Sodium Carbonate → HCID 135965689, compound

HRID 1185351Notes

Reaction equation

HRID 1185351 reaction equation
C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.C([O-])([O-])=O.[Na+].[Na+].[OH:45][C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[C:48]([C:55]([F:58])([F:57])[F:56])[CH:47]=1>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]>[NH2:30][C:29]1[S:28][C:27]([C:49]2[CH:50]=[CH:51][C:46]([OH:45])=[CH:47][C:48]=2[C:55]([F:56])([F:57])[F:58])=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 44754759[4-Hydroxy-2-(trifluoromethyl)phenyl]boronic acidHCID 58464898tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate

Product 1

HCID 135965689HCID 135965689, compoundYield 48.4%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
130 °C

Procedure

A mixture of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate (0.123 g, 0.20 mmol), Na2CO3 (42 mg, 0.40 mmol) and 4-hydroxy-2-(trifluoromethyl)benzeneboronic acid (66 mg, 0.32 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, 0.02 mmol) was then added and the mixture degassed for a further 10 min before being heated in a microwave at 130° C. for 40 min. The solvents were removed under reduced pressure and the residue purified via silica gel column chromatography (0-100% EtOAc/isohexane). The isolated intermediate was dissolved in a solution of HCl in 1,4-dioxane (4 M, 2 mL) and stirred at room temperature for 16 hr. The solvent was removed under reduced pressure and the residue purified by preparative HPLC to yield 278 as a pale brown solid (48 mg, 48%). 1H NMR (400 MHz, d4-MeOD) δ 7.59 (s, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.15 (d, J=2.5 Hz, 1H), 6.98 (dd, J=8.5, 2.5 Hz, 1H), 3.72 (s, 3H), 3.22-3.10 (m, 4H), 2.71 (d, J=6.8 Hz, 2H), 1.85 (d, J=12.6 Hz, 2H), 1.66-1.55 (m, 1H), 1.47-1.33 (m, 2H). LCMS (ES+) m/z 496 (M+1).

Workup

  1. additionwas then added
  2. customthe mixture degassed for a further 10 min
  3. customThe solvents were removed under reduced pressure
  4. customthe residue purified via silica gel column chromatography (0-100% EtOAc/isohexane)
  5. dissolutionThe isolated intermediate was dissolved in a solution of HCl in 1,4-dioxane (4 M, 2 mL)
  6. customThe solvent was removed under reduced pressure
  7. customthe residue purified by preparative HPLC

Sources & evidence

ORD record
ord-b5cff87f758044018e07a51d28b54500
Source dataset
uspto-grants-2014_03
Patent number
US08669361B2

Reaction notes

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