CN114605360A - Preparation method of 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine - Google Patents
Preparation method of 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine Download PDFInfo
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Abstract
The invention provides a preparation method of 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine, and relates to the technical field of chemical synthesis. Mixing furfuryl alcohol, a transition metal catalyst, cysteamine and an alkane solvent, and carrying out condensation reaction in the atmosphere of dimethylamine and formaldehyde to obtain a crude product liquid; the obtained crude product liquid is distilled and purified to obtain 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine. The preparation method provided by the invention adopts the transition metal catalyst to carry out catalytic reaction, adopts the cysteamine to replace the traditional cysteamine hydrochloride as the preparation raw material, avoids the generation of sodium chloride by-products in the condensation reaction process, and has the advantages of high yield of more than 92.1 percent, high yield and high purity. Moreover, the preparation method provided by the invention can complete the purification process through distillation without alkalization and organic solvent extraction, and has the advantages of simple post-treatment steps and low organic solvent consumption.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, and particularly relates to a preparation method of 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine.
Background
2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine also known as aminoethyl thioether is a medical intermediate which is mainly used as an intermediate for synthesizing ranitidine hydrochloride serving as a gastric medicament. Chinese patent CN106986847A discloses a preparation method of 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine, comprising the steps of mixing dimethylamine hydrochloride alcohol solution, paraformaldehyde and quaternary ammonium salt, heating to 50-70 ℃, adding furfuryl alcohol into a reaction system, and carrying out a first condensation reaction to obtain an intermediate; mixing the intermediate with cysteamine hydrochloride, concentrated hydrochloric acid and perchloric acid, keeping the system temperature at 15-25 ℃, and performing a second condensation reaction to obtain a mixed solution containing 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine hydrochloride; alkalifying the mixed solution, extracting by using dichloromethane, and distilling the obtained extract to obtain 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine, wherein the yield is 86-88%, and the purity is 98.7-99%. However, the above method produces 1000kg of 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine by producing about 700kg of sodium chloride as a by-product and a large amount of sodium chloride as a by-product.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for preparing 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine, wherein the method does not produce sodium chloride as a byproduct.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine, which is characterized by comprising the following steps:
mixing furfuryl alcohol, a transition metal catalyst, cysteamine and an alkane solvent, and carrying out condensation reaction in the atmosphere of dimethylamine and formaldehyde to obtain a crude product liquid;
the obtained crude product liquid is distilled and purified to obtain 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine.
2. The method for preparing according to claim 1, wherein the molar ratio of furfuryl alcohol to cysteamine is 1: 0.98 to 1.05.
Preferably, the transition metal catalyst comprises nanosized copper;
the mass ratio of the furfuryl alcohol to the transition metal catalyst is 1: 0.01 to 0.05.
Preferably, the molar ratio of furfuryl alcohol to dimethylamine is 1: 0.98 to 1.05.
Preferably, the molar ratio of dimethylamine to formaldehyde is 0.98-1.05: 0.98 to 1.05.
Preferably, the alkane solvent comprises cyclohexane.
Preferably, the condensation reaction is carried out at the temperature of 75-95 ℃ for 5-11 h.
Preferably, the distillative purification comprises performing a first distillation and a second distillation in sequence;
the pressure of the first distillation is-0.09 MPa, and the temperature is 20-120 ℃;
the pressure of the second distillation is 50-150 Pa, and the temperature is 121-145 ℃.
The invention provides a preparation method of 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine, which comprises the following steps: mixing furfuryl alcohol, a transition metal catalyst, cysteamine and an alkane solvent, and carrying out condensation reaction in the atmosphere of dimethylamine and formaldehyde to obtain a crude product liquid; the obtained crude product liquid is distilled and purified to obtain 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine. The preparation method provided by the invention adopts the transition metal catalyst to carry out catalytic reaction, and adopts the cysteamine to replace the traditional cysteamine hydrochloride as the preparation raw material, thereby avoiding the generation of sodium chloride by-product in the condensation reaction process and having high product yield. Moreover, the preparation method provided by the invention can complete the purification process through distillation without alkalization and organic solvent extraction, and has the advantages of simple post-treatment steps and low organic solvent consumption. As shown in the test results of the examples, the total yield of the 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine prepared by the preparation method provided by the invention is more than 92.1%, and the purity is more than 99.1%.
Detailed Description
The invention provides a preparation method of 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine, which comprises the following steps:
mixing furfuryl alcohol, a transition metal catalyst, cysteamine and an alkane solvent, and carrying out condensation reaction in the atmosphere of dimethylamine and formaldehyde to obtain a crude product liquid;
the obtained crude product liquid is distilled and purified to obtain 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine.
In the present invention, all the raw material components are commercially available products well known to those skilled in the art unless otherwise specified.
Mixing furfuryl alcohol, a transition metal catalyst, cysteamine and an alkane solvent, and carrying out condensation reaction in the atmosphere of dimethylamine and formaldehyde to obtain a crude product liquid.
In the present invention, the molar ratio of furfuryl alcohol to cysteamine is preferably 1: 0.98-1.05, more preferably 1: 1 to 1.04, and more preferably 1: 1.02 to 1.03.
In the present invention, the transition metal catalyst preferably comprises nanosized copper; the particle size of the transition metal catalyst is preferably 5-20 nm, and more preferably 5-10 nm. In the present invention, the mass ratio of the furfuryl alcohol to the transition metal catalyst is preferably 1: 0.01 to 0.05, more preferably 1: 0.02 to 0.04, and more preferably 1: 0.02-0.03.
In the present invention, the molar ratio of furfuryl alcohol to dimethylamine is preferably 1: 0.98-1.05, more preferably 1: 1 to 1.04, and more preferably 1: 1.02-1.03. In the present invention, the dimethylamine is preferably subjected to a drying treatment before use, and the drying treatment is not particularly limited in the present invention, and a drying operation of dimethylamine well known to those skilled in the art may be employed.
In the present invention, the molar ratio of dimethylamine to formaldehyde is preferably 0.98 to 1.05: 0.98 to 1.05, more preferably 1 to 1.04: 1 to 1.04, preferably 1.02 to 1.03: 1.02 to 1.03. In the present invention, the formaldehyde is preferably dried before use, and the drying process is not particularly limited in the present invention, and a drying operation of formaldehyde known to those skilled in the art may be employed.
In the present invention, the alkane solvent preferably includes cyclohexane. In the present invention, the mass ratio of the furfuryl alcohol to the alkane solvent is preferably 1: 1-3, more preferably 1: 1 to 2.5, and more preferably 1: 1 to 2.
In the invention, the condensation reaction is carried out at a temperature of 75-95 ℃ for 5-10 h, and under a pressure of 0-0.15 MPa, preferably 0.01-0.12 MPa, and more preferably 0.05-0.1 MPa. In the invention, the condensation reaction preferably comprises a first condensation reaction and a second condensation reaction which are sequentially carried out, wherein the temperature of the first condensation reaction is preferably 75-85 ℃, more preferably 78-84 ℃, and the time is preferably 4-8 h, more preferably 5-6 h. In the invention, the temperature of the second condensation reaction is preferably 90-95 ℃, and the time is preferably 1-3 h, and more preferably 1.5-2 h. In the present invention, the water produced during the condensation reaction is removed to ensure that the water content in the system is less than or equal to 0.2 wt%, more preferably less than or equal to 0.1 wt%; the condensation reaction is preferably carried out in a closed reaction water collecting kettle (water separator); the dimethylamine and the formaldehyde are preferably introduced into a closed reaction water collection kettle through a dryer pipeline; the flow velocity of the dimethylamine and the formaldehyde is not particularly limited, and the pressure of the closed reaction water collection kettle can be ensured to be 0-0.15 MPa. In the present invention, the reaction occurring during the condensation reaction is represented by the formula (1):
in a specific embodiment of the present invention, the furfuryl alcohol, the transition metal catalyst, the cysteamine and the alkane solvent are mixed, and the condensation reaction is preferably carried out in an atmosphere of dimethylamine and formaldehyde: firstly mixing furfuryl alcohol with an alkane solvent to obtain a furfuryl alcohol solution; secondly, mixing the furfuryl alcohol solution with a transition metal catalyst, firstly heating the obtained furfuryl alcohol-catalyst mixed solution to a first temperature, and then introducing mixed gas of dimethylamine and formaldehyde to perform a first condensation reaction to obtain a reaction system; and (3) heating the reaction system to a second temperature, and then dropwise adding cysteamine to perform a second condensation reaction. In the present invention, the first mixing and the second mixing are preferably performed by stirring, and the speed and time of stirring and mixing are not particularly limited, and the raw materials may be uniformly mixed. In the invention, the temperature rise rate of the first temperature rise is preferably 15-25 ℃/h, and more preferably 20-22 ℃/h; the first temperature is preferably 75-85 ℃, and more preferably 78-84 ℃. In the present invention, the water produced during the first condensation reaction is removed to ensure that the water content in the system is less than or equal to 0.2 wt%. In the invention, the temperature rise rate of the second temperature rise is preferably 15-25 ℃/h, and more preferably 20-22 ℃/h; the second temperature is preferably 85-95 ℃, and more preferably 90-95 ℃. In the invention, the dropwise adding time of the cysteamine is preferably 2-4 h, and more preferably 3-4 h. In the invention, the water generated in the second condensation reaction process is removed to ensure that the water content in the system is less than or equal to 0.2 wt%
After the condensation reaction, the invention preferably further comprises the step of carrying out solid-liquid separation on the reaction liquid obtained by the condensation reaction to obtain a solid component and a liquid component; washing the solid component with an alkane solvent to obtain a washing solution; combining the washing liquid with the liquid component to obtain a crude product liquid. In the invention, the temperature of the solid-liquid separation is preferably 85-95 ℃, and more preferably 90-95 ℃; the solid-liquid separation mode is not particularly limited, and the solid-liquid separation mode known to those skilled in the art can be adopted, such as filtration; the purpose of the solid-liquid separation is to recover the transition metal catalyst. In the present invention, the alkane solvent preferably includes cyclohexane; the mass ratio of the furfuryl alcohol to the organic solvent is preferably 1: 0.01 to 0.2, more preferably 1: 0.05 to 0.1.
After the crude product liquid is obtained, the obtained crude product liquid is distilled and purified to obtain 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine.
In the present invention, the distillative purification includes sequentially performing a first distillation and a second distillation. In the invention, the pressure of the first distillation is preferably-0.09 to 0.09MPa, more preferably-0.09 to 0MPa, and even more preferably-0.09 to-0.05 MPa; the temperature of the first distillation is preferably 20-120 ℃, and more preferably 50-120 ℃; fraction I from the first distillation comprises the alkane solvent as well as unreacted starting materials (such as furfuryl alcohol and formaldehyde). In the invention, the pressure of the second distillation is preferably 50-150 Pa, more preferably 80-130 Pa, and further preferably 90-100 Pa; the second distillation temperature is preferably 121-145 ℃, and more preferably 130-145 ℃; the fraction obtained by the second distillation is 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine. In the present invention, the distillation is preferably carried out in a still.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. 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.
Example 1
Adding 98.1kg of furfuryl alcohol and 120kg of cyclohexane into a 300L closed reaction water collecting kettle, stirring and mixing uniformly, adding 2kg of copper powder with the particle size of 10nm, stirring and mixing uniformly, heating to 81 ℃ at the heating rate of 20 ℃/h, introducing dimethylamine and formaldehyde gas through a pipeline of a dryer, and pre-reacting for 6 hours at the temperature of 79 ℃ and the pressure of 0.07MPa to obtain a pre-reaction system; 46kg of dimethylamine gas and 30.5kg of formaldehyde gas were introduced in total, and water produced during the reaction was removed to maintain the water content in the reaction system at 0.07 wt%.
Heating a closed reaction water collection kettle to 95 ℃ at a heating rate of 20 ℃/h, dropwise adding 78.5kg of cysteamine, carrying out heat preservation condensation reaction for 2h after dropwise adding, filtering at 95 ℃ to obtain a liquid component and a solid component, washing the solid component with 5kg of cyclohexane, and combining the obtained washing liquid and the liquid component to obtain a crude product liquid; wherein, the adding time of the cysteamine is 4.5h, 18.1kg of water is collected in the condensation reaction process, and the water content in the reaction system is kept to be 0.07 wt%; 3.8kg of wet catalyst was recovered.
Putting the crude product liquid into a 300L distillation kettle, starting a vacuum pump to control the vacuum degree of the distillation kettle to be-0.09 MPa, then starting temperature rise, collecting fraction I in the first distillation process, and stopping temperature rise collection when the temperature of the distillation kettle rises to 120 ℃ to obtain fraction I (121.6kg, the cyclohexane content is 99.5 wt%, the furfuryl alcohol content is 0.15 wt%, and the formaldehyde content is 0.09 wt%); controlling the vacuum degree to be 1000Pa by using a vacuum pump, continuously vacuumizing until the vacuum degree is 65Pa after the vacuum degree is stabilized, starting to heat and collect 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine, and stopping distilling when the temperature of a distillation kettle is raised to 142 ℃ to obtain the 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine (205.3kg, the purity is 99.1 percent, and the total yield is 95.8 percent).
Example 2
Adding 98.1kg of furfuryl alcohol and 100kg of cyclohexane into a 300L closed reaction water collecting kettle, stirring and mixing uniformly, adding 3kg of copper powder with the particle size of 10nm, stirring and mixing uniformly, heating to 83 ℃ at the heating rate of 22 ℃/h, introducing dimethylamine and formaldehyde gas through a pipeline of a dryer, and pre-reacting for 5.5h under the conditions of 83 ℃ and 0.09MPa to obtain a pre-reaction system; 45kg of dimethylamine gas and 30kg of formaldehyde gas are added in a cumulative way, 16.9kg of water is adopted in the reaction process, and the water content in the reaction system is kept to be 0.08 wt%.
Heating a closed reaction water collection kettle to 90 ℃ at a heating rate of 20 ℃/h, dropwise adding 77.1kg of cysteamine, carrying out heat preservation condensation reaction for 2h after dropwise adding, filtering at 90 ℃ to obtain a liquid component and a solid component, washing the solid component with 5kg of cyclohexane, and combining the obtained washing liquid and the liquid component to obtain a crude product liquid; wherein the adding time of the cysteamine is 4.3h, and water generated in the reaction process is removed to keep the water content in the reaction system to be 0.08 wt%; 5.5kg of wet catalyst was recovered.
Putting the crude product liquid into a 300L distillation kettle, starting a vacuum pump to control the vacuum degree of the distillation kettle to be-0.09 MPa, then starting temperature rise, collecting fraction I in the first distillation process, and stopping temperature rise collection when the temperature of the distillation kettle rises to 120 ℃ to obtain fraction I (100.9kg, the cyclohexane content is 99.4 wt%, the furfuryl alcohol content is 0.17 wt%, and the formaldehyde content is 0.02 wt%); controlling the vacuum degree to be 1000Pa by using a vacuum pump, continuously vacuumizing until the vacuum degree is stable to be 110Pa after the vacuum degree is stable, starting to heat and collect 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine, and stopping distilling when the temperature of a distillation kettle is raised to 143 ℃ to obtain the 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine (197.4kg, the purity is 99.4 percent, and the total yield is 92.11 percent).
Example 3
Adding 98.1kg of furfuryl alcohol and 140kg of cyclohexane into a 300L closed reaction water collecting kettle, stirring and mixing uniformly, adding 4kg of copper powder with the particle size of 5nm, stirring and mixing uniformly, heating to 80 ℃ at the heating rate of 20 ℃/h, introducing dimethylamine and formaldehyde gas through a pipeline of a dryer, and pre-reacting for 6h under the conditions of 80 ℃ and 0.08MPa to obtain a pre-reaction system; 44.1kg of dimethylamine gas and 29.5kg of formaldehyde gas were introduced in a cumulative manner, and water produced during the reaction was removed to maintain the water content in the reaction system at 0.09% by weight.
Heating a closed reaction water collection kettle to 95 ℃ at a heating rate of 20 ℃/h, dropwise adding 77.1kg of cysteamine, carrying out heat preservation condensation reaction for 2h after dropwise adding, filtering at 90 ℃ to obtain a liquid component and a solid component, washing the solid component with 5kg of cyclohexane, and combining the obtained washing liquid and the liquid component to obtain a crude product liquid; wherein, the adding time of the cysteamine is 4.3h, 18.4kg of water is collected in the condensation reaction process, and the water content in the reaction system is kept to be 0.07 wt%; 6kg of wet catalyst was recovered.
Putting the crude product liquid into a 300L distillation kettle, starting a vacuum pump to control the vacuum degree of the distillation kettle to be-0.09 MPa, then starting temperature rise, collecting fraction I in the first distillation process, and stopping temperature rise collection when the temperature of the distillation kettle rises to 120 ℃ to obtain fraction I (142.1kg, the cyclohexane content is 99.0 wt%, the furfuryl alcohol content is 0.72 wt%, and the formaldehyde content is 0.01 wt%); controlling the vacuum degree to be 1000Pa by using a vacuum pump, continuously vacuumizing until the vacuum degree is stabilized to be 110Pa after the vacuum degree is stabilized, starting to heat up and collect 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine, and stopping distilling when the temperature of a distillation kettle is raised to 142 ℃ to obtain the 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine (195.6kg, the purity is 99.2 percent, and the total yield is 92.17 percent).
Comparative example 1
Adding 98.1kg of furfuryl alcohol and 50kg of cyclohexane into a 300L closed reaction water collecting kettle, stirring and mixing uniformly, adding 4kg of copper powder with the particle size of 10nm, stirring and mixing uniformly, heating to 80 ℃ at the heating rate of 20 ℃/h, introducing dimethylamine and formaldehyde gas through a pipeline of a dryer, and pre-reacting for 3h under the conditions of 80 ℃ and 0.04MPa to obtain a pre-reaction system; 44.3kg of dimethylamine gas and 29.7kg of formaldehyde gas were introduced in cumulative amounts, and water produced during the reaction was removed to maintain the water content in the reaction system at 0.09% by weight.
Heating a closed reaction water collection kettle to 85 ℃ at a heating rate of 20 ℃/h, dropwise adding 77.1kg of cysteamine, carrying out heat preservation condensation reaction for 2h after dropwise adding, filtering at 90 ℃ to obtain a liquid component and a solid component, washing the solid component with 5kg of cyclohexane, and combining the obtained washing liquid and the liquid component to obtain a crude product liquid; wherein, the adding time of the cysteamine is 4.3h, 18.4kg of water is collected in the condensation reaction process, and the water content in the reaction system is kept to be 0.08 wt%; 6.5kg of wet catalyst was recovered.
Putting the crude product liquid into a 300L distillation kettle, starting a vacuum pump to control the vacuum degree of the distillation kettle to be-0.09 MPa, then starting temperature rise, collecting fraction I in the first distillation process, and stopping temperature rise collection when the temperature of the distillation kettle rises to 120 ℃ to obtain fraction I (39.8kg, the cyclohexane content is 98.2 wt%, the furfuryl alcohol content is 1.72 wt%, and the formaldehyde content is 0.08 wt%); controlling the vacuum degree to be 1000Pa by using a vacuum pump, continuously vacuumizing until the vacuum degree is stabilized to be 75Pa after the vacuum degree is stabilized, starting to heat and collect 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine, and stopping distilling when the temperature of a distillation kettle is raised to 142 ℃ to obtain the 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine (148.5kg, the purity is 99.1 percent, and the total yield is 69.9 percent).
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 amendments can be made without departing from the principle of the present invention, and these modifications and amendments should also be considered as the protection scope of the present invention.
Claims (8)
1. A preparation method of 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine is characterized by comprising the following steps:
mixing furfuryl alcohol, a transition metal catalyst, cysteamine and an alkane solvent, and carrying out condensation reaction in the atmosphere of dimethylamine and formaldehyde to obtain a crude product liquid;
the obtained crude product liquid is distilled and purified to obtain 2- [ [ [5- (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethylamine.
2. The method for preparing according to claim 1, wherein the molar ratio of furfuryl alcohol to cysteamine is 1: 0.98 to 1.05.
3. The production method according to claim 1, wherein the transition metal catalyst comprises nanosized copper;
the mass ratio of the furfuryl alcohol to the transition metal catalyst is 1: 0.01 to 0.05.
4. The method according to claim 1, wherein the molar ratio of furfuryl alcohol to dimethylamine is from 1: 0.98 to 1.05.
5. The method according to claim 1, wherein the molar ratio of dimethylamine to formaldehyde is 0.98-1.05: 0.98 to 1.05.
6. The method of claim 1, wherein the alkane solvent comprises cyclohexane.
7. The method according to any one of claims 1 to 6, wherein the condensation reaction is carried out at a temperature of 75 to 95 ℃ for 5 to 11 hours.
8. The production method according to claim 1, wherein the distillative purification comprises performing a first distillation and a second distillation in this order;
the pressure of the first distillation is-0.09 MPa, and the temperature is 20-120 ℃;
the pressure of the second distillation is 50-150 Pa, and the temperature is 121-145 ℃.
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