CN107382780B - Preparation method of amide compound - Google Patents
Preparation method of amide compound Download PDFInfo
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- CN107382780B CN107382780B CN201710682214.5A CN201710682214A CN107382780B CN 107382780 B CN107382780 B CN 107382780B CN 201710682214 A CN201710682214 A CN 201710682214A CN 107382780 B CN107382780 B CN 107382780B
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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
Abstract
The invention discloses a preparation method of an amide compound. The preparation method comprises the following steps: reacting a solution A containing a compound I with a solution B containing n-butyllithium at-80-10 ℃, and then reacting with a solution C containing a compound II at-80-10 ℃; the concentration of the compound I in the solution A is 5 wt% -40 wt%, the concentration of the compound II in the solution C is 5 wt% -50 wt%, the flow rates of the solution A and the solution C are 0.1-25L/s and 0.1-1.5L/s respectively, n is an integer of 0-5, and R is1Each independently is C1～C6Alkyl radical, C1～C6Alkoxy or "substituted or unsubstituted C6～C10Aryl "; r2Is hydrogen, C1～C6Alkyl or "substituted or unsubstituted phenyl", the substituent of the substituted phenyl being C1～C6Alkyl or C1～C6An alkoxy group; r3Is C1～C6Alkyl or "methyl substituted with one or more phenyl".
Description
Technical Field
The invention relates to a preparation method of an amide compound.
Background
Amides are a very widely used class of compounds in organic synthesis (j.biotechhol.2016, 235, 32; curr.pharma.des.2016,22,5029; org.biomol.chem.2016,14,10134; eur.j.med.chem.2015,91, 15).
In the synthesis of amides, the acylation of amines is the most direct and efficient method to obtain such compounds (org. processsres. dev.2016,20, 140; photochem. rev.2016,15,729; mol. bio. syst.2015,11,338; sci. synth. biocatal. org. synth.2015,1, 329).
In the acylation reaction of amine compounds, the reaction of n-butyllithium as an added base has the remarkable advantages of short time, high efficiency and good yield (chem. Rev.2016,116, 12029); however, because n-butyllithium has high reaction activity and participates in the reaction, the system can quickly release a large amount of heat, so that the reaction is uncontrollable, and therefore, the reaction is usually carried out at a very low temperature (-80 to-50 ℃), and the reaction conditions are severe; in addition, in the process of dropwise adding the n-butyllithium, if leakage occurs, safety accidents such as fire disasters are easy to cause; in general industrial production, n-butyl lithium is slowly dripped in a low-temperature environment, but the reaction time is prolonged, the industrial production period is prolonged, and the production efficiency is low. Therefore, the development of an amine acylation production process with participation of n-butyllithium, mild reaction conditions, good safety, high production efficiency and easy operation is an urgent problem to be solved in the field.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of an amide compound, which has the advantages of good safety, mild reaction conditions, high production efficiency and easiness in operation, in order to overcome the defects of poor safety, harsh reaction conditions, long reaction time, low production efficiency and the like in the preparation process of the amide compound in the prior art. The preparation method depends on the kinetic energy of the fluid to carry out mass transfer and heat transfer, does not need mechanical stirring, does not need a continuous reaction process outside a reaction channel, and can obtain the yield higher than that of the traditional reactor. Compared with the traditional process, the preparation method can accurately control the reaction conditions, ensure that the reaction raw materials are converted in a very short time, reduce the formation of byproducts, avoid the fluctuation of temperature and concentration, ensure the safety of the reaction process and realize continuous production.
The invention solves the technical problems through the following technical scheme:
the invention provides a preparation method of an amide compound, which is carried out in a tubular reactor, wherein the tubular reactor comprises a first reaction zone and a second reaction zone;
the preparation method comprises the following steps:
(1) reacting an organic solution A containing a compound I and an organic solution B containing n-butyllithium in the first reaction zone at-80-10 ℃ to obtain a reaction solution;
(2) reacting the reaction solution with an organic solution C containing a compound II in the second reaction zone at-80-10 ℃;
the general reaction formula for the reaction of said compound I and said compound II is as follows:
wherein the mass fraction of the compound I in the organic solution A is 5-40%, and the flow rate of the organic solution A is 0.1-25L/s; the mass fraction of the compound II in the organic solution C is 5-50%, and the flow rate of the organic solution C is 0.1-1.5L/s; the number of the substituent groups on the benzene ring of the compound I is n, n is 0,1, 2, 3, 4 or 5, and R1Each independently is C1～C6Alkyl radical, C1～C6Alkoxy or "substituted or unsubstituted C6～C10Aryl "; r2Is hydrogen, C1～C6Alkyl or "substituted or unsubstituted phenyl", the substituent of said substituted phenyl being C1～C6Alkyl or C1～C6An alkoxy group; r3Is C1～C6Alkyl or "methyl substituted with one or more phenyl".
In the present invention, the diameter of the tubular reactor may be 1 to 30mm, and the material of the tubular reactor is preferably stainless steel or tetrafluoroethylene-perfluoroalkylvinylether copolymer (PFA).
In the present invention, the tubular reactor generally comprises a first pipeline, a second pipeline, a third pipeline, a first tubular reactor and a second tubular reactor, the first pipeline, the second pipeline and the head end of the first tubular reactor are communicated with each other through a tee conventionally used in the art, and the tail end of the first tubular reactor, the head end of the second tubular reactor and the third pipeline are communicated with each other through a tee conventionally used in the art.
In the present invention, the first reaction zone means an internal channel formed on the outer wall of the first tubular reactor for performing the reaction in the aforementioned step (1), and the second reaction zone means an internal channel formed on the outer wall of the second tubular reactor for performing the reaction in the aforementioned step (2).
In the using process, the organic solution A containing the compound I flowing out through the first pipeline and the organic solution B containing n-butyllithium flowing out through the second pipeline enter the first reaction zone through the head end of the first tubular reactor, and after the reaction is finished, the reaction liquid flowing out through the tail end of the first tubular reactor and the organic solution C containing the compound II flowing out through the third pipeline simultaneously enter the second reaction zone through the head end of the second tubular reactor to react.
In the present invention, the organic solvent in the organic solution a, the organic solution B or the organic solution C may be an organic solvent conventionally used in the art, and may be, for example, an ether solvent and/or an alkane solvent.
Among them, the ether solvent is preferably one or more of methyl t-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and 1, 4-dioxane.
Wherein, the alkane solvent is preferably one or more of petroleum ether, n-pentane, n-hexane, cyclohexane and heptane.
In the step (1), the reaction temperature is preferably-10 to 10 ℃, more preferably 0 to 5 ℃.
In the step (1), the reaction pressure is preferably 0.5 to 2MPa, more preferably 0.5 to 1.5MPa, for example, 1.0 MPa.
In the step (1), the residence time of the reaction is preferably 10 to 100s, for example, 20s, 30s, 45 s.
In the step (1), the mass fraction of the compound I in the organic solution a is preferably 11% to 16%, and may be 12%, for example.
In the step (1), the flow rate of the organic solution A is preferably 2 to 5.5L/s, for example, 2.12L/s, 2.54L/s, and 5.31L/s.
In the step (1), the flow rate of the organic solution A is preferably 5 to 100mL/min, more preferably 10 to 25mL/min, for example, 12 mL/min.
In the step (1), the mass fraction of n-butyllithium in the organic solution B is preferably 15% to 25%, more preferably 20%.
In the step (1), the flow rate of the organic solution B is preferably 1-3L/s, for example, 1.27L/s, 1.70L/s, 2.55L/s.
In the step (1), the flow rate of the organic solution B is preferably 1 to 100mL/min, more preferably 6 to 12mL/min, and for example, may be 8 mL/min.
In the step (1), the molar ratio of the compound I to the n-butyllithium is preferably 1:1 to 1: 10.
In the step (1), the flow ratio of the organic solution A to the organic solution B is preferably 10:1 to 1: 10.
In the step (1), the flow rate ratio of the organic solution A to the organic solution B is preferably 10:1 to 1: 10.
In the step (2), the reaction temperature is preferably-10 to 10 ℃, more preferably 0 to 5 ℃.
In the step (2), the reaction pressure is preferably 0.5 to 2MPa, more preferably 0.5 to 1.5MPa, for example, 1.0 MPa.
In the step (2), the residence time of the reaction is preferably 10 to 100s, for example, 20s, 40s, 45 s.
In the step (2), the mass fraction of the compound II in the organic solution C is preferably 30% to 40%, and may be, for example, 35% or 36%.
In the step (2), the flow rate of the organic solution C is preferably 0.4-0.7L/s, such as 0.42L/s, 0.53L/s, and 0.64L/s.
In the step (2), the flow rate of the organic solution C is preferably 0.6 to 5mL/min, more preferably 2 to 3mL/min, for example, 2.5 mL/min.
In the present invention, preferably, R is1Each independently is one or more of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy or phenyl.
In the present invention, R is2Preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl, p-tolyl, o-tolyl, m-tolyl, p-methoxyphenyl, o-methoxyphenyl or m-methoxyphenyl.
In the present invention, R is3Preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, benzyl or benzhydryl.
In the present invention, preferably, R is1Is hydrogen, said R2Is methyl, ethyl or phenyl, said R3Is methyl, ethyl or benzyl.
In the invention, after the step (2) is finished, the post-treatment mode of the obtained product can be a post-treatment mode conventionally adopted in the field, and preferably, the obtained product is mixed with dilute hydrochloric acid, concentrated, heated, mixed with toluene and layered to obtain a first organic phase; mixing with dilute hydrochloric acid, and layering to obtain a second organic phase; cooling, crystallizing, filtering, washing and drying to obtain the product.
Wherein the temperature rise end point temperature is preferably 65-80 ℃;
wherein the final temperature of the cooling is preferably 0-5 ℃;
among them, toluene is preferably used for the washing.
In the present invention, the residence time refers to the total residence time of the material particles in the tubular reactor from the time of entering the tubular reactor to the time of leaving the tubular reactor.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the invention provides a preparation method of an amide compound, which has the advantages of good safety, mild reaction conditions, high production efficiency and easy operation, and can realize mass transfer and heat transfer by relying on the kinetic energy of fluid, without mechanical stirring or continuous reaction process outside a reaction channel, thereby obtaining the yield higher than that of the traditional reactor. Compared with the traditional process system, the process system can accurately control the reaction conditions, ensure that the reaction raw materials are converted in a very short time, reduce the formation of byproducts, avoid the fluctuation of temperature and concentration, ensure the safety of the reaction process and realize continuous production.
Drawings
FIG. 1 is a process flow diagram of a preparation method of an amide compound of the present invention.
FIG. 2 is an HPLC chromatogram of the product obtained in example 1.
FIG. 3 is an HPLC chromatogram of the product obtained in example 2.
FIG. 4 is an HPLC chromatogram of the product obtained in example 3.
FIG. 5 is an HPLC chromatogram of the product obtained in comparative example 1.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In the following examples, the purity of the product obtained is HPLC purity, and the detection conditions are as follows:
high performance liquid chromatograph: agilent 1200(LC chemical workstation) or an equivalent HPLC system; a chromatographic column: agilent XDB-C18, 150X 4.6mm 5 μm or equivalent;
main reagents and materials: acetonitrile (HPLC grade) Water (Milli-Q) phosphoric acid (analytical grade)
Chromatographic conditions are as follows: detection wavelength: 210 nm; flow rate: 1.0 mL/min; column temperature: 25 ℃; sample introduction amount: 5 mu l of the solution; operating time: 22 min; mobile phase A: 0.1% phosphoric acid in water; mobile phase B: and (3) acetonitrile.
Gradient elution procedure:
| time/min | Mobile phase A/%) | Mobile phase B/%) |
| 0 | 90 | 10 |
| 12.0 | 20 | 80 |
| 17.0 | 20 | 80 |
| 17.1 | 90 | 10 |
| 22.0 | 90 | 10 |
Example 1
The reaction formula is as follows:
preparing raw materials: weighing 10.7g of the compound I-1 to prepare a tetrahydrofuran solution containing 12 wt% of the compound I-1, and placing the tetrahydrofuran solution in a raw material tank 1; weighing 34mL of 20% n-butyllithium cyclohexane solution, and placing the solution in a raw material tank 2; 13.4g of dimethyl carbonate was weighed to prepare a tetrahydrofuran solution containing 50 wt% of the compound II-1, which was placed in a stock tank 3.
The process flow diagram of fig. 1 is adopted, wherein the pipe diameter of the tubular reactor is 10mm, the reaction pressure is 1.0MPa, and the following steps are adopted: a tetrahydrofuran solution containing a compound I-1 in a raw material tank 1 enters a first reaction zone through a metering pump 1, and an n-butyllithium cyclohexane solution in a raw material tank 2 enters the first reaction zone through a metering pump 2; setting the flow rates of the tetrahydrofuran solution and the n-butyllithium cyclohexane solution of the compound I-1 controlled by the metering pumps 1 and 2 to be 25mL/min and 12mL/min respectively, setting the corresponding flow rates to be 5.31L/s and 2.55L/s respectively, setting the temperature of a heat exchanger to be 0 ℃, and setting the reaction retention time to be 20 s; the tetrahydrofuran solution containing dimethyl carbonate in the raw material tank 3 enters a second reaction zone through a metering pump 3; setting a metering pump 3 to control the flow of the tetrahydrofuran solution containing the dimethyl carbonate to be 3.0mL/min, and setting the corresponding flow rate to be 0.64L/s; setting the temperature of the heat exchanger to be 0 ℃, and reacting with the mixture passing through the first reaction zone for 20 s; after the reaction in the second reaction zone, the product is continuously discharged into a collecting tank 4. Adding dilute hydrochloric acid, concentrating at normal pressure to evaporate the low-boiling-point solvent; heating to 65-80 ℃, adding toluene, standing for layering, collecting an upper organic layer, and discarding a lower water layer; adding dilute hydrochloric acid solution, standing for layering, collecting an upper organic layer, and discarding a lower water layer; and cooling and crystallizing to 0-5 ℃, filtering, washing with toluene, and drying to obtain the product.
When the spectrum of the reaction product III-1 was compared with the spectrum of a reference (j.org.chem.2008,73,1559), the result was consistent, and it was determined to be N-methyl-N-methoxycarbonylaniline, the yield was 85.7%, and the purity was 90.5% by high performance liquid chromatography.
Example 2
The reaction formula is as follows:
preparing raw materials: weighing 16.9g of the compound I-2 to prepare a 1, 4-dioxane solution containing 11 wt% of the compound I-2, and placing the solution in a raw material tank 1; weighing 40mL of 20% n-butyllithium cyclohexane solution, and placing the solution in a raw material tank 2; 18.0g of diethyl carbonate was weighed to prepare a solution of 1, 4-dioxane containing 35 wt% of compound II-2, which was placed in a stock tank 3.
The process flow diagram of fig. 1 is adopted, wherein the pipe diameter of the tubular reactor is 10mm, the reaction pressure is 1.0MPa, and the following steps are adopted: enabling the 1, 4-dioxane solution containing the compound I-2 in the raw material tank 1 to enter a first reaction zone through a metering pump 1, and enabling the n-butyllithium cyclohexane solution in the raw material tank 2 to enter the first reaction zone through a metering pump 2; setting the flow rates of the 1, 4-dioxane solution and the n-butyllithium cyclohexane solution of the compound I-2 controlled by the metering pumps 1 and 2 to be 10mL/min and 6mL/min respectively, the corresponding flow rates to be 2.12L/s and 1.27L/s respectively, setting the temperature of the heat exchanger to be 5 ℃ and setting the reaction residence time to be 30 s; 1, 4-dioxane solution containing dimethyl carbonate enters a second reaction zone through a metering pump 3; setting a metering pump 3 to control the flow of the 1, 4-dioxane solution containing the dimethyl carbonate to be 2.0mL/min, and setting the corresponding flow rate to be 0.42L/s; setting the temperature of the heat exchanger to be 0 ℃, and reacting with the mixture passing through the first reaction zone for 40 s; after the reaction in the second reaction zone, the product is continuously discharged into a collecting tank 4. Adding dilute hydrochloric acid, concentrating at normal pressure to evaporate the low-boiling-point solvent; heating to 65-80 ℃, adding toluene, standing for layering, collecting an upper organic layer, and discarding a lower water layer; adding dilute hydrochloric acid solution, standing for layering, collecting an upper organic layer, and discarding a lower water layer; and cooling and crystallizing to 0-5 ℃, filtering, washing with toluene, and drying to obtain the product.
When the spectrum of the reaction product III-2 was compared with that of a reference (Bull. chem. Soc. Jpn.1988,61,2913), the result was consistent and it was confirmed to be N-phenyl-N-ethoxycarbonylaniline with a yield of 84.7% and a purity of 88.6% by high performance liquid chromatography.
Example 3
The reaction formula is as follows:
preparing raw materials: weighing 12.1g of the compound I-3, preparing a methyl tert-butyl ether solution containing 16 wt% of the compound I-3, and placing the solution in a raw material tank 1; weighing 35mL of 20% n-butyllithium cyclohexane solution, and placing the solution in a raw material tank 2; 26.4g of dibenzyl carbonate was weighed to prepare a methyl t-butyl ether solution containing 36 wt% of Compound II-3, and the solution was placed in a stock tank 3.
The process flow diagram of fig. 1 is adopted, wherein the pipe diameter of the tubular reactor is 10mm, the reaction pressure is 1.0MPa, and the following steps are adopted: feeding a methyl tert-butyl ether solution containing a compound I-3 in a raw material tank 1 into a first reaction zone through a metering pump 1, and feeding an n-butyl lithium cyclohexane solution in a raw material tank 2 into the first reaction zone through a metering pump 2; setting the flow rates of the methyl tert-butyl ether solution containing the compound I-3 and the n-butyl lithium cyclohexane solution controlled by the metering pumps 1 and 2 to be 12mL/min and 8mL/min respectively, setting the corresponding flow rates to be 2.55L/s and 1.70L/s respectively, setting the temperature of a heat exchanger to be 5 ℃ and setting the reaction retention time to be 45 s; feeding the methyl tert-butyl ether solution containing dimethyl carbonate into a second reaction zone through a metering pump 3; setting a metering pump 3 to control the flow of the methyl tert-butyl ether solution containing the dimethyl carbonate to be 2.5mL/min, and setting the corresponding flow rate to be 0.53L/s; setting the temperature of the heat exchanger to be 0 ℃, and reacting with the mixture passing through the first reaction zone for 45 s; after the reaction in the second reaction zone, the product is continuously discharged into a collecting tank 4. Adding dilute hydrochloric acid, concentrating at normal pressure to evaporate the low-boiling-point solvent; heating to 65-80 ℃, adding toluene, standing for layering, collecting an upper organic layer, and discarding a lower water layer; adding dilute hydrochloric acid solution, standing for layering, collecting an upper organic layer, and discarding a lower water layer; and cooling and crystallizing to 0-5 ℃, filtering, washing with toluene, and drying to obtain the product.
When the spectrum of the reaction product III-3 was compared with that of a reference (J.org.chem.1960,25,1874), the result was consistent and it was determined to be N-ethyl-N-benzyloxycarbonylaniline with a yield of 86.3% and a purity of 91.2% by HPLC analysis.
Example 4
The reaction formula is as follows:
preparing raw materials: preparing a tetrahydrofuran solution containing 5 wt% of a compound I-1, and placing the tetrahydrofuran solution in a raw material tank 1; preparing a 15% n-butyllithium cyclohexane solution, and placing the solution in a raw material tank 2; a tetrahydrofuran solution containing 5 wt% of Compound II-1 was prepared and placed in stock tank 3.
The process flow diagram of fig. 1 is adopted, wherein the pipe diameter of the tubular reactor is 30mm, the reaction pressure is 0.5MPa, and the following steps are carried out: a tetrahydrofuran solution containing a compound I-1 in a raw material tank 1 enters a first reaction zone through a metering pump 1, and an n-butyllithium cyclohexane solution in a raw material tank 2 enters the first reaction zone through a metering pump 2; setting the flow rates of the tetrahydrofuran solution and the n-butyllithium cyclohexane solution of the compound I-1 controlled by the metering pumps 1 and 2 to be 0.1L/s and 0.4L/s respectively, setting the temperature of a heat exchanger to be-80 ℃ and setting the reaction residence time to be 10 s; the tetrahydrofuran solution containing dimethyl carbonate in the raw material tank 3 enters a second reaction zone through a metering pump 3; setting a metering pump 3 to control the flow rate of the tetrahydrofuran solution containing the dimethyl carbonate to be 0.1L/s; setting the temperature of the heat exchanger to be-80 ℃, and reacting with the mixture passing through the first reaction zone for 10 s; after the reaction in the second reaction zone, the product is continuously discharged into a collecting tank 4. Adding dilute hydrochloric acid, concentrating at normal pressure to evaporate the low-boiling-point solvent; heating to 65-80 ℃, adding toluene, standing for layering, collecting an upper organic layer, and discarding a lower water layer; adding dilute hydrochloric acid solution, standing for layering, collecting an upper organic layer, and discarding a lower water layer; and cooling and crystallizing to 0-5 ℃, filtering, washing with toluene, and drying to obtain the product.
When the spectrum of the reaction product III-3 was compared with that of a reference (J.org.chem.1960,25,1874), the result was consistent, and it was determined to be N-methyl-N-methoxycarbonylaniline, the yield was 82.1%, and the purity was 90.2% by high performance liquid chromatography.
Example 5
The reaction formula is as follows:
preparing raw materials: preparing a tetrahydrofuran solution containing 40 wt% of the compound I-1, and placing the tetrahydrofuran solution in a raw material tank 1; preparing a 25% n-butyllithium cyclohexane solution, and placing the solution in a raw material tank 2; a tetrahydrofuran solution containing 40 wt% of Compound II-1 was prepared and placed in stock tank 3.
The process flow diagram of fig. 1 is adopted, wherein the pipe diameter of the tubular reactor is 1mm, the reaction pressure is 2.0MPa, and the following steps are adopted: a tetrahydrofuran solution containing a compound I-1 in a raw material tank 1 enters a first reaction zone through a metering pump 1, and an n-butyllithium cyclohexane solution in a raw material tank 2 enters the first reaction zone through a metering pump 2; setting the flow rates of the tetrahydrofuran solution and the n-butyllithium cyclohexane solution of the compound I-1 controlled by the metering pumps 1 and 2 to be 25L/s and 0.7L/s respectively, setting the temperature of a heat exchanger to be 10 ℃ and setting the reaction residence time to be 100 s; the tetrahydrofuran solution containing dimethyl carbonate in the raw material tank 3 enters a second reaction zone through a metering pump 3; setting a metering pump 3 to control the flow rate of the tetrahydrofuran solution containing the dimethyl carbonate to be 1.5L/s; setting the temperature of the heat exchanger to be 10 ℃, and reacting with the mixture passing through the first reaction zone for 100 s; after the reaction in the second reaction zone, the product is continuously discharged into a collecting tank 4. Adding dilute hydrochloric acid, concentrating at normal pressure to evaporate the low-boiling-point solvent; heating to 65-80 ℃, adding toluene, standing for layering, collecting an upper organic layer, and discarding a lower water layer; adding dilute hydrochloric acid solution, standing for layering, collecting an upper organic layer, and discarding a lower water layer; and cooling and crystallizing to 0-5 ℃, filtering, washing with toluene, and drying to obtain the product.
When the spectrum of the reaction product III-3 was compared with that of a reference (J.org.chem.1960,25,1874), the result was consistent, and it was determined to be N-methyl-N-methoxycarbonylaniline, the yield was 81.5%, and the purity was 89.6% by high performance liquid chromatography.
Comparative example 1
Weighing 10.7g of compound I-1 to prepare a tetrahydrofuran solution containing 12 wt% of the compound I-1, stirring and dissolving, cooling to below-50 ℃, dropwise adding 34mL of 20% n-butyllithium cyclohexane solution for about 2h, dropwise adding 13.4g of dimethyl carbonate, continuing to react for 2-3h, adding dilute hydrochloric acid, and concentrating at normal pressure to evaporate the low-boiling-point solvent. Heating to 65-80 ℃, adding toluene, collecting an upper organic layer, and discarding a lower water layer; and adding a dilute hydrochloric acid solution, standing for layering, collecting an upper organic layer, discarding a lower water layer, cooling, crystallizing to 0-5 ℃, filtering, washing with toluene, and drying to obtain the product. The yield was 82% and the purity was 85.7%.
Comparative example 2
Preparing raw materials: weighing 10.7g of the compound I-1 to prepare a tetrahydrofuran solution containing 12 wt% of the compound I-1, and placing the tetrahydrofuran solution in a raw material tank 1; weighing 34mL of 20% n-butyllithium cyclohexane solution, and placing the solution in a raw material tank 2; 13.4g of dimethyl carbonate was weighed to prepare a tetrahydrofuran solution containing 50 wt% of the compound II-1, which was placed in a stock tank 3.
The process flow diagram of fig. 1 is adopted, wherein the pipe diameter of the tubular reactor is 10mm, the reaction pressure is 1.0MPa, and the following steps are adopted: a tetrahydrofuran solution containing a compound I-1 in a raw material tank 1 enters a first reaction zone through a metering pump 1, and an n-butyllithium cyclohexane solution in a raw material tank 2 enters the first reaction zone through a metering pump 2; setting the flow rates of the tetrahydrofuran solution and the n-butyllithium cyclohexane solution of the compound I-1 controlled by the metering pumps 1 and 2 to be 100mL/min and 48mL/min respectively, setting the corresponding flow rates to be 21.2L/s and 10.2L/s respectively, setting the temperature of a heat exchanger to be 0 ℃, and setting the reaction retention time to be 5 s; the tetrahydrofuran solution containing dimethyl carbonate in the raw material tank 3 enters a second reaction zone through a metering pump 3; setting a metering pump 3 to control the flow of the tetrahydrofuran solution containing the dimethyl carbonate to be 12.0mL/min, and setting the corresponding flow rate to be 2.55L/s; setting the temperature of the heat exchanger to be 0 ℃, and reacting with the mixture passing through the first reaction zone for 5 s; after the mixed reaction in the second reaction zone, the product is continuously discharged into a collecting tank 4. Adding dilute hydrochloric acid, concentrating at normal pressure to evaporate the low-boiling-point solvent; heating to 65-80 ℃, adding toluene, collecting an upper organic layer, and discarding a lower water layer; adding dilute hydrochloric acid solution, standing for layering, collecting an upper organic layer, and discarding a lower water layer; and cooling and crystallizing to 0-5 ℃, filtering, washing with toluene, and drying to obtain the product. The yield was 65.2% and the purity was 77.1%.
Comparative example 3
Preparing raw materials: weighing 10.7g of the compound I-1 to prepare a tetrahydrofuran solution containing 12 wt% of the compound I-1, and placing the tetrahydrofuran solution in a raw material tank 1; weighing 34mL of 20% n-butyllithium cyclohexane solution, and placing the solution in a raw material tank 2; 13.4g of dimethyl carbonate was weighed to prepare a tetrahydrofuran solution containing 50 wt% of the compound II-1, which was placed in a stock tank 3.
The process flow diagram of fig. 1 is adopted, wherein the pipe diameter of the tubular reactor is 10mm, the reaction pressure is 1.0MPa, and the following steps are adopted: a tetrahydrofuran solution containing a compound I-1 in a raw material tank 1 enters a first reaction zone through a metering pump 1, and an n-butyllithium cyclohexane solution in a raw material tank 2 enters the first reaction zone through a metering pump 2; setting the flow rates of the tetrahydrofuran solution containing the compound I-1 and the n-butyllithium cyclohexane solution controlled by the metering pumps 1 and 2 to be 5mL/min and 2.4mL/min respectively, setting the corresponding flow rates to be 1.06L/s and 0.51L/s respectively, setting the temperature of a heat exchanger to be 0 ℃, and setting the reaction retention time to be 110 s; the tetrahydrofuran solution containing dimethyl carbonate in the raw material tank 3 enters a second reaction zone through a metering pump 3; setting a metering pump 3 to control the flow of the tetrahydrofuran solution containing the dimethyl carbonate to be 0.6mL/min, and setting the corresponding flow rate to be 0.13L/s; setting the temperature of the heat exchanger to be 0 ℃, and reacting with the mixture passing through the first reaction zone for 110 s; after the mixed reaction in the second reaction zone, the product is continuously discharged into a collecting tank 4. Adding dilute hydrochloric acid, concentrating at normal pressure to evaporate the low-boiling-point solvent; heating to 65-80 ℃, adding toluene, collecting an upper organic layer, and discarding a lower water layer; adding dilute hydrochloric acid solution, standing for layering, collecting an upper organic layer, and discarding a lower water layer; and cooling and crystallizing to 0-5 ℃, filtering, washing with toluene, and drying to obtain the product. The yield was 62.2% and the purity was 73.1%.
Claims (18)
1. A preparation method of amide compounds is characterized in that the preparation method is carried out in a tubular reactor, and the tubular reactor comprises a first reaction zone and a second reaction zone;
the preparation method comprises the following steps:
(1) reacting an organic solution A containing a compound I and an organic solution B containing n-butyllithium in the first reaction zone at-80-10 ℃ to obtain a reaction solution;
(2) reacting the reaction solution with an organic solution C containing a compound II in the second reaction zone at-80-10 ℃;
the general reaction formula for the reaction of said compound I and said compound II is as follows:
the mass fraction of the compound I in the organic solution A is 5-40%, and the flow rate of the organic solution A is 5-100 mL/min; in the step (1), the residence time of the reaction is 10-100 s; the mass fraction of the compound II in the organic solution C is 5-50%, and the flow rate of the organic solution C is 0.6-5 mL/min; substituent R on benzene ring of the compound I1N is 0,1, 2, 3, 4 or 5, and R1Each independently is C1～C6Alkyl radical, C1～C6Alkoxy or "unsubstituted C6～C10Aryl "; r2Is C1～C6Alkyl or "substituted or unsubstituted phenyl", the substituent of said substituted phenyl being C1～C6Alkyl or C1～C6An alkoxy group; r3Is C1～C6Alkyl or "methyl substituted with one or more phenyl".
2. The method according to claim 1, wherein the solvent of the organic solution A, the solvent of the organic solution B or the solvent of the organic solution C is an ether solvent and/or an alkane solvent.
3. The method according to claim 2, wherein the ethereal solvent is one or more of methyl t-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and 1, 4-dioxane.
4. The method of claim 2, wherein the alkane solvent is one or more of petroleum ether, n-pentane, n-hexane, cyclohexane and heptane.
5. The preparation method according to claim 1, wherein in the step (1), the reaction temperature is-10 to 10 ℃;
in the step (1), the reaction pressure is 0.5-2 MPa;
and/or in the step (1), the residence time of the reaction is 20-45 s.
6. The preparation method according to claim 5, wherein in the step (1), the reaction temperature is 0-5 ℃;
and/or in the step (1), the pressure of the reaction is 0.5-1.5 MPa.
7. The preparation method according to claim 1, wherein in the step (1), the mass fraction of the compound I in the organic solution a is 11% to 16%;
in the step (1), the mass fraction of the n-butyllithium in the organic solution B is 15-25%.
8. The method according to claim 7, wherein in the step (1), the mass fraction of n-butyllithium in the organic solution B is 20%.
9. The preparation method according to claim 1, wherein in the step (1), the molar ratio of the compound I to the n-butyllithium is 1:1 to 1: 10;
in the step (1), the flow ratio of the organic solution A to the organic solution B is 10: 1-1: 10;
and/or in the step (1), the flow rate ratio of the organic solution A to the organic solution B is 10: 1-1: 10.
10. The preparation method according to claim 1, wherein in the step (2), the reaction temperature is-10 to 10 ℃;
in the step (2), the pressure of the reaction is 0.5-2 MPa;
and/or in the step (2), the residence time of the reaction is 10-100 s.
11. The method according to claim 10, wherein in the step (2), the reaction temperature is 0 to 5 ℃;
in the step (2), the reaction pressure is 0.5-1.5 MPa;
and/or in the step (2), the residence time of the reaction is 20-45 s.
12. The method according to claim 1, wherein in the step (2), the mass fraction of the compound II in the organic solution C is 30 to 40%.
13. The method according to claim 11, wherein in the step (2), the flow rate of the organic solution C is 2 to 3 mL/min.
14. The method of claim 1, wherein R is1Each independently is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy or phenyl;
the R is2Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl, p-tolyl, o-tolyl, m-tolyl, p-methoxyphenyl, o-methoxyphenyl or m-methoxyphenyl;
and/or, said R3Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, benzyl or benzhydryl.
15. The preparation method according to claim 1, wherein after the step (2) is finished, the obtained product is mixed with dilute hydrochloric acid, concentrated, heated, mixed with toluene and layered to obtain a first organic phase; mixing with dilute hydrochloric acid, and layering to obtain a second organic phase; cooling, crystallizing, filtering, washing and drying to obtain the product.
16. The method according to claim 15, wherein the temperature rise end point temperature is 65 to 80 ℃.
17. The method according to claim 15, wherein the final temperature of the temperature reduction is 0 to 5 ℃.
18. The method of claim 15, wherein the washing is with toluene.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4395565A (en) * | 1981-01-28 | 1983-07-26 | Anic S.P.A. | Preparing aromatic urethans |
| CN104230775A (en) * | 2013-06-18 | 2014-12-24 | 中国石油化工股份有限公司 | Method for preparing dialkyl aminodithioformic acid by using one-step method |
| CN104557644A (en) * | 2013-10-09 | 2015-04-29 | 中国石油化工股份有限公司 | Method for preparing dialkyl dithiocarbamate by utilization of continuous flow tubular reactor |
| CN105111106A (en) * | 2015-08-14 | 2015-12-02 | 陕西煤业化工技术开发中心有限责任公司 | Method for catalytically synthesizing toluene dicarbamate |
| CN109180530A (en) * | 2018-09-11 | 2019-01-11 | 江西禾益化工股份有限公司 | A kind of method using micro passage reaction preparation 3,5- dichlorophenyl isocyanate |
-
2017
- 2017-08-10 CN CN201710682214.5A patent/CN107382780B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4395565A (en) * | 1981-01-28 | 1983-07-26 | Anic S.P.A. | Preparing aromatic urethans |
| CN104230775A (en) * | 2013-06-18 | 2014-12-24 | 中国石油化工股份有限公司 | Method for preparing dialkyl aminodithioformic acid by using one-step method |
| CN104557644A (en) * | 2013-10-09 | 2015-04-29 | 中国石油化工股份有限公司 | Method for preparing dialkyl dithiocarbamate by utilization of continuous flow tubular reactor |
| CN105111106A (en) * | 2015-08-14 | 2015-12-02 | 陕西煤业化工技术开发中心有限责任公司 | Method for catalytically synthesizing toluene dicarbamate |
| CN109180530A (en) * | 2018-09-11 | 2019-01-11 | 江西禾益化工股份有限公司 | A kind of method using micro passage reaction preparation 3,5- dichlorophenyl isocyanate |
Non-Patent Citations (1)
| Title |
|---|
| 碳酸二甲酯胺解合成氨基甲酸酯催化剂的研究进展;康武魁等;《工业催化》;20051130;第13卷(第11期);第30-35页 * |
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