Cesium carbonate → (3aR,7aR)-tert-butyl 4-(5-cyano-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)octahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

HRID 1050592Notes

Reaction equation

HRID 1050592 reaction equation
Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]3[N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16][C@@H:9]23)[CH:5]=[N:4][C:3]=1[C:24]#[N:25].Cl.[CH:27]1([N:32]2[CH2:37][CH2:36][CH:35]([C:38]3[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=3)[CH2:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]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:24]([C:3]1[N:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]3[N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16][C@@H:9]23)=[N:7][C:2]=1[NH:42][C:41]1[CH:43]=[CH:44][C:38]([CH:35]2[CH2:36][CH2:37][N:32]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:33][CH2:34]2)=[CH:39][CH:40]=1)#[N:25]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 1181146604-(1-Cyclopentylpiperidin-4-yl)aniline hydrochlorideHCID 118114837(3aR,7aR)-tert-butyl 4-(6-chloro-5-cyanopyrazin-2-yl)octahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

Product 1

HCID 118115456(3aR,7aR)-tert-butyl 4-(5-cyano-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)octahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylateYield 76.3%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
115 °C

Procedure

The mixture of (3aR,7aR)-tert-butyl 4-(6-chloro-5-cyanopyrazin-2-yl)octahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (417) (400 mg, 1.10 mmol), 4-(1-cyclopentylpiperidin-4-yl)aniline hydrochloride (304) (340 mg, 1.21 mmol), fine-powder cesium carbonate (1.08 g, 3.30 mmol), Pd(OAc)2 (74 mg, 0.33 mmol), BINAP (206 mg, 0.33 mmol) in 40 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 1.5 hour. The mixture was cooled to RT, diluted with 150 mL EtOAc, and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 6% MeOH in DCM to isolate (3aR,7aR)-tert-butyl 4-(5-cyano-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)octahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (418) (480 mg, 76%). It was dissolved in 25 mL MeOH and 2 mL DMSO. To it were added fine-powder Cs2CO3 (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, concentrated in vacuo to give crude (3aR,7aR)-tert-butyl 4-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)octahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (419). It was treated with 1:1 TFA/DCM at RT for 5 min, concentrated in vacuo, and subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate 3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((3aR,7aR)-dihydro-1H-pyrrolo[3,2-b]pyridin-4(2H,5H,6H,7H,7aH)-yl)pyrazine-2-carboxamide (420) as HCl salt. LC-MS (ESI): m/z (M+1) 490.4. UV: λ=263, 272, 303, 334, 370 nm. Proton NMR (CD3OD): δ 7.68 (1H, s), 7.57 (2H, d, J=8.5 Hz), 7.30 (2H, d, J=9.0 Hz), 5.16 (1H, m), 4.21 (1H, m), 3.85 (1H, m), 3.72 (2H, d, J=13.0 Hz), 3.58 (2H, m), 3.42 (1H, m), 3.12 (3H, m), 2.89 (1H, m), 2.35 (1H, m), 2.20 (2H, m), 2.14-1.71 (15H, m) 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-b2190b35599645dbab5fdd7594958e63
Source dataset
uspto-grants-2016_07
Patent number
US09382246B2

Reaction notes

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