Sodium Hydroxide → N-[(4-fluoro-3'-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-3-(4-piperidinylmethyl)benzamide

HRID 2080315Notes

Reaction equation

HRID 2080315 reaction equation
[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[C@@H:19]([CH3:30])[CH2:18]3)[CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9].CC(OC([N:38]1[CH2:43][CH2:42][CH:41]([CH2:44][C:45]2[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=2)[C:48](O)=[O:49])[CH2:40][CH2:39]1)=O)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[OH-].[Na+]>CN(C=O)C.CCOC(C)=O.C(Cl)Cl>[F:9][C:8]1[CH:7]=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]3[CH2:22][CH2:21][NH:20][C@@H:19]([CH3:30])[CH2:18]3)[CH:11]=2)=[CH:4][C:3]=1[CH2:2][NH:1][C:48](=[O:49])[C:47]1[CH:51]=[CH:52][CH:53]=[C:45]([CH2:44][CH:41]2[CH2:40][CH2:39][NH:38][CH2:43][CH2:42]2)[CH:46]=1

Participants

9

Reactant 5

HCID 14798Sodium HydroxideHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 450739593-((1-(tert-Butoxycarbonyl)piperidin-4-yl)methyl)benzoic acidHCID 577367151,1-Dimethylethyl (2S)-4-{[3'-(aminomethyl)-4'-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate

Product 1

HCID 11642057N-[(4-fluoro-3'-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-3-(4-piperidinylmethyl)benzamideYield 67.1%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 1,1-dimethylethyl (2S)-4-{[3′-(aminomethyl)-4′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (0.108 g, 0.261 mmol) in DMF (2.5 mL) was added the commercially available 3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]benzoic acid (0.083 g, 0.261 mmol), HATU (0.110 g, 0.290 mmol), and diisopropylethylamine (0.10 mL, 0.574 mmol). The reaction was allowed to stir at room temperature for 2 days. The reaction was diluted with EtOAc (75 mL), washed with 1N HCl (2×20 mL), then saturated NaHCO3 (3×20 mL), then brine (2×20 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was taken up in MeOH (4 mL) and HCl (4N in 1,2-dioxane, 2.5 mL) was added. The reaction was allowed to stir at room temperature overnight. The reaction was concentrated under vacuum, and the residue was taken up in 1 DMSO/1 MeOH and purified via MDAP (10-90% CH3CN/H2O/(0.1% TFA)). The desired fractions were isolated, and then taken up in DCM (8 mL) and 1N NaOH (8 mL) and allowed to stir for 1 hour. The DCM was isolated using a phase separator and then concentrated under vacuum to give the title compound (84.6 mg, 67.1%). El-MS m/z 515(M−H)+.

Workup

  1. washwashed with 1N HCl (2×20 mL)
  2. dry with materialThe organic layer was dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated under vacuum
  5. additionHCl (4N in 1,2-dioxane, 2.5 mL) was added
  6. stirringto stir at room temperature overnight
  7. concentrationThe reaction was concentrated under vacuum
  8. custompurified via MDAP (10-90% CH3CN/H2O/(0.1% TFA))
  9. customThe desired fractions were isolated
  10. stirringto stir for 1 hour
  11. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-b19f238949d44eb1a962355689e51575
Source dataset
uspto-grants-2011_04
Patent number
US07932247B2

Reaction notes

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