Cesium carbonate → tert-butyl 4-(4-(3-cyano-6-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazin-2-ylamino)phenyl)-4-methylpiperidine-1-carboxylate

HRID 1050568Notes

Reaction equation

HRID 1050568 reaction equation
Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[C@H:9]2[CH3:20])[CH:5]=[N:4][C:3]=1[C:21]#[N:22].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2([CH3:43])[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:21]([C:3]1[C:2]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3([CH3:43])[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]3)=[CH:26][CH:25]=2)=[N:7][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]([N:16]([CH3:18])[CH3:17])=[O:19])[C@H:9]2[CH3:20])=[CH:5][N:4]=1)#[N:22]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 118115227Tert-butyl 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylateHCID 118115647US9656988, Example 237

Product 1

HCID 118114817tert-butyl 4-(4-(3-cyano-6-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazin-2-ylamino)phenyl)-4-methylpiperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
115 °C

Procedure

The mixture of 3-((2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea (326) (300 mg, 0.93 mmol), tert-butyl 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate (287) (325 mg, 1.12 mmol), fine-powder cesium carbonate (1300 mg, 4.00 mmol), Pd(OAc)2 (67 mg, 0.30 mmol), BINAP (190 mg, 0.30 mmol) in 45 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 3 hours. The mixture was cooled to RT, diluted with 150 mL EtOAc, and filtered using ChemGlass OP-6602-12 disposable funnel. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 5% MeOH in DCM to isolate tert-butyl 4-(4-(3-cyano-6-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazin-2-ylamino)phenyl)-4-methylpiperidine-1-carboxylate (337). It was dissolved in 20 mL MeOH and 4 mL DMSO. To it were added one NaOH solid bead (about 100 mg) and then 1 mL 30% H2O2. The mixture was stirred at RT for 1 hour, diluted with 10 mL MeCN, stirred for 5 min, and concentrated on rotavap. The residue was diluted with 150 mL EtOAc, washed with water (×2), dried, and subjected to silica flash column using 0 to 5% MeOH in DCM to isolate tert-butyl 4-(4-(3-carbamoyl-6-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazin-2-ylamino)phenyl)-4-methylpiperidine-1-carboxylate (338). It was treated with 2:1 DCM and TFA (10 mL/5 mL) at RT for 30 min and concentrated to dryness to give crude 5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)-3-(4-(4-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (339) as TFA salt. Half of this salt was dissolved in 10 mL 1,2-dichloroethane (DCE) and 2 mL NMP. To it were added DIEA (700 μL, 4.0 mmol) and cyclopentanone (1.06 mL, 12.0 mmol). The mixture was stirred at RT for 2 hours. To it were then added acetic acid (450 μL, 8.0 mmol) and then NaBH(OAc)3 (510 mg, 2.4 mmol). The mixture was stirred at RT for overnight, diluted with 20 mL MeOH, concentrated in vacuo, acidified with TFA (1 mL). and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate 3-(4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide (340) as HCl salt (142 mg, 54% overall yield for 4 steps). LC-MS (ESI): m/z (M+1) 564.0. UV: λ=268, 278, 306, 336, 372 nm. Proton NMR (CD3OD): δ 7.73-7.63 (3H, m), 7.34 (2H, m), 5.05 (1H, m), 4.33 (1H, m), 3.87 (1H, m), 3.64-3.50 (2H, m), 3.06 (1H, m), 2.96 (6H, s), 2.89-2.63 (3H, m), 2.23-2.09 (4H, m), 2.01-1.91 (4H, m), 1.89-1.62 (8H, m), 1.41-1.27 (3H, s), 1.17 (3H, d, J=7.0 Hz) ppm.

Workup

  1. customwas degassed with nitrogen stream for 3 min
  2. temperatureThe mixture was cooled to RT
  3. additiondiluted with 150 mL EtOAc
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated in vacuo

Sources & evidence

ORD record
ord-51a80044e4114d1aa8122f10ae7c6b54
Source dataset
uspto-grants-2016_07
Patent number
US09382246B2

Reaction notes

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