2,6-Lutidine → HCID 67188933, compound

HRID 546135Notes

Reaction equation

HRID 546135 reaction equation
C(OC(=O)NC1C=CC=[C:10]([CH2:14][N:15]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:40])[C@@H:22]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31](Cl)[CH:30]=3)[CH2:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:16]2)C=1)(C)(C)C.[C:42](Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[C:56]([Si:60]([CH3:71])([CH3:70])[O:61]CCN1C=CC(N)=N1)([CH3:59])([CH3:58])[CH3:57]>C(Cl)Cl.CO>[C:56]([Si:60]([CH3:71])([CH3:70])[O:61][CH2:10][CH2:14][N:15]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:40])[C@@H:22]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([CH3:42])[CH:30]=2)[CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)=[N:16]1)([CH3:59])([CH3:58])[CH3:57]

Participants

7

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 593449471-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamineHCID 67190452HCID 67190452, compound

Product 1

HCID 67188933HCID 67188933, compoundYield 94%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent4×

Conditions

Temperature
25 °C

Procedure

Cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 57, 193 mg, 0.62 mmol) was dissolved in methylene chloride (4 mL) and N,N-dimethylfomamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 320 μL, 0.65 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes. After this time, the reaction was cooled to 0° C. and 2,6-lutidine (150 μL, 1.24 mmol) was added to the flask and it was stirred for 15 min. To this was then added a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 150 mg, 0.62 mmol) in methylene chloride (2 mL) and the reaction was allowed to warm up to 25° C. and stirred for 2 h. After this time the reaction was diluted with a small amount of methanol in methylene chloride and concentrated in vacuo with silica gel (2 g) and purified by Biotage Flash Chromatography (40S column, Silica gel, 50% ethyl acetate/hexanes). The combined fractions were then washed with a 1 N aqueous hydrochloric acid solution and then a saturated brine solution, dried over sodium sulfate and concentrated in vacuo to afford N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (309 mg, 94%) as a colorless gum: [α]30589=−9.70° (c=0.33, methanol); ES-HRMS m/e calcd for C27H43N3O4SSi (M+H)+ 534.2817, observed 534.2814; 1H NMR (300 MHz, DMSO-d6) δ ppm −0.09 (s, 6H, 2×SiCH3), 0.78 (s, 9H, 3×CH3), 1.02-1.20 (m, 2H, CH2), 1.36-1.84 (m, 8H, 4×CH2), 2.04-2.17 (m, 1H, CH), 2.62 (s, 3H, ArCH3), 3.17 (s, 3H, SO2CH3), 3.80-3.90 (m, 3H, ArCH and SiOCH2), 4.04 (t, J=5.4 Hz, 2H, NCH2), 6.41 (d, J=2.3 Hz, 1H, Ar), 7.41-7.47 (m, 2 H, Ar), 7.51 (d, J=2.3 Hz, 1H, Ar), 7.84 (d, Jo=8.8 Hz, 1H, Ar), 10.73 (s, 1H, NH)

Workup

  1. customat 25° C.
  2. customproduced gas evolution and it
  3. temperatureAfter this time, the reaction was cooled to 0° C.
  4. stirringwas stirred for 15 min
  5. temperatureto warm up to 25° C.
  6. stirringstirred for 2 h
  7. concentrationconcentrated in vacuo with silica gel (2 g)
  8. custompurified by Biotage Flash Chromatography (40S column, Silica gel, 50% ethyl acetate/hexanes)
  9. washThe combined fractions were then washed with a 1 N aqueous hydrochloric acid solution
  10. dry with materiala saturated brine solution, dried over sodium sulfate
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-f5279e0b619f4574ab94007b1c68d69f
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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