CN102249990B - Process for synthesizing 6-(trifluoromethyl)pyridine-3-carboxaldehyde - Google Patents
Process for synthesizing 6-(trifluoromethyl)pyridine-3-carboxaldehyde Download PDFInfo
- Publication number
- CN102249990B CN102249990B CN 201110152006 CN201110152006A CN102249990B CN 102249990 B CN102249990 B CN 102249990B CN 201110152006 CN201110152006 CN 201110152006 CN 201110152006 A CN201110152006 A CN 201110152006A CN 102249990 B CN102249990 B CN 102249990B
- Authority
- CN
- China
- Prior art keywords
- trifluoromethyl
- reaction
- add
- cigarette aldehyde
- butyllithium
- 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.)
- Expired - Fee Related
Links
Landscapes
- Pyridine Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention belongs to the technical field of medicinal intermediate organic synthesis, and relates to a process for synthesizing 6-(trifluoromethyl)pyridine-3-carboxaldehyde. The process is characterized by comprising the following steps of: under the protection of nitrogen, adding 1eq of 5-bromo-2-(trifluoromethyl)pyridine in a stoichiometric ratio into a reaction container, dissolving in an organic solvent, controlling the temperature to be between -20 and 10DEG C, adding 1.0 to 5.0eq of stabilizer, dripping 1.0 to 2.0eq of butyllithium hexane solution with full stirring, stirring overnight, and recrystallizing and purifying a crude product. The process has the advantages that: by introducing the stabilizer, the activity of butyllithium is partially reduced, the stability of the reaction intermediate state is improved, side reactions at high reaction temperature are inhibited, the reaction with the dimethylformamide is ensured, and the yield is improved; meanwhile, the problems of high energy consumption and no suitability for industrialization brought by ultralow temperature in the prior art are avoided; and the product can be continuously produced on general equipment, the product quality is stable and reliable, and the purity is over 98 percent.
Description
Technical field
The present invention relates to the synthesis technique by 2-trifluoromethyl-5-bromopyridine reaction preparation 6-trifluoromethyl cigarette aldehyde, belong to the medicine intermediate technical field of organic synthesis.
Background technology
6-trifluoromethyl cigarette aldehyde as a kind of important medicine intermediate, is used increasingly extensive at pharmacy field.6-trifluoromethyl cigarette aldehyde relies on unique effect and the reactive behavior of itself and biomass cells, and in the drug research to various diseases, the screening aspect of active medicine shows good effect.For example, it has stronger restraining effect to leukemia cell and people's larynx squamous cell carcinoma; The phosphodiesterase inhibitor that comprises 6-trifluoromethyl cigarette aldehyde fragment aspect the treatment of nerve conduction and nervous disorders effect significantly (J. Med. Chem. 2009,52,7946-7949); Some compounds that synthesize take 6-trifluoromethyl cigarette aldehyde as raw material also have good curative effect (WO2011004017, WO2011033115, WO2010111060 etc.) at aspects such as expelling parasite, hepatitis treatment, pain therapies.
The synthetic method of 6-trifluoromethyl cigarette aldehyde, bibliographical information is few, and the report method have many disadvantages, substantially there is no the value of suitability for industrialized production.The synthesis technique of bibliographical information can be summarized as two classes substantially:
1) from the 6-trifluoromethyl nicotinic acid, adopt first reduction, the method for rear oxidation obtains 6-trifluoromethyl cigarette aldehyde.
Wherein reduction process generally adopts tetrahydrochysene lithium aluminium (LiAlH
4) etc. reagent, oxidising process adopts Manganse Dioxide (MnO
2), Martin reagent or adopt catalytic oxidation (WO2008148853, WO2007110667 etc.).The disadvantage of these methods is that the raw material preparation is very difficult, expensive, causes the cost of the finished product very high, does not have actual production to be worth, and adopts in addition tetrahydrochysene lithium aluminium (LiAlH
4) etc. during reductive agent, operating process produces a large amount of hydrogen, easily causes combustion explosion, has potential safety hazard when producing especially in a large number.
2) take 2-trifluoromethyl-5-bromopyridine as raw material, by butyllithium (BuLi) reaction, prepare 6-trifluoromethyl cigarette aldehyde.
This class reaction requirement (78 ℃ or lower) under very low temperature is carried out, and due to the high reactivity of butyllithium, requires the strict anhydrous and oxygen-free of reaction system simultaneously, cause the reaction process energy consumption very high, operational requirement is very harsh, and for different replacement groups, reaction yield alters a great deal.Generally all more than 90%, and when changing trifluoromethyl into, because electronic effect changes, yield reduces rapidly, only has 30～50% such as 6 yields of bibliographical information when being methoxyl group.After the temperature of reaction of system raises (30 ℃), basically can not get the product that needs.
6-trifluoromethyl cigarette aldehyde in the market only have the reagent product of small packages, and price is very expensive, and the synthetic and large-scale production of the industry of this product is on market or blank.Along with the increase of the 6-trifluoromethyl cigarette aldehyde market requirement, people urgently wish to search out one can industrial amplification 6-trifluoromethyl cigarette aldehyde synthesis technique.Therefore, the extensive synthetic and process exploitation research of 6-trifluoromethyl cigarette aldehyde has vast potential for future development and good market using value.
Summary of the invention
The purpose of this invention is to provide a kind of simple, environmental protection and energy saving, the raw material cost that is easy to get low, can realize the 6-trifluoromethyl cigarette aldehyde synthesis technique of the large production of technical scale.
For achieving the above object, the technical scheme that adopts is: a kind of synthesis technique of 6-trifluoromethyl cigarette aldehyde: comprise crude product extraction extraction and recrystallization purifying, it is characterized in that: under nitrogen protection, in reaction vessel in stoichiometric ratio, add 2-trifluoromethyl-5-bromopyridine 1eq, use organic solvent dissolution, controlling temperature of reaction is-20～10 ℃, add stablizer 1.0～5.0eq, drip 1.0～2.0eq butyllithium hexane solution under whipped state, continue stirring and add again dimethyl formamide 1.5～3.0eq after 2 hours, naturally heat up, stirring is spent the night; The TLC thin-layer chromatography is followed the tracks of, add entry after 2-trifluoromethyl in reaction solution-5-bromopyridine completely dissolve, use dichloromethane extraction, concentrating under reduced pressure is removed dissolving raw material organic solvent and extraction agent methylene dichloride, with the methylene dichloride dissolving, washing, drying concentrate again, underpressure distillation obtains 6-trifluoromethyl cigarette aldehyde crude product.
Described organic solvent is tetrahydrofuran (THF), ether, normal hexane, a kind of in methyl tertiary butyl ether.
Described stablizer is quadrol, piperidines, 2,2,6,6-tetramethyl piperidine, N, N '-Tetramethyl Ethylene Diamine, Cadmium chloride fine powder, magnesium chloride, one or more in zinc chloride.
Each reactant is in stoichiometric ratio in reaction vessel, preferred 2-trifluoromethyl-5-bromopyridine 1eq, butyllithium 1.0～1.5 eq, dimethyl formamide 1.5 eq, stablizer 1.0～3.5 eq.
Preferred-20～0 ℃ of described temperature of reaction.
positively effect of the present invention is: take 2-trifluoromethyl-5-bromopyridine as raw material, react by butyllithium, in the technique of preparation 6-trifluoromethyl cigarette aldehyde, introduce stablizer, part reduces the activity of butyllithium, increase the stability of Intermediates, suppressed the generation of side reaction under the higher reaction temperatures, thereby greatly promoted temperature of reaction, guaranteed the reaction with dimethyl formamide, improved the yield of 6-trifluoromethyl cigarette aldehyde, avoided simultaneously the high energy consumption that in the prior art, condition of ultralow temperature is brought and can not industrial problems, can produce continuously on general-purpose equipment, stable and reliable product quality, purity reaches more than 98%.
Embodiment
Below the invention will be further described with embodiment, in order to make those of ordinary skills can understand and implement the present invention.
Embodiment 1:
Under nitrogen protection; in the 1L three-necked bottle, add 2-trifluoromethyl-5-bromopyridine 22.6g(1eq), add simultaneously the 400mL tetrahydrofuran (THF) that it is dissolved; reaction system is cooled to-20 ℃ with ice-ethanol bath; add 2,2,6; 6-tetramethyl piperidine 21.1g (1.5eq); fully stir after 0.5 hour butyllithium (2.5M, hexane solution) 48mL(1.2eq) slowly be added drop-wise in reaction system, add and continue to stir 2 hours.Then add and pass through in advance hydrolith (CaH
2) dry, dimethyl formamide 11.6mL (1.5eq) that distillation is processed, the reaction nature heats up, and stirring is spent the night.Thin plate chromatography (TLC) is followed the tracks of reaction, after 2-trifluoromethyl-5-bromopyridine completely dissolve, add 400mL water in reaction solution, system layering, separating funnel is told organic phase, water merges organic phase with twice of dichloromethane extraction (300mL*2), and the water pump concentrating under reduced pressure is removed dissolving raw material organic solvent and extraction agent methylene dichloride.Resistates is washed twice (200mL*2) with methylene dichloride 350mL dissolving, and saturated aqueous common salt 200mL washes once, anhydrous sodium sulfate drying, and concentrated, underpressure distillation obtains crude product 6-trifluoromethyl cigarette aldehyde 14.4g.Nuclear magnetic resonance spectrum (
1HNMR, CDCl
3Solvent) contain the 5%(mol ratio in the demonstration product) dimethyl formamide and 3%(mol ratio) 2,2,6, the 6-tetramethyl piperidine.The sherwood oil recrystallization gets white solid powder 12.4g, yield 70.8%, and purity 98.5%,
1HNMR(400Hz, CDCl
3): 10.22 (s, 1H), 9.20 (s, 1H), 8.39 (d, 1H), 8.37 (d, 1H).
Embodiment 2:
Under nitrogen protection; with 2-trifluoromethyl-5-bromopyridine 22.6g(1eq) add in the 1L three-necked bottle; add simultaneously the 400mL tetrahydrofuran (THF) that it is dissolved; reaction system is cooled to-20 ℃ with ice-ethanol bath; add N, N '-Tetramethyl Ethylene Diamine 23.2g (2.0eq) anhydrous chlorides of rase cadmium 27.4g (1.5eq) fully stirs after 1 hour butyllithium (2.5M; hexane solution) 60mL(1.5eq) slowly be added drop-wise in reaction system, add rear continuation and stirred 2 hours.Then add and pass through in advance hydrolith (CaH
2) dry, dimethyl formamide 11.6mL (1.5eq) that distillation is processed, the reaction nature heats up, and stirring is spent the night.TLC follows the tracks of reaction, and treatment process gets crude product 6-trifluoromethyl cigarette aldehyde 13.5g with embodiment 1.The sherwood oil recrystallization gets white solid powder 11.6g, yield 66.3%, purity 98.8%.
Embodiment 3:
Under nitrogen protection; 2-trifluoromethyl-5-bromopyridine 22.6g (1eq) is added the 1L three-necked bottle; add simultaneously the 500mL anhydrous diethyl ether that it is dissolved, reaction system is cooled to-10 ℃ with ice-acetone bath, adds 2; 2; 6,6-tetramethyl piperidine 14.1g (1.0eq) fully stirs after 0.5 hour butyllithium (2.5M; hexane solution) 40mL(1.0eq) slowly add in reaction soln, add and continue to stir 3 hours.Then add and pass through in advance hydrolith (CaH
2) dry, dimethyl formamide 15.5mL (2.0eq) that distillation is processed, the reaction nature heats up, and stirring is spent the night.TLC follows the tracks of reaction, and treatment process obtains crude product 6-trifluoromethyl cigarette aldehyde 13.9g with embodiment 1.Sherwood oil carries out recrystallization, gets white solid powder 11.8g, yield 67.4%, purity 98.7%.
Embodiment 4:
Under nitrogen protection; 2-trifluoromethyl-5-bromopyridine 22.6g (1eq) is added the 1L three-necked bottle; add simultaneously the 400mL methyl tertiary butyl ether that it is dissolved; reaction system is bathed with cryosel and is cooled to 0 ℃; add piperidinyl-1 2.8g (1.5eq), Magnesium Chloride Anhydrous 14.3g(1.5eq), fully stir after 1 hour butyllithium (2.5M; hexane solution) 60mL(1.5eq) slowly add in reaction soln, add and continue to stir 1 hour.Then add and pass through in advance hydrolith (CaH
2) dry, dimethyl formamide 11.6mL (1.5eq) that distillation is processed, the reaction nature heats up, and stirring is spent the night.Treatment process obtains crude product 6-trifluoromethyl cigarette aldehyde 12.9g with embodiment 1.Sherwood oil carries out recrystallization, gets white solid powder 10.8g, yield 61.7%, purity 98.3 %.
Embodiment 5:
Under nitrogen protection; add 2-trifluoromethyl-5-bromopyridine 22.6g (1eq) in the 1L three-necked bottle; add simultaneously the 400mL tetrahydrofuran (THF) that it is dissolved; reaction system is cooled to 10 ℃ with ice-water bath; add N, N '-Tetramethyl Ethylene Diamine 34.8g (3.0eq) Zinc Chloride Anhydrous 36.5g (2.0eq) fully stirs after 1 hour butyllithium (2.5M; hexane solution) 80mL(2.0eq) slowly be added drop-wise in reaction system, add rear continuation and stirred 2 hours.Then add and pass through in advance hydrolith (CaH
2) dry, dimethyl formamide 23mL (3eq) that distillation is processed, the reaction nature heats up, and stirring is spent the night.Treatment process gets crude product 6-trifluoromethyl cigarette aldehyde 8.6g with embodiment 1.The sherwood oil recrystallization gets white solid powder 7.1g, yield 40.6%, purity 98.1%.
Claims (4)
1. 6-trifluoromethyl cigarette aldehyde synthesis technique, comprise crude product extraction extraction and recrystallization purifying, it is characterized in that: under nitrogen protection, in reaction vessel in stoichiometric ratio, add 2-trifluoromethyl-5-bromopyridine 1eq, use organic solvent dissolution, controlling temperature of reaction is-20～10 ℃, add stablizer 1.0～5.0eq, drip 1.0～2.0eq butyllithium hexane solution under whipped state, continue stirring and add dimethyl formamide 1.5～3.0eq after 2 hours again, naturally heat up, stirring is spent the night; The TLC thin-layer chromatography is followed the tracks of, add entry after 2-trifluoromethyl in reaction solution-5-bromopyridine completely dissolve, use dichloromethane extraction, concentrating under reduced pressure is removed dissolving raw material organic solvent and extraction agent methylene dichloride, with the methylene dichloride dissolving, washing, drying concentrate again, underpressure distillation obtains 6-trifluoromethyl cigarette aldehyde crude product; Described stablizer is quadrol, piperidines, 2,2,6,6-tetramethyl piperidine, N, N '-Tetramethyl Ethylene Diamine, Cadmium chloride fine powder, one or more in magnesium chloride and zinc chloride.
2. a kind of 6-trifluoromethyl cigarette aldehyde synthesis technique according to claim 1, it is characterized in that: described organic solvent is tetrahydrofuran (THF), ether, normal hexane, a kind of in methyl tertiary butyl ether.
3. a kind of 6-trifluoromethyl cigarette aldehyde synthesis technique according to claim 1, it is characterized in that: in reaction vessel each reactant in stoichiometric ratio, preferred 2-trifluoromethyl-5-bromopyridine 1eq, butyllithium 1.0～1.5eq, dimethyl formamide: 1.5 eq, stablizer 1.0～3.5eq.
4. a kind of 6-trifluoromethyl cigarette aldehyde synthesis technique according to claim 1, is characterized in that: preferred-20～0 ℃ of described temperature of reaction.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110152006 CN102249990B (en) | 2011-06-08 | 2011-06-08 | Process for synthesizing 6-(trifluoromethyl)pyridine-3-carboxaldehyde |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110152006 CN102249990B (en) | 2011-06-08 | 2011-06-08 | Process for synthesizing 6-(trifluoromethyl)pyridine-3-carboxaldehyde |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102249990A CN102249990A (en) | 2011-11-23 |
| CN102249990B true CN102249990B (en) | 2013-06-12 |
Family
ID=44977602
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110152006 Expired - Fee Related CN102249990B (en) | 2011-06-08 | 2011-06-08 | Process for synthesizing 6-(trifluoromethyl)pyridine-3-carboxaldehyde |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102249990B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110396119B (en) * | 2018-04-24 | 2022-11-08 | 上海迪赛诺药业股份有限公司 | Preparation method of canagliflozin intermediate |
| CN109627209B (en) * | 2018-12-24 | 2020-09-01 | 浙江工业大学上虞研究院有限公司 | Preparation method of 2- (trifluoromethyl) pyridine-3-formaldehyde (I) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0606015D0 (en) * | 2006-03-28 | 2006-05-03 | Merck Sharp & Dohme | therapeutic agents |
| GB0710865D0 (en) * | 2007-06-06 | 2007-07-18 | Glaxo Group Ltd | Novel compounds |
-
2011
- 2011-06-08 CN CN 201110152006 patent/CN102249990B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN102249990A (en) | 2011-11-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102816200B (en) | Method for preparing abiraterone acetate | |
| CN102584795B (en) | Preparing method of crizotinib | |
| CN105330616A (en) | Preparation method of cariprazine | |
| CN102249990B (en) | Process for synthesizing 6-(trifluoromethyl)pyridine-3-carboxaldehyde | |
| CN103204801A (en) | Synthesis method for N-Boc-3-piperidone | |
| CN105646532B (en) | A kind of synthetic method of diaza spiro [5.6] dodecane of 2 tertbutyloxycarbonyl, 10 carbonyl, 8 oxo 2,11 | |
| CN107266361A (en) | The synthetic method of the picoline of 2 amino 5 | |
| CN105440012A (en) | Lenalidomide and lenalidomide intermediate preparation method | |
| CN103724203A (en) | Preparation method of o-methyl hydroxyphenylacetate | |
| CN102875544A (en) | Preparation technology of solifenacin succinate | |
| CN104262236B (en) | Method for preparing corresponding pyridine compound from 1,4-dihydropyridine compound | |
| CN105732648A (en) | Nitrogen heterocyclic ring compound of pyrrolofuran and synthetic method | |
| CN102532010B (en) | Preparation method of 2-chloro-3-aminopyridine | |
| CN105111155A (en) | Synthesis method of tert-butyl 4,7-diazaspiro[2.5]octyl-7-formate | |
| CN101623648A (en) | Catalyst of picolinic acid synthesized by selectively oxygenizing picoline as well as preparation method and application thereof | |
| CN102993092A (en) | Synthetic method for 2-Chloronicotinicacid | |
| CN103755631B (en) | The direct aromatize technique of pyridine derivate | |
| CN103242226A (en) | Preparation method of medicine intermediate 3-[(3-amino-4-methylaminobenzoyl) (pyridine-2-yl)amino] ethyl propionate | |
| CN104910068A (en) | 2-cyano isonicotinic acid hydrazide 1.5 p-toluenesulfonate synthetic method | |
| CN101985451A (en) | Preparation method of prasugrel intermediate | |
| CN104387317A (en) | Preparation method and separation and purification method for 6-chloronicotinic acid | |
| CN101544651B (en) | Method for synthesizing polysubstitution pyridinone compounds | |
| CN104447523B (en) | Method for synthesizing aminopyridine with pyridine base mixture as well as separation and purification method of aminopyridine | |
| CN103214413B (en) | Heterocycle-containing trifluoromethyl ketone compound and preparation method thereof | |
| CN103172527A (en) | Method for preparing clopidogrel synthetic intermediate-L-2-chlorophenylglycine methyl ester |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130612 Termination date: 20210608 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |