CN104119292A - Preparation method of dasatinib intermediate - Google Patents
Preparation method of dasatinib intermediate Download PDFInfo
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- CN104119292A CN104119292A CN201410354582.3A CN201410354582A CN104119292A CN 104119292 A CN104119292 A CN 104119292A CN 201410354582 A CN201410354582 A CN 201410354582A CN 104119292 A CN104119292 A CN 104119292A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
The invention discloses a preparation method of a dasatinib intermediate. The preparation method comprises the following steps: carrying out amido protection based on di-tert-butyl dicarbonate and alkaline hydrolysis on 2-amido-5-thiazole ethyl formate used as a raw material thereby obtaining 2-(N-tert-butyloxycarbonyl amido)-5-thiazole formate; reacting the 2-(N-tert-butyloxycarbonyl amido)-5-thiazole formate with oxalyl chloride to obtain 2-(N-tert-butyloxycarbonyl amido)-5-thiazole formyl chloride, reacting the 2-(N-tert-butyloxycarbonyl amido)-5-thiazole formyl chloride with 2-chlorine-6-methylaniline to obtain 5-(2-chlorine-6-methoxyphenyl carbamino)thiazole-2-group]-tert-butyl carbamate, unprotecting the 5-(2-chlorine-6-methoxyphenyl carbamino)thiazole-2-group]-tert-butyl carbamate in a tetrahydrofuran solution of concentrated hydrochloric acid to obtain 2-amido-N-(2-chlorine-6-methoxyphenyl)-5-thiazole formamide. Compared with a preparation method publicly reported at present, the preparation method disclosed by the invention has the advantages of being simple and convenient in operation, higher in yield, low in cost and beneficial to industrial production.
Description
Technical field
The invention belongs to medical technical field, particularly relate to the preparation method of a kind of Dasatinib intermediate 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-)-5-thiazole carboxamides.
Background technology
The chemical name of Dasatinib (dasatinib) is N-(the chloro-6-aminomethyl phenyl of 2-)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidyl] amino]-5-thiazole carboxamides, the oral multiple tyrosine kinase inhibitor of Shi You U.S. Bristol-Myers Squibb Co. research and development, the kinases suppressing comprises (McIntyre JA etal, 2006) such as Bcr-Abl, Src kinases family (comprising Fgr, Fyn, Hck, Lck, Lyn and Yes), c-Kit and PDGFR-β.Its monohydrate is in 2006 by preferentially the examining of U.S. FDA, and the clinical chronic myelogenous leukemia that is used for the treatment of, also can treat the acute lymphoblastic leukemia of Philadelphia chromatin-positive.This product all has restraining effect to the kinase whose various mutations body of Bcr-Abl, and inhibition strength improves a lot compared with imatinib (imatinib), and does not find resistance (Das J etal, 2003).
J reaches this synthetic method that equals to disclose in Chinese invention patent application that on May 8th, 2002 is CN1348370A at publication number a kind of Dasatinib.It is starting raw material that the method be take 2-(N-t-butoxycarbonyl amino)-5-thiazole ethyl formate, by the synthetic Dasatinib of following route:
The advantage of the method is that operation is simple, be easy to produce, but that shortcoming is total recovery is very low, and be only 14.9%, and consumption of organic solvent is large, energy consumption is high.
Safe and comfortable grade improved this technique; it take thiazolamine-5-methyl-formiate is starting raw material; amino is protected and carried out methyl esters hydrolysis; take PhosphorodichloridicAcid Acid Phenyl Ester after condensing agent and the condensation of the chloro-6-monomethylaniline of 2-; the intermediate obtaining makes Dasatinib with the chloro-2-methylpyrimidine of 4,6-bis-, N-hydroxyethyl piperazine generation substitution reaction successively.The method has improved yield, but has increased condensing agent, so not only can not reduce unit cost, but also has increased environmental pollution.
Summary of the invention
In order to address the above problem, the object of the present invention is to provide that a kind of yield is high, cost is low, simple to operate, security good, environmentally friendly, and the preparation method of the Dasatinib intermediate 2-amino-N-of applicable suitability for industrialized production (the chloro-6-aminomethyl phenyl of 2-)-5-thiazole carboxamides.
(1) using DMAP as catalyzer, use tert-Butyl dicarbonate to carry out amido protecting 2-amino-5-thiazole ethyl formate, generate 2-(N-t-butoxycarbonyl amino)-5-thiazole ethyl formate;
(2) 2-(N-t-butoxycarbonyl amino)-5-thiazole ethyl formate is hydrolyzed in alkali lye, then acid out obtains 2-(N-t-butoxycarbonyl amino)-5-thiazol formic-acid;
(3) oxalyl chloride is joined in 2-(N-t-butoxycarbonyl amino)-5-thiazol formic-acid, reaction generates 2-(N-t-butoxycarbonyl amino)-5-thiazole formyl chloride;
(4) use mineral alkali as acid binding agent, 2-(N-t-butoxycarbonyl amino)-5-thiazole formyl chloride reacted with the chloro-6-monomethylaniline of 2-and generate 5-(the chloro-6-aminomethyl phenyl of 2-carbamyl) thiazol-2-yl]-ammonia t-butyl formate;
(5) by 5-(the chloro-6-aminomethyl phenyl of 2-carbamyl) thiazol-2-yl]-ammonia t-butyl formate utilizes concentrated hydrochloric acid deprotection to obtain 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-)-5-thiazole carboxamides in organic solvent.
Synthetic route is as follows:
In described step (1), the mol ratio of tert-Butyl dicarbonate and 2-amino-5-thiazole ethyl formate is 1.0-1.5:1, preferably 1.05-1.2:1.
Alkali in described step (2) is selected from least one in potassium hydroxide, sodium hydroxide, sodium carbonate and salt of wormwood; The mol ratio of alkali and 2-(N-t-butoxycarbonyl amino)-5-thiazole ethyl formate is 2-6:1, preferably 3-4:1; During acid out, the pH value of system is 2-3.
The mol ratio of described step (3) medium-height grass acyl chlorides and 2-(N-t-butoxycarbonyl amino)-5-thiazol formic-acid is 0.95-1.2:1, preferably 1.05-1.1:1.
Mineral alkali in described step (4) is selected from least one in potassium hydroxide, sodium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate and saleratus; The mol ratio of alkali and 2-(N-t-butoxycarbonyl amino)-5-thiazol formic-acid is 2-6:1, preferably 2-3:1; The mol ratio of the chloro-6-monomethylaniline of 2-and 2-(N-t-butoxycarbonyl amino)-5-thiazol formic-acid is 1.0-1.2:1, preferably 1.05-1.1:1.
Concentrated hydrochloric acid and 5-(the chloro-6-aminomethyl phenyl of 2-carbamyl) thiazol-2-yl in described step (5)] weight ratio of-ammonia t-butyl formate is 0.5-2:1, preferred 1.0-1.2:1; Organic solvent is selected from least one in tetrahydrofuran (THF), methyl alcohol, ethanol, Virahol and acetonitrile; While carrying out deprotection reaction, the temperature of reaction solution is 40-80 ℃, preferably 50-60 ℃.
The preparation method of Dasatinib intermediate provided by the invention is that to take 2-amino-5-thiazole ethyl formate be raw material, uses tert-Butyl dicarbonate to carry out amido protecting, after alkaline hydrolysis, obtains 2-(N-t-butoxycarbonyl amino)-5-thiazol formic-acid, 2-(N-t-butoxycarbonyl amino)-5-thiazol formic-acid and oxalyl chloride effect are obtained to 2-(N-t-butoxycarbonyl amino)-5-thiazole formyl chloride, 2-(N-t-butoxycarbonyl amino)-5-thiazole formyl chloride and the chloro-6-monomethylaniline of 2-obtain 5-(the chloro-6-aminomethyl phenyl of 2-carbamyl) thiazol-2-yl]-ammonia t-butyl formate, 5-(the chloro-6-aminomethyl phenyl of 2-carbamyl) thiazol-2-yl]-ammonia t-butyl formate deprotection in the tetrahydrofuran solution of concentrated hydrochloric acid obtains 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-)-5-thiazole carboxamides, this preparation method is compared to the preparation method who openly reports at present, easy and simple to handle, yield is higher, cost is low, and be beneficial to suitability for industrialized production.
Embodiment
Below in conjunction with specific embodiment, the preparation method of Dasatinib intermediate 2-amino-N-provided by the invention (the chloro-6-aminomethyl phenyl of 2-)-5-thiazole carboxamides is elaborated.
Embodiment 1:
In a 2L four-hole bottle with mechanical stirrer, thermometer, add 300g (1.74mol, 1eq) 2-amino-5-thiazole ethyl formate and as the 1.5L methylene dichloride of solvent, stir and form suspension liquid, then add 13.4g (0.11mol, 0.065eq) DMAP, be cooled between 0-10 ℃, drip 414g (1.9mol, 1.1eq) (BOC)
2o, in dropping process, interior temperature surpasses 25 ℃, and after dropwising, stirring at room 12h, finishes reaction.Under stirring, there are a large amount of white solids to produce, suction filtration, dry 2-(N-the t-butoxycarbonyl amino)-5-thiazole ethyl formate that obtains 425g, yield 90%, purity 99.5% (HPLC).
In a dry four-hole boiling flask of the 5L that mechanical stirrer, thermometer be housed, add 188g (4.7mol, 3eq) sodium hydroxide and 3L water, stir and make its dissolving.Add 425g (1.56mol, 1.0eq) 2-(N-t-butoxycarbonyl amino)-5-thiazole ethyl formate, stir and form suspension liquid, temperature control is at 50-60 ℃.Stir 4h, solid all dissolves, and finishes reaction.Slowly drip 380mL36% hydrochloric acid soln, in whipping process, have a large amount of white solids and produce, regulate pH=2-3, suction filtration obtains white solid, dry, weighs, obtain 2-(N-t-butoxycarbonyl amino)-5-thiazol formic-acid of 362g, yield 95%, purity 99.5% (HPLC).
In a dry four-hole bottle of the 1L that mechanical stirrer, thermometer, constant pressure funnel be housed, add 30g (0.123mol, 1eq) 2-(N-t-butoxycarbonyl amino)-5-thiazol formic-acid, 300mL is as anhydrous DCM and the 1mLDMF of solvent, be cooled between 0-10 ℃, drip 17.1g (0.135mol, 1.1eq) oxalyl chloride, in in dropping process, temperature is not over 20 ℃, after dropwising, stirring at room 2h, finishes reaction.The dichloromethane solution of the 2-making in reaction flask (N-t-butoxycarbonyl amino)-5-thiazole formyl chloride is transferred to (abbreviation solution of acid chloride) in 500mL constant pressure funnel, then in this reaction flask, add 300mL acetonitrile, 19.1g (0.135mol, 1.1eq) the chloro-6-monomethylaniline of 2-and 26g (0.246mol, 2eq) sodium carbonate, control 0-10 ℃ of liquid temperatures and stir 30min, utilize above-mentioned constant pressure funnel to drip the solution of acid chloride in it, dropping temperature is controlled at 0-10 ℃, within about 30 minutes, dropwise, at 5-10 ℃, stir 2-3 hour, a large amount of white solids are separated out, rise to gradually 20-30 ℃ and stir 6h.In reaction flask, add 800mL water, stir 2h, decompress filter; filter cake, with being transferred in 1L four-hole bottle after 50mL washing, adds tetrahydrofuran (THF), is heated to reflux; stir 2h; ice bath is cooling, decompress filter, 50mL0-10 ℃ of tetrahydrofuran (THF) drip washing for filter cake; 50 ℃ of forced air dryings; obtain white solid 5-(the chloro-6-aminomethyl phenyl of 2-carbamyl) thiazol-2-yl]-ammonia t-butyl formate 31g, yield 70%, product purity: 97.5% (HPLC).
In a 250mL four-hole bottle that mechanical stirrer, thermometer, constant pressure funnel be housed, add 20g (0.054mol; 1eq) 5-(the chloro-6-aminomethyl phenyl of 2-carbamyl) thiazol-2-yl]-ammonia t-butyl formate; 100mL is as THF and the 20mL36% hydrochloric acid of solvent; after backflow 3h; finish heating; cooling reaction solution, to room temperature, drips saturated solution of sodium carbonate, regulates pH=8-9.Decompression steams THF in system, separates out a large amount of white solids, decompress filter, filter cake 50mL water wash, 50 ℃ of forced air dryings, obtain white solid 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-)-5-thiazole carboxamides 14g, yield 96%, product purity: 99.5% (HPLC).
Embodiment 2:
In a 2L four-hole bottle with mechanical stirrer, thermometer, add 300g (1.74mol, 1eq) 2-amino-5-thiazole ethyl formate and as the 1.5L methylene dichloride of solvent, stir and form suspension liquid, then add 13.4g (0.11mol, 0.065eq) DMAP, be cooled between 0 ℃-10 ℃, drip 379g (1.74mol, 1.0eq) (BOC)
2o, in dropping process, interior temperature surpasses 25 ℃, and after dropwising, stirring at room 12h, finishes reaction.Under stirring, there are a large amount of white solids to produce, suction filtration, dry 2-(N-the t-butoxycarbonyl amino)-5-thiazole ethyl formate that obtains 411g, yield 87%, purity 99.5% (HPLC).
In a dry four-hole boiling flask of the 5L that mechanical stirrer, thermometer be housed, add 437g (7.8mol, 5eq) potassium hydroxide and 3L water, stir and make its dissolving.Add 425g (1.56mol, 1.0eq) 2-(N-t-butoxycarbonyl amino)-5-thiazole ethyl formate, stir and form suspension liquid, temperature control is at 50-60 ℃.Stir 4h, solid all dissolves, and finishes reaction.Slowly drip 380mL36% hydrochloric acid soln, in whipping process, have a large amount of white solids and produce, regulate pH=2-3, suction filtration obtains white solid, dry, weighs, obtain 2-(N-t-butoxycarbonyl amino)-5-thiazol formic-acid of 350g, yield 92%, purity 99.5% (HPLC).
In a dry four-hole bottle of the 1L that mechanical stirrer, thermometer, constant pressure funnel be housed, add 30g (0.123mol, 1eq) 2-(N-t-butoxycarbonyl amino)-5-thiazol formic-acid, 300mL is as anhydrous DCM and the 1mLDMF of solvent, be cooled between 0-10 ℃, drip 14.8g (0.117mol, 0.95eq) oxalyl chloride, in in dropping process, temperature is not over 20 ℃, after dropwising, stirring at room 2h, finishes reaction.The dichloromethane solution of the 2-making in reaction flask (N-t-butoxycarbonyl amino)-5-thiazole formyl chloride is transferred in 500mL constant pressure funnel, in reaction flask, add 300mL acetonitrile, 17.4g (0.123mol, 1.0eq) the chloro-6-monomethylaniline of 2-and 41g (0.492mol, 4eq) sodium bicarbonate, control 0-10 ℃ of liquid temperatures and stir 30min, utilize above-mentioned constant pressure funnel to drip the solution of acid chloride in it, dropping temperature is controlled at 0-10 ℃, within about 30 minutes, dropwise, at 5-10 ℃, stir 2-3 hour, a large amount of white solids are separated out, rise to gradually 20-30 ℃ and stir 6h.In reaction flask, add 800mL water, stir 2h, decompress filter; filter cake, with being transferred in 1L four-hole bottle after 50mL washing, adds tetrahydrofuran (THF), is heated to reflux; stir 2h; ice bath is cooling, decompress filter, 50mL0-10 ℃ of tetrahydrofuran (THF) drip washing for filter cake; 50 ℃ of forced air dryings; obtain white solid 5-(the chloro-6-aminomethyl phenyl of 2-carbamyl) thiazol-2-yl]-ammonia t-butyl formate 30g, yield 68%, product purity: 97.5% (HPLC).
In a 250mL four-hole bottle that mechanical stirrer, thermometer, constant pressure funnel be housed, add 20g (0.054mol; 1eq) 5-(the chloro-6-aminomethyl phenyl of 2-carbamyl) thiazol-2-yl]-ammonia t-butyl formate; 100mL is as methyl alcohol and the 8mL36% hydrochloric acid of solvent; after backflow 3h; finish heating; cooling reaction solution, to room temperature, drips saturated solution of sodium carbonate, regulates pH=8-9.Decompression steams methyl alcohol in system, separates out a large amount of white solids, decompress filter, filter cake 50mL water wash, 50 ℃ of forced air dryings, obtain white solid 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-)-5-thiazole carboxamides 14g, yield 96%, product purity: 99.5% (HPLC).
Embodiment 3:
In a 2L four-hole bottle with mechanical stirrer, thermometer, add 300g (1.74mol, 1eq) 2-amino-5-thiazole ethyl formate and as the 1.5L methylene dichloride of solvent, stir and form suspension liquid, then add 13.4g (0.11mol, 0.065eq) DMAP, be cooled between 0-10 ℃, drip 565g (2.6mol, 1.5eq) (BOC)
2o, in dropping process, interior temperature surpasses 25 ℃, and after dropwising, stirring at room 12h, finishes reaction.Under stirring, there are a large amount of white solids to produce, suction filtration, dry 2-(N-the t-butoxycarbonyl amino)-5-thiazole ethyl formate that obtains 401g, yield 85%, purity 99.5% (HPLC).
In a dry four-hole boiling flask of the 5L that mechanical stirrer, thermometer be housed, add 996g (9.4mol, 6eq) sodium carbonate and 3L water, stirring and dissolving.Add 425g (1.56mol, 1.0eq) 2-(N-t-butoxycarbonyl amino)-5-thiazole ethyl formate, stir and form suspension liquid, temperature control is at 50-60 ℃.Stir 4h, solid all dissolves, and finishes reaction.Slowly drip 380mL36% hydrochloric acid soln, in whipping process, have a large amount of white solids and produce, regulate pH=2-3, suction filtration obtains white solid, dry, weighs, obtain 2-(N-t-butoxycarbonyl amino)-5-thiazol formic-acid of 351g, yield 92%, purity 99.5% (HPLC).
In a dry four-hole bottle of the 1L that mechanical stirrer, thermometer, constant pressure funnel be housed, add 30g (0.123mol, 1eq) 2-(N-t-butoxycarbonyl amino)-5-thiazol formic-acid, 300mL is as anhydrous DCM and the 1mLDMF of solvent, be cooled between 0 ℃-10 ℃, drip 18.7g (0.147mol, 1.2eq) oxalyl chloride, in in dropping process, temperature is not over 20 ℃, after dropwising, stirring at room 2h, finishes reaction.The dichloromethane solution of making 2-(N-t-butoxycarbonyl amino)-5-thiazole formyl chloride in reaction flask is transferred in 500mL constant pressure funnel, in reaction flask, add 300mL acetonitrile, 20.9g (0.148mol, 1.2eq) the chloro-6-monomethylaniline of 2-and 96g (0.738mol, 6eq) salt of wormwood, control 0-10 ℃ of liquid temperatures and stir 30min, utilize above-mentioned constant pressure funnel to drip the solution of acid chloride in it, dropping temperature is controlled at 0-10 ℃, within about 30 minutes, dropwise, at 5-10 ℃, stir 2-3 hour, a large amount of white solids are separated out, and rise to gradually 20-30 ℃ and stir 6h.In reaction flask, add water, stir 2h, decompress filter; filter cake, with being transferred in 1L four-hole bottle after 50mL washing, adds tetrahydrofuran (THF), is heated to reflux; stir 2h; ice bath is cooling, decompress filter, 50mL0-10 ℃ of tetrahydrofuran (THF) drip washing for filter cake; 50 ℃ of forced air dryings; obtain white solid 5-(the chloro-6-aminomethyl phenyl of 2-carbamyl) thiazol-2-yl]-ammonia t-butyl formate 32g, yield 72%, product purity: 97.8% (HPLC).
In a 250mL four-hole bottle that mechanical stirrer, thermometer, constant pressure funnel be housed, add 20g (0.054mol; 1eq) 5-(the chloro-6-aminomethyl phenyl of 2-carbamyl) thiazol-2-yl]-ammonia t-butyl formate; 100mL is as ethanol and the 33mL36% hydrochloric acid of solvent; after backflow 3h; finish heating; cooling reaction solution, to room temperature, drips saturated solution of sodium carbonate, regulates pH=8-9.Decompression steams ethanol in system, separates out a large amount of white solids, decompress filter, filter cake 50mL water wash, 50 ℃ of forced air dryings, obtain white solid 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-)-5-thiazole carboxamides 13.7g, yield 94%, product purity: 99.5% (HPLC).
Claims (6)
1. a preparation method for Dasatinib intermediate, is characterized in that, described preparation method comprises the following step carrying out in order:
(1) using DMAP as catalyzer, use tert-Butyl dicarbonate to carry out amido protecting 2-amino-5-thiazole ethyl formate, generate 2-(N-t-butoxycarbonyl amino)-5-thiazole ethyl formate;
(2) 2-(N-t-butoxycarbonyl amino)-5-thiazole ethyl formate is hydrolyzed in alkali lye, then acid out obtains 2-(N-t-butoxycarbonyl amino)-5-thiazol formic-acid;
(3) oxalyl chloride is joined in 2-(N-t-butoxycarbonyl amino)-5-thiazol formic-acid, reaction generates 2-(N-t-butoxycarbonyl amino)-5-thiazole formyl chloride;
(4) use mineral alkali as acid binding agent, 2-(N-t-butoxycarbonyl amino)-5-thiazole formyl chloride reacted with the chloro-6-monomethylaniline of 2-and generate 5-(the chloro-6-aminomethyl phenyl of 2-carbamyl) thiazol-2-yl]-ammonia t-butyl formate;
(5) by 5-(the chloro-6-aminomethyl phenyl of 2-carbamyl) thiazol-2-yl]-ammonia t-butyl formate utilizes concentrated hydrochloric acid deprotection to obtain 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-)-5-thiazole carboxamides in organic solvent.
2. preparation method according to claim 1, is characterized in that: in described step (1), the mol ratio of tert-Butyl dicarbonate and 2-amino-5-thiazole ethyl formate is 1.0-1.5:1, preferably 1.05-1.2:1.
3. preparation method according to claim 1, is characterized in that: the alkali in described step (2) is selected from least one in potassium hydroxide, sodium hydroxide, sodium carbonate and salt of wormwood; The mol ratio of alkali and 2-(N-t-butoxycarbonyl amino)-5-thiazole ethyl formate is 2-6:1, preferably 3-4:1; During acid out, the pH value of system is 2-3.
4. preparation method according to claim 1, is characterized in that: the mol ratio of described step (3) medium-height grass acyl chlorides and 2-(N-t-butoxycarbonyl amino)-5-thiazol formic-acid is 0.95-1.2:1, preferably 1.05-1.1:1.
5. preparation method according to claim 1, is characterized in that: the mineral alkali in described step (4) is selected from least one in potassium hydroxide, sodium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate and saleratus; The mol ratio of alkali and 2-(N-t-butoxycarbonyl amino)-5-thiazol formic-acid is 2-6:1, preferably 2-3:1; The chloro-6-monomethylaniline of 2-is 1.0-1.2:1 with the mol ratio of (2-(N-t-butoxycarbonyl amino)-5-thiazole formyl chloride), preferably 1.05-1.1:1.
6. preparation method according to claim 1, is characterized in that: concentrated hydrochloric acid and 5-(the chloro-6-aminomethyl phenyl of 2-carbamyl) thiazol-2-yl in described step (5)] weight ratio of-ammonia t-butyl formate is 0.5-2:1, preferred 0.8-1.2:1; Organic solvent is selected from least one in tetrahydrofuran (THF), methyl alcohol, ethanol, Virahol and acetonitrile; While carrying out deprotection reaction, the temperature of reaction solution is 40-80 ℃, preferably 50-60 ℃.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1348370A (en) * | 1999-04-15 | 2002-05-08 | 布里斯托尔-迈尔斯斯奎布公司 | Cyclic protein tyrosine kinase inhibitors |
| CN1764454A (en) * | 2003-03-24 | 2006-04-26 | 布里斯托尔-迈尔斯斯奎布公司 | Cyclic protein tyrosine kinase inhibitors |
| WO2007019210A1 (en) * | 2005-08-05 | 2007-02-15 | Bristol-Myers Squibb Company | Preparation of 2-amino-thiazole-5-carboxylic-acid derivatives |
| US20070219370A1 (en) * | 2006-03-15 | 2007-09-20 | Bristol-Myers Squibb Company | Process for preparing n-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino] -5-thiazolecarboxamide and related metabolites thereof |
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2014
- 2014-07-23 CN CN201410354582.3A patent/CN104119292A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1348370A (en) * | 1999-04-15 | 2002-05-08 | 布里斯托尔-迈尔斯斯奎布公司 | Cyclic protein tyrosine kinase inhibitors |
| CN1764454A (en) * | 2003-03-24 | 2006-04-26 | 布里斯托尔-迈尔斯斯奎布公司 | Cyclic protein tyrosine kinase inhibitors |
| WO2007019210A1 (en) * | 2005-08-05 | 2007-02-15 | Bristol-Myers Squibb Company | Preparation of 2-amino-thiazole-5-carboxylic-acid derivatives |
| US20070219370A1 (en) * | 2006-03-15 | 2007-09-20 | Bristol-Myers Squibb Company | Process for preparing n-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino] -5-thiazolecarboxamide and related metabolites thereof |
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| 张少宁等: "达沙替尼的合成", 《中国医药工业杂志》, vol. 41, no. 3, 31 March 2010 (2010-03-31) * |
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Application publication date: 20141029 |