Water → HCID 86610684, compound

HRID 506402Notes

Reaction equation

HRID 506402 reaction equation
[F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][C:7]1[C:12]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:11][N:10]=[C:9]([NH:19][C@@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[N:28]=3)[NH:23][C@H:22]([CH2:32][CH3:33])[CH2:21]2)[N:8]=1.C([N:45]([CH2:48]C)CC)C.Cl[C:51](Cl)([O:53]C(=O)OC(Cl)(Cl)Cl)Cl.[OH2:62]>C(Cl)Cl>[CH3:51][O:53][NH:45][C:48]([N:23]1[C:24]2[C:29](=[N:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C@@H:20]([NH:19][C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=3)[C:12]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[CH:11][N:10]=2)[CH2:21][C@H:22]1[CH2:32][CH3:33])=[O:62]

Participants

6

Reactant 4

HCID 962WaterHCID 8471TriethylamineHCID 94429TriphosgeneHCID 86610671HCID 86610671, compound

Product 1

HCID 86610684HCID 86610684, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)-pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-1,2,3,4-tetrahydro-[1,5]naphthyridine (250 mg) is dissolved in methylene chloride (2.0 ml), and thereto is added triethylamine (118 μl), then added triphosgene (50 mg) under water-cooling. The mixture is stirred at the same temperature for 30 minutes under nitrogen flow. To the reaction mixture is added water, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is dissolved in a mixture of tetrahydrofuran (2.5 ml) and N,N-dimethylformamide (1 ml), and thereto are added O-methylhydroxylamine hydrochloride (70 mg) and triethylamine (230 μl). The mixture is stirred at room temperature for 4 days under nitrogen flow. To the reaction mixture is added water, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=2:1→chloroform:methanol=19:1) to give (2R,4S)-4-{[3,5-bis-(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid methoxyamide (57 mg). MS (m/z): 670 [M+H]+.

Workup

  1. extractionthe mixture is extracted with ethyl acetate
  2. washThe organic layer is washed with saturated brine
  3. dry with materialdried over magnesium sulfate
  4. concentrationconcentrated under reduced pressure
  5. dissolutionThe resulting residue is dissolved in a mixture of tetrahydrofuran (2.5 ml) and N,N-dimethylformamide (1 ml)
  6. additionare added O-methylhydroxylamine hydrochloride (70 mg) and triethylamine (230 μl)
  7. stirringThe mixture is stirred at room temperature for 4 days under nitrogen flow
  8. additionTo the reaction mixture is added water
  9. extractionthe mixture is extracted with ethyl acetate
  10. washThe organic layer is washed with saturated brine
  11. dry with materialdried over magnesium sulfate
  12. concentrationconcentrated under reduced pressure
  13. customThe resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=2:1→chloroform:methanol=19:1)

Sources & evidence

ORD record
ord-de25ca43a5d942cc8a96bd5de07c4ba9
Source dataset
uspto-grants-2010_08
Patent number
US07781443B2

Reaction notes

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