1-Hydroxybenzotriazole → 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

HRID 2111332Notes

Reaction equation

HRID 2111332 reaction equation
[CH:1]1([N:6]2[CH2:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.[NH2:67][CH:68]1[CH2:73][CH2:72][N:71]([CH3:74])[CH2:70][CH2:69]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([CH3:13])([CH3:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[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:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

6

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 27375314-Amino-1-methylpiperidineHCID 426107874-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acidHCID 178484289HCID 178484289, compound

Product 1

HCID 250154654-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamideYield 75.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a suspension of 16.67 g (0.0379 mole) of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-38) in 500 mL of dimethylformamide was added 8.26 g (0.0612 mole) of 1-hydroxybenzotriazole, 22.44 g (0.0592 mole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred for 30 minutes and then 6.60 g (0.0580 mole) of 4-amino-1-methylpiperidine was added. The reaction mixture was stirred for an additional and then concentrated under reduced pressure. The residue was partitioned between 800 mL of ethyl acetate and 200 mL of water. The aqueous layer was extracted with twice with 300 mL of ethyl acetate. The combined organic extracts were washed successively three times with 1 M sodium hydroxide, twice with 200 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol-isopropylamine (190:10:1-160:40:1) to give 15.32 g of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-39).

Workup

  1. stirringThe reaction mixture was stirred for an additional and
  2. concentrationthen concentrated under reduced pressure
  3. customThe residue was partitioned between 800 mL of ethyl acetate and 200 mL of water
  4. extractionThe aqueous layer was extracted with twice with 300 mL of ethyl acetate
  5. washThe combined organic extracts were washed successively three times with 1 M sodium hydroxide
  6. dry with materialtwice with 200 mL of brine, dried over anhydrous sodium sulfate
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by silica gel chromatography
  9. washeluting with dichloromethane-methanol-isopropylamine (190:10:1-160:40:1)

Sources & evidence

ORD record
ord-42a5cc8f421c4ac08f3a343025fd9ecf
Source dataset
uspto-grants-2009_04
Patent number
US07517873B2

Reaction notes

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