3-Fluoro-4-sulfamoylbenzoic acid → 4-fluoro-2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzenesulfonamide

HRID 1992128Notes

Reaction equation

[NH2:1][S:2]([C:5]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:4])=[O:3].NS(C1C=CC(C(O)=O)=CC=1F)(=O)=O.Cl.Cl.[CH3:31][C:32]1[N:36]([CH:37]2[CH2:43][CH:42]3[N:44]([CH2:45][CH2:46][C:47]4([C:53]5[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=5)[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]4)[CH:39]([CH2:40][CH2:41]3)[CH2:38]2)[C:35]2[CH:59]=[CH:60][CH:61]=[CH:62][C:34]=2[N:33]=1.CC1N(C2CC3N(CCC4(C5C=CC=CC=5)CCN(C(C5C=CC=CC=5S(NC(=O)OC(C)(C)C)(=O)=O)=O)CC4)C(CC3)C2)C2C=CC=CC=2N=1>>[F:14][C:11]1[CH:12]=[CH:13][C:5]([S:2]([NH2:1])(=[O:3])=[O:4])=[C:6]([C:7]([N:50]2[CH2:49][CH2:48][C:47]([CH2:46][CH2:45][N:44]3[CH:39]4[CH2:40][CH2:41][CH:42]3[CH2:43][CH:37]([N:36]3[C:35]5[CH:59]=[CH:60][CH:61]=[CH:62][C:34]=5[N:33]=[C:32]3[CH3:31])[CH2:38]4)([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:52][CH2:51]2)=[O:9])[CH:10]=1

Participants

Reactant 4

HCID 112529583-Fluoro-4-sulfamoylbenzoic acid

HCID 58728709tert-butyl {2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl piperidin-1-yl)carbonyl]phenyl}sulfonylcarbamate

HCID 686757782-methyl-1-{8-[2-(4-phenyl piperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride

HCID 686771355-Fluoro-2-sulfamoylbenzoic acid

Product 1

HCID 587285764-fluoro-2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzenesulfonamideYield 20%

Procedure

The title compound was prepared from a mixture of 2-(aminosulfonyl)-5-fluorobenzoic acid and 4-(aminosulfonyl)-3-fluorobenzoic acid 6b and endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-aza bicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydro-chloride II following the general procedure for tert-butyl {2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]phenyl}sulfonylcarbamate 1c. The desired regioisomer was purified by column chromatography on silica gel eluting with 20% methanol in ethyl acetate to afford 4-fluoro-2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzenesulfonamide 6 as a white solid (9.8 mg, 20% yield). 1H NMR (400 MHz, CDCl3) δ 7.90 (t, 1H. J=7.7 Hz), 7.64 (m, 1H), 7.39 (m, 2H), 7.30-7.12 (m, 8H), 5.69 (broad s, 2H), 4.59 (m, 1H), 4.20 (m, 1H), 3.48-3.19 (m, 5H), 2.52 (s, 3H), 2.40-2.32 (m, 3H), 2.18 (m, 1H), 2.04-1.70 (m, 10H), 1.62 (m, 2H). ES-LCMS m/z 630.19 (M+H). Analytical HPLC (Method Y) Rt 4.16 (90.0%).

Workup

customThe desired regioisomer was purified by column chromatography on silica gel eluting with 20% methanol in ethyl acetate

Sources & evidence

ORD record: ord-d46571b3cc7e48d2be93df471acc7d51
Source dataset: uspto-grants-2010_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07645771B2

Reaction notes

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