Chlorosulfonic acid → HCID 89761958, compound

HRID 528613Notes

Reaction equation

HRID 528613 reaction equation
[F:1][C:2]1[C:11]2[N:10]([C:12]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:24][S:25](O)(=[O:27])=[O:26]>C(Cl)Cl>[C:14]([C:13]1[CH:16]=[C:17]([C:20]([F:23])([F:21])[F:22])[CH:18]=[CH:19][C:12]=1[N:10]1[CH2:9][CH2:8][O:7][C:6]2[CH:5]=[C:4]([S:25]([Cl:24])(=[O:27])=[O:26])[CH:3]=[C:2]([F:1])[C:11]1=2)#[N:15]

Participants

4

Reactant 2

HCID 24638Chlorosulfonic acidHCID 89762096HCID 89762096, compound

Product 1

HCID 89761958HCID 89761958, compoundYield 21.17%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a vial charged with 2-(5-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)benzonitrile (0.445 g, 1.381 mmol) was added DCM (5.52 ml). The resulting solution was cooled in an ice water bath prior to the addition of chlorosulfonic acid (0.367 ml, 5.52 mmol), faster than dropwise. After 90 mins of stirring LC-MS of the resulting yellow/brown suspension indicated two peaks (˜2:1) with desired product mass as the main mass (M+23) with consumption of starting material. The mixture was added to ice, diluted with water and extracted with EtOAc (2×). The combined organics were dried under reduced pressure and purified with a 40 HP spherical silica column (15 m spherical, Interchim) ramping EtOAc in heptane (0-35%, 10% DCM throughout) yielding near complete separation of isomers. NMR analysis of the first eluted peak confirmed the desired regiochemistry 4-(2-cyano-4-(trifluoromethyl)phenyl)-5-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (0.123 g, 0.292 mmol, 21.17% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.91-4.02 (m, 2 H) 4.37 (br. s., 2 H) 6.97 (dd, J=9.10, 1.56 Hz, 1 H) 7.20 (d, J=8.61 Hz, 1 H) 7.64 (dd, J=9.10, 7.34 Hz, 1 H) 7.77 (dd, J=8.61, 2.15 Hz, 1 H) 7.97 (d, J=1.76 Hz, 1 H). m/z (ESI) 443.1 (M+Na)+.

Workup

  1. temperatureThe resulting solution was cooled in an ice water bath
  2. customtwo peaks (˜2:1) with desired product mass as the main mass (M+23) with consumption of starting material
  3. additionThe mixture was added to ice
  4. additiondiluted with water
  5. extractionextracted with EtOAc (2×)
  6. customThe combined organics were dried under reduced pressure
  7. custompurified with a 40 HP spherical silica column (15 m spherical, Interchim)
  8. customyielding near complete separation of isomers

Sources & evidence

ORD record
ord-507b979efb1142e3bf148d08c858b2d1
Source dataset
uspto-grants-2016_05
Patent number
US09346798B2

Reaction notes

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