Hydrochloric Acid → HCID 21109700, compound

HRID 1766445Notes

Reaction equation

HRID 1766445 reaction equation
C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](Br)[C:7](Cl)=[N:6][CH:5]=1.[CH2:13]([OH:16])[CH2:14][CH3:15].N12CCCN=C1CCCCC2.[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].[OH-].[K+].Cl>C1COCC1.C1(C)C=CC=CC=1.O>[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[C:8]1[C:7]([O:16][CH2:13][CH2:14][CH3:15])=[N:6][CH:5]=[C:4]([CH:9]=1)[C:3]([OH:2])=[O:12]

Participants

11

Reactant 7

HCID 313Hydrochloric AcidHCID 10311-PropanolHCID 10340Sodium CarbonateHCID 14797Potassium HydroxideHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 2734659(2,4-Dichlorophenyl)boronic acidHCID 2764313Methyl 5-bromo-6-chloronicotinate

Product 1

HCID 21109700HCID 21109700, compoundYield 16.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
74 °C

Procedure

A mixture of 1.5 g (6 mmol) 5-bromo-6-chloro-nicotinic acid methyl ester, 1.8 g (30 mmol) propanol, 1.82 g (12 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene in 6 mL THF was heated to 74° C. over night. Evaporation of THF was followed by addition of water and ethyl acetate. The organic phase was washed with 1M KHSO4 aq. and the combined aqueous phases re-extracted with ethyl acetate. The combined organic phases were dried with MgSO4 and evaporated to dryness. The crude intermediate was used in the consecutive step without further purification. The residue was partitioned to affect several consecutive reactions and ½ of the residue, 856 mg (4.49 mmol) 2,4-dichloro-phenylboronic acid, 109 mg (0.15 mmol) [1,1′-bis(diphenylphospino)ferrocene] palladium(II) dichloride dichloromethane complex (1:1), 4.49 mL 2N Na2CO3 aq., in 10 mL toluene and 4.5 mL water was heated to 80° C. over night. KOH was added and heating to 80° C. was continued for 2 h. The mixture was acidified with 4N HCl aq. and extracted with ethyl acetate and evaporated. The residue was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/HCOOH. The combined product fractions were evaporated to yield 236 mg of 5-(2,4-dichloro-phenyl)-6-propoxy-nicotinic acid. MS (m/e): 324.2 (M−H).

Workup

  1. customEvaporation of THF
  2. additionwas followed by addition of water and ethyl acetate
  3. washThe organic phase was washed with 1M KHSO4 aq.
  4. extractionthe combined aqueous phases re-extracted with ethyl acetate
  5. dry with materialThe combined organic phases were dried with MgSO4
  6. customevaporated to dryness
  7. customThe crude intermediate was used in the consecutive step without further purification
  8. customThe residue was partitioned
  9. temperatureheating to 80° C.
  10. extractionextracted with ethyl acetate
  11. customevaporated
  12. customThe residue was purified by preparative HPLC on reversed phase
  13. washeluting with a gradient
  14. customformed from acetonitrile/water/HCOOH
  15. customThe combined product fractions were evaporated

Sources & evidence

ORD record
ord-4dc1be17d0e243558425965a3343db7c
Source dataset
uspto-grants-2007_06
Patent number
US07229999B2

Reaction notes

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