Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2001-07-19
2003-04-15
Bernhardt, Emily (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
active
06548670
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a method for preparing 5- and 6-benzyl functionalized quinoxalines.
The disclosures referred to herein to illustrate the background of the invention and to provide additional detail with respect to its practice are incorporated herein by reference and, for convenience, are numerically referenced in the following text and respectively grouped in the appended bibliography.
Substituted quinoxalines are important chemical intermediates for the preparation of pharmaceutical compounds, such as AMPHAKINE CX516® [1-(quinoxalin-6-ylcarbonyl)piperidine]. Substituted quinoxalines are typically prepared by condensation of substituted ortho-diaminobenzenes with sodium glyoxal bisulfite as set out below (1).
For example, 7-methoxy-5-aminoquinoxaline has been prepared by condensation of 3,4,5-triaminoanisole with sodium glyoxal bisulfite (2).
Similarly, 7-methoxy-5-aminoquinoxaline and 7-methoxy-5-hydroxyaminoquinoxaline have been prepared from 3,5-dinitro-4-aminoanisole, which in turn was prepared by nitration of m-nitrobenzenesulfonyl-p-aminoanisole (3).
Nevertheless, there are no reported procedures for preparing 6-hydroxymethylquinoxaline by condensation of 3,4-diaminohydroxymethylbenzene with sodium glyoxal bisulfite, presumably because such a method is not trivial and requires multiple steps. Because attempts to prepare 5- and 6-benzyl functionalized quinoxalines via a one-step selective reaction of the benzyl group were not successful, a two-step method to prepare 5- and 6-benzyl functionalized quinoxalines was developed.
BRIEF SUMMARY OF THE INVENTION
In a first embodiment, the present invention pertains to a method for preparing a compound having Formula (I).
In this first embodiment, the method comprises contacting an aqueous suspension of a compound having Formula (II) with a water-soluble nucleophile, N
1
, containing moiety Y; wherein X is chloro or bromo; R
1
is selected from the group consisting of hydrogen and branched and unbranched alkyl and aryl groups having from 1 to 9 carbon atoms; Y is selected from the group consisting of —OR
2
, —NHR
2
, —NR
2
R
3
, —SR
2
, and —CN; and R
2
and R
3
are independently selected from the group consisting of hydrogen and branched and unbranched alkyl groups having from 1 to 4 carbon atoms.
In a second embodiment, the present invention pertains to a method for preparing a compound having Formula (I).
In this second embodiment, the method comprises contacting a compound having Formula (II) with an organic solvent-soluble nucleophile, N
2
, containing moiety Y, in an inert polar organic solvent; wherein X is chloro or bromo; R
1
is selected from the group consisting of hydrogen and branched and unbranched alkyl and aryl groups having from 1 to 9 carbon atoms; Y is selected from the group consisting of —OR
2
, —NHR
2
, —NR
2
R
3
, and —SR
2
; and R
2
and R
3
are independently selected from the group consisting of hydrogen and branched and unbranched alkyl and aryl groups having from 5 to 9 carbon atoms.
In a third embodiment, the present invention pertains to a method for preparing a compound having Formula (I).
In this third embodiment, the method comprises contacting a compound having Formula (II) in an organic solvent with an aqueous solution of a water-soluble nucleophile, N
1
, containing moiety Y, in the presence of a phase transfer catalyst; wherein X is chloro or bromo; R
1
is selected from the group consisting of hydrogen and branched and unbranched alkyl and aryl groups having from 1 to 9 carbon atoms; Y is selected from the group consisting of —OR
2
, —NHR
2
, —NR
2
R
3
, —SR
2
, and —CN; and R
2
and R
3
are independently selected from the group consisting of hydrogen and branched and unbranched alkyl groups having from 1 to 4 carbon atoms.
DETAILED DESCRIPTION OF THE INVENTION
The present invention pertains to methods for preparing 5- and 6-benzyl functionalized quinoxalines. In a first embodiment, the method comprises contacting an aqueous suspension of a 5- and 6-halomethyl quinoxaline with a water-soluble nucleophile. In a second embodiment, the method comprises contacting a 5- and 6-halomethyl quinoxaline with an organic solvent-soluble nucleophile in an inert polar organic solvent. In a third embodiment, the method comprises contacting a 5- and 6-halomethyl quinoxaline in an organic solvent with an aqueous solution of a water-soluble nucleophile in the presence of a phase transfer catalyst.
The 5- and 6-halomethyl quinoxalines may be prepared from 5- and 6-methyl quinoxalines, which in turn may be prepared from ortho-diaminotoluenes, such as 2,3-and 3,4-diaminotoluene, by condensation with sodium glyoxal bisulfite. The preparation of ortho-diaminotoluenes is not trivial because the nitration of toluene yields mainly 2,4-dinitrotoluene, the precursor of 2,4-diaminotoluene (TDA, toluene-diamine), and only 4% or less of the ortho-isomers. However, 2,4-diaminotoluene is a bulk chemical, from which the ortho-diamine isomers are removed by distillation, and consequently uses for the ortho-diamine by-products are desired. The present invention provides a simple route to compounds such as 6-hydroxymethyl-quinoxaline by taking advantage of the availability of ortho-toluene diamine (OTD) using selective functionalization of the methyl group without affecting the aromatic rings.
Because attempts to prepare 5- and 6-benzyl functionalized quinoxalines via a one-step selective reaction of the benzyl group were not successful, a two-step method to prepare 5- and 6-benzyl functionalized quinoxalines was developed.
In the first step, a 5- or 6-benzyl-quinoxaline is halogenated to provide the corresponding 5- or 6-halomethyl-quinoxaline intermediate.
X is halogen. The term “halogen”, as used herein, refers to fluorine, chlorine, bromine, and iodine. Preferred halogens are chlorine and bromine.
In the first step of the synthesis, a benzylic methyl heterocyclic compound and a halogenating agent, such as N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS), are reacted in the presence of a radical initiator, such as benzoyl peroxide or azobisisobutyronitrile, in a suitable solvent, to form the respective 5- or 6-halomethyl quinoxaline (I). Suitable solvents may be selected from the group consisting of fluorobenzene, difluorobenzenes, trifluorobenzenes, chlorobenzene, dichlorobenzenes, trichlorobenzenes, &agr;,&agr;,&agr;-trifluorotoluene and &agr;,&agr;,&agr;-trichlorotoluene. The method typically affords good yields of halomethyl-quinoxalines when [6QX]/[benzoyl peroxide]≦40 while maintaining a temperature in the range of 60° C. to 115° C. for a period of 1 to 12 hours. Yields for benzylic brominations (conversions≧95%, selectivities≧97%) are in general better than for benzylic chlorinations (conversions 60%, selectivities~75-80%). The 5- or 6-halomethyl quinoxaline may be a 5-halomethyl quinoxaline or may be a 6-halomethyl quinoxaline. The halomethyl may be a chloromethyl or may be a bromomethyl.
This first step is more fully described in a patent application Ser. No. 09/909,000, now U.S. Pat. No. 6,492,517 entitled “Method For Preparing Halomethyl Heterocyclic Compounds” filed by Applicant concurrently on Jul. 19, 2001 with the present patent application, and assigned to the assignee of this application, which is hereby incorporated by reference.
In the second step, the 5- or 6-halomethyl-quinoxaline intermediate (II) is contacted with a nucleophile to yield the corresponding 5- or 6-benzyl functionalized quinoxaline (I).
In a first embodiment, the present invention pertains to a method for preparing a compound having Formula (I) which comprises contacting an aqueous suspension of a compound having Formula (II) with a water-soluble nucleophile, N
1
, containing moiety Y.
In this first embodiment, the compound having Formula (I) may be:
or may be
R
1
may be selected from the group consisting of hydrogen and branched and unbranched alkyl and aryl groups having from 1 to 9 carbon atoms. Preferably, R
1
is selected from the g
Air Products and Chemicals Inc.
Bernhardt Emily
Leach Michael
LandOfFree
Methods for preparing 5- and 6-benzyl-functionalized... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods for preparing 5- and 6-benzyl-functionalized..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods for preparing 5- and 6-benzyl-functionalized... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3081274