Methanesulfonyl chloride → HCID 44198415, compound

HRID 1406428Notes

Reaction equation

HRID 1406428 reaction equation
CCN(C(C)C)C(C)C.C(OC([N:17]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26]O)=[CH:23][CH:24]=2)[CH:19]=[C:18]1[C:28]1[C:29](=[O:57])[N:30](COCC[Si](C)(C)C)[CH:31]=[C:32]([NH:34][C:35]([C:37]2[CH:38]=[N:39][N:40]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:41]=2)=[O:36])[CH:33]=1)=O)(C)(C)C.CS(Cl)(=O)=O.[CH3:63][C@H:64]1[CH2:69][CH2:68][CH2:67][C@@H:66]([CH3:70])[NH:65]1>ClCCCl.C(OCC)(=O)C>[CH3:63][C@H:64]1[CH2:69][CH2:68][CH2:67][C@@H:66]([CH3:70])[N:65]1[CH2:26][C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[NH:17][C:18]([C:28]1[C:29](=[O:57])[NH:30][CH:31]=[C:32]([NH:34][C:35]([C:37]3[CH:38]=[N:39][N:40]([CH2:42][C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH:41]=3)=[O:36])[CH:33]=1)=[CH:19]2

Participants

7

Reactant 4

HCID 31297Methanesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 641768rel-(2R,6S)-2,6-DimethylpiperidineHCID 66853479HCID 66853479, compound

Product 1

HCID 44198415HCID 44198415, compound

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

The title compound was prepared by the route outlined in Scheme 8, following the same experimental procedures as for Example 51, with the following modification. Deprotection of intermediate (8e), 5-(tert-Butyl-dimethyl-silanyloxymethyl)-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester, in the usual manner, yielded 2-[5-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester. DIPEA (153 μL, 0.9 mmol) and 2-[5-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester (0.2 g, 0.3 mmol) were stirred in 1,2-dichloroethane (5 mL) and cooled to 0° C. Methanesulfonyl chloride (27 μL, 0.36 mmol) was added drop wise at 0° C. and stirred for a further 2 hours at 0° C. cis-2,6-Dimethylpiperidine (118 μL 0.9 mmol) was added drop wise at 0° C. and then the reaction was allowed to attain ambient temperature. The reaction mixture was heated at reflux overnight followed by cooling to ambient temperature. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (30 mL), saturated sodium hydrogen carbonate solution (30 mL), brine, dried (Na2SO4) and concentrated in vacuo. The resultant crude product was taken up in methanol (1 mL) and loaded onto a 5 g SCX column. The column was flushed with methanol and then eluted with ammonia solution 7N in methanol. The eluent was concentrated in vacuo to afford the title compound as a light brown solid, 120 mg, 53%.

Workup

  1. additionwas added drop wise at 0° C.
  2. customto attain ambient temperature
  3. temperatureThe reaction mixture was heated
  4. temperatureat reflux overnight
  5. temperatureby cooling to ambient temperature
  6. washwashed with water (30 mL), saturated sodium hydrogen carbonate solution (30 mL), brine
  7. dry with materialdried (Na2SO4)
  8. concentrationconcentrated in vacuo
  9. customThe column was flushed with methanol
  10. washeluted with ammonia solution 7N in methanol
  11. concentrationThe eluent was concentrated in vacuo

Sources & evidence

ORD record
ord-a72b7519afcd4128a8d7bb5b40bfc89e
Source dataset
uspto-grants-2014_12
Patent number
US08916591B2

Reaction notes

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