CN103524449B - Method for synthesizing 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide - Google Patents
Method for synthesizing 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide Download PDFInfo
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- CN103524449B CN103524449B CN201310504458.6A CN201310504458A CN103524449B CN 103524449 B CN103524449 B CN 103524449B CN 201310504458 A CN201310504458 A CN 201310504458A CN 103524449 B CN103524449 B CN 103524449B
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- 0 Cc1ccccc1* Chemical compound Cc1ccccc1* 0.000 description 6
- OCKYMBMCPOAFLL-UHFFFAOYSA-N CCc1c(C)cccc1O Chemical compound CCc1c(C)cccc1O OCKYMBMCPOAFLL-UHFFFAOYSA-N 0.000 description 1
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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
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- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention discloses a method for synthesizing 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide. The method comprises the following steps: performing amino protection on 2-aminothiazole-5-ethyl formate as a raw material by adopting CBZ (carbamazepine) to obtain a compound II, and performing decarboxylation protection on the compound II to obtain a compound III; adding the compound III into methylsufonyl chloride activated carboxyl, then adding 2-chloro-6-methylaniline for amidation so as to obtain a compound IV, and removing CBZ protection of the compound IV by using aluminum trichloride-anisole to obtain a product of the 2-amino-N-(2-chloro-6-methylphenyl) thiazole-5-carboxamide. The method has the characteristics of mild condition, simplification after treatment, environment friendliness, suitability for industrial production and the like.
Description
Technical field
The present invention relates to the chloro-6-aminomethyl phenyl of a kind of Dasatinib intermediate 2-amino-N-(2-) synthetic method of thiazole-5-methane amide, belong to medical art.
Background technology
Dasatinib (Dasatinib), trade(brand)name SPRYCEL
tM, be a kind of oral tyrosine kinase inhibitor researched and developed by BMS company, for Adult chronic's myelogenous leukemia (CML), also can be used for the acute lymphoblastic leukemia for the treatment of Philadelphia Chromosome Positive.The chloro-6-aminomethyl phenyl of 2-amino-N-(2-as the formula (1)) thiazole-5-methane amide be synthesis Dasatinib key intermediate, the technique accuracy of its synthesis will directly have influence on the height of Dasatinib purity, and has direct impact to the height of Dasatinib raw materials cost.
2-amino-N-(2-chloro-6-the aminomethyl phenyl announced at present) synthetic method of thiazole-5-methane amide is a lot.To print in the Dasatinib synthesis scheme of vol.25, No.6 Jun.6.2011 summary about the synthetic route of this intermediate as shown in route 1-2 when chemical industry:
It is low that said synthesis route deposits yield, and cost is high, and pollute large, raw material is rare, the problems such as unfavorable production.
Summary of the invention
The technical problem to be solved in the present invention overcomes prior art to prepare 2-amino-N-(2-chloro-6-aminomethyl phenyl) yield that exists in thiazole-5-amide Method is low, cost is high, pollute large, the problems such as the rare unfavorable production of raw material, a kind of succinct preparation method is efficiently provided.
Be achieved through the following technical solutions for realizing the object of the invention: the chloro-6-aminomethyl phenyl of a kind of 2-amino-N-(2-) synthetic method of thiazole-5-methane amide, it is characterized in that, obtain 2-CBZ-aminothiazole-5-ethyl formate (compound ii) with thiazolamine-5-ethyl formate for raw material adopts chloroformic acid benzyl ester (CBZ) to carry out amido protecting, the protection of compound ii decarboxylation obtains 2-CBZ-aminothiazole-5-formic acid (compound III); Compound III adds Methanesulfonyl chloride activated carboxyl; then add the amidation of 2-chloro-6-monomethylaniline and obtain the chloro-6-aminomethyl phenyl of 2-CBZ-amino-N-(2-) thiazole-5-methane amide (compounds Ⅳ), compounds Ⅳ removes CBZ protection with aluminum chloride-methyl-phenoxide and obtains the chloro-6-aminomethyl phenyl of product 2-amino-N-(2-) thiazole-5-methane amide.As shown in synthetic route 3.
Specifically comprise the following steps:
(1) thiazolamine-5-ethyl formate is suspended in non-protonic solvent, adds acid binding agent and stir, and be cooled to 10-15 DEG C simultaneously; Then drip chloroformic acid benzyl ester, rise to 10-50 DEG C of reaction 2-10 hour after dropwising, obtain compound ii through aftertreatment;
Described aftertreatment is preferably: reaction terminates rear solvent evaporated, and after then adding purified water and methyl alcohol/Glacial acetic acid making beating respectively, be down to 0-5 DEG C of stirred crystallization, suction filtration, drying obtains compound ii;
The mol ratio of described thiazolamine-5-ethyl formate, chloroformic acid benzyl ester and acid binding agent is 1:1.2-1.8:1.2-2.5, is preferably 1:1.5:2.0; The add-on of described making beating Glacial acetic acid is the 8-12% of methanol quality, the preferred room temperature of temperature of reaction.
(2) sodium hydroxide is dropped into 20%-40%(volume ratio, lower same; Preferred concentration is 30%) aqueous ethanolic solution in, control temperature less than 30 DEG C, stirring and dissolving, to clarification, and drops into compound ii at this temperature; 25-35 DEG C of insulation reaction 5-12 hour; Be cooled to 0-5 DEG C, drip concentrated hydrochloric acid and regulate PH to 2.5-3.5, obtain compound III through suction filtration, drying.
The add-on of described aqueous ethanolic solution is 10-20 times of sodium hydroxide quality, is preferably 15 times; Described compound ii is 1:2-5 with the molar weight ratio of sodium hydroxide.
(3) compound III is dropped in solvent pyridine, be cooled to 0-25 DEG C, drip Methanesulfonyl chloride, drip off this thermotonus 3-8 hour of rear maintenance, then add the chloro-6-monomethylaniline of 2-, be slowly warming up to 60-120 DEG C, insulation reaction 5-10 hour at this temperature, obtains compounds Ⅳ through aftertreatment;
The mol ratio of the chloro-6-monomethylaniline of described compound III, Methanesulfonyl chloride and 2-is 1:1.0-1.2:1.0-1.2; Pyridine solvent consumption is 3-10 times of compound III quality, is preferably 5 times.The preferred 3-5 DEG C of mixed anhydride synthesis temperature, amidation temperature is preferably 80 DEG C;
Described aftertreatment is preferably: reaction terminates rear solvent evaporated, then adds 40-60%(preferably 50%) methanol-water making beating, suction filtration, drying obtain compounds Ⅳ.Methanol aqueous solution consumption is 3-10 times of compound III quality, is preferably 5 times.
(4) be dissolved in methyl-phenoxide by aluminum chloride, add compounds Ⅳ under room temperature, be warming up to 25-60 DEG C, insulation reaction is spent the night, and obtains product through aftertreatment.
Described aftertreatment is preferably: after reaction terminates, poured into by reaction solution in frozen water, then through extraction into ethyl acetate, is cooled to 0 DEG C of insulated and stirred crystallization 0.5-2 hour, suction filtration after concentrated, dries, obtain finished product.
The mol ratio of described compounds Ⅳ and aluminum chloride is 1:2-5, preferred 1:3, and the consumption of described methyl-phenoxide is 3-8 times of compounds Ⅳ quality, is preferably 5 times.Temperature of reaction preferably 35 DEG C.
In the reaction of described step (1) amido protecting; the chloroformic acid benzyl ester lower by price replaces price tert-Butyl dicarbonate costly, and reaction solvent can be methylene dichloride, ethylene dichloride; acetonitrile; tetrahydrofuran (THF), the non-protonic solvents such as dioxane, acid binding agent used can be organic bases pyridine; triethylamine etc.; mineral alkali sodium bicarbonate, saleratus etc., prioritizing selection sodium bicarbonate of the present invention.
Described step (3) adopts mixed anhydride method activated carboxyl, select Methanesulfonyl chloride, then carry out condensation with amino and prepare the chloro-6-aminomethyl phenyl of 2-CBZ-amino-N-(2-) thiazole-5-methane amide, avoid 5 thiazol formic-acid chlorides difficult, or adopt condensing agent or dewatering agent generation impurity to be difficult to the problem removed.The present invention adopt pyridine to be solvent methylsulfonyl chloride by activated carboxylic again amidation one pot complete, substantially increase reaction yield, solvent for use energy recovery, cost-saving, reduce and pollute.
Described step (4) is with the chloro-6-aminomethyl phenyl of 2-CBZ-amino-N-(2-) thiazole-5-methane amide is the deprotection that raw material carries out amido protecting; amino logical method is protected generally to remove with hydrogenating reduction for CBZ; present method considers material dissolution sex chromosome mosaicism; aluminum chloride methyl-phenoxide is adopted to carry out removing CBZ; raw material is easy to get, and low price.
The invention has the beneficial effects as follows: avoid 5 thiazol formic-acid chlorides difficult, or adopt condensing agent or dewatering agent generation impurity to be difficult to the problem removed.Difficult point during this product is synthesized is simplified, and is conducive to the enforcement of suitability for industrialized production.
Embodiment
Embodiment 1
By 172g(1mol) thiazolamine-5-ethyl formate is suspended in 1000g methylene dichloride, add sodium bicarbonate 168g(2mol), stir, and be cooled to 10-15 DEG C simultaneously, control rate of addition in 3 hours by 255g(1.5mol) chloroformic acid benzyl ester instillation mixed solution in, dropping process has bubble to emerge, and after dropwising, rises to room temperature reaction 5 hours.40 DEG C of water-bath reclaim under reduced pressure methylene dichloride.Add 2000g purified water after evaporate to dryness to pull an oar 30 minutes, suction filtration is washed, and dropped into by filter cake in 1000g methyl alcohol, add 100g glacial acetic acid, room temperature is pulled an oar 30 minutes, and be down to 0-5 DEG C and stir 1 hour, suction filtration obtains off-white color solid.50 DEG C of forced air dryings, obtain product compound II 275g, yield 90%.
Embodiment 2
100g sodium hydroxide is dropped into 30% aqueous ethanolic solution 1500g, control temperature less than 30 DEG C.Stirring and dissolving to clarification, and drops into the product 308g(1mol of embodiment 1 at this temperature).30 DEG C of insulation reaction 8 hours.Be cooled to 0-5 DEG C, drip 2N concentrated hydrochloric acid and regulate PH to 3, a large amount of precipitation off-white color solid, 0-5 DEG C is stirred suction filtration after 1 hour, and 1000g purified water washing leaching cake, drains 80 DEG C of forced air dryings and obtain compound III dry product 260g, yield 93%.
Embodiment 3
Product 280g(1mol by embodiment 2) drop into pyridine 1000g, be cooled to 0-5 DEG C, drip Methanesulfonyl chloride 125g(1.1mol) dripped off in 1 hour, drip off this thermotonus of rear maintenance 5 hours, add 2-chloro-6-monomethylaniline 156g (1.1mol) again and be slowly warming up to 80 DEG C, insulation reaction 8 hours at this temperature, reclaim under reduced pressure pyridine, steams near dry.Add 50% methanol-water 2000g room temperature to pull an oar 3 hours, suction filtration, 80 DEG C of forced air dryings obtain compounds Ⅳ dry product 350g, yield 85%.
Embodiment 4
Product 280g(1mol by embodiment 2) drop into pyridine 1400g, be cooled to 0-5 DEG C, drip Methanesulfonyl chloride 125g(1.1mol) dripped off in 1 hour, drip off this temperature 3-5 of rear maintenance DEG C of reaction 8 hours, add 2-chloro-6-monomethylaniline 156g (1.1mol) again and be slowly warming up to 100 DEG C, insulation reaction 8 hours at this temperature, reclaim under reduced pressure pyridine, steams near dry.Add 50% methanol-water 2000g room temperature to pull an oar 3 hours, suction filtration, 80 DEG C of forced air dryings obtain compounds Ⅳ dry product 340g, yield 83%.
Embodiment 5
By 332g(2.5mol) aluminum chloride is dissolved in 1500g methyl-phenoxide, adds the product 403g(1mol of embodiment 3 under room temperature), be warming up to 35 DEG C, insulation reaction is spent the night, and after reaction terminates, is poured into by reaction solution in 5000g frozen water, add ethyl acetate 2500g to extract once, organic phase washed with water 500g washes twice, and separates organic layer, decompression steams ethyl acetate, remaining liq is cooled to 0 DEG C of insulated and stirred 1 hour, suction filtration, 80 DEG C of decompression dryings, obtain dry product 200g, yield 92%.
Embodiment 6
398g(3mol is added by under room temperature) aluminum chloride is dissolved in 1500g methyl-phenoxide, the product 403g(1mol of embodiment 3), add wherein in batches, be warming up to 35 DEG C, insulation reaction is spent the night, after reaction terminates, poured into by reaction solution in 5000g frozen water, add ethyl acetate 2500g and extract once, organic phase washed with water 500g washes twice, separate organic layer, decompression steams ethyl acetate, and remaining liq is cooled to 0 DEG C of insulated and stirred 1 hour, suction filtration, 80 DEG C of decompression dryings, obtain dry product 210g, yield 93%.
Claims (8)
1. the chloro-6-aminomethyl phenyl of 2-amino-N-(2-) synthetic method of thiazole-5-methane amide, it is characterized in that, obtain 2-CBZ-aminothiazole-5-ethyl formate with thiazolamine-5-ethyl formate for raw material adopts chloroformic acid benzyl ester to carry out amido protecting, the protection of 2-CBZ-aminothiazole-5-ethyl formate decarboxylation obtains 2-CBZ-aminothiazole-5-formic acid; 2-CBZ-aminothiazole-5-formic acid adds Methanesulfonyl chloride activated carboxyl, then add the amidation of 2-chloro-6-monomethylaniline and obtain the chloro-6-aminomethyl phenyl of 2-CBZ-amino-N-(2-) thiazole-5-methane amide, 2-CBZ-amino-N-(2-chloro-6-aminomethyl phenyl) thiazole-5-methane amide with aluminum chloride-methyl-phenoxide remove CBZ protection obtain the chloro-6-aminomethyl phenyl of product 2-amino-N-(2-) thiazole-5-methane amide; Specifically comprise the following steps:
(1) thiazolamine-5-ethyl formate is suspended in non-protonic solvent, adds acid binding agent and stir, and be cooled to 10-15 DEG C simultaneously; Then drip chloroformic acid benzyl ester, rise to 10-50 DEG C of reaction 2-10 hour after dropwising, obtain 2-CBZ-aminothiazole-5-ethyl formate through aftertreatment; Described non-protonic solvent is methylene dichloride; Acid binding agent used is sodium bicarbonate or saleratus;
(2) drop in the aqueous ethanolic solution of 20%-40% by sodium hydroxide, control temperature less than 30 DEG C, stirring and dissolving to clarification, and drops into 2-CBZ-aminothiazole-5-ethyl formate at this temperature; 25-35 DEG C of insulation reaction 5-12 hour; Be cooled to 0-5 DEG C, drip concentrated hydrochloric acid and regulate pH to 2.5-3.5, obtain 2-CBZ-aminothiazole-5-formic acid through suction filtration, drying;
(3) 2-CBZ-aminothiazole-5-formic acid is dropped in solvent pyridine, be cooled to 0-25 DEG C, drip Methanesulfonyl chloride, drip off this thermotonus 3-8 hour of rear maintenance, add the chloro-6-monomethylaniline of 2-again, slowly be warming up to 60-120 DEG C, at this temperature insulation reaction 5-10 hour, obtain the chloro-6-aminomethyl phenyl of 2-CBZ-amino-N-(2-through aftertreatment) thiazole-5-methane amide;
(4) aluminum chloride is dissolved in methyl-phenoxide, under room temperature, adds the chloro-6-aminomethyl phenyl of 2-CBZ-amino-N-(2-) thiazole-5-methane amide, be warming up to 25-60 DEG C, insulation reaction is spent the night, and obtains product through aftertreatment.
2. the chloro-6-aminomethyl phenyl of 2-amino-N-(2-as claimed in claim 1) synthetic method of thiazole-5-methane amide, it is characterized in that, in step (1), the mol ratio of described thiazolamine-5-ethyl formate, chloroformic acid benzyl ester and acid binding agent is 1:1.2-1.8:1.2-2.5.
3. the chloro-6-aminomethyl phenyl of 2-amino-N-(2-as claimed in claim 1 or 2) synthetic method of thiazole-5-methane amide, it is characterized in that, the aftertreatment of step (1) is: reaction terminates rear solvent evaporated, then after adding purified water and methyl alcohol/Glacial acetic acid making beating respectively, be down to 0-5 DEG C of stirred crystallization, suction filtration, drying obtains 2-CBZ-aminothiazole-5-ethyl formate; The add-on of described making beating Glacial acetic acid is the 8-12% of methanol quality.
4. the chloro-6-aminomethyl phenyl of 2-amino-N-(2-as claimed in claim 1) synthetic method of thiazole-5-methane amide, it is characterized in that, the add-on of aqueous ethanolic solution described in step (2) be the 10-20 of sodium hydroxide quality doubly; The mol ratio of described 2-CBZ-aminothiazole-5-ethyl formate and sodium hydroxide is 1:2-5.
5. the chloro-6-aminomethyl phenyl of 2-amino-N-(2-as claimed in claim 1) synthetic method of thiazole-5-methane amide, it is characterized in that, aftertreatment is in step (3): reaction terminates rear solvent evaporated, then adds the methanol-water making beating of 40-60%, suction filtration, drying obtain the chloro-6-aminomethyl phenyl of compound 2-CBZ-amino-N-(2-) thiazole-5-methane amide.
6. the chloro-6-aminomethyl phenyl of 2-amino-N-(2-as described in claim 1 or 5) synthetic method of thiazole-5-methane amide, it is characterized in that, the mol ratio of the formic acid of 2-CBZ-aminothiazole-5-described in step (3), Methanesulfonyl chloride and the chloro-6-monomethylaniline of 2-is 1:1.0-1.2:1.0-1.2; Described pyridine solvent consumption is 3-10 times of 2-CBZ-aminothiazole-5-formic acid quality.
7. the chloro-6-aminomethyl phenyl of 2-amino-N-(2-as claimed in claim 1) synthetic method of thiazole-5-methane amide, it is characterized in that, step (4) aftertreatment is: after reaction terminates, reaction solution is poured in frozen water, then through extraction, after concentrated, 0 DEG C of insulated and stirred crystallization 0.5-2 hour is cooled to, suction filtration, dry, obtain finished product.
8. the chloro-6-aminomethyl phenyl of 2-amino-N-(2-as described in claim 1 or 7) synthetic method of thiazole-5-methane amide, it is characterized in that, the chloro-6-aminomethyl phenyl of described 2-CBZ-amino-N-(2-) thiazole-5-methane amide and aluminum chloride mol ratio be 1:2-5; Described methyl-phenoxide is the chloro-6-aminomethyl phenyl of 2-CBZ-amino-N-(2-) thiazole-5-methane amide quality 3-8 is doubly.
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| WO2010085851A1 (en) * | 2009-01-29 | 2010-08-05 | Commonwealth Scientific And Industrial Research Organisation | Molecularly imprinted polymers |
| WO2011115758A1 (en) * | 2010-03-18 | 2011-09-22 | Takeda San Diego, Inc. | Process for the production of 2-amino-5-fluorothiazole |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010085851A1 (en) * | 2009-01-29 | 2010-08-05 | Commonwealth Scientific And Industrial Research Organisation | Molecularly imprinted polymers |
| WO2011115758A1 (en) * | 2010-03-18 | 2011-09-22 | Takeda San Diego, Inc. | Process for the production of 2-amino-5-fluorothiazole |
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| Ceftibuten: Development of a Commercial Process Based on Cephalosporin C.Part III. Process for the Conversion of 3-Exomethylene-7(R)-glutaroylaminocepham-4-carboxylic Acid 1(S)-Oxide to Ceftibuten;Ermanno Bernasconi et al.;《Organic Process Research & Development》;20020216;第6卷(第2期);169－177 * |
| 达沙替尼的合成;张少宁 等.;《中国医药工业杂志》;20100310;第41卷(第3期);161－163 * |
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