Water → (R)-2-(3,5-Dichloro-4'-fluoro-biphenyl-4-ylmethyl)-4-[(S)-(4,5,6,7-tetrahydro-1H-indazol-5-yl)amino]-butyric acid

HRID 1013830Notes

Reaction equation

HRID 1013830 reaction equation
[NH:1]1[C:9]2[CH2:8][CH2:7][C@H:6]([NH2:10])[CH2:5][C:4]=2[CH:3]=[N:2]1.[Cl:11][C:12]1[CH:13]=[C:14]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:15]=[C:16]([Cl:26])[C:17]=1[CH2:18][C@@H:19]1[CH2:23][CH:22](O)[O:21][C:20]1=[O:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(#N)C>[Cl:11][C:12]1[CH:13]=[C:14]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[CH:15]=[C:16]([Cl:26])[C:17]=1[CH2:18][C@H:19]([CH2:23][CH2:22][NH:10][C@H:6]1[CH2:7][CH2:8][C:9]2[NH:1][N:2]=[CH:3][C:4]=2[CH2:5]1)[C:20]([OH:25])=[O:21]

Participants

6

Reactant 4

HCID 962WaterHCID 5049666Sodium triacetoxyborohydride2×HCID 24762810HCID 24762810, compoundHCID 27973891(S)-4,5,6,7-Tetrahydro-1H-indazol-5-amine

Product 1

HCID 24762811(R)-2-(3,5-Dichloro-4'-fluoro-biphenyl-4-ylmethyl)-4-[(S)-(4,5,6,7-tetrahydro-1H-indazol-5-yl)amino]-butyric acidYield 66.6%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of 0.30 g (2.2 mmoles) of (S)-(4,5,6,7-tetrahydro-1H-indazol-5-yl)amine in 15 mL of ACN at 43° C., add 0.732 g (2.05 mmoles) of (R)-3-(3,5-Dichloro-4′-fluoro-biphenyl-4-ylmethyl)-5-hydroxy-dihydro-furan-2-one. Heat the mixture at 50° C. for 0.5 h and allow to cool to room temperature. Add 0.70 g (3.3 mmoles) of sodium triacetoxyborohydride. After 2.5 h, add an additional charge of sodium triacetoxyborohydride (100 mg). After 1 h, heat to 50° C. and add 15 mL of water slowly. Allow to cool to room temperature and stir the slurry overnight. Collect the solids by filtration and rinse with water (2×5 mL). Stir the wet cake with 15 mL of acetonitrile and filter. Rinse the cake with acetonitrile (2×5 mL) and dry in a vacuum oven to afford 0.65 g (62%) of the title compound as a solid. MS (m/z): 476 (M+1, 35Cl), 478 (M+1, 37Cl).

Workup

  1. temperatureto cool to room temperature
  2. additionadd
  3. waitAfter 1 h
  4. temperatureheat to 50° C.
  5. temperatureto cool to room temperature
  6. customCollect the solids
  7. filtrationby filtration
  8. washrinse with water (2×5 mL)
  9. stirringStir the wet cake with 15 mL of acetonitrile
  10. filtrationfilter
  11. washRinse the cake with acetonitrile (2×5 mL)
  12. customdry in a vacuum oven

Sources & evidence

ORD record
ord-5ce39bef04c14debbc7a8a4d9ef2dbe9
Source dataset
uspto-grants-2011_07
Patent number
US07981918B2

Reaction notes

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