Lithium Hexamethyldisilazide → (S)-7-(2-fluoropyridin-3-yl)-3-((R)-3-fluoropyrrolidin-1-yl)-2',6'-dihydrospiro[chromeno [2,3-b]pyridine-5,3'-[1,4]oxazin]-5'-amine

HRID 455724Notes

Reaction equation

HRID 455724 reaction equation
Cl.[F:2][C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.Br[C:9]1[CH:10]=[C:11]2[C@@:22]3([N:27]=[C:26]([NH2:28])[CH2:25][O:24][CH2:23]3)[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:29]4[C:30]([F:35])=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:20]=3)[O:15][C:12]2=[N:13][CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(OC)(C)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1COCC1>[F:35][C:30]1[C:29]([C:19]2[CH:20]=[C:21]3[C@:22]4([N:27]=[C:26]([NH2:28])[CH2:25][O:24][CH2:23]4)[C:11]4[C:12](=[N:13][CH:14]=[C:9]([N:5]5[CH2:6][CH2:7][C@@H:3]([F:2])[CH2:4]5)[CH:10]=4)[O:15][C:16]3=[CH:17][CH:18]=2)=[CH:34][CH:33]=[CH:32][N:31]=1

Participants

6

Reactant 3

HCID 2733832Lithium Hexamethyldisilazide2×HCID 2759162(3R)-3-fluoropyrrolidine hydrochlorideHCID 67436956(S)-3-bromo-7-(2-fluoropyridin-3-yl)-2',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,3'-[1,4]oxazin]-5'-amine

Product 1

HCID 58465994(S)-7-(2-fluoropyridin-3-yl)-3-((R)-3-fluoropyrrolidin-1-yl)-2',6'-dihydrospiro[chromeno [2,3-b]pyridine-5,3'-[1,4]oxazin]-5'-amineYield 35.4%

Reagents, catalysts & solvents 2

HCID 66572931HCID 66572931, compoundCatalyst2×HCID 8028TetrahydrofuranSolvent

Procedure

A vial was charged with (R)-3-fluoropyrrolidine HCl (0.021 g, 0.170 mmol), (S)-3-bromo-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.050 g, 0.113 mmol) and RuPhos palladacycle (9.05 mg, 0.011 mmol). THF (1 mL) and LiHMDS (1N in THF; 0.567 mL, 0.567 mmol) were added, and the reaction mixture was allowed to stir at RT overnight. Additional RuPhos palladacycle (9.05 mg, 0.011 mmol) and LiHMDS solution (0.567 mL, 0.567 mmol) were added, and the reaction mixture was heated to 45° C. for 2 hours. The reaction mixture was then quenched with MeOH and concentrated under reduced pressure. Purification of the crude residue by column chromatography [0-100% (90:10:1 DCM/MeOH/NH4OH)/DCM] gave (S)-7-(2-fluoropyridin-3-yl)-3-((R)-3-fluoropyrrolidin-1-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.018 g, 0.040 mmol, 35.3% yield).

Workup

  1. temperaturethe reaction mixture was heated to 45° C. for 2 hours
  2. customThe reaction mixture was then quenched with MeOH
  3. concentrationconcentrated under reduced pressure
  4. customPurification of the crude residue by column chromatography [0-100% (90:10:1 DCM/MeOH/NH4OH)/DCM]

Sources & evidence

ORD record
ord-53db8d6fd0184a74aaa2e1229532e76c
Source dataset
uspto-grants-2013_07
Patent number
US08497264B2

Reaction notes

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