p-Toluenesulfonic acid monohydrate → HCID 68683094, compound

HRID 2234339Notes

Reaction equation

HRID 2234339 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:42]=[CH:41][C:27]([C:28]([NH:30][CH:31]2[CH2:38][C@H:37]3[N:39]([CH3:40])[C@H:33]([CH2:34][CH2:35][CH2:36]3)[CH2:32]2)=[O:29])=[CH:26][C:25]=1[F:43].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([CH2:20][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:42]=[CH:41][C:27]([C:28]([NH:30][CH:31]5[CH2:38][C@H:37]6[N:39]([CH3:40])[C@H:33]([CH2:34][CH2:35][CH2:36]6)[CH2:32]5)=[O:29])=[CH:26][C:25]=4[F:43])=[N:12][C:11]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1

Participants

6

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 67159129HCID 67159129, compound2×

Product 1

HCID 68683094HCID 68683094, compoundYield 48%

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 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; 97 mg, 0.3 mmol) and 4-amino-3-fluoro-N-(9-methyl-9-azabicyclo[3.3.1]non-7-yl)benzamide (Intermediate 162; 88 mg, 0.3 mmol) were combined with p-toluenesulphonic acid monohydrate (143 mg, 0.75 mmol) in 4-methyl-2-pentanol (2 mL) and heated by microwave irradiation for 30 minutes at 160° C. The cooled reaction mixture was diluted with methanol (5 mL) and loaded onto an SCX-3 (5 g) cartridge pre-wet with methanol. The cartridge was washed with methanol (2×10 mL) and product eluted with 7 N methanolic ammonia (20 mL). Product containing fractions were evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (82 mg, 48%).

Workup

  1. customThe cooled reaction mixture
  2. washThe cartridge was washed with methanol (2×10 mL) and product
  3. washeluted with 7 N methanolic ammonia (20 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-63062f8eb3aa481495115071c9f83d2e
Source dataset
uspto-grants-2010_05
Patent number
US07709471B2

Reaction notes

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