Hydrochloric Acid → tert-Butyl 3-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate

HRID 592370Notes

Reaction equation

C[O:2][C:3]([C:5]1([C:8]2[CH:43]=[CH:42][CH:41]=[CH:40][C:9]=2[CH2:10][CH2:11][C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]4)=[CH:25][CH:24]=3)[N:13]=2)[CH2:7][CH2:6]1)=O.O[Li].O.Cl.C1C=CC2N(O)N=[N:54]C=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CO.O.CCOC(C)=O>[C:3]([C:5]1([C:8]2[CH:43]=[CH:42][CH:41]=[CH:40][C:9]=2[CH2:10][CH2:11][C:12]2[C:17]([C:18]([F:21])([F:19])[F:20])=[CH:16][N:15]=[C:14]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:30][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH2:32]4)=[CH:25][CH:24]=3)[N:13]=2)[CH2:6][CH2:7]1)(=[O:2])[NH2:54]

Participants

Conditions

Temperature: 35 °C

Procedure

A solution of tert-butyl 3-(4-((4-(2-(1-(methoxycarbonyl)cyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate (A8) (347 mg, 0.582 mmol) and LiOH.H2O (293 mg, 6.98 mmol) in THF (7.0 mL), MeOH (7.0 mL) and H2O (2.0 mL) was stirred at room temperature for 3 days. LiOH.H2O (147 mg, 3.49 mmol) was added and the resulting mixture was heated at 35° C. for 16 hours. EtOAc (50 mL) and aqueous HCl (2 M, 50 mL) were added cautiously, then the layers were separated and the aqueous phase was extracted with EtOAc (2×50 mL). The organic layers were combined, washed with brine, dried (MgSO4) then evaporated to dryness. The residue was dissolved in THF (12 mL) and DMF (2.0 mL), to which HOBt (157 mg, 1.16 mmol), EDCl.HCl (223 mg, 1.16 mmol) and DIPEA (0.507 mL, 2.91 mmol) were added under an atmosphere of nitrogen. After 10 minutes ammonium carbonate (280 mg, 2.91 mmol) was added in one portion and the resulting mixture was stirred at room temperature for 16 hours, then 40° C. for a further 24 hours. The volatiles were removed in vacuo and EtOAc (20 mL) and saturated NaHCO3 (20 mL) were added. The layers were separated then the aqueous phase extracted with EtOAc (2×20 mL). The organic extracts were combined, washed with brine, dried (MgSO4) then evaporated to dryness. The residue was purified by silica gel column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 10-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound A9 as a white solid (179 mg, 53%); 1H NMR (400 MHz, d6-DMSO) δ 10.22 (s, 1H), 8.69 (s, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.37-7.27 (m, 5H), 7.26-7.19 (m, 1H), 6.98 (s, 1H), 5.99 (s, 1H), 4.23 (t, J=7.7 Hz, 2H), 3.88-3.70 (m, 3H), 3.21-3.14 (m, 2H), 3.14-3.07 (m, 2H), 1.44 (d, J=3.5 Hz, 2H), 1.40 (s, 9H), 0.97 (s, 2H). LCMS-A: rt 6.168 min; m/z 582 [M+H]+.

Workup

customthe layers were separated
extractionthe aqueous phase was extracted with EtOAc (2×50 mL)
washwashed with brine
dry with materialdried (MgSO4)
customthen evaporated to dryness
dissolutionThe residue was dissolved in THF (12 mL)
wait40° C. for a further 24 hours
customThe volatiles were removed in vacuo and EtOAc (20 mL) and saturated NaHCO3 (20 mL)
additionwere added
customThe layers were separated
extractionthe aqueous phase extracted with EtOAc (2×20 mL)
washwashed with brine
dry with materialdried (MgSO4)
customthen evaporated to dryness
customThe residue was purified by silica gel column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 10-50% EtOAc in petroleum benzine 40-60° C.)

Sources & evidence

ORD record: ord-27a6a9c2e6364beab778a7a00f4b5dcb
Source dataset: uspto-grants-2016_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09238644B2

Reaction notes

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