Lithium Hydroxide → racemic N-{4-[4,4,4-trifluoro-1-({6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}amino)butyl]benzoyl}-beta-alanine

HRID 1520957Notes

Reaction equation

HRID 1520957 reaction equation
[F:1][C:2]([F:39])([F:38])[CH2:3][CH2:4][CH:5]([C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:24][CH:23]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]([N:13]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[N:14]2)=[CH:11][CH:12]=1.O1CCCC1.[OH-].[Li+]>CO>[F:39][C:2]([F:1])([F:38])[CH2:3][CH2:4][CH:5]([C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][CH:23]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]([N:13]2[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[N:14]2)=[CH:11][CH:12]=1

Participants

5

Reactant 3

HCID 3939Lithium HydroxideHCID 8028TetrahydrofuranHCID 86669095(+/-)-ethyl N-{4-[4,4,4-trifluoro-1-({6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}amino)butyl]benzoyl}-beta-alaninate

Product 1

HCID 88851218racemic N-{4-[4,4,4-trifluoro-1-({6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}amino)butyl]benzoyl}-beta-alanine

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

A mixture of crude (+/−)-ethyl N-{4-[4,4,4-trifluoro-1-({6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}amino)butyl]benzoyl}-beta-alaninate (52 mg, 0.093 mmol) was dissolved in methanol (0.20 ml) and tetrahydrofuran (0.10 ml) and treated with aqueous lithium hydroxide (0.093 ml, 0.19 mmol, 2.0M). The mixture was stirred at ambient temperature for 1 hour. The crude reaction mixture was concentrated in vacuo and the residual solid was dissolved in water (0.50 ml) and treated with aqueous 1.0M hydrochloric acid until approximately pH 6 was reached, resulting in the precipitation of racemic N-{4-[4,4,4-trifluoro-1-({6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}amino)butyl]benzoyl}-beta-alanine as a white gummy solid. The two enantiomeric products were separated by chiral SFC Column: Chiralpak AD-H. Dimensions: 21×250 mm. Mobile Phase: 70/30 CO2/methanol, (peak 1, 0.30 g, 22% and peak 2, 0.30 g, 22%). Flow Rate: 65 mL/min. Modifier: none. Analytical SFC: Chiralpak AD-H, 4.6 mm×25 cm; SFC Mobile Phase 70:30 CO2/Methanol, 2.5 mL/min, analytical retention time: 2.97 min (Isomer 1) and 5.15 (Isomer 2). 1H NMR (400 MHz, CDCl3): δ 8.64 (s, 1H), 7.73-7.84 (m, 4H), 7.70 (d, J=8.8 Hz, 1H), 7.37-7.43 (m, 2H), 6.98 (br. dd, J=8.6, 2.0 Hz, 1H), 6.73-6.86 (m, 1H), 4.48 (br. t, J=6.3 Hz, 1H), 3.73 (br. q, J=5.9 Hz, 2H), 2.72 (br. t, J=5.8 Hz, 2H), 2.06-2.34 (m, 4H). MS (M+1): 530.3.

Workup

  1. customThe crude reaction mixture
  2. concentrationwas concentrated in vacuo
  3. dissolutionthe residual solid was dissolved in water (0.50 ml)
  4. additiontreated with aqueous 1.0M hydrochloric acid until approximately pH 6

Sources & evidence

ORD record
ord-d1b74ffa259946d9b6b4f170b621dc4a
Source dataset
uspto-grants-2015_07
Patent number
US09073871B2

Reaction notes

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