Isobutyronitrile → HCID 57544703, compound

HRID 2355505Notes

Reaction equation

HRID 2355505 reaction equation
[Cl:1][C:2]1[C:3]([F:36])=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][C@@H:25]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:26][NH:27][CH3:28])=[O:23])[CH2:17]2)(O)[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.[C:37](#[N:41])[CH:38]([CH3:40])[CH3:39].C([O-])([O-])=[O:43].[K+].[K+]>OS(O)(=O)=O.O>[Cl:1][C:2]1[C:3]([F:36])=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][C@@H:25]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:26][NH:27][CH3:28])=[O:23])[CH2:17]2)([NH:41][C:37](=[O:43])[CH:38]([CH3:40])[CH3:39])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 3

HCID 6559IsobutyronitrileHCID 11430Potassium CarbonateHCID 44143403HCID 44143403, compound

Product 1

HCID 57544703HCID 57544703, compoundYield 14%

Reagents, catalysts & solvents 2

HCID 962WaterCatalystHCID 1118Sulfuric AcidCatalyst

Procedure

(3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide (70 mg, 0.133 mmol) was mixed with isobutyronitrile (8 mL) and conc H2SO4 (23 drops). After stirring vigorously overnight at rt, the mixture was neutralized with K2CO3 (ca. 100 mg). A few drops of water were added and the mixture was filtered. The filtrate was concentrated and the residue was purified by preparative HPLC to afford (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-(isobutyramido)-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide (11.4 mg, 14%) as a TFA salt. 1H NMR (400 MHz, CDCl3): 7.94 (s, 1H), 7.41 (td, 1H), 7.27 (td, 1H), 7.15 (t, 1H), 4.25 (d, 1H), 4.11 (m, 1H), 3.92 (d, 1H), 3.37 (t, 1H), 3.28 (s, 3H), 3.07 (dd, 1H), 2.96 (dd, 1H), 2.71 (s, 3H), 2.66 (m, 1H), 2.54 (td, 1H), 1.14 (dd, 6H). 3 min. LC-MS: R/T 1.59 min., m/z 596 (M+H+). In addition, (3R)-3-((R)-1-(3-chloro-2-fluorophenyl)-1-(isobutyramido)-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide and (S)-3-(1-(3-chloro-2-fluorophenyl)-1-(isobutyramido)-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)piperidine-1-carboxamide and (S)-3-(1-(3-chloro-2-fluorophenyl)-5-methoxypent-1-enyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide were isolated.

Workup

  1. filtrationthe mixture was filtered
  2. concentrationThe filtrate was concentrated
  3. customthe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-5a4cd996a104499bb5d496d7447ef6cb
Source dataset
uspto-grants-2010_07
Patent number
US07754737B2

Reaction notes

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