p-Toluidine → (R)-benzyl 1-(1-(5-cyano-3-fluoro-6-(p-tolylamino)pyridin-2-ylamino)propyl)cyclopropylcarbamate

HRID 84914Notes

Reaction equation

Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:12]2([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[CH2:10][CH3:11])[C:5]([F:26])=[CH:4][C:3]=1[C:27]#[N:28].[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1.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.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:27]([C:3]1[CH:4]=[C:5]([F:26])[C:6]([NH:8][C@@H:9]([C:12]2([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[CH2:10][CH3:11])=[N:7][C:2]=1[NH:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)#[N:28]

Participants

Conditions

Temperature: 80 °C

Procedure

To a solution of (R)-benzyl 1-(1-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)propyl)cyclopropylcarbamate (100 mg, 0.25 mmol) in dioxane (1.5 mL) was added p-toluidine (32 mg, 0.30 mmol), BINAP (31 mg, 0.05 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol) and Cs2CO3 (244.5 mg, 0.75 mmol). After degassed with Argon, the mixture was heated at 80° C. for 5 h. The mixture was diluted with dioxane, precipitate was filtered off, filter cake was washed with ACN, the filtrate was concentrated and purified by column to give of (R)-benzyl 1-(1-(5-cyano-3-fluoro-6-(p-tolylamino)pyridin-2-ylamino)propyl)cyclopropylcarbamate (80 mg).

Workup

customAfter degassed with Argon
additionThe mixture was diluted with dioxane, precipitate
filtrationwas filtered off
filtrationfilter cake
washwas washed with ACN
concentrationthe filtrate was concentrated
custompurified by column

Sources & evidence

ORD record: ord-c19b67f6aba04898bbc1e6cca7b2f120
Source dataset: uspto-grants-2014_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08846928B2

Reaction notes

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