Sodium Bicarbonate → HCID 71549378, compound

HRID 709354Notes

Reaction equation

HRID 709354 reaction equation
[F:1][C:2]1([F:38])[CH2:6][N:5]([C:7](=[O:17])[C@@H:8]([NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:9]([CH3:11])[CH3:10])[C@H:4]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:3]1.Br[C:40]1[CH:45]=[CH:44][C:43]([C:46]2[NH:50][C:49]([C@H:51]3[N:56]4[C:57](=[O:68])[C@@H:58]([NH:63][C:64](=[O:67])[O:65][CH3:66])[CH2:59][CH2:60][C:61](=[O:62])[N:55]4[CH2:54][CH2:53][CH2:52]3)=[N:48][CH:47]=2)=[CH:42][CH:41]=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>[CH3:66][O:65][C:64](=[O:67])[NH:63][C@H:58]1[CH2:59][CH2:60][C:61](=[O:62])[N:55]2[CH2:54][CH2:53][CH2:52][C@@H:51]([C:49]3[NH:50][C:46]([C:43]4[CH:42]=[CH:41][C:40]([C:26]5[CH:25]=[CH:24][C:23]([C:20]6[NH:19][C:18]([C@@H:4]7[CH2:3][C:2]([F:1])([F:38])[CH2:6][N:5]7[C:7](=[O:17])[C@@H:8]([NH:12][C:13]([O:14][CH3:15])=[O:16])[CH:9]([CH3:11])[CH3:10])=[N:22][CH:21]=6)=[CH:28][CH:27]=5)=[CH:45][CH:44]=4)=[CH:47][N:48]=3)[N:56]2[C:57]1=[O:68]

Participants

6

Reactant 3

HCID 516892Sodium BicarbonateHCID 68214975HCID 68214975, compoundHCID 89510258HCID 89510258, compound

Product 1

HCID 71549378HCID 71549378, compoundYield 33.2%

Reagents, catalysts & solvents 2

HCID 178477754HCID 178477754, compoundCatalystHCID 6386tert-ButanolSolvent

Conditions

Temperature
90 °C

Procedure

In a 10 mL seal tube, methyl (S)-1-((S)-4,4-difluoro-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (52 mg, 97.7 μmol), methyl (4S,7S)-4-(5-(4-bromophenyl)-1H-imidazol-2-yl)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-ylcarbamate (46.5 mg, 97.7 μmol) and sodium bicarbonate (sat. solution, 400 μl, excess) were combined with tert-butanol (2.00 ml) to give a light brown suspension and degassed for 5 min. PdCl2(DPPF) (7.15 mg, 9.77 μmol) was added and flushed with nitrogen. It was sealed heating at 90° C. for 4 hr, diluted with EtOAc (10 ml), filtered and concentrated in vacuo. The crude mixture was purified on a silica gel column (CH2Cl2, 2%, 3%, 5%, 8% MeOH/CH2Cl2) to afford {(4S,7S)-4-[5-(4′-{2-[(S)-4,4-Difluoro-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 methyl ester as a light yellow solid (26 mg, 31.5%). ESI-LRMS m/e calcd for C40H45F2N9O7, [M+] 801. found 802 [M+H]. 1H NMR (DMSO-d6) δ: 12.23 (br. s., 1H), 11.98 (br. s., 1H), 7.72-7.84 (m, 4H), 7.62-7.72 (m, 5H), 7.57 (d, J=1.8 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H), 5.81 (br. s., 1H), 5.30 (t, J=7.5 Hz, 1H), 4.39-4.55 (m, 3H), 3.94 (t, J=8.2 Hz, 1H), 3.56 (s, 4H), 3.55 (br. s., 3H), 2.84-2.95 (m, 1H), 2.18-2.35 (m, 3H), 2.12 (dd, J=13.1, 6.5 Hz, 1H), 1.86-2.03 (m, 4H), 1.64 (d, J=13.3 Hz, 1H), 1.09-1.26 (m, 1H), 0.92 (d, J=6.5 Hz, 1H), 0.85 (d, J=6.5 Hz, 6H).

Workup

  1. customIn a 10 mL seal tube
  2. customto give a light brown suspension
  3. customdegassed for 5 min
  4. customflushed with nitrogen
  5. customIt was sealed
  6. additiondiluted with EtOAc (10 ml)
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude mixture was purified on a silica gel column (CH2Cl2, 2%, 3%, 5%, 8% MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-1fe87ae89e504a308a15876d1b48000e
Source dataset
uspto-grants-2015_11
Patent number
US09180193B2

Reaction notes

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