CN110590706B - Preparation method of N-methylpyrrolidine - Google Patents
Preparation method of N-methylpyrrolidine Download PDFInfo
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- CN110590706B CN110590706B CN201911075851.1A CN201911075851A CN110590706B CN 110590706 B CN110590706 B CN 110590706B CN 201911075851 A CN201911075851 A CN 201911075851A CN 110590706 B CN110590706 B CN 110590706B
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- methylamine
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- dichlorobutane
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/023—Preparation; Separation; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
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Abstract
The invention relates to preparation of organic base of medicine and chemical raw materials, in particular to a preparation method of N-methylpyrrolidine, which comprises the following steps: a) under the catalysis of potassium iodide, 1, 4-dichlorobutane and methylamine water solution are mixed and reacted in an ether solvent to obtain N-methylpyrrolidine; the ether solvent can form hydrogen bond with methylamine, and the boiling point is larger than the azeotropic point of methylamine and water in the mixed system. The preparation method provided by the invention has the advantages of rich sources of raw materials, simple synthesis process route, no need of high-pressure reaction conditions, reduced equipment investment, simplified production management, reduced comprehensive cost, excellent economy and wide popularization prospect. Experimental results show that when the method is used for preparing the N-methylpyrrolidine, the preparation yield is more than 88 percent, and the product purity is more than 99 percent.
Description
Technical Field
The invention relates to preparation of organic base of medicine and chemical raw materials, in particular to a preparation method of N-methylpyrrolidine.
Background
N-methylpyrrolidine is an organic base which can be used for the manufacture of pharmaceuticals and other fine chemicals. There are five known methods for preparing N-methylpyrrolidine, three representative of which are the first: the catalytic hydrogenation method of N-methyl pyrrolidone is characterized in that N-methyl pyrrolidone and hydrogen are prepared in a high-pressure device under the action of catalysts such as Cr-Al or Cu-Cr and the like under the conditions of 180-285 ℃/150-280 atm, the conversion rate is 85%, and the selectivity is 85%. The disadvantages of this method are: the reaction is carried out under high pressure, the requirements on equipment are strict, and the investment is large. In addition, the production needs to be matched with the construction of a hydrogen production device, and the industrial production is limited. The second method is as follows: the method comprises the following steps of carrying out methylation reaction on pyrrolidine and formaldehyde in a formic acid medium at normal temperature and normal pressure, adding hydrochloric acid after the reaction to prepare N-methylpyrrolidine hydrochloride, removing formic acid and excessive formaldehyde through distillation, neutralizing the N-methylpyrrolidine hydrochloride with NaOH to prepare a crude N-methylpyrrolidine product, and carrying out secondary rectification to prepare the N-methylpyrrolidine with the yield of 92%. The disadvantages of this method are: the price of the main raw material pyrrolidine is too high, so that the production cost of the product is high; in addition, the consumption of formic acid, formaldehyde, hydrochloric acid and sodium hydroxide is large, and the recovered formic acid and formaldehyde can not be directly reused; the treatment of the three wastes is difficult. The third method is: under the catalytic action of II-X-zeolite, pyrrolidine and methanol are subjected to methylation reaction at 300 ℃ to prepare N-methylpyrrolidine, wherein the conversion rate is 99% and the selectivity is 92%. The method has more reports and high yield. The disadvantages of this method are: the main raw material of pyrrolidine has high content of pyrrolidine and large investment on production devices. Other preparation methods include a N-methyl pyrrole catalytic hydrogenation method and a methylbutylamine chlorination cyclization method, and the methods have high raw material price and complex process.
In recent years, two preparation methods of N-methylpyrrolidine are also worthy of attention, one is to prepare the N-methylpyrrolidine by reacting tetrahydrofuran with methylamine under the catalysis of solid super acid, although the raw materials are easy to obtain, a super acid catalyst needs to be prepared, gas-solid heterogeneous reaction is carried out in a tubular reactor, a laboratory can easily obtain satisfactory results, and problems are often encountered during industrial scale-up; the other is the reaction of 1, 4-dichlorobutane with methylamine under high pressure, which is carried out under high pressure and has high requirements on equipment and production management, although the raw materials are cheap and easily available.
Therefore, it is an urgent technical problem to be solved in the art to explore a preparation method of N-methylpyrrolidine, which has rich raw material sources, simple process and easy industrialization.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for preparing N-methylpyrrolidine, which has advantages of rich raw material source, simple process and easy industrialization.
The invention provides a preparation method of N-methylpyrrolidine, which comprises the following steps:
a) under the catalysis of potassium iodide, 1, 4-dichlorobutane and methylamine water solution are mixed and reacted in an ether solvent to obtain N-methylpyrrolidine;
the ether solvent can form hydrogen bond with methylamine, and the boiling point is larger than the azeotropic point of methylamine and water in the mixed system.
Preferably, the ether solvent includes diglyme and/or anisole.
Preferably, the molar ratio of 1, 4-dichlorobutane to methylamine is < 1: 1.
Preferably, the molar ratio of 1, 4-dichlorobutane to methylamine is 1: (3.5-4.5).
Preferably, the molar ratio of the potassium iodide to the 1, 4-dichlorobutane is (2.5-6): 100.
preferably, the concentration of the methylamine water solution is 30-50 wt%.
Preferably, the dosage ratio of the ether solvent to the 1, 4-dichlorobutane is (400-800) mL: 1 mol.
Preferably, the pressure of the mixing reaction is normal pressure.
Preferably, the temperature of the mixing reaction is 100-120 ℃; the mixing reaction time is 3-8 h.
Preferably, step a) specifically comprises:
a1) under the catalysis of potassium iodide, 1, 4-dichlorobutane and methylamine water solution are mixed and reacted in an ether solvent to obtain reaction liquid containing N-methylpyrrolidine and methylamine hydrochloride;
a2) adding alkali into the reaction liquid to adjust the pH value of the reaction liquid to be 12-13, then distilling and collecting fractions with different distillation ranges to respectively obtain an azeotrope of methylamine and water, N-methylpyrrolidine, water and an ether solvent.
Compared with the prior art, the invention provides a preparation method of N-methylpyrrolidine. The preparation method provided by the invention comprises the following steps: a) under the catalysis of potassium iodide, 1, 4-dichlorobutane and methylamine water solution are mixed and reacted in an ether solvent to obtain N-methylpyrrolidine; the ether solvent can form hydrogen bond with methylamine, and the boiling point is larger than the azeotropic point of methylamine and water in the mixed system. The invention adopts the ether solvent with high boiling point which can form hydrogen bond with methylamine, improves the solubility of methylamine in the reaction system, reduces the gas phase partial pressure of methylamine, and ensures that the concentration of methylamine in the solution is still larger even if the reaction temperature is above the azeotropic point of methylamine and water; meanwhile, potassium iodide is added to perform halogen exchange reaction and then substitution, so that the activation energy of nucleophilic substitution reaction is reduced, and the reaction rate is increased. Based on the two improvements, the invention can lead the synthesis reaction of the N-methyl pyrrolidine to be carried out at relatively higher temperature under normal pressure. The preparation method provided by the invention has the advantages of rich sources of raw materials, simple synthesis process route, no need of high-pressure reaction conditions, reduced equipment investment, simplified production management, reduced comprehensive cost, excellent economy and wide popularization prospect. Experimental results show that when the method is used for preparing the N-methylpyrrolidine, the preparation yield is more than 88 percent, and the product purity is more than 99 percent.
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In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.
FIG. 1 is a chromatogram of N-methylpyrrolidine provided in example 4 of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides a preparation method of N-methylpyrrolidine, which comprises the following steps:
a) under the catalysis of potassium iodide, 1, 4-dichlorobutane and methylamine water solution are mixed and reacted in an ether solvent to obtain N-methylpyrrolidine;
the ether solvent can form hydrogen bond with methylamine, and the boiling point is larger than the azeotropic point of methylamine and water.
In the preparation method provided by the invention, 1, 4-dichlorobutane, methylamine water solution and potassium iodide are directly mixed and reacted in an ether solvent to prepare the N-methylpyrrolidine, and the process specifically comprises the following steps:
a1) under the catalysis of potassium iodide, 1, 4-dichlorobutane and methylamine water solution are mixed and reacted in an ether solvent to obtain reaction liquid containing N-methylpyrrolidine and methylamine hydrochloride;
a2) adding alkali into the reaction liquid to adjust the pH value of the reaction liquid to be 12-13, then distilling and collecting fractions with different distillation ranges to respectively obtain an azeotrope of methylamine and water, N-methylpyrrolidine, water and an ether solvent.
In the preparation method provided by the invention, in the step a1), the ether solvent can form hydrogen bonds with methylamine, and the boiling point of the ether solvent is more than the azeotropic point of methylamine and water in a mixed system; the ether solvent preferably includes diglyme and/or anisole; the dosage ratio of the ether solvent to the 1, 4-dichlorobutane is preferably (400-800) mL: 1mol, specifically 400 mL: 1mol, 500 mL: 1mol, 600 mL: 1mol, 700 mL: 1mol or 800 mL: 1 mol.
In the preparation method provided by the invention, in the step a1), the concentration of the methylamine aqueous solution is preferably 30-50 wt%, and specifically can be 30 wt%, 35 wt%, 40 wt%, 45 wt% or 50 wt%; the molar ratio of 1, 4-dichlorobutane to methylamine in the aqueous methylamine solution is preferably < 1:1, more preferably 1: (3.5 to 4.5), specifically 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4, 1:4.1, 1:4.2, 1:4.3, 1:4.4 or 1: 4.5.
In the preparation method provided by the invention, in the step a1), the molar ratio of potassium iodide to 1, 4-dichlorobutane is preferably (2.5-6): 100, specifically 2.5:100, 2.6:100, 2.7:100, 2.8:100, 2.9:100, 3:100, 3.1:100, 3.2:100, 3.3:100, 3.4:100, 3.5:100, 3.6:100, 3.7:100, 3.8:100, 3.9:100, 4:100, 4.1:100, 4.2:100, 4.3:100, 4.4:100, 4.5:100, 4.6:100, 4.7:100, 4.8:100, 4.9:100, 5:100, 5.1:100, 5.2:100, 5.3:100, 5.4:100, 5.5:100, 5.6:100, 5.7:100, 5.8:100, 5.9:100, or 6: 100.
In the preparation method provided by the invention, in the step a1), the pressure of the mixing reaction is preferably normal pressure; the temperature of the mixing reaction is preferably 100-120 ℃, and specifically can be 100 ℃, 105 ℃, 110 ℃, 115 ℃ or 120 ℃; the mixing reaction time is preferably 3-8 h, and specifically can be 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h or 8 h.
In the preparation method provided by the invention, in the step a1), the chemical reaction equation involved is as follows:
in the preparation method provided by the invention, in the step a2), the alkali is preferably sodium hydroxide, and the alkali is preferably added to the reaction solution in the form of an aqueous alkali solution.
In the preparation method provided by the invention, in the step a2), the specific process of distilling and collecting the fractions with different distillation ranges comprises the following steps: firstly, carrying out atmospheric distillation, and respectively collecting fractions with distillation ranges of 50-51 ℃, 81-83 ℃ and 101-103 ℃, wherein the fraction with the temperature of 50-51 ℃ is an azeotrope of methylamine and water, the fraction with the temperature of 81-83 ℃ is N-methylpyrrolidine, and the fraction with the temperature of 101-103 ℃ is water; then, the mixture was distilled under reduced pressure to recover the ether solvent.
In the preparation method provided by the invention, in the step a2), the chemical reaction equation involved is as follows, taking alkali as sodium hydroxide as an example:
H3C-NH2HCI+NaOH→H3C-NH2+NaCI+H2O。
the invention adopts the ether solvent with high boiling point which can form hydrogen bond with methylamine, improves the solubility of methylamine in the reaction system, reduces the gas phase partial pressure of methylamine, and ensures that the concentration of methylamine in the solution is still larger even if the reaction temperature is above the azeotropic point of methylamine and water; meanwhile, potassium iodide is added to perform halogen exchange reaction and then substitution, so that the activation energy of nucleophilic substitution reaction is reduced, and the reaction rate is increased. Based on the two improvements, the invention can lead the synthesis reaction of the N-methyl pyrrolidine to be carried out at relatively higher temperature under normal pressure.
The preparation method provided by the invention has the advantages of rich sources of raw materials, simple synthesis process route, no need of high-pressure reaction conditions, reduced equipment investment, simplified production management, reduced comprehensive cost, excellent economy and wide popularization prospect. Experimental results show that when the method is used for preparing the N-methylpyrrolidine, the preparation yield is more than 88 percent, and the product purity is more than 99 percent.
For the sake of clarity, the following examples are given in detail.
Example 1
Into a 1L four-necked glass reaction flask equipped with a mechanical stirrer, a thermometer and a brine-cooled reflux condenser were charged 300mL of diglyme, 63.5g (0.5mol) of 1, 4-dichlorobutane, 136g (1.75mol) of a 40 wt% aqueous methylamine solution and 2.1g (0.013mol) of potassium iodide in the order named, the molar ratio of 1, 4-dichlorobutane, methylamine and potassium iodide being 1:3.5: 0.026. Heating with an electric heating jacket under stirring, heating to 110 ℃ for 2h, and reacting for 4h under heat preservation. And then, changing the water bath cooling to 30 ℃, slowly adding 10 wt% of sodium hydroxide aqueous solution at the constant temperature of 30 ℃, and adjusting the pH value to 12-13. And then, changing the reflux device into an atmospheric distillation device, collecting 50-51 ℃ distillate as an azeotrope of methylamine and water, 81-83 ℃ N-methylpyrrolidine, 101-103 ℃ distillate as water, then, changing into reduced pressure distillation, recovering diglyme, and mainly using inorganic salt as residue at the bottom of the kettle. The yield of N-methylpyrrolidine was 93.3% and the gas chromatography purity was 99.2%.
Example 2
N-methylpyrrolidine was prepared according to the method steps of example 1, with the difference that the solvent was changed to anisole.
The results show that: the yield of N-methylpyrrolidine was 88.2% and the gas chromatography purity was 99.3%.
Example 3
N-methylpyrrolidine was prepared according to the process steps of example 1 except that the molar ratio of 1, 4-dichlorobutane to methylamine to potassium iodide was changed to 1:4.5: 0.026.
The results show that: the yield of N-methylpyrrolidine was 95.6% and the purity by gas chromatography was 99.7%.
Example 4
N-methylpyrrolidine was prepared according to the process steps of example 1 except that the molar ratio of 1, 4-dichlorobutane to methylamine to potassium iodide was changed to 1:3.5: 0.052.
The results show that: the yield of N-methylpyrrolidine was 98.1%, and the gas chromatography purity was as shown in FIG. 1 (99.67%).
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (9)
1. A preparation method of N-methylpyrrolidine comprises the following steps:
a) under the catalysis of potassium iodide, 1, 4-dichlorobutane and methylamine water solution are mixed and reacted in an ether solvent to obtain N-methylpyrrolidine;
the concentration of the methylamine water solution is 30-50 wt%;
the ether solvent can form hydrogen bond with methylamine, and the boiling point is larger than the azeotropic point of methylamine and water in the mixed system.
2. The method according to claim 1, wherein the ether solvent is diglyme and/or anisole.
3. The process according to claim 1, wherein the molar ratio of 1, 4-dichlorobutane to methylamine is < 1: 1.
4. The process according to claim 3, wherein the molar ratio between 1, 4-dichlorobutane and methylamine is 1: (3.5-4.5).
5. The preparation method according to claim 1, wherein the molar ratio of the potassium iodide to the 1, 4-dichlorobutane is (2.5-6): 100.
6. the method according to claim 1, wherein the ether solvent and 1, 4-dichlorobutane are used in a ratio of (400 to 800) mL: 1 mol.
7. The production method according to claim 1, wherein the pressure of the mixing reaction is normal pressure.
8. The preparation method according to claim 7, wherein the temperature of the mixing reaction is 100-120 ℃; the mixing reaction time is 3-8 h.
9. The method according to claim 1, wherein step a) comprises in particular:
a1) under the catalysis of potassium iodide, 1, 4-dichlorobutane and methylamine water solution are mixed and reacted in an ether solvent to obtain reaction liquid containing N-methylpyrrolidine and methylamine hydrochloride;
a2) adding alkali into the reaction liquid to adjust the pH value of the reaction liquid to be 12-13, then distilling and collecting fractions with different distillation ranges to respectively obtain an azeotrope of methylamine and water, N-methylpyrrolidine, water and an ether solvent.
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Citations (2)
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| CN1810787A (en) * | 2005-01-25 | 2006-08-02 | 四平市精细化学品有限公司 | Prepn process of methyl pyrrolidine |
| CN107207489A (en) * | 2014-12-17 | 2017-09-26 | 吉恩基奥泰克斯瑞士股份有限公司 | It is used as the acylamino- thiadiazoles derivative of nadph oxidase inhibitor |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1810787A (en) * | 2005-01-25 | 2006-08-02 | 四平市精细化学品有限公司 | Prepn process of methyl pyrrolidine |
| CN107207489A (en) * | 2014-12-17 | 2017-09-26 | 吉恩基奥泰克斯瑞士股份有限公司 | It is used as the acylamino- thiadiazoles derivative of nadph oxidase inhibitor |
Non-Patent Citations (2)
| Title |
|---|
| N-Heterocyclic dicarboxylic acids: Broad-spectrum inhibitors of metallo-b-lactamases with co-antibacterial effect against antibiotic-resistant bacteria.;FENG，Lei等;《Bioorganic & Medicinal Chemistry Letters》;20120701;第22卷;第5185-5189页 * |
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