Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-11-07
2004-01-06
Qazi, Sabiha (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S062000, C546S073000, C546S095000, C546S152000
Reexamination Certificate
active
06673930
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an efficient process for the preparation of the selective glucocorticoid receptor agents which are useful 5-(substituted)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolines.
BACKGROUND OF THE INVENTION
The glucocorticoid receptor (GR) has an essential role in regulating human physiology and immune response. Steroids which interact with GR have been shown to be potent anti-inflammatory agents. Steroidal GR ligands, however, have side effects associated with chronic dosing believed to be the result of cross-reactivity with other steroid receptors such as estrogen, progesterone, androgen, and mineralocorticoid receptors which have somewhat homologous ligand binding domains. Therefore, nonsteroidal agents selective for GR are actively being researched for the treatment of inflammation, inflamatory disease, immune and autoimmune diseases.
SUMMARY OF THE INVENTION
The present invention is directed to an efficient process for the preparation of 5-(substituted)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolines. In particular the present invention is directed to, 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline in an overall yield of 24% and with elimination of all column chromatography purification steps.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to an improved seven-step process that eliminates column chromatography, improves throughput and increases the overall yield for the preparation of (5S) 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline. The improved seven-step process, described in Scheme 2 and more particularly in Examples 1-8, allows for the preparation of (5S) 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline on a larger scale than the processes reported in International Patent PublicationNumber WO 99/41256 and J. Med. Chem., 41 (1998) 303-310.
The process comprising treating 2-bromo-1,3-dimethoxybenzene, 2-iodo-1,3-dimethoxybenzene or 1,3-dimethoxybenzene with an organolithium reagent in a first solvent at a temperature of about −5° C. to about 15° C., preferably about 0° C. to about 5° C., after complete addition of the organolithium reagent, the temperature is allowed to warm to ambient temperature and the reaction mixture is stirred for about 1 to 4 hours, preferably about 2 hours, recooling the reaction mixture to about 0° C. and then adding ZnCl
2
while maintaining the temperature between −5° C. and 15° C., preferably about −5° C. to about 5° C., after complete addition of ZnCl
2
allowing the temperature to warm to ambient temperature and allowing the reaction mixture to stir for about 1 to 4 hours, preferably about 2 hours, recooling the reaction mixture to about 0° C. and adding methyl 2-bromo-5-nitrobenzoate, methyl 2-iodo-5-nitrobenzoate or methyl 5-nitro-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate followed by addition of first transition metal catalyst and maintaining the reaction temperature between about 10° C. and about 55° C., preferably between about 20° C. and about 45° C., about 30 minutes after complete addition of first transition metal catalyst adding isopropylacetate and stirring for about 20 to about 90 minutes and then filtering to provide methyl 2′,6′-dimethoxy-4-nitro-1,1′-biphenyl-2-carboxylate;
treating 2′,6′-dimethoxy-4-nitro-1,1′-biphenyl-2-carboxylate with tribromoborane in a second solvent to provide 1-hydroxy-8-nitro-6H-benzo[c]chromen-6-one;
treating 1-hydroxy-8-nitro-6H-benzo[c]chromen-6-one with a second transition metal catalyst under a hydrogen atmosphere at a pressure of about 20 to about 60 psi, preferably about 40 psi, in a third solvent, preferably N-methylpyrrolidin-2-one (NMP) at a concentration of about 0.5M to about 1.0M, preferably 0.7M, to provide 8-amino-1-hydroxy-6H-benzo[c]chromen-6-one in NMP;
treating 8-amino-1-hydroxy-6H-benzo[c]chromen-6-one in NMP with acetone and iodine and heating the reaction mixture to a temperature of about 95° C. to about 115° C., preferably about 105° C., for about 60 to about 90 hours, preferably 72 hours, allowing the reaction mixture to cool to ambient temperature, filtering, concentrating and then adding ethyl acetate, washing the ethyl acetate solution with 10% sodium thiosulfate, water and then filtering the organics through a pad of celite, adding charcoal to the filtrate and heating the filtrate to reflux for 1 hour, passing the filtrate through a silica gel pad using ethyl acetate, concentrating the filtrate to provide a residue, diluting and reconcentrating the residue about 3 times, drying the residue under reduced pressure, adding acetone and 12M HCl to provide 10-hydroxy-2,2,4-trimethyl-1,2-dihydro-5H-chromeno[3,4-f]quinolin-5-one hydrochloride;
treating 10-hydroxy-2,2,4-trimethyl-1,2-dihydro-5H-chromeno[3,4-f]quinolin-5-one hydrochloride with a base and a methylating reagent in a fourth solvent to provide 10-methoxy-2,2,4-trimethyl-1,2-dihydro-5H-chromeno[3,4-f]quinolin-5-one;
treating 10-methoxy-2,2,4-trimethyl-1,2-dihydro-5H-chromeno[3,4-f]quinolin-5-one with a reducing agent in a fifth solvent to provide 10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-ol;
isolating 10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-ol;
treating 10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-ol with allyltrimethylsilane and a Lewis acid to provide 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline; and
Isolating 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline; and
resolving 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolinem to provide (5S) 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline and (5R) 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline.
As used throughout this specification and the appended claims, the following terms have the following meanings:
The term “acid” as used herein, means an organic or inorganic acid. Representative examples of organic acid include, but are not limited to oxalic acid, tartaric acid, acetic acid, formic acid, trifluoroacetic acid and p-tolouenesulfonic acid. Representative examples of inorganic acid include, but are not limited to, hydrochloric acid (HCl) and hydrobromic acid (HBr). A preferred acid is HCl. A most preferred acid is 12M HCl.
The term “alkyl” as used herein, means a straight or branched chain hydrocarbon containing from 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and tert-butyl.
The term “base” as used herein, means any molecular moiety that can remove the hydrogen from an OH group that is attached to an unsubstituted or substituted phenyl group. Representative examples of base include, but are not limited to, alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide and potassium tert-butoxide; hydrides such as sodium hydride, potassium hydride and lithium hydride; amides such as lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide and sodium bis(trimethylsilyl)amide. A preferred base is potassium tert-butoxide.
The term “Lewis acid” as used herein, means a chemical species, other than a proton, that has a vacant orbital or accepts an electron pair. It is to be understood that Lewis acids can be purchased or prepared as complexes including but not limited to, etherates, hydrates, and thioetherates. Representative examples of Lewis acid include, but are not limited to, aluminum chloride, bismuth(III) chloride, boron trifluoride, iron(II) chloride, iron(III) chloride, magn
Fitzgerald Mike A.
Grieme Timothy A.
Ku Yi-Yin
Morton Howard E.
Raje Prasad S.
Becker Cheryl L.
Qazi Sabiha
Rogers Christopher P.
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