4396 J . Org. Chem., Vol. 63, No. 13, 1998
Coop et al.
was extracted with CHCl3:MeOH (3:1, 5 × 60 mL). Removal
of the solvents gave 7 (751 mg, 62%).
filtration and shown to be impure noroxymorphone (20)35 (510
mg). The CHCl3 extracts were washed with brine and dried
(Na2SO4). The solvent was removed, and the resulting crude
material was subjected to column chromatography (EtOAc:
MeOH:NH3, 95:5:0.5) to give 19 (321 mg, 29%).
14-Hyd r oxycod ein on e (6).19 2 (500 mg, 1.6 mmol) was
treated with m-CPBA as for 3 above. The product was
extracted into CHCl3 (3 × 30 mL) and, after removal of the
solvent, recrystallized from EtOH containing a little CHCl3
to give 6 (439 mg, 87%).
Nor cod ein e (22).36 Carbamate 2137 (5.4 g, 16 mmol) was
treated with L-Selectride (130 mL, 0.5 M in THF) at room
temperature for 48 h. After quenching of the reaction with
water (50 mL), HCl (3 M, 50 mL) was added and the mixture
was cooled in an ice bath. Simple filtration gave 22‚HCl‚3H2O
(5.45 g, 92%).
Mor p h in e (1).3 Codeine (8) (482 mg, 1.6 mmol) was treated
with 2.5 equiv of L-Selectride at reflux for 3.5 h. After aqueous
workup, crystallization from water gave 1‚H2O (355 mg, 73%).
Starting material 8 was recovered from the nonphenolic
extracts and purified by crystallization from water (71 mg,
14%).
Nor m or p h in e (23).36 Meth od A. Norcodeine (22) (450
mg, 1.6 mmol) was treated with 6 equiv of L-Selectride at
reflux for 18 h. The reaction was quenched with water, and
the THF was removed. The resulting mixture was acidified
to pH 1 (3 M HCl) and rebasified to pH 9 with ammonia, and
the solid was collected by filtration. Recystallization from
water gave 23‚1.5H2O (273 mg, 58%).
20-Meth ylor vin ol (5).5 20-Methylthevinol (9)5 (1.78 g, 4.48
mmol) was treated with 3 equiv of L-Selectride at reflux for 3
h. After aqueous workup, crystallization from acetone gave 5
(1.25 g, 73%).
iso-Or vin ol (11).5 iso-Thevinol (10)5 (550 mg, 1.3 mmol)
was treated with 5 equiv of L-Selectride (0.25 M in THF) at
reflux for 48 h. After aqueous workup, purification via column
chromatography (silica, EtOAc:NH3 99:1) gave 11 (370 mg,
71%).
Meth od B. Carbamate 2137 (565 mg, 1.65 mmol) was
treated with 6 equiv of L-Selectride as in method A to give
23‚1.5H2O (275 mg, 56%).
Dih ydr on or m or ph in on e 6-Eth ylen e Ketal (26). Meth od
A. A mixture of dihydrocodeinone 6-ethylene ketal (24)38 (461
mg, 1.34 mmol), methyl chloroformate (0.5 mL), and K2CO3
(1.5 g) in dry CHCl3 (20 mL) was heated under reflux for 18
h. After cooling, water (50 mL) was added and the products
were extracted into CHCl3 (3 × 50 mL). The organic extracts
were washed with brine (50 mL), dried (K2CO3), and concen-
trated to give a foam (510 mg). This crude carbamate was
treated with 5 equiv of L-Selectride at reflux for 4.5 h. After
the solution was cooled to room temperature, the reaction was
quenched with water (10 mL) and NaOH (1 M, 5 mL). The
THF was removed under reduced pressure, and the mixture
was washed with CH2Cl2, acidified (pH 1) with HCl (10%), and
rebasified (pH 9) with an ammonia solution. The aqueous
solution was saturated with salt and extracted with CHCl3:
MeOH (3:1). After removal of the solvents, the product was
isolated as the HCl salt from MeOH (280 mg, 59%): mp >300
Oxym or p h in d ole (13a ).24 Oxycodone indole (12a )32 (1.12
g, 2.90 mmol) was treated with 3.5 equiv of L-Selectride at
reflux for 18 h. After aqueous workup, the product was
isolated as the methanesulfonic acid salt from MeOH (943 mg,
69%).
Na ltr in d ole (13b).24 A mixture of 12b24 (240 mg, 0.56
mmol) and L-Selectride (1 M in THF, 2.5 mL) was heated at
reflux for 4 h. After cooling, the reaction was quenched with
water (10 mL) and NaOH (15%, 10 mL). After removal of the
THF, the aqueous solution was extracted with CH2Cl2 (2 ×
20 mL). (Note: naltrindole did not remain in the basic
aqueous phase.) The organic extracts were then washed with
brine (30 mL) and dried (Na2SO4) and the solvent was removed
to give a foam. Formation of the HCl salt in MeOH followed
by replacement of the solvent with 2-propanol gave 13b‚HCl
(226 mg, 82%).
1
°C (dec); H NMR (300 MHz, D2O) (HCl salt) δ 2.98 (1H, d J
Oxym or p h on e (15).19 A solution of 14‚HCl (2.5 g, 6.9
mmol), ethylene glycol (5 mL), and catalytic toluenesulfonic
acid in dry toluene (200 mL) was heated at reflux for 1 h with
azeotropic removal of water. After cooling, the solution was
basified with ammonia solution and partitioned between water
and CHCl3 and the aqueous phase was further extracted with
CHCl3. The organic extracts were washed with brine and
dried (Na2SO4). Removal of the solvent gave the crude ketal
(2.46 g). The crude ketal was treated with 3 equiv of
L-Selectride (0.5 M in THF) at reflux for 23 h. After aqueous
workup, the crude product was redissolved in MeOH (40 mL),
water (20 mL), and HCl (20%, 20 mL) and the solution was
refluxed for 1 h. After cooling, the reaction was diluted with
water (50 mL), basified with ammonia (pH 9), saturated with
salt, and extracted into CHCl3 (3 × 70 mL). After removal of
the solvent, the product (15) was crystallized as the oxalic acid
salt from EtOH (2.11 g, 78%).
) 18.5 Hz, 10â-H), 4.70 (1H, s, 5-H), 6.76 (1H, d J ) 8.2 Hz,
1-H), 6.82 (1H, d J ) 8.2 Hz, 2-H); MS m/z (CS LSIMS) 316
(M + 1, 100%). Anal. Calcd for C18H22NO4Cl: C, 61.45; H,
6.30; N, 3.98. Found: C, 61.28; H, 6.30; N, 3.93.
Dih ydr on or m or ph in on e 6-Eth ylen e Ketal (26). Meth od
B. A mixture of dihydrocodeinone 6-ethylene ketal (24)38 (1.41
g, 4.11 mmol) and cyanogen bromide (1.4 mL, 3 M in CH2Cl2)
in dry CHCl3 (30 mL) was heated under reflux for 24 h. After
cooling, NaHCO3 (50 mL) and NaOH (5 mL) were added and
the mixture was stirred for 1 h. The product was extracted
into CHCl3 (3 × 50 mL), and the organic extracts were washed
with brine (50 mL), HCl (10%, 50 mL), and NaHCO3 (50 mL),
dried (K2CO3), and concentrated to give a foam (1.25 g). This
crude cyanamide was treated with 5 equiv of L-Selectride as
in method A and isolated as the HCl salt from MeOH (589
mg, 41%).
Dih yd r om or p h in e (17).31,33 Dihydrocodeinone (16) (540
mg, 1.8 mmol) was treated with 3 equiv of L-Selectride at room
temperature for 0.5 h, followed by reflux for 3 h. After aqueous
workup, crystallization from water gave 17‚H2O (230 mg, 42%).
Na ltr exon e (19).31 Ketal 1834 (1.34 g, 3.24 mmol) was
treated with 5 equiv of L-Selectride at reflux for 16 h. After
cooling, the reaction was quenched with water (30 mL) and
then acidified to pH 1 with HCl (10%). The solution was
heated at reflux for 0.75 h and then allowed to cool overnight.
After removal of the THF, the solution was basified to pH 14
with NaOH (15%), washed with CH2Cl2 (50 mL), acidified with
HCl (10%), and then rebasified to pH 9 with an ammonia
solution. Attempted extraction into CHCl3 revealed material
soluble in neither phase; this material was recovered by
Ack n ow led gm en t. We thank Noel Whittaker and
Wesley White for technical assistance and Mallinckrodt
and Co. for the generous gift of the opiates used in this
work.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR and mass
spectral data for compounds 1, 5, 6, 7, 11, 13a, 13b, 15, 17,
19, 22, and 23 (2 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information
J O9801972
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