CN116891418A - Method for synthesizing amide by directly oxidizing and coupling amine - Google Patents
Method for synthesizing amide by directly oxidizing and coupling amine Download PDFInfo
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- CN116891418A CN116891418A CN202310810991.9A CN202310810991A CN116891418A CN 116891418 A CN116891418 A CN 116891418A CN 202310810991 A CN202310810991 A CN 202310810991A CN 116891418 A CN116891418 A CN 116891418A
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- amine
- amide
- catalyst
- sodium persulfate
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- 150000001408 amides Chemical class 0.000 title claims abstract description 33
- 150000001412 amines Chemical class 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title claims abstract description 26
- 230000001590 oxidative effect Effects 0.000 title claims abstract description 16
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 15
- 230000008878 coupling Effects 0.000 title claims abstract description 9
- 238000010168 coupling process Methods 0.000 title claims abstract description 9
- 238000005859 coupling reaction Methods 0.000 title claims abstract description 9
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000003054 catalyst Substances 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 claims abstract description 18
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 11
- 238000000926 separation method Methods 0.000 claims abstract description 8
- 239000007800 oxidant agent Substances 0.000 claims abstract description 6
- -1 amine compounds Chemical class 0.000 claims abstract description 5
- 230000008569 process Effects 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000000047 product Substances 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 8
- 238000005691 oxidative coupling reaction Methods 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 239000013067 intermediate product Substances 0.000 abstract description 2
- 229910052751 metal Inorganic materials 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract description 2
- 239000003960 organic solvent Substances 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 9
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 150000003939 benzylamines Chemical class 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- KBTJYNAFUYTSNN-UHFFFAOYSA-N [Na].OO Chemical compound [Na].OO KBTJYNAFUYTSNN-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000012822 chemical development Methods 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 238000007813 chromatographic assay Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing amide by directly oxidizing and coupling amine, which uses nitrogen-doped carbon as a catalyst, sodium persulfate as a main oxidant and hydrogen peroxide as an auxiliary oxidant, and oxidizes and couples amine compounds in a water phase to generate amide. Compared with the prior art, the invention has the following advantages: 1) The method adopts the one-step method to directly synthesize the amide by amine coupling, has short process route, does not need intermediate product separation steps, has simple operation and low cost, and is easy to realize industrialization; 2) The catalyst is prepared by adopting metal-free doped carbon, so that the catalyst cost is low, and metal pollution is avoided; 3) The cheap and common hydrogen peroxide and sodium persulfate are used as the oxidizing reagent, so that the oxidizing capability is strong, and the reaction condition is mild; 4) The reaction process uses water as a solvent, does not need any organic solvent, and is environment-friendly.
Description
Technical Field
The invention belongs to the field of fine chemical synthesis, relates to a method for synthesizing amide by directly oxidizing and coupling amine, and in particular relates to a process for synthesizing amide by coupling nitrogen-doped carbon-catalyzed hydrogen peroxide-sodium persulfate synergistic amine oxide amine.
Background
The amide structure, which is taken as a basic skeleton in organic chemistry, has the characteristics of high polarity, high stability and conformational diversity, is an important branch in organic functional groups, and is also an important chemical tie in protein structures; in particular, about 25% of drugs or drug intermediates contain amide structures in terms of pharmaceutical chemistry, so that amide compounds are an important class of organic compounds and have wide application in the fields of chemistry, chemical engineering and biology.
Many methods for synthesizing amides are available, and the conventional method for synthesizing amides is a two-step method for synthesizing amides, which is widely applied to commercial production, by activating carboxylic acid to form an active intermediate and then acylating the active intermediate with amine through nucleophilic substitution reaction. From the point of atomic utilization, the method has lower atom economy, serious environmental pollution and higher cost. Therefore, an amide synthesis route which is simple in development, efficient, environment-friendly and low in cost is imperative.
The amide is synthesized by the amine-amine direct oxidative coupling route, so that the synthesis steps can be simplified, the use of toxic reagents is avoided, and the requirements of green chemical development are met. However, the direct oxidative coupling of amine amines to amides is currently not available in a mature process and is still in a very early stage of development.
Disclosure of Invention
In order to solve the problems, the invention provides a method for synthesizing amide by directly oxidizing and coupling amine, which uses nitrogen doped carbon as a catalyst, sodium persulfate as a main oxidant and hydrogen peroxide as an auxiliary oxidant, and oxidizes and couples amine compounds in a water phase to generate amide.
Preferably, the method comprises the following steps:
step one: dissolving sodium persulfate in water, pouring the water into a reaction kettle, sequentially adding raw material amine and 30% hydrogen peroxide by mass fraction, adding a nitrogen-doped carbon catalyst, vigorously stirring, keeping the room temperature, and reacting for 2-6 hours;
step two: adding raw material amine into the reaction mixed solution, heating to 40-80 ℃, and reacting for 3-6 hours;
step three: after the reaction is completed, cooling to room temperature, and then filtering the catalyst for reuse; adding ethyl acetate into the filtrate to extract a product, and analyzing the composition and the content of the product by adopting GC and GC-MS on an organic phase after liquid separation operation; the extract liquid is distilled under reduced pressure to obtain crude amide, and the crude amide is recrystallized to obtain a pure amide product.
Preferably, the mass ratio of sodium persulfate to water is 1:4-8, the molar ratio of the sodium persulfate to the hydrogen peroxide is 1:0.3-0.6.
Preferably, the molar ratio of sodium persulfate to the total amount of amine is 1:1-2.
Preferably, in the second step, the amount of the substance added with amine is 0.3 to 0.6 times that of the first step.
Preferably, the amount of amine catalyst is 10 to 40 g per mole of starting amine catalyst.
Preferably, the amines are mainly benzylamines and benzylamines with benzene ring substituents.
Compared with the prior art, the invention has the following characteristics and advantages:
1) The method adopts the one-step method to directly synthesize the amide by amine coupling, has short process route, does not need intermediate product separation steps, has simple operation and low cost, and is easy to realize industrialization;
2) The catalyst is prepared by adopting metal-free doped carbon, so that the catalyst cost is low, and metal pollution is avoided;
3) The cheap and common hydrogen peroxide and sodium persulfate are used as the oxidizing reagent, so that the oxidizing capability is strong, and the reaction condition is mild;
4) The reaction process uses water as a solvent, does not need any organic solvent, and is environment-friendly.
Detailed Description
The present invention will be described in further detail with reference to the following examples, which are only for the purpose of illustrating the invention and are not to be construed as limiting the scope of the invention.
Example 1
Taking 3.72 kg of sodium persulfate, adding 18.6 kg of water to form a uniform solution, adding 1.072 kg of benzyl amine serving as a raw material and 0.53 kg of 30% hydrogen peroxide into the solution, adding 0.2 kg of nitrogen doped carbon catalyst, stirring vigorously, and maintaining room temperature for reaction for 3 hours. Then adding 0.32 kg of aniline, heating to 70 ℃, keeping for 5 hours, cooling to room temperature after the reaction is completed, and filtering the catalyst for repeated use; ethyl acetate was added to the filtrate to extract the product, and after the liquid separation operation, the composition and content of the product were analyzed by GC, GC-MS on the organic phase.
Example 2
Taking 4.64 kg of sodium persulfate, adding 23.2 kg of water to form a uniform solution, adding 1.072 kg of benzyl amine serving as a raw material and 0.66 kg of 30% hydrogen peroxide into the solution, adding 0.2 kg of nitrogen doped carbon catalyst, stirring vigorously, and maintaining room temperature for reaction for 3 hours. Then adding 0.32 kg of aniline, heating to 70 ℃, keeping for 5 hours, cooling to room temperature after the reaction is completed, and filtering the catalyst for repeated use; ethyl acetate was added to the filtrate to extract the product, and after the liquid separation operation, the composition and content of the product were analyzed by GC, GC-MS on the organic phase.
Example 3
Taking 4.64 kg of sodium persulfate, adding 23.2 kg of water to form a uniform solution, adding 1.072 kg of benzyl amine serving as a raw material and 1.11 kg of 30% hydrogen peroxide into the solution, adding 0.2 kg of nitrogen doped carbon catalyst, stirring vigorously, and maintaining room temperature for reaction for 3 hours. Then adding 0.32 kg of aniline, heating to 70 ℃, keeping for 5 hours, cooling to room temperature after the reaction is completed, and filtering the catalyst for repeated use; ethyl acetate was added to the filtrate to extract the product, and after the liquid separation operation, the composition and content of the product were analyzed by GC, GC-MS on the organic phase.
Example 4
Taking 4.64 kg of sodium persulfate, adding 23.2 kg of water to form a uniform solution, adding 1.072 kg of benzyl amine serving as a raw material and 1.11 kg of 30% hydrogen peroxide into the solution, adding 0.3 kg of nitrogen doped carbon catalyst, stirring vigorously, and maintaining room temperature for reaction for 3 hours. Then adding 0.32 kg of aniline, heating to 70 ℃, keeping for 5 hours, cooling to room temperature after the reaction is completed, and filtering the catalyst for repeated use; ethyl acetate was added to the filtrate to extract the product, and after the liquid separation operation, the composition and content of the product were analyzed by GC, GC-MS on the organic phase.
Example 5
The reaction procedure was as in example 4, and the reactivity of the different substrates was examined, and the experimental results are shown in Table 2.
TABLE 1 results of the synthesis method of the invention
| Sequence number | Conversion (%) | Selectivity (%) |
| Example 1 | 98 | 84 |
| Example 2 | 100 | 90 |
| Example 3 | 100 | 94 |
| Example 4 | 100 | 97 |
Table 2H 2 O 2 Auxiliary Na 2 S 2 O 8 Synthesis of amides by oxidation of various amines
a Yield of chromatographic assay
The above description is only illustrative of the invention and is not intended to limit the invention in any way, and any person skilled in the art will make many possible variations and modifications to the solution of the invention using the method disclosed above without departing from the scope of the invention, which is defined in the claims.
Claims (7)
1. A method for synthesizing amide by directly oxidizing and coupling amine is characterized in that nitrogen doped carbon is used as a catalyst, sodium persulfate is used as a main oxidant, hydrogen peroxide is used as an auxiliary oxidant, and amine compounds are oxidized and coupled in a water phase to generate amide.
2. A method for synthesizing amide by direct oxidative coupling of amine as claimed in claim 1, comprising the steps of:
step one: dissolving sodium persulfate in water, pouring the water into a reaction kettle, sequentially adding raw material amine and 30% hydrogen peroxide by mass fraction, adding a nitrogen-doped carbon catalyst, vigorously stirring, keeping the room temperature, and reacting for 2-6 hours;
step two: adding raw material amine into the reaction mixed solution, heating to 40-80 ℃, and reacting for 3-6 hours;
step three: after the reaction is completed, cooling to room temperature, and then filtering the catalyst for reuse; adding ethyl acetate into the filtrate to extract a product, and analyzing the composition and the content of the product by adopting GC and GC-MS on an organic phase after liquid separation operation; the extract liquid is distilled under reduced pressure to obtain crude amide, and the crude amide is recrystallized to obtain a pure amide product.
3. The method for synthesizing amide by directly oxidative coupling of amine as claimed in claim 2, wherein the mass ratio of sodium persulfate to water is 1:4-8, the molar ratio of the sodium persulfate to the hydrogen peroxide is 1:0.3-0.6.
4. The method for synthesizing amide by directly oxidative coupling of amine according to claim 2, wherein the molar ratio of sodium persulfate to the total amount of amine is 1:1-2.
5. The method for synthesizing amide by directly oxidative coupling of amine according to claim 2, wherein in the second step, the amount of the substance added with amine is 0.3-0.6 times that of the first step.
6. A process for the direct oxidative coupling of an amine to an amide as claimed in claim 2 wherein the amount of amine catalyst used is from 10 to 40 grams per mole of starting amine catalyst.
7. The method for synthesizing amide by directly oxidative coupling of amine according to claim 2, wherein the amine is mainly benzylamine and benzylamine with benzene ring substituent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310810991.9A CN116891418A (en) | 2023-07-04 | 2023-07-04 | Method for synthesizing amide by directly oxidizing and coupling amine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310810991.9A CN116891418A (en) | 2023-07-04 | 2023-07-04 | Method for synthesizing amide by directly oxidizing and coupling amine |
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| Publication Number | Publication Date |
|---|---|
| CN116891418A true CN116891418A (en) | 2023-10-17 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310810991.9A Pending CN116891418A (en) | 2023-07-04 | 2023-07-04 | Method for synthesizing amide by directly oxidizing and coupling amine |
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| Country | Link |
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| CN (1) | CN116891418A (en) |
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- 2023-07-04 CN CN202310810991.9A patent/CN116891418A/en active Pending
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