CN107602457A - The method of the aminoisonicotinic acid of 6 methyl of one pot process 2 - Google Patents
The method of the aminoisonicotinic acid of 6 methyl of one pot process 2 Download PDFInfo
- Publication number
- CN107602457A CN107602457A CN201710936150.7A CN201710936150A CN107602457A CN 107602457 A CN107602457 A CN 107602457A CN 201710936150 A CN201710936150 A CN 201710936150A CN 107602457 A CN107602457 A CN 107602457A
- Authority
- CN
- China
- Prior art keywords
- methyl
- reaction
- isonicotinic
- hydroxyl
- pot process
- 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
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses the method for the aminoisonicotinic acid of 6 methyl of one pot process 2, this method is initiation material using the methyl-isonicotinic acid of 2 hydroxyl 6, is reacted under alkali effect with methylsufonyl chloride, then the aminoisonicotinic acid of 6 methyl 2 is made through amination reagent amination.The present invention uses new initiation material, and one pot of two-step reaction, aminating reaction mild condition, yield is higher, and product purity is higher, suitable for commercial application.
Description
Technical field
The invention belongs to the synthesis technical field of medicine intermediate, and in particular to a kind of one pot process 6- methyl -2- ammonia
The method of base-isonicotinic acid.
Background technology
6- methyl-2-aminos-isonicotinic acid is important medicine intermediate, ester type compound, the amide-type of its derivatization
Compound exists in many medicines structures.But the synthetic method for the 6- methyl-2-aminos-isonicotinic acid reported at present is simultaneously few.Specially
Sharp US2010/261687, WO201245803 and US2012264729 use the chloro- 6- methyl-isonicotinic acids of 2-（From 2- hydroxyls -6-
Methyl-isonicotinic acid is made with POCl3, thionyl chloride reaction）For starting material, in 155 DEG C in sulfuric acid in autoclave
In the presence of copper and vulcanized sodium, concentrated ammonia liquor synthesizes target product as amination reagent.With acetamide acetone in patent WO20171670
Acetoacetic ester and amidine ethyl acetate hydrochloride flow back in caustic alcohol ethanol and hydrolyze the different cigarette of obtained 2- amino -3- carboxyl -6- methyl
Acid, due to amino first on, so decarboxylation difficulty is slightly larger, patent in N-methyl pyrroles using using lithium chloride and the concentrated sulfuric acid
6- methyl-2-aminos-isonicotinic acid is made in decarboxylation.Therefore the gentle synthesis technique meaning weight of 6- methyl-2-aminos-isonicotinic acid is established
Greatly.
The content of the invention
Present invention solves the technical problem that a kind of method of one pot process 6- methyl-2-aminos-isonicotinic acid is there is provided,
This method is initiation material using 2- hydroxyl -6- methyl-isonicotinic acids, is reacted under alkali effect with methylsufonyl chloride, then through amination
6- methyl-2-aminos-isonicotinic acid is made in reagent amination.
The present invention is to solve above-mentioned technical problem to adopt the following technical scheme that, one pot process 6- methyl-2-aminos-different cigarette
The method of acid, it is characterised in that concretely comprise the following steps：2- hydroxyl -6- methyl-isonicotinic acids, solvent and alkali are added into reaction vessel,
Wherein solvent is DMF or DMAC, and alkali is potassium carbonate or sodium carbonate, and the control of mixed system reaction temperature is added dropwise into methyl sulphur at 0 DEG C
Acyl chlorides, it is added dropwise and is warming up to room temperature reaction；Reaction terminates to add amination reagent in backward reaction system, and wherein amination reagent is
Ammonium formate or ammonium acetate, it is warming up to 80-100 DEG C of reaction and 6- methyl-2-aminos-isonicotinic acid is made.
Further preferably, the charge ratio of the solvent and 2- hydroxyl -6- methyl-isonicotinic acids is 2-5mL:1g.
Further preferably, the molar ratio of the alkali and 2- hydroxyl -6- methyl-isonicotinic acids is 1:1.
Further preferably, the molar ratio of the amination reagent and 2- hydroxyl -6- methyl-isonicotinic acids is 1-1.5:1.
The present invention has advantages below compared with prior art：It is anti-using new initiation material, one pot of two-step reaction, amination
Mild condition is answered, yield is higher, and product purity is higher, suitable for commercial application.
Embodiment
The above of the present invention is described in further details by the following examples, but this should not be interpreted as to this
The scope for inventing above-mentioned theme is only limitted to following embodiment, and all technologies realized based on the above of the present invention belong to this hair
Bright scope.
Embodiment 1
The g of 2- hydroxyl -6- methyl-isonicotinic acids 153 is added in reaction bulb（1 mmol）, solvent DMF（306 mL）And sodium carbonate
106g（1mmol）, mixed system reaction temperature is controlled at 0 DEG C, the mL of methylsufonyl chloride 78 is added dropwise, is added dropwise, slowly rises to
Room temperature reaction, reaction terminate to add the g of ammonium formate 63 in backward reaction system, are warming up to 80 DEG C of reactions, and reaction is depressurized after terminating steams
Recycling design is evaporated, residue is added in mixture of ice and water, glacial acetic acid regulation pH=3-4, separates out the g of white solid 150, yield
98.6%, purity 99.2%.
Embodiment 2
The g of 2- hydroxyl -6- methyl-isonicotinic acids 153 is added in reaction bulb（1 mmol）, solvent DMF（765 mL）And potassium carbonate
138 g（1 mmol）, mixed system reaction temperature is controlled at 0 DEG C, the mL of methylsufonyl chloride 78 is added dropwise, is added dropwise, slowly rises
To room temperature reaction, reaction terminates to add the g of ammonium formate 95 in backward reaction system, is warming up to 100 DEG C of reactions, and reaction subtracts after terminating
Pressure is distilled to recover solvent, and residue is added in mixture of ice and water, glacial acetic acid regulation pH=3-4, separates out the g of white solid 149, yield
98.0%, purity 99.3%.
Embodiment 3
The g of 2- hydroxyl -6- methyl-isonicotinic acids 153 is added in reaction bulb（1 mmol）, solvent DMAC（306 mL）And sodium carbonate
106g（1 mmol）, mixed system reaction temperature is controlled at 0 DEG C, the mL of methylsufonyl chloride 78 is added dropwise, is added dropwise, slowly rises
To room temperature reaction, reaction terminates to add the g of ammonium acetate 77 in backward reaction system, is warming up to 80 DEG C of reactions, and reaction is depressurized after terminating
Solvent is distilled to recover, residue is added in mixture of ice and water, glacial acetic acid regulation pH=3-4, separates out the g of white solid 140, yield
92.1%, purity 99.5%.
Embodiment 4
The g of 2- hydroxyl -6- methyl-isonicotinic acids 153 is added in reaction bulb（1 mmol）, solvent DMAC（765 mL）And sodium carbonate
106g（1 mmol）, mixed system reaction temperature is controlled at 0 DEG C, the mL of methylsufonyl chloride 78 is added dropwise, is added dropwise, slowly rises
To room temperature reaction, reaction terminates to add the g of ammonium acetate 116 in backward reaction system, is warming up to 100 DEG C of reactions, and reaction subtracts after terminating
Pressure is distilled to recover solvent, and residue is added in mixture of ice and water, glacial acetic acid regulation pH=3-4, separates out the g of white solid 145, yield
95.4%, purity 99.0%.
Product1H NMR (400 MHz, DMSO-d6)：δ=6.61 (s, 1H), 6.35 (s, 1H), 2.21 (s,
3H). ESI MS [M+1] 153。
Embodiment above describes the general principle of the present invention, main features and advantages, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, the original for simply illustrating the present invention described in above-described embodiment and specification
Reason, under the scope for not departing from the principle of the invention, various changes and modifications of the present invention are possible, and these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (4)
1. the method for one pot process 6- methyl-2-aminos-isonicotinic acid, it is characterised in that concretely comprise the following steps：Into reaction vessel
2- hydroxyl -6- methyl-isonicotinic acids, solvent and alkali are added, wherein solvent is DMF or DMAC, and alkali is potassium carbonate or sodium carbonate, will be mixed
Methylsufonyl chloride is added dropwise at 0 DEG C in the reaction temperature control of zoarium system, is added dropwise and is warming up to room temperature reaction；Reaction terminates backward reaction
Amination reagent is added in system, wherein amination reagent is ammonium formate or ammonium acetate, be warming up to 80-100 DEG C of reaction be made 6- methyl-
2- amino-isonicotinic acids.
2. the method for one pot process 6- methyl-2-aminos-isonicotinic acid according to claim 1, it is characterised in that：It is described
The charge ratio of solvent and 2- hydroxyl -6- methyl-isonicotinic acids is 2-5mL:1g.
3. the method for one pot process 6- methyl-2-aminos-isonicotinic acid according to claim 1, it is characterised in that：It is described
The molar ratio of alkali and 2- hydroxyl -6- methyl-isonicotinic acids is 1:1.
4. the method for one pot process 6- methyl-2-aminos-isonicotinic acid according to claim 1, it is characterised in that：It is described
The molar ratio of amination reagent and 2- hydroxyl -6- methyl-isonicotinic acids is 1-1.5:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710936150.7A CN107602457A (en) | 2017-10-10 | 2017-10-10 | The method of the aminoisonicotinic acid of 6 methyl of one pot process 2 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710936150.7A CN107602457A (en) | 2017-10-10 | 2017-10-10 | The method of the aminoisonicotinic acid of 6 methyl of one pot process 2 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107602457A true CN107602457A (en) | 2018-01-19 |
Family
ID=61067716
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710936150.7A Pending CN107602457A (en) | 2017-10-10 | 2017-10-10 | The method of the aminoisonicotinic acid of 6 methyl of one pot process 2 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107602457A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101400668A (en) * | 2006-03-15 | 2009-04-01 | 田边三菱制药株式会社 | 2-(cyclic amino)-pyrimidone derivatives as TPK1 inhibitors |
| CN102388032A (en) * | 2009-04-08 | 2012-03-21 | 贝林格尔.英格海姆国际有限公司 | Substituted piperidines as CCR3 antagonists |
| CN102516249A (en) * | 2011-12-08 | 2012-06-27 | 成都苑东药业有限公司 | Anticoagulant diamine derivative |
| WO2014137723A1 (en) * | 2013-03-04 | 2014-09-12 | Merck Sharp & Dohme Corp. | Compounds inhibiting leucine-rich repeat kinase enzyme activity |
-
2017
- 2017-10-10 CN CN201710936150.7A patent/CN107602457A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101400668A (en) * | 2006-03-15 | 2009-04-01 | 田边三菱制药株式会社 | 2-(cyclic amino)-pyrimidone derivatives as TPK1 inhibitors |
| CN102388032A (en) * | 2009-04-08 | 2012-03-21 | 贝林格尔.英格海姆国际有限公司 | Substituted piperidines as CCR3 antagonists |
| CN102516249A (en) * | 2011-12-08 | 2012-06-27 | 成都苑东药业有限公司 | Anticoagulant diamine derivative |
| WO2014137723A1 (en) * | 2013-03-04 | 2014-09-12 | Merck Sharp & Dohme Corp. | Compounds inhibiting leucine-rich repeat kinase enzyme activity |
Non-Patent Citations (1)
| Title |
|---|
| DAI-SHI SU ET AL.: "Biaryl Ethersas Novel Non-nucleoside Reverse Transcriptase Inhibitors with Improved Potency against Key Mutant Viruses", 《J.MED.CHEM.》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104974060A (en) | Method for preparing sodium, 8-(2-hydroxybenzamido)octanoate | |
| WO2017096996A1 (en) | Preparation method for cobimetinib | |
| CN100591649C (en) | Method of preparing R-(+)-3-chlorophenylpropanol | |
| CN108912004B (en) | Synthetic method of pregabalin intermediate | |
| WO2009103773A1 (en) | A one-pot process for preparing 3-(2,2,2-trimethylhydrazinium)propionate dihydrate | |
| CN103435567A (en) | Valsartan refining method | |
| CN107602457A (en) | The method of the aminoisonicotinic acid of 6 methyl of one pot process 2 | |
| CN105524042A (en) | Method for preparing trelagliptin | |
| CN105440012A (en) | Lenalidomide and lenalidomide intermediate preparation method | |
| JP4095010B2 (en) | Improved method for producing rebamipide | |
| CN106831768A (en) | A kind of synthetic method of 2,6 dichloropyridines [3,4 B] pyrazine | |
| CN105461691B (en) | A kind of preparation method of Azelnidipine | |
| WO2016037588A2 (en) | New intermediate for synthesis of anti-aids drug enhancer cobicistat | |
| CN107382761B (en) | A kind of synthetic method that 3- amino -3- (4- hydroxy phenyl) propionic acid is split | |
| CN105777581A (en) | Cis-1-cyano-4-methoxycyclohexyl-2-(2, 5-dimethylphenyl)acetamide, preparation method and application thereof | |
| EP3153498B1 (en) | N-substituted phenyl glycine preparation method | |
| WO2018121050A1 (en) | Preparation method for 3-cyano-4-hydroxybenzoic acid methyl ester | |
| WO2018121051A1 (en) | Preparation method for methyl 3-cyano-4-isopropoxybenzoate | |
| CN104628518A (en) | Method for synthesizing repaglinide key intermediate | |
| CN103755577B (en) | A kind of method reclaiming Transbroncho alkali from Ambroxol HCl refinement mother liquor | |
| CN108976140B (en) | Preparation method and intermediate of 2-amino-6-ethylbenzoic acid | |
| EP3312174B1 (en) | Method for preparing trityl candesartan | |
| CN110872279B (en) | High-yield synthesis method of nilotinib | |
| CN111925340A (en) | Preparation process of methyl mercapto thiadiazole | |
| WO2016034150A1 (en) | Method for preparing bosutinib and crystal thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180119 |