Trifluoroacetic acid → 3-{1-[4-(4-Amino-3-chloro-5-trifluoromethyl-phenyl)-3-(1-piperidin-4-ylmethyl-1H-benzimidazol-2-yl)-butyryl]-piperidin-4-yl}-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

HRID 494754Notes

Reaction equation

HRID 494754 reaction equation
[NH2:1][C:2]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][C:5]([CH2:6][CH:7]([CH2:10][C:11](=[O:30])[N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:29])[CH2:14][CH2:13]2)[CH:8]=O)=[CH:4][C:3]=1[Cl:37].[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH:45][CH2:46][CH:47]1[CH2:52][CH2:51][N:50](C(OC(C)(C)C)=O)[CH2:49][CH2:48]1.C(O)(C(F)(F)F)=O>CN(C=O)C.ClCCl>[NH2:1][C:2]1[C:32]([C:33]([F:34])([F:36])[F:35])=[CH:31][C:5]([CH2:6][CH:7]([C:8]2[N:45]([CH2:46][CH:47]3[CH2:48][CH2:49][NH:50][CH2:51][CH2:52]3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[N:38]=2)[CH2:10][C:11]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:29])[CH2:16][CH2:17]2)=[O:30])=[CH:4][C:3]=1[Cl:37]

Participants

6

Reactant 3

HCID 6422Trifluoroacetic acidHCID 221845352-(4-Amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butyraldehyde2×HCID 53255822tert-Butyl 4-(((2-aminophenyl)amino)methyl)piperidine-1-carboxylate2×

Product 1

HCID 102404223-{1-[4-(4-Amino-3-chloro-5-trifluoromethyl-phenyl)-3-(1-piperidin-4-ylmethyl-1H-benzimidazol-2-yl)-butyryl]-piperidin-4-yl}-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 537 mg (1.000 mmol) 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butyraldehyde (Intermediate product 36) in 10 mL DMF was added tert. butyl 4-[(2-amino-phenylamino)-methyl]-piperidin-1-carboxylate (Intermediate product 34) and the mixture was stirred for 16 hours in an atmosphere of air at RT. The reaction mixture was poured onto ice water, the precipitate formed was filtered off, washed with water and dried i. vac. (Yield: 790 mg, 96% of theory). 1 mL of TFA was added to a solution of 580 mg (0.705 mmol) of the crude product in 10 mL dichloromethane and the mixture was stirred for 16 hours at RT. The reaction mixture was diluted with dichloromethane, the org. phase was washed with sat. aqueous sodium bicarbonate solution, dried over sodium sulphate and evaporated i. vac. The residue was dissolved in 3.5 mL DMF and purified by HPLC-MS (Zorbax Bonus C18 amide-phase 5 μm, gradient 0.15% formic acidin water/acetonitrile 10/90→90/10 v/v) and then lyophilised.

Workup

  1. additionThe reaction mixture was poured onto ice water
  2. customthe precipitate formed
  3. filtrationwas filtered off
  4. washwashed with water
  5. customdried i
  6. stirringthe mixture was stirred for 16 hours at RT
  7. washphase was washed with sat. aqueous sodium bicarbonate solution
  8. dry with materialdried over sodium sulphate
  9. customevaporated i
  10. dissolutionThe residue was dissolved in 3.5 mL DMF
  11. custompurified by HPLC-MS (Zorbax Bonus C18 amide-phase 5 μm, gradient 0.15% formic acidin water/acetonitrile 10/90→90/10 v/v)

Sources & evidence

ORD record
ord-69b29c714d8d48c68778a852c284ddb7
Source dataset
uspto-grants-2009_05
Patent number
US07538115B2

Reaction notes

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