4-amino-N-[3-(dimethylamino)propyl]benzamide → 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-benzamide

HRID 1676561Notes

Reaction equation

HRID 1676561 reaction equation
Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:33][C:34]1[CH:48]=[CH:47][C:37]([C:38]([NH:40][CH2:41][CH2:42][CH2:43][N:44]([CH3:46])[CH3:45])=[O:39])=[CH:36][CH:35]=1>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:34]4[CH:48]=[CH:47][C:37]([C:38]([NH:40][CH2:41][CH2:42][CH2:43][N:44]([CH3:45])[CH3:46])=[O:39])=[CH:36][CH:35]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1

Participants

5

Reactant 3

HCID 4282134-amino-N-[3-(dimethylamino)propyl]benzamideHCID 124969952-Methylbenzenesulfonic acid hydrateHCID 866375032-Chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one

Product 1

HCID 445474954-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-benzamideYield 87.5%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Procedure

A mixture of 0.0673 g (0.22 mmole) 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 0.0634 g (0.33 mmole) of toluenesulfonic acid monohydrate, 0.0492 g (0.22 mmole) of 4-amino-N-(3-dimethylamino-propyl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 22 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (85:15:1) to give 0.0938 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-benzamide (I-19)

Workup

  1. temperaturewas heated in a sealed vessel at 140 degrees for 22 hours
  2. temperaturecooled
  3. concentrationconcentrated under reduced pressure
  4. washwashed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine
  5. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by silica gel chromatography
  9. washeluting with acetonitrile-methanol-triethylamine (85:15:1)

Sources & evidence

ORD record
ord-bc2cf368b53441e89e0d68e085b889a7
Source dataset
uspto-grants-2011_08
Patent number
US08003785B2

Reaction notes

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