Diisopropylethylamine → Tak-960

HRID 1676707Notes

Reaction equation

HRID 1676707 reaction equation
[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:67][CH:68]1[CH2:73][CH2:72][N:71]([CH2:74]C)[CH2:70][CH2:69]1>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:67][CH:68]5[CH2:73][CH2:72][N:71]([CH3:74])[CH2:70][CH2:69]5)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 37349901-Ethylpiperidin-4-amineHCID 252536794-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acidHCID 178484289HCID 178484289, compound

Product 1

HCID 53357478Tak-960Yield 61.5%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a mixture of 0.05 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-benzoic acid (I-169), 0.06 g (0.16 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.06 mL (0.32 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes 0.04 g (0.32 mmole) of 4-amino-1-ethylpiperidine was added. The mixture was stirred at room temperature for 18 hours, then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with 1M sodium hydroxide solution then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient, 0:100-20:80) to give 0.038 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-175).

Workup

  1. additionwas added
  2. extractionThe aqueous phase was extracted twice with ethyl acetate
  3. washThe combined organic layers were washed with 1M sodium hydroxide solution
  4. dry with materialbrine, dried over anhydrous magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by silica gel chromatography
  8. washeluting with methanol-dichloromethane (gradient, 0:100-20:80)

Sources & evidence

ORD record
ord-17e2df19c1ad4b2fa45b1ea8e36c5042
Source dataset
uspto-grants-2011_08
Patent number
US08003785B2

Reaction notes

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