4'-Fluoroacetophenone → (RS)-1-(4-Fluorophenyl)-4-(1-{1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]-methanoyl}-piperidin-2-yl)-butane-1,3-dione

HRID 549348Notes

Reaction equation

HRID 549348 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][C:23]([OH:25])=O)=[O:15])=[CH:4][CH:3]=1.C(OC(Cl)=O)C(C)C.[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:43])[CH3:42])=[CH:37][CH:36]=1.C([N-]C(C)C)(C)C.[Li+]>O1CCCC1.C(N(CC)CC)C>[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:43])[CH2:42][C:23](=[O:25])[CH2:22][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][N:16]2[C:14]([C:9]2[N:10]=[C:11]([CH3:13])[S:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:15])=[CH:37][CH:36]=1

Participants

7

Reactant 4

HCID 98284'-FluoroacetophenoneHCID 62365Isobutyl chloroformateHCID 2724682Lithium diisopropylamideHCID 23146320(1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-yl)-acetic acid

Product 1

HCID 67158631(RS)-1-(4-Fluorophenyl)-4-(1-{1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]-methanoyl}-piperidin-2-yl)-butane-1,3-dione

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8471TriethylamineSolvent

Conditions

Temperature
-20 °C

Procedure

(1-{-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]-methanoyl}-piperidin-2-yl)-acetic acid (0.500 g) was dissolved in dry tetrahydrofuran (15 ml) and cooled to −20° C. under an atmosphere of argon. Triethylamine (0.231 ml) and isobutylchloroformate (0.215 ml) were added and the solution was stirred at −20° C. for 1 hour. The solution was then cooled to −78° C. B. A solution of 4′-fluoroacetophenone (0.229 g) in THF (15 ml) was cooled to 20° C. under an atmosphere of argon. A solution of lithium diisopropylamide (0.830 ml; 2M solution in THF) was added and stirring continued at −20° C. for 30 minutes. The solution was then cooled to −78° C. C. The solution from part B was added to the stirred solution of part A by way of a cannula. Stirring was continued at −78° C. under an atmosphere of argon for 2 hours before being quenched by the addition of saturated ammonium chloride solution. After reaching room temperature, the reaction solution was partitioned between ethyl acetate and water. The organic solution was washed with brine, dried (MgSO4) and evaporated. The residue was chromatographed over silica gel, eluting with a gradient of 10 to 75% ethyl acetate in hexane. The title compound was obtained as a colourless oil (0.560 g) mass spectrum (API+) 483 [MH+], (API−) 481 [(M-H)−] C26H24F2N2O3S requires 482.

Workup

  1. temperatureThe solution was then cooled to −78° C
  2. stirringstirring
  3. waitcontinued at −20° C. for 30 minutes
  4. temperatureThe solution was then cooled to −78° C
  5. additionThe solution from part B was added to the stirred solution of part A by way of a cannula
  6. stirringStirring
  7. waitwas continued at −78° C. under an atmosphere of argon for 2 hours
  8. custombefore being quenched by the addition of saturated ammonium chloride solution
  9. customAfter reaching room temperature
  10. customthe reaction solution was partitioned between ethyl acetate and water
  11. washThe organic solution was washed with brine
  12. dry with materialdried (MgSO4)
  13. customevaporated
  14. customThe residue was chromatographed over silica gel
  15. washeluting with a gradient of 10 to 75% ethyl acetate in hexane

Sources & evidence

ORD record
ord-beb0a474ef6643278b236ddc5aa1f431
Source dataset
uspto-grants-2011_05
Patent number
US07943645B2

Reaction notes

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