Sodium Carbonate → (E)-tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2-cyclohexylvinyl)thiazol-5-ylcarbamate

HRID 1185354Notes

Reaction equation

[CH2:1]([O:5][C:6]([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:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:24])[CH2:12][CH2:11]1)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[Na+].[Na+].[CH:45]1(/[CH:51]=[CH:52]/B(O)O)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]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]>[CH2:1]([O:5][C:6]([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](/[CH:52]=[CH:51]/[CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)[S:28][C:29]=2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:24])[CH2:12][CH2:11]1)=[O:7])[CH2:2][CH2:3][CH3:4]

Participants

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 (0.203 g, 0.33 mmol), Na2CO3 (70 mg, 0.66 mmol) and trans-(2-cyclohexylvinyl)boronic acid (0.102 g, 0.66 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) (27 mg, 0.033 mmol) was then added and the mixture degassed for a further 10 min before being heated in a microwave at 130° C. for 45 min. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were passed through a phase separator cartridge and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane) to afford (E)-tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2-cyclohexylvinyl)thiazol-5-ylcarbamate as a brown gum (0.144 g, 68%). A solution of this gum (0.142 g, 0.22 mmol) in MeOH (5 mL) and acetic acid (0.5 mL) was passed through the H-Cube® (70 bar, 70° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford crude tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2-cyclohexylethyl)thiazol-5-ylcarbamate as a clear gum (0.122 g, 99%). This gum (0.122 g, 0.188 mmol) was stirred in HCl in 1,4-dioxane (4.0 M, 2 mL) at room temperature for 18 hr. The solvents were removed under reduced pressure and the crude residue was re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and 7 N ammonia in MeOH to yield 281 as a pink solid (39 mg, 63%). 1H NMR (400 MHz, d4-MeOD) δ 7.43 (s, 1H), 3.71 (s, 3H), 3.21-3.06 (m, 4H), 2.86 (t, J=7.8 Hz, 2H), 2.62 (d, J=6.6 Hz, 2H), 1.87-1.59 (m, 9H), 1.58-1.45 (m, 1H), 1.43-1.15 (m, 6H), 0.99 (q, J=11.9 Hz, 2H). LCMS (ES+) m/z 446 (M+1)

Workup

additionwas then added
customthe mixture degassed for a further 10 min
additionThe reaction mixture was diluted with water
extractionextracted with EtOAc
concentrationconcentrated under reduced pressure
customThe residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane)

Sources & evidence

ORD record: ord-74a8529476c14997b0ec5cfab80ed57f
Source dataset: uspto-grants-2014_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08669361B2

Reaction notes

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