Proton sponge → HCID 49806608, compound

HRID 576096Notes

Reaction equation

HRID 576096 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([C:18]4[N:23]=[N:22][C:21]([N:24](C)[C:25](=O)OC(C)(C)C)=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)[CH2:11][N:10](C)[CH2:9]2)=[CH:4][CH:3]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.ClC(OC(Cl)C)=O>ClCCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([C:18]4[N:23]=[N:22][C:21]([NH:24][CH3:25])=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)[CH2:11][NH:10][CH2:9]2)=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 88675Proton spongeHCID 5213051-Chloroethyl chloroformateHCID 68660645HCID 68660645, compound

Product 1

HCID 49806608HCID 49806608, compoundYield 20.2%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

To a mixture of the product from Step A (428 mg, 0.96 mmol) and proton sponge (102 mg, 0.50 mmol) in 1,2-dichloroethane (3 mL) was added 1-chloroethyl chloroformate (208 μL, 1.91 mmol) at 0° C. under a nitrogen atmosphere. The reaction mixture was allowed to warm to ambient temperature over a weekend and concentrated in vacuo. The intermediate 2-chloroethylcarbamate was purified by flash column chromatography (dichloromethane) and refluxed in methanol for 3 hours. The resulting solution was concentrated under reduced pressure and treated with trifluoroacetic acid (5 mL) in dichloromethane (5 mL) for 1 hour. After concentration in vacuo, the residue was partitioned between dichloromethane (30 mL) and 2N aqueous sodium hydroxide (10 mL). The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give the crude material which was purified by flash column chromatography (90:10 to 50:50 ethyl acetate/ethyl acetate:methanol:ammonium hydroxide) to give 6-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-methylpyridazin-3-amine (65 mg, 20%) as a colorless oil: [α]D=+18.0° (0.05, methanol): 1H NMR (CDCl3, 300 MHz) δ 7.76 (d, J=1.2 Hz, 1H), 7.66 (dd, J=8.1 Hz, 1.8 Hz, 1H), 7.58 (d, J=9.6 Hz, 1H), 7.12-7.06 (m, 2H), 7.03-6.95 (m, 2H), 6.99 (t, J=8.4 Hz, 1H), 6.72 (d, J=9.3 Hz, 1H), 4.95 (d, J=5.1 Hz, 1H), 4.26-4.09 (m, 2H), 3.42 (dd, J=12.9 Hz, 5.1 Hz, 1H), 3.11-3.05 (m, 4H), 1.96 (br s, 2H); ESI MS m/z 335 [M+H]+.

Workup

  1. concentrationconcentrated in vacuo
  2. customThe intermediate 2-chloroethylcarbamate was purified by flash column chromatography (dichloromethane)
  3. temperaturerefluxed in methanol for 3 hours
  4. concentrationThe resulting solution was concentrated under reduced pressure
  5. additiontreated with trifluoroacetic acid (5 mL) in dichloromethane (5 mL) for 1 hour
  6. concentrationAfter concentration in vacuo
  7. customthe residue was partitioned between dichloromethane (30 mL) and 2N aqueous sodium hydroxide (10 mL)
  8. washThe organic layer was washed with brine
  9. dry with materialdried over sodium sulfate
  10. concentrationconcentrated in vacuo
  11. customto give the crude material which
  12. customwas purified by flash column chromatography (90:10 to 50:50 ethyl acetate/ethyl acetate:methanol:ammonium hydroxide)

Sources & evidence

ORD record
ord-94859edd69184f898c2cca9ccaf114ec
Source dataset
uspto-grants-2015_05
Patent number
US09034899B2

Reaction notes

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