L-Malic Acid → (3S,5S,6R)-3-Amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one (S)-2-hydroxysuccinate

HRID 706393Notes

Reaction equation

HRID 706393 reaction equation
[NH2:1][CH:2]1[CH2:7][C@@H:6]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:9]=2[F:16])[C@@H:5]([CH3:17])[N:4]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:3]1=[O:23].[CH2:24]([C:30]([OH:32])=[O:31])[C@H:25]([OH:29])[C:26]([OH:28])=[O:27]>C1COCC1>[OH:29][C@@H:25]([CH2:24][C:30]([OH:32])=[O:31])[C:26]([OH:28])=[O:27].[NH2:1][C@H:2]1[CH2:7][C@@H:6]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:9]=2[F:16])[C@@H:5]([CH3:17])[N:4]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:3]1=[O:23]

Participants

4

Reactant 2

HCID 222656L-Malic AcidHCID 89821839(5S,6R)-3-Amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one

Product 1

HCID 72196085(3S,5S,6R)-3-Amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one (S)-2-hydroxysuccinateYield 73.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
58 °C

Procedure

To a solution of 48 (0.24 g, 0.72 mmol) in THF (3.7 mL) was added L-(−)-malic acid (0.10 g, 0.75 mmol). The homogeneous reaction was heated to 58° C. and aged for 3 h. After the reaction was complete, the slurry was cooled to 20-25° C. and aged for 16 h. The solids were filtered, washed twice with ice-cold THF, and dried to give product 49 (0.25 g, 73% yield) as crystals. 1H NMR (400 MHz, DMSO-d6): δ 7.50-7.54 (m, 1H), 7.01-7.06 (m, 1H), 4.68 (dq, J=15.3, 9.6 Hz, 1H), 4.05 (dd, J=11.6, 6.7 Hz, 1H), 3.91-3.92 (m, 2H), 3.84-3.87 (m, 2H), 2.51 (m, 1H), 2.45 (m, 1H), 2.33 (dd, J=15.6, 4.4 Hz, 1H), 2.15 (dd, J=12.3, 6.7 Hz, 1H), 0.97 (d, J=6.4 Hz, 3H); 13C NMR (100 MHz, DSMO-d6): δ 176.3, 172.0, 168.4, 157.4 (ddd, J=243, 11, 2 Hz), 150.0 (dt, J=248, 14 Hz), 144.7 (ddd, J=242, 13, 4 Hz), 130.4 (dd, J=13, 9 Hz), 124.8 (q, J=281 Hz), 110.9 (dt, J=26, 3 Hz), 105.1 (dd, J=28, 21 Hz), 66.1, 56.0, 49.6, 44.5 (q, J=33 Hz), 41.3, 35.1, 25.1, 13.8; 19F NMR (377 MHz, DMSO-d6): δ −69.3, −114.6 (d, J=14.9 Hz), −134.7 (d, J=21.8 Hz), −148.8 (dd, J=21.8, 14.9 Hz).

Workup

  1. customThe homogeneous reaction
  2. temperaturethe slurry was cooled to 20-25° C. and aged for 16 h
  3. filtrationThe solids were filtered
  4. washwashed twice with ice-cold THF
  5. customdried

Sources & evidence

ORD record
ord-c25bd53fd5c04650ae0951b8323e51bf
Source dataset
uspto-grants-2015_11
Patent number
US09174989B2

Reaction notes

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