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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 1472457
Notes
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Reaction equation

HRID 1472457 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
ParticipantsProcedureWorkupSources & evidenceReaction notes

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 2-fluoropyridin-3-ylboronic acid (0.094 g, 0.667 mmol), PdCl2(dppf)-CH2Cl2-adduct (0.026 g, 0.032 mmol), (S)-3-bromo-7-iodo-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.300 g, 0.635 mmol), and potassium carbonate (0.351 g, 2.54 mmol). Dioxane (3.5 mL) and water (1.5 mL) were added. The vial was flushed with argon, sealed and heated to 80° C. for 1 hour. The reaction mixture was then diluted with EtOAc, dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography [0-80% (90:10:1 DCM/MeOH/NH4OH)/DCM] gave (S)-3-bromo-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.202 g, 0.458 mmol) Step 2: 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-ac2946db4b2f42209933882898084864
Source dataset
uspto-grants-2015_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09012446B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes