CN103275068A - Preparation method of nilotinib - Google Patents
Preparation method of nilotinib Download PDFInfo
- Publication number
- CN103275068A CN103275068A CN2013101962057A CN201310196205A CN103275068A CN 103275068 A CN103275068 A CN 103275068A CN 2013101962057 A CN2013101962057 A CN 2013101962057A CN 201310196205 A CN201310196205 A CN 201310196205A CN 103275068 A CN103275068 A CN 103275068A
- Authority
- CN
- China
- Prior art keywords
- buddhist nun
- preparation
- lip river
- condensation reaction
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of nilotinib, which comprises the following steps of: under the effect of organic base and a condensing agent, performing further condensation reaction between 4-(3-pyridyl)-2-pyrimidone (II) and 3-amino-4-methyl-N-[3-(4-methyl-1H-imidazole-1-yl)-5-trifluorotolylmethyl]benzamide (III) to obtain nilotinib (I). The preparation method disclosed by the invention has the advantages that the raw materials are easily available, the technology is simple, the conditions are mild, the environment is optimized, and the quality is improved; and moreover, the preparation method is suitable for industrial production and promotes the development of the economic technology of raw material medicines.
Description
Technical field
The invention belongs to organic synthesis highway route design and bulk drug thereof and intermediate preparation technical field, particularly a kind of Buddhist nun Lip river is for the Buddhist nun preparation method.
Background technology
Ni Luo is the oral tyrosine kinase inhibitor of being developed by company of Switzerland Novartis (Novartis) of highly selective for Buddhist nun (Nilotinib).Its mono-hydrochloric salts monohydrate obtains FDA (Food and Drug Adminstration) (FDA) approval listing in October, 2007, and commodity are called Tasigna (Da Xina).Be used for the treatment of the invalid chronic myelocytic leukemia of imatinib mesylate clinically.The Philadelphia chromosome positive chronic granulocyte leukemia that this medicine can cause by the sudden change of targeting selectivity restraint of tyrosinase and encoding gene thereof, patient tolerability is good, and selectivity is strong, and is evident in efficacy.
Ni Luo is by name for Buddhist nun's chemistry: chemistry 4-methyl-3-[4-(3-pyridyl) by name-2-pyrimidyl] amino-N-[5-(4-methyl isophthalic acid H-imidazoles-1-yl)-3-(trifluoromethyl) phenyl] benzamide.
Patent WO2004/00528 number, WO2006/135641 number, WO2010/060074 number and reported the synthetic method of Buddhist nun Lip river for the Buddhist nun for WO2010/009402 number.This method is utilized the guanidine radicals fragment that forms when structural units such as p-methylbenzoic acid and phenylimidazole carry out acidylate or condensation, directly cyclization obtains pyrimidine ring, thereby makes the Buddhist nun Lip river for Buddhist nun (I).The related raw material of this method all is not commercially available conventional raw material, and industrial the needs makes by oneself.Simultaneously, form guanidine radicals by anils, become the yield of pyrimidine ring not high through DMF-DMA again, and the reaction times is longer, is unfavorable for suitability for industrialized production.
WO2004/005281 number, CN102321073 number and the 2121st page of another kind of method of having reported that the Buddhist nun Lip river is synthesized for the Buddhist nun of " Synthesis " 2007 the 14th volumes; be starting raw material with 3-iodo-4-methyl benzoyl chloride; carry out acidylate and obtain intermediate (IV) with 3-trifluoromethyl-5-(4-methyl isophthalic acid H-1-imidazolyl) aniline; halogen bromine or iodine in the intermediate (IV) carries out halogenating reaction with 4-(3-pyridyl)-2-PYRIMITHAMINE (V) again, makes the Buddhist nun Lip river for Buddhist nun (I).There are two defectives in this method, the one, raw material 3-iodo-4-methyl benzoyl chloride and 4-(3-pyridyl)-2-PYRIMITHAMINE (V) is difficult the acquisition, the 2nd, intermediate (IV) need use expensive palladium metal catalyst with nucleophilic substitution (V), has limited the use of this route.
Investigate present Buddhist nun Lip river for Buddhist nun's preparation method, problem such as have all that raw material is rare, step is long, cost is higher and yield is on the low side.So be necessary to seek a kind of new Buddhist nun Lip river that can simplify processing step, minimizing environmental pollution and reduce production costs for Buddhist nun's (I) preparation method.
Summary of the invention
The object of the present invention is to provide a kind of improved Buddhist nun Lip river for Buddhist nun's (I) preparation method, this preparation method's technology is succinct, and raw material is easy to get, and is quality controllable, is fit to suitability for industrialized production.
For achieving the above object, the present invention has adopted following main technical schemes: Buddhist nun's (I) preparation method is replaced in a kind of Buddhist nun Lip river,
It is characterized in that: described preparation method comprises the steps: 4-(3-pyridyl)-2-pyrimidone (II) and 3-amino-4-methyl-N-[3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-phenylfluoroform ylmethyl] benzamide (III) under organic bases and condensing agent effect, carry out a step condensation reaction and make the Buddhist nun Lip river for Buddhist nun (I).
In addition, the present invention also comprises following attached technical scheme:
The raw material 4-of condensation reaction (3-pyridyl)-2-pyrimidone (II) and 3-amino-4-methyl-N-[3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-phenylfluoroform ylmethyl] molar ratio of benzamide (III) is 1: 1-2, preferred 1: 1.3-1.6.
The condensing agent of described condensation reaction is N, N,-dicyclohexylcarbodiimide (DCC), carbonyl dimidazoles (CDI), N, N '-DIC (DIC), 1-hydroxyl-benzotriazole (HOBt), O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid ester (TBTU), O-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU), benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU) or benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP), preferred benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU) or benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP).
The alkali promotor of described condensation reaction is triethylamine (TEA), pyridine, 2, the 6-lutidine, 4-Dimethylamino pyridine (DMAP), N-methylmorpholine (NMM), N-ethylmorpholine (NEM), diisopropylethylamine (DIEA), 1,5-diazabicylo [4.3.0]-ninth of the ten Heavenly Stems-5-alkene (DBN), 1,8-diazabicyclo [5.4.0]-11-7-alkene (DBU) or 1,4-diazabicylo [2.2.2] octane (DABCO), preferred 1,8-diazabicyclo [5.4.0]-11-7-alkene (DBU) or 1,5-diazabicylo [4.3.0]-ninth of the ten Heavenly Stems-5-alkene (DBN) or 1,4-diazabicylo [2.2.2] octane (DABCO).
The solvent of described condensation reaction is toluene, dimethylbenzene, ethyl acetate, isopropyl acetate, butylacetate, chloroform, methyl-sulphoxide, N, dinethylformamide or acetonitrile, preferred acetonitrile.
The temperature of described condensation reaction is 0-120 ℃, preferred 80-90 ℃.
Than prior art, the invention has the advantages that: Buddhist nun provided by the present invention Lip river is for Buddhist nun's preparation method, application by condensing agent, make 4-(3-pyridyl)-2-pyrimidone (II) and 3-amino-4-methyl-N-[3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-phenylfluoroform ylmethyl] benzamide (III) carry out one the step condensation reaction, can obtain target compound, Atom economy, the selectivity of reaction and the controllability of operation have been improved, make the Buddhist nun Lip river more controlled for Buddhist nun's production, quality product increases, and promotes the development of the economic technology of this bulk drug.
Embodiment
Below in conjunction with several preferred embodiments technical solution of the present invention is done further nonrestrictive detailed description.
Embodiment one:
Under the nitrogen protection, in there-necked flask, add 4-(3-pyridyl)-2-pyrimidone (II) (1.73g, 10mmol), benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP) (6.63g, 15mmol) and acetonitrile 50mL.Stir down, (2.28g 15mmol), drips and finishes room temperature reaction 12 hours to drip 1,8-diazabicyclo [5.4.0]-11-7-alkene (DBU).Be warming up to 90 ℃, continue reaction 12 hours.The underpressure distillation desolventizing adds ethyl acetate 100mL dissolving, and washs with 2M sodium hydroxide 20mL.Tell organic phase, drying, concentrating under reduced pressure.Resistates dissolves with the 100mL tetrahydrofuran (THF), add 3-amino-4-methyl-N-[3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-phenylfluoroform ylmethyl] benzamide (III) (4.86g, 13mmol) and sodium hydride (0.37g, 15mmol), be warming up to 80 ℃, stirring reaction 5 hours, the TLC monitoring reaction finishes.With saturated aqueous common salt cancellation reaction, tell organic phase, drying, vacuum distillation recovered solvent gets the off-white color solid.Get white solid Buddhist nun Lip river for Buddhist nun (I) 4.50g with tetrahydrofuran (THF)/ethyl acetate (4: 1) recrystallization, yield is 85.1%.
Embodiment two:
Under the nitrogen protection, in there-necked flask, add 4-(3-pyridyl)-2-pyrimidone (II) (1.73g, 10mmol), benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP) (6.63g, 15mmol) and acetonitrile 50mL.Stir down, dropping 1,5-diazabicylo [4.3.0]-ninth of the ten Heavenly Stems-(1.86g 15mmol), drips and finishes room temperature reaction 12 hours 5-alkene (DBN).Be warming up to 90 ℃, continue reaction 12 hours.The underpressure distillation desolventizing adds ethyl acetate 100mL dissolving, and washs with 2M sodium hydroxide 20mL.Tell organic phase, drying, concentrating under reduced pressure.Resistates dissolves with the 100mL tetrahydrofuran (THF), add 3-amino-4-methyl-N-[3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-phenylfluoroform ylmethyl] benzamide (III) (4.86g, 13mmol) and sodium hydride (0.37g, 15mmol), be warming up to 80 ℃, stirring reaction 5 hours, the TLC monitoring reaction finishes.With saturated aqueous common salt cancellation reaction, tell organic phase, drying, vacuum distillation recovered solvent gets the off-white color solid.Get white solid Buddhist nun Lip river for Buddhist nun (I) 4.36g with tetrahydrofuran (THF)/ethyl acetate (4: 1) recrystallization, yield is 82.4%.
Embodiment three:
Under the nitrogen protection; in there-necked flask, add 4-(3-pyridyl)-2-pyrimidone (II) (1.73g; 10mmol), benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP) (6.63g; 15mmol), 3-amino-4-methyl-N-[3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-phenylfluoroform ylmethyl] benzamide (III) (4.86g; 13mmol) and N, dinethylformamide 50mL.Stir down, (2.28g 15mmol), drips and finishes room temperature reaction 12 hours to drip 1,8-diazabicyclo [5.4.0]-11-7-alkene (DBU).Be warming up to 90 ℃, continue reaction 12 hours.The underpressure distillation desolventizing adds ethyl acetate 100mL dissolving, and washs with 2M sodium hydroxide 20mL.Tell organic phase, drying, concentrating under reduced pressure.Resistates gets off-white color solid Buddhist nun Lip river for Buddhist nun (I) 3.90g with tetrahydrofuran (THF)/ethyl acetate (4: 1) recrystallization, and yield is 73.7%.
It is pointed out that above-described embodiment only is explanation technical conceive of the present invention and characteristics, its purpose is to allow the personage who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalences that spirit is done according to the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (6)
1. a Buddhist nun Lip river is for Buddhist nun's preparation method,
It is characterized in that described preparation method comprises the steps: 4-(3-pyridyl)-2-pyrimidone (II) and 3-amino-4-methyl-N-[3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-phenylfluoroform ylmethyl] benzamide (III) under organic bases and condensing agent effect, carry out a step condensation reaction and make the Buddhist nun Lip river for Buddhist nun (I).
According to the described Buddhist nun of claim 1 Lip river for Buddhist nun's preparation method, it is characterized in that: the raw material 4-of described condensation reaction (3-pyridyl)-2-pyrimidone (II) and 3-amino-4-methyl-N-[3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-phenylfluoroform ylmethyl] molar ratio of benzamide (III) is 1: 1-2.
3. according to the preparation method of the described Buddhist nun of claim 1 Lip river for the Buddhist nun, it is characterized in that: the condensing agent of described condensation reaction is N, N,-dicyclohexylcarbodiimide, carbonyl dimidazoles, N, N '-DIC, 1-hydroxyl-benzotriazole, O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid ester, O-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester, benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester or benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate.
4. according to the preparation method of the described Buddhist nun of claim 1 Lip river for the Buddhist nun, it is characterized in that: the alkali promotor of described condensation reaction is triethylamine, pyridine, 2,6-lutidine, 4-Dimethylamino pyridine, N-methylmorpholine, N-ethylmorpholine, diisopropylethylamine, 1,5-diazabicylo [4.3.0]-ninth of the ten Heavenly Stems-5-alkene, 1,8-diazabicyclo [5.4.0]-11-7-alkene or 1,4-diazabicylo [2.2.2] octane.
5. according to the preparation method of the described Buddhist nun of claim 1 Lip river for the Buddhist nun, it is characterized in that: the solvent of described condensation reaction is toluene, dimethylbenzene, ethyl acetate, isopropyl acetate, butylacetate, chloroform, methyl-sulphoxide, N, dinethylformamide or acetonitrile.
6. according to the preparation method of the described Buddhist nun of claim 1 Lip river for the Buddhist nun, it is characterized in that: the temperature of described condensation reaction is 0-120 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013101962057A CN103275068A (en) | 2013-05-23 | 2013-05-23 | Preparation method of nilotinib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013101962057A CN103275068A (en) | 2013-05-23 | 2013-05-23 | Preparation method of nilotinib |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103275068A true CN103275068A (en) | 2013-09-04 |
Family
ID=49057713
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2013101962057A Pending CN103275068A (en) | 2013-05-23 | 2013-05-23 | Preparation method of nilotinib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103275068A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105198821A (en) * | 2015-10-26 | 2015-12-30 | 苏州明锐医药科技有限公司 | Preparation method of Rociletinib |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101184748A (en) * | 2005-06-09 | 2008-05-21 | 诺瓦提斯公司 | Process for the syntesis of 5-(methyl-1h-imidazol-1-yl)-3-(tri fluorome th yl)-benzeneamine |
| CN101497601A (en) * | 2008-01-29 | 2009-08-05 | 上海百灵医药科技有限公司 | Process for synthesizing imatinib |
-
2013
- 2013-05-23 CN CN2013101962057A patent/CN103275068A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101184748A (en) * | 2005-06-09 | 2008-05-21 | 诺瓦提斯公司 | Process for the syntesis of 5-(methyl-1h-imidazol-1-yl)-3-(tri fluorome th yl)-benzeneamine |
| CN101497601A (en) * | 2008-01-29 | 2009-08-05 | 上海百灵医药科技有限公司 | Process for synthesizing imatinib |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105198821A (en) * | 2015-10-26 | 2015-12-30 | 苏州明锐医药科技有限公司 | Preparation method of Rociletinib |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102153519B (en) | Preparation method of quinazoline derivative | |
| CN102633713A (en) | Dabigatran etexilate intermediate, preparation method for same and method for preparing dabigatran etexilate | |
| CN103288804A (en) | Preparation method of nilotinib | |
| CN103857672B (en) | Be used to prepare 1- (4- (4- (the chloro- 2- fluoroanilino of 3,4- bis-) -7- methoxyquinazoline hydrochloride -6- base oxygroup) piperidin-1-yl) -propyl- 2- alkene -1- keto hydrochloride method and its used in intermediate product | |
| CN105399736A (en) | Novel preparation method of brexpiprazole | |
| CN102584795A (en) | Preparing method of crizotinib | |
| CN103288808B (en) | A kind of Ah method is for the preparation method of Buddhist nun | |
| CN104926788A (en) | Substituted piperidin derivative, and pharmaceutical composition containing substituted piperidin derivative and application thereof in antitumor | |
| CN105061506A (en) | Preparation method for anti-tumor drug AP26113 | |
| CN103288837A (en) | Preparation method of ticagrelor | |
| CN102796079B (en) | A kind of preparation method of methanesulfonic acid fluorine imatinib | |
| CN105198821A (en) | Preparation method of Rociletinib | |
| CN103242303A (en) | Afatinib preparation method | |
| CN103613619A (en) | Preparation method of N-4-benzenesulfonamido-N'-1-deoxy-beta-D-pyran glucuronyl-thiourea compounds and medical application | |
| CN103265482A (en) | Preparation method of bosutinib | |
| CN104910118B (en) | One marcumar class compound and its production and use | |
| CN103254175A (en) | Preparation method of nilotinib | |
| CN103275068A (en) | Preparation method of nilotinib | |
| CN105130887A (en) | Regorafenib preparation method | |
| CN102603710A (en) | Preparation method of imatinib intermediate | |
| CN104016877A (en) | Acetylaniline compounds and application thereof in preparation of mirabegron | |
| CN103265530A (en) | Preparation method of neratinib | |
| CN103304575A (en) | Neogambogic acid derivative, preparation method thereof and pharmaceutical application | |
| CN103275072A (en) | Preparation method of saracatinib | |
| JP2007332061A (en) | NEW PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVE AND USE THEREOF |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20130904 |