Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-03-10
1997-04-29
Rotman, Alan L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D40306, C07D45304
Patent
active
056250665
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE
This application is a 371 of PCT/FR 93/00848.
DESCRIPTION OF THE INVENTION
The present invention relates to optically active hydroquinine 1-(3-aminophenyl)ethanesulphonate (Form A), its preparation and its use as intermediate in the preparation of enantiomers which can be used as antagonists of cholecystokinin and of gastrin.
Hydroquinine 1-(3-aminophenyl)ethanesulphonate (Form A) can be prepared by the following process: (RS)-1-(1-bromoethyl)-3-nitrobenzene and conversion to the potassium salt to obtain (RS)-potassium 1-(3-nitrophenyl)ethanesulphonate, benzylquininium 1-(3-nitrophenyl)ethanesulphonate and isolation of Form A,
It is particularly advantageous to perform stage a) in aqueous medium at a temperature of between 50.degree. C. and 100.degree. C. and preferably at 80.degree. C.
The alkali metal sulphite is preferably sodium or potassium sulphite.
To recover the product, it is preferable to convert it into tetraalkylammonium or trialkylphenylalkylammonium salt, to isolate it and then to convert it back into the potassium salt form.
Stage b) is performed by means of an N-benzylquininium halide and especially the chloride, in the presence of potassium dihydrogenphosphate, in aqueous medium, at a temperature of between 10.degree. and 30.degree. C. and preferably of 20.degree. C.
The reduction in stage c) is generally performed by means of hydrogen under pressure, in the presence of a catalyst such as palladium, at a temperature of between 10.degree. C. and 30.degree. C. The hydrogen is generally employed at a pressure of 100 kPa.
(RS)-1-(1-Bromoethyl)-3-nitrobenzene can be prepared by the method described by E. Felder et al., J. Med. Chem., 13, 559 (1970).
Hydroquinine 1-(3-aminophenyl)ethanesulphonate (Form A) is of particular interest as intermediate for the preparation of the enantiomers of the compounds of formula: ##STR1## in which Y denotes:
A) a --CH.sub.2 --CO--NR.sub.1 R.sub.2 residue in which R.sub.1 denotes a radical which is (a) phenyl optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, hydroxyl polyfluoroalkyl, nitro, alkylthio, alkoxycarbonyl, carboxyl, acylamino, methylenedioxy, polyfluoroalkoxy, trifluoromethylthio, phenoxy, phenyl, benzyl, phenylamino and CONR.sub.3 R.sub.4 radicals in which R.sub.3 and R.sub.4, which are identical or different, denote a hydrogen atom, an alkyl, phenyl (optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals), indanyl, cycloalkylalkyl, cycloalkyl or phenylalkyl radical or else R.sub.3 and R.sub.4 together with the nitrogen atom to which they are attached form a saturated or unsaturated mono- or polycyclic heterocyclic ring containing 4 to 9 carbon atoms and 1 or more heteroatoms (O, N, S) and optionally substituted by one several alkyl, alkoxy, alkoxycarbonyl, dialkylcarbamoyl or phenyl radicals or in combination with a carbon atom of the heterocyclic ring by a 4- or 5-membered spiromonocyclic ring optionally containing one several heteroatoms (O, S, N); (b) pyridyl, (c) isoquinolyl, (d) quinolyl, (e) quinoxalinyl (these heterocyclic rings being optionally substituted by one or more substituents chosen from alkyl and phenyl radicals and halogen atoms), (f) alkyl, (g) phenylalkyl, (h) naphthyl, (i) 5,6,7,8-tetrahydronaphthyl, (j) 1,2,3,4-tetrahydronaphthyl, (k) alkoxycarbonylalkyl or (1) cycloalkyl, R.sub.2 denotes a --CH(R.sub.5)--CO--R.sub.6 chain in which R.sub.5 denotes a hydrogen atom or an alkyl, alkoxycarbonyl or phenyl radical (optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, alkylthio, nitro and amino radicals) and R.sub.6 denotes an alkoxy, cycloalkyloxy (optionally substituted by at least one alkyl radical), cycloalkylalkyloxy, phenylalkyloxy, polyfluoroalkyloxy, cinnamyloxy and --NR.sub.3 R.sub.4 radical,
B) a residue of the formula: ##STR2## in which:
either R denotes a methylene, ethylene, SO, SO.sub.2 or CHOH radical or a sulphur atom, R.sub.7 denotes a pyridyl radica
REFERENCES:
patent: 5093498 (1992-03-01), Dolling et al.
patent: 5162339 (1992-11-01), Lowe, III
Rhone-Poulenc Rorer S.A.
Rotman Alan L.
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