CN109748866B - Preparation method of N, N-diethylnicotinamide - Google Patents
Preparation method of N, N-diethylnicotinamide Download PDFInfo
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- CN109748866B CN109748866B CN201811523387.3A CN201811523387A CN109748866B CN 109748866 B CN109748866 B CN 109748866B CN 201811523387 A CN201811523387 A CN 201811523387A CN 109748866 B CN109748866 B CN 109748866B
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Abstract
The invention belongs to the field of organic chemistry, in particular to a preparation method of N, N-diethylnicotinamide, experimental verification shows that an activator is used in the reaction process, more or less byproducts are generated, so that the treatment difficulty of waste gas and waste water after reaction is increased, the application does not need the activator in the reaction process, the treatment after reaction is simple, a specific catalyst is added for catalytic reaction, the activity of reactants is increased, hydrogen chloride and water generated in a reaction system are taken away as far as possible by a distilling agent to promote equilibrium reaction, the high-purity and high-yield N, N-diethylnicotinamide is obtained after reduced pressure distillation, hydrogen chloride is generated in the reaction process, the pH is adjusted by a liquid alkali aqueous solution after water absorption, the post-treatment of the reaction is only sodium chloride, the activator bringing various waste gases or waste liquids is abandoned, the treatment is easy, the environmental protection is realized, and simultaneously, the raw materials used in the reaction are low in price, and the reaction cost is reduced.
Description
Technical Field
The invention belongs to the field of organic chemistry, and particularly relates to a preparation method of N, N-diethylnicotinamide.
Background
N, N-diethyl nicotinamide, another name is Nicorm, ketamine and nicotinamide, the pharmacological function can selectively excite medulla oblongata respiratory center, and can excite the respiratory center through the reflection of carotid body and aorta body chemoreceptor to accelerate the respiration, when the respiratory center is inhibited, the excitation is more obvious, and N, N-diethyl nicotinamide is mainly used for the respiratory and circulatory failure caused by diseases or central depressant poisoning, and can also be used for the rescue after inhalation anesthetic poisoning.
The traditional production mode of N, N-diethylnicotinamide generally takes nicotinic acid and diethylamine as raw materials, but the direct reaction activities of the two are not enough from the aspect of organic synthesis, and an activating reagent is generally used, for example, patent document (US1403117) adopts thionyl chloride as the activating reagent, and patent document (PL43588) adopts phosphorus oxychloride as an activating agent, and the activating agents have the function of converting nicotinic acid into active intermediate acyl halide or anhydride or ester to further react with diethylamine in the reaction process, but the post-treatment waste water or waste gas generated by the reaction of the activating agents is large in amount, generates at least two components of acid or salt, is complex in component, and greatly increases the treatment difficulty of three wastes.
Aiming at the problems, the invention provides a method for preparing N, N-diethylnicotinamide, which comprises the steps of preparing the N, N-diethylnicotinamide by reacting diethylamine with high boiling point with nicotinic acid, adding a specific catalyst for catalytic reaction, and increasing the activity of reactants.
Disclosure of Invention
In order to solve the problems of more by-products, large difficulty in post-reaction treatment and the like in the preparation of N, N-diethylnicotinamide by the prior art, the invention provides a method for preparing N, N-diethylnicotinamide, which utilizes diethylamine with higher boiling point to replace diethylamine to improve the reaction temperature with nicotinic acid, adds a specific catalyst to catalyze the reaction, increases the activity of reactants, takes away hydrogen chloride and water generated by a reaction system as much as possible by using a distilling agent to promote an equilibrium reaction, regulates the pH value by using a liquid alkali aqueous solution, only contains sodium chloride in the post-treatment of the reaction, abandons an activating agent bringing various waste gases or waste liquids, reduces three wastes and also reduces the reaction cost.
The technical scheme adopted by the invention for solving the technical problem is as follows:
a process for the preparation of N, N-diethylnicotinamide, said process comprising the steps of:
s1, adding a sufficient amount of solvent and a certain amount of nicotinic acid into the reaction bottle, and mixing and stirring for 5-10 minutes;
s2, adding a certain amount of supported catalyst into the mixed solution obtained in the step S1, adding a certain amount of diethylamine salt, continuously stirring for 10-20 minutes, heating to 100-220 ℃, and carrying out heat preservation and distillation for 60-90 minutes under normal pressure;
the supported catalyst comprises a carrier and an active component, wherein the active component is metallic nickel or/and an oxide thereof, and the carrier is a random cross network structure formed by winding and lapping mixed fibers;
s3, stopping distillation after the reaction is finished, taking out the supported catalyst after the mixture is cooled to room temperature, adding distilled water into a reaction bottle, adjusting the pH value of the water phase to 8-9 by using a liquid caustic soda aqueous solution, and separating out an organic phase;
s4, carrying out vacuum distillation on the separated organic phase to recover the solvent, wherein the recovery temperature of the solvent is as follows:
and (3) carrying out reduced pressure distillation on the residual liquid at the temperature of 48-105 ℃/10mmHg to obtain a product, wherein the collection temperature of the product is as follows: 152-155 ℃/10 mmHg.
The reaction formula for preparing N, N-diethyl nicotinoyl by reacting nicotinic acid and diethylamine salt is as follows:
wherein X is Cl-、Br-Or I-。
Preferably, the supported catalyst comprises a carrier and an active component, wherein the mass fraction of the active component is 5-30%, the balance is the carrier, and the total amount is 100%;
the mixed fiber is prepared from alumina fiber, potassium hexatitanate whisker and sepiolite fiber according to the mass ratio (15-45%): (30-60%): (10% -40%) of the components;
the preparation method of the supported catalyst comprises the following steps:
and (3) soaking the carrier into the aqueous solution of the precursor of the active component, vacuum-soaking at room temperature for 1-3 hours, taking out, drying and sintering the carrier loaded with the active component to obtain the supported catalyst.
The aqueous solution of the precursor of the active component is an aqueous solution of nickel salt, wherein the nickel salt is nickel sulfate, nickel nitrate, nickel oxalate or nickel acetate, and the supported catalyst containing the active component with different mass fractions is obtained by preparing aqueous solutions of nickel salts with different concentrations.
Three fiber raw materials of the alumina fiber, the potassium hexatitanate whisker and the sepiolite fiber are easy to obtain, the advantages of the fibers are complementary through a plurality of levels of irregular cross network structures formed by winding and lapping, active components are easy to absorb, deformation can not occur in the reaction process, the specific surface area can be increased, the reaction process is accelerated, and the recovery is convenient.
Preferably, the solvent is any one of o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, bromobenzene, chlorobenzene, xylene (mixed o-m-p-xylene), toluene and nitrobenzene.
More preferably, the solvent is ortho-dichlorobenzene. The o-dichlorobenzene has low price and good effect.
Preferably, the diethylamine salt is diethylamine hydrochloride, diethylamine hydrobromide or diethylamine hydroiodide.
More preferably, the diethylamine salt is diethylamine hydrochloride. The price of the diethylamine hydrochloride is low, and the yield of the product synthesized by the diethylamine hydrochloride is high.
Preferably, the ratio of the volume mL of the solvent to the mass g of nicotinic acid and the mass g of diethylamine salt is 5: (3-4): (3-4).
Preferably, the solvent recovery temperature in step S5 is 76 to 90 ℃/10 mmHg. The reduced pressure distillation temperature of the solvent is 48-105 ℃/10mmHg, the reaction is slow when the temperature is low, the sublimation of diethylamine hydrohalide is serious when the temperature is high, and the optimal temperature is 76-90 ℃/10 mmHg.
Preferably, the preparation method of the N, N-diethylnicotinoyl comprises the following steps:
s1, adding 300mL of o-dichlorobenzene and 123g of nicotinic acid into the reaction bottle, mixing and stirring for 8 minutes;
s2, adding 12g of supported catalyst into the mixed solution obtained in the step S1, adding 120.5g of diethylamine salt, continuing stirring for 10 minutes, heating to 100-220 ℃, and carrying out heat preservation and distillation for 90 minutes at normal pressure;
s3, after the reaction is finished, cooling the mixture to room temperature, taking out the supported catalyst, adding 100mL of distilled water into a reaction bottle, adjusting the pH value to 8-9 by using a sodium hydroxide solution, and separating an organic phase;
s4, carrying out vacuum distillation on the separated organic phase to recover o-dichlorobenzene, wherein the recovery temperature of the o-dichlorobenzene is as follows: and (3) continuing carrying out reduced pressure distillation on the residual liquid at the temperature of 76-90 ℃/10mmHg to obtain a product, wherein the collection temperature of the product is as follows: 152-155 ℃/10 mmHg.
Experimental verification finds that byproducts are generated more or less as long as an activating agent is used in the reaction process, so that the treatment difficulty of the waste gas and the waste water after the reaction is increased, the activating agent is not needed in the reaction process, and the reaction post-treatment is simple.
The invention has the beneficial effects that:
the invention provides a preparation method of N, N-diethylnicotinamide, which does not need an activating agent, utilizes diethylamine with higher boiling point to replace diethylamine to increase the reaction temperature with nicotinic acid, adds a specific catalyst to catalyze the reaction, increases the activity of reactants, takes away hydrogen chloride and water generated in a reaction system as much as possible by a distilling agent to promote a balanced reaction, obtains the N, N-diethylnicotinamide with high purity and high yield after reduced pressure distillation, generates hydrogen chloride in the reaction process, adjusts the pH value by a liquid alkali aqueous solution after water absorption, has sodium chloride only after the post-treatment of the reaction, abandons the activating agent bringing various waste gases or waste liquids, is easy to treat, is green and environment-friendly, simultaneously has low price of raw materials used in the reaction, and reduces the reaction cost.
Detailed Description
The technical solution of the present invention is further explained by the following specific examples.
Example 1:
a process for the preparation of N, N-diethylnicotinamide, said process comprising the steps of:
s1, adding 300mL of o-dichlorobenzene and 123g of nicotinic acid into the reaction bottle, mixing and stirring for 8 minutes;
s2, adding 12g of supported catalyst into the mixed solution obtained in the step S1, adding 120.5g of diethylamine salt, continuing stirring for 10 minutes, heating to 100-220 ℃, and carrying out heat preservation and distillation for 90 minutes at normal pressure;
s3, after the reaction is finished, cooling the mixture to room temperature, taking out the catalyst, adding 100mL of distilled water into a reaction bottle, adjusting the pH value of the water phase to 8-9 by using a sodium hydroxide solution, and separating out an organic phase;
s4, carrying out vacuum distillation on the separated organic phase to recover o-dichlorobenzene, wherein the recovery temperature of the o-dichlorobenzene is as follows: and (3) continuing carrying out reduced pressure distillation on the residual liquid at the temperature of 76-90 ℃/10mmHg to obtain a product, wherein the collection temperature of the product is as follows: 152-155 ℃/10 mmHg.
The preparation method of the supported catalyst comprises the following steps:
the alumina fiber, the potassium hexatitanate whisker and the sepiolite fiber are 20 percent by mass: 50%: obtaining carrier raw material fibers with the total mass of 9g in 30 percent, and winding and lapping the fibers to form a random cross network structure;
soaking the carrier into 0.5mol/L nickel nitrate water solution, vacuum soaking at room temperature for 1 hour, taking out, drying and sintering the carrier loaded with the active component to obtain the supported catalyst, wherein the sintering temperature is not lower than 400 ℃.
The final yield of N, N-diethylnicotinamide was 87%.
Example 2:
a process for the preparation of N, N-diethylnicotinamide, said process comprising the steps of:
s1, adding 400mL of o-dichlorobenzene and 246g of nicotinic acid into the reaction bottle, mixing and stirring for 10 minutes;
s2, adding 24g of supported catalyst into the mixed solution obtained in the step S1, adding 241g of diethylamine salt, continuing stirring for 10 minutes, heating to 100-220 ℃, and carrying out heat preservation and distillation for 90 minutes under normal pressure;
s3, stopping distillation after the reaction is finished, taking out the catalyst after the mixture is cooled to room temperature, adding 150mL of distilled water into a reaction bottle, adjusting the pH value of the water phase to 8-9 by using a sodium hydroxide solution, and separating out an organic phase;
s4, carrying out vacuum distillation on the separated organic phase to recover o-dichlorobenzene, wherein the recovery temperature of the o-dichlorobenzene is as follows: and (3) continuing carrying out reduced pressure distillation on the residual liquid at the temperature of 76-90 ℃/10mmHg to obtain a product, wherein the collection temperature of the product is as follows: 152-155 ℃/10 mmHg.
The preparation method of the supported catalyst comprises the following steps:
the alumina fiber, the potassium hexatitanate whisker and the sepiolite fiber are 15% in mass ratio: 55%: 40 percent of carrier raw material fiber is obtained, the total mass of the raw material fiber is 20g, and the fiber is wound and lapped to form a random cross network structure;
soaking the carrier into 0.8mol/L nickel oxalate water solution, vacuum soaking at room temperature for 2 hours, taking out, drying and sintering the carrier loaded with the active component to obtain the supported catalyst, wherein the sintering temperature is not lower than 400 ℃.
The final yield of N, N-diethylnicotinamide was 85.6%.
The above-described embodiments are merely preferred embodiments of the present invention, which is not intended to be limiting in any way, and other variations and modifications are possible without departing from the scope of the invention as set forth in the appended claims.
Claims (10)
1. A preparation method of N, N-diethylnicotinamide, which is characterized by comprising the following steps:
s1, adding a sufficient amount of solvent and a certain amount of nicotinic acid into the reaction bottle, and mixing and stirring for 5-10 minutes;
s2, adding a certain amount of supported catalyst into the mixed solution obtained in the step S1, adding a certain amount of diethylamine salt, continuously stirring for 10-20 minutes, heating to 100-220 ℃, and carrying out heat preservation distillation for 60-90 minutes under normal pressure;
the supported catalyst comprises a carrier and an active component, wherein the active component is metallic nickel or/and an oxide thereof, and the carrier is a random cross network structure formed by winding and lapping mixed fibers;
s3, stopping distillation after the reaction is finished, taking out the supported catalyst after the mixture is cooled to room temperature, adding distilled water into a reaction bottle, adjusting the pH value of the water phase to 8-9 by using a liquid caustic soda aqueous solution, and separating out an organic phase;
s4, carrying out vacuum distillation on the separated organic phase to recover the solvent, wherein the recovery temperature of the solvent is as follows: and (3) carrying out reduced pressure distillation on the residual liquid at the temperature of 48-105 ℃/10mmHg to obtain a product, wherein the collection temperature of the product is as follows: 152-155 ℃/10 mmHg.
2. The method of preparing N, N-diethylnicotinamide of claim 1, wherein the mass fraction of active ingredient is 5% to 30%, the balance is carrier, and the total amount is 100%;
the preparation method of the supported catalyst comprises the following steps:
and (3) soaking the carrier into the aqueous solution of the precursor of the active component, vacuum-soaking at room temperature for 1-3 hours, taking out, drying and sintering the carrier loaded with the active component to obtain the supported catalyst.
3. The method of claim 2, wherein the precursor of the active ingredient is a nickel salt, and the nickel salt is nickel sulfate, nickel nitrate, nickel oxalate or nickel acetate.
4. The method for producing N, N-diethylnicotinamide of claim 1, wherein the mixed fiber is prepared from alumina fiber, potassium hexatitanate whisker and sepiolite fiber in a mass ratio (15% to 45%): (30-60%): (10% -40%) of the composition.
5. The method of claim 1, wherein the solvent is any one of o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, bromobenzene, chlorobenzene, xylene, toluene and nitrobenzene.
6. The method of claim 4, wherein said solvent is ortho-dichlorobenzene.
7. The method of preparing N, N-diethylnicotinamide of claim 1, wherein the diethylamine salt is diethylamine hydrochloride, diethylamine hydrobromide or diethylamine hydroiodide.
8. The process for the preparation of N, N-diethylnicotinamide of claim 6, wherein said diethylamine salt is diethylamine hydrochloride.
9. The method of preparing N, N-diethylnicotinamide of claim 1, wherein the ratio of volume mL of solvent to mass g of nicotinic acid and mass g of diethylamine salt is 5: (3-4): (3-4).
10. The method of claim 1, wherein the solvent is recovered at a temperature of 76-90 ℃/10mmHg in step S4.
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