2-Methylbenzenesulfonic acid hydrate → 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(tetrahydro-pyran-4-yl)-benzamide

HRID 1676794Notes

Reaction equation

HRID 1676794 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[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:50]=[CH:49][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[O:41])=[CH:38][CH:37]=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:35][C:36]4[CH:37]=[CH:38][C:39]([C:40]([NH:42][CH:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)=[O:41])=[CH:49][CH:50]=4)=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1

Participants

5

Reactant 3

HCID 124969952-Methylbenzenesulfonic acid hydrateHCID 436095624-amino-N-(oxan-4-yl)benzamideHCID 579555542-Chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one

Product 1

HCID 580150524-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(tetrahydro-pyran-4-yl)-benzamideYield 54.1%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Procedure

A mixture of 0.0562 g (0.18 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.0514 g (0.27 mmole) of toluenesulfonic acid monohydrate, 0.0396 g (0.18 mmole) of 4-amino-N-(tetrahydro-pyran-4-yl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 16.5 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 recrystallized from acetonitrile to give 0.0501 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(tetrahydro-pyran-4-yl)-benzamide (I-263) as a white solid.

Workup

  1. temperaturewas heated in a sealed vessel at 140 degrees for 16.5 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 recrystallized from acetonitrile

Sources & evidence

ORD record
ord-7dd5afab02cd468386c0b803bebd358d
Source dataset
uspto-grants-2011_08
Patent number
US08003785B2

Reaction notes

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