Toluene → (S)-N-(7-((3-ethoxypyridin-2-yl)amino)-4-fluoro-9-(2-hydroxyethyl)-2-methoxy-9H-xanthen-9-yl)cyanamide

HRID 931628Notes

Reaction equation

HRID 931628 reaction equation
[CH2:1]([O:3][C:4]1[C:5]([NH2:10])=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].Br[C:12]1[CH:25]=[C:24]2[C:15]([O:16][C:17]3[C:18]([F:34])=[CH:19][C:20]([O:32][CH3:33])=[CH:21][C:22]=3[C@@:23]32[CH2:30][CH2:29][O:28][C:27]([NH2:31])=[N:26]3)=[CH:14][CH:13]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.O.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]>[CH2:1]([O:3][C:4]1[C:5]([NH:10][C:12]2[CH:25]=[C:24]3[C:15]([O:16][C:17]4[C:18]([F:34])=[CH:19][C:20]([O:32][CH3:33])=[CH:21][C:22]=4[C@:23]3([NH:26][C:27]#[N:31])[CH2:30][CH2:29][OH:28])=[CH:14][CH:13]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]

Participants

8

Reactant 4

HCID 1140TolueneHCID 5866303-ethoxypyridin-2-amineHCID 23676156Sodium t-butoxideHCID 58465963(S)-7'-bromo-4'-fluoro-2'-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9'-xanthen]-2-amine

Product 1

HCID 89461784(S)-N-(7-((3-ethoxypyridin-2-yl)amino)-4-fluoro-9-(2-hydroxyethyl)-2-methoxy-9H-xanthen-9-yl)cyanamideYield 55.9%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

A 20 mL resealable tube was charged with 3-ethoxypyridin-2-amine (176 mg, 1.272 mmol), (S)-7′-bromo-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthen]-2-amine (250 mg, 0.636 mmol), Pd2 dba3 (29.1 mg, 0.032 mmol), t-BuXPhos (47.2 mg, 0.111 mmol) and sodium t-butoxide (244 mg, 2.54 mmol). Toluene (6 ml) was added, the mixture was stirred for 2 min at room temperature, then heated at 100° C. for 1.5 hr. The solution was diluted with ethyl acetate and water. The organic layer was separated and concentrated. The product was purified via silica gel column chromatography (RediSep 40 g column) using 20-80% ethyl acetate in heptane to afford (S)—N-(7-((3-ethoxypyridin-2-yl)amino)-4-fluoro-9-(2-hydroxyethyl)-2-methoxy-9H-xanthen-9-yl)cyanamide (160 mg, 0.355 mmol, 55.9% yield). MS m/z=451.0 [M+H].

Workup

  1. temperatureheated at 100° C. for 1.5 hr
  2. customThe organic layer was separated
  3. concentrationconcentrated
  4. customThe product was purified via silica gel column chromatography (RediSep 40 g column)

Sources & evidence

ORD record
ord-91e0711138884b4ab217aea47c6b51f1
Source dataset
uspto-grants-2016_03
Patent number
US09296759B2

Reaction notes

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