Sodium Carbonate → (R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-dichlorophenyl)thiazole-4-carboxamide

HRID 2089437Notes

Reaction equation

HRID 2089437 reaction equation
Br[C:2]1[S:3][C:4]([NH:30]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:29])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:28])[C:13]=2[N:14]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21]C(=O)C(F)(F)F)[CH2:16][CH2:15]2)[N:6]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][C:46]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CO.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]>[NH2:30][C:4]1[S:3][C:2]([C:49]2[CH:50]=[C:45]([Cl:44])[CH:46]=[CH:47][C:48]=2[Cl:51])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:28])[C:13]=1[N:14]1[CH2:20][CH2:19][CH2:18][C@@H:17]([NH2:21])[CH2:16][CH2:15]1)=[O:29]

Participants

9

Reactant 4

HCID 10340Sodium CarbonateHCID 11430Potassium CarbonateHCID 27733712,5-Dichlorobenzeneboronic acidHCID 86658426(R)-tert-butyl 2-bromo-4-(1-methyl-5-(4-(2,2,2-trifluoroacetamido)-azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

Product 1

HCID 58464789(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-dichlorophenyl)thiazole-4-carboxamideYield 29%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolventHCID 22242641Methanol--water (1/1)Solvent

Conditions

Temperature
130 °C

Procedure

A mixture of (R)-tert-butyl 2-bromo-4-(1-methyl-5-(4-(2,2,2-trifluoroacetamido)-azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (122 mg, 0.20 mmol), Na2CO3 (42 mg, 0.40 mmol) and 2,5-dichlorobenzeneboronic acid (38 mg, 0.20 mmol) in DME (1.5 mL) and water (0.5 mL) was degassed by gently bubbling nitrogen through the mixture for 15 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (16 mg, 0.020 mmol) was added and the mixture degassed for a further 10 min before being heated in a microwave at 130° C. for 35 min. Water was added and the mixture extracted with EtOAc. The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane). The isolated intermediate was dissolved in a mixture of DCM (1.5 mL) and TFA (0.5 mL) and stirred at room temperature for 6 hr. The solvents were removed under reduced pressure and the residue dissolved in a mixture of MeOH/water (3 mL, 1:1) and K2CO3 (55 mg, 0.40 mmol) added. The mixture was heated at 60° C. for 3 hr. The mixture was concentrated under reduced pressure and the residue purified by preparative HPLC to yield 350 as a yellow solid (12 mg, 29%). 1H NMR (400 MHz, d4-MeOD) δ 8.35 (d, J=2.6 Hz, 1H), 7.56 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.39 (dd, J=8.6, 2.6 Hz, 1H), 3.76 (s, 3H), 3.35-3.31 (m, 4H), 3.11-3.09 (m, 1H), 2.04-1.91 (m, 3H), 1.76-1.67 (m, 3H). LCMS (ES+) m/z 480 (M+1).

Workup

  1. additionwas added
  2. customthe mixture degassed for a further 10 min
  3. additionWater was added
  4. extractionthe mixture extracted with EtOAc
  5. customThe combined organic layers were passed through a phase separation cartridge
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane)
  8. dissolutionThe isolated intermediate was dissolved in a mixture of DCM (1.5 mL) and TFA (0.5 mL)
  9. customThe solvents were removed under reduced pressure
  10. additionadded
  11. temperatureThe mixture was heated at 60° C. for 3 hr
  12. concentrationThe mixture was concentrated under reduced pressure
  13. customthe residue purified by preparative HPLC

Sources & evidence

ORD record
ord-891419474060435c9ad5551307f1e018
Source dataset
uspto-grants-2013_05
Patent number
US08436001B2

Reaction notes

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