2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 5,7-Difluoro-3-methyl-n-(5-(3-methylmorpholino)-2-morpholinopyridin-3-yl)-2-(pyridin-3-yl)quinolin-4-amine

HRID 1431525Notes

Reaction equation

HRID 1431525 reaction equation
C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[CH3:35][CH:36]1[N:41]([C:42]2[CH:43]=[C:44]([NH2:54])[C:45]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[N:46][CH:47]=2)[CH2:40][CH2:39][O:38][CH2:37]1.Cl[C:56]1[C:65]2[C:60](=[CH:61][C:62]([F:67])=[CH:63][C:64]=2[F:66])[N:59]=[C:58]([C:68]2[CH:69]=[N:70][CH:71]=[CH:72][CH:73]=2)[C:57]=1[CH3:74].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:66][C:64]1[CH:63]=[C:62]([F:67])[CH:61]=[C:60]2[C:65]=1[C:56]([NH:54][C:44]1[C:45]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[N:46][CH:47]=[C:42]([N:41]3[CH2:40][CH2:39][O:38][CH2:37][CH:36]3[CH3:35])[CH:43]=1)=[C:57]([CH3:74])[C:58]([C:68]1[CH:69]=[N:70][CH:71]=[CH:72][CH:73]=1)=[N:59]2

Participants

7

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 596314335-(3-Methylmorpholino)-2-morpholinopyridin-3-amineHCID 596315314-Chloro-5,7-difluoro-3-methyl-2-(pyridin-3-yl)quinoline

Product 1

HCID 675080085,7-Difluoro-3-methyl-n-(5-(3-methylmorpholino)-2-morpholinopyridin-3-yl)-2-(pyridin-3-yl)quinolin-4-amine

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

The Buchwald coupled products were prepared according to Procedure H using a solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.021 g, 0.044 mmol), 5-(3-methylmorpholino)-2-morpholinopyridin-3-amine (0.092 g, 0.33 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-3-yl)quinoline (0.08 g, 0.28 mmol), Pd2dba3 (0.010 g, 0.011 mmol) and sodium tert-butoxide (0.066 g, 0.69 mmol) in toluene (2.8 mL) at 100° C. for 27 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/MeOH/ammonium hydroxide (90/9/1)) to give the desired product 5,7-difluoro-3-methyl-N-(5-(3-methylmorpholino)-2-morpholinopyridin-3-yl)-2-(pyridin-3-yl)quinolin-4-amine. The mixture of enantiomers was separated on chiral IC (3×8×15 cm) using 30% isopropanol (0.1% DEA)/CO2, at a flow rate of 100 bar 70 mL/min, (230 nM, injection vol.: 1.5 mL, 4 mg/mL) to give both enantiomers with an ee of 99%; The initial peak (R)-5,7-difluoro-3-methyl-N-(5-(3-methylmorpholino)-2-morpholinopyridin-3-yl)-2-(pyridin-3-yl)quinolin-4-amine or (S)-5,7-difluoro-3-methyl-N-(5-(3-methylmorpholino)-2-morpholinopyridin-3-yl)-2-(pyridin-3-yl)-quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.89 (1H, m), 8.01 (1H, td, J=7.8, 1.8 Hz), 7.90 (1H, m), 7.77 (1H, br. s), 7.66 (1H, m), 7.53-7.46 (3H, m), 6.33 (1H, m), 3.82-3.47 (10H, m), 3.02-2.88 (5H, m), 2.12 (3H, s), 0.92 (3H, br. s.). Mass Spectrum (ESI) m/e=533.2 (M+1). Further elution gave (S)-5,7-difluoro-3-methyl-N-(5-(3-methylmorpholino)-2-morpholinopyridin-3-yl)-2-(pyridin-3-yl)quinolin-4-amine or (R)-5,7-difluoro-3-methyl-N-(5-(3-methylmorpholino)-2-morpholinopyridin-3-yl)-2-(pyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.89 (1H, m), 8.01 (1H, td, J=7.8, 1.8 Hz), 7.90 (1H, m), 7.77 (1H, br. s), 7.66 (1H, m), 7.53-7.46 (3H, m), 6.33 (1H, m), 3.82-3.47 (10H, m), 3.02-2.88 (5H, m), 2.12 (3H, s), 0.92 (3H, br. s.). Mass Spectrum (ESI) m/e=533.2 (M+1). These compounds were arbitrarily assigned as R and S.

Workup

  1. customwere prepared
  2. customat 100° C.
  3. customfor 27 h
  4. customThe crude product was purified by column chromatography on silica gel (0 to 100% DCM/MeOH/ammonium hydroxide (90/9/1))

Sources & evidence

ORD record
ord-9633cef0218744d2a58595d07f0df23c
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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