Dichloromethane → 6-Chloro-7-(4-(4-chloro-2-hydroxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid

HRID 1021557Notes

Reaction equation

HRID 1021557 reaction equation
B(Cl)(Cl)Cl.ClCCl.[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:39])[NH:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[O:37]C)=[CH:22][CH:21]=1)[O:15][CH2:14][CH2:13][CH:12]2[C:40]([OH:42])=[O:41]>>[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:39])[NH:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[OH:37])=[CH:22][CH:21]=1)[O:15][CH2:14][CH2:13][CH:12]2[C:40]([OH:42])=[O:41]

Participants

4

Reactant 3

HCID 6344DichloromethaneHCID 25135Boron TrichlorideHCID 670802136-Chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid

Product 1

HCID 670802276-Chloro-7-(4-(4-chloro-2-hydroxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acidYield 20%

Procedure

To a stirred, chilled (0° C.) solution of boron trichloride in dichloromethane (13.6 mL; 1.0 M; 7 eq.) was added, portionwise over 2 minutes, solid 6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (1.0 g; 1.94 mmol) under nitrogen atmosphere. The resulting mixture was allowed to warm to ambient temperature, stirred for 8 hours and then heated to 35° C. for 24 hours. The reaction was quenched with 5 mL water (significant effervescence observed while adding first 2 mL) and then 6 mL of saturated Na2CO3 was added to bring the pH to 4. During the last 1 mL of addition, significant amounts of precipitates formed in the lower organic layer. The warm bath was removed and replaced with an ice bath. The material was stirred for 5 minutes in ice bath, then solids collected on a medium frit, washing once with 5 mL chilled MTBE. This material was purified via Biotage chromatography with methanol in ethyl acetate to provide the desired 6-chloro-7-(4-(4-chloro-2-hydroxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (195 mg). MS (apci, neg) m/z=500. 1H NMR (400 MHz, D6 DMSO) δ 8.45 (t, 1H), 7.82, (d, 2H), 7.46 (s, 1H), 7.06 (d, 1H), 6.95 (d, 2H), 6.83 (d, 1H), 6.75 (dd, 1H), 6.60 (s, 1H), 4.22 (m, 1H), 4.12 (t, 1H), 3.72 (br s, 1H), 3.60 (t, 1H), 2.76 (t, 2H), 2.22 (m, 1H), 1.99 (m, 1H), 1.76 (m, 1H).

Workup

  1. additionwas added, portionwise over 2 minutes
  2. temperatureheated to 35° C. for 24 hours
  3. customThe reaction was quenched with 5 mL water (significant effervescence observed while adding first 2 mL)
  4. addition6 mL of saturated Na2CO3 was added
  5. additionDuring the last 1 mL of addition, significant amounts
  6. customof precipitates
  7. customformed in the lower organic layer
  8. customThe warm bath was removed
  9. customreplaced with an ice bath
  10. stirringThe material was stirred for 5 minutes in ice bath
  11. customsolids collected on a medium frit
  12. washwashing once with 5 mL
  13. temperaturechilled MTBE
  14. customThis material was purified via Biotage chromatography with methanol in ethyl acetate

Sources & evidence

ORD record
ord-e74197a47f204415b320154edbd37a9a
Source dataset
uspto-grants-2014_05
Patent number
US08716498B2

Reaction notes

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