Sodium Bicarbonate → {(4S,7S)-4-[5-(4'-{2-[(S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl}-carbamic acid benzyl ester

HRID 709352Notes

Reaction equation

[CH3:1][CH:2]([CH3:36])[C@H:3]([NH:31][C:32](=[O:35])[O:33][CH3:34])[C:4](=[O:30])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1.Br[C:38]1[CH:43]=[CH:42][C:41]([C:44]2[NH:48][C:47]([C@H:49]3[N:54]4[C:55](=[O:72])[C@@H:56]([NH:61][C:62](=[O:71])[O:63][CH2:64][C:65]5[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=5)[CH2:57][CH2:58][C:59](=[O:60])[N:53]4[CH2:52][CH2:51][CH2:50]3)=[N:46][CH:45]=2)=[CH:40][CH:39]=1.C(=O)(O)[O-].[Na+]>C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].C(O)(C)(C)C>[CH2:64]([O:63][C:62](=[O:71])[NH:61][C@H:56]1[CH2:57][CH2:58][C:59](=[O:60])[N:53]2[CH2:52][CH2:51][CH2:50][C@@H:49]([C:47]3[NH:48][C:44]([C:41]4[CH:42]=[CH:43][C:38]([C:18]5[CH:17]=[CH:16][C:15]([C:12]6[NH:11][C:10]([C@@H:6]7[CH2:7][CH2:8][CH2:9][N:5]7[C:4](=[O:30])[C@@H:3]([NH:31][C:32]([O:33][CH3:34])=[O:35])[CH:2]([CH3:36])[CH3:1])=[N:14][CH:13]=6)=[CH:20][CH:19]=5)=[CH:39][CH:40]=4)=[CH:45][N:46]=3)[N:54]2[C:55]1=[O:72])[C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1

Participants

Conditions

Temperature: 90 °C

Procedure

In a 10 mL seal tube, methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (55 mg, 111 μmol) (Intermediate 1), benzyl (4S,7S)-4-(5-(4-bromophenyl)-1H-imidazol-2-yl)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-ylcarbamate (61.2 mg, 111 μmol) (Intermediate 6) and sodium bicarbonate (sat. solution, 600 μl, excess) were combined with tert-butanol (3.00 ml) to give a light brown suspension and degassed for 5 min. PdCl2(DPPF) (8.11 mg, 11.1 μmol) was added and flushed with nitrogen. It was sealed heating at 90° C. for 4 hr then diluted with EtOAc (10 ml), filtered and concentrated. The crude was purified on a silica gel column (CH2Cl2, 2%, 3%, 5%, 8% MeOH/CH2Cl2) to afford {(4S,7S)-4-[5-(4′-{2-[(S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl}-carbamic acid benzyl ester as a light yellow solid (30 mg, 30.6%). ESI-LRMS m/e calcd for C46H51N9O7, [M+] 841. found 842 [M+H]. 1H NMR (DMSO-d6) δ: 12.23 (br. s., 1H), 11.66-11.89 (m, 1H), 7.72-7.85 (m, 5H), 7.58-7.92 (m, 4H), 7.48-7.55 (m, 1H), 7.34-7.43 (m, 3H), 7.22-7.35 (m, 1H), 7.19-7.45 (m, 3H), 5.81 (br. s., 1H), 5.77-5.86 (m, 1H), 5.01-5.13 (m, 3H), 4.92-5.21 (m, 2H), 4.47 (d, J=11.5 Hz, 1H), 4.33-4.59 (m, 1H), 4.00-4.13 (m, 1H), 3.95-4.13 (m, 1H), 3.72-3.86 (m, 1H), 3.81 (br. s., 1H), 3.54 (s, 3H), 3.45-3.64 (m, 2H), 2.82-3.00 (m, 1H), 2.79-2.96 (m, 1H), 2.08-2.35 (m, 2H), 1.76-2.05 (m, 3H), 1.50-1.67 (m, 1H), 0.80-0.95 (m, 6H).

Workup

customIn a 10 mL seal tube
customto give a light brown suspension
customdegassed for 5 min
customflushed with nitrogen
customIt was sealed
additionthen diluted with EtOAc (10 ml)
filtrationfiltered
concentrationconcentrated
customThe crude was purified on a silica gel column (CH2Cl2, 2%, 3%, 5%, 8% MeOH/CH2Cl2)

Sources & evidence

ORD record: ord-dd58dd6ce2c74f72964380e2399ac31b
Source dataset: uspto-grants-2015_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09180193B2

Reaction notes

Loading…