Sodium Carbonate → 4-(7,7-difluoro-9-isopropyl-5-methyl-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 1676831Notes

Reaction equation

HRID 1676831 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]([CH3:18])[CH3:17])[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.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)(C)C>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]2[N:19]=[C:2]([NH:20][C:21]3[CH:36]=[CH:35][C:24]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]4)=[O:26])=[CH:23][C:22]=3[O:37][CH3:38])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 521998p-Toluenesulfonic acid monohydrateHCID 115290634-Amino-3-methoxy-n-(1-methylpiperidin-4-yl)benzamideHCID 866359002-Chloro-7,7-difluoro-9-isopropyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one

Product 1

HCID 445468884-(7,7-difluoro-9-isopropyl-5-methyl-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 30.6%

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 0.07 g (0.24 mmole) of 2-chloro-7,7-difluoro-9-isopropyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-292b), 0.070 g (0.26 mmole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.069 g (0.36 mmole) of p-toluenesulfonic acid monohydrate and 4 mL of isopropanol was heated in a pressure tube at 140 degrees overnight. After cooling, dichloromethane and saturated sodium carbonate were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-40:60) gave 0.038 g of 4-(7,7-difluoro-9-isopropyl-5-methyl-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-293) as a white solid.

Workup

  1. temperaturewas heated in a pressure tube at 140 degrees overnight
  2. temperatureAfter cooling
  3. extractionThe mixture was extracted with dichloromethane twice
  4. washThe combined organic layers were washed three times with sodium carbonate, times with brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customPurification by silica gel chromatography
  9. washeluting with dichloromethane-methanol (gradient, 100:0-40:60)

Sources & evidence

ORD record
ord-1042f9087c944168a11895e3c5a928e0
Source dataset
uspto-grants-2011_08
Patent number
US08003785B2

Reaction notes

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