CN103483289B - A kind of synthetic method of 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide - Google Patents
A kind of synthetic method of 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide Download PDFInfo
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- CN103483289B CN103483289B CN201310412312.9A CN201310412312A CN103483289B CN 103483289 B CN103483289 B CN 103483289B CN 201310412312 A CN201310412312 A CN 201310412312A CN 103483289 B CN103483289 B CN 103483289B
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- aminomethyl phenyl
- thiazole
- ethoxy
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- QDLFCQOOYGPPGN-UHFFFAOYSA-N CC(C=CCC1Cl)=C1N Chemical compound CC(C=CCC1Cl)=C1N QDLFCQOOYGPPGN-UHFFFAOYSA-N 0.000 description 1
- HALBQHADMUAZKW-YVMONPNESA-N Cc(cccc1Cl)c1NC(/C(/Cl)=C/Cl)=O Chemical compound Cc(cccc1Cl)c1NC(/C(/Cl)=C/Cl)=O HALBQHADMUAZKW-YVMONPNESA-N 0.000 description 1
- KCPLVEMVCCAESS-UHFFFAOYSA-N Cc(cccc1Cl)c1NC(C(Cl)=C(OC)OC)=O Chemical compound Cc(cccc1Cl)c1NC(C(Cl)=C(OC)OC)=O KCPLVEMVCCAESS-UHFFFAOYSA-N 0.000 description 1
- 0 Cc(cccc1Cl)c1NC(c1cnc(N*)[s]1)=O Chemical compound Cc(cccc1Cl)c1NC(c1cnc(N*)[s]1)=O 0.000 description 1
- RBCCLWUFGUGGFY-UPHRSURJSA-N O=C(/C(/Cl)=C/Cl)Cl Chemical compound O=C(/C(/Cl)=C/Cl)Cl RBCCLWUFGUGGFY-UPHRSURJSA-N 0.000 description 1
- YQYHCJZVJNOGBP-UPHRSURJSA-N OC(/C(/Cl)=C/Cl)=O Chemical compound OC(/C(/Cl)=C/Cl)=O YQYHCJZVJNOGBP-UPHRSURJSA-N 0.000 description 1
- ZAKLKBFCSHJIRI-UHFFFAOYSA-N OC(C(Cl)=C1Cl)OC1=O Chemical compound OC(C(Cl)=C1Cl)OC1=O ZAKLKBFCSHJIRI-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
A kind of synthetic method of 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide, this compound is a key intermediate of synthesis Dasatinib.Comprise the following steps: 1) by trichoroacetic chloride and ethyl vinyl ether through nucleophilic substitution, hydrolysis reaction one pot process 3-ethoxy-c olefin(e) acid; 2) by 3-ethoxy-c olefin(e) acid through chloride, amidate action one pot process N-(the chloro-6-aminomethyl phenyl of 2-)-3-ethanol acrylamides; 3) N-(2-chloro-6-aminomethyl phenyl)-3-ethanol acrylamides and NBS and thiocarbamide are obtained by reacting 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide.The synthetic method that this invention provides, improves yield, reduces cost, simplifies operation, have larger implementary value.
Description
Technical field
The present invention relates to a kind of synthetic method of pharmaceutical intermediate, the synthetic method of special design 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide, this compound is a key intermediate of synthesis Dasatinib.
Background technology
Dasatinib (Dasatinib, commodity are called Sprycel) be a kind of oral TYR kinase inhibitor researched and developed by hundred Shi Meishi your company, its chemistry N-(the chloro-6-aminomethyl phenyl of 2-)-2-[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidyl] amino-5-thiazole carboxamides monohydrate by name.This medicine obtains FDA approval listing in June, 2006, is used for the treatment of the patients with chronic myeloid leukemia: that maybe cannot tolerate imatinib-resistant; Meanwhile, be also used for the treatment of other therapies resistance or the acute lymphoblastic leukemia adult patient of Philadelphia Chromosome Positive that do not tolerate.Namely this medicine achieved the sales volume of 1.3 hundred million dollars in 2009, and it serves to show its good development trend, market potential is huge.
2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide is a key intermediate of synthesis Dasatinib, is shown below.
According to bibliographical information, 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide mainly contains three kinds of synthetic methods, is now described below.
1) patent WO2005077945 and document JMedChem; 2006; 49 (23): 6819-6832 report with thiazolamine-5-ethyl formate for raw material, through N-Boc protection, be hydrolyzed into acid, become acid amides through acyl chlorides, de-Boc protecting group obtains target compound, as follows:
And about the synthesis of raw material thiazolamine-5-ethyl formate, mainly contain two kinds of methods: first method is document TetraLett, 2001,42 (11): 2101-2102 and the report such as patent WO2006/8556Al with trichoroacetic chloride and ethyl vinyl ether for starting raw material, synthetic route is as follows:
Second method is document Heterocycles, 1991,32 (4): 693-701 and the report such as patent WO2004/80996Al with ethyl chloroacetate and ethyl formate for starting raw material, synthetic route is as follows:
No matter with which kind of method synthesis material thiazolamine-5-ethyl formate, because subsequent synthetic procedures is long, generally speaking, there is route length, complex operation, shortcoming that cost is high in this method synthesis target compound 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide.
2) patent US200737978 reports another kind of method; take mucochloric acid as starting raw material; first be hydrolyzed into 2; the acid of 3-dichloropropylene; then be processed into acyl chlorides with sulfur oxychloride, then connect with the chloro-6-monomethylaniline of 2-, then generate dimethylacetal with methyl alcohol-sodium methylate process; last deprotection in acid condition original position and thiocarbamide close ring obtains target compound, synthetic route is as follows:
This method main raw material mucochloric acid price is higher, and total cost of production is higher, and relates to multi-step pressure reducing distillation in reaction process, energy consumption and higher to equipment requirements.
3) document Synthesis, 2001,2:239-242 and patent WO2005077945A2 reports the third synthetic method, with oxalyl chloride and ethyl vinyl ether for starting raw material, first produce 4-oxyethyl group-3-oxo crotonyl chloride, reheat and be degraded into 3-ethoxy propylene acyl chlorides, the latter and the chloro-6-monomethylaniline of 2-react and connect, obtain N-(the chloro-6-aminomethyl phenyl of 2-)-3-ethanol acrylamides, then be obtained by reacting target compound with NBS, thiocarbamide, reaction scheme is as follows.
The method synthetic route is shorter, a kind of being applicable to well synthesize thinking, but there is following shortcoming in this method: second step will at high temperature be degraded decarboxylation, with this understanding, second step product 3-ethoxy propylene acyl chlorides is easily polymerized, cause that productive rate reduces, intermediate product is impure, need underpressure distillation to purify, the requirement of energy consumption to equipment is higher; In addition, the 3rd step and the 4th step use solvents tetrahydrofurane and dioxane respectively, and cost cost is also higher.
4) patent WO2010/144338 reports another kind of synthetic method, the alkaline hydrolysis of 3-ethoxy ethyl acrylate becomes 3-ethoxy-c olefin(e) acid sodium, the latter directly obtains 3-ethoxy propylene acyl chlorides with sulfur oxychloride process, subsequent step is with method 3), raw material 3-ethoxy-c diluted acid ethyl ester is obtained by trichoroacetic chloride and ethyl vinyl ether, and whole synthetic route is as follows:
This method improves the synthesis of 3-ethoxy propylene acyl chlorides, overcomes method 3) Problems existing, but synthetic route is elongated, complex operation.
In sum, the method for bibliographical information is not all be applicable to amplifying the best synthesis technique produced.
Summary of the invention
The object of this invention is to provide the synthetic method of 2-amino-N-(the chloro-6-aminomethyl phenyl of the 2-) thiazole-5-methane amide of the applicable amplification that a kind of synthetic route is short, cost is low, low for equipment requirements, easy and simple to handle.
The invention provides the synthetic method of a kind of 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide, comprise the following steps:
1) by trichoroacetic chloride and ethyl vinyl ether first after nucleophilic substitution, basic hydrolysis one pot process 3-ethoxy-c olefin(e) acid;
2) 3-ethoxy-c olefin(e) acid is through chloride, amidation one pot process N-(the chloro-6-aminomethyl phenyl of 2-)-3-ethanol acrylamides;
3) N-(2-chloro-6-aminomethyl phenyl)-3-ethanol acrylamides and N-bromo-succinimide (NBS) and thiocarbamide are obtained by reacting 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide.Reaction scheme is shown below:
Wherein, the method producing 3-ethoxy-c olefin(e) acid is, by trichoroacetic chloride and ethyl vinyl ether cold condition (less than 0 degree, as: adopt cryosel cooling) under react and generate 4-oxyethyl group-1,1,1-tri-chloro-3-butene-2-one, then hydrolyzed under basic conditions obtains.
N-(the chloro-6-aminomethyl phenyl of 2-)-3-ethanol acrylamides, first generates 3-ethoxy propylene acyl chlorides by 3-ethoxy-c olefin(e) acid under sulfur oxychloride effect, and then chloro-6-monomethylaniline amidate action obtains with 2-.Its amidate action solvent is the one in methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, and temperature of reaction is normal temperature, reaction times 0.5-4 hour.
Described the 3rd) reaction solvent of step synthesis 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide is the one in methyl alcohol, ethanol, Virahol and n-propyl alcohol, and temperature of reaction is 10-100 DEG C, reaction times 4-12 hour.
The present invention is at literature method 3) basis on, integrated approach 4) some thinkings, for the shortcoming that two kinds of methods exist, carried out useful improvement and optimization: 3-ethoxy-c olefin(e) acid adopts trichoroacetic chloride and ethyl vinyl ether through nucleophilic substitution and alkaline hydrolysis one pot process, easy and simple to handle, product is easy to purify; Because aforesaid method gained-3-ethoxy-c olefin(e) acid purity is high, so gained 3-ethoxy propylene acyl chlorides can be directly used in next step amidate action, without the need to underpressure distillation, simplifies operation, reduce energy consumption and cost; Amidate action adopts low-carbon (LC) halogenated hydrocarbon solvent cheap and easy to get to replace tetrahydrofuran (THF), the 3rd) ring closure reaction in step adopts low-carbon alcohol kind solvent to replace dioxane, and these two reduce cost.
Advantage of the present invention is: synthetic route is short, cost is low, low for equipment requirements, easy and simple to handle, applicable amplification, has larger implementary value.
Embodiment
Be described in detail to technical scheme of the present invention below by specific embodiment, cited embodiment is to describe technical scheme of the present invention in detail, but not limits the scope of the invention.
Embodiment 1
1) by trichoroacetic chloride and ethyl vinyl ether first after nucleophilic substitution, basic hydrolysis one pot process 3-ethoxy-c olefin(e) acid, concrete grammar is:
In 3L reaction flask, add trichoroacetic chloride 2kg, stir lower cryosel and be cooled to less than-5 DEG C, then drip ethyl vinyl ether 1kg, warm < 0 DEG C in controlling.After dripping, react 24h at keeping temperature < 0 DEG C, then naturally rise again stir about 24h, GC detect extremely without trichoroacetic chloride.Water pump underpressure distillation, reaction solution gradient increased temperature to 100 DEG C, is distilled to reaction solution and produces without gas.To lower the temperature to obtain black liquor crude product, be directly used in next step.
Toward in 10L reaction flask, add sodium hydroxide 500g and water 4L, stir clearly molten, be then cooled to room temperature.Stir lower dropping previous step gained crude product, temperature of reaction system controls at 20-30 DEG C.After dripping, stir under normal temperature and spend the night.TLC detects extremely without raw material.Reaction solution washed with dichloromethane twice, water layer activated carbon decolorizing, filtration, filtrate is cooled to 0 DEG C, drips hydrochloric acid and adjusts pH to 2-3, separate out solid, filter, water stirs and wash, dry 950g off-white color solid is 3-ethoxy-c olefin(e) acid.HPLC > 98%, two step overall yield 74.4%.
1HNMR(CDCl
3，500MHz)：δ1.36(t，J=7.5Hz，3H，CH
3)，3.95(q，J=7.5Hz，2H，CH
2)，5.18(d，J=12.5Hz，1H，=CH)，7.67(d，J=12.5Hz，1H，HC=)。
2) 3-ethoxy-c olefin(e) acid is through chloride, amidation one pot process N-(the chloro-6-aminomethyl phenyl of 2-)-3-ethanol acrylamides, and concrete grammar is:
Toward in 2L reaction flask, add 200g3-ethoxy-c olefin(e) acid and 1L toluene, be warming up to 65-70 DEG C under stirring, question response liquid is clearly molten, starts to drip thionyl chloride 400g, control < 75 DEG C during dropping.After dripping off, control temperature stirs 4h at about 70 DEG C, produces to without hydrogen chloride gas, stops heating.Reaction solution is cooled to about 40 DEG C and starts underpressure distillation, be warming up to 50 DEG C and be distilled to without after cut outflow, add 0.4L toluene, again underpressure distillation, be warming up to 65 DEG C and flow out without cut.Be down to room temperature and obtain 250g black liquor, be directly used in next step.
The chloro-6-monomethylaniline of 180g2-, 150g pyridine and 0.8L chloroform is added, after stirring in 2L reaction flask.By the 0.2L chloroform dilution of previous step gained crude product, drop in reaction flask, control temperature < 30 DEG C during dropping.Drip rear continuation and stir 1.5h.TLC detects complete to raw material reaction.Reaction solution is cooled to 0 DEG C, drips 10% dilute hydrochloric acid and adjust pH=3, in controlling during dropping, temperature is less than 5 degree.After dripping off, stir 0.5h, separate out solid filtering, washing, chloroform, then filter, dry 210g off-white color solid is N-(the chloro-6-aminomethyl phenyl of 2-)-3-ethanol acrylamides.HPLC > 98%, two step overall yield 68.9%.
1HNMR(CDCl
3，500MHz)：δ1.26(t，J=7Hz，3H，CH
3)，2.15(s，3H，CH
3)，3.94(q，J=7Hz，2H，CH
2)，5.58(d，J=12.5Hz，1H，HC=)，7.10-7.27(m，2H，BzH)，7.27-7.37(m，1H，BzH)，7.45(d，J=12.5Hz，=CH)，1H，9.28(s，1H，NH)。
3) N-(2-chloro-6-aminomethyl phenyl)-3-ethanol acrylamides and NBS and thiocarbamide are obtained by reacting 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide, concrete grammar is:
Toward in 5L reaction flask, add 350gN-(the chloro-6-aminomethyl phenyl of 2-)-3-ethanol acrylamides and 3.5L Virahol, under stirring, add 300gNBS in batches, control temperature < 25 DEG C time reinforced.After adding, insulated and stirred 4h, then adds 130g thiocarbamide, adds temperature rising reflux 5h.TLC detects complete to raw material reaction.Reaction solution is down to room temperature, drips ammoniacal liquor and adjust pH=8-9.Reaction solution is concentrated into half volume, cooling analysis of material, filters, washes, obtain yellow solid crude product, with Virahol: the mixed solvent recrystallization of water=1:3, obtains 360g yellow solid and be target compound 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide.HPLC > 98%, productive rate 92.1%.
1HNMR(DMSO-d
6，500MHz)：δ2.21(s，3H，CH
3)，7.21-7.27(m，2H，BzH)，7.36-7.38(m，1H，BzH)，7.62(s，2H，NH
2)，7.87(s，1H，ArH)，9.64(s，1H，NH)。
Claims (3)
1. a synthetic method for 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide, comprises the following steps:
1) by trichoroacetic chloride and ethyl vinyl ether below 0 degree Celsius through nucleophilic substitution, react and generate the chloro-3-butene-2-one of 4-oxyethyl group-1,1,1-tri-, then obtain 3-ethoxy-c olefin(e) acid through one kettle way hydrolysis in the basic conditions;
2) under sulfur oxychloride effect, 3-ethoxy propylene acyl chlorides is generated by 3-ethoxy-c olefin(e) acid, then chloro-6-monomethylaniline synthesizes N-(the chloro-6-aminomethyl phenyl of 2-)-3-ethanol acrylamides in one pot through amidate action with 2-, described amidate action temperature is normal temperature, reaction times 0.5-4 hour;
3) N-(2-chloro-6-aminomethyl phenyl)-3-ethanol acrylamides and NBS and thiocarbamide are obtained by reacting 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-) thiazole-5-methane amide, and temperature of reaction is 10-100 DEG C, reaction times 4-12 hour.
2. synthetic method according to claim 1, is characterized in that described amidate action solvent is the one in methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride and trichloroethane.
3. synthetic method according to claim 1, is characterized in that described step 3) reaction solvent is one in methyl alcohol, ethanol, Virahol and n-propyl alcohol.
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| WO2005077945A2 (en) * | 2004-02-06 | 2005-08-25 | Bristol-Myers Squibb Company | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
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| WO2005077945A2 (en) * | 2004-02-06 | 2005-08-25 | Bristol-Myers Squibb Company | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
| CN102573485A (en) * | 2009-06-08 | 2012-07-11 | 加利福尼亚资本权益有限责任公司 | Triazine derivatives and their therapeutical applications |
| CN102295640A (en) * | 2011-06-29 | 2011-12-28 | 南京工业大学 | 3-heterocycle schiff base-5-fluorine-indole-2-ketone compounds, preparation method thereof and application thereof |
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