Methanol → 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-(1-ethyl-4-piperidyl)-2-fluoro-5-methoxy-benzamide

HRID 2234343Notes

Reaction equation

HRID 2234343 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[C:40]([O:41][CH3:42])=[CH:39][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]2)=[O:29])=[C:26]([F:43])[CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>CC(C)CC(O)C>[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[C:40]([O:41][CH3:42])=[CH:39][C:27]([C:28]([NH:30][CH:31]5[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]5)=[O:29])=[C:26]([F:43])[CH:25]=4)=[N:12][C:11]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1

Participants

6

Reactant 4

HCID 887MethanolHCID 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 686817954-amino-N-(1-ethyl-4-piperidyl)-2-fluoro-5-methoxy-benzamide2×

Product 1

HCID 250052974-(9'-cyclohexyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-1,7'-pyrimido[5,4-b][1,4]diazepine]-2'-ylamino)-N-(1-ethyl-4-piperidyl)-2-fluoro-5-methoxy-benzamideYield 49%

Reagents, catalysts & solvents 1

HCID 79104-Methyl-2-PentanolSolvent

Conditions

Temperature
110 °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; 54 mg, 0.17 mmol), 4-amino-N-(1-ethyl-4-piperidyl)-2-fluoro-5-methoxy-benzamide (Intermediate 205; 50 mg, 0.17 mmol), and p-toluenesulphonic acid monohydrate (81 mg, 0.43 mmol) were stirred together in 4-methyl-2-pentanol (3 mL) and heated at 110° C. for 18 hours. The cooled reaction mixture was loaded onto an SCX-3 (5 g) column pre-wet with MeOH. The column was washed with MeOH (2 column volumes) and eluted with 2M NH3/MeOH. Solvent evaporation of the combined ammoniacal fractions gave a brown gum which was purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (48 mg, 49%)

Workup

  1. customThe cooled reaction mixture
  2. washThe column was washed with MeOH (2 column volumes)
  3. washeluted with 2M NH3/MeOH
  4. customSolvent evaporation of the combined ammoniacal fractions
  5. customgave a brown gum which
  6. customwas purified by base modified reverse phase preparative HPLC

Sources & evidence

ORD record
ord-7a0a1317907e4371a46f00eb3a259066
Source dataset
uspto-grants-2010_05
Patent number
US07709471B2

Reaction notes

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