Acetonitrile → Avagacestat

HRID 660273Notes

Reaction equation

HRID 660273 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:24]([CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:25]([NH2:27])=[O:26])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[N:21][OH:22])[NH2:20])=[CH:15][C:14]=2[F:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:34](#N)C.C(OCC)(OCC)OCC.FC(F)(F)C(O)=O>O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[CH:34][O:22][N:21]=3)=[CH:15][C:14]=2[F:23])[C@H:24]([CH2:28][CH2:29][C:30]([F:32])([F:33])[F:31])[C:25]([NH2:27])=[O:26])(=[O:10])=[O:9])=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 6342AcetonitrileHCID 6422Trifluoroacetic acidHCID 31214Ethyl orthoformateHCID 86630001(R)-2-(4-Chloro-N-(2-fluoro-4-(N'-hydroxycarbamimidoyl)benzyl)-phenylsulfonamido)-5,5,5-trifluoropentanamide

Product 1

HCID 46883536AvagacestatYield 90%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
45 °C

Procedure

(R)-2-(4-Chloro-N-(2-fluoro-4-(N′-hydroxycarbamimidoyl)benzyl)-phenylsulfonamido)-5,5,5-trifluoropentanamide (246 g) was charged to a reactor followed by dry acetonitrile (509 mL), triethyl orthoformate (120 mL), and trifluoroacetic acid (7 mL). The solution was heated to 40-50° C. until the reaction was complete by HPLC (<0.15 relative AP starting material). Methanol (1.48 L) was charged in one portion, followed by water (1.034 L), keeping the batch at 45-50° C. The batch was then cooled to 15-20° C. and filtered. The cake was washed with 2:6:5 MeCN:MeOH:water and tray dried under vacuum at 50-60° C., giving the title compound as a white solid (228 g, 90% yield). 1H NMR, (CDCl3, 300 MHz) δ: 1.40-1.58 (m, 1 H) 1.75-1.90 (m, 1 H) 1.92-2.07 (m, 1 H) 2.10 -2.26 (m, 1 H) 4.37 (dd, J=8.67, 6.22 Hz, 1 H) 4.48 (d, J=15.64 Hz, 1 H) 4.64 (d, J=15.82 Hz, 1 H) 5.54 (s, 1 H) 6.33 (s, 1 H) 7.44-7.54 (m, 2 H) 7.62 (t, J=7.72 Hz, 1 H) 7.68-7.76 (m, 3 H) 7.85 (dd, J=7.91, 1.51 Hz, 1H) 8.76 (s, 1 H). 13C NMR, (DMSO-d6, 75 MHz) δ: 170.34, 167.75, 165.80, 159.64 (d, J=244.5 Hz, 1C), 138.19, 137.64, 131.25 (d, J=3.75 Hz, 1C), 129.31, 129.23, 129.05 (d, J=14.25 Hz, 1C), 126.74 (q, J=274.5 Hz, 1C), 126.91, 126.80, 123.12 (d, J=3.75 Hz, 1C), 113.7 (d, J=24.0 Hz, 1 C), 57.92, 41.38 (d, J=4.5 Hz, 1 C), 30.04 (d, J=30.0 Hz, 1C), 22.90. 19F NMR, (CDCl3, 282 MHz) δ: −116.3, −66.5. IR (KBr): 3454, 334, 3286, 2952, 1705, 1432, 1325, 1260, 1167, 1084, 828 cm−1.

Workup

  1. customat 45-50° C
  2. temperatureThe batch was then cooled to 15-20° C.
  3. filtrationfiltered
  4. washThe cake was washed with 2:6:5 MeCN
  5. dry with materialMeOH:water and tray dried under vacuum at 50-60° C.

Sources & evidence

ORD record
ord-977669fbd19a4f7b890b57624a640162
Source dataset
uspto-grants-2011_12
Patent number
US08084477B2

Reaction notes

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