Acetonitrile → HCID 66611667, compound

HRID 1621802Notes

Reaction equation

HRID 1621802 reaction equation
CS(O[CH:6]([C:8]1[CH:9]=[N:10][C:11]([NH:40][C:41]2[CH:42]=[N:43][C:44]([O:48][CH3:49])=[C:45]([F:47])[CH:46]=2)=[C:12]([C:14]2[N:19]=[C:18]([N:20]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:17]=[C:16]([CH3:39])[N:15]=2)[CH:13]=1)[CH3:7])(=O)=O.CC#N.CC1(C)CCCC(C)(C)N1.[CH3:63][C@@H:64]1[NH:69][CH2:68][CH2:67][N:66]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:65]1>O.C(Cl)Cl>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:20]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[C:18]2[N:17]=[C:16]([CH3:39])[N:15]=[C:14]([C:12]3[CH:13]=[C:8]([C@@H:6]([N:69]4[CH2:68][CH2:67][N:66]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:65][C@@H:64]4[CH3:63])[CH3:7])[CH:9]=[N:10][C:11]=3[NH:40][C:41]3[CH:42]=[N:43][C:44]([O:48][CH3:49])=[C:45]([F:47])[CH:46]=3)[N:19]=2)=[CH:27][CH:26]=1.[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:20]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[C:18]2[N:17]=[C:16]([CH3:39])[N:15]=[C:14]([C:12]3[CH:13]=[C:8]([C@H:6]([N:69]4[CH2:68][CH2:67][N:66]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:65][C@@H:64]4[CH3:63])[CH3:7])[CH:9]=[N:10][C:11]=3[NH:40][C:41]3[CH:42]=[N:43][C:44]([O:48][CH3:49])=[C:45]([F:47])[CH:46]=3)[N:19]=2)=[CH:27][CH:26]=1

Participants

8

Reactant 4

HCID 6342AcetonitrileHCID 130352,2,6,6-TetramethylpiperidineHCID 7023035(S)-1-Boc-3-methylpiperazineHCID 71500537HCID 71500537, compound

Product 2

HCID 66611667HCID 66611667, compoundYield 17.8%HCID 66611851HCID 66611851, compoundYield 17.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

A stirred solution of crude 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethyl methanesulfonate (0.492 g, 0.713 mmol) in CH3CN (10.00 mL, 191 mmol) was treated with 2,2,6,6-tetramethylpiperidine (0.182 mL, 1.070 mmol) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (Aldrich, St. Louis, Mo., 0.186 g, 0.927 mmol) and the mixture was heated at reflux overnight. The mixture was then allowed to cool to room temperature, and the resulting suspension was diluted with water and DCM (20 mL each). The organic layer was separated, and the aqueous layer was extracted with DCM (2×20 mL). All organic layers were then combined, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography (silica gel, 0% to 15% ethyl acetate/DCM, followed elution with 5% MeOH/DCM) to give the two separated diasteromers (S)-tert-butyl 4-((S)-1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (first eluting diastereomer; 101 mg, 17.8%) and (S)-tert-butyl 4-((R)-1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (second eluting diastereomer; 101 mg, 17.8%). Absolute stereochemistries of the two diastereomers were determined by co-crystal structure of Example 272 (derived from the second eluting distereomer) in complex with PI3Kγ at 2.9 Å resolution. m/z (ESI, +ve ion) 794 (M+H)+.

Workup

  1. temperaturethe mixture was heated
  2. temperatureat reflux overnight
  3. customThe organic layer was separated
  4. extractionthe aqueous layer was extracted with DCM (2×20 mL)
  5. washwashed with brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated
  8. customThe residue was purified by flash column chromatography (silica gel, 0% to 15% ethyl acetate/DCM, followed elution with 5% MeOH/DCM)

Sources & evidence

ORD record
ord-c9b2624ede2d4432a8c6aa8b5b800d00
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

Loading…