide, white solid is precipitated in stirring, filters, and does
It is dry, product 76.5g, yield 85% are obtained, HPLC-Ms is measured：Impurity N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）-
2- pyrimidines amine content is less than 2ppm.
Embodiment 17
By 4- [(4- methyl-1s-piperazinyl) methyl]-N- [4- methyl -3- [4- (3- pyridyl groups) -2- pyrimidine radicals] amino]
Phenyl] benzamide crude product 90g（HPLC is measured, impure N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）- 2- pyrimidines
Amine 0.8%）It adds in into the four-neck flask of 3L, adds in isopropyl ether 1800ml, potassium carbonate 27g, phthalic anhydride 18.9g are stirred
It mixes, is heated to 60-63 DEG C, flow back 2 hours, be cooled to 20-25 DEG C, add in 1% sodium hydrate aqueous solution 900ml, stir 30 points
Clock, liquid separation, organic layer are washed to pH as 7-8, water 1800ml are added in into organic layer, is 3-4 with salt acid for adjusting pH, separates organic
Layer, water layer washed once with isopropyl ether 900ml, liquid separation.PH to 10 is adjusted with ammonium hydroxide, white solid is precipitated in stirring, filters, and does
It is dry, product 76.5g, yield 85% are obtained, HPLC-Ms is measured：Impurity N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）-
2- pyrimidines amine content is less than 2ppm.
Embodiment 18
By 4- [(4- methyl-1s-piperazinyl) methyl]-N- [4- methyl -3- [4- (3- pyridyl groups) -2- pyrimidine radicals] amino]
Phenyl] benzamide crude product 90g（HPLC is measured, impure N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）- 2- pyrimidines
Amine 0.9%）It adds in into the four-neck flask of 3L, adds in chloroform 1800ml, pyridine 16g, succinic anhydride 13.5g, stirring adds
Heat flows back 2 hours to 60-63 DEG C, is cooled to 20-25 DEG C, adds in 1% sodium hydrate aqueous solution 900ml, stirs 30 minutes, point
Liquid, organic layer are washed to pH as 7-8, water 1800ml are added in into organic layer, is 3-4 with salt acid for adjusting pH, separates organic layer, water
Layer washed once with chloroform 900ml, liquid separation.PH to 10 is adjusted with ammonium hydroxide, white solid is precipitated in stirring, filters, dry, obtains
Product 76.5g, yield 85%, HPLC-Ms are measured：Impurity N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）- 2- pyrimidines
Amine content is less than 2ppm..
Embodiment 19
By 4- [(4- methyl-1s-piperazinyl) methyl]-N- [4- methyl -3- [4- (3- pyridyl groups) -2- pyrimidine radicals] amino]
Phenyl] benzamide crude product 9kg（HPLC is measured, impure N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）- 2- pyrimidines
Amine 0.9%）It adds in into the reaction kettle of 500L, adds in chloroform 180L, potassium carbonate 2.7kg, succinic anhydride 1.35kg, stir,
60-63 DEG C is heated to, flows back 2 hours, is cooled to 20-25 DEG C, adds in 1% sodium hydrate aqueous solution 90L, is stirred 30 minutes, point
Liquid, organic layer are washed to pH as 7-8, water 180L are added in into organic layer, is 3-4 with salt acid for adjusting pH, separates organic layer, water layer
It washed once with chloroform 90L, liquid separation.PH to 10 is adjusted with ammonium hydroxide, white solid is precipitated in stirring, filters, dry, obtains product
7.65kg, yield 85%, HPLC-Ms are measured：Impurity N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）- 2- pyrilamines
Content is less than 2ppm.
Embodiment 20
By Hydrochioro（The chemicals of purchase）Crude product 90g（HPLC is measured, impure 3-Aminotrifluorotoluene 1.8%）Add
Enter into the four-neck flask of 3L, add in chloroform 1800ml, potassium carbonate 27g, succinic anhydride 13.5g, stirring is heated to 60-
It 63 DEG C, flows back 2 hours, is cooled to 20-25 DEG C, add in 1% sodium hydrate aqueous solution 900ml, stir 30 minutes, liquid separation is organic
Layer is washed to pH as 7-8, and water 1800ml is added in into organic layer, is 3-4 with salt acid for adjusting pH, separates organic layer, and water layer is with three
Chloromethanes 900ml washed once, liquid separation.PH to 10 is adjusted with ammonium hydroxide, white solid is precipitated in stirring, filters, dry, obtains product
76.5g, yield 85%, HPLC-Ms are measured：Impurity 3-Aminotrifluorotoluene content is less than 2ppm.
Embodiment 21
By Hydrochioro crude product 90g（HPLC is measured, impure 3-Aminotrifluorotoluene 1.2%）It adds in four necks of 3L and burns
In bottle, chloroform 1800ml, potassium carbonate 27g, maleic anhydride 13.5g are added in, stirring is heated to 60-63 DEG C, flows back 2 hours,
20-25 DEG C is cooled to, adds in 1% sodium hydrate aqueous solution 900ml, is stirred 30 minutes, liquid separation, organic layer is washed to pH as 7-
8, water 1800ml is added in into organic layer, is 3-4 with salt acid for adjusting pH, separates organic layer, water layer is washed with chloroform 900ml
Once, liquid separation.PH to 10 is adjusted with ammonium hydroxide, white solid is precipitated in stirring, filters, dry, obtains product 76.5g, yield 85%,
HPLC-Ms is measured：Impurity 3-Aminotrifluorotoluene content is less than 2ppm.
Embodiment 22
By Hydrochioro crude product 90g（HPLC is measured, impure 3-Aminotrifluorotoluene 0.5%）It adds in four necks of 3L and burns
In bottle, chloroform 1800ml, potassium carbonate 27g, phthalic anhydride 18.9g are added in, stirring is heated to 60-63 DEG C, reflux 2
Hour, 20-25 DEG C is cooled to, adds in 1% sodium hydrate aqueous solution 900ml, is stirred 30 minutes, liquid separation, organic layer is washed to pH
For 7-8, water 1800ml is added in into organic layer, is 3-4 with salt acid for adjusting pH, separates organic layer, water layer chloroform 900ml
It washed once, liquid separation.PH to 10 is adjusted with ammonium hydroxide, white solid is precipitated in stirring, filters, dry, obtains product 76.5g, yield is
85%, HPLC-Ms are measured：Impurity 3-Aminotrifluorotoluene content is less than 2ppm.
Embodiment 23
By Hydrochioro crude product 90g（HPLC is measured, impure 3-Aminotrifluorotoluene 0.7%）It adds in four necks of 3L and burns
In bottle, dichloromethane 1800ml, potassium carbonate 27g, phthalic anhydride 12.5g are added in, stirring is heated to 60-63 DEG C, reflux 2
Hour, 20-25 DEG C is cooled to, adds in 1% sodium hydrate aqueous solution 900ml, is stirred 30 minutes, liquid separation, organic layer is washed to pH
For 7-8, water 1800ml is added in into organic layer, is 3-4 with salt acid for adjusting pH, separates organic layer, water layer dichloromethane 900ml
It washed once, liquid separation.PH to 10 is adjusted with ammonium hydroxide, white solid is precipitated in stirring, filters, dry, obtains product 76.5g, yield is
85%, HPLC-Ms are measured：Impurity 3-Aminotrifluorotoluene content is less than 2ppm.
Embodiment 24
By Hydrochioro crude product 90g（HPLC is measured, impure 3-Aminotrifluorotoluene 0.8%）It adds in four necks of 3L and burns
In bottle, isopropyl ether 1800ml, potassium carbonate 27g, phthalic anhydride 12.5g are added in, stirring is heated to 60-63 DEG C, and reflux 2 is small
When, 20-25 DEG C is cooled to, adds in 1% sodium hydrate aqueous solution 900ml, is stirred 30 minutes, liquid separation, organic layer is washed to pH and is
7-8 adds in water 1800ml into organic layer, is 3-4 with salt acid for adjusting pH, separates organic layer, water layer is washed with isopropyl ether 900ml
Once, liquid separation.PH to 10 is adjusted with ammonium hydroxide, white solid is precipitated in stirring, filters, dry, obtains product 76.5g, yield 85%,
HPLC-Ms is measured：Impurity 3-Aminotrifluorotoluene content is less than 2ppm.
Embodiment 25
By Hydrochioro crude product 90g（HPLC is measured, impure 3-Aminotrifluorotoluene 0.9%）It adds in four necks of 3L and burns
In bottle, toluene 1800ml, pyridine 16g, succinic anhydride 13.5g are added in, stirring is heated to 60-63 DEG C, flows back 2 hours, is cooled to
20-25 DEG C, 1% sodium hydrate aqueous solution 900ml is added in, is stirred 30 minutes, liquid separation, organic layer is washed to pH as 7-8, Xiang You
Water 1800ml is added in machine layer, is 3-4 with salt acid for adjusting pH, separates organic layer, water layer washed once with toluene 900ml, liquid separation.
PH to 10 is adjusted with ammonium hydroxide, white solid is precipitated in stirring, filters, dry, obtains product 76.5g, yield 85%, and HPLC-Ms is surveyed
It is fixed：Impurity 3-Aminotrifluorotoluene content is less than 2ppm.
Embodiment 26
By Hydrochioro crude product 90g（HPLC is measured, impure 3-Aminotrifluorotoluene 0.9%）It adds in the reaction of 500L
In kettle, toluene 180L, potassium carbonate 2.7kg, succinic anhydride 1.35kg are added in, stirring is heated to 60-63 DEG C, flows back 2 hours, cold
But to 20-25 DEG C, 1% sodium hydrate aqueous solution 90L is added in, is stirred 30 minutes, liquid separation, organic layer is washed to pH as 7-8, to
Water 180L is added in organic layer, is 3-4 with salt acid for adjusting pH, separates organic layer, water layer washed once with toluene 90L, liquid separation.With
Ammonium hydroxide adjusts pH to 10, and white solid is precipitated in stirring, filters, dry, obtains product 7.65kg, yield 85%, and HPLC-Ms is measured：
Impurity 3-Aminotrifluorotoluene content is less than 2ppm.
Embodiment 27
By 4- [(4- methyl-1s-piperazinyl) methyl]-N- [4- methyl -3- [4- (3- pyridyl groups) -2- pyrimidine radicals] amino]
Phenyl] benzamide crude product 90g（HPLC is measured, impure N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）- 2- pyrimidines
Amine 0.8%）It adds in into the four-neck flask of 3L, adds in tetrahydrofuran 1800ml, potassium carbonate 27g, succinic anhydride 13.5g, stir,
60-63 DEG C is heated to, flows back 2 hours, is cooled to 20-25 DEG C, adds in 1% sodium hydrate aqueous solution 900ml, is stirred 30 minutes,
Liquid separation, organic layer are washed to pH as 7-8, water 1800ml are added in into organic layer, is 3-4 with salt acid for adjusting pH, separates organic layer,
Water layer washed once with chloroform 900ml, liquid separation.PH to 10 is adjusted with ammonium hydroxide, white solid is precipitated in stirring, filters, dry,
Product 76.5g, yield 85% are obtained, HPLC-Ms is measured：Impurity N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）- 2- is phonetic
Pyridine amine content is less than 2ppm.
Embodiment 28
By 4- [(4- methyl-1s-piperazinyl) methyl]-N- [4- methyl -3- [4- (3- pyridyl groups) -2- pyrimidine radicals] amino]
Phenyl] benzamide crude product 90g（HPLC is measured, impure N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）- 2- pyrimidines
Amine 0.6%）It adds in into the four-neck flask of 3L, adds in tetrahydrofuran 1800ml, potassium carbonate 27g, maleic anhydride 13.5g, stir,
60-63 DEG C is heated to, flows back 2 hours, is cooled to 20-25 DEG C, adds in 1% sodium hydrate aqueous solution 900ml, is stirred 30 minutes,
Liquid separation, organic layer are washed to pH as 7-8, water 1800ml are added in into organic layer, is 3-4 with salt acid for adjusting pH, separates organic layer,
Water layer washed once with chloroform 900ml, liquid separation.PH to 10 is adjusted with ammonium hydroxide, white solid is precipitated in stirring, filters, dry,
Product 76.5g, yield 85% are obtained, HPLC-Ms is measured：Impurity N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）- 2- is phonetic
Pyridine amine content is less than 2ppm.
Embodiment 29
By 4- [(4- methyl-1s-piperazinyl) methyl]-N- [4- methyl -3- [4- (3- pyridyl groups) -2- pyrimidine radicals] amino]
Phenyl] benzamide crude product 90g（HPLC is measured, impure N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）- 2- pyrimidines
Amine 0.5%）It adds in into the four-neck flask of 3L, adds in tetrahydrofuran 1800ml, potassium carbonate 27g, phthalic anhydride 18.9g are stirred
It mixes, is heated to 60-63 DEG C, flow back 2 hours, be cooled to 20-25 DEG C, add in 1% sodium hydrate aqueous solution 900ml, stir 30 points
Clock, liquid separation, organic layer are washed to pH as 7-8, water 1800ml are added in into organic layer, is 3-4 with salt acid for adjusting pH, separates organic
Layer, water layer washed once with chloroform 900ml, liquid separation.PH to 10 is adjusted with ammonium hydroxide, white solid is precipitated in stirring, filters, and does
It is dry, product 76.5g, yield 85% are obtained, HPLC-Ms is measured：Impurity N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）-
2- pyrimidines amine content is less than 2ppm.
Embodiment 30
By 4- [(4- methyl-1s-piperazinyl) methyl]-N- [4- methyl -3- [4- (3- pyridyl groups) -2- pyrimidine radicals] amino]
Phenyl] benzamide crude product 90g（HPLC is measured, impure N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）- 2- pyrimidines
Amine 0.9%）It adds in into the four-neck flask of 3L, adds in tetrahydrofuran 1800ml, pyridine 16g, succinic anhydride 13.5g, stirring adds
Heat flows back 2 hours to 60-63 DEG C, is cooled to 20-25 DEG C, adds in 1% sodium hydrate aqueous solution 900ml, stirs 30 minutes, point
Liquid, organic layer are washed to pH as 7-8, water 1800ml are added in into organic layer, is 3-4 with salt acid for adjusting pH, separates organic layer, water
Layer washed once with chloroform 900ml, liquid separation.PH to 10 is adjusted with ammonium hydroxide, white solid is precipitated in stirring, filters, dry, obtains
Product 76.5g, yield 85%, HPLC-Ms are measured：Impurity N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）- 2- pyrimidines
Amine content is less than 2ppm..
Embodiment 31
By 4- [(4- methyl-1s-piperazinyl) methyl]-N- [4- methyl -3- [4- (3- pyridyl groups) -2- pyrimidine radicals] amino]
Phenyl] benzamide crude product 9kg（HPLC is measured, impure N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）- 2- pyrimidines
Amine 0.9%）It adds in into the reaction kettle of 500L, adds in tetrahydrofuran 180L, potassium carbonate 2.7kg, succinic anhydride 1.35kg, stir,
60-63 DEG C is heated to, flows back 2 hours, is cooled to 20-25 DEG C, adds in 1% sodium hydrate aqueous solution 90L, is stirred 30 minutes, point
Liquid, organic layer are washed to pH as 7-8, water 180L are added in into organic layer, is 3-4 with salt acid for adjusting pH, separates organic layer, water layer
It washed once with chloroform 90L, liquid separation.PH to 10 is adjusted with ammonium hydroxide, white solid is precipitated in stirring, filters, dry, obtains product
7.65kg, yield 85%, HPLC-Ms are measured：Impurity N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）- 2- pyrilamines
Content is less than 2ppm.
Claims (1)
1. a kind of sweep-out method of primary aromatic amine class impurity in drug or pharmaceutical intermediate, it is characterised in that：By 4- [(4- first
Base -1- piperazinyls) methyl]-N- [4- methyl -3- [4- (3- pyridyl groups) -2- pyrimidine radicals] amino] phenyl] benzamide crude product
90g, HPLC are measured, impure N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）- 2- pyrilamines 0.8% are added in 3L's
In four-neck flask, chloroform 1800ml, potassium carbonate 27g, succinic anhydride 13.5g are added in, stirring is heated to 60-63 DEG C, reflux
2 hours, 20-25 DEG C is cooled to, adds in 1% sodium hydrate aqueous solution 900ml, is stirred 30 minutes, liquid separation, organic layer is washed to
PH is 7-8, and water 1800ml is added in into organic layer, is 3-4 with salt acid for adjusting pH, separates organic layer, water layer chloroform
900ml washed once, liquid separation;PH to 10 is adjusted with ammonium hydroxide, white solid is precipitated in stirring, filters, dry, obtains product 76.5g, receives
Rate is that 85%, HPLC-Ms is measured：Genotoxicity impurity N-（2- methyl -5- aminocarbonyl phenyls）-4-（3- pyridyl groups）- 2- pyrilamines contain
Amount is less than 2ppm.
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