Hydroxylamine → Avagacestat

HRID 1803744Notes

Reaction equation

HRID 1803744 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=2[F:31])[C@H:12]([CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:32][OH:33].[NH2:34]O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:34]=[CH:32][O:33][N:30]=3)=[CH:25][C:24]=2[F:31])[C@H:12]([CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([NH2:15])=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 787HydroxylamineHCID 887MethanolHCID 56953105(2R)-2-[[(4-Chlorophenyl)sulfonyl][(4-cyano-2-fluorophenyl)methyl]amino]-5,5,5-trifluoropentanamide

Product 1

HCID 46883536AvagacestatYield 96%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
47.5 °C

Procedure

(2R)-2-[[(4-Chlorophenyl)sulfonyl][(4-cyano-2-fluorophenyl)methyl]amino]-5,5,5-trifluoropentanamide (399 g) and methanol (1.6 L) were charged to a reactor followed by hydroxylamine (50% solution in water, 93 mL, 1.8 eq). The mixture was heated to 45-50° C. until complete reaction by HPLC (<0.15 relative AP starting material). Water (0.5 L) was charged slowly, keeping the batch temperature between 30-50° C. The batch was allowed to stand until crystallization started and then water (2.7 L) was charged. The batch was cooled to 15-20° C. and filtered. The cake was washed with 2:1 MeOH:water (2 L) and then dried under vacuum at 50° C. to give the title compound as white solid (415 g, 96% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.43-1.64 (m, 1H) 1.77-1.93 (m, 1H) 1.93-2.17 (m, 2H) 4.41 (dd, J=8.48, 6.03 Hz, 1H) 4.60 (d, J=17.14 Hz, 1H) 4.94 (d, J=16.77 Hz, 1H) 5.81-5.98 (m, 2 H) 7.19-7.27 (m, 1H) 7.37-7.47 (m, 2H) 7.52 (d, J=4.14 Hz, 2H) 7.64 (d, J=8.67, Hz, 2H) 7.85 (d, J=8.85 Hz, 2H) 9.71-9.83 (m, 1H). IR (KBr): 3491, 3379, 1680, 1651, 1592, 1433, 1343.

Workup

  1. custombetween 30-50° C
  2. customto stand until crystallization
  3. additionwater (2.7 L) was charged
  4. temperatureThe batch was cooled to 15-20° C.
  5. filtrationfiltered
  6. washThe cake was washed with 2:1 MeOH
  7. dry with materialwater (2 L) and then dried under vacuum at 50° C.

Sources & evidence

ORD record
ord-03630bf3a72c47c088e5e45fac153dd4
Source dataset
uspto-grants-2013_01
Patent number
US08350084B2

Reaction notes

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