Patent GB-1298295-A (GB)
Title: Improvements in or relating to antibiotic derivatives and the preparation thereof
IPC: C07H15/16
Filed: 1971-04-19
Abstract: 1298295 Lincomycin and lincosaminide derivatives UPJOHN CO 19 April 1971 [20 April 1970] 25655/71 Headings C2C and C2P The invention comprises compounds of the Formula I the zwitterion form thereof and the salts thereof, where Y is -SR, 2-(2-hydroxyphenylcarbonyloxy)ethylthio or 2-hydroxyethylthio, R 1  is H or cis or trans C 1-8  alkyl, R 2  is H, methyl or ethyl, X is OH, Cl, Br, I or OR 3 , each in the (R) or (S) configuration, R is C 1-6  alkyl, R 3  is C 1-6  alkyl or cycloalkyl, alkoxyalkyl, or hydroxyalkyl, and Z is a nucleoside-5<SP>1</SP>- phosphate group where the nucleoside is adenosine, guanosine, cytidine or uridine. The compounds of the invention may be prepared by incorporating a compound of the Formula I in which Z is hydrogen in the fermentation medium of a Streptomyces fermentation, and may be subsequently isolated from the fermentation medium by (a) filtering the fermentation medium, (b) absorbing the filtrate on a suitable absorbent to remove water-soluble impurities, (c) chromatographing the eluate from the absorbent on an anion exchange resin, (d) subjecting fractions from the anion exchange resin to countercurrent distribution and (e) separating the individual 3-nucleotides by chromatography. Methyl - 6,7 - aziridino - 6 - deamino - 7 - deoxy- α-thio -lincosaminide, (Compound VI) is prepared by reacting methyl 7(S)-chloro-7-deoxy-α-thiolincosaminide with sodium carbonate. Methyl N acetyl 6,7 - aziridino - 6 - deamino - 7 - deoxy - α - thiolincosaminide (Compound XIII) is prepared by reacting compound VI with acetic anhydride in isopropyl alcohol. Methyl N - acetyl - 7(S) - methoxy - 7 - deoxy- α-thiolincosaminide (Compound VII) is prepared by reacting compound VI with methanol and acetic anhydride, or by reacting compound XIII with methanol and acetic acid under reflux. Methyl N - acetyl - 6,7 - aziridino - 6 - deamino- 7 - deoxy - 2,3,4 - tri - O - acetyl - α - thiolincosaminide (Compound X) is prepared by reacting compound VI with acetic anhydride in pyridine. Methyl N - acetyl - 2,3,4 - tri - O - acetyl - 7- deoxy - 7(S) - methoxy - α - thiolincosaminide (Compound XI) is prepared by reacting compound X with methanol and glacial acetic acid. A mixture of compound XI and the 2,3-di-O- acetyl compound is obtained by reacting compound VII with acetic anhydride in pyridine. The 2,3-di-O-acetyl compound is converted to compound XI by acetylation. Methyl - 7 - deoxy - 7(S) - methoxy - α - thiolincosaminide (Compound VIII) is obtained by hydrazinolysis of compound VII or of compound XI. 7 - Deoxy - 7(S) - methoxy lincomycin hydrochloride is prepared by reacting compound VIII with trans - 1 - methyl - 4 - propyl - L - 2 - pyrrolidine-carboxylic acid hydrochloride, and subsequently dissolving the free base formed in hydrochloric acid. 7 - Deoxy - 7(S) - ethoxylincomycin hydrochloride is prepared in a similar way from compound XIII, via methyl N-acetyl-7-deoxy-7(S)- ethoxy - 1 - thio - α - lincosaminide, methyl N- acetyl - 2,3,4 - triacetyl (or 2,3 - diacetyl) - 7- deoxy - 7(S) - ethoxy - α - thiolincosaminide and 7 - deoxy - 7(S) - ethoxy - α - thiolincosaminide. 7 - Deoxy - 7(S) - propoxylincomycin hydrochloride is prepared from compound XIII via methyl N - acetyl - 7 - deoxy - 7(S) - propoxy- α-thiolmcosaminide, methyl N-acetyl-2,3,4-tri- O - acetyl (or 2,3 - diacetyl) - 7(S) - propoxy - 7- deoxy-α-thiolincosaminide and methyl 7-deoxy- 7(S)-propoxy-α-thiolincosaminide. 7 - Deoxy - 7(S) - isopropoxylincomycin hydrochloride is obtained from compound XIII via methyl N - acetyl - 2,3,4 - tri - O - acetyl - 7- deoxy - 7(S) - isopropoxy - α - thiolincosaminide and methyl 7 - deoxy - 7(S) - isopropoxy - α- thiolincosaminide. 7(S) -Cyclohexyloxy - 7 - deoxylincomycin hydrochloride is obtained from compound XIII via methyl N - acetyl - 2,3,4 - tri - O - acetyl- 7 - deoxy - 7(S) - cyclohexyloxy - α - thiolincosaminide and methyl 7-deoxy-7(S)-cyclohexyloxy-α-thiolincosaminide. 7 - Deoxy - 7(S) - 2<SP>1</SP> - hydroxyethoxylincomycin hydrochloride is prepared from compound VI in a similar way to compound IX via methyl N- acetyl - 7 - deoxy - 7(S) - 2<SP>1</SP> - hydroxyethoxy - α- thiolincosaminide, its 2,3,4-tri-O-acetyl derivative and methyl 7-deoxy-7(S)-2<SP>1</SP>-hydroxy-eth - oxy-α-thiolincosaminide. 7 - Deoxy - 7(S) - 2<SP>1</SP> - methoxyethoxylincomycin hydrochloride is prepared from compound VI via methyl N - acetyl - 7 - deoxy - 7(S) - 2<SP>1</SP>- methoxyethoxy - α - thiolincosaminide, its 2,3,4- tri-O-acetyl derivative and methyl 7-deoxy-7(S)- 2<SP>1</SP>-methoxyethoxy-a-thiolincosaminide. Methyl 7 - deoxy - 7(S) - hydroxy - α - thiolincosaminide is prepared from compound VI via methyl N - acetyl - 7 - deoxy - 7(S)- hydroxy -α-thiolincosaminide. A mixture of methyl N.acetyl.2,3,4-tri-O. acetyl - 7(S) - ethoxy - 7 - deoxy - α - thiolincosaminide and methyl N-acetyl-2,3,4-tri-O-acetyl- 7(S) - acetoxy - 7 - deoxy - α - thiolincosaminide is prepared by reacting compound X with glacial acetic acid and ethanol. 7 - O - Methyllincomycin hydrochloride is prepared from 2<SP>1</SP>-hydroxyethyl 1-thio-α-celestosaminide via 2<SP>1</SP>-hydroxyethyl N-acetyl-2<SP>1</SP>,2,3,4. tetra - O - acetyl - 7 - O - methyl - 1 - thio - α- lincosaminide, 1 - bromo - 7 - O - methyl - #. lincosamine tetraacetate, methyl N-acetyl-2,3, 4 - tri - O - acetyl - 7 - O - methyl - 1 - thio - α- and #-lincosaminides and methyl 7-O-methyl-1- thio-α-lincosaminide. Methyl' N - acetyl - 7 - O - methyl - 1 - thio - α- lincosaminide and its triacetate are prepared from methyl 6 - N,7 - O - ethylidyne - 3,4 - O-, isopropylidene - 1 - thio - α - lincosaminide via its 2-O-acetyl derivative, methyl N-acetyl-2-O- acetyl - 3,4 - O - isopropylidene - 1 - thio - α- lincosaminide and its 7-O-methyl derivative. Compounds of the Formula II and the corresponding 7-O-ethyl, propyl, butyl, isobutyl, sec-butyl and tert-butyl derivatives are prepared by methods similar to those described above. The compounds of the invention are antibacterial agents and may be made up into pharmaceutical compositions with suitable carriers.