Hydrochloric Acid → (S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester

HRID 879664Notes

Reaction equation

HRID 879664 reaction equation
[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@@:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=5)=[CH:22][CH:21]=4)(O)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:4].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)(O)[O-].[Na+].Cl>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=5)=[CH:22][CH:21]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:4]

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 6422Trifluoroacetic acidHCID 12052TriethylsilaneHCID 90495Di-tert-butyl dicarbonateHCID 516892Sodium BicarbonateHCID 66719236(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-3-hydroxy-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester

Product 1

HCID 66719287(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl esterYield 61.4%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of (S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-3-hydroxy-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester (122 mg) in DCM (10 mL) were added TFA (1 mL) and triethylsilane (3 eq) at −10° C. and the reaction mixture were stirred and allowed to warm up to room temperature within 3 h. Then the reaction mixture was concentrated in vacuo. To this residue di-tert-butyl dicarbonate (2 eq) and sodium bicarbonate (3.0 eq) were added in the presence of ethyl acetate (25 mL) and stirred at r.t. for 4 h. After t-boc protection was complete the reaction mixture was then slowly acidified with dilute HCl (25 mL, 1.0 M solution), extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with 1 N HCl (25 mL), water (25 mL) and brine (25 mL) dried over sodium sulfate, filtered, and concentrated to provide a yellow solid. The residue was then purified by silica gel chromatography (10/90 to 30/70 ethyl acetate/hexanes in 10% increments) to obtain a white solid of (S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester (73 mg).

Workup

  1. concentrationThen the reaction mixture was concentrated in vacuo
  2. stirringstirred at r.t. for 4 h
  3. extractionextracted with ethyl acetate (2×25 mL)
  4. washThe combined organic extracts were washed with 1 N HCl (25 mL), water (25 mL) and brine (25 mL)
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto provide a yellow solid
  9. customThe residue was then purified by silica gel chromatography (10/90 to 30/70 ethyl acetate/hexanes in 10% increments)

Sources & evidence

ORD record
ord-dba122875a224c60add53ea6f6f46503
Source dataset
uspto-grants-2015_03
Patent number
US08987295B2

Reaction notes

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