Patent IL-136864-A (IL)
Title: Method of preparing enantiomerically-enriched tetrahydrobenzothiepine oxides
IPC: C07D487/08
Filed: 1998-12-16
Abstract: A method of preparing an enantiomerically-enriched tetrahydrobenzothiepine-1-oxide of the formula wherein: R1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl; R3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR24, SR15, S(O)R15, SO2R15, and SO3R15, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the 1930 ז' באב התשס" ד - July 25, 2004 group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR19, NR19R20, SR19, S(O)R19, SO2R19, SO3R19OR20, NR19NR20R21, NO2, CO2R19, CN, OM, SO2OM, SO2NR19R20, C(O) NR19R20, C(O)OM, COR19, P(O)R19R20, P+R19R20R21A-, P(OR10)OR20, S+R19R20A-, and N+R15R17R18A-, wherein: A- is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation; said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR13, NR13R14, SR13, S(O)R13, SO2R13, SO3R13, CO2R13, CN, oxo, CONR13R14, N+R13R14R15A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R13R14, P+R13R14R15A-, and P(O) (OR13)OR14, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR13, N+R13R14A-, S, SO, SO2, S+R13A-, PR13, P(O)R13, P+R13R14A-, or phenylene; R19, R20, and R21 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, polyether, alkylarlylalkyl, alkylheteroarylalkyl, alkylheterocycloalkyl, R13 and R14 are independently selected from the group consisting of hydrogen and alkyl; R15 and R16 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, heteroarylalkyl, heterocyclealkyl, and alkylammoniumalkyl; and R17 and R18 and independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR15, NR15R16, SR15 S(O)R15, SO2R15, SO3R15, CO3R15, CN, halogen, oxo, and CONR15R16, wherein R15 and R16 are as defined above, or R17 and R18 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; and R4, R5, R6, and R7 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halo, alkoxy, aryloxy, -NO2, and -NR9R10; R9 and R10 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, butoxycarbonyl, and carbobenzyloxy; R3 and the hydroxyl at the 4-position of the enantiomerically-enriched tetrahydrobenzothiepine-1-oxide are in a syn-conformation with respect to each other; alkyl, alkenyl, alknyl, cycloalkyl, aryl, heteroaryl, alkoxy, and aryloxy can optionally be substitued with one or more moieties selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, -NO2, and halo; and the sulfur at the 1-position of the seven-member ring and the carbons at the 4-position and the 5-position of the seven member ring are chiral centers; wherein the method comprises cyclizing an enantiomerically-enriched aryl- 3-propanalsulfoxide of the formula 1931 ז' באב התשס" ד - July 25, 2004