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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)-3-methoxy-N-(tetrahydro-2H-pyran-4-yl)benzamide

HRID 1676784
Notes
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Reaction equation

HRID 1676784 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][C:37]=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:35][C:36]4[CH:50]=[CH:49][C:39]([C:40]([NH:42][CH:43]5[CH2:44][CH2:45][O:46][CH2:47][CH2:48]5)=[O:41])=[CH:38][C:37]=4[O:51][CH3:52])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 124969952-Methylbenzenesulfonic acid hydrateHCID 579555542-Chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-oneHCID 670758624-Amino-3-methoxy-N-(tetrahydro-2H-pyran-4-yl)benzamide

Product 1

HCID 252546174-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(tetrahydro-2H-pyran-4-yl)benzamideYield 65.6%

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, 0.0451 g (0.18 mmole) of 4-amino-3-methoxy-N-(tetrahydro-2H-pyran-4-yl) benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 16 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 ethyl acetate to give 0.0643 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)-3-methoxy-N-(tetrahydro-pyran-4-yl)-benzamide (I-252) as a white solid.

Workup

  1. temperaturewas heated in a sealed vessel at 140 degrees for 16 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 ethyl acetate

Sources & evidence

ORD record
ord-b2f3c3dc61034f2dab40bef603a4e2e5
Source dataset
uspto-grants-2011_08
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08003785B2

Reaction notes

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