Benzoic Acid → HCID 86304145, compound

HRID 1778187Notes

Reaction equation

Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17]C(C)(C)C)=O)[CH2:10]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[C:31]([C:37]([F:40])([F:39])[F:38])=[N:32][C:33]([NH2:36])=[N:34][CH:35]=2)O1.C(=O)([O-])[O-].[K+].[K+].O.Cl.O1CCOCC1.C(O)(=O)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(#N)C.CN(C=O)C.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].CO>[NH2:36][C:33]1[N:32]=[C:31]([C:37]([F:38])([F:39])[F:40])[C:30]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)=[O:17])[CH2:10]3)[CH:3]=2)=[CH:35][N:34]=1

Participants

Conditions

Temperature: 90 °C

Procedure

A solution of tert-butyl 3-(6-chloro-2-methyl-pyrimidin-4-yl)piperidine-1-carboxylate (40 mg, 0.13 mmol, 1.00 equiv), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine (40 mg, 0.14 mmol, 1.10 equiv) and [1,1′-BIS(DIPHENYLPHOSPHINO)FERROCENE]DICHLOROPALLADIUM(II) (10 mg, 0.013 mmol, 0.1 equiv) in Acetonitrile (1.0 mL) was mixed with 1M potassium carbonate solution in water (420 uL, 0.42 mmol, 3.2 equiv) and stirred at 90° C. for 2 hr. The reaction mixture was extracted with DCM (3 mL) and H2O (2 mL). The organic phase was removed, dried over sodium sulfate, and passed through a filter. The resulting organic phase was concentrated under vacuum. The crude product was mixed with methanol (1.0 mL) and 4M hydrogen chloride in dioxane (325 uL, 1.3 mmol, 10 equiv). The resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. A solution of crude product, benzoic acid (15 mg, 0.13 mmol, 1.0 equiv), HBTU (50 mg, 0.13 mmol, 1.0 equiv) and Triethylamine (90 uL, 0.65 mmol, 5.0 equiv) in DMF (1.0 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the crude product was purified by Prep-HPLC (Column, Sunfire C18 19×150; mobile phase, CH3CN:NH4CO3/H2O (10 mmol/L)=5%-85%, 10 min; Detector, UV 254 nm) to give 21.8 mg (38%) of [3-[6-[2-amino-4-(trifluoromethyl)pyrimidin-5-yl]-2-methyl-pyrimidin-4-yl]-1-piperidyl]-phenyl-methanone as an off white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.66 (s, 2H), 7.46-7.42 (m, 3H), 7.42-7.36 (m, 2H), 7.01 (s, 1H), 4.65-4.37 (m, 1H), 4.08 (q, J=5.3 Hz, 1H), 3.77-3.51 (m, 1H), 3.17 (d, J=5.3 Hz, 2H), 3.14-2.89 (m, 3H), 2.10-2.02 (m, 1H), 1.91-1.50 (m, 3H).

Workup

extractionThe reaction mixture was extracted with DCM (3 mL) and H2O (2 mL)
customThe organic phase was removed
dry with materialdried over sodium sulfate
concentrationThe resulting organic phase was concentrated under vacuum
stirringThe resulting solution was stirred at room temperature overnight
concentrationThe reaction mixture was concentrated under vacuum
concentrationThe reaction mixture was concentrated under vacuum
customthe crude product was purified by Prep-HPLC (Column, Sunfire C18 19×150; mobile phase, CH3CN:NH4CO3/H2O (10 mmol/L)=5%-85%, 10 min; Detector, UV 254 nm)

Sources & evidence

ORD record: ord-2cc032b2fa144d889f6e738d0be40ae0
Source dataset: uspto-grants-2016_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09266862B2

Reaction notes

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