CN109678806B - Efficient monomethylation synthesis method of aromatic primary amine - Google Patents
Efficient monomethylation synthesis method of aromatic primary amine Download PDFInfo
- Publication number
- CN109678806B CN109678806B CN201811582412.5A CN201811582412A CN109678806B CN 109678806 B CN109678806 B CN 109678806B CN 201811582412 A CN201811582412 A CN 201811582412A CN 109678806 B CN109678806 B CN 109678806B
- Authority
- CN
- China
- Prior art keywords
- monomethylation
- primary amine
- aromatic primary
- halogen
- substituted
- 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
Abstract
The invention relates to the field of organic synthesis, in particular to a high-efficiency synthetic method for monomethylation of aromatic primary amine, which comprises the following steps: aromatic primary amine is taken as a raw material and reacts with formaldehyde or paraformaldehyde to obtain a corresponding hexahydro-1, 3, 5-triaryl-1, 3, 5-triazine compound; then carrying out catalytic hydrogenation with Pd/C catalyst to obtain the monomethylation product of aromatic primary amine. The method has the greatest characteristics of simple operation, mild conditions, cheap and easily-obtained raw materials, and capability of obtaining the monomethylation product of the aromatic primary amine with high yield and high selectivity. The post-treatment is simple, the production efficiency is improved, the industrial large-scale production can be easily realized, and the equipment corrosion and the environmental pollution can not be caused.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a high-efficiency monomethylation synthesis method of aromatic primary amine.
Background
The monomethylation method of aromatic primary amine is widely applied to the field of organic synthesis, but few methods can be used for the methylation reaction of the aromatic primary amine staying in the monomethyl stage, so that the finding of a suitable monomethylation method of the aromatic primary amine is particularly important.
Chinese patent publication No. CN103172523A discloses a method for selective N-methylated primary amine, and specifically discloses that N-methylated primary amine is obtained by reacting a primary amine derivative (formula II) with methanol (formula III) in the presence of a metal iridium or ruthenium complex and an alkali.
Chinese patent publication No. CN107056681A discloses a method for preparing 1-benzyl-3-methylamino-4-methylpiperidine dihydrochloride, an intermediate compound of tofacitinib, and paragraph 0086 of specification 0084 discloses a method for preparing compound i, in which a primary amine compound is reacted with a methylating agent and a base, and then reduced with sodium borohydride to obtain monomethylated primary amine; the overall yield of the reaction is low and it can only be used for monomethylation of primary aliphatic amines.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: provided is a method.
In the first aspect of the invention, a high-efficiency monomethylation synthesis method of aromatic primary amine is provided, which comprises the following steps:
(1) aromatic primary amine shown in a formula (I) is used as a raw material and reacts with formaldehyde or paraformaldehyde to obtain a corresponding hexahydro-1, 3, 5-triaryl-1, 3, 5-triazine compound (II);
(2) Carrying out catalytic hydrogenation on a compound shown as a formula (II) and a Pd/C catalyst to obtain a monomethylation product (III) of aromatic primary amine;
preferably, the R group is selected from H, halogen, C1～6Alkyl radical, C1～6Alkoxy or substituted C1～6An alkyl group; said substitution C1～6Alkyl means C substituted by at least one halogen1～6An alkyl group; further, the R group is selected from H, halogen and C1～4Alkyl radical, C1～4Alkoxy or substituted C1～4An alkyl group; said substitution C1～4Alkyl means C substituted by at least one halogen1～4An alkyl group.
Preferably, the halogen is selected from fluorine, chlorine, bromine or iodine.
Preferably, the R group is ortho, meta or para substituted.
Preferably, a catalyst triethylamine is also added in the step (1); the molar ratio range of the aromatic primary amine, the formaldehyde/paraformaldehyde and the triethylamine is 1: 0.2-2: 0.01 to 0.5; further, the molar ratio of the aromatic primary amine, the formaldehyde/paraformaldehyde and the triethylamine is in the range of 1: 1-2: 0.1 to 0.5; when the reaction raw material is paraformaldehyde, the molar quantity of the formaldehyde unit in the paraformaldehyde is taken as the molar quantity of the paraformaldehyde.
Preferably, the solvent used in step (1) is selected from toluene, dichloromethane or other non-polar organic solvents.
Preferably, the mass ratio of hexahydro-1, 3, 5-triaryl-1, 3, 5-triazine compound (II) to Pd/C in step (2) is in the range of 1: 0.01 to 0.1; further, in the step (2), the mass ratio of the hexahydro-1, 3, 5-triaryl-1, 3, 5-triazine compound (II) to the Pd/C is in the range of 1: 0.015 to 0.043.
Preferably, the hydrogen pressure in the step (2) is 1.0-10.0 Mpa, and the reaction temperature is 0-100 ℃.
Preferably, the solvent used in step (2) is selected from tetrahydrofuran, dioxane, dichlorohexane or dichloroethane; the dichloroethane is selected from 1, 1-dichloroethane or 1, 2-dichloroethane; the dichlorohexane is selected from 1, 6-dichlorohexane.
The Chinese naming of the compounds of the present invention conflicts with the structural formula, whichever is more.
The high-efficiency synthetic method for the monomethylation of the aromatic primary amine, provided by the invention, has the advantages of simple operation, mild conditions, cheap and easily available raw materials, and can obtain the monomethylation product of the aromatic primary amine with high yield and high selectivity; and the post-treatment is simple, the production efficiency is improved, the industrial large-scale production can be easily realized, and the equipment corrosion and the environmental pollution can not be caused.
Detailed Description
The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.
Example 1
(1) Synthesis of hexahydro-1, 3, 5-tri- (4-F phenyl) -1,3, 5-triazine
A250 mL four-necked flask was charged with 22g of 4-fluoroaniline (molecular weight: 111.1, 0.20mol), 6.0g of paraformaldehyde (equivalent to 0.20mol of formaldehyde), 2.0g of triethylamine (molar weight: 101.2, 0.02mol) and 120g of toluene, slowly raised in temperature to 60 ℃ and then kept at that temperature for 1 hour, and then raised in temperature and refluxed for 3 hours to complete the reaction. After the reaction, toluene was evaporated to dryness to obtain 24g of white solid hexahydro-1, 3, 5-tris- (4-fluorophenyl) -1,3, 5-triazine with a yield of 96%.
(2) Synthesis of N-methyl-4-fluoroaniline
To a 100mL autoclave were added 6g of hexahydro-1, 3, 5-tris- (4-F-phenyl) -1,3, 5-triazine, 0.17g Pd/C (palladium content 1% wt), 40mL THF, the reactor was closed, the air was replaced with hydrogen, and the pressure in the flask was maintained with 60 kg of hydrogen, and the mixture was stirred at room temperature for 12 hours. After the reaction, the reaction solution was taken out, the catalyst was removed by filtration, and THF was removed from the filtrate to obtain 5.8g (yield 95%, quantitative 97%) of N-methyl-4-fluoroaniline as a product
Example 2
(1) Synthesis of hexahydro-1, 3, 5-tri- (2-methylphenyl) -1,3, 5-triazine
21g of 2-methylaniline (molecular weight 107.2, 0.20mol), 12g of paraformaldehyde (equivalent to 0.40mol of formaldehyde), 10.1g of triethylamine (molar weight 101.2, 0.1mol) and 120g of toluene were added to a 250mL four-necked flask, the temperature was slowly raised to 60 ℃, the mixture was kept warm for 1 hour, and the temperature was raised again to carry out a reflux reaction for 3 hours to complete the reaction. After the reaction, toluene was evaporated to dryness to obtain 23g of white solid hexahydro-1, 3, 5-tris- (2-methylphenyl) -1,3, 5-triazine with a yield of 98%.
(2) Synthesis of N-methyl-2-methylaniline
To a 100mL autoclave were added 5.8g of hexahydro-1, 3, 5-tris- (2-methylphenyl) -1,3, 5-triazine, 0.25g Pd/C (palladium content 1% wt), 40mL THF, the reactor was closed, the air was replaced with hydrogen, and the pressure in the flask was maintained with 60 kg of hydrogen, and the mixture was stirred at room temperature for 12 hours. After the reaction, the reaction mixture was taken out, the catalyst was removed by filtration, and THF was removed from the filtrate to obtain 5.7g of N-methyl-2-methylaniline (yield 96%, quantitative 98%)
Example 3
(1) Synthesis of hexahydro-1, 3, 5-tri- (3-methoxyphenyl) -1,3, 5-triazine
A300 mL four-necked flask was charged with 24.5g of 3-methoxyaniline (molecular weight: 123.2, 0.20mol), 7.2g of paraformaldehyde (equivalent to 0.24mol of formaldehyde), 6.1g of triethylamine (molar weight: 101.2, 0.06mol), and 150g of dichloromethane, slowly heated to 60 ℃ and then incubated for 1 hour, and then heated to reflux for 3 hours to complete the reaction. After the reaction, toluene was evaporated to dryness to obtain 24.5g of pale yellow solid hexahydro-1, 3, 5-tris- (3-methoxyphenyl) -1,3, 5-triazine with a yield of 92%.
(2) Synthesis of N-methyl-3-methoxyaniline
To a 100mL autoclave were added 6.6g of hexahydro-1, 3, 5-tris- (3-methoxyphenyl) -1,3, 5-triazine, 0.10g Pd/C (palladium content 1% by weight), 40mL THF, the reactor was closed, the air was replaced with hydrogen, and the pressure in the flask was maintained with 60 kg of hydrogen, and the mixture was stirred at room temperature for 12 hours. After the reaction, the reaction solution was taken out, and the catalyst was removed by filtration, and THF was removed from the filtrate to obtain 6.2g (yield 92%, quantitative 95%) of N-methyl-3-methoxyaniline as a product.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these changes and modifications are all within the scope of the present invention.
Claims (5)
1. A high-efficiency synthetic method for monomethylation of aromatic primary amine is characterized by comprising the following steps:
(1) aromatic primary amine shown in a formula (I) is used as a raw material and reacts with formaldehyde or paraformaldehyde to obtain a corresponding hexahydro-1, 3, 5-triaryl-1, 3, 5-triazine compound (II); the R group is substituted at ortho, meta or para position; the R group is selected from H, halogen and C1～6Alkyl radical, C1～6Alkoxy or substituted C1～6An alkyl group; said substitution C1～6Alkyl means C substituted by at least one halogen1～6An alkyl group;
(2) carrying out catalytic hydrogenation on a compound shown in a formula (II) under the action of a Pd/C catalyst to obtain a monomethylation product (III) of aromatic primary amine;
wherein, in the step (2), the mass ratio of the hexahydro-1, 3, 5-triaryl-1, 3, 5-triazine compound (II) to the Pd/C is in the range of 1: 0.01 to 0.1;
the hydrogen pressure in the step (2) is 1.0-10.0 Mpa, and the reaction temperature is 0-100 ℃;
the solvent used in the step (2) is selected from tetrahydrofuran, dioxane, dichlorohexane or dichloroethane; the dichloroethane is selected from 1, 1-dichloroethane or 1, 2-dichloroethane; the dichlorohexane is 1, 6-dichlorohexane;
2. The process for the monomethylation of a highly efficient primary aromatic amine according to claim 1, wherein the R group is selected from H, halogen, C1～4Alkyl radical, C1～4Alkoxy or substituted C1～4An alkyl group; said substitution C1～4Alkyl means C substituted by at least one halogen1～4An alkyl group.
3. The process for the monomethylation of a highly efficient primary aromatic amine according to claim 1, wherein the halogen is selected from the group consisting of fluorine, chlorine, bromine and iodine.
4. The process for the monomethylation of a highly efficient primary arylamine according to claim 1, wherein the catalyst triethylamine is further added in the step (1); the molar ratio range of the aromatic primary amine, the formaldehyde/paraformaldehyde and the triethylamine is 1: 0.2-2: 0.01 to 0.5.
5. The process for the monomethylation of a highly efficient primary aromatic amine according to claim 1, wherein the solvent used in the step (1) is selected from toluene and dichloromethane.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811582412.5A CN109678806B (en) | 2018-12-24 | 2018-12-24 | Efficient monomethylation synthesis method of aromatic primary amine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811582412.5A CN109678806B (en) | 2018-12-24 | 2018-12-24 | Efficient monomethylation synthesis method of aromatic primary amine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109678806A CN109678806A (en) | 2019-04-26 |
| CN109678806B true CN109678806B (en) | 2022-06-28 |
Family
ID=66188195
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811582412.5A Active CN109678806B (en) | 2018-12-24 | 2018-12-24 | Efficient monomethylation synthesis method of aromatic primary amine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109678806B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101265255A (en) * | 2008-04-28 | 2008-09-17 | 四川大学 | Method for preparing benzoxazine intermediate containing triazine structure |
| CN106316866A (en) * | 2015-06-29 | 2017-01-11 | 中国科学院上海应用物理研究所 | Preparation method of N-methylamine compound |
-
2018
- 2018-12-24 CN CN201811582412.5A patent/CN109678806B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101265255A (en) * | 2008-04-28 | 2008-09-17 | 四川大学 | Method for preparing benzoxazine intermediate containing triazine structure |
| CN106316866A (en) * | 2015-06-29 | 2017-01-11 | 中国科学院上海应用物理研究所 | Preparation method of N-methylamine compound |
Non-Patent Citations (2)
| Title |
|---|
| Bequeme Darstellung von reinen N-Methylalkylaminen durch Zink/Salzsaure-Reduktion von 1,3,5-Tris( alkyl)-hexahydro-1,3,5-triazine;Mohammed A1 Shaik et al.;《Arch.Pharm.》;19841231;第317卷;第214-219页 * |
| Facile Method for the Monomethylation of Anilines;Hyun-Joon Ha et al.;《Synthetic Communications》;19971231;第1543-1546页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109678806A (en) | 2019-04-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Qiu et al. | Direct conversion of phenols into primary anilines with hydrazine catalyzed by palladium | |
| CN111732493B (en) | Synthesis process of arylamine compound | |
| JP6441478B2 (en) | Process for preparing disubstituted 1,4-benzenediamine and salts thereof | |
| Tian et al. | Copper-catalyzed ring-opening C (sp 3)–N coupling of cycloketone oxime esters: access to 1°, 2° and 3° alkyl amines | |
| CN103224436A (en) | Preparation method of o-amino diaryl ketone compound | |
| Wang et al. | Access to diverse primary, secondary, and tertiary amines via the merger of controllable cleavage of triazines and site-selective functionalization | |
| Jin et al. | Aerobic cross-dehydrogenative coupling of terminal alkynes and tertiary amines by a combined catalyst of Zn 2+ and OMS-2 | |
| CN111662184A (en) | Synthetic method of boscalid intermediate 2- (4' -chlorphenyl) aniline | |
| CN110054593B (en) | Method for synthesizing 1,3, 5-triazine derivative | |
| CN109678806B (en) | Efficient monomethylation synthesis method of aromatic primary amine | |
| CA2608258A1 (en) | Bis-amination of aryl halides | |
| Bouillon et al. | The 4.4′-benzidine rearrangement of 4-alkyl substituted hydrazobenzenes | |
| Chen et al. | Palladium–copper-catalyzed desulfitative amination of benzo [d] oxazole C–H bond | |
| Barluenga et al. | Palladium catalyzed amination of vinyl chlorides: a new entry to imines, enamines and 2-amino-1, 3-butadienes | |
| US5808086A (en) | Process for preparing bis (2-hydroxyphenyl-3-benztriazole) methanes | |
| CN105481702B (en) | The method of one pot process m-phenetidine | |
| Kraxner et al. | Traceless Linking of Indoles: General Methodology and Application to Solid Phase Supported Mannich and Stille Reactions | |
| Sharma et al. | Eco-friendly reactions in PEG-400: a highly efficient and green approach for stereoselective access to multisubstituted 3, 4-dihydro-2 (1 H)-quinazolines using 2-aminobenzylamines | |
| JP2006008686A (en) | Process for preparing imiquimod | |
| CN112225685B (en) | 3-cyanoindole compound, preparation method and application thereof | |
| JP6106056B2 (en) | New allyl glycolurils | |
| Nagarajan et al. | Condensed heterotricycles: synthesis of pyrazolo [3, 4-c] qumoline derivatives | |
| JP2019156749A (en) | Process for producing diamino-p-quarterphenyl | |
| JP2005320332A (en) | Method for producing monoarylpiperazine | |
| CN114644565B (en) | Synthesis method of key intermediate of imidazolinone compound |
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 | ||
| CB02 | Change of applicant information |
Address after: 223000 No. 2, Yannan Avenue, Yanhua new material industrial park, Huai'an City, Jiangsu Province Applicant after: HUAI'AN GUORUI CHEMICAL Co.,Ltd. Address before: 223100 No. 2 Guoqiao Road, Salt Chemical Zone, Hongze County, Huaian City, Jiangsu Province Applicant before: HUAI'AN GUORUI CHEMICAL Co.,Ltd. |
|
| CB02 | Change of applicant information | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |