p-Toluenesulfonic acid monohydrate → (Rac)-4-(9-cyclobutyl-5,7-dimethyl-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

HRID 2111380Notes

Reaction equation

HRID 2111380 reaction equation
Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:26])=[CH:23][C:22]=1[O:37][CH3:38].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:15]1([N:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:20][C:21]4[CH:36]=[CH:35][C:24]([C:25]([NH:27][CH:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[O:26])=[CH:23][C:22]=4[O:37][CH3:38])=[N:19][C:6]2=3)[CH2:18][CH2:17][CH2:16]1

Participants

5

Reactant 3

HCID 521998p-Toluenesulfonic acid monohydrateHCID 115290634-Amino-3-methoxy-n-(1-methylpiperidin-4-yl)benzamideHCID 87618676(Rac)-2-chloro-9-cyclobutyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one

Product 1

HCID 25015539(Rac)-4-(9-cyclobutyl-5,7-dimethyl-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)-benzamideYield 58.6%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Procedure

A solution of 0.050 g (0.00018 mole) of (rac)-2-chloro-9-cyclobutyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-52), 0.047 g (0.00018 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.053 g (0.00028 mole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 180 degrees for 2 hours in a microwave reactor. The reaction mixture was concentrated and the residue diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-methanol (100:0-75:25 n) to give 0.0535 g of (rac)-4-(9-cyclobutyl-5,7-dimethyl-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-52) as white powder. HRMS (ES+) m/z Calcd for C27H37N7O3+H [(M+H)+]: 508.3031. Found: 508.3031.

Workup

  1. concentrationThe reaction mixture was concentrated
  2. additionthe residue diluted with dichloromethane
  3. washwashed twice with saturated sodium bicarbonate solution
  4. extractionThe aqueous phase was extracted with dichloromethane
  5. washThe combined organic phases were washed with brine
  6. dry with materialdried over anhydrous magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified by silica gel chromatography
  10. washeluting with dichloromethane-methanol (100:0-75:25 n)

Sources & evidence

ORD record
ord-ac7826e29e0141f2a823b9b016964e4f
Source dataset
uspto-grants-2009_04
Patent number
US07517873B2

Reaction notes

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