p-Toluenesulfonic acid monohydrate → 3-methoxy-4-[[6-methyl-2-[(4-methylpentan-2-yloxycarbonimidoyl)methyl]-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl]amino]-N-(1-methyl-4-piperidyl)benzamide

HRID 2234296Notes

Reaction equation

HRID 2234296 reaction equation
Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH2:13][C:14]#[N:15])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:24])=[CH:21][C:20]=1[O:35][CH3:36].[OH2:37].[C:38]1([CH3:48])[CH:43]=C[C:41](S(O)(=O)=O)=[CH:40][CH:39]=1>CC(C)CC(O)C.O.CO.C(O)(C)C>[CH3:36][O:35][C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][C:19]=1[NH:18][C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH2:13][C:14]([O:37][CH:40]([CH2:39][CH:38]([CH3:48])[CH3:43])[CH3:41])=[NH:15])=[CH:4][N:3]=1)[C:23]([NH:25][CH:26]1[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]1)=[O:24]

Participants

8

Reactant 3

HCID 521998p-Toluenesulfonic acid monohydrate2×HCID 115290634-Amino-3-methoxy-n-(1-methylpiperidin-4-yl)benzamide2×HCID 866175502-(10-Chloro-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-2-yl)acetonitrile2×

Product 1

HCID 686818073-methoxy-4-[[6-methyl-2-[(4-methylpentan-2-yloxycarbonimidoyl)methyl]-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl]amino]-N-(1-methyl-4-piperidyl)benzamideYield 9.3%

Reagents, catalysts & solvents 4

HCID 887MethanolSolvent3×HCID 962WaterSolventHCID 3776IsopropanolSolventHCID 79104-Methyl-2-PentanolSolvent

Procedure

2-(10-chloro-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-2-yl)acetonitrile (Intermediate 155; 97 mg, 0.39 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 124 mg, 0.47 mmol) and p-toluenesulphonic acid monohydrate (148 mg, 0.78 mmol) were heated together in 4-methyl-2-pentanol (4 mL) at 100° C. for 24 hours. The reaction mixture was diluted with water and methanol and the solution loaded onto an SCX-2 (5 g) column pre-wet with methanol. The column was washed with methanol (×2) and eluted with 2M NH3/MeOH. Fractions containing product identified as the addition product of the solvent and nitrile group were combined and evaporated. To the residue was added 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220 62 mg, 0.24 mmol) and p-toluenesulphonic acid monohydrate (74 mg, 0.39 mmol) and the mixture heated by microwave irradiation in isopropanol (4 mL) for 20 minutes at 150° C. The cooled mixture was loaded onto an SCX-2 (5 g) column pre-wet with MeOH. The column was washed with MeOH and eluted with 2M NH3/MeOH. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a light brown solid (21 mg, 9%).

Workup

  1. washThe column was washed with methanol (×2)
  2. washeluted with 2M NH3/MeOH
  3. additionFractions containing product
  4. customevaporated
  5. washThe column was washed with MeOH
  6. washeluted with 2M NH3/MeOH
  7. additionProduct containing fractions
  8. customevaporated
  9. customthe resultant material purified by base modified reverse phase preparative HPLC

Sources & evidence

ORD record
ord-a20ee55c1f3645858bde928d4d52a1a6
Source dataset
uspto-grants-2010_05
Patent number
US07709471B2

Reaction notes

Loading…