Methyl 4-aminobenzoate → Methyl 4-{[cyclohexyl(3-methylthieno[2,3-b]pyridin-2-yl)methyl]amino}benzoate

HRID 2091309Notes

Reaction equation

HRID 2091309 reaction equation
[CH:1]1([C:7]([C:9]2[S:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10]=2[CH3:18])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(Cl)Cl.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=2)[C:9]2[S:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10]=2[CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

10

Reactant 4

HCID 12082Methyl 4-aminobenzoateHCID 516892Sodium Bicarbonate2×HCID 5003444Sodium cyanoborohydrideHCID 66777829HCID 66777829, compound

Product 1

HCID 86761830Methyl 4-{[cyclohexyl(3-methylthieno[2,3-b]pyridin-2-yl)methyl]amino}benzoateYield 64.1%

Reagents, catalysts & solvents 5

HCID 24193Titanium TetrachlorideCatalystHCID 176Acetic AcidSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolvent

Procedure

To a mixture of cyclohexyl(3-methylthieno[2,3-b]pyridin-2-yl)methanone (1.00 g) synthesized above, methyl 4-aminobenzoate (642 mg), triethylamine (4.31 mL) and methylene chloride (20 mL) was added titanium (IV) chloride (508 μL) at 0° C., and the mixture was stirred at room temperature for 1.5 days under argon atmosphere. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown solid. To a solution (20 mL) of the obtained solid in tetrahydrofuran were added acetic acid (442 μL) and sodium cyanoborohydride (485 mg), and the mixture was stirred at room temperature for 1.5 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (975 mg, 64%) as a pale-brown solid.

Workup

  1. customto quench
  2. customthe reaction
  3. extractionthe reaction mixture was extracted with ethyl acetate
  4. washThe extract was washed with saturated brine
  5. dry with materialdried over magnesium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customto give a dark brown solid
  8. stirringthe mixture was stirred at room temperature for 1.5 hr
  9. customto quench
  10. customthe reaction
  11. extractionthe reaction mixture was extracted with ethyl acetate
  12. washThe extract was washed with saturated brine
  13. dry with materialdried over magnesium sulfate
  14. concentrationconcentrated under reduced pressure
  15. customThe residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane)

Sources & evidence

ORD record
ord-83eae030063f42719b4b0ff9d52c24f7
Source dataset
uspto-grants-2013_05
Patent number
US08436043B2

Reaction notes

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