Sodium Carbonate → (S)-methyl 4-((Z)-((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-(tert-butyldimethylsilyloxy)butanoate

HRID 1917516Notes

Reaction equation

HRID 1917516 reaction equation
[NH2:1][C:2]1[N:3]=[C:4]([CH3:37])[C:5]2=[C:6]([CH2:8][C@H:9]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3Br)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][CH2:15][C@H:16]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:17]([O:19][CH3:20])=[O:18])[N:7]=1.B1([C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([O:58][CH3:59])[N:53]=2)OCCN(C2C=CC=CC=2)CCO1.C([O-])([O-])=O.[Na+].[Na+]>CC(N(C)C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:3]=[C:4]([CH3:37])[C:5]2=[C:6]([CH2:8][C@H:9]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([O:58][CH3:59])[N:53]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][CH2:15][C@H:16]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:17]([O:19][CH3:20])=[O:18])[N:7]=1

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 162178652-(6-Methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocaneHCID 178501473(S)-methyl 4-((Z)-((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-(tert-butyldimethylsilyloxy)butanoate

Product 1

HCID 178501474(S)-methyl 4-((Z)-((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-(tert-butyldimethylsilyloxy)butanoate

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 31374DimethylacetamideSolvent

Conditions

Temperature
85 °C

Procedure

To a solution of (S)-methyl 4-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-(tert-butyldimethylsilyloxy)butanoate (91 g, 244 mg, 0.41 mmol) in DMA was added 6-methoxypyridine-2-boronic acid N-phenyldiethanolamine ester (488 mg, 1.64 mmol), Pd(dppf)2Cl2 (66 mg, 0.08 mmol), and 2 N Na2CO3 (2 mL, 4.1 mmol). The resultant mixture was degassed with N2 for 5 min then heated in a sealed tube at 85° C. for 14 h. The reaction was allowed to cool to r.t. and filtered through a pad of Celite topped with anhydrous Na2SO4, rinsing with EtOAc and CH3OH. The filtrate was concentrated to provide a black residue which was purified by preparative HPLC eluting with TFA/ACN/H2O. The fractions were dried down in vacuo to yield (S)-methyl 4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-(tert-butyldimethylsilyloxy)butanoate. This material was directly taken up in dioxane (700 μL) and treated with 1:9 TFA:H2O (1 mL) for 3 h. The solvents were removed in vacuo to yield (S)-methyl 4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-hydroxybutanoate (91h, 15 mg, 0.03 mmol). [M+H] calc'd for C25H27FN6O5, 511; found, 511.

Workup

  1. customThe resultant mixture was degassed with N2 for 5 min
  2. temperatureto cool to r.t.
  3. filtrationfiltered through a pad of Celite
  4. washrinsing with EtOAc and CH3OH
  5. concentrationThe filtrate was concentrated
  6. customto provide a black residue which
  7. customwas purified by preparative HPLC
  8. washeluting with TFA/ACN/H2O
  9. customThe fractions were dried down in vacuo

Sources & evidence

ORD record
ord-660a0dddf5e344fa8022e8c0aa8c49c7
Source dataset
uspto-grants-2013_12
Patent number
US08618290B2

Reaction notes

Loading…