Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-07-26
2000-03-28
Lambkin, Deborah C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D33338
Patent
active
060433795
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to processes and intermediates for preparing 3-substituted-2-oxindoles of the formula II below. 5-Fluorothiophen-2-ylcarboxylic acid, and its derivatives, of the general formula (I), below, are useful in the preparation of compounds of the formula II wherein n is 0 and Q is ##STR5## Compounds II, their pharmaceutically acceptable salts and prodrugs (hereafter "the active compounds") are useful as inhibitors of prostaglandin H.sub.2 synthase, 5-lipoxygenase and interleukin-1 biosynthesis. They are also useful as analgesic, antiinflammatory and antiarthritic agents in the treatment of chronic inflammatory diseases.
U.S. Pat. No. 5,290,802 (hereafter "the 802 patent"), assigned to the Assignee of this application and incorporated herein in its entirety, discloses compounds of the formula ##STR6## wherein Q, X, Y, n and R.sup.2 are defined therein, their preparation from compounds of the formula Q--(CH).sub.2 CO.sub.2 H, and methods for preparing compounds of the formula Q--(CH).sub.2 CO.sub.2 H, wherein Q is defined therein.
Gronowitz, S. and Rosen, U, (Chemica Scripta 1971, 1, 33-43) describe a preparation of I starting from lithiated compounds.
SUMMARY OF THE INVENTION
According to a first embodiment of the invention there is provided a method for preparing a compound of the formula ##STR7## wherein R.sup.1 is OH, which comprises treating the compound of formula ##STR8## with a metallic fluoride (M.sup.2 F), wherein M.sup.2 is an alkali metal cation wherein the metal is, preferably, selected from K'Cs and Rb, at a high temperature, in an inert solvent. The reaction is effected in the presence of a mixture of compounds of the formulae (R.sup.4).sub.4 P.sup.+ Z.sup.- and R.sup.5 vic(COW).sub.2, wherein "vic" indicates that the "COW" groups are attached to adjacent ("vicinal") C atoms on the R.sup.5 group; and R.sup.4 is selected from optionally substituted (C.sub.1 -C.sub.6)alkyl and optionally substituted (C.sub.6 -C.sub.10)aryl, such as n-butyl and phenyl, respectively, and Z is selected from Br and Cl, R.sup.5 is (C.sub.6 -C.sub.10)aryl, such as phenyl or naphthyl, or (C.sub.1 -C.sub.6)alkyl, such as butyl, and W is selected from Cl and F, to form the compound of the formula ##STR9##
Compound IV is then heated with an aqueous solution of MOH, wherein M is an alkali metal, preferably selected from Li, Na and K, and the resultant product is treated with a mineral acid, preferably selected from HCl, H.sub.2 SO.sub.4 and H.sub.3 PO.sub.4, to form the compound of formula I wherein R.sup.1 is OH.
Another aspect of the above embodiment provides a method for preparing a compound of formula I, wherein R.sup.1 is a halogen atom, by treating the corresponding compound of formula I wherein R.sup.1 is OH with a halogenating agent.
Yet another aspect provides a method for preparing a compound of formula I, wherein R.sup.1 is selected from amino, mono(C.sub.1 -C.sub.6)alkylamino, di(C.sub.1 -C.sub.6)alkylamino, (C.sub.6 -C.sub.10)aroyloxy, (C.sub.1 -C.sub.6)acyloxy, (C.sub.6 -C.sub.10)aryloxy, and (C.sub.1 -C.sub.6)alkoxy, which comprises treating the corresponding compound wherein R.sup.1 is a halogen atom with an appropriate amine; aromatic or alkyl carboxylic acid or salt thereof; phenol or alkanol.
Another embodiment of the invention provides a compound of formula I wherein R.sup.1 is an amino, mono(C.sub.1 -C.sub.6)alkylamino, di(C.sub.1 -C.sub.6)alkylamino, (C.sub.6 -C.sub.10)aroyloxy, (C.sub.1 -C.sub.6)acyloxy, (C.sub.6 -C.sub.10)aryloxy, or (C.sub.2 -C.sub.6)alkoxy group.
DETAILED DESCRIPTION OF THE INVENTION
In the Schemes and the following discussion M.sup.2, X, Y, Z, W, R.sup.1-, R.sup.4 and R.sup.5 and formulae I, II, III and IV have the meanings given above. ##STR10##
As shown in Scheme 1 compound III is converted to compound IV by treatment with a fluoride of the formula M.sup.2 F wherein M.sup.2 is an alkali metal cation, preferably selected from K, Cs and Rb, in an inert solvent at a temperature from about 140 to about 220.degree. C. The reaction i
REFERENCES:
patent: 5047554 (1991-09-01), Ehrgott et al.
Gronowitz, S.--Chem. Abst.--vol. 75, No. 3, Jul. 19, 1971, Abst No. 20080c, Nuclear Magnetic Resonance of aromatic heterocyclics. III On the synthesis of substituted fluorothiophenes.
Gronowitz, S.--Chem.Scripta, vol. 1., pp. 33-43, 19/1, Nuclear Magnetic Resonance of aromatic heterocyclics. III On the synthesis of substituted fluorothiophenes.
Suzuki, H.--Chem. Soc. Japan, Bull Chem Soc. Jpn. vol 63., No. 7, pp. 2010-2017, (1990) General & Highly Eff. Syntheses of m-Fluoro Arenes Using Potassium Fluorido Exchange Method.
Yazawa. N.--Chem. Letters (1980) pp2213-2216, Chem Soc. Of Japan--Tetraphenylphosphonium Bromide Catalyzed . . . Compound.
Heinz, P.--Chem. Abst., vol. 80, p. 663--Abst. No. 163322h--Nov. 6, 1978--Some thieny analogs of amidinomycin.
Dann, O.--Chem. Abst. vol. 37, No. 21--Col. 6260, Nov. 10, 1943--Aminocarboxylic ester of furan. thiophene & thiazole.
CA 115: 471386 Preparation of . . . biosynthesis. Ehrgott et al., Sep. 1999.
CA 98: 16219 Protonation of . . . -carboxamides. Alberghina et al., 1983.
Chambers Robert James
Marfat Anthony
Appleman Jolene W.
Ginsburg Paul H.
Lambkin Deborah C.
Pfizer Inc.
Richardson Peter C.
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