Dichloromethane → 3-Bromo-4-(2-hydroxyethoxy)-5-(3-chloro4-fluorophenyl)benzoic acid ethyl ester

HRID 1884705Notes

Reaction equation

HRID 1884705 reaction equation
C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15](I)[C:14]([O:18][CH2:19][CH2:20][OH:21])=[C:13]([Br:22])[CH:12]=1)[CH3:8].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[F:31].C(Cl)Cl>O.Cl.O1CCOCC1>[CH2:7]([O:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([C:27]2[CH:28]=[CH:29][C:30]([F:31])=[C:25]([Cl:24])[CH:26]=2)[C:14]([O:18][CH2:19][CH2:20][OH:21])=[C:13]([Br:22])[CH:12]=1)[CH3:8]

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 27346603-Chloro-4-fluorophenylboronic Acid (contains varying amounts of Anhydride)HCID 113389853-Bromo-4-(2-hydroxyethoxy)-5-iodobenzoic acid ethyl ester

Product 1

HCID 541260063-Bromo-4-(2-hydroxyethoxy)-5-(3-chloro4-fluorophenyl)benzoic acid ethyl ester

Reagents, catalysts & solvents 3

HCID 313Hydrochloric AcidSolventHCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Procedure

To a stirred solution of K2CO3 (4.99 g, 36.1 mmol) in 18 mL H2O was added 145 mL dioxane, 3-bromo-4-(2-hydroxyethoxy)-5-iodobenzoic acid ethyl ester (5.0 g, 12.04 mmol), and 3-chloro-4-fluorophenylboronic acid (2.1 g, 12.04 mmol) at room temperature. This mixture was stirred for 5 min then degassed twice. Then [1,1í-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with CH2Cl2 (49 mg, 0.06 mmol) was added. The reaction was stirred for three hours then 98 mg, 0.12 mmol, of the catalyst was added. The reaction was allowed to stir for five days at room temperature before being worked up in the following manner. The reaction was diluted with 1N HCl and H2O and extracting with EtOAc three times. The combined organic extracts were dried over Na2SO4 and filtered. Removal of the solvent in vacuo gave crude material which was subjected to prep HPLC to yield 2 g, 35.5% of the bis arylated product 1H NMR (CDCl3) δ 1.40 (t, J=8.18 Hz, 3H); 1.945 (s, 1H); 3.712 (m, 4H); 4.36 (q, J=8.18 Hz, 2H); 7.19-7.23 (m, 1H); 7.40-7.45 (m, 1H); 7.60-7.65 (dd, J=8.18 Hz, 2.73 Hz, 1H); 7.91 (d, J=2.73 Hz, 1H); 8.24 (d, J=2.73 Hz, 1H); and 860 mg, 17.1% of the mono arylated product 1H NMR (CDCl3) δ 1.29 (bs, 1H); 1.41 (t, J=8.18 Hz, 3H); 3.40 (m, 4H); 4.40 (q, J=8.18 Hz, 2H); 7.20-7.28, (m, 2H); 7.454-7.545 (m, 2H); 7.69 (dd, J=8.18 Hz, 2.73 Hz, 2H); 8.013 (s, 1H); and 38% recovered SM.

Workup

  1. customthen degassed twice
  2. stirringThe reaction was stirred for three hours
  3. addition98 mg, 0.12 mmol, of the catalyst was added
  4. stirringto stir for five days at room temperature
  5. extractionextracting with EtOAc three times
  6. dry with materialThe combined organic extracts were dried over Na2SO4
  7. filtrationfiltered
  8. customRemoval of the solvent in vacuo
  9. customgave crude material which
  10. customto yield 2 g, 35.5% of the bis
  11. customand 38% recovered SM

Sources & evidence

ORD record
ord-bf2087f043754dc7a810c377855112e8
Source dataset
uspto-grants-2004_07
Patent number
US06765021B2

Reaction notes

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