CN104387319A - Method for preparing N,N-diethyl-3-pyridine carboxamide - Google Patents
Method for preparing N,N-diethyl-3-pyridine carboxamide Download PDFInfo
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- CN104387319A CN104387319A CN201410732805.5A CN201410732805A CN104387319A CN 104387319 A CN104387319 A CN 104387319A CN 201410732805 A CN201410732805 A CN 201410732805A CN 104387319 A CN104387319 A CN 104387319A
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- diethyl
- pyridine carboxamide
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- preparation
- nicotinic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses a method for preparing N,N-diethyl-3-pyridine carboxamide. The method comprises the following steps: adding nicotinic acid and dichloromethane into a reaction bottle and dropwise adding oxalyl chloride at the temperature of 0 DEG C; after oxalyl chloride is added dropwise, stirring and reacting at the temperature of 0 DEG C for 0.5-1 hour and reacting at room temperature for 4-6 hours; after the reaction is ended, dropwise adding a sodium hydroxide solution for regulating the pH value of the reaction solution to 7, slowly dropwise adding diethylamine at the temperature of 5 DEG C below zero to 10 DEG C; after diethylamine is added dropwise, reacting at the room temperature for 6-8 hours; after the reaction is finished, adding a sodium carbonate solution, stirring, standing for layering, removing the lower water layer, drying the organic layer, thereby obtaining a crude product of N,N-diethyl-3-pyridine carboxamide; adding the crude product of N,N-diethyl-3-pyridine carboxamide into dichloromethane, discoloring, oxidizing, removing dichloromethane, performing reduced-pressure distillation, thereby obtaining the finished product of N,N-diethyl-3-pyridine carboxamide. The method is low in equipment requirement, slight in environmental pollution and low in danger coefficient and is a synthesis method which is environment-friendly and very suitable for industrial production.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of preparation method of central nervous system stimulants, particularly a kind of preparation method of N, N-diethyl-3-pyridine carboxamide.
Background technology
N, N-diethyl-3-pyridine carboxamide, popular name Nikethamide, has another name called Ventramine, is central nervous system stimulants, be mainly used in central breathe and circulatory failure, narcotic, other central depressants poisoning first-aid, can for injection, also can be oral.
Nanjing pharmaceutical college 1978 editions " pharmaceutical chemistry " 323rd ~ 4 pages provides N, a kind of synthetic method of N-diethyl-3-pyridine carboxamide, it is with nicotinic acid and diethylamine salify, again with phosphorus oxychloride effect, dehydration generates hydrochloric acid Nikethamide, again through sodium hydroxide neutralization, organic solvent extraction, underpressure distillation obtains.Reaction formula is as follows:
Yuan Wenfu improves above-mentioned technique, gets rid of solvent extraction, adds soda ash in reaction solution after the neutralization, makes Nikethamide and water stratification.Although this improvement enormously simplify operation, turn eliminate the murder by poisoning of organic solvent to human body and the pollution to environment, avoid alcohol dissolubility impurity and bring rear operation into, the yield of product and first-time qualification rate are all increased.
But above-mentioned technique exists a fatal shortcoming, be just the use of hypertoxic raw material phosphorus oxychloride.This compound is met water and is acutely decomposed, and produces a large amount of heats and dense smoke, even explodes, and be corrosive under a lot of metal especially damp atmosphere condition.Therefore use this phosphorus oxychloride to prepare Nikethamide, danger coefficient is too large, and higher to operational requirement, is unfavorable for suitability for industrialized production.Therefore, reality is in the urgent need to a kind of operational safety, simple, and N is prepared in environmental protection, the method that yield is high, N-diethyl-3-pyridine carboxamide.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, provide a kind of low for equipment requirements, operational safety, simple, the preparation method of the N that environmental friendliness, yield are high, N-diethyl-3-pyridine carboxamide.
For achieving the above object, the concrete technical scheme that the present invention adopts is: a kind of preparation method of N, N-diethyl-3-pyridine carboxamide, is realized by following steps:
Nicotinic acid and methylene dichloride are dropped in reaction flask, 0 DEG C drips oxalyl chloride, after dripping off, 0 DEG C of stirring reaction 0.5 ~ 1h, 4 ~ 6h is reacted under room temperature, reaction terminates rear dropping sodium hydroxide solution and regulates reaction solution pH=7, then slowly diethylamine is dripped at-5 ~ 10 DEG C, after dropwising, room temperature reaction 6 ~ 8h, add sodium carbonate solution after completion of the reaction, stratification after stirring, divide the water layer gone below, organic layer drying obtains N, N-diethyl-3-pyridine carboxamide crude product, by N, N-diethyl-3-pyridine carboxamide crude product adds in methylene dichloride, through decolouring, after oxidation, underpressure distillation obtains N, N-diethyl-3-pyridine carboxamide finished product.The reaction formula of this preparation method is as follows:
The cut of what underpressure distillation in above-mentioned steps was collected is 160 ~ 170 DEG C/10 ~ 15 mmHg.
The massfraction of the sodium hydroxide solution in above-mentioned steps is 30%, and the massfraction of sodium carbonate solution is 25%.
The mol ratio of the nicotinic acid in above-mentioned steps, oxalyl chloride and methylene dichloride is 1: 1 ~ 3: 20 ~ 30.
Nicotinic acid in above-mentioned steps and the mol ratio of diethylamine are 1: 1 ~ 3.
Nicotinic acid in above-mentioned steps and the mol ratio of sodium carbonate are 1: 0.4 ~ 0.8.
Compared with prior art, the present invention has following beneficial effect: (1) this preparation method does not use phosphorus oxychloride poisonous reagent, and production security significantly improves; (2) reaction that the present invention relates to substantially at room temperature is carried out, lower to the requirement of equipment; (3) there is not the problem that ethanoyl comes off in reaction process, side reaction is few, and reaction yield is higher, and product purification process is simple; (4) S0 is not produced in reaction process
2gas, environmental protection; (5) boiling point of oxalyl chloride used of the present invention is lower, and part excessive in chloride process is easily distilled out of, thus less on the impact of follow-up amidation process.
Embodiment
Below in conjunction with embodiment, the present invention is elaborated, instead of limit protection scope of the present invention.
Embodiment 1
12.3g(is about 0.1mol) nicotinic acid and 128 ml methylene dichloride drop in reaction flask, stir, after dissolving completely, reaction flask being put into frozen water control temperature is 0 DEG C, slow dropping 12.8 ml oxalyl chloride, after dripping off, keep 0 DEG C of stirring reaction 0.5 ~ 1h, then room temperature is warming up to, reaction 4 ~ 6h, reaction terminates rear dropping 30% sodium hydroxide solution and regulates reaction solution pH=7, then controlling reaction mixture temperature is-5 ~ 10 DEG C of slowly dropping 15.5ml diethylamine, after dropwising, room temperature reaction 6 ~ 8h, add sodium carbonate solution 17 ml of 25% after completion of the reaction, stratification after stirring, divide the water layer gone below, organic layer drying obtains N, N-diethyl-3-pyridine carboxamide crude product, by N, N-diethyl-3-pyridine carboxamide crude product adds in methylene dichloride, through decolouring, oxidation, underpressure distillation after removing methylene dichloride, collect the cut of 160 ~ 170 DEG C/10 ~ 15 mmHg, obtain N, N-diethyl-3-pyridine carboxamide finished product 16.2g(yield is 91%).
Embodiment 2
12.3g(is about 0.1mol) nicotinic acid and 160 ml methylene dichloride drop in reaction flask, stir, after dissolving completely, reaction flask being put into frozen water control temperature is 0 DEG C, slow dropping 15.4 ml oxalyl chloride, after dripping off, keep 0 DEG C of stirring reaction 0.5 ~ 1h, then room temperature is warming up to, reaction 4 ~ 6h, reaction terminates rear dropping 30% sodium hydroxide solution and regulates reaction solution pH=7, then controlling reaction mixture temperature is-5 ~ 10 DEG C of slowly dropping 19.5ml diethylamine, after dropwising, room temperature reaction 6 ~ 8h, add sodium carbonate solution 20 ml of 25% after completion of the reaction, stratification after stirring, divide the water layer gone below, organic layer drying obtains N, N-diethyl-3-pyridine carboxamide crude product, by N, N-diethyl-3-pyridine carboxamide crude product adds in methylene dichloride, through decolouring, oxidation, underpressure distillation after removing methylene dichloride, collect the cut of 160 ~ 170 DEG C/10 ~ 15 mmHg, obtain N, N-diethyl-3-pyridine carboxamide finished product 15.9 g(yield is 89.3%).
Embodiment 3
12.3g(is about 0.1mol) nicotinic acid and 190 ml methylene dichloride drop in reaction flask, stir, after dissolving completely, reaction flask being put into frozen water control temperature is 0 DEG C, slow dropping 25 ml oxalyl chloride, after dripping off, keep 0 DEG C of stirring reaction 0.5 ~ 1h, then room temperature is warming up to, reaction 4 ~ 6h, reaction terminates rear dropping 30% sodium hydroxide solution and regulates reaction solution pH=7, then controlling reaction mixture temperature is-5 ~ 10 DEG C of slowly dropping 30 ml diethylamine, after dropwising, room temperature reaction 6 ~ 8h, add sodium carbonate solution 33 ml of 25% after completion of the reaction, stratification after stirring, divide the water layer gone below, organic layer drying obtains N, N-diethyl-3-pyridine carboxamide crude product, by N, N-diethyl-3-pyridine carboxamide crude product adds in methylene dichloride, through decolouring, oxidation, underpressure distillation after removing methylene dichloride, collect the cut of 160 ~ 170 DEG C/10 ~ 15 mmHg, obtain N, N-diethyl-3-pyridine carboxamide finished product 16.5 g(yield is 92.7%).
Claims (6)
1. the preparation method of a N, N-diethyl-3-pyridine carboxamide, be is characterized in that: realized by following steps:
Nicotinic acid is dissolved in methylene dichloride, 0 DEG C drips oxalyl chloride, after dripping off, 0 DEG C of stirring reaction 0.5 ~ 1h, 4 ~ 6h is reacted under room temperature, reaction terminates rear dropping sodium hydroxide solution and regulates reaction solution pH=7, then slowly diethylamine is dripped at-5 ~ 10 DEG C, after dropwising, room temperature reaction 6 ~ 8h, add sodium carbonate solution after completion of the reaction, stratification after stirring, divide the water layer gone below, organic layer drying obtains N, N-diethyl-3-pyridine carboxamide crude product, by N, N-diethyl-3-pyridine carboxamide crude product adds in methylene dichloride, through decolouring, after oxidation, underpressure distillation obtains N, N-diethyl-3-pyridine carboxamide finished product.
2. the preparation method of a kind of N, N-diethyl-3-pyridine carboxamide as claimed in claim 1, is characterized in that: the cut of what described underpressure distillation was collected is 160 ~ 170 DEG C/10 ~ 15 mmHg.
3. the preparation method of a kind of N, N-diethyl-3-pyridine carboxamide as claimed in claim 1, it is characterized in that: the massfraction of described sodium hydroxide solution is 30%, the massfraction of sodium carbonate solution is 25%.
4. the preparation method of a kind of N, N-diethyl-3-pyridine carboxamide as claimed in claim 1, is characterized in that: the mol ratio of described nicotinic acid, oxalyl chloride and methylene dichloride is 1: 1 ~ 3: 20 ~ 30.
5. the preparation method of a kind of N, N-diethyl-3-pyridine carboxamide as claimed in claim 1, is characterized in that: described nicotinic acid and the mol ratio of diethylamine are 1: 1 ~ 3.
6. the preparation method of a kind of N, N-diethyl-3-pyridine carboxamide as claimed in claim 1, is characterized in that: described nicotinic acid and the mol ratio of sodium carbonate are 1: 0.4 ~ 0.8.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201410732805.5A CN104387319A (en) | 2014-12-07 | 2014-12-07 | Method for preparing N,N-diethyl-3-pyridine carboxamide |
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| CN201410732805.5A CN104387319A (en) | 2014-12-07 | 2014-12-07 | Method for preparing N,N-diethyl-3-pyridine carboxamide |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108675956A (en) * | 2018-04-12 | 2018-10-19 | 杭州金仕源医药化工有限公司 | A kind of preparation method of nikethamidum |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2182903C2 (en) * | 2000-08-30 | 2002-05-27 | Антонова Наталья Николаевна | Method of synthesis of nicotinic acid diethylamide |
| WO2004032908A2 (en) * | 2002-10-04 | 2004-04-22 | Abbott Laboratories | Method of inhibiting angiogenesis |
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2014
- 2014-12-07 CN CN201410732805.5A patent/CN104387319A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2182903C2 (en) * | 2000-08-30 | 2002-05-27 | Антонова Наталья Николаевна | Method of synthesis of nicotinic acid diethylamide |
| WO2004032908A2 (en) * | 2002-10-04 | 2004-04-22 | Abbott Laboratories | Method of inhibiting angiogenesis |
Non-Patent Citations (1)
| Title |
|---|
| YIGANG ZHAO等: "C-H Activation by Amide Chelation Control: Ruthenium-Catalyzed Direct Synthesis of 2-Aryl-3-furanamides", 《ADVANCED SYNTHESIS & CATALYSIS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108675956A (en) * | 2018-04-12 | 2018-10-19 | 杭州金仕源医药化工有限公司 | A kind of preparation method of nikethamidum |
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Application publication date: 20150304 |