Sulfur Dioxide → 2-(4-(4-((6-Chloro-5-fluoro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol

HRID 1972643Notes

Reaction equation

HRID 1972643 reaction equation
Br[C:2]1[CH:3]=[C:4]([F:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[Li]CCCC.[S:15](=[O:17])=[O:16].C1C(=O)N(Cl)C(=O)C1.[F:26][C:27]([F:50])([F:49])[C:28]([C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH:41]2[C:46]#[C:47][CH3:48])=[CH:36][CH:35]=1)([OH:33])[C:29]([F:32])([F:31])[F:30].C(N(CC)CC)C>C(Cl)Cl.C(OCC)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([S:15]([N:43]2[CH2:44][CH2:45][N:40]([C:37]3[CH:36]=[CH:35][C:34]([C:28]([OH:33])([C:29]([F:30])([F:31])[F:32])[C:27]([F:50])([F:26])[F:49])=[CH:39][CH:38]=3)[CH:41]([C:46]#[C:47][CH3:48])[CH2:42]2)(=[O:17])=[O:16])=[CH:3][C:4]=1[F:9]

Participants

9

Reactant 6

HCID 1119Sulfur DioxideHCID 8471TriethylamineHCID 31398ChlorosuccinimideHCID 27632855-Bromo-2-chloro-3-fluoropyridineHCID 866704221,1,1,3,3,3-Hexafluoro-2-(4-(2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-2-propanolHCID 178418339Butyllithium

Product 1

HCID 866704242-(4-(4-((6-Chloro-5-fluoro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanolYield 36%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
-78 °C

Procedure

A 50-mL round-bottomed flask solution was cooled to −78° C. and charged with 5-bromo-2-chloro-3-fluoropyridine (259 mg, 1.23 mmol, Asymchem Laboratories, Inc., Morrisville, N.C.) and diethylether (10 mL). n-BuLi (0.49 mL, 2.5M solution in hexanes, 1.23 mmol) was added and after 5 min. Sulfur dioxide (52.5 mg, 0.819 mmol, Sigma-Aldrich, St. Louis, Mo.) was then bubbled through the cold solution for 1 min. The mixture was then allowed to warm to room temperature and concentrated. To this was solid was added CH2Cl2 (10 mL) and NCS (152 mg, 1.15 mmol, Alfa Aesar, Ward Hill, Mass.) added. After 20 min, 1,1,1,3,3,3-hexafluoro-2-(4-(2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-2-propanol (300 mg, 0.819 mmol, Example 241, Step 3) and triethylamine (0.457 mL, 3.28 mmol) were added to the reaction mixture. After a further 10 min at room temperature, the reaction was quenched with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organics were dried (Na2SO4), filtered, and concentrated to give an oil that was purified via column chromatography on silica gel (0 to 100% EtOAc in hexanes) to give 2-(4-(4-((6-chloro-5-fluoro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (165 mg) as a mixture of two isomers

Workup

  1. temperatureto warm to room temperature
  2. concentrationconcentrated
  3. additionadded
  4. waitAfter a further 10 min at room temperature
  5. customthe reaction was quenched with water (50 mL)
  6. extractionextracted with EtOAc (3×100 mL)
  7. dry with materialThe combined organics were dried (Na2SO4)
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customto give an oil that
  11. customwas purified via column chromatography on silica gel (0 to 100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-140053b3197f4787ba7c72f149cb7827
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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