Method for preparing N-alkyl pyrrolidine

Abstract

The present invention discloses a preparation method of N-alkyl pyrrolidine which is an intermediate used for the pharmaceutical and chemical materials. The method is that ammonia or organic amine aqueous solution is controlled at 30 DEG C, at the same time cis-1, 4-dihalogen-butylene and organic alkali or inorganic alkali solution is dripped within one to five hours, the pH value is controlled between 11 to 12, after dripping, the solution continuously reacts for one to ten hours under 30 DEG C to 100 DEG C to generate N-alkyl-3-dihydropyrrole; then organic inert solvent, the N-alkyl-3-dihydropyrrole and 5 percent of Pd / C catalyst are added into a high-pressure vessel to be heated to 30 DEG C to 100 DEG C to be led to H2O, the system pressure is controlled as 0.2 to 1.0MPa, and the N-alkyl pyrrolidine is generated after the reaction for two to twelve hours. The source of the materials of the present invention is abundant; the product has the high yield and good purity and is easy forpurifying; the requirement of required equipments is comparatively low; the present invention causes little pollution, is in favor of treating the three wastes and is easy for realizing the industrialized production.

Description

technical field

[0001] The invention belongs to the field of medicine and pesticide intermediates, and relates to a synthesis method of an intermediate of cephalosporin antibiotics, in particular to pyrrolidine or N-alkylpyrrolidine and a preparation method thereof. Background technique

[0002] Pyrrolidine or N-alkylpyrrolidine is an important pharmaceutical and pesticide intermediate, especially N-methylpyrrolidine is an indispensable intermediate for cefepime.

[0003] European patent EP 34480 discloses a method for preparing N-alkylpyrrolidones and hydrogen under the action of catalysts such as Zn-Cu under high temperature and high pressure conditions. In addition, U.S. Patent No. 4,892,959 also discloses a method for preparing N-alkylpyrrolidines using copper chromite as a catalyst under high temperature and high pressure. The disadvantage of this type of method is that it needs to be reacted in a high-pressure device, and the equipment investment is large, which is no...

Examples

Embodiment 1

[0027] (1) Preparation of N-methyl-3-dihydropyrrole

[0028] Add 40% 233.3g (3.0mol) monomethylamine aqueous solution to a 500ml reaction flask equipped with a thermometer, condenser, magnetic stirring and constant pressure dropping funnel, control it at 30°C, and add 125.0g (1.0mol) ) cis-1,4-dichloro-2-butene and 40% NaOH solution, the pH of the system is controlled at 11~12. After the dropwise addition, the temperature was raised to 60° C., the pH of the system was controlled to be 11-12, and the reaction was continued for 3 hours. After the reaction was finished, 63.5 g of N-methyl-3-dihydropyrrole was obtained through two rectifications, with a yield of 76.5%.

[0029] (2) Preparation of N-Methylpyrrolidine

[0030] In a 2L autoclave, add 500g tetrahydrofuran, 83.0g (1.0mol) N-methyl-3-dihydropyrrole and 4.2g 5% Pd / C catalyst (the mass percentage of Pd is 5%), and the temperature is raised to 60°C , start to pass H after purging the air with nitrogen 2 , control the p...

Embodiment 2

[0032] (1) Preparation of N-ethyl-3-dihydropyrrole

[0033] Add 50% 180.0g (2.0mol) monoethylamine aqueous solution to a 500ml reaction flask equipped with a thermometer, condenser tube, magnetic stirring and constant pressure dropping funnel, control it at 30°C, and drop 214.0g (1.0mol) ) cis-1,4-dibromo-2-butene and saturated Na 2 CO 3 solution, the pH of the system is controlled at 11-12. After the dropwise addition, the temperature was raised to 100° C., the pH of the system was controlled to be 11-12, and the reaction was continued for 1 h. After the reaction was finished, 58.5 g of N-ethyl-3-dihydropyrrole was obtained through two rectifications, with a yield of 60.3%.

[0034] (2) Preparation of N-ethylpyrrolidine

[0035] Add 97g of methanol, 97.0g (1.0mol) of N-ethyl-3-dihydropyrrole and 1.0g of 5% Pd / C catalyst into a 2L autoclave, raise the temperature to 100°C, and start to pass H after purging the air with nitrogen 2 , control the pressure of the reaction sys...

Embodiment 3

[0037] (1) Preparation of 3-dihydropyrrole

[0038] Add 10% 680.0g (4.0mol) of ammonia water to a 1000ml reaction flask equipped with a thermometer, magnetic stirring and constant pressure dropping funnel, control at 30°C, and dropwise add 125.0g (1.0mol) of cis-1,4 -Dichloro-2-butene. After the dropwise addition, the temperature was raised to 30° C., and the reaction was continued for 8 hours. After the reaction, 37.4 g of 3-dihydropyrrole was obtained through two rectifications, with a yield of 54.2%.

[0039] (2) Preparation of pyrrolidine

[0040] In a 2L autoclave, add 621g of isopropanol, 69.0g (1.0mol) of 3-dihydropyrrole and 3.5g of 10% Pd / C catalyst (the mass percent of Pd is 10%), heat up to 30°C, and purge with nitrogen Start to pass H after the air 2 , control the pressure of the reaction system to 1.0 MPa, stir the reaction for 2 hours, and cool down to room temperature after the reaction. The Pd / C catalyst was recovered by filtration, and the liquid was rect...

technical field

[0001] The invention belongs to the field of medicine and pesticide intermediates, and relates to a synthesis method of an intermediate of cephalosporin antibiotics, in particular to pyrrolidine or N-alkylpyrrolidine and a preparation method thereof. Background technique

[0002] Pyrrolidine or N-alkylpyrrolidine is an important pharmaceutical and pesticide intermediate, especially N-methylpyrrolidine is an indispensable intermediate for cefepime.

[0003] European patent EP 34480 discloses a method for preparing N-alkylpyrrolidones and hydrogen under the action of catalysts such as Zn-Cu under high temperature and high pressure conditions. In addition, U.S. Patent No. 4,892,959 also discloses a method for preparing N-alkylpyrrolidines using copper chromite as a catalyst under high temperature and high pressure. The disadvantage of this type of method is that it needs to be reacted in a high-pressure device, and the equipment investment is large, which is no...

Examples

Embodiment 1

[0027] (1) Preparation of N-methyl-3-dihydropyrrole

[0028] Add 40% 233.3g (3.0mol) monomethylamine aqueous solution to a 500ml reaction flask equipped with a thermometer, condenser, magnetic stirring and constant pressure dropping funnel, control it at 30°C, and add 125.0g (1.0mol) ) cis-1,4-dichloro-2-butene and 40% NaOH solution, the pH of the system is controlled at 11~12. After the dropwise addition, the temperature was raised to 60° C., the pH of the system was controlled to be 11-12, and the reaction was continued for 3 hours. After the reaction was finished, 63.5 g of N-methyl-3-dihydropyrrole was obtained through two rectifications, with a yield of 76.5%.

[0029] (2) Preparation of N-Methylpyrrolidine

[0030] In a 2L autoclave, add 500g tetrahydrofuran, 83.0g (1.0mol) N-methyl-3-dihydropyrrole and 4.2g 5% Pd / C catalyst (the mass percentage of Pd is 5%), and the temperature is raised to 60°C , start to pass H after purging the air with nitrogen 2 , control the p...

Embodiment 2

[0032] (1) Preparation of N-ethyl-3-dihydropyrrole

[0033] Add 50% 180.0g (2.0mol) monoethylamine aqueous solution to a 500ml reaction flask equipped with a thermometer, condenser tube, magnetic stirring and constant pressure dropping funnel, control it at 30°C, and drop 214.0g (1.0mol) ) cis-1,4-dibromo-2-butene and saturated Na 2 CO 3 solution, the pH of the system is controlled at 11-12. After the dropwise addition, the temperature was raised to 100° C., the pH of the system was controlled to be 11-12, and the reaction was continued for 1 h. After the reaction was finished, 58.5 g of N-ethyl-3-dihydropyrrole was obtained through two rectifications, with a yield of 60.3%.

[0034] (2) Preparation of N-ethylpyrrolidine

[0035] Add 97g of methanol, 97.0g (1.0mol) of N-ethyl-3-dihydropyrrole and 1.0g of 5% Pd / C catalyst into a 2L autoclave, raise the temperature to 100°C, and start to pass H after purging the air with nitrogen 2 , control the pressure of the reaction sys...

Embodiment 3

[0037] (1) Preparation of 3-dihydropyrrole

[0038] Add 10% 680.0g (4.0mol) of ammonia water to a 1000ml reaction flask equipped with a thermometer, magnetic stirring and constant pressure dropping funnel, control at 30°C, and dropwise add 125.0g (1.0mol) of cis-1,4 -Dichloro-2-butene. After the dropwise addition, the temperature was raised to 30° C., and the reaction was continued for 8 hours. After the reaction, 37.4 g of 3-dihydropyrrole was obtained through two rectifications, with a yield of 54.2%.

[0039] (2) Preparation of pyrrolidine

[0040] In a 2L autoclave, add 621g of isopropanol, 69.0g (1.0mol) of 3-dihydropyrrole and 3.5g of 10% Pd / C catalyst (the mass percent of Pd is 10%), heat up to 30°C, and purge with nitrogen Start to pass H after the air 2 , control the pressure of the reaction system to 1.0 MPa, stir the reaction for 2 hours, and cool down to room temperature after the reaction. The Pd / C catalyst was recovered by filtration, and the liquid was rect...

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