Dichloromethane → HCID 57695489, compound

HRID 1517358Notes

Reaction equation

HRID 1517358 reaction equation
[Cl:1][C:2]1[C:3]([F:47])=[C:4]([CH:44]=[CH:45][CH:46]=1)[C:5]([N:7]([CH2:30][CH2:31][CH2:32][NH:33]C(=O)OCC1C=CC=CC=1)[C@@H:8]([C:12]1[N:13]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:14](=[O:22])[C:15]2[N:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:9][C:10]#[CH:11])=[O:6].I[Si](C)(C)C.C([O-])(O)=O.[Na+].ClCCl>C(#N)C>[NH2:33][CH2:32][CH2:31][CH2:30][N:7]([C@@H:8]([C:12]1[N:13]([NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:14](=[O:22])[C:15]2[N:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:9][C:10]#[CH:11])[C:5](=[O:6])[C:4]1[CH:44]=[CH:45][CH:46]=[C:2]([Cl:1])[C:3]=1[F:47]

Participants

6

Reactant 4

HCID 6344DichloromethaneHCID 85247Trimethylsilyl iodideHCID 516892Sodium BicarbonateHCID 57695493HCID 57695493, compound

Product 1

HCID 57695489HCID 57695489, compoundYield 50.4%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a solution of (R)-benzyl 3-(3-chloro-2-fluoro-N-(1-(4-oxo-3-(phenylamino)-3,4-dihydropyrido[3,2-d]pyrimidin-2-yl)but-3-ynyl)benzamido)propylcarbamate (100 mg, 0.153 mmol) in acetonitrile (2 ml) was slowly added iodotrimethylsilane (83 μl, 0.613 mmol) at 0° C. After stirring for 10 minutes, 0.5 ml of sat.NaHCO3 solution was added to quench the reaction. 100 ml of dichloromethane was added to the reaction mixture, then washed with water (30 ml), brine (30 ml), dried over Na2SO4 and concentrated to dryness under reduced pressure. The crude product was purified by preparative HPLC. The resulted product (TFA salt) was dissolved in dichloromethane (100 ml) and washed with sat.NaHCO3 solution (20 ml), sat.NaCl solution (20 ml), dried over Na2SO4 and concentrated to dryness under reduced pressure. To a solution of the residue in EtOAc (2 ml) was added HCl:EtOAc (3.0 M, 1.0 ml). The mixture was stirred at room temperature for 30 minutes and concentrated to afford (R)-N-(3-aminopropyl)-3-chloro-2-fluoro-N-(1-(4-oxo-3-(phenylamino)-3,4 dihydropyrido[3,2-d]pyrimidin-2-yl)but-3-ynyl)benzamide (40 mg, 44%, 2HCl) as a pale yellow solid, M.p. 198-200° C. LCMS: m/e 519 [M+H]. 1H NMR (CD3OD): δ 8.93 (s. 1H), 8.59 (d, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.52 (s, 1H), 7.27 (d, J=6.4 Hz, 2H), 7.10 (s, 2H), 7.00 (m, 1H), 6.85 (s, 1H), 6.53 (s, 1H), 6.38 (s, 1H), 5.51 (s, 1H), 5.26 (s, 1H), 3.73-3.59 (m, 2H), 2.65-2.29 (m, 2H), 2.01-1.59 (m, 2H), 1.19 (m, 4H).

Workup

  1. customat 0° C
  2. customto quench
  3. customthe reaction
  4. washwashed with water (30 ml), brine (30 ml)
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated to dryness under reduced pressure
  7. customThe crude product was purified by preparative HPLC
  8. dissolutionThe resulted product (TFA salt) was dissolved in dichloromethane (100 ml)
  9. washwashed
  10. dry with materialNaCl solution (20 ml), dried over Na2SO4
  11. concentrationconcentrated to dryness under reduced pressure
  12. additionTo a solution of the residue in EtOAc (2 ml) was added HCl
  13. stirringThe mixture was stirred at room temperature for 30 minutes
  14. concentrationconcentrated

Sources & evidence

ORD record
ord-d16c5f4cc811473f8e7be31a792c3948
Source dataset
uspto-grants-2012_07
Patent number
US08232285B2

Reaction notes

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