p-Toluenesulfonic acid monohydrate → 4-(9'-cyclohexyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-1,7'-pyrimido[5,4-b][1,4]diazepine]-2'-ylamino)-N-(3-dimethylamino-2,2-dimethyl-propyl)-3-methoxy-benzamide

HRID 2234342Notes

Reaction equation

HRID 2234342 reaction equation
Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3([CH2:20][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:23][C:24]1[CH:40]=[CH:39][C:27]([C:28]([NH:30][CH2:31][C:32]([CH3:38])([CH3:37])[CH2:33][N:34]([CH3:36])[CH3:35])=[O:29])=[CH:26][C:25]=1[O:41][CH3:42].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.CO.O>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:20][CH2:19]3)[C:7](=[O:21])[N:6]([CH3:22])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:40]=[CH:39][C:27]([C:28]([NH:30][CH2:31][C:32]([CH3:37])([CH3:38])[CH2:33][N:34]([CH3:35])[CH3:36])=[O:29])=[CH:26][C:25]=4[O:41][CH3:42])=[N:12][C:11]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1

Participants

7

Reactant 3

HCID 521998p-Toluenesulfonic acid monohydrateHCID 579698842'-chloro-9'-cyclohexyl-5'-methyl-8',9'-dihydrospiro[cyclopropane-1,7'-pyrimido[5,4-b][1,4]diazepin]-6'(5'H)-one2×HCID 592951104-amino-N-(3-dimethylamino-2,2-dimethyl-propyl)-3-methoxy-benzamide2×

Product 1

HCID 686819304-(9'-cyclohexyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-1,7'-pyrimido[5,4-b][1,4]diazepine]-2'-ylamino)-N-(3-dimethylamino-2,2-dimethyl-propyl)-3-methoxy-benzamideYield 55%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 79104-Methyl-2-PentanolSolvent

Conditions

Temperature
160 °C

Procedure

2′-chloro-9′-cyclohexyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 270; 86 mg, 0.27 mmol) and 4-amino-N-(3-dimethylamino-2,2-dimethyl-propyl)-3-methoxy-benzamide (Intermediate 22; 75 mg, 0.27 mmol) were taken up in 4-methyl-2-pentanol (3 mL) and p-toluenesulphonic acid monohydrate (102 mg, 0.54 mmol) added. The reaction mixture was heated at 160° C. for 1 hour by microwave irradiation. After cooling, the reaction mixture was diluted with methanol (5 mL) and water (5 mL) and the resultant solution loaded onto an SCX-3 (5 g) cartridge. The cartridge was washed with methanol (40 mL) and then eluted with 2M ammonia in methanol (25 mL). Evaporation of the ammoniacal solution gave an opaque cream coloured film which was purified by base modified reverse phase preparative HPLC to yield the title compound as a white foam (83 mg, 55%)

Workup

  1. temperatureAfter cooling
  2. washThe cartridge was washed with methanol (40 mL)
  3. washeluted with 2M ammonia in methanol (25 mL)
  4. customEvaporation of the ammoniacal solution
  5. customgave an opaque cream coloured film which
  6. customwas purified by base modified reverse phase preparative HPLC

Sources & evidence

ORD record
ord-3253ab2f85064ba98d8e86ec10e00c63
Source dataset
uspto-grants-2010_05
Patent number
US07709471B2

Reaction notes

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