Sodium Carbonate → HCID 71506861, compound

HRID 1915845Notes

Reaction equation

HRID 1915845 reaction equation
Br[C:2]1[S:3][C:4]([NH:34]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:33])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:29][CH:30]([F:32])[F:31])[C:13]=2[N:14]2[CH2:20][CH2:19][CH2:18][C@@H:17]([N:21]([CH3:28])C(=O)C(F)(F)F)[CH2:16][CH2:15]2)[N:6]=1.C([O-])([O-])=O.[Na+].[Na+].[F:48][C:49]1[CH:54]=[CH:53][C:52]([F:55])=[CH:51][C:50]=1B(O)O>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:34][C:4]1[S:3][C:2]([C:53]2[CH:54]=[C:49]([F:48])[CH:50]=[CH:51][C:52]=2[F:55])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH2:29][CH:30]([F:32])[F:31])[C:13]=1[N:14]1[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][CH3:28])[CH2:16][CH2:15]1)=[O:33]

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 2734335(2,5-Difluorophenyl)boronic acidHCID 86679966HCID 86679966, compound

Product 1

HCID 71506861HCID 71506861, compound

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of (R)-tert-butyl 2-bromo-4-(1-(2,2-difluoroethyl)-5-(4-(2,2,2-trifluoro-N-methylacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (200 mg, 0.29 mmol), Na2CO3 (62 mg, 0.59 mmol) and 2,5-difluorobenzeneboronic acid (66 mg, 0.41 mmol) in DME (3 mL) and water (1 mL) was degassed by gently bubbling nitrogen through the mixture for 5 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (30 mg, 0.037 mmol) was then added and the mixture heated in a microwave at 120° C. for 60 min. The solvents were removed under reduced pressure and the residue dissolved in a solution of HCl in 1,4-dioxane (4 M, 5 mL) and MeOH (5 mL) and stirred at 70° C. for 48 hr. The solvent was removed under reduced pressure and the residue dissolved in MeOH/DCM and passed through an SCX cartridge washing with DCM and MeOH and eluting with 1 N ammonia in MeOH. The solvent was removed under reduced pressure and the residue purified by preparative HPLC to yield 108 as the mono formate salt as a pale brown solid (21 mg, 14% over two steps). 1H NMR (400 MHz, d4-MeOD) δ 8.53 (s, 1H), 8.15-7.95 (m, 1H), 7.58 (s, 1H), 7.35-7.05 (m, 2H), 6.25 (tt, J=55.6, 4.1 Hz, 1H), 4.54-4.43 (m, 2H), 3.43-3.22 (m, 5H), 2.68 (s, 3H), 2.28-1.74 (m, 6H). LCMS (ES+) m/z 512 (M+1).

Workup

  1. additionwas then added
  2. customThe solvents were removed under reduced pressure
  3. dissolutionthe residue dissolved in a solution of HCl in 1,4-dioxane (4 M, 5 mL) and MeOH (5 mL)
  4. customThe solvent was removed under reduced pressure
  5. dissolutionthe residue dissolved in MeOH/DCM
  6. washwashing with DCM and MeOH
  7. washeluting with 1 N ammonia in MeOH
  8. customThe solvent was removed under reduced pressure
  9. customthe residue purified by preparative HPLC

Sources & evidence

ORD record
ord-c783fdd55ede42d19c01d8f0fd3e0a95
Source dataset
uspto-grants-2013_12
Patent number
US08614206B2

Reaction notes

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