CN101391984B - Method for carrying out methylation to pyrimidine heterocyclic compound containing sulfhydryl by dimethyl carbonate - Google Patents
Method for carrying out methylation to pyrimidine heterocyclic compound containing sulfhydryl by dimethyl carbonate Download PDFInfo
- Publication number
- CN101391984B CN101391984B CN200810202419XA CN200810202419A CN101391984B CN 101391984 B CN101391984 B CN 101391984B CN 200810202419X A CN200810202419X A CN 200810202419XA CN 200810202419 A CN200810202419 A CN 200810202419A CN 101391984 B CN101391984 B CN 101391984B
- Authority
- CN
- China
- Prior art keywords
- sulfydryl
- heterocyclic compound
- pyrimidine heterocyclic
- mercaptopyrimidine
- methylcarbonate
- 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.)
- Expired - Fee Related
Links
Landscapes
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a method for carrying out methylate to sulfydryl-contained pyrimidine heterocyclic compounds by methyl carbonate, which comprises the steps: (1) the sulfydryl-contained pyrimidine heterocyclic compounds and the methyl carbonate are mixed according to the mol ratio of 1:10 to 20, and added with catalyst, the dosage of which is 3 to 80 percent of the gross weight of the reactants, and then added with alkali, the mol ratio of which to the sulfydryl-contained pyrimidine heterocyclic compounds is 1 to 2:1, then the mixture is stirred and the temperature is raised to 50 to 130 DEG C for reaction for 0.5 to 15 hours, and TLC or HPLC is used for monitoring; and (2) after the reaction is finished, the temperature is reduced to room temperature, 20 to 50ml of water is added, and the mixture is stirred for 0.5 hour and rested for delamination, the organic phases are separated out while the aqueous phase is extracted by using 10 to 30ml of methyl tert-butyl ether or aether, then the organic phases are combined, washed by 20 to 50ml of water for two times, dried by anhydrous sodium sulfate, filtered and concentrated by pressure reduction, and the solvent is recycled, thus obtaining the final product. The preparation method has the advantages of simple and safe operation, easy solvent recovery, high product yield, environmental protection and being suitable for industrial production.
Description
Technical field
The pyrimidine heterocyclic compound that the invention belongs to containing sulfydryl carries out methylated preparation field, particularly relates to a kind of methylcarbonate the pyrimidine heterocyclic compound that contains sulfydryl is carried out methylated method.
Background technology
4,6-two replacement-2-methylthiopyrimidines are important intermediate of synthetic plant-growth regulator, weedicide, sterilant and pharmaceutical prod.Relevant report PCT Int.Appl., 2003013545 and Bollettino Chimico Farmaceutico. (2004,143 (7): 275-279) show that 6-two replacement-2-mercaptopyrimidines methylate by 4, selected methylating reagent is methyl iodide or methyl-sulfate.Yet methyl iodide and methyl-sulfate belong to highly toxic product, and methyl iodide costs an arm and a leg, and these reagent are in the real reaction operation and have serious hidden danger aspect the environmental protection.Japanese Patent JP2008184397 is disclosed in sulfuric acid and exists down, impels 4 with microwave, and methylating of sulfydryl carried out in 6-dimethyl-2-mercaptopyrimidine and methyl alcohol reaction, and yield only is 13%, and reaction conditions is unfavorable for industrial production.Therefore, need non-environmental-pollution and be easy to real reaction operation contain mercaptopyrimidine compound methylation method.
Although existing patent CN01808303.X and report Synthetic Communications. (2005,35:3021-3026) show that methylcarbonate DMC can be used for that N-methylates on the nitrogen heterocyclic ring, but nobody proposes with DMC sulfydryl on the pyrimidine heterocyclic compound to be carried out methylation reaction.
Summary of the invention
Technical problem to be solved by this invention provides a kind of methylcarbonate the pyrimidine heterocyclic compound that contains sulfydryl is carried out methylated method, preparation method of the present invention has easy and simple to handle, safety, solvent easily reclaims, the advantage that product yield is high, main is environmental protection, is easy to suitability for industrialized production.
A kind of methylcarbonate of the present invention carries out methylated method to the pyrimidine heterocyclic compound that contains sulfydryl, comprising:
(1) pyrimidine heterocyclic compound that will contain sulfydryl by 1:10～20 mol ratios mixes with methylcarbonate, add catalyzer, consumption is 3%～80% of a reactant gross weight, and the pyrimidine heterocyclic compound mol ratio that adds and contain sulfydryl is the alkali of 1～2:1, stirring is warming up to 50～130 ℃, reacted TLC or HPLC monitoring 0.5～15 hour;
(2) after reaction finishes, reduce to room temperature, add water 20～50ml, stirred 0.5 hour, standing demix is told organic phase, water is with methyl tertiary butyl ether or the extracted with diethyl ether of 10～30ml, merge organic phase, with 20～50ml washing twice, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure reclaims solvent, promptly.
The general formula of the pyrimidine heterocyclic compound that contains sulfydryl in the described step (1) is:
R wherein
1And R
2Represent H ,-CH
3,-Et or-OCH
3
The pyrimidine heterocyclic compound that contains sulfydryl in the described step (1) is a 2-mercaptopyrimidine, 4,6-dimethyl-2-mercaptopyrimidine, 4,6-dimethoxy-2-mercaptopyrimidine or 4,6-diethyl-2-mercaptopyrimidine;
Catalyzer in the described step (1) is Tetrabutyl amonium bromide or tetraethylammonium bromide;
Preferred catalyzer is a Tetrabutyl amonium bromide;
Alkali in the described step (1) is salt of wormwood, sodium hydroxide or potassium hydroxide;
Preferred alkali is salt of wormwood;
Temperature of reaction in the described step (1) is 75～110 ℃;
Product general formula in the described step (2) is,
R wherein
1And R
2Represent H ,-CH
3,-Et or-OCH
3
Product in the described step (2) is a 2-methylthiopyrimidine, 4,6-dimethyl-2-methylthiopyrimidine, 4,6-dimethoxy-2-methylthiopyrimidine or 4,6-diethyl-2-methylthiopyrimidine.
Beneficial effect
Preparation method of the present invention has easy and simple to handle, safety, and solvent easily reclaims, the advantage that product yield is high, main is environmental protection, is easy to suitability for industrialized production.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Embodiment 1
The preparation of 2-methylthiopyrimidine
At the reaction flask of 150ml, and adding 2-mercaptopyrimidine (11.2g, 0.1mol), salt of wormwood (5.0g, 0.036mol), Tetrabutyl amonium bromide (2g), and methylcarbonate (10.8g, 0.12mol), stir down and progressively be warming up to 75～110 ℃, reacted 0.5～3 hour, TLC or HPLC monitoring; Reaction finishes, and is cooled to room temperature, adds water (20～50ml), stirred 0.5 hour, standing demix is told organic phase, (10～30ml) extractions merge organic phase to water, and (20～50ml) wash twice water with methyl tertiary butyl ether or ether, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure reclaims solvent, product vacuum-drying gets 12.1g, yield 96%.
Embodiment 2
4, the preparation of 6-dimethyl-2-methylthiopyrimidine
At the reaction flask of 150ml, add 4,6-dimethyl-2-mercaptopyrimidine (28g, 0.2mol), salt of wormwood (2.5g, 0.018mol), Tetrabutyl amonium bromide (5g), methylcarbonate (32.4g, 0.36mol), stir down and progressively be warming up to 75～110 ℃, reacted TLC or HPLC monitoring 0.5～3 hour; Reaction finishes, and is cooled to room temperature, adds water (20～50ml), stirred 0.5 hour, standing demix is told organic phase, (10～30ml) extractions merge organic phase to water, and (20～50ml) wash twice water with methyl tertiary butyl ether or ether, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure reclaims solvent, vacuum-drying gets the 30.2g product, yield 98%.
Embodiment 3
4, the preparation of 6-dimethoxy-2-methylthiopyrimidine
Reaction flask at 150ml, add 4, and 6-dimethoxy-2-mercaptopyrimidine (51.7g, 0.3mol), salt of wormwood (7.5g, 0.054mol), Tetrabutyl amonium bromide (8g), methylcarbonate (43.2g, 0.48mol), stir down and progressively be warming up to 75～110 ℃, reacted 0.5～10 hour, TLC or HPLC monitoring; Reaction finishes, and is cooled to room temperature, adds water (20～50ml), stirred 0.5 hour, standing demix is told organic phase, (10～30ml) extractions merge organic phase to water, and (20～50ml) wash twice water with methyl tertiary butyl ether or ether, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure reclaims solvent, product vacuum-drying gets 31.3g, yield 56%.
Embodiment 4
4, the preparation of 6-diethyl-2-methylthiopyrimidine
At the reaction flask of 150ml, add 4,6-diethyl-2-mercaptopyrimidine (67.3g, 0.4mol), salt of wormwood (10g, 0.072mol), Tetrabutyl amonium bromide (10g), methylcarbonate (54g, 0.6mol), stir down and progressively be warming up to 75～110 ℃, reacted TLC or HPLC monitoring 0.5～8 hour; Reaction finishes, and is cooled to room temperature, adds water (20～50ml), stirred 0.5 hour, standing demix is told organic phase, (10～30ml) extractions merge organic phase to water, and (20～50ml) wash twice water with methyl tertiary butyl ether or ether, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure reclaims solvent, product vacuum-drying gets 67.1g, yield 92%.
Claims (3)
1. a methylcarbonate carries out methylated method to the pyrimidine heterocyclic compound that contains sulfydryl, comprising:
(1) pyrimidine heterocyclic compound that will contain sulfydryl by 1: 10～20 mol ratios mixes with methylcarbonate, add catalyzer, consumption is 3%～80% of a reactant gross weight, and the pyrimidine heterocyclic compound mol ratio that adds and contain sulfydryl is 1～2: 1 alkali, stirring is warming up to 50～130 ℃, reacted TLC or HPLC monitoring 0.5～15 hour; Described catalyzer is Tetrabutyl amonium bromide or tetraethylammonium bromide; Described alkali is salt of wormwood, sodium hydroxide or potassium hydroxide; The described general formula that contains the pyrimidine heterocyclic compound of sulfydryl is,
R wherein
1And R
2Represent H ,-CH
3,-Et or-OCH
3
(2) after reaction finishes, reduce to room temperature, add water 20～50ml, stirred 0.5 hour, standing demix is told organic phase, water is with methyl tertiary butyl ether or the extracted with diethyl ether of 10～30ml, merge organic phase, with 20～50ml washing twice, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure reclaims solvent, promptly gets product.
2. a kind of methylcarbonate according to claim 1 carries out methylated method to the pyrimidine heterocyclic compound that contains sulfydryl, it is characterized in that: the pyrimidine heterocyclic compound that contains sulfydryl in the described step (1) is a 2-mercaptopyrimidine, 4,6-dimethyl-2-mercaptopyrimidine, 4,6-dimethoxy-2-mercaptopyrimidine or 4,6-diethyl-2-mercaptopyrimidine.
3. a kind of methylcarbonate according to claim 1 carries out methylated method to the pyrimidine heterocyclic compound that contains sulfydryl, it is characterized in that: the temperature of reaction in the described step (1) is 75～110 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810202419XA CN101391984B (en) | 2008-11-07 | 2008-11-07 | Method for carrying out methylation to pyrimidine heterocyclic compound containing sulfhydryl by dimethyl carbonate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810202419XA CN101391984B (en) | 2008-11-07 | 2008-11-07 | Method for carrying out methylation to pyrimidine heterocyclic compound containing sulfhydryl by dimethyl carbonate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101391984A CN101391984A (en) | 2009-03-25 |
| CN101391984B true CN101391984B (en) | 2010-12-08 |
Family
ID=40492518
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200810202419XA Expired - Fee Related CN101391984B (en) | 2008-11-07 | 2008-11-07 | Method for carrying out methylation to pyrimidine heterocyclic compound containing sulfhydryl by dimethyl carbonate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101391984B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102898382B (en) * | 2012-11-07 | 2015-01-28 | 东南大学 | Method for synthesizing 2-amino-4,6-dimethoxypyrimidine |
| CN103351381B (en) * | 2013-07-26 | 2014-10-22 | 天津法莫西医药科技有限公司 | Preparation method of imatinib and mesylate of imatinib |
| CN103396395B (en) * | 2013-07-26 | 2014-09-03 | 天津法莫西医药科技有限公司 | Method for synthesizing N-(5-nitryl-2-methyl pyridyl-3-)-4-(3-pyridyl)-2-pyrilamine and intermediate thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1633294A (en) * | 2001-08-13 | 2005-06-29 | 詹森药业有限公司 | 2,4,5-trisubstituded thiazolyl derivatives and their antiinflammatory activity |
-
2008
- 2008-11-07 CN CN200810202419XA patent/CN101391984B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1633294A (en) * | 2001-08-13 | 2005-06-29 | 詹森药业有限公司 | 2,4,5-trisubstituded thiazolyl derivatives and their antiinflammatory activity |
Non-Patent Citations (3)
| Title |
|---|
| Manfred Lissel, et.al..Dimethylcarbonat als Methylierungsmittel unter phasen-transfer-katalytischen Bedingungen.Synthesis.1986,1986(5),382-383. * |
| Pietro Tundo, et.al..Continuous-flow processes under gas-liquid phase-transfer catalysis (GL-PTC) conditions: the reaction of dialkyl carbonates with phenols, alcohols, and mercaptans.Ind.Eng.Chem.Res..1988,27(9),1565-1571. * |
| Wang Xi-Cun, et.al..An environmentally benign access to dimethylated 1,6-dihydropyrimidines using dimethyl carbonate as methylating agent under microwave.Chinese Journal of Chemistry.2008,26(2),368-372. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101391984A (en) | 2009-03-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101456855B (en) | Method for preparing 1,3-propanesultone | |
| CN101891649B (en) | Novel 3-cyano methyl benzoate preparing method | |
| CN104478797A (en) | Preparation method of nicotinamide fungicide namely boscalid | |
| CN101391984B (en) | Method for carrying out methylation to pyrimidine heterocyclic compound containing sulfhydryl by dimethyl carbonate | |
| CN103193608B (en) | A kind of take veratrole as the method that veratraldehyde prepared by raw material | |
| CN103012074B (en) | Prepare the method for aromatic methyl ether compound | |
| CN109111357A (en) | It is a kind of can volume production rhodium caprylate dimer synthetic method | |
| CN103553931A (en) | Method for synthesizing chiral diketone compound | |
| CN110950778A (en) | Process and catalyst system for preparing aromatic malononitrile | |
| CN103012215B (en) | Azo dodecanedioic acid dialkyl ester preparation method | |
| CN103086898B (en) | Preparation method of diphenylamine or ring-substituted derivative thereof | |
| CN101514190B (en) | Method for preparing heterocyclic compounds of methyl mercapto under ionic liquid catalysis | |
| CN101781230A (en) | Method for synthesizing imine by catalytic dehydration | |
| CN101519373A (en) | Method for synthesizing 2,6-difluoropyridine | |
| CN103755706B (en) | A kind of environment-friendly preparation method synthesizing folic acid | |
| CN109438402B (en) | Benzofuranone derivatives and synthesis method thereof | |
| CN103554019B (en) | A kind of synthetic method of tilbroquinol | |
| CN101703906A (en) | Cationic gemini surfactant containing tri-ester groups and preparation method thereof | |
| CN102127044A (en) | Method for synthesizing 5,7-dihydroxy flavone | |
| EP3558925B1 (en) | Process for the preparation of levulinate esters | |
| CN102199076B (en) | Method for preparing sevoflurane | |
| CN113121317B (en) | Synthesis method of 1, 4-dichloro-2- (chloromethyl) -5-ethoxybenzene | |
| CN105237340A (en) | Novel synthesis method for 4,4,4-trifluorobutanol | |
| CN102574814B (en) | The preparation method of pyrimidyl acetonitrile derivative and synthetic intermediate thereof | |
| CN104230990A (en) | 2-((4R,6S)-6-triphenylphosphoalkenylmethylene-2,2-disubstituted-1,3-dioxyhexacyclo-4-yl)acetate, and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20101208 Termination date: 20131107 |