Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1995-01-30
2002-10-22
Stockton, Laura L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C560S023000
Reexamination Certificate
active
06469181
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to preparing 2-oxindoles and N-hyroxy-2-oxindoles. 2-oxindoles are also known as 2-oxoindolines and as indole-2(3H)-ones, and oxindole(s) as used herein, refers to 2-oxindole(s). More specifically, this invention relates to preparing 2-oxindoles and N-hyroxy-2-oxindoles via reduction of 2-nitroarylmalonate diesters. It further relates to preparing 2-nitroarylmalonate diesters from 2-halonitroarenes, for subsequent reduction to prepare 2-oxindoles or a N-hyroxy-2-oxindoles.
2-oxindoles are valuable pharmaceutical agents and/or intermediates for the production of pharmaceutical agents, including analgesic and anti-inflammatory agents (U.S. Pat. No. 4,721,712), anti-anxiolytic agents (U.S. Pat. No. 3,882,236), and sleep-inducing agents (U.S. Pat. No. 4,160,032). N-hyroxy-2-oxindoles are useful intermediates in the preparation of certain 5-substituted-2-oxindoles (U.S. Pat. No. 5,210,212).
BACKGROUND OF THE INVENTION
Sundberg,
The Chemistry of the Indoles
; Academic, New York, 1970, p. 341 and Sumpter,
Chem. Rev., vol
. 37 (1945), 443 give overviews of the synthesis and chemistry of oxindoles. U.S. Pat. Nos. 3,634,453; 4,556,672; and 4,569,942 describe preparations of 2-oxindoles. Oxindoles can be prepared by the reduction of isatins, for example by Wolff-Kishner reduction using first hydrazine hydrate, then sodium alcoholate in alcohol. (See Examples in U.S. Pat. No. 4,721,712.) This method has the drawback of using hydrazine, and for substituted oxindoles, is limited by the availability 30 and difficulty of producing appropriately substituted isatins.
Quallich et al.,
Synthesis, vol
. 1993 (1993), p. 51 summarizes methods for preparing oxindoles. Noting that a general synthetic method for preparing oxindoles which controls the regiochemistry about the aromatic ring was desired, Quallich et al. state, (inserting footnoted references in brackets): “Many oxindole synthesis in the literature have not controlled the aromatic substitution pattern because they were based on intramolecular bond connections of aniline derivatives which did not effectively discriminate between the two available ortho positions. [The Sundberg and Sumpter references are cited.] These include the Friedel-Crafts alkylations of &agr;-chloro acetanilides [Abramovitch et al.
J. Chem. Soc., vol
. 1954, p. 1697], Gassman cyclization of azasulfonium salts [Gassman et al.,
J. Am. Chem. Soc., vol
96 (1974), p. 5508], and thermally induced cyclization of N-acyl phenylhydrazides [Carlson et al.,
J. Chem. Soc., vol
. 1965, p. 5419; Endler et al.,
Org Synth. Vol. IV
(1963), 657]. Ring closure to the oxindole by the aforementioned methods often afforded a mixture of products unless the starting material was symmetrical (para-substituted). In addition, other limitations are imposed on the ring substituents due to the harsh conditions of the preceding methods. Vicarious nucleophilic substitution [Mudryk et al.,
Synthesis, vol
. 1988, p. 1007] and addition of ketene silyl acetals [Rajanbabu et al.,
J. Org. Chem., vol
. 51 (1986), p. 1704] to nitrobenzenes has also been employed to prepare oxindoles, but these methods do not always provide regiocontrol. One method which had given control over oxindole regiochemistry was the funtionalization of nitrotoluenes [Beckett et al.,
Tetrahedron, vol
1968, 6093], but the lack of commercial availability of these compounds was a limitation. Substitution of a triflate [Atkinson et al.,
Tetrahedron Lett., vol
1979, 2857] or bromide [Walsh et al.,
J. Med. Chem., vol
27 (1984), p. 1379] in a nitrobenzene by malonate and subsequent conversion into an oxindole was precedented although the generality of these routes was not known.”
Quallich et al. discloses a three-step process to produce oxindoles from 2-halonitrobenzenes. In the first step, a 2-halonitrobenzene is reacted with a malonate diester anion (generated from the malonate diester by sodium hydride) to produce, after acidification, a 2-nitrophenylmalonate diester, which was isolated. In the second step, the 2-nitrophenylmalonate diester was treated with one equivalent of water and two equivalents of lithium chloride in dimethylsulfoxide to effect the Krapcho hydrolysis and decarboxylation of one of the ester groups, affording the 2-nitrophenylacetate ester, which was isolated. In the third step, the nitro group of the 2-nitrophenylacetate ester was reduced with a four mole ratio of elemental iron powder in acetic acid at 100° C. to yield, after isolation, the oxindole. This process has the drawback of multiple process steps, with intermediate isolations of process intermediates as purified solids and cumulative low yields. For example, the overall mole yields of 5-chloro-2-oxindole, 6-chloro-2-oxindole, and 6-methoxy-2-oxindole from the corresponding substituted 2-chlorobenzenes, calculated from the reported yields of the individual steps, is 31%, 49%, and 16%, respectively. This also has the drawback of generating substantial waste streams, including multiple stoichiometric quantities of iron wastes.
Quallich et al. further disclose that the 2-nitrophenylmalonate diesters are formed in good yield in the first step except where an electron-donating substituent is present. This is exemplified by only 33% yield of 4-methoxy-2-nitrophenylmalonate diester from 2-chloro-5-methoxynitrobenzene, containing the electron-donating methoxy group para to the chloride being substituted, compared to 80% yield for the 6-chloro-2-nitrophenylmalonate diester from the corresponding 2,5-dichloronitrobenzenes, containing chloride in that para position, and further compared to their 76% and 85% yields for 4-bromo- and 4-fluoro-2-nitrophenylmalonate diesters from the corresponding 2,5-dibromo- and 2,5-difluoro- halonitrobenzenes, respectively.
Simet,
J. Org. Chem, vol
. 28 (1963), p. 3580 reports a similar process for preparing 6-trifluoromethyl-2-oxindole from 5-trifluoromethyl-2-chloronitrobenzene, by reaction with a malonate diester anion, followed by caustic hydrolysis and decarboxylation to obtain the 4-trifluromethyl-2-nitrophenylacetic acid. After isolation, this was reduced to the 6-trifluoromethyl-2-oxindole with about a 5 mole ratio of mossy tin metal in 9 N hydrochloric acid (called the Baeyer method). This process likewise has the drawback of multiple process steps, and the severe drawback of generating substantial waste streams, including multiple stoichiometric quantities of tin wastes.
Giovannini et al.,
Helv., vol
. 31 (1948), p. 1392, reports a related multistep process for preparing 6-carboxy-2-oxindole from 4-cyano-2-bromo-nitrobenzene, using iron(II)sulfate in ammoniacal water to reduce the nitro group in the substituted 2-nitrophenylacetic acid to produce the 2-oxindole.
There are other reports of the conversion substituted 2-nitrophenylacetic acids or esters (which are derived by methods other than via the 2-nitrophenylmalonate diester) to substituted 2-oxindoles, and sometimes N-hydroxy-2-oxindoles, by reduction with active metals, typically iron metal, tin metal, or zinc metal, and acid. (See the Sumpter reference; Simet,
J. Org. Chem, vol
. 28 (1963), p. 3580; Wright et al,
J. Am. Chem. Soc., vol
78 (1956), p. 221.) These processes have the common drawback of using excess active metal reductants in acids with the resulting generation of large amounts of spent metal wastes.
A couple reports disclose converting 2-nitrophenylmalonate diesters to oxindoles, without prior hydrolysis and decarboxylation to the 2-nitrophenylacetate ester or free acid, by using such stoichiometric active metal reductants. Jackson et al.,
Am. Chem. J., vol. XII
(1890), p. 23 reduces a dibromodinitrophenylmalonate diester with tin and concentrated hydrochloric acid in methanol to obtain a bromoamido-oxindole. Similarly, Walsh et al. (cited above in the quote from Quallich et al.) reduces 4-benzoyl-2-nitrophenylmalonate diester with tin, at greater than 3 mole equivalents, and concentrated hyd
Bulls A. Ray
Grate John H.
Gruber John M.
Catalytica Inc.
Stockton Laura L.
Townsend and Townsend / and Crew LLP
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