Hydrochloric Acid → HCID 73213873, compound

HRID 1398359Notes

Reaction equation

HRID 1398359 reaction equation
[CH:1]1([CH2:4][C@H:5]([NH:25]C(=O)OC(C)(C)C)[CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[C:20]4[C:15](=[C:16]([CH3:21])[N:17]=[CH:18][CH:19]=4)[C:14](=[O:22])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[CH2:3][CH2:2]1.Cl>C(OCC)C>[NH2:25][C@@H:5]([CH2:4][CH:1]1[CH2:3][CH2:2]1)[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:20]3[C:15](=[C:16]([CH3:21])[N:17]=[CH:18][CH:19]=3)[C:14](=[O:22])[N:13]([CH3:23])[C:12]=2[CH:24]=1

Participants

4

Reactant 2

HCID 313Hydrochloric AcidHCID 86710353HCID 86710353, compound

Product 1

HCID 73213873HCID 73213873, compoundYield 22%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Procedure

An ambient temperature suspension of (S)-tert-butyl (1-cyclopropyl-3-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)propan-2-yl)carbamate (50 mg, 0.114 mmol) (prepared as described in Example 16 using (S)-tert-butyl (1-cyclopropyl-3-hydroxypropan-2-yl)carbamate (0.287 g, 1.334 mmol) in Part H) in diethyl ether (1 mL) was treated with HCl (4M in 1,4-dioxane) (0.571 mL, 2.286 mmol) and stirred for 1 h. The resulting mixture was concentrated under reduced pressure to a yellow solid. The crude material was purified by reverse phase high performance liquid chromatography (Phenomenex Luna C18 30×100 mm 10 micron; water/methanol/TFA gradient elution). Fractions containing product were concentrated under reduced pressure. The resulting residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The layers were separated and the aqueous was extracted twice more with ethyl acetate. The pooled organics were washed once with brine, dried over magnesium sulfate, filtered, and concentrated to afford (S)-8-(2-amino-3-cyclopropylpropoxy)-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (9.0 mg, 0.025 mmol, 22% yield for the final step) as a white solid. LC/MS, (ESI) m/z 338.2 [(M+H)+, calcd for C20H24N3O2 338.2]; HPLC retention time (method C): tR=13.05 min; HPLC retention time (method D): tR=13.88 min; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.65 (d, J=5.8 Hz, 1H), 8.16 (d, J=8.8 Hz, 1H), 7.83 (d, J=5.5 Hz, 1H), 6.92 (dd, J=8.9, 2.4 Hz, 1H), 6.87 (d, J=2.3 Hz, 1H), 4.15 (dd, J=8.9, 3.9 Hz, 1H), 3.97 (dd, J=8.8, 7.0 Hz, 1H), 3.75 (s, 3H), 3.48-3.35 (m, 1H), 3.17 (s, 3H), 1.59-1.42 (m, 2H), 0.87-0.74 (m, 1H), 0.64-0.47 (m, 2H), 0.25-0.17 (m, 1H), 0.16-0.10 (m, 1H).

Workup

  1. concentrationThe resulting mixture was concentrated under reduced pressure to a yellow solid
  2. customThe crude material was purified by reverse phase high performance liquid chromatography (Phenomenex Luna C18 30×100 mm 10 micron; water/methanol/TFA gradient elution)
  3. additionFractions containing product
  4. concentrationwere concentrated under reduced pressure
  5. customThe resulting residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate
  6. customThe layers were separated
  7. extractionthe aqueous was extracted twice more with ethyl acetate
  8. washThe pooled organics were washed once with brine
  9. dry with materialdried over magnesium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-0657dd163c8141b98c72a012cf0bb30d
Source dataset
uspto-grants-2014_12
Patent number
US08901305B2

Reaction notes

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