Potassium Phosphate, Tribasic → Racemic ethyl 3-[[5-fluoro-2-(5-fluoro-1-trityl-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl]amino]-3-(1-methylcyclopentyl)propanoate

HRID 2171908Notes

Reaction equation

HRID 2171908 reaction equation
[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[C:10]1[N:15]=[C:14]([NH:16][CH:17]([C:24]2([CH3:29])[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]([F:30])=[CH:12][N:11]=1.[F:31][C:32]1[CH:33]=[C:34]2[C:40](B3OC(C)(C)C(C)(C)O3)=[N:39][N:38]([C:50]([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:35]2=[N:36][CH:37]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)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]>[F:30][C:13]1[C:14]([NH:16][CH:17]([C:24]2([CH3:29])[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:15][C:10]([C:40]2[C:34]3[C:35](=[N:36][CH:37]=[C:32]([F:31])[CH:33]=3)[N:38]([C:50]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[N:39]=2)=[N:11][CH:12]=1

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 679757175-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridine2×HCID 86714769(+/-)-Ethyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)-3-(1-methylcyclopentyl)propanoate2×

Product 1

HCID 86714770Racemic ethyl 3-[[5-fluoro-2-(5-fluoro-1-trityl-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl]amino]-3-(1-methylcyclopentyl)propanoate

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolvent

Conditions

Temperature
135 °C

Procedure

A solution of K3PO4 (0.464 g, 2.183 mmol), racemic ethyl 3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-3-(1-methylcyclopentyl)propanoate, 147a, (0.180 g, 0.546 mmol) and 5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-pyrazolo[3,4-b]pyridine, 135a, (303.4 mg, 0.6004 mmol) in 2-Methyl THF (3.240 mL) and H2O (0.360 mL) was degassed under a stream of nitrogen for 30 minutes. To this mixture was added X-phos (0.031 g, 0.066 mmol) and Pd2(dba)3 (0.013 g, 0.014 mmol). The reaction mixture was stirred at 135° C. in a pressure tube for 1 hour. The organic phase was filtered through a pad of celite and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (30% EtOAc/Hexanes) to afford 240 mg of the desired product: 1H NMR (400 MHz, CDCl3) δ 8.55 (dd, J=8.5, 2.7 Hz, 1H), 8.15 (d, J=2.4 Hz, 2H), 7.27 (dd, J=11.0, 5.0 Hz, 15H), 5.38 (d, J=9.7 Hz, 1H), 4.89 (dd, J=9.7, 6.0 Hz, 1H), 3.99 (q, J=7.1 Hz, 2H), 2.73 (dd, J=14.7, 3.8 Hz, 1H), 2.52 (dd, J=14.8, 9.4 Hz, 1H), 1.68 (dd, J=12.0, 6.6 Hz, 2H), 1.64-1.52 (m, 4H), 1.47-1.36 (m, 1H), 1.30 (dt, J=14.3, 7.2 Hz, 2H), 1.11-0.99 (m, 4H). LCMS Gradient 60-98%, formic acid, 7 minutes, C18/can, Retention Time=3.24 minutes (M+H) 672.85.

Workup

  1. filtrationThe organic phase was filtered through a pad of celite
  2. concentrationconcentrated in vacuo
  3. customThe resulting residue was purified by silica gel chromatography (30% EtOAc/Hexanes)

Sources & evidence

ORD record
ord-cc78e3058fcf4c74b43fd6a069fe87a6
Source dataset
uspto-grants-2015_06
Patent number
US09051319B2

Reaction notes

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