Cesium carbonate → US9656988, Example 252

HRID 1050577Notes

Reaction equation

HRID 1050577 reaction equation
Cl[C:2]1[C:3]([C:22]#[N:23])=[N:4][CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]3[CH2:18][CH2:17][N:16]([CH3:19])[C:15]3=[O:20])[C@H:9]2[CH3:21])[N:7]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2([CH3:44])[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)=[CH:27][CH:26]=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:22]([C:3]1[C:2]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3([CH3:44])[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]3)=[CH:27][CH:26]=2)=[N:7][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]3[CH2:18][CH2:17][N:16]([CH3:19])[C:15]3=[O:20])[C@H:9]2[CH3:21])=[CH:5][N:4]=1)#[N:23]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 118115227Tert-butyl 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylateHCID 1181334303-chloro-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile

Product 1

HCID 118133432US9656988, Example 252

Reagents, catalysts & solvents 2

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

Conditions

Temperature
115 °C

Procedure

The mixture of 3-chloro-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile (357) (100 mg, 0.60 mmol), tert-butyl 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate (287) (175 mg, 0.60 mmol), fine-powder cesium carbonate (590 mg, 1.80 mmol), Pd(OAc)2 (45 mg, 0.2 mmol), BINAP (125 mg, 0.2 mmol) in 30 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 70 min. The mixture was cooled to RT, diluted with 120 mL EtOAc, and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 4% MeOH in chloroform to isolate tert-butyl 4-(4-(3-cyano-6-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-ylamino)phenyl)-4-methylpiperidine-1-carboxylate (358). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were added fine-powder Cs2CO3 (50 mg) and then 1 mL 30% H2O2. The mixture was stirred at RT for 30 min, diluted with 10 mL MeCN, stirred for 5 min, and concentrated on rotavap. The residue was diluted with 150 mL EtOAc, washed with water ×3, dried, concentrated in vacuo, and subjected to silica flash column using 0 to 4% MeOH in DCM to isolate tert-butyl 4-(4-(3-carbamoyl-6-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-ylamino)phenyl)-4-methylpiperidine-1-carboxylate (359). It was treated with 2:1 DCM/TFA (12 mL/6 mL) at RT for 30 min. The mixture was concentrated in vacuo. One third of the residue was dissolved in MeOH/water and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate 5-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(4-(4-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (360) as HCl salt (65 mg). LC-MS (ESI): m/z (M+1) 507.8. UV: λ=268, 277, 306, 336, 372 nm. Proton NMR (CD3OD): δ 7.68 (2H, d, J=9.0 Hz), 7.62 (1H, s), 7.35 (2H, d, J=8.5 Hz), 5.11 (1H, m), 4.28 (1H, m), 3.89 (1H, m), 3.53 (2H, m), 3.38 (2H, m), 3.30 (2H, m), 3.06 (3H, m), 2.81 (3H, s), 2.42 (2H, m), 2.03 (1H, m), 1.95 (3H, m), 1.83 (1H, m), 1.68 (1H, m), 1.31 (3H, s), 1.21 (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 120 mL EtOAc
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated in vacuo

Sources & evidence

ORD record
ord-fc0e8def1d864f148e918095e22267ed
Source dataset
uspto-grants-2016_07
Patent number
US09382246B2

Reaction notes

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