Lithium Hexamethyldisilazide → (S)-3-(3,3-difluoropyrrolidin-1-yl)-7-(pyridin-3-yl)-5'H-spiro[chromeno[2,3-c]pyridine-5,4'-oxazol]-2'-amine

HRID 335929Notes

Reaction equation

Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:11][CH:10]=3.Cl.[F:28][C:29]1([F:34])[CH2:33][CH2:32][NH:31][CH2:30]1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:28][C:29]1([F:34])[CH2:33][CH2:32][N:31]([C:2]2[N:7]=[CH:6][C:5]3[O:8][C:9]4[C:14]([C@@:15]5([CH2:19][O:18][C:17]([NH2:20])=[N:16]5)[C:4]=3[CH:3]=2)=[CH:13][C:12]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:11][CH:10]=4)[CH2:30]1

Participants

Conditions

Temperature: 90 °C

Procedure

To a resealable tube charged with a mixture of (S)-3-chloro-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (0.085 g, 0.233 mmol), 3,3-difluoropyrrolidine HCl (0.100 g, 0.699 mmol), pd2(dba)3 (10.67 mg, 0.012 mmol), and 2-(dicyclohexylphosphino)-2′-(n,n-dimethylamino)biphenyl (0.014 g, 0.035 mmol) was added 1.0 M lithium bis(trimethylsilyl)amide (1.398 mL, 1.398 mmol) in THF and the resulting mixture was heated at 90° C. for 17 h. The mixture was concentrated and purified by reverse phase HPLC to afford (S)-3-(3,3-difluoropyrrolidin-1-yl)-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine.

Workup

concentrationThe mixture was concentrated
custompurified by reverse phase HPLC

Sources & evidence

ORD record: ord-fa09d4e3b55c4240b703d5b6df481d62
Source dataset: uspto-grants-2014_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08883782B2

Reaction notes

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