Sodium Bicarbonate → N,N'-(4,4'-biphenyldiylbis(1H-imidazole-4,2-diyl(2S)-2,1-pyrrolidinediyl((2S)-3-methyl-1-oxo-1,2-butanediyl)))bis(1,3-thiazol-2-amine)

HRID 80400Notes

Reaction equation

[CH3:1][CH:2]([CH3:37])[C@H:3]([NH:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1)[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][CH:17]=2)=[CH:14][N:15]=1)=[O:5].Br[C:39]1[CH:44]=[CH:43][C:42]([C:45]2[NH:49][C:48]([C@@H:50]3[CH2:54][CH2:53][CH2:52][N:51]3[C:55](=[O:66])[C@@H:56]([NH:60][C:61]3[S:62][CH:63]=[CH:64][N:65]=3)[CH:57]([CH3:59])[CH3:58])=[N:47][CH:46]=2)=[CH:41][CH:40]=1.C([O-])(O)=O.[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]1([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[N:49]=[C:48]([C@@H:50]4[CH2:54][CH2:53][CH2:52][N:51]4[C:55](=[O:66])[C@@H:56]([NH:60][C:61]4[S:62][CH:63]=[CH:64][N:65]=4)[CH:57]([CH3:59])[CH3:58])[NH:47][CH:46]=3)=[CH:41][CH:40]=2)[CH:20]=[CH:21][C:16]([C:13]2[N:12]=[C:11]([C@@H:7]3[CH2:8][CH2:9][CH2:10][N:6]3[C:4](=[O:5])[C@@H:3]([NH:31][C:32]3[S:33][CH:34]=[CH:35][N:36]=3)[CH:2]([CH3:37])[CH3:1])[NH:15][CH:14]=2)=[CH:17][CH:18]=1

Participants

Conditions

Temperature: 80 °C

Procedure

A mixture of (S)-3-methyl-1-((S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-(thiazol-2-ylamino)butan-1-one (275 mg, 0.527 mmol), (S)-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-2-(thiazol-2-ylamino)butan-1-one (250 mg, 0.527 mmol), NaHCO3 (133 mg, 1.582 mmol) and Pd(Ph3P)4 (60.9 mg, 0.053 mmol) in DME (3 mL) and Water (1 mL) was degassed by passing a stream of N2 through the mixture. The vessel was sealed and the reaction was heated at 80° C. overnight. The reaction mixture was diluted with H2O and extracted with EtOAc containing ca. 5% MeOH (×3). The combined org layers were concentrated, dissolved in MeOH and loaded onto an MCX cartridge. The cartridge was washed with MeOH and then NH3 in MeOH (2M). The appropriate fractions were concentrated in vacuo and the residue was purified by prep HPLC (CH3CN—H2O—NH4OAc). The material was purified by column chromatography (biotage) eluting with 0 to 20% MeOH in EtOAc. Further purification by prep HPLC (CH3CN—H2O—NH4OAc) followed by lyophilization afforded the title compound as a colorless solid (6.9 mg, 2%). 1HNMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 11.75 (s, 2H), 7.75-7.80 (m, 4H), 7.68-7.71 (m, 4H), 7.49 (s, 2H), 6.99 (d, J=3.7 Hz, 2H), 6.57 (d, J=3.7 Hz, 2H), 5.34-5.36 (m, 1H), 5.07 (app dd, J=3.7, 7.0 Hz, 2H), 4.42 (t, J=8.4 Hz, 2H), 3.98-4.05 (m, 2H), 3.79-3.85 (m, 2H), 3.44-3.56 (m, 1H), 1.97-2.21 (m, 8H), 1.01 and 0.95 (d, J=7.0 Hz, 6H, rotamers, 1:3 ratio), 0.99 and 0.92 (d, J=7.0 Hz, 6H, rotamers, 1:3 ratio). LCMS: Anal. Calcd. for C42H48N10O2S2: 788; found: 789 (M+H)+.

Workup

customwas degassed
customThe vessel was sealed
additionThe reaction mixture was diluted with H2O
extractionextracted with EtOAc containing ca. 5% MeOH (×3)
concentrationThe combined org layers were concentrated
dissolutiondissolved in MeOH
washThe cartridge was washed with MeOH
concentrationThe appropriate fractions were concentrated in vacuo
customthe residue was purified by prep HPLC (CH3CN—H2O—NH4OAc)
customThe material was purified by column chromatography (biotage)
washeluting with 0 to 20% MeOH in EtOAc
customFurther purification by prep HPLC (CH3CN—H2O—NH4OAc)

Sources & evidence

ORD record: ord-1f8d93354793482cb4e2fc73bdfb4242
Source dataset: uspto-grants-2014_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08846023B2

Reaction notes

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