Patent GB-1467206-A (GB)
Title: Oxa-, thia- and aza-tetracycline derivatives and their preparation
IPC: A61K31/24
Filed: 1975-09-04
Abstract: 1467206 6-(Oxa, thia or aza)tetracyclines MERCK PATENT GmbH 4 Sept 1975 [6 Sept 1974] 36524/75 Heading C2C [Also in Division A5] Novel 6-(oxa, thia or aza)tetracyclines of the general Formula I wherein each of R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP> and R<SP>4</SP> is H or alkyl, R<SP>5</SP> is H, F, Cl, Br, CF 3 , OH, alkyl, alkoxy, NO 2 , NH2, alkylamino, dialkylamino or acylamino and X is O, S, SO, SO2, NH, N-alkyl or N-acyl, the alkyl and alkoxy groups having in each case 1-3 C atoms and the acyl groups having in each case 1-4 C atoms and, if R<SP>5</SP> is methoxy and X is simultaneously S, R<SP>5</SP> is in the 8- or 9- position, and their physiologically acceptable acid addition salts are prepared (a) by treating a compound which corresponds to Formula I, but wherein at least one hydroxyl or amino group is present in functionally modified form, with a solvolysing or hydrogenolysing agent in order to liberate the hydroxyl or amino group(s); or (b) by treating a compound of the general Formula II with a hydroxylating agent; and (c) optionally treating the product of (a) or (b) with a solvolysing, alkylating, acylating, oxidizing, nitrating and/or reducing agent in order to convert one or more of R<SP>1</SP>, R<SP>2</SP>, R<SP>5</SP> and X to a different meaning within the above definitions; (d) optionally epimerizing the NR<SP>1</SP>R<SP>2</SP> group in the product of (a), (b) or (c); and (e) optionally salifying a base resulting from (a), (b), (c) or (d) with an appropriate acid. The 6-(oza, thia or aza)tetracycline starting materials are prepared by condensing an aldehyde of the general formula III in which the hydroxyl and/or keto group may be present in functionally modified form, with an unsaturated azlactone or thioazlactone, reacting the resulting oxazolinone or thiazolinone of the general Formula IV wherein Y is O or S and K<SP>6</SP> is H, SH, C 1-4  alkylthio, benzylthio, C 1-10  alkyl, or phenyl, benzyl, phenoxymethyl or phenoxypropyl optionally mono- or di-substitued by C 1-4  alkyl, OH, temporarily protected OH, CH 2 OH with optionally temporarily protected OH, NO 2 , NH 2 , mono- or di-alkylamino, acylamino, halogen, COOH, COOalkyl CONH 2  or CONH- alkyl and in which the OH and/or keto group may be present in functionally modified form, in the presence of a basic condensation agent, with wherein R<SP>10</SP> is C 1-6  alkyl and R<SP>11</SP> is H or C 1-6  alkyl, and converting the resulting 4-(acylamino or thioacylarnino)-6-oxa, thia or aza)- tetracycline of the general Formula VI in which the 10-OH group may be present in functionally modified form, to the desired product by solvolysis, hydrogenolysis and/or 12a-hydroxylation. The aldehydes (III) may be prepared by reacting a phenol of the general Formula VII in which the hydroxyl group may be present in functionally modified form and the R<SP>5</SP> group is optionally temporarily protected, with a glutaconic acid dialkyl ester, followed by saponification, cyclizing the resulting 3-aryl-X-glutaric acid of the general Formula VIII in which the hydroxyl group may be present in functionally modified form and reducing the resulting acid, e.g. via the acid chloride, amide and nitrile. 2-Chloro-5-methoxy-thiophenol is prepared by reacting 2-chloro-5-methoxy-aniline with a diazotizing agent and then potassium ethylxanthate, followed by saponification with ethanolic KOH. 3,5-Dimethoxythiophenol is prepared by reacting 3,5-dimethoxyphenol with N,N - dimethylthiocarbamoyl chloride in the presence of NaH, heating the resulting 1-dimethylaminothiocarbonyloxy - 3,5 - dimethoxybenzene and saponifying the resulting 1-dimethylaminocarbonylmercapto - 3,5 - dimethoxybenzene with ethanolic KOH, and 2-nitro-5- methoxy-thiophenol is prepared analogously. 2 - (1 - Carbamoyl - 1 - methylethyl) - 5,7- dimethoxy - 4 - chromanone is prepared by methylating 2,4,6 - trihydroxyacetophenone, reacting the resulting 2-hydroxy-4,6-dimethoxyacetophenone with dimethylcyanoacetic acid ethyl ester in the presence of NaH, heating the resulting 2,2 - dimethyl - 3,5 - dixoo - 5 - (2- hydroxy - 4,6 - dimethoxyphenyl) - pentanonitrile with cone. H 2 SO 4  and hydrogenating the resulting 2 - (1 - carbamoyl - 1 - methylethyl) 5,7-dimethoxychromon in the presence of PdO on BaSO 4 .