Patent DE-102008022017-A1 (DE)
Title: Preparing 1,4-benzothiepin-1,1-dioxide derivative, comprises e.g. reacting mercaptomethyl-hexanol compound with difluorobenzoyl-azinic acid compound and converting into e.g. benzo(b)thiepin-4-ol compound followed by isolating and purifying
IPC: C07C323/19
Filed: 2008-05-02
Abstract: Preparation of 1,4-benzothiepin-1,1-dioxide derivative (I), comprises e.g. reacting (S)-2-ethyl-2-mercaptomethyl-hexan-1-ol (V) with [3-(2,5-difluorobenzoyl)phenyl]azinic acid (VIII), followed by converting (VIII) into 2-(S)-2-ethyl-2-hydroxymethyl-hexylsulfanyl compound (X), (X) into (S)-2-ethyl-2-4-fluoro-2-(3-nitro-benzyl) compound (XII), (XII) into 4-fluoro-2-(3-nitro-benzyl)-benzenesulfonylmethyl-heptanal compound (XIII), (XIII) into 2,3,4,5-tetrahydro-1H-benzo[b]thiepin-4-ol compound (XVI), converting into diastereoisomers of (XVI) and then isolating and purifying. Preparation of 1,4-benzothiepin-1,1-dioxide derivative of formula (I), comprises reacting (S)-2-ethyl-2-mercaptomethyl-hexan-1-ol (V) with [3-(2,5-difluorobenzoyl)phenyl]azinic acid (VIII) to obtain [2-((S)-2-ethyl-2-hydroxymethyl-hexylsulfanyl)-5-fluoro-phenyl]-(3-nitro-phenyl)-methanone (X); converting (X) in the presence of boron trifluoride and triethylsilane to obtain (S)-2-ethyl-2-[4-fluoro-2-(3-nitro-benzyl)-phenylsulfanylmethyl]-hexan-1-ol of formula (XI); converting (XI) in the presence of hydrogen peroxide to obtain (S)-2-ethyl-2-[4-fluoro-2-(3-nitro-benzyl)-benzenesulfonylmethyl]-hexan-1-ol (XII); reacting (XII) in the presence of (2,2,6,6-tetramethylpiperidinyloxyl) to obtain (S)-3-ethyl-3-[4-fluoro-2-(3-nitro-benzyl)-benzenesulfonylmethyl]-heptanal (XIII); reacting (XIII) in the presence of potassium tert-butoxide in tetrahydrofuran to obtain two diastereoisomers of (S)-3-butyl-3-ethyl-7-fluoro-5-(3-nitro-phenyl)-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-4-ol (XV) or (XVa); isolating (XV); converting (XV) with auxiliary agent of hydrogen/palladium-on carbon to obtain (3S,4R,5R)-5-(3-amino-phenyl)-3-butyl-3-ethyl-7-fluoro-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-4-ol (XVI); converting (XVI) in the presence of dimethylamine to obtain two diastereoisomers of (S)-5-(3-amino-phenyl)-3-butyl-7-dimethylamino-3-ethyl-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-4-ol (XVII) or (XVIIa); isolating (XVII) with isocyanate compound of formula (XVIII) to obtain (3S,4R,5R)-3-butyl-7-dimethylamino-3-ethyl-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-4-ol compound of formula (XIX); and purifying (XIX). R 2>, R2a, R 3>, R3a, R 4>, R4a, R 5>, R5a : H, Cl, Br, I, OH, -(CH 2)-OH, CF 3, NO 2, N 3, CN, S(O) p-R 6>, O-S(O) p-R 6>, (1-6C)-alkylen-S(O) p-R 6>, (1-6C)-alkylene-O-S(O) p-R 6>, COOH, COO(1-6C)alkyl, CONH 2, CONH(1-6C)alkyl, CON[(1-6C)alkyl] 2, (1-6C)-alkyl, (2-6C)-alkenyl, (2-6C)-alkynyl, O-(1-6C)-alkyl (where in the alkyl residue one, more or all H atoms are optionally replaced by F), phenyl, -(CH 2)-phenyl, -(CH 2) n-phenyl, O-phenyl, O-(CH 2) m-phenyl or -(CH 2)-O-(CH 2) m-phenyl (where the phenyl ring is 1-3 times optionally substituted by F, Cl, Br, I, OH, CF 3, NO 2, CN, OCF 3, O-(1-6C)-alkyl, (1-6C)-alkyl, NH 2, NH-(1-6C)alkyl, N((1-6C)-alkyl) 2, SO 2-CH 3, COOH, COO-(1-6C)-alkyl or CONH 2), where at least one of R 2>, R2a, R 3>, R3a, R 4>, R4a, R 5>, R5a contains O-(CH 2) m-phenyl or -(CH 2)-O-(CH 2) m-phenyl; R 6>H, OH, (1-6C)-alkyl, NH 2, NH(1-6C)-alkyl, N((1-6C)-alkyl) 2; n : 2-6; m : 1-6; and p : 0-2. Independent claims are included for intermediate compounds comprising (R)-2-ethyl-2-hydroxymethyl-hexanoic acid (II), (R)-(6-methoxy-quinolin-4-yl)-(5-vinyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methanol (IIa), (R)-2-ethyl-2-hydroxymethyl-hexanoic acid (III), (S)-2-acetylsulfanylmethyl-2-ethyl-hexanoic acid (IV), (S)-2-ethyl-2-mercaptomethyl-hexan-1-ol (V) with [3-(2,5-difluorobenzoyl)phenyl]azinic acid (VIII), [2-((S)-2-ethyl-2-hydroxymethyl-hexylsulfanyl)-5-fluoro-phenyl]-(3-nitro-phenyl)-methanone (X), (S)-2-ethyl-2-[4-fluoro-2-(3-nitro-benzyl)-phenylsulfanylmethyl]-hexan-1-ol (XI), (S)-2-ethyl-2-[4-fluoro-2-(3-nitro-benzyl)-benzenesulfonylmethyl]-hexan-1-ol (XII), (S)-3-ethyl-3-[4-fluoro-2-(3-nitro-benzyl)-benzenesulfonylmethyl]-heptanal (XIII), (S)-3-butyl-3-ethyl-7-fluoro-5-(3-nitro-phenyl)-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-4-ol (XV), (3S,4R,5R)-5-(3-amino-phenyl) -3-butyl-3-ethyl-7-fluoro-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-4-ol (XVI) and (S)-5-(3-amino-phenyl)-3-butyl-7-dimethylamino-3-ethyl-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-4-ol (XVII). [Image] [Image].