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Cesium carbonate → 5-Cyano-3-methyl-pyridine-2-carboxylic acid [4-(5-amino-6,6-bis-fluoromethyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide

HRID 538373
Notes
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Reaction equation

HRID 538373 reaction equation
[C:1]([C:3]1[CH:4]=[C:5]([CH3:12])[C:6]([C:9]([NH2:11])=[O:10])=[N:7][CH:8]=1)#[N:2].Br[C:14]1[CH:19]=[C:18]([C:20]2([CH3:31])[CH2:25][O:24][C:23]([CH2:28][F:29])([CH2:26][F:27])[C:22]([NH2:30])=[N:21]2)[C:17]([F:32])=[CH:16][N:15]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[NH2:30][C:22]1[C:23]([CH2:26][F:27])([CH2:28][F:29])[O:24][CH2:25][C:20]([C:18]2[C:17]([F:32])=[CH:16][N:15]=[C:14]([NH:11][C:9]([C:6]3[C:5]([CH3:12])=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)=[O:10])[CH:19]=2)([CH3:31])[N:21]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)2×HCID 666659355-Cyano-3-methyl-2-pyridinecarboxamideHCID 866680815-(2-Bromo-5-fluoro-pyridin-4-yl)-2,2-bis-fluoromethyl-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

Product 1

HCID 77831077
5-Cyano-3-methyl-pyridine-2-carboxylic acid [4-(5-amino-6,6-bis-fluoromethyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-amide

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of 5-cyano-3-methyl-pyridine-2-carboxylic acid amide (see Intermediates Amide 1, 96 mg, 0.596 mmol), 5-(2-bromo-5-fluoro-pyridin-4-yl)-2,2-bis-fluoromethyl-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (210 mg, 0.596 mmol), Xantphos (31.1 mg, 0.054 mmol) and Cs2CO3 (272 mg, 0.835 mmol) in dioxane (6 ml) was degassed with argon, Pd2(dba)3 (16.38 mg, 0.018 mmol) was added and the reaction mixture was stirred at 60° C. for 16 h. More Pd2(dba)3 (8.19 mg, 0.009 mmol) and Xantphos (15.60 mg, 0.027 mmol) was added and stirring was continued at 60° C. for 4 h. The reaction mixture was filtered through celite and the celite pad rinsed with DCM. The combined filtrates were concentrated and the resulting crude title compound was purified by NP-HPLC (Alltech Grom Saphir65 Si 10 μm column, 150×30 mm, gradient n-heptane:EtOAc:MeOH 68:30:2 to 0:65:35), then by RP-HPLC (Waters SunFire C18 column, 5 μM, 30×100 mm, gradient 10 to 30% ACN+0.1% TFA) and obtained as a free base after filtration over an SCX cartridge.

Workup

  1. additionwas added
  2. stirringstirring
  3. waitwas continued at 60° C. for 4 h
  4. filtrationThe reaction mixture was filtered through celite
  5. washthe celite pad rinsed with DCM
  6. concentrationThe combined filtrates were concentrated
  7. customthe resulting crude title compound was purified by NP-HPLC (Alltech Grom Saphir65 Si 10 μm column, 150×30 mm, gradient n-heptane:EtOAc:MeOH 68:30:2 to 0:65:35), then by RP-HPLC (Waters SunFire C18 column, 5 μM, 30×100 mm, gradient 10 to 30% ACN+0.1% TFA)
  8. customobtained as a free base
  9. filtrationafter filtration over an SCX cartridge

Sources & evidence

ORD record
ord-ecea7acdb5004c8c8cc31744a4e7737d
Source dataset
uspto-grants-2014_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08865712B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes