Potassium Iodide → HCID 77461264, compound

HRID 1499956Notes

Reaction equation

HRID 1499956 reaction equation
ClC1C(F)=C(C2CNC(=O)C2)C(OCC)=C(C(Cl)C)C=1.CC1C2C(=NC=NC=2N)NN=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C@H:51]([C:53]3[C:54]([O:67][CH2:68][CH3:69])=[C:55]([C@@H:61]4[CH2:65][NH:64][C:63](=[O:66])[CH2:62]4)[C:56]([F:60])=[C:57]([Cl:59])[CH:58]=3)[CH3:52])[N:48]=[C:49]([CH3:50])[C:42]=12.NC1N=CN=C2N([C@@H](C3C(OCC)=C([C@H]4CNC(=O)C4)C(F)=C(Cl)C=3)C)N=C(C)C=12.NC1N=CN=C2N([C@@H](C3C(OCC)=C([C@@H]4CNC(=O)C4)C(F)=C(Cl)C=3)C)N=C(C)C=12>CN(C)C=O.O>[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([CH:51]([C:53]3[C:54]([O:67][CH2:68][CH3:69])=[C:55]([CH:61]4[CH2:65][NH:64][C:63](=[O:66])[CH2:62]4)[C:56]([F:60])=[C:57]([Cl:59])[CH:58]=3)[CH3:52])[N:48]=[C:49]([CH3:50])[C:42]=12

Participants

10

Reactant 7

HCID 4875Potassium IodideHCID 10796Cesium carbonateHCID 86677872HCID 86677872, compoundHCID 86677874ParsaclisibHCID 86677875HCID 86677875, compoundHCID 86677876HCID 86677876, compoundHCID 178434474HCID 178434474, compound

Product 1

HCID 77461264HCID 77461264, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

The mixture of diastereoisomers from step 7 were each processed individually to the final products. A mixture of 4-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-fluorophenyl]pyrrolidin-2-one (0.36 g, 1.1 mmol) (from Step 7), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.19 g, 1.3 mmol), cesium carbonate (0.54 g, 1.7 mmol) and potassium iodide (18 mg, 0.11 mmol) in N,N-dimethylformamide (7.4 mL) was heated at 100° C. for 4.5 h. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (3×50 mL) to give a mixture of diastereoisomer ((S)-4-(34(S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one; (R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one; (S)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one; and (R)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one). The mixture of diastereoisomers were purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired products [from peak 1 were isolated peak A (compound 345) (0.13 g, 54%) and peak B (compound 346) (0.11 g, 46%); from peak 2 were isolated peak A (compound 347) (0.15 g, 63%) and peak B (compound 348) (0.14 g, 55%)]. Compound 346: 1H NMR (300 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.82 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.30 (br s, 1H), 6.23 (q, J=7.0 Hz, 1H), 4.05-3.90 (m, 1H), 3.88-3.78 (m, 2H), 3.63-3.53 (m, 1H), 3.29-3.20 (m, 1H), 2.54 (s, 3H), 2.38-2.21 (m, 1H), 1.70 (d, J=7.1 Hz, 3H), 1.39 (t, J=6.9 Hz, 3H). LCMS for C20H23ClFN6O2 (M+H)+: m/z=433.2; Found: 433.1. Compound 347:

Workup

  1. additionThe mixture of diastereoisomers from step 7
  2. extractionextracted with ethyl acetate (3×50 mL)
  3. customto give
  4. additionThe mixture of diastereoisomers
  5. customwere purified by preparative LCMS (XBridge C18 column
  6. washeluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min)

Sources & evidence

ORD record
ord-c8977bbe4385484287485a74975f893f
Source dataset
uspto-grants-2015_12
Patent number
US09199982B2

Reaction notes

Loading…