Phenethylamine → Thiazole derivative, 29c

HRID 1011661Notes

Reaction equation

HRID 1011661 reaction equation
[S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=[CH:2]1.[Li]CCCC.CN(OC)[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18].[CH:24]1[CH:25]=[CH:26][C:27]2N(O)N=N[C:28]=2[CH:29]=1.C[CH2:35][N:36]=[C:37]=NCCCN(C)C.C(CN)C1C=CC=CC=1>C1COCC1.CN(C=O)C>[CH2:35]([N:36]([CH3:37])[C:6]([C:5]1[S:1][C:2]([C:16](=[O:21])[C:17]([F:18])([F:19])[F:20])=[N:3][CH:4]=1)=[O:8])[C:28]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:29]=1

Participants

9

Reactant 6

HCID 1001PhenethylamineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 84494Thiazole-5-carboxylic acidHCID 27823822,2,2-Trifluoro-N-methoxy-N-methylacetamideHCID 178418339Butyllithium

Product 1

HCID 25023818Thiazole derivative, 29cYield 3%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution (0.2 M) of 1,3-thiazole-5-carboxylic acid (from Combi-blocks) in dry THF a solution of BuLi (1.6 M solution in hexane, 2.2 eq.) was added dropwise at −78° C. and stirred at −78° C. for 45 min. A solution (1 M) of N-methyl-N-methoxytrifluoroacetamide (1.5 eq.) in dry THF was added at −78° C. to the reaction mixture and stirred for 1 h at −60° C. The reaction mixture was quenched by adding NH4Cl solution, then extracted with DCM. The combined organic layer was washed with brine and dried. Evaporation of the solvent gave a residue (LC-MS (ES+) C6H2F3NO3S requires: 225, found: 226 (M+H)+. Retention time: 2.26 min) that was dissolved in DMF. To the resulting solution (0.5 M), HOBt (1.5 eq.) and EDCI (1.5 eq.) were added and stirring was continued for 1 h. N-benzylmethylamine (1.5 eq.) was added and the reaction mixture was stirred at RT O/N. The crude was purified by RP-HPLC to yield (3%) the title compound as a solid.

Workup

  1. stirringstirred for 1 h at −60° C
  2. customThe reaction mixture was quenched
  3. additionby adding NH4Cl solution
  4. extractionextracted with DCM
  5. washThe combined organic layer was washed with brine
  6. customdried
  7. customEvaporation of the solvent
  8. customgave a residue (LC-MS (ES+) C6H2F3NO3S requires: 225, found: 226 (M+H)+. Retention time: 2.26 min) that
  9. stirringstirring
  10. waitwas continued for 1 h
  11. stirringthe reaction mixture was stirred at RT O/N
  12. customThe crude was purified by RP-HPLC

Sources & evidence

ORD record
ord-8f43e912f1674a448129df8912985ea5
Source dataset
uspto-grants-2011_07
Patent number
US07977374B2

Reaction notes

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