Cesium carbonate → 3-((2R,3R)-1-(5-cyano-6-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea

HRID 1050566Notes

Reaction equation

HRID 1050566 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].[CH:23]1([N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)[CH2:25][CH2:24]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[N:4]=[CH:5][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])=[N:7][C:2]=1[NH:36][C:35]1[CH:37]=[CH:38][C:32]([CH:29]2[CH2:30][CH2:31][N:26]([CH:23]3[CH2:25][CH2:24]3)[CH2:27][CH2:28]2)=[CH:33][CH:34]=1)#[N:22]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 686729414-(1-Cyclopropylpiperidin-4-yl)anilineHCID 118115647US9656988, Example 237

Product 1

HCID 1181361193-((2R,3R)-1-(5-cyano-6-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea

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) (80 mg, 0.25 mmol), 4-(1-cyclopropylpiperidin-4-yl)aniline (322, HCl salt, 76 mg, 0.30 mmol), fine-powder cesium carbonate (326 mg, 1.00 mmol), Pd(OAc)2 (18 mg, 0.08 mmol), BINAP (50 mg, 0.08 mmol) in 15 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 100 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 3-((2R,3R)-1-(5-cyano-6-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea (327). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were added 100 μL Et3N, 100 mg powder cesium carbonate, and then 0.5 mL 30% H2O2. The mixture was stirred at RT for 1.5 hour, diluted with 10 mL MeCN, stirred for 5 mM, concentrated on rotavap. The residue was treated 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 3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide (328) as HCl salt (76 mg, 58% yield). LC-MS (ESI): m/z (M+1) 521.8. UV: λ=268, 277, 306, 336, 372 nm. Proton NMR (CD3OD): δ 7.64 (1H, s), 7.61 (2H, d, J=8.5 Hz), 7.20 (2H, d, J=8.5 Hz), 4.98 (1H, m), 4.34 (1H, m), 3.87 (1H, m), 3.77 (1H, s), 3.74 (1H, s), 3.34 (2H, m), 3.02 (1H, m), 2.95 (6H, s), 2.90 (1H, m), 2.85 (1H, m), 2.15 (2H, m), 1.95-1.65 (6H, m), 1.17 (3H, d, J=7.0 Hz), 1.02 (4H, m) ppm.

Workup

  1. customwas degassed with nitrogen stream for 3 min
  2. temperatureThe mixture was cooled to RT
  3. additiondiluted with 100 mL EtOAc
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated in vacuo

Sources & evidence

ORD record
ord-300f5812007144a1bda3c632c642abf7
Source dataset
uspto-grants-2016_07
Patent number
US09382246B2

Reaction notes

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