Methylation of indole compounds using dimethyl carbonate

Details Methylation of indole compounds using dimethyl carbonate Methylation of indole compounds using dimethyl carbonate

2001-04-05

2001-12-04

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S502000, C548S483000, C548S494000, C548S492000

Reexamination Certificate

active

06326501

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field
The invention relates to the use of dimethyl carbonate (“DMC”) for the N-methylation of indole compounds.
2. Description
The compound 3-(1-methylindol-3-yl)4-(1-methyl-6-nitroindol-3-yl)-1 H-pyrrole-2,5-dione is a selective inhibitor of protein kinase C (“PKC”) and is useful as an antimitotic agent for oral treatment of solid tumors as well as treating autoimmune diseases such as rheumatoid arthritis. This compound is described in U.S. Pat. No. 5,057,614, the contents of which are herein incorporated by reference. A synthetic route for preparing this compound uses methyl iodide as a methylating agent (see for example, U.S. application Ser. No. 09/268,887, the contents of which are herein incorporated by reference, which shows the use of methyl iodide for the N-methylation of an indole to synthesize similar compounds). Unfortunately, methyl iodide is highly toxic and has a low boiling point. The release of methyl iodide into the air is highly restricted. Accordingly, there exists a need for environmentally friendly methods for methylating indole compounds.
The following scheme shows a method for preparing 3-(1-methyl-3-indolyl)4-(1-methyl-6-nitro-3-indolyi)-1 H-pyrrole-2,5-dione.
Common methylating agents, such as methyl halides (MeX; X═CI, Br, I) and dimethylsulfate (“DMS”, can be used to methylate O—, C— and N— under mild reaction conditions. However, as described above for methyl iodide, these agents pose severe concerns from environmental and process safety standpoints. On the other hand, dimethyl carbonate is a comparatively safe, non toxic and environmentally friendly methylating agent. The by-products of its use, methanol and carbon dioxide, are not associated with disposal problems. Moreover, for the manufacture of antimitotic agents of the above class, which require two indole ring methylations, the need is double. Although it has been reported (Tondo, P., Selva, M., and Bomben, A.,
Org, Synth
. 1998, 76, 169) that DMC can be used to methylate the alpha position of an arylacetonitrile, nowhere has it been suggested to use DMC for methylating indole ring containing compounds, much less the N-methylation of indole rings.
Unfortunately, the use of DMC in prior art processes typically requires high reaction temperatures (>180° C.), a stainless steel autoclave, high pressure, and a large excess of dimethyl carbonate (as solvent and methylating agent). With the help of catalysts, lower reaction temperatures (100° C.) can be used. However, such catalysts (e.g. crown ether) are generally very toxic and pressurized reaction chambers are required.
The inventive use of dimethyl carbonate for N-methylation of an indole ring forms a part of the subject invention and was disclosed in U.S. Provisional Patent Application No. 60/171,557, filed Dec. 22, 1999, which is not publicly available. Although disclosed in this provisional application, the subject invention was not invented by the inventors named in the mentioned provisional patent application and forms no part of the invention claimed in that application.
Therefore, the subject invention fulfills a need in the art for a green process for methylating the nitrogen atom in an indole compound under conditions that do not require high pressure or temperature.
SUMMARY OF THE INVENTION
The subject invention provides a process for manufacturing a methylated indole compounds of the formula:
where R
1
is selected from the group consisting of halogen, C1-C6 alkyl, C
1
-C
6
alkenyl, —OCH
3
, —NO
2
, —CHO, —CO
2
CH
3
, and —CN, and R
2
is selected from the group consisting of C
1
-C
6
alkyl, —CO
2
CH
3
, —CN, —CHO, —NH
2
, —N(C
1
-C
6
alkyl)
2
, —(CH
2
)
n
COOH, and —(CH
2
)
n
CN, where n is an integer from 1 to 4, inclusive. The process comprises reacting a compound of the formula:
wherein R
1
and R
2
are as above, with dimethyl carbonate in the presence of a suitable base or catalyst at ambient pressure.
Typically, the reacting is at a temperature between about 120° C. and about 134° C., more preferrably between about 126° C. and about 130° C.
It is preferred that the reacting is in the presence of a solvent, such as N,N-dimethylformamide and 1-methyl-2-pyrrolidinone, the most preferred solvent being N,N-dimethylformamide.
Favorably, the reacting is in the presence of a phase transfer catalyst, such as tetrabutylammonium bromide or 18-crown-6, the most favorable catalyst being tetrabutylammonium bromide.
The process can involve reacting is in the presence of a base, such as potassium hydroxide, sodium hydroxide, and potassium carbonate, the most favorable base being potassium carbonate.
Of course the reacting can in the presence of both a base and a catalyst. For example, it is favored where the base is selected from the group consisting of potassium hydroxide, sodium hydroxide, and potassium carbonate, and the catalyst is a phase transfer catalyst. Favored bases are selected from the group consisting of potassium hydroxide, sodium hydroxide, and potassium carbonate, and favored catalysts are selected from the group consisting of tetrabutylammonium bromide and 18-crown-6.
The reaction time can vary but is readily determined by the skilled artisan. Favorable reations times are between 0.75 hour and 36 hours, preferrably between 1 hour and 26 hours, and most preferrably between 1 hour and 10 hours.
Favored compounds include those where R
1
is at position 6 and R
2
is hydrogen (R
1
is favorably nitro) and those where R
1
is hydrogen and R
2
is acetonitrile.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting.
The subject N-methylation process typically requires only 2.2 equivalents of dimethyl carbonate, reasonable temperature, and ambient pressure. The term “ambient pressure” is used herein to reflect normal atmospheric pressure. The exemplified processes below generally needs only catalytic amounts of tetrabutylammonium bromide (“TBAB”) or 18-crown-6 without the use of a base. Altematively, or additionally, a base such as potassium hydroxide, sodium hydroxide, or potassium carbonate can by utilized. Both potassium carbonate and TBAB are easily eliminated from the product by the following an isolation procedure that involves the addition of water. Catalytic amounts of TBAB or 18-crown-6, as well as appropriate amounts of base, for example potassium hydroxide, sodium hydroxide or potassium carbonate, are readily determinable by the skilled artisan. Generally, these amounts will be for TBAB in the range of about five percent (5%) by weight to about eighty percent (80%) by weight of catalyst to substrate. A preferred range is from about twenty percent (20%) by weight to about forty percent (40%) by weight of catalyst to substrate, with the range of from about twenty percent (20%) by weight to about thirty percent (30%) by weight of catalyst to substrate being most preferred. For 18-crown-6, the amounts will generally be in the range of about five percent (5%) by weight to about ten percent (10%) by weight of catalyst to substrate. Preferably, the 18-crown-6 is present at about five percent (5%) by weight of catalyst to substrate.
The subject process can proceed by mixing an indole substrate with dimethyl carbonate in the presence of a base or a catalyst in a suitable solvent, such as N,N-dimethylformamide (“DMF”) or 1-methyl-2-pyrrolidinone (“NMP”), followed by heating the reaction mixture to reflux for a short time (normally 2 to 3 hours). The choice of reaction temperature is readily determinable by the skilled artisan. The reaction temperature will normally be above the boiling point of the reagent, around 90° C. for DMC. The reaction can be quenched by adding water, after which the product can be obtained either by filtration or by extraction with a suitable solvent. The subject process typically results in the desired product in good yield with high quality. For example, when 6-nitroindole was used

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