p-Toluenesulfonic acid monohydrate → HCID 68683188, compound

HRID 2234321Notes

Reaction equation

HRID 2234321 reaction equation
Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[CH:41]=[CH:40][C:26]([C:27]([NH:29][CH:30]2[CH2:37][C@H:36]3[N:38]([CH3:39])[C@H:32]([CH2:33][CH2:34][CH2:35]3)[CH2:31]2)=[O:28])=[CH:25][C:24]=1[F:42].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.CO>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:19][CH2:18]3)[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:41]=[CH:40][C:26]([C:27]([NH:29][CH:30]5[CH2:37][C@H:36]6[N:38]([CH3:39])[C@H:32]([CH2:33][CH2:34][CH2:35]6)[CH2:31]5)=[O:28])=[CH:25][C:24]=4[F:42])=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1

Participants

6

Reactant 3

HCID 521998p-Toluenesulfonic acid monohydrateHCID 579699392-chloro-9-cyclopentyl-8,9-dihydro-5-methylspiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1'-cyclopropan]-6(7H)-one2×HCID 67159129HCID 67159129, compound2×

Product 1

HCID 68683188HCID 68683188, compoundYield 28%

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 79104-Methyl-2-PentanolSolvent

Conditions

Temperature
160 °C

Procedure

2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 108 mg, 0.35 mmol) and 4-amino-3-fluoro-N-(9-methyl-9-azabicyclo[3.3.1]non-7-yl)benzamide (Intermediate 162; 102 mg, 0.35 mmol) were combined with p-toluenesulphonic acid monohydrate (167 mg, 0.88 mmol) in 4-methyl-2-pentanol (2 mL) and heated by microwave irradiation for 25 minutes at 160° C. The cooled reaction mixture was diluted with methanol (10 mL) and loaded onto an SCX-3 cartridge (5 g) pre-wet with methanol. The cartridge was washed with methanol (2×5 mL) and eluted with 7 N methanolic ammonia (10 mL). Product containing fractions were evaporated and the resultant material purified by base modified reverse phase preparative HPLC to give the title compound as a white solid (54 mg, 28%).

Workup

  1. customThe cooled reaction mixture
  2. washThe cartridge was washed with methanol (2×5 mL)
  3. washeluted with 7 N methanolic ammonia (10 mL)
  4. additionProduct containing fractions
  5. customwere evaporated
  6. customthe resultant material purified by base modified reverse phase preparative HPLC

Sources & evidence

ORD record
ord-4e67e5cbc242451087beb5c7655b99f6
Source dataset
uspto-grants-2010_05
Patent number
US07709471B2

Reaction notes

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