Sodium Bicarbonate → HCID 178461456, compound

HRID 625653Notes

Reaction equation

HRID 625653 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[NH:16][C:15]([C@@H:17]3[CH2:21][C@H:20]([CH3:22])[CH2:19][N:18]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[N:14][C:13]=1[Cl:30])[CH:6]=[CH:5]2.[CH3:31][C@@H:32]1[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:34]([C:44]2[NH:45][C:46]([C:49]3[CH:54]=[CH:53][C:52](B4OC(C)(C)C(C)(C)O4)=[CH:51][CH:50]=3)=[CH:47][N:48]=2)[CH2:33]1.C([O-])(O)=O.[Na+]>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:40]([O:39][C:37]([N:35]1[CH2:36][C@@H:32]([CH3:31])[CH2:33][C@H:34]1[C:44]1[NH:45][C:46]([C:49]2[CH:50]=[CH:51][C:52]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[CH:8]=[C:7]([C:12]3[NH:16][C:15]([C@@H:17]5[CH2:21][C@H:20]([CH3:22])[CH2:19][N:18]5[C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[N:14][C:13]=3[Cl:30])[CH:6]=[CH:5]4)=[CH:53][CH:54]=2)=[CH:47][N:48]=1)=[O:38])([CH3:41])([CH3:42])[CH3:43]

Participants

5

Reactant 3

HCID 516892Sodium BicarbonateHCID 58501718HCID 58501718, compoundHCID 178461458HCID 178461458, compound

Product 1

HCID 178461456HCID 178461456, compoundYield 78.1%

Reagents, catalysts & solvents 1

HCID 178418397HCID 178418397, compoundCatalyst

Conditions

Temperature
85 °C

Procedure

Pd(Ph3P)4 (27.1 mg, 0.023 mmol) was added to a nitrogen purged suspension of (2S,4S)-tert-butyl 2-(5-(6-bromonaphthalen-2-yl)-4-chloro-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate, (230 mg, 0.469 mmol), (2S,4S)-tert-butyl 4-methyl-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (234 mg, 0.515 mmol) and NaHCO3 (197 mg, 2.34 mmol) in an argon-degassed solution of DME (4 mL) and water (1 mL). The pressure vessel was charged with argon, sealed, and immersed into a pre-heated oil bath (85° C.) and stirred for 14 h. The mixture was diluted with EtOAc (Note: THF and MeOH were added to aid dissolution) and washed with sat′d NaHCO3 soln, brine, dried (Na2SO4), filtered and concentrated. The residue was purified utilizing a Thompson 90 g SiO2 column (Gradient elution 5% to 100% B for 2 L and hold for 0.5 L Solvent B=ethyl acetate and Solvent A=hexanes) to yield (2S,4S)-tert-butyl 2-(5-(6-(4-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-4-chloro-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (270 mg, 70%) as a foam. For the purpose of characterization approx. 20 mg was dissolved in MeOH (up to 2 mL) and subject to prep HPLC vial (0 to 100% B over a 30 min gradient at 40 ml/min) using a PHENOMENEX® Luna column (30×100 mm, S10) where B=95% CH3CN-5% H2O-10 mM NH4OAc and A=5% CH3CN-95% H2O-10 mM NH4OAc. LC-MS retention time 3.90 min; calcd. for C42H50ClN6O4: 737.36 m/z. found 737.43 [M+H]. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min and an analysis time of 5 min where Solvent A was 5% methanol/95% water/0.1% TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 8.21 (s, 1H), 8.16 (s, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.99 (d, J=8.6 Hz, 2H), 7.91-7.81 (m, 6H), 7.42 (s, 1H), 4.86 (under MeOH, 1H), 4.80-4.877 (m, 1H), 3.82-3.77 (m, 2H), 3.20 (t, J=10.4 Hz, 2H), 2.52-2.47 (m, 2H), 2.37-2.34 (m, 2H), 1.83-1.73 (m, 2H), 1.46/1.26/1.23 (s, 18H), 1.16 (m, 6H).

Workup

  1. custompurged
  2. customdegassed solution of DME (4 mL) and water (1 mL)
  3. additionThe pressure vessel was charged with argon
  4. customsealed
  5. customimmersed into a pre-heated oil bath
  6. additionThe mixture was diluted with EtOAc (Note: THF and MeOH were added to aid dissolution)
  7. washwashed with sat′d NaHCO3 soln
  8. dry with materialbrine, dried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe residue was purified
  12. washa Thompson 90 g SiO2 column (Gradient elution 5% to 100% B for 2 L and hold for 0.5 L Solvent B=ethyl acetate and Solvent A=hexanes)

Sources & evidence

ORD record
ord-c4c7212d349a490f818472b0780fcecb
Source dataset
uspto-grants-2016_04
Patent number
US09303007B2

Reaction notes

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