Sodium Carbonate → Phenylmethyl (2S)-4-({2'-fluoro-5'-[({[3-(4-piperidinyl)phenyl]carbonyl}amino)methyl]-3-biphenylyl}methyl)-2-methyl-1-piperazinecarboxylate

HRID 2080325Notes

Reaction equation

HRID 2080325 reaction equation
CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)[CH2:10][CH2:9]1)=O)(C)C.[NH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([F:55])=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[O:45])[C@@H:40]([CH3:54])[CH2:39]3)[CH:32]=2)[CH:30]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[F:55][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][NH:23][C:17]([C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:15]=2)=[O:19])=[CH:30][C:29]=1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])[C@@H:40]([CH3:54])[CH2:39]2)[CH:32]=1

Participants

8

Reactant 5

HCID 10340Sodium CarbonateHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 450737913-(1-(tert-Butoxycarbonyl)piperidin-4-yl)benzoic acidHCID 57730446Phenylmethyl (2S)-4-{[5'-(aminomethyl)-2'-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate

Product 1

HCID 57736691Phenylmethyl (2S)-4-({2'-fluoro-5'-[({[3-(4-piperidinyl)phenyl]carbonyl}amino)methyl]-3-biphenylyl}methyl)-2-methyl-1-piperazinecarboxylateYield 43%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of the commercially available 3-(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)benzoic acid (183 mg, 0.60 mmol) in 2 mL of dry DMF was added phenylmethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (250 mg, 0.60 mmol), DIPEA (0.2 ml, 1.4 mmol), and HATU (251 mg, 0.66 mmol). The reaction mixture was stirred at room temperature for 2 h before addition of 2 mL of saturated Na2CO3 and 10 mL of EtOAc. The organic layer was separated, dried over Na2SO4, and filtered. The filtrate was concentrated and the residue was mixed with 4M HCl in 1,4-dioxane (5 mL). The resulting mixture was stirred at room temperature for 1 h. After removal of the solvent, the residue was purified by Gilson reverse phase HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 70/30, v/v, over 12 min), to give the title compound (162 mg, 43%). LC/MS: m/z, 635 (M+H), 1.75 min.

Workup

  1. customThe organic layer was separated
  2. dry with materialdried over Na2SO4
  3. filtrationfiltered
  4. concentrationThe filtrate was concentrated
  5. additionthe residue was mixed with 4M HCl in 1,4-dioxane (5 mL)
  6. customAfter removal of the solvent
  7. customthe residue was purified by Gilson reverse phase HPLC
  8. washeluting with acetonitrile/water/0.1% TFA (10/90 to 70/30, v/v, over 12 min)

Sources & evidence

ORD record
ord-62c1683a158041a183376bf0584bc667
Source dataset
uspto-grants-2011_04
Patent number
US07932247B2

Reaction notes

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