CN117603133A - Application of quaternary ammonium salt in continuous flow Curtius rearrangement reaction - Google Patents

Application of quaternary ammonium salt in continuous flow Curtius rearrangement reaction Download PDF

Info

Publication number
CN117603133A
CN117603133A CN202311595496.7A CN202311595496A CN117603133A CN 117603133 A CN117603133 A CN 117603133A CN 202311595496 A CN202311595496 A CN 202311595496A CN 117603133 A CN117603133 A CN 117603133A
Authority
CN
China
Prior art keywords
reaction
reactor
quaternary ammonium
azide
ammonium salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202311595496.7A
Other languages
Chinese (zh)
Inventor
罗力军
许伟泽
金君世
张振峰
陈仟
陈笑敏
司马炜
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ruibo Suzhou Pharmaceutical Co Ltd
Original Assignee
Ruibo Suzhou Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ruibo Suzhou Pharmaceutical Co Ltd filed Critical Ruibo Suzhou Pharmaceutical Co Ltd
Priority to CN202311595496.7A priority Critical patent/CN117603133A/en
Publication of CN117603133A publication Critical patent/CN117603133A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C07C269/02—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 isocyanates with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
    • C07C273/1818—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety from -N=C=O and XNR'R"
    • C07C273/1827—X being H
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D305/08—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/44—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing eight carbon atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention provides a reaction for preparing primary amine, urea derivatives or carbamate by continuous flow Curtius rearrangement, which comprises the following steps: a) Mixing quaternary ammonium salt and carboxylic acid compound for reaction, and extracting with toluene to obtain extractive solution; mixing the extracting solution with an azide reagent in a first continuous reactor to obtain an acyl azide reaction solution; b) Reacting the acyl azide reaction liquid through a second continuous reactor to obtain isocyanate; c) Reacting electrophile with isocyanate in a third continuous reactor to obtain rearranged product; the electrophile is selected from one of water, amine and alcohol compound solutions; d) Quenching and separating the rearranged product to obtain feed liquid and water phase, and crystallizing the feed liquid to obtain the product. The present invention has been found to use quaternary ammonium salts such as: tetrabutylammonium bromide, tetrabutylammonium chloride and the like can replace alkali to carry out Curtius rearrangement reaction, and byproducts are dissolved in an organic solvent without separating out solids to block the reactor.

Description

Application of quaternary ammonium salt in continuous flow Curtius rearrangement reaction
Technical Field
The invention relates to the technical field of organic synthesis, in particular to application of quaternary ammonium salt in a continuous flow Curtius rearrangement reaction.
Background
Rearrangement reactions in organic chemistry can be generally classified into nucleophilic rearrangements, electrophilic rearrangements, radical rearrangements, alpha-migration rearrangements, and the like. As an important representation of electrophilic rearrangements, the Curtius rearrangement reaction converts carboxylic acids into isocyanates, which in turn can be conveniently converted into primary amines, urea derivatives or carbamates, and is thus of great importance in synthetic chemistry. However, many azides are toxic and potentially explosive, so there is still a need to consider the use of more green, safer synthetic routes to replace them in large-scale industrial production.
The method adopts the continuous flow technology to carry out the amplified production of Curtius rearrangement reaction, can solve the safety risk existing in a large amount of azide, and can effectively and safely carry out the Curtius rearrangement reaction through continuous flow experiments. However, the risk of plugging the reactor by precipitation of the azide reagent and the salt of the base byproduct was found by long-term amplification.
It is therefore highly desirable to provide a Curtius rearrangement reaction that does not plug the reactor.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a reaction for preparing primary amine, urea derivative or carbamate by continuous flow Curtius rearrangement, the reaction of the present invention does not block the reactor, and the purity and the yield are high.
The invention provides application of quaternary ammonium salt as an acid binding agent in a continuous flow Curtius rearrangement reaction.
Preferably, the quaternary ammonium salt is tetrabutylammonium bromide or tetrabutylammonium chloride.
The invention provides a reaction for preparing primary amine, urea derivatives or carbamate by continuous flow Curtius rearrangement, which comprises the following steps:
a) Mixing quaternary ammonium salt and carboxylic acid compound for reaction, and extracting with toluene to obtain extractive solution; mixing the extracting solution with an azide reagent in a first continuous reactor to obtain an acyl azide reaction solution;
b) Reacting the acyl azide reaction liquid through a second continuous reactor to obtain isocyanate;
c) Reacting electrophile with isocyanate in a third continuous reactor to obtain rearranged product; the electrophile is selected from one of water, amine and alcohol compound solutions;
d) Quenching and separating the rearranged product to obtain feed liquid and water phase, and crystallizing the feed liquid to obtain the product.
Preferably, the quaternary ammonium salt is tetrabutylammonium bromide or tetrabutylammonium chloride; the carboxylic acid compound is pyridine dichloropicolinate;
the azide reagent is one or more of azido trimethylsilane, diphenyl azide phosphate, p-dodecylbenzenesulfonyl azide or methanesulfonyl azide.
Preferably, the molar ratio of quaternary ammonium salt, carboxylic acid compound and azide reagent in step a) is 1: (1-1.2): (1-1.3);
the feeding flow rate of the extracting solution is 6.7-0.67 mL/min; the feeding flow rate of the azide reagent is 3.3-0.33 mL/min.
Preferably, the temperature of the first continuous reactor is 20-50 ℃; the reaction time is 1-10 min; the acyl azide reaction liquid is obtained by a first continuous reaction
Preferably, the temperature of the second continuous reactor is 100-150 ℃ and the reaction time is 0.5-5 min.
Preferably, the molar ratio of electrophile to isocyanate is (1-1.5): 1, a step of;
the feeding flow rate of the electrophile is 1.6-0.16 mL/min.
Preferably, the reaction temperature of the third continuous reactor in the step C) is 100-150 ℃ and the reaction time is 0.5-5 min.
Preferably, the rearranged product comprises a primary amine, urea derivative or carbamate.
Compared with the prior art, the invention provides a reaction for preparing primary amine, urea derivatives or carbamate by continuous flow Curtius rearrangement, which comprises the following steps: a) Mixing quaternary ammonium salt and carboxylic acid compound for reaction, and extracting with toluene to obtain extractive solution; mixing the extracting solution with an azide reagent in a first continuous reactor to obtain an acyl azide reaction solution; b) Reacting the acyl azide reaction liquid through a second continuous reactor to obtain isocyanate; c) Reacting electrophile with isocyanate in a third continuous reactor to obtain rearranged product; the electrophile is selected from one of water, amine and alcohol compound solutions; d) Quenching and separating the rearranged product to obtain feed liquid and water phase, and crystallizing the feed liquid to obtain the product. The present invention has been found to use quaternary ammonium salts such as: tetrabutylammonium bromide, tetrabutylammonium chloride and the like can replace alkali to carry out Curtius rearrangement reaction, and byproducts are dissolved in an organic solvent without separating out solids to block the reactor.
Drawings
FIG. 1 is a schematic diagram of the process flow of the present invention.
Detailed Description
The invention provides application of quaternary ammonium salt in a continuous flow Curtius rearrangement reaction, and a person skilled in the art can properly improve process parameters by referring to the content of the quaternary ammonium salt. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and they are intended to be within the scope of the present invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the relevant art that the invention can be practiced and practiced with modification and alteration and combination of the methods and applications herein without departing from the spirit and scope of the invention.
In the present application, the term "and/or" describes an association relationship of an association object, which means that three relationships may exist, for example, a and/or B may mean that a exists alone, a and B exist together, and B exists alone. Wherein A, B may be singular or plural.
In the present application, "at least one" means one or more, and "a plurality" means two or more. "at least one of" or the like means any combination of these items, including any combination of single item(s) or plural items(s).
It should be understood that, in various embodiments of the present application, the sequence number of each process does not mean that the sequence of execution is sequential, and some or all of the steps may be executed in parallel or sequentially, where the execution sequence of each process should be determined by its functions and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.
The invention provides application of quaternary ammonium salt as an acid binding agent in a continuous flow Curtius rearrangement reaction.
According to the invention, the quaternary ammonium salt is tetrabutylammonium bromide or tetrabutylammonium chloride.
The inventive discovery of the present invention uses quaternary ammonium salts such as: tetrabutylammonium bromide, tetrabutylammonium chloride and the like can replace alkali to carry out Curtius rearrangement reaction, and byproducts are dissolved in an organic solvent without separating out solids to block the reactor.
The Curtius rearrangement reaction has good applicability to a plurality of carboxylic acids containing different functional groups. If it is desired to isolate the Curtius rearranged product isocyanate, the reaction is carried out in a solvent which is not nucleophilic. If water, an amine or an alcohol is introduced into the Curtius rearrangement reaction system, the reaction product will be the corresponding primary amine, urea derivative or carbamate.
FIG. 1 is a schematic diagram of the process flow of the present invention. The reaction system of the invention is back-pressed to 4-10 bar through a back-pressure valve.
The invention provides a reaction for preparing primary amine, urea derivatives or carbamate by continuous flow Curtius rearrangement, which comprises the following steps:
a) Mixing quaternary ammonium salt and carboxylic acid compound for reaction, and extracting with toluene to obtain extractive solution; mixing the extracting solution with an azide reagent in a first continuous reactor to obtain an acyl azide reaction solution;
b) Reacting the acyl azide reaction liquid through a second continuous reactor to obtain isocyanate;
c) Reacting electrophile with isocyanate in a third continuous reactor to obtain rearranged product; the electrophile is selected from one of water, amine and alcohol compound solutions;
d) Quenching and separating the rearranged product to obtain feed liquid and water phase, and crystallizing the feed liquid to obtain the product.
The reaction provided by the invention can prepare continuous flow Curtius rearrangement to prepare primary amine, urea derivatives or carbamate.
Wherein the electrophile is water and the product is primary amine.
If the electrophile of the present invention is an amine, the product is a urea derivative of formula (I), including aniline, benzylamine, and the like.
If the electrophile is an alcohol, the product is a carbamate. If the electrophile is tertiary butanol, the product is Boc-aminopyridine;
if the electrophile is methoxybenzyl alcohol, the product is butylene oxide aminomethoxybenzyl ester;
if the electrophile is methanol, the product is a carbamate.
Firstly, quaternary ammonium salt and carboxylic acid compound are mixed and reacted, and the extract is obtained by toluene extraction. The reaction temperature is 20-40 ℃.
Adding quaternary ammonium salt and carboxylic acid compound into the first continuous reactor, stirring, adding toluene into the first continuous reactor, stirring, extracting, standing and layering.
The quaternary ammonium salt is tetrabutylammonium bromide or tetrabutylammonium chloride.
The carboxylic acid compound is pyridine dichloropicolinate;
in some embodiments, the molar ratio of quaternary ammonium salt, carboxylic acid compound, and azide reagent is 1: (1-1.2): (1-1.3).
Mixing the extracting solution with the azide reagent in a first continuous reactor to obtain an acyl azide reaction solution. The temperature of the first continuous reactor is 20-50 ℃; the reaction time is 1-10 min.
The azide reagent is one or more of azido trimethylsilane, diphenyl azide phosphate, p-dodecylbenzenesulfonyl azide or methanesulfonyl azide.
According to the invention, the feeding flow rate of the extracting solution is 6.7-0.67 mL/min; the feeding flow rate of the azide reagent is 3.3-0.33 mL/min. The reaction flow rate is fixed by the liquid holdup of the laboratory reactor, and is correspondingly adjusted according to the reaction time.
The acyl azide reaction liquid is a mixed liquid of diphenyl azide phosphate and toluene.
The invention can monitor and detect in real time through the on-line detector.
And (3) reacting the acyl azide reaction liquid through a second continuous reactor to obtain isocyanate.
The temperature of the second continuous reactor is 100-150 ℃, and the reaction time is 0.5-5 min.
Reacting electrophile with isocyanate in a third continuous reactor to obtain rearranged product; the electrophile is selected from one of water, amine and alcohol compound solutions.
Specifically, the molar ratio of the electrophile to isocyanate is (1-1.5): 1, a step of; including but not limited to 1:1, a step of; 1:1.1;1:1.2;1:1.3;1:1.4;1:1.5.
the feeding flow rate of the electrophile is 1.6-0.16 mL/min.
The reaction temperature of the third continuous reactor is 100-150 ℃ and the reaction time is 0.5-5 min.
And (3) carrying out the next reaction of the isocyanate in the reaction liquid in the third continuous reactor to obtain a rearranged product, and carrying out real-time monitoring detection by using an online detector.
The rearranged products of the invention comprise primary amine, urea derivatives or carbamate.
Quenching and separating the rearranged product to obtain feed liquid and water phase, and crystallizing the feed liquid to obtain the product.
The invention finally quenches the solution and carries on the separation of the online continuous organic phase and water phase through the liquid-liquid separator, the liquid-liquid is to carry on the crystallization treatment, the water phase carries on the three wastes treatment.
The method uses quaternary ammonium salt to replace alkali to carry out Curtius rearrangement reaction of continuous flow, and can realize continuous flow amplification production without risk of blocking the reactor after long-time amplification.
Firstly, a continuous flow technology is adopted, so that the problem of safety of the Curtius rearrangement reaction batch kettle is solved (the risk of an azide reagent and a large amount of gas can be generated in the reaction process, the batch kettle is controlled improperly and is easy to flush materials), the reaction can be safely and efficiently commercialized, and secondly, the yield and quality of the product are obviously improved.
The invention provides a reaction for preparing primary amine, urea derivatives or carbamate by continuous flow Curtius rearrangement, which comprises the following steps: a) Mixing quaternary ammonium salt and carboxylic acid compound for reaction, and extracting with toluene to obtain extractive solution; mixing the extracting solution with an azide reagent in a first continuous reactor to obtain an acyl azide reaction solution; b) Reacting the acyl azide reaction liquid through a second continuous reactor to obtain isocyanate; c) Reacting electrophile with isocyanate in a third continuous reactor to obtain rearranged product; the electrophile is selected from one of water, amine and alcohol compound solutions; d) Quenching and separating the rearranged product to obtain feed liquid and water phase, and crystallizing the feed liquid to obtain the product. The present invention has been found to use quaternary ammonium salts such as: tetrabutylammonium bromide, tetrabutylammonium chloride and the like can replace alkali to carry out Curtius rearrangement reaction, and byproducts are dissolved in an organic solvent without separating out solids to block the reactor.
To further illustrate the present invention, the following describes in detail the use of a quaternary ammonium salt according to the present invention in a continuous flow Curtius rearrangement reaction, in conjunction with examples.
Example 1
Feed pump A, material A is quaternary ammonium salt of pyridine carboxylic acid, feed pump B, material B is azide reagent, feed pump C: material C t-butanol, feed pump D: quenching solution
The reaction system is back-pressed to 5bar through a back-pressure valve, a flow rate of 6.7ml/min is set by a feed pump A, a flow rate of 3.3ml/min is set by a feed pump B, and the reaction system is pumped into a pipeline reactor (pipeline reactor A) through a static mixer, wherein the temperature of the reactor is 20 ℃, and the reaction time is 1 minute; and then the isocyanate is obtained by reaction for 0.5 minutes through a pipeline reactor B at the temperature of 130 ℃. The feeding pump C is set at a flow rate of 1.6ml/min, materials are mixed and reacted through a static mixer and a pipeline reactor (pipeline reactor A.B), the temperature of the reactor is set at 130 ℃, the reaction time is 1 minute, the feeding pump D pumps quenching solution to quench reaction liquid through the static mixer, after quenching, the quenching solution passes through a liquid-liquid separator, and an organic layer and a water layer are separated and collected separately. The obtained organic layer is subjected to reduced pressure distillation, and crystallization to obtain the product Boc-aminopyridine with the yield of 91% and the purity of 99.1%. The whole reaction process has stable pressure, no blocking phenomenon, and continuous feeding can be realized.
Example 2
Feed pump A is quaternary ammonium salt of carboxylic acid butylene oxide, feed pump B is azide reagent, feed pump C: material C p-methoxybenzyl alcohol, feed pump D: quenching solution
The reaction system is back-pressed to 7bar through a back-pressure valve, the flow rate of a feed pump A is set to be 0.6ml/min, the flow rate of a feed pump B is set to be 0.3ml/min, and the reaction system is pumped into a pipeline reactor (pipeline reactor A) through a static mixer, wherein the temperature of the reactor is 40 ℃ and the reaction time is 40 minutes; and then reacting for 5 minutes through a reactor B at 130 ℃ to obtain isocyanate. The feeding pump C is set with the flow rate of 0.15ml/min, materials are mixed and reacted through a static mixer and a pipeline reactor (pipeline reactor A.B), the temperature of the reactor is set to 130 ℃, the reaction time is 3 minutes, the feeding pump D pumps quenching solution to quench reaction liquid through the static mixer, after quenching, the quenching solution passes through a liquid-liquid separator, and an organic layer and a water layer are separated and collected separately. The obtained organic layer is subjected to detection purity of 92%, alkali extraction, reduced pressure distillation and crystallization to obtain the product of the epoxybutane amino methoxybenzyl ester with the yield of 81% and the purity of 99.4%.
Example 3
Feed pump A, material A is quaternary ammonium salt of carboxylic acid lactam, feed pump B, material B is azide reagent, feed pump C: material C water, feed pump D: quenching solution
The reaction system is back-pressed to 4bar through a back-pressure valve, a flow rate of 3ml/min is set for a feed pump A, a flow rate of 1.5ml/min for a feed pump B, and the reaction system is pumped into a pipeline reactor (pipeline reactor A) through a static mixer, wherein the temperature of the reactor is 30 ℃, and the reaction time is 2 minutes; and then the isocyanate is obtained through the reaction of the reactor B at the temperature of 110 ℃ for 0.5 minutes. The feeding pump C is set with the flow rate of 0.8ml/min, materials are mixed and reacted through the static mixer and the pipeline reactor (pipeline reactor A.B) to enter the reactor C, the temperature of the reactor is set to 130 ℃, the reaction time is 1 minute, the feeding pump D pumps quenching solution to quench reaction liquid through the static mixer, after quenching, the quenching solution passes through the liquid-liquid separator, and an organic layer and a water layer are separated and collected separately. The obtained organic layer has the purity of 90 percent, the chiral purity of 99 percent, and the yield of the amino compound of the product is 80 percent and the purity of 98.7 percent by vacuum distillation and crystallization.
Example 4
Feed pump A, feed pump B, feed pump C, wherein material A is quaternary ammonium salt of cyclohexane carboxylate, material B is azide reagent: material C methanol, feed pump D: quenching solution
The reaction system is back-pressed to 8bar through a back-pressure valve, a flow rate of 5ml/min is set for a feed pump A, a flow rate of 2.5ml/min for a feed pump B, and the reaction system is pumped into a pipeline reactor (pipeline reactor A) through a static mixer, wherein the temperature of the reactor is 20 ℃, and the reaction time is 3 minutes; and then the isocyanate is obtained by reaction for 0.5 minutes through a pipeline reactor B at the temperature of 130 ℃. The feeding pump C is set at a flow rate of 1.4ml/min, materials are mixed and reacted through a static mixer and a pipeline reactor (pipeline reactor A.B), the temperature of the reactor is set at 130 ℃, the reaction time is 1 minute, the feeding pump D pumps quenching solution to quench reaction liquid through the static mixer, after quenching, the quenching solution passes through a liquid-liquid separator, and an organic layer and a water layer are separated and collected separately. The obtained organic layer is subjected to vacuum distillation, crystallization to obtain the product carbamate with the yield of 90% and the purity of 99.6% after detection of the purity of 95%.
Example 5
Feed pump A, material A is quaternary ammonium salt of benzoic acid, feed pump B, material B is azide reagent, feed pump C: material C aniline, feed pump D: quenching solution
The reaction system is back-pressed to 7bar through a back-pressure valve, a flow rate of 3ml/min is set for a feed pump A, a flow rate of 1.7ml/min for a feed pump B, and the reaction system is pumped into a pipeline reactor (pipeline reactor A) through a static mixer, wherein the temperature of the reactor is 30 ℃, and the reaction time is 3 minutes; and then the isocyanate is obtained after 2 minutes of reaction through a reactor B at the temperature of 120 ℃. The feeding pump C is set with the flow rate of 0.8ml/min, materials are mixed and reacted through the static mixer and the pipeline reactor (pipeline reactor A.B) to enter the reactor C, the temperature of the reactor is set to 120 ℃, the reaction time is 1 minute, the feeding pump D pumps quenching solution to quench reaction liquid through the static mixer, after quenching, the quenching solution passes through the liquid-liquid separator, and an organic layer and a water layer are separated and collected separately. The obtained organic layer has the detected purity of 91 percent, is distilled under reduced pressure, and is crystallized to obtain the diphenyl urea product with the yield of 86 percent and the purity of 99.6 percent
Comparative example 1
Toluene 5W was added to the reaction vessel R1, and pyridine dichlorocarboxylate (1.0W) was added to R1 with stirring. Controlling the internal temperature of R1 to 20 ℃, sucking 1.1 eq) of organic alkali into R1, and stirring to dissolve. And (3) press-filtering the dissolved materials of the reaction kettle R1 into a reaction kettle R2 for standby, wherein the inner temperature of the reaction kettle R2 is controlled to be 20 ℃. The diphenyl azide phosphate 1.2eq and toluene 3W are pumped into a reaction kettle R3 for stirring and mixing, and the internal temperature is controlled to be 20 ℃. Tertiary butanol is pumped into reaction vessel R4. The first temperature zone was controlled at 50℃and the second temperature zone was controlled at 130℃with a back pressure valve pressure of 8bar. Carboxylic acid compound feed pump was controlled at 6.7ml/min [ (equation=low temperature Duan Guandao reactor hold-up/reaction time) ], azide feed pump was controlled at 3.3ml/min [ (equation=low temperature Duan Guandao reactor hold-up/reaction time) ]), tert-butanol feed pump was controlled at 1.5 ml/min. Starting feeding, collecting materials in the first 30 minutes separately, switching to a clean receiving kettle, sampling and detecting carboxylic acid compounds to be less than or equal to 1 percent (if the carboxylic acid compounds are continuously received in a central control manner, switching to other clean receiving kettles in a disqualification manner, sampling and detecting) and finishing single batch feeding, transferring reaction liquid to R6, adding domestic drinking water (3W) for water washing and layering, extracting a water layer by toluene (4) (0.8W), merging organic layers, performing reduced pressure distillation, and crystallizing to obtain a product Boc amino dichloropyridine with the yield of 91 percent and the purity of 99.1 percent. Continuous flow was run for 3 hours to see pressure fluctuations and the reactor was run for 1 hour more to plug. The reactor was unpicked and washed and a large amount of white water-soluble solids were found to plug the reactor in the tube.
Comparative example 2
Toluene 5W was added to the reaction vessel R1, and butylene oxide carboxylate (1.0W) was added to R1 with stirring. Controlling the internal temperature of R1 to 20 ℃, pumping 1.2 eq) of organic alkali into R1, and stirring to dissolve. And (3) press-filtering the dissolved materials of the reaction kettle R1 into a reaction kettle R2 for standby, wherein the inner temperature of the reaction kettle R2 is controlled to be 20 ℃. The diphenyl azide phosphate 1.3eq and toluene 3W are pumped into a reaction kettle R3 for stirring and mixing, and the internal temperature is controlled to be 20 ℃. And pumping the p-methoxybenzyl alcohol into a reaction kettle R4. The first temperature zone was controlled at 40℃and the second temperature zone was controlled at 130℃with a back pressure valve pressure of 8bar. The carboxylic acid compound feed pump was controlled at 3ml/min [ (formula=low temperature Duan Guandao reactor hold-up/reaction time) ], the azide feed pump was controlled at 1.5ml/min [ (formula=low temperature Duan Guandao reactor hold-up/reaction time) ]), and the p-methoxybenzyl alcohol feed pump was controlled at 0.7 ml/min. Starting feeding, collecting materials in the first 30 minutes separately, switching to a clean receiving kettle, sampling and detecting carboxylic acid compounds to be less than or equal to 1 percent (if the carboxylic acid compounds are continuously received in a central control manner, switching to other clean receiving kettles in a disqualification manner, sampling and detecting) and finishing single batch feeding, transferring reaction liquid to R6, adding domestic drinking water (3W) for water washing and layering, extracting a water layer by toluene (4) (0.8W), merging organic layers, performing reduced pressure distillation, and crystallizing to obtain the epoxybutane amino methoxybenzyl ester with the yield of 85 percent and the purity of 99.1 percent. Continuous flow was run for 1 hour to see pressure fluctuations and the reactor was run for 0.5 hour to plug. The reactor was unpicked and washed and a large amount of white water-soluble solids were found to plug the reactor in the tube.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.

Claims (10)

1. The quaternary ammonium salt is applied as an acid binding agent in a continuous flow Curtius rearrangement reaction.
2. The use according to claim 1, wherein the quaternary ammonium salt is tetrabutylammonium bromide or tetrabutylammonium chloride.
3. A reaction for preparing primary amine, urea derivative or carbamate by continuous flow Curtius rearrangement, which is characterized by comprising the following steps:
a) Mixing quaternary ammonium salt and carboxylic acid compound for reaction, and extracting with toluene to obtain extractive solution; mixing the extracting solution with an azide reagent in a first continuous reactor to obtain an acyl azide reaction solution;
b) Reacting the acyl azide reaction liquid through a second continuous reactor to obtain isocyanate;
c) Reacting electrophile with isocyanate in a third continuous reactor to obtain rearranged product; the electrophile is selected from one of water, amine and alcohol compound solutions;
d) Quenching and separating the rearranged product to obtain feed liquid and water phase, and crystallizing the feed liquid to obtain the product.
4. The reaction of claim 1, wherein the quaternary ammonium salt is tetrabutylammonium bromide or tetrabutylammonium chloride; the carboxylic acid compound is pyridine dichloropicolinate;
the azide reagent is one or more of azido trimethylsilane, diphenyl azide phosphate, p-dodecylbenzenesulfonyl azide or methanesulfonyl azide.
5. The reaction of claim 1, wherein the molar ratio of quaternary ammonium salt, carboxylic acid compound and azide reagent of step a) is 1: (1-1.2): (1-1.3);
the feeding flow rate of the extracting solution is 6.7-0.67 mL/min; the feeding flow rate of the azide reagent is 3.3-0.33 mL/min.
6. The reaction of claim 1, wherein the first continuous reactor temperature is 20-50 ℃; the reaction time is 1-10 min.
7. The reaction according to claim 1, wherein the temperature of the second continuous reactor is 100 to 150 ℃ and the reaction time is 0.5 to 5min.
8. The reaction of claim 1, wherein the molar ratio of electrophile to isocyanate is (1-1.5): 1, a step of;
the feeding flow rate of the electrophile is 1.6-0.16 mL/min.
9. The reaction according to claim 1, wherein the reaction temperature of the third continuous reactor in step C) is 100 to 150 ℃ and the reaction time is 0.5 to 5min.
10. The reaction of claim 1, wherein the post-rearrangement product comprises a primary amine, urea derivative, or carbamate.
CN202311595496.7A 2023-11-27 2023-11-27 Application of quaternary ammonium salt in continuous flow Curtius rearrangement reaction Pending CN117603133A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202311595496.7A CN117603133A (en) 2023-11-27 2023-11-27 Application of quaternary ammonium salt in continuous flow Curtius rearrangement reaction

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202311595496.7A CN117603133A (en) 2023-11-27 2023-11-27 Application of quaternary ammonium salt in continuous flow Curtius rearrangement reaction

Publications (1)

Publication Number Publication Date
CN117603133A true CN117603133A (en) 2024-02-27

Family

ID=89949345

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202311595496.7A Pending CN117603133A (en) 2023-11-27 2023-11-27 Application of quaternary ammonium salt in continuous flow Curtius rearrangement reaction

Country Status (1)

Country Link
CN (1) CN117603133A (en)

Similar Documents

Publication Publication Date Title
EP1935877B1 (en) Process for the preparation of toluene diisocyanate
AU2006324124B2 (en) Process for preparing diaminodiphenylmethanes
CN108218710B (en) Comprehensive utilization method of m-methylbenzoic acid nitration solid waste
EP2323990B1 (en) Methods for the production of 2-halo-4-nitroimidazole and intermediates thereof
CN117417305A (en) Synthesis method of high-purity 2- (4-methoxyphenyl) -4, 6-bis (2, 4-dihydroxyphenyl) -1,3, 5-triazine
US20120065423A1 (en) Reactive distillation process for preparation of acetaminophen
CN112062726B (en) Preparation method of 2-amino-4, 6-dichloro-5-formamido pyrimidine
CN117603133A (en) Application of quaternary ammonium salt in continuous flow Curtius rearrangement reaction
CN111138351A (en) Synthetic method of 2-aminomethyl-3-chloro-5-trifluoromethylpyridine acetate
CN117447427A (en) Preparation method of furosemide
CN115043758B (en) Method for preparing isocyanate by combining supercritical phosgenation method and pipelining method
US20090112018A1 (en) Method for producing polyisocyanates
EP3941894B1 (en) Process to recover 3-methyl-but-3-en-1-ol
CN102924255A (en) Method for preparing 9-fluorenone through liquid-phase oxidation
CN112079772A (en) Method for ammoniation reaction in 4-trifluoromethyl nicotinic acid
EP0307481A1 (en) Process for preparing 3-chloro-4-fluoronitrobenzene
US6486346B1 (en) Process for the preparation of durene diisocyanate
DE19810036A1 (en) Continuous preparation of propargyl chloride with reduced production of dichloropropene by-products
CN118388401B (en) Preparation method of 4-amino-2-chloronicotinaldehyde
CN114349690B (en) Synthesis method of doravirine intermediate
CN110590654A (en) Synthesis method of 4-fluoro-3-substituent-pyridine-2-formate compound
CN1204116C (en) Process for synthesizing isoprotuion herbicide
CN114249627B (en) Method for preparing E-1-chloro-3, 3, 3-trifluoropropene
CZ2004409A3 (en) The title is not available
CA1084066A (en) Process for the preparation of polyamines

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination