Organic Process Research & Development
Technical Note
Evaporation of the solvent gave the demethylated product as a
pale-yellow powder (5 g). Mp 128−130 °C; [α]25D +130.6 (c 1,
MeOH).
composition for 5 min more before the end of analysis.
Detection wavelength, 220 nm. Retention times: (−)-mandelic
acid, 10.19 min; (−)-octabase, 13.97 min; (+)-N-formyl
octabase 3, 21.56 min.
(+)-3-Methoxy-N-formylmorphinan and (+)-3-hydroxy-N-
formylmorphinan: Column RP-8 (250 mm × 4.6 mm), Merck
KGa, Germany. Mobile phase 70% MeOH−30% water
containing 0.1% TFA; flow rate 0.7 mL/min; detection
wavelength, 280 nm. Retention times: (+)-3-hydroxy-N-
formylmorphinan, 6.9 min; (+)-3-methoxy-N-formylmorphinan
4, 11.4 min; (+)-N-formyl octabase 3, 12.74 min.
Determination of enantiomeric purity by chiral HPLC:
Column Chiralcel-OD (250 mm × 5 mm), Daicel Chemical
Industries, Japan. Mobile phase, 15% 2-propanol in hexane.
Detection wavelength, 220 nm. Flow rate, 0.5 mL/min.
Retention times: (+)-N-phenylacetyl octabase, 12.2 min;
(−)-N-phenylacetyl octabase, 13.9 min. Flow rate 0.4 mL/
min, retention times: (−)-3-methoxy-N-phenylacetylmor-
phinan, 18.0 min; (+)-3-methoxy-N-phenylacetylmorphinan,
19.7 min.
1H NMR (CDCl3, δ) 1.07−1.83 (m, 18H), 2.29−2.69 (m,
4H), 2.93−3.30 (m, 3H), 3.66−3.71 (m, 1H), 4.12−4.19 (m,
1H), 4.61−4.64 (m, 1H), 5.3 (s, 1H), 6.24 (br s, 1H), 6.26 (br
s, 1H), 6.67 (dd, J = 1, 2.5 Hz, 1H), 6.69 (dd, J = 1, 2.5 Hz,
1H), 6.80 (s, 1H), 6.81 (s, 1H), 6.94 (t, J = 8.5 Hz, 2H), 7.99
(s, 1H), 8.15 (s, 1H). HRMS [ESI, (M + H)+]: m/z calcd for
C17H22NO2: 272.16451; found: 272.16509.
Recovery of the Resin and Phosphoric Acid. The
recovered resin was washed with methanol, dried in the oven at
60 °C, and reused. The aqueous layer was heated to 90 °C and
treated with activated charcoal (10 g) for 10 min and then
filtered. Water was removed from the light-yellow phosphoric
acid solution under reduced pressure on rotavapor at 90 °C.
The recovered phosphoric acid could be recycled three times
without developing impurities in the product. However, after
the third recycle, phosphoric acid had to be discarded.
N-Phenylacetyl Octabase. The octabase (rac- or enantio-
merically pure, 1 g) was added to 4 N NaOH solution (10 mL).
Phenylacetyl chloride (0.7 g) was added, and the contents were
vigorously stirred for 10 min. The reaction mixture was
extracted with ethyl acetate (2 × 5 mL). Evaporation of ethyl
acetate gave the N-phenylacetyl derivative (1.45 g, 99%). The
crude product was directly analyzed by chiral HPLC for
determination of ee. A part of crude product was purified by
column chromatography (Rf = 0.6, hexane/ethyl acetate, 3:2 v/
CONCLUSION
■
We have developed an efficient and environmentally friendly
process for the synthesis of 3-methoxy-N-formylmorphinan, a
key intermediate for production of DXM. The N-formylation of
(−)-octabase can be done directly by refluxing with ethyl
formate, and cyclization of the N-formylated product is
efficiently catalyzed by Amberlyst 15 resin. Most of the
reagents can be easily recovered and recycled.
v) for characterization. Mp 84−86 °C. [α]25 + 50.84 (c 1,
D
MeOH) (ee 96%, chiral HPLC).
1H NMR (CDCl3, δppm) 1.42−1.71(m, 8H), 1.73−1.92 (m,
8H), 2.01−2.29(m, 4H), 2.68−2.74 (m, 1H), 2.80−3.09 (m,
3H), 3.50−3.68 (m, 2H), 3.78 (s, 3H), 3.81 (s, 3H), 4.70 (dd, J
= 6.56, 13.12 Hz, 1H), 4.98(m, 1H), 6.78 (J = 8.54 Hz, 2H),
6.9 (J = 8.54 Hz, 2H), 6.98−7.30 (m, 4H). IR (neat) 3000
cm−1, 2927 cm−1, 2832 cm−1, 1629 cm−1 (CO), 1511 cm−1,
1244 cm−1; HRMS ESI−MS: m/z [M + H]+calcd for
C25H30NO2: 376.2276; found: 376.2267.
AUTHOR INFORMATION
Corresponding Author
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank CSIR New Delhi for financial support under XII 5
year plan CSC0108-ORIGIN
■
3-Methoxy-N-phenylacetylmorphinan. The N-formyl
derivative 4 (enantiomerically pure or racemic) was deformy-
lated to obtain 5 by refluxing the compound (1 g) in methanol
(20 mL) and NaOH (2.5 N, 10 mL) overnight. Methanol was
removed on rotavapor, and the crude amine was treated with
phenylacetyl chloride in NaOH (as described above) to obtain
the N-phenylacetyl derivative. The enantiomerically pure
derivative was purified by column chromatography (Rf = 0.6,
REFERENCES
■
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+
D
1H NMR (CDCl3, δ) 1.18−1.68 (m, 24H), 2.28−2.46 (m,
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dx.doi.org/10.1021/op400309q | Org. Process Res. Dev. 2014, 18, 174−178