Trifluoroacetic anhydride → Methyl 6-methylisoquinoline-3-carboxylate

HRID 890959

Reaction equation

HRID 890959 reaction equation
C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14](=[O:33])[CH:15]([NH:22]C(OCC1C=CC=CC=1)=O)P(OC)(OC)=O.[CH3:34][C:35]1[CH:36]=[C:37]([CH:43]=O)[C:38](=[CH:41][CH:42]=1)[CH:39]=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:34][C:35]1[CH:36]=[C:37]2[C:38](=[CH:41][CH:42]=1)[CH:39]=[N:22][C:15]([C:14]([O:13][CH3:12])=[O:33])=[CH:43]2

Participants

6

Reactant 4

HCID 9845Trifluoroacetic anhydrideHCID 811841,8-Diazabicyclo(5.4.0)undec-7-ene2×HCID 5769234-MethylphthalaldehydeHCID 2734718Methyl 2-{[(benzyloxy)carbonyl]amino}-2-(dimethyl phosphono)acetate

Product 1

HCID 22243644Methyl 6-methylisoquinoline-3-carboxylateYield 14.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

DBU (4.71 mL, 31.5 mmol) and methyl{[(benzyloxy)carbonyl]amino}(dimethoxyphosphoryl)acetate (10.43 g, 31.5 mmol) are dissolved in CH2Cl2 (175 mL). The resulting solution is added drop-wise a solution of 4-methylphthalaldehyde (4.24 g, 28.6 mmol) in CH2Cl2 (200 mL) at 0° C. The reaction is stirred cold for 1 hour at 0° C. and then for an additional 18 hours at rt. The volatiles are evaporated to an orange oil, which is dissolved in CHCl3 (200 mL). DBU (4.79 mL, 32.0 mmol) and TFAA (4.52 mL, 32.0 mmol) are added. The reaction is stirred under N2 for 3 hours. Upon completion, the reaction is quenched with 250 mL of saturated NaHCO3 solution. The organic layer is separated and the aqueous layer is extracted with 2×250 mL of CHCl3. The organic layers are combined, dried (MgSO4), filtered, and concentrated. The crude reaction mixture is purified by column chromatography using a step gradient of 20% EtOAc to 26% EtOAc in hexanes in 2% intervals. The resulting product-containing fractions are concentrated and purified via preparative achiral HPLC to yield 0.84 g of methyl 6-methyl-isoquinoline-3-carboxylate as a yellow solid. HRMS (FAB) calculated for C12H11N O2+H+: 202.0868, found 202.0863.

Workup

  1. waitfor an additional 18 hours at rt
  2. customThe volatiles are evaporated to an orange oil, which
  3. dissolutionis dissolved in CHCl3 (200 mL)
  4. stirringThe reaction is stirred under N2 for 3 hours
  5. customUpon completion, the reaction is quenched with 250 mL of saturated NaHCO3 solution
  6. customThe organic layer is separated
  7. extractionthe aqueous layer is extracted with 2×250 mL of CHCl3
  8. dry with materialdried (MgSO4)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe crude reaction mixture
  12. customis purified by column chromatography
  13. additionThe resulting product-containing fractions
  14. concentrationare concentrated
  15. custompurified via preparative achiral HPLC

Sources & evidence

ORD record
ord-ea234bf37dca49df8faa135537a67864
Source dataset
uspto-grants-2006_02
Patent number
US07001900B2

Linked notes

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