Hydrochloric Acid → 2-(5-Bromo-2-chloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid

HRID 1986169Notes

Reaction equation

HRID 1986169 reaction equation
C([Li])CCC.[S:6]1[CH:10]=[CH:9][C:8]2[C:11]([C:15]([OH:17])=[O:16])=[CH:12][CH:13]=[CH:14][C:7]1=2.[Br:18][C:19]1[CH:20]=[N:21][C:22]([Cl:25])=[N:23][CH:24]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.Cl>C1COCC1.C(O)(=O)C>[Br:18][C:19]1[C:20]([C:10]2[S:6][C:7]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([OH:17])=[O:16])[C:8]=3[CH:9]=2)=[N:21][C:22]([Cl:25])=[N:23][CH:24]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 67752,3-Dichloro-5,6-dicyano-1,4-benzoquinoneHCID 6066655-Bromo-2-chloropyrimidineHCID 1051638Benzo[b]thiophene-4-carboxylic acidHCID 178418339Butyllithium

Product 1

HCID 866253422-(5-Bromo-2-chloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acidYield 42%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

Butyllithium (2.5 M in hexane, 14.1 mL) is added dropwise to a stirred solution of benzo[b]thiophene-4-carboxylic acid (3.00 g, 16.8 mmol) in anhydrous THF (50 mL) at −78° C. under nitrogen. The resultant mixture is allowed to stir for 45 minutes at −78° C. before it is added, via cannula, to a stirred cold solution of 5-bromo-2-chloropyrimidine (3.26 g, 16.8 mmol) in anhydrous THF (50 mL) at −30° C. Upon the completion of the addition, the reaction mixture is stirred for 30 minutes at −30° C., then at ambient temperature for another 1.5 hours. Acetic acid (2.4 mL) is added to the reaction mixture, after 5 minutes, followed by the addition of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (4.01 g, 17.7 mmol) dissolved in THF (10 mL). The mixture is allowed to stir for 10 minutes before it is treated dropwise with HCl (37%, 30 mL), then the mixture is stirred for another 1 hour. THF is evaporated off and the mixture becomes a suspension. The solid is filtered off, washed with water (100 mL×2), and then dried under vacuum. The dry solid is suspended in dichloromethane (45 mL) and ethanol (5 mL) and stirred for 30 minutes. After filtration, the solid is resuspended in ether (50 mL) and the suspension is stirred for another 30 minutes. After filtration and vacuum drying, the title compound is obtained as a yellow solid. (2.64 g, 42% yield).

Workup

  1. additionUpon the completion of the addition
  2. stirringthe reaction mixture is stirred for 30 minutes at −30° C.
  3. waitat ambient temperature for another 1.5 hours
  4. stirringto stir for 10 minutes before it
  5. stirringthe mixture is stirred for another 1 hour
  6. customTHF is evaporated off
  7. filtrationThe solid is filtered off
  8. washwashed with water (100 mL×2)
  9. customdried under vacuum
  10. stirringethanol (5 mL) and stirred for 30 minutes
  11. filtrationAfter filtration
  12. stirringthe suspension is stirred for another 30 minutes
  13. filtrationAfter filtration and vacuum
  14. customdrying

Sources & evidence

ORD record
ord-84a7f018b79c405b928672263d38585f
Source dataset
uspto-grants-2009_06
Patent number
US07547691B2

Reaction notes

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