Potassium hydroxy sulfite → HCID 131734347, compound

HRID 1505008Notes

Reaction equation

HRID 1505008 reaction equation
[C:1](S[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[CH:11][CH:10]=[C:9]2[Cl:17])([CH3:4])([CH3:3])[CH3:2].[C:18](S[C:23]1[C:24]([F:34])=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[C:26]2[Cl:33])([CH3:21])([CH3:20])[CH3:19].O[O:36][S:37]([O-:39])=O.[K+]>CCOC(C)=O.O>[C:18]([S:37]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[CH:11][CH:10]=[C:9]2[Cl:17])(=[O:39])=[O:36])([CH3:21])([CH3:20])[CH3:19].[C:1]([S:37]([C:23]1[C:24]([F:34])=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[C:26]2[Cl:33])(=[O:39])=[O:36])([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 23707502Potassium hydroxy sulfite5×HCID 90046906HCID 90046906, compoundHCID 90046973HCID 90046973, compound

Product 1

HCID 131734347HCID 131734347, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolvent3×HCID 8857Ethyl AcetateSolvent3×

Procedure

A mixture of 6-(tert-butylthio)-4-chloro-7-fluoroquinoline and 6-(tert-butylthio)-4-chloro-5-fluoroquinoline (21.24 g, 79 mmol) and oxone (48.4 g, 79 mmol) in EtOAc (200 ml) and water (200 ml) was stirred at RT overnight. LCMS showed sulfoxide as well as sulfone. Added an additional 15 g of Oxone and stirred for 3 hours; the sulfoxide was still present. Added 15 g more of Oxone and stirred for 3 hours more. Sulfoxide was still present. Added 5 g more of Oxone and stirred overnight. Note each time more Oxone was added the amounts of EtOAc and water needed to be increased as well. The final amounts of solvent were ˜500 mL EtOAc and ˜500 mL water. The layers were separated and the aqueous layer was extracted once with ethyl acetate. The combined organics were filtered and concentrated. Split material into 2 batches for purification. Each batch was purified as follows: The crude sample was purified via Isco normal phase chromatography (330 g Gold column, 0%-20%, E/H). This purification yielded separation of the regioisomers. The two batches of purified products were recombined. Peak 1 was the 6-(tert-butylthio)-4-chloro-7-fluoroquinoline product (9.86 g) as a creamy white solid. 1H NMR (ACETONITRILE-d3) δ ppm 8.96 (d, 1H), 8.77 (d, J=7.3 Hz, 1H), 7.99 (d, J=11.4 Hz, 1H), 7.74 (d, J=4.8 Hz, 1H), 1.41 (d, J=1.0 Hz, 9H). MS: m/z: 302.0 [M+H]+. Peak 2 was the 6-(tert-butylsulfonyl)-4-chloro-5-fluoroquinoline product (1.71 g) as a white powder. 1H NMR (ACETONITRILE-d3) δ ppm 8.94 (d, 1H), 8.04-8.15 (m, 2H), 7.75 (d, J=4.8 Hz, 1H), 1.41 (d, J=1.3 Hz, 9H). MS: m/z: 302.0 [M+H]+.

Workup

  1. stirringstirred for 3 hours
  2. stirringstirred for 3 hours more
  3. stirringstirred overnight
  4. temperatureto be increased as well
  5. customThe layers were separated
  6. extractionthe aqueous layer was extracted once with ethyl acetate
  7. filtrationThe combined organics were filtered
  8. concentrationconcentrated
  9. customSplit material into 2 batches for purification
  10. customEach batch was purified
  11. customThe crude sample was purified via Isco normal phase chromatography (330 g Gold column, 0%-20%, E/H)
  12. customThis purification
  13. customyielded
  14. customseparation of the regioisomers

Sources & evidence

ORD record
ord-ef8482dea2564201bf11a42efb97afc6
Source dataset
uspto-grants-2015_12
Patent number
US09216965B2

Reaction notes

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