1-Methyl-1H-1,2,3-triazole → HCID 118006276, compound

HRID 926590Notes

Reaction equation

HRID 926590 reaction equation
C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[N:8]1.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[N:29]([CH3:30])[C:28]([CH3:31])=[N:27][CH:26]=3)=[O:24])[CH:21]=2)[N:16]=[C:15]([CH2:32][CH3:33])[C:14]=1[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=1>O1CCCC1>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[N:29]([CH3:30])[C:28]([CH3:31])=[N:27][CH:26]=3)([C:11]3[N:7]([CH3:6])[N:8]=[N:9][CH:10]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([CH2:32][CH3:33])[C:14]=1[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=1

Participants

5

Reactant 3

HCID 1401191-Methyl-1H-1,2,3-triazoleHCID 118006240HCID 118006240, compound2×HCID 178418339Butyllithium

Product 1

HCID 118006276HCID 118006276, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of n-butyllithium in hexanes (2.5 M, 0.17 mL, 0.43 mmol) was added dropwise to a stirring solution of 1-methyl-1H-1,2,3-triazole (38.3 mg, 0.461 mmol, prepared according to PCT Int. Appl., 2008098104) in tetrahydrofuran (1.5 mL) at −50° C. After 20 minutes at −50° C., a solution of (4-chloro-2-ethyl-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone (0.145 g, 0.307 mmol, Intermediate 25: step b) in tetrahydrofuran (1.5 mL) was added dropwise. After 5 minutes at −50° C., the flask was allowed to warm to 0° C. After 30 minutes, the mixture was partitioned between half-saturated aqueous sodium chloride solution (25 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer was dried with sodium sulfate. The dried solution was filtered. Silica gel (3 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash column chromatography purification. Elution with dichloromethane initially, grading to 10% methanol-dichloromethane provided the title compound as an off-white solid. The solid was further purified by chiral SFC (Chiralpak AD-H, 5 μm, 250×20 mm, mobile phase: 75% CO2, 25% ethanol containing 0.03% isopropylamine) to provide two enantiomers. The first eluting enantiomer was Example 25b: 1H NMR (600 MHz, CDCl3) δ ppm 8.30 (d, J=2.1 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.57-7.49 (m, 3H), 7.21 (d, J=7.9 Hz, 2H), 7.17 (s, 1H), 6.18 (s, 1H), 4.91 (s, 1H), 4.49 (s, 2H), 3.95 (s, 3H), 3.40 (s, 3H), 3.00-2.90 (m, 2H), 2.30 (s, 3H), 1.35-1.28 (m, 3H); MS (ESI): mass calcd. for C28H26ClF3N6O, 554.2. m/z found, 555.2 [M+H]+. and the second eluting enantiomer was Example 25c: 1H NMR (600 MHz, CDCl3) δ ppm 8.32 (d, J=2.1 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.56-7.51 (m, 3H), 7.21 (d, J=7.9 Hz, 2H), 7.12 (s, 1H), 6.14 (s, 1H), 5.83 (s, 1H), 4.48 (s, 2H), 3.93 (s, 3H), 3.38 (s, 3H), 2.98-2.90 (m, 2H), 2.24 (s, 3H), 1.34-1.27 (m, 3H); MS (ESI): mass calcd. for C28H26ClF3N6O, 554.2. m/z found, 555.0 [M+H]+.

Workup

  1. waitAfter 5 minutes at −50° C.
  2. waitAfter 30 minutes
  3. customthe mixture was partitioned between half-saturated aqueous sodium chloride solution (25 mL) and ethyl acetate (50 mL)
  4. customThe layers were separated
  5. dry with materialthe organic layer was dried with sodium sulfate
  6. filtrationThe dried solution was filtered
  7. additionSilica gel (3 g) was added to the filtrate
  8. concentrationthe mixture was concentrated by rotary evaporation
  9. customto afford a free-flowing powder
  10. customThe powder was loaded onto a silica gel column for flash column chromatography purification
  11. washElution with dichloromethane initially

Sources & evidence

ORD record
ord-79b8ece8d7484b98a379e26d98c5cdf5
Source dataset
uspto-grants-2016_03
Patent number
US09284308B2

Reaction notes

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