Cesium carbonate → HCID 118114582, compound

HRID 1050604Notes

Reaction equation

HRID 1050604 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]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]([CH:23]=[CH:24][N:25]=4)[CH:22]=3)=[O:16])[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:26]#[N:27].[O:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH2:30][CH2:29]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.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:26]([C:3]1[N:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]([CH:23]=[CH:24][N:25]=4)[CH:22]=3)=[O:16])[CH2:9]2)=[N:7][C:2]=1[NH:38][C:37]1[CH:39]=[CH:40][C:34]([CH:31]2[CH2:30][CH2:29][O:28][CH2:33][CH2:32]2)=[CH:35][CH:36]=1)#[N:27]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 203654724-(Oxan-4-yl)anilineHCID 118115159HCID 118115159, compound

Product 1

HCID 118114582HCID 118114582, compound

Reagents, catalysts & solvents 2

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

Conditions

Temperature
115 °C

Procedure

(R)-5-(3-Aminopiperidin-1-yl)-3-chloropyrazine-2-carbonitrile (221, HCl salt, 350 mg, 1.28 mmol) was dissolved in 10 mL DMF. To it were added imidazo[1,2-a]pyridine-6-carboxylic acid (310 mg, 1.92 mmol), DIEA (890 μL, 5.12 mmol) and then PyBOP (1.00 g, 1.92 mmol). The mixture was stirred at RT for 1 hour, diluted with 100 mL EtOAc, washed with water ×3, dried, concentrated, and subjected to silica flash column using 0 to 7% MeOH in DCM to isolate (R)—N-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide (473). Compound 473 (75 mg, 0.20 mmol) was mixed with 4-(tetrahydro-2H-pyran-4-yl)aniline (106 mg, 0.60 mmol), fine-powder cesium carbonate (326 mg, 1.00 mmol), palladium acetate (22 mg, 0.10 mmol), BINAP (62 mg, 0.10 mmol) in 15 mL dioxane. The mixture was degassed using nitrogen stream for 3 min, and stirred in nitrogen atmosphere at 115° C. for 1 hour. It was cooled to RT, diluted with 50 mL EtOAc, stirred and filtered. The filtrate was concentrated and subjected to silica flash column using 0 to 11% MeOH in DCM to isolate (R)—N-(1-(5-cyano-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide (474). It was dissolved in 10 mL MeOH and 3 mL DMSO. To it were added one NaOH solid bead (about 100 mg) and 1 mL 30% H2O2. The mixture was stirred at RT for 1.5 hour, quenched with 5 mL MeCN, stirred, concentrated, acidified with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate the title compound, (R)—N—O-(5-carbamoyl-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide (475) (24 mg) as HCl salt, and also the by-product, (R)—N—O-(5-carbamoyl-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-yl)-5-hydroxyimidazo[1,2-a]pyridine-6-carboxamide (476) (15 mg) as HCl salt. For compound 475, LC-MS (ESI): m/z (M+1) 541.3. UV: λ=304, 336, 373 nm. Proton NMR (CD3OD): δ 9.26 (1H, s), 8.30 (2H, m), 8.14 (1H, d, J=2.0 Hz), 7.99 (1H, d, J=9.5 Hz), 7.66 (1H, s), 7.51 (2H, d, J=9.0 Hz), 7.11 (2H, d, J=9.0 Hz), 4.41 (1H, m), 4.21 (1H, m), 4.10 (1H, m), 3.92 (2H, m), 3.44 (4H, m), 2.66 (1H, m), 2.16 (1H, m), 1.97 (1H, m), 1.84 (1H, m), 1.76 (1H, m), 1.62 (3H, m), 1.56 (1H, m) ppm.

Workup

  1. customThe mixture was degassed
  2. customfor 3 min
  3. temperatureIt was cooled to RT
  4. additiondiluted with 50 mL EtOAc
  5. stirringstirred
  6. filtrationfiltered
  7. concentrationThe filtrate was concentrated

Sources & evidence

ORD record
ord-7959991aeae547a98007e51542e86ee6
Source dataset
uspto-grants-2016_07
Patent number
US09382246B2

Reaction notes

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