2-Methylbenzenesulfonic acid hydrate → 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-(1-ethyl-piperidin-4-yl)-3-methoxy-benzamide

HRID 1676550Notes

Reaction equation

HRID 1676550 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:50]=[CH:49][C:37]([C:38]([NH:40][CH:41]2[CH2:46][CH2:45][N:44]([CH2:47][CH3:48])[CH2:43][CH2:42]2)=[O:39])=[CH:36][C:35]=1[O:51][CH3:52]>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:50]=[CH:49][C:37]([C:38]([NH:40][CH:41]5[CH2:42][CH2:43][N:44]([CH2:47][CH3:48])[CH2:45][CH2:46]5)=[O:39])=[CH:36][C:35]=4[O:51][CH3:52])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1

Participants

5

Reactant 3

HCID 124969952-Methylbenzenesulfonic acid hydrateHCID 580150934-amino-N-(1-ethyl-4-piperidyl)-3-methoxy-benzamideHCID 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 445472054-(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-(1-ethyl-piperidin-4-yl)-3-methoxy-benzamideYield 41.6%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Procedure

A mixture of 0.0605 g (0.20 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), 0.0571 g (0.30 mmole) of toluenesulfonic acid monohydrate, 0.0555 g (0.20 mmole) of 4-amino-N-(1-ethyl-piperidin-4-yl)-3-methoxy-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 25 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 (90:10:1) and then recrystallization from acetonitrile to give 0.0452 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-(1-ethyl-piperidin-4-yl)-3-methoxy-benzamide (I-10) as a white solid.

Workup

  1. temperaturewas heated in a sealed vessel at 140 degrees for 25 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 (90:10:1)
  10. customrecrystallization from acetonitrile

Sources & evidence

ORD record
ord-659b3d3e6c7c4ee4a5ee0073996972c1
Source dataset
uspto-grants-2011_08
Patent number
US08003785B2

Reaction notes

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