Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-17
2003-07-22
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C564S305000
Reexamination Certificate
active
06596877
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides an accelerated process for preparing a O-methyl phenol (anisole), N-methyl heteroaromatic compound, or a methyl aminophenol, comprising reacting a phenol, an NH-containing heteroaromatic compound, or an aminophenol having at least one N—H, with dimethyl carbonate in the presence of a catalyst selected from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); 1,4-diazabicyclo[2.2.2]octane (DABCO); and dimethylaminopyridine (DMAP).
BACKGROUND OF THE INVENTION
Methylation of alcohols and amines is an important process in chemistry. However, due to the environmental and human impact of using toxic and unsafe methylating reagents such as methyl iodide or dimethyl sulfate, the investigation of safer, generally applicable alternatives continues. As an alternative to these toxic methylating agents, dimethyl carbonate (DMC) has attracted considerable attention for the methylation of phenols, anilines, and activated methylenes. DMC is non-toxic and generates CO
2
and methanol as by-products during methylations. DMC is also a volatile liquid with a boiling point of 90° C. Hence, the unreacted DMC can be easily recovered by distillation from the reaction mixture and reused. Furthermore, DMC has been shown to be quite selective in monomethylation of primary aromatic amines and C-methylation of arylacetonitriles and arylacetoesters.
U.S. Pat. No. 4,513,146 describes a method for producing esters from highly hindered carboxylic acids and carbonates. The method involves reacting the highly hindered carboxylic acid with a carbonate with or without a catalyst at a temperature of 175° C. according to the examples. U.S. Pat. No. 4,513,146 states that exemplary cataysts are nitrogen-containing heterocyclic catalysts such as pyridine, 4-(dimethylamino)pyridine, imidazole, 2,6-lutidine, and 2,4,6-collidine.
Shimizu, I; Lee, Y.,
Synlett,
pg. 1063 (1998) discloses methylation of 1-naphthol with DMC using Na
2
CO
3
which required 168 hours at 120° C. for 91% completion. Lissel, M.; Schmidt, S.; Neumann, B.,
Synthesis,
pg. 382 (1986) discloses N-methylation of benzimidazole with DMC using K
2
CO
3
18-crown-6, which required 8 hours at 100° C. for 81% yield.
Therefore, it would be advantageous from a production standpoint to develop a more efficient process which utilizes dimethyl carbonate as a reactant in the production of O-methyl phenols, N-methyl heteroaromatic compounds, and methyl aminophenols.
SUMMARY OF THE INVENTION
The invention provides an accelerated process for preparing an O-methyl phenol (anisole) comprising reacting a phenol with dimethyl carbonate in the presence of a catalyst selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,4-diazabicyclo[2.2.2]octane; dimethylaminopyridine; and combinations thereof.
According to another aspect, the invention provides an accelerated process for preparing an N-methyl heteroaromatic compound comprising reacting an NH-containing heteroaromatic compound with dimethyl carbonate in the presence of a catalyst selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,4-diazabicyclo[2.2.2]octane; dimethylaminopyridine; and combinations thereof.
According to another aspect, the invention provides an accelerated process for preparing a methylated aminophenol comprising reacting an aminophenol having at least one N—H with dimethyl carbonate in the presence of a catalyst selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene 1,4-diazabicyclo[2.2.2]octane; dimethylaminopyridine; and combinations thereof.
The process of the invention is especially advantageous for preparing O-methyl phenols, N-methyl heteroaromatic compounds, and methyl aminophenols, since the process: (1) utilizes an environmentally friendly methylating reagent, dimethylcarbonate; (2) produces a high yield of the O-methyl phenols, N-methyl heteroaromatic compounds, and methylated aminophenols, generally 97-100% conversion; and (3) does not require a high-pressure (autoclave) reactor.
DESCRIPTION OF THE INVENTION
The process of the invention is used to prepare an O-methyl phenol and/or an N-methyl heteroaromatic compound, and/or a methylated aminophenol, depending on the choice of reactant. In one embodiment of the invention, the process involves reacting a phenol with dimethyl carbonate to form an O-methyl phenol. As used herein, “phenol” refers to a reactant and “O-methyl phenol” refers to the product. The phenol may be unsubstituted or substituted with one or more substituent groups or combinations of substituent groups. In addition, the substituent groups attached to the phenol may be combined together with carbon atoms on the phenol to form a 5 to 7 membered aromatic or hetero aromatic ring. Suitable substituent groups on the phenol are groups which do not preclude formation of the O-methyl phenol. Examples of substituent groups on the phenol include, but are not limited to, alkyl, alkenyl, aryl, (cycloalkyl)alkyl, arylalkyl, cycloalkyl, and halogen. Such substituent groups may be unsubstituted or contain groups such as mercapto, hydroxyl, amino, selenyl or carboxyl. When an aryl group or a group containing an aryl portion is used as a substituent group, it may be homocyclic or heterocyclic, and it may comprise a single ring or it may comprise a ring assembly.
Preferred phenols include the following:
In another embodiment of the invention, the process involves reacting an NH-containing heteroaromatic compound with dimethyl carbonate to form an N-methyl heteroaromatic compound. As used herein, “NH-containing heteroaromatic compound” refers to a reactant having at least one aromatic group and at least one N—H attached to the aromatic group, and “N-methyl heteroaromatic compound” refers to the product. The NH-containing heteroaromatic compound may be unsubstituted or substituted with one or more substituent groups or combinations of substituent groups. In addition, the substituent groups attached to the NH-containing heteroaromatic compound may be combined together with carbon atoms on the NH-containing heteroaromatic compound to form a 5 to 7 membered aromatic or heteroaromatic ring. Suitable substituent groups on the NH-containing heteroaromatic compound are groups which do not preclude formation of the N-methyl heteroaromatic compound. Examples of substituent groups on the NH-containing heteroaromatic compound include, but are not limited to, alkyl, alkenyl, aryl, (cycloalkyl)alkyl, arylalkyl, cycloalkyl, and halogen. Such substituent groups may be unsubstituted or contain groups such as mercapto, hydroxyl, amino, selenyl or carboxyl. When an aryl group or a group containing an aryl portion is used as a substituent group, it may be homocyclic or heterocyclic, and it may comprise a single ring or it may comprise a ring assembly.
Preferred NH-containing heteroaromatic compounds include the following:
In another embodiment of the invention, the process involves reacting an aminophenol having at least one N—H with dimethyl carbonate to form a methylated aminophenol. As used herein, “aminophenol having at least one N—H” refers to a reactant having a phenol group and at least one N—H directly attached to the aromatic ring of the phenol group, and “methylated aminophenol” refers to the product which contains at least one methoxy or N—CH
3
group. The aminophenol having at least one N—H may be unsubstituted or substituted with one or more substituent groups or combinations of substituent groups. In addition, the substituent groups attached to the aminophenol having at least one N—H may be combined together with carbon atoms on the aromatic ring of the phenol group to form a 5 to 7 membered aromatic or hetero aromatic ring. Suitable substituent groups on the aminophenol having at least one N—H are groups which do not preclude formation of the methylated aminophenol. Examples of substituent groups on the methylated aminophenol include, but are not limited to, alkyl, alkenyl, aryl, (cycloalkyl)alkyl, arylalkyl, cy
Dell Steven
Shieh Wen-Chung
Novartis AG
Thallemer John D.
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