1,2,3,4-Tetrahydroisoquinoline → [4-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)-6,8-dimethoxy-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester

HRID 14629

Reaction equation

HRID 14629 reaction equation
[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](O)=[O:25])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][NH:28]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:15]2[C:14](=[CH:19][C:18]([O:20][CH3:21])=[CH:17][C:16]=2[O:22][CH3:23])[C:13]([C:24]([N:28]2[CH2:29][CH2:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27]2)=[O:25])=[CH:12][N:11]=1)([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 4

HCID 70461,2,3,4-TetrahydroisoquinolineHCID 8471TriethylamineHCID 76257Diethyl cyanophosphonateHCID 593410981-(Tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid

Product 1

HCID 59341075[4-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)-6,8-dimethoxy-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl esterYield 66%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

According to the procedure of Yamada et al. (Note 2), a solution of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid (100 mg, 0.3 mmol) and 1,2,3,4-tetrahydro-isoquinoline (44 mg, 0.33 mmol) in 5 mL of THF was stirred at 0° C. under a nitrogen atmosphere. Diethyl cyanophosphonate (54 mg, 0.33 mmol) in 2 mL of THF was added followed by triethylamine (77 μL, 0.55 mmol). The reaction was stirred at 0° C. for 30 minutes and then at room temperature for 15 h. The reaction was diluted with EtOAc and then washed with water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with NH4OH (10% solution in H2O) and then with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated. The resulting residue was triturated with ether to give 87 mg (66%) of the desired product. H1-NMR (CDCl3): δ 8.30 (s, 1H), 7.27 (broad m, 4H), 6.75 (m, 1H), 6.58 (m, 2H), 5.09 (m, 2H), 4.41 (m, 2H), 3.98 (m, 2H), 3.83 (s, 2H), 3.50 (s, 3H), 3.09 and 2.77 (m, 1H each), 1.52 (s, 9H), [Note: broadening of peaks observed due to Boc group, rotamers also observed.] MS: APCI (M+H) calc'd for C27H31N3O5+H 478.6; found 478.0.

Workup

  1. waitat room temperature for 15 h
  2. washwashed with water
  3. extractionThe aqueous layer was extracted with EtOAc
  4. washthe combined organic layers were washed with NH4OH (10% solution in H2O)
  5. dry with materialThe organic layer was then dried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe resulting residue was triturated with ether

Sources & evidence

ORD record
ord-222d1897163f464689acf5cfd644a6f7
Source dataset
uspto-grants-2010_06
Patent number
US07732446B1

Linked notes

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