Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-01-09
2001-07-31
Huang, Evelyn Mei (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06268500
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the art of synthetic organic chemistry. Specifically, the invention is a process to selectively separate compounds from a mixture, which compounds are useful as intermediates in syntheses of other organic compounds.
BACKGROUND OF THE INVENTION
When quinoline (Formula (1)) is nitrated,
a mixture of nitroquinoline position isomers is formed, which includes 5-nitroquinoline, 8-nitroquinoline and relatively small amounts of other nitroquinoline compounds.
5-nitroquinoline (Formula (2)) is a useful intermediate
for certain organic syntheses. Among other utilities, 5-nitroquinoline can be used as an intermediate in the synthesis of 10,11-cyclopropyldibenzosuberane derivatives as described in PCT Patent Application No. PCT/US94/04215 (Publication Number WO 94/24107).
8-Nitroquinoline (Formula (3)) is also a useful intermediate for certain organic syntheses.
Among other utilities, 8-nitroquinoline can be used in the synthesis of 8-aminoquinoline, which can be used in a number of syntheses of organic products, see e.g. EP 388619 (synthesis of pyridine-2,3-dicarboxylic acid),
Merck Index
, Tenth Edition, Merck & Co., 1983, pg. 707 (synthesis of 8-hydroxyquinoline) and
Merck
, pg. 1037 (synthesis of 1,10-phenanthroline).
The mixture of products obtained during the nitration of quinoline was disclosed in a report published in 1885 by Claus and Kramer in
Chem. Ber
., (1885), 18, 1243. Seven years later, S. F. Dufton in
J. Chem. Soc
., (1892), 61, 783, reported that by dissolving the mixture of nitro products in a large quantity of very dilute nitric acid and cooling, the 5-nitroquinoline isomer selectively separated as the nitrate salt. Later work by W. Meigan (
J. Prakt. Chem
., (1908), 77, 472); R. P. Dickshoorn (
Rec. Trav. Chim
., (1929), 48, 147); L. F. Fieser and E. B. Herschberg (
J. Am. Chem. Soc
., (1940), 62, 1640); and V. M. Dziomko and I. A. Krasavin (
Khim Geterotsikl. Soedin
., Sb. 1, Azotsoderzhashchie Geterosikly, 1967, 281; C.A., 1969, 70, 77748c), utilized this technique to prepare and separate quantities of 5-nitroquinoline and 8-nitroquinoline.
It must be noted that the use of a large volume of dilute acid is typically undesirable in any chemical process because of waste disposal issues.
What is needed are processes to selectively separate 5-nitroquinoline and 8-nitroquinoline from a mixture of nitroquinoline position isomers that provides a good separation of each isomer in relatively pure form, without the use of a large volume of dilute acid.
SUMMARY OF THE INVENTION
A first aspect of this invention is a process to separate 5-nitroquinoline hydrohalide from a mixture of nitroquinoline position isomer hydrohalide salts comprising:
(A) heating a slurry comprising a mixture of nitroquinoline position isomer hydrohalide salts in wet dimethylformamide to form a solution; and
(B) cooling the solution of Step (A) until a precipitate comprising 5-nitroquinoline hydrohalide is formed.
A second aspect of this invention is a process to separate 8-nitroquinoline from a mixture of nitroquinoline position isomer hydrohalide salts comprising:
(i) adding a mixture of nitroquinoline position isomer hydrohalide salts to water or a mixture of water and a water-miscible liquid to form a slurry; and
(ii) increasing the pH of the slurry of Step (i) until a precipitate comprising 8-nitroquinoline is formed.
A third aspect of this invention is a compound which is the hydrochloride salt of 5-nitroquinoline, namely 5-nitroquinoline HCl.
A further aspect of this invention is a process for preparing 5-nitroquinoline hydrohalide comprising:
(A) heating a slurry comprising a mixture of nitroquinoline position isomer hydrohalide salts in wet dimethylformamide to form a solution;
(B) cooling the solution of Step (A) until a precipitate comprising 5-nitroquinoline hydrohalide is formed; and
(C) collecting the precipitate.
DETAILED DESCRIPTION OF THE INVENTION
The terms and abbreviations used in the instant examples have their normal meanings unless otherwise designated. Throughout this application, all percentages are weight percentages and all ratios are ratios based on weight.
The first aspect of the invention is a process to separate 5-nitroquinoline hydrohalide from a mixture of nitroquinoline position isomer hydrohalide salts. This process achieves good separation of 5-nitroquinoline hydrohalide from a mixture of nitroquinoline position isomer hydrohalide salts when wet dimethylformamide (“Wet DMF”) is used as the solvent for the solution of step (A). Wet DMF describes dimethylformamide which has a small amount of water present in it. The amount of water present in Wet DMF is from about 0.5% to about 10%, preferably from about 0.5% to about 5% and most preferably about 1.25%. It has been found that when Wet DMF is used as the solvent, the selectivity of the separation is dramatically enhanced with the solid formed containing at least 99% 5-nitroquinoline hydrohalide and less than 1% other material(s). Wet DMF provided a high degree of selectivity of separation. Solvents other than Wet DMF either failed to produce a solid or produced a solid that still contained both 5-nitroquinoline and 8-nitroquinoline with the non-5-nitroquinoline portion of the solid being at least about 35%.
To obtain a good separation of 5-nitroquinoline hydrohalide from a mixture of nitroquinoline position isomer hydrohalide salts, the ratio of 5-nitroquinoline hydrohalide salt to the rest of the mixture should be at least about 4 (40%) to 6(60%). Preferably the ratio of 5-nitroquinoline hydrohalide salt to the rest of the mixture is at least about 5 (50%) to 5(50%). Of course, as the amount of 5-nitro-quinoline hydrohalide salt increases relative to the rest of the components in the mixture, the claimed separation process will continue to be effective. Therefore, although there is a practical lower limit (about 40%) to the amount of 5-nitroquinoline hydrohalide salt that should be present in the mixture in order to achieve an effective separation using the instant claimed process, there is no upper limit.
In order to obtain a mixture of nitroquinoline position isomer hydrohalide salts suitable for use in the instant claimed process, a mixture of nitroquinoline position isomers can be created and then contacted with a suitable hydrohalide to create nitroquinoline position isomer hydrohalide salts. A mixture of nitroquinoline position isomers can be made, using readily available commercial products, by nitration of quinoline using a combination of nitric acid and sulfuric acid. Procedures for nitration of quinoline using a combination of nitric and sulfuric acid are known in the literature (see, e.g., the references cited in the BACKGROUND OF THE INVENTION section of this application).
Preferable conditions, in terms of maximizing the yields of both 5-nitroquinoline and 8-nitroquinoline, are for the nitration reaction to be run at from about 95° C. to about 100° C. for about 1 to about 2 hours, using about 1.5 equivalents of nitric acid.
The typical mixture thusly created contains from about 40% to about 60% 5-nitroquinoline, from about 30% to about 50% 8-nitroquinoline with the remainder of the mixture containing other material(s) which can include non-reacted reagent(s), other nitroquinolines (such as 3-, 6-, and 7-nitroquinoline, and 5-hydroxy-6,8-dinitroquinoline) and other unidentified materials. Within these ranges, the amount of each component is such that the total percentage of all components in the mixture adds up to 100%. If desired, mixtures containing more than about 60% 5-nitroquinoline can be created by adding a suitable amount of 5-nitroquinoline to a mixture of nitroquinoline position isomers made by this procedure.
The precursor mixture for use in the process of the first aspect of this invention should contain at least about 40% 5-nitroquinoline, from about 30% to about 60% 8-nitroquinoline and at most about 30% other material(s). Preferably the mixture contains at most about 20% of other material(s), and most preferably the mixture contains at mos
Kress Thomas J.
Wepsiec James P.
Boudreaux William R.
Dawalt Elizabeth A.
Eli Lilly and Company
Huang Evelyn Mei
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