Synthesis of buprenorphine from oripavine via N-demethylation of oripavine quaternary salts

Article abstract of DOI:10.1021/jo200567n

Buprenorphine was synthesized from oripavine by a sequence involving the conversion of oripavine into its cyclopropylmethyl quaternary salt, N-demethylation with thiolate to N-cyclopropylmethyl nororipavine, and conversion of this material to the title compound by previously available methods. The new synthesis avoids toxic reagents used previously, is shorter, and proceeds in comparable yields. Experimental and spectral data are provided for all new compounds.

Full text of DOI:10.1021/jo200567n

ARTICLE
pubs.acs.org/joc
Synthesis of Buprenorphine from Oripavine via N-Demethylation
of Oripavine Quaternary Salts
Lukas Werner,† Ales Machara,† David R. Adams,† D. Phillip Cox,‡ and Tomas Hudlicky*,†
†Chemistry Department and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario L2S 3A1,
Canada
‡Noramco, Inc., 503 Carr Road, Suite 200, Wilmington, Delaware 19809, United States
S Supporting Information
b
ABSTRACT: Buprenorphine was synthesized from oripavine
by a sequence involving the conversion of oripavine into its
cyclopropylmethyl quaternary salt, N-demethylation with thio-
late to N-cyclopropylmethyl nororipavine, and conversion of this
material to the title compound by previously available methods.
The new synthesis avoids toxic reagents used previously, is
shorter, and proceeds in comparable yields. Experimental and
spectral data are provided for all new compounds.
’ INTRODUCTION
Buprenorphine (1), Figure 1, is a semisynthetic opiate used to
treat moderate to severe chronic pain at low dosages. At higher
dosages it is used to treat opiate addiction, sometimes in
combination therapy with naloxone (Suboxone). It acts as a
partial agonist at the μ- and δ-receptors and has a competitive
antagonist activity at the κ-receptors.
One of the current routes to buprenorphine is an eight-step
sequence from thebaine (2) proceeding as shown in Scheme 1. 1
It employs cyanogen bromide in a von Braun N-demethylation2 of
5 to N-nitrile 6, which is then hydrolyzed to the secondary amine 7.
Figure 1. Buprenorphine synthesis from thebaine.
Oripavine was converted to its quaternary salts by heating
with cyclopropylmethyl bromide in DMF (0.67 M mixture
of oripavine). This procedure provided for a ratio of S- and
R-isomers varying between 1.8:1 and 2.6:1, detected in aliquots
from the reaction mixture; however, the solid precipitate con-
sisted of almost pure R-isomer. The pure R-isomer was isolated
from the mixture by careful precipitation, in an approximate yield
of 20%.
The use of dimethylacetamide (DMA, 0.67 M mixture of
oripavine) as solvent in the above quaternization provided a
reaction mixture as a thick slurry. Isolation consisted of filtration
and furnished 94% of mass as a solid in 98% purity by HPLC
(S/R ratio = 1.5: 1). The use of N-methylpyrrolidone (NMP)
and DMF as the solventmixture (1:1, 0.84 M mixture of oripavine)
provided cyclopropylmethyloripavine salt as a solid precipitate in
28% yield (S/R ratio = 0.26:1) and in 56% yield from mother liquor
with a purity of 97% by HPLC (S/R ratio = 7.1:1).
Alkylation of 7 with cyclopropylmethyl carbonyl chloride followed
by lithium aluminum hydride reduction andthen O-demethylation
then furnishes buprenorphine (1). While this sequence is both
efficient and performed at industrial scales it could be vastly
improved by eliminating the cyanogen bromide step and replacing
it with a milder as well as environmentally more benign protocol.
’ RESULTS AND DISCUSSION
In this paper we report on an improved synthesis of the title
compound. The literature synthesis contains two demethylation
steps: one N-demethylation of 5 performed with cyanogen
bromide and the other, the final O-demethylation of 8, accom-
plished with a KOH/digol. Various methods for O-demethyla-
tion of aryl alkyl ethers also reported in the literature employed
thioethoxide,3 thiopropoxide,4 BBr3,5 or NbCl5.6 It would be
beneficial if these demethylation steps could either be avoided or
at least combined into one operation. To this end we examined
the conversion of oripavine to the cyclopropylmethyl derivative
10 by thiolate-induced N-demethylation of the quaternary salts
9, prepared as a mixture of S- and R-stereoisomers as shown in
Scheme 2.7
The quaternization of oripavine proceeded quantitatively in
various polar aprotic solvents, provided two cycles were used: the
Received: March 17, 2011
Published: April 15, 2011
r
2011 American Chemical Society
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Scheme 1
Scheme 2
Table 1. Summary of Conditions for the N-Demethylations
of 9
crude product was resubjected to treatment with additional
cyclopropylmethyl bromide with heating in order to provide the
full conversion. The mixture of diastereomeric salts 9 was used in
the synthesis of R-methylnaltrexone as described recently.8
The use of thiolate anions, such as PhSNa, as soft nucleophiles
for the N-demethylation of morphine alkaloids was previously
reported.9 The N-demethylation of the quaternary ammonium
salt of oripavine was also performed with tert-dodecanethiol as
the nucleophilic reagent and sodium ethoxide or sodium tert-
butoxide as the base. We found that the diastereomers yielded
N-methylcyclopropyl nororipavine at different rates and in differ-
ent yields, as shown in Table 1, where the conditions and the
yields are summarized.
substrate/
(mg)
time
yield
(%)
entry
solvent T (°C) (min)
base
1
2
3
4
(R) salt
(R) salt
(S) salt
DMSO
DMSO
DMSO
80
45
10
55
55
NaOEt
NaOEt
NaOEt
NaOt-Bu
71b
77b
63b
67c
100
80
(S,R) salta DMSO
80
a Mixture in 1.9/1 ratio. b Isolated by column chromatography, 200 mg scale.
c Isolated by crystallization, 1 g scale.
mixtures during workup has significantly improved. It is also
noteworthy to mention that the R-isomer of 9 reacts at a faster
rate than the corresponding S-isomer.
In addition to the noticeable increase in yield in the experi-
ments on small scale, the appearance and handling of the reaction
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Scheme 3
With the N-cyclopropylmethyl nororipavine 10 in hand, we
turned our attention to its conversion to buprenorphine. Two
routes, depicted in Scheme 3, were investigated and compared in
terms of overall efficiency. The DielsꢀAlder cycloaddition of
methylvinyl ketone with the diene system of oripavine produced
the adduct 11 in high yield.
A small amount (4ꢀ8%) of byproduct resulting from the 1,4-
addition of the phenol to methyl vinyl ketone, namely com-
pound 18, Figure 2, was formed in this reaction, but the crude
product was easily purified by crystallization (see the Experi-
mental Section for the spectral data of the byproduct). Hydro-
genation of 11 in water containing tartaric acid gave cleanly 12,
in which the phenol hydroxyl was protected as its ethyl
carbonate 13. The second route involved the protection of
the phenol as its carbonate 14 prior to performing the
DielsꢀAlder reaction that provided the cycloadduct 15 in
92% yield. Hydrogenation of 15 then furnished carbonate 13,
converging with the previous sequence. The comparison of the
two routes provided the following conclusion: The overall
yield of buprenorphine (1) via 11, 12, and 13 was 32%, while
the route via 14 and 15 gave 23% overall yield of the title
Figure 2. Byproduct from the DielsꢀAlder cycloaddition of unpro-
tected nororipavine.
compound. The former route is more convenient because
the intermediates 11 and 12 were crystalline, thus simplifying
purification.
The attainment of 13 left only the Grignard addition to
complete the synthesis. Ketone 13 was treated with 6 equiv of
Grignard reagent, which was prepared as a slurry, to produce 76% of
carbonate 16, Scheme 3. When the reaction was performed with
10 equiv of Grignard reagent, the yield of 16 was diminished and
a byproduct, identified as the pivalate ester 17, appeared, along
with ∼5% of buprenorphine produced by the full cleavage of the
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carbonate. With 17 equiv of the Grignard reagent, the proportion
of the pivalate 17 and buprenorphine increased to 30%, respec-
tively, Scheme 3. The mixture of 16 and 17 obtained under any of
these conditions was then treated with sodium hydroxide in
methanol/dichloromethane to furnish buprenorphine, identical
in all respects with the known standard. The direct conversion
of the O-unprotected intermediate 12 to buprenorphine with
excessGrignardreagentwas also performed, asshown in Scheme 3.
However, the yield of buprenorphine from 12 was never higher
than ∼30% at the expense of recovered starting material and a
minor byproduct that was not further identified. If this reaction
mixture was subjected to a second cycle, the yield of buprenor-
phine increased to 42%. This protocol was not investigated in
detail in view of the much higher-yielding route via carbonate 13.
In the future, a better protecting group for the phenol may be
an acetate as it would be more easily cleaved by the Grignard
reagent.
The filtered solid was washed with MeOH (1.5 mL), and the product
precipitated by slow, inverse addition of the reaction mixture to a
vigorously stirred volume of toluene (∼100 mL). The precipitate was
filtered and washed with toluene (2 ꢁ 10 mL), and the solid was
collected and dried under vacuum to provide a slightly off-white solid in
greater than quantitative yield. This crude material was triturated in
acetone (50 mL) at room temperature for 2 h prior to a second filtration.
The solid was collected and dried under vacuum to yield 2.60 g (94%
yield) of N-cyclopropylmethyl oripavine ammonium bromide salt (9) as
a white, free-flowing solid; mp 194ꢀ200 °C; isomeric ratio determined
by HPLC (S:R) 2.6:1.
R-Isomer. mp 219ꢀ221 °C (EtOH); Rf 0.30 (DCM þ 20% meth-
anol); [R]20D ꢀ109.38 (c = 1, MeOH); 1H NMR (600 MHz, DMSO-d6)
δ 9.37 (s, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.55 (d, J = 8.1 Hz, 1H), 6.01 (d,
J = 6.6 Hz, 1H), 5.42 (s, 1H), 5.29 (d, J = 6.6 Hz, 1H), 4.67 (d, J = 7.2 Hz,
1H) 3.71 (m, 1H), 3.70 (m, 1H), 3.61 (s, 3H), 3.45 (dd, J = 13.5, 4.6 Hz,
1H), 3.39 (dd, J = 13.7, 7.6 Hz, 1H), 3.29 (ddd, J = 13.2, 13.2, 4.0 Hz,
1H) 3.19 (s, 3H), 3.06 (dd, J = 19.4, 7.2 Hz, 1H), 2.59 (ddd, J = 14.1,
14.1, 5.1 Hz, 1H), 1.86 (dd, J = 14.2, 2.9 Hz, 1H), 1.21 (m, 1H), 0.75
(m, 2H), 0.51 (m, 1H), 0.44 (m, 1H); 13C NMR (150 MHz, DMSO-d6)
δ 154.6, 143.5, 140.4, 132.6, 124.1, 122.5, 120.2, 119.8, 117.6, 96.1, 87.2,
68.1, 67.1, 55.6, 54.0, 46.1, 44.2, 31.5, 30.4, 5.1, 4.4, 4.2.
S-Isomer. mp 195ꢀ197 °C (MeOH þ i-PrOH); Rf 0.28 (DCM þ
20% methanol); [R]20D ꢀ43.73 (c = 1, MeOH); 1H NMR (600 MHz,
DMSO-d6) δ 9.37 (s, 1H), 6.63 (d, J = 8.0 Hz, 1H), 6.57 (d, J = 8.0 Hz,
1H), 5.98 (d, J = 6.6 Hz, 1H), 5.39 (s, 1H), 5.26 (d, J = 6.6 Hz, 1H), 4.75
(d, J = 6.9 Hz, 1H), 3.77 (d, J = 19.6 Hz, 1H), 3.64 (dd, J = 13.4, 6.1 Hz,
1H), 3.60 (s, 3H), 3.49 (dd, J = 13.4, 3.2 Hz, 1H), 3.35 (m, 1H), 3.29
(s, 3H), 3.28 (m, 1H), 3.06 (dd, J = 19.5, 7.0 Hz, 1H), 2.56 (ddd, J = 14.0,
14.0, 4.5 Hz, 1H), 1.79 (d, J = 11.9 Hz, 1H), 1.21 (m, 1H), 0.72 (m, 2H),
0.52 (m, 1H), 0.39 (m, 1H); 13C NMR (150 MHz, DMSO-d6) δ 154.6,
143.4, 140.4, 132.6, 124.1, 122.6, 120.2, 119.7, 117.6, 96.0, 87.3, 68.6,
63.9, 55.58, 54.0, 48.6, 43.7, 31.3, 30.6, 4.9, 4.6, 4.3; MS (FABþ) m/z
(%): 55 (31), 98 (24), 112 (38), 239 (12), 352 (100); HRMS calcd for
C22H26NO3þ 352.1907, found 352.1898.
N-Cyclopropylmethyl Nororipavine (10). To a slurry of
sodium tert-butoxide (0.67 g; 7.04 mmol) in freshly distilled DMSO
(4.7 mL) was added tert-dodecanethiol (1.42 g; 7.04 mmol, distilled) in
one portion. The resulting mixture was vigorously stirred and immersed
in a preheated oil bath at 90 °C for 10 min prior to decreasing the
temperature to 80 °C. A solution of N-cyclopropylmethyl oripavine
ammonium bromide 9 (1.01 g, 2.34 mmol) in DMSO (4.7 mL) was
added to the preformed mixture of tert-dodecanethiolate at 80 °C over
10 min. A sharp color change from a clear, slightly yellow solution to a
brown colored mixture occurred after the addition of the first several
drops of the N-cyclopropylmethyl oripavine ammonium bromide solu-
tion. The reaction mixture was allowed to stir at 80 °C for 40 min
following the addition, and the progress was monitored by HPLC
(285 nm). After the complete consumption of starting material, the
reaction mixture was allowed to cool to room temperature with stirring
and poured into H2O (40 mL). The pH of the aqueous mixture was
adjusted to pH 2 with HCl (6 M) and washed with hexanes (2 ꢁ 20 mL).
The pH of the aqueous mixture (milky yellow suspension) was read-
justed to pH 8 with NaOH (aq, 15%). A fine, white precipitate was
observed upon pH adjustment and was cleared by extraction with EtOAc
(1 ꢁ 20 mL, 1 ꢁ 10 mL). The pH of the aqueous phase was adjusted
again to pH 8 (white precipitate was observed) and extracted with
EtOAc (3 ꢁ 10 mL). The organic layers were combined and washed
with H2O (1 ꢁ 10 mL) and brine (1 ꢁ 10 mL). The organic layers
were dried over MgSO4, filtered, and concentrated to provide crude
material, which was crystallized from acetone/cyclohexane mixture
(1:1). The yield of the crystallization was 0.48 g (61%). The mother
liquor was chromatographed on silica gel (20% MeOH/EtOAc) and
crystallized from acetone/cyclohexane to afford additional 0.05 g
’ CONCLUSIONS
The synthesis of buprenorphine described in this paper
proceeds in seven chemical steps but is reducible to just four
operations, as some of the steps may be combined without isolation
of the intermediates. The major improvement over the previous
synthesis is the elimination of cyanogen bromide as the agent of
N-demethylation and avoidance of O-demethylation required in
the route from thebaine. The synthesis is amenable to scale up and
proceeds with the overall yield of 32% from oripavine.
’ EXPERIMENTAL SECTION
All nonaqueous reactions were conducted in an argon atmosphere
using standard Schlenk techniques for the exclusion of moisture and air.
All solvents were distilled unless otherwise noted. Analytical thin layer
chromatography was performed on silica gel 60 Å 250 μm TLC plates
with F-254 indicator. Flash column chromatography was performed
using silica gel (230ꢀ400 mesh). Melting points are uncorrected. IR
spectra were obtained on a FT-IR spectrometer. Optical rotations was
1
measured on a polarimeter at a wavelength of 589 nm. H and 13C
spectra were recorded on a 300 and 600 MHz spectrometer. All chemical
shifts are referenced to TMS or residual undeuterated solvent. Data for
proton spectra are reported as follows: chemical shift (multiplicity
[singlet (s), doublet (d), triplet (t), quartet (q) and multiplet (m)],
coupling constants (Hz), integration). Carbon spectra were recorded
with complete proton decoupling and the chemical shifts are reported in
ppm (C) relative to TMS.
N-Cyclopropylmethyl Oripavine Ammonium Bromide (9).
To a flame-dried, argon purged round-bottom flask with attached reflux
condenser was charged a suspension of oripavine (3) (1.84 g, 6.18
mmol) in anhydrous DMF (10 mL). (Bromomethyl)cyclopropane
(1.8 mL, 18.5 mmol, 3.0 equiv) was added in one portion to the vigor-
ously stirred suspension of oripavine at room temperature. The reaction
mixture was immersed in a preheated oil bath at 80 °C and allowed to
stir under argon atmosphere for 12 h. The reaction mixture was cooled,
and an aliquot was analyzed by HPLC (285 nm) and determined to
contain approximately 4% (as determined by integration) of oripavine
(as the HBr salt). NaHCO3 (21 mg, 0.24 mmol, 4 mol %) was add-
ed to the reaction mixture and allowed to stir for 1 h prior to the
addition of (bromomethyl)cyclopropane (0.30 mL, 3.1 mmol, 0.5 equiv)
at room temperature. The reaction mixture was immersed in the
preheated oil bath at 80 °C for an additional 8 h prior to analysis by
HPLC (285 nm). It was observed that approximately 1% oripavine
remained in the reaction mixture. The reaction mixture (fine beige slurry)
was cooled to room temperature and filtered through a fine-fritted funnel.
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(6%) of N-cyclopropylmethyl nororipavine 10 as a pale-yellow, crys-
talline solid; Rf 0.25 (20% MeOH/EtOAc); mp 165ꢀ166 °C (DCM),
[7r-Acetyl-17-(cyclopropylmethyl)-6,14-endo(ethano)tetra-
hydronororipavine]. 1-[(5r,7r)-17-(Cyclopropylmethyl)-4,5-epoxy-
3-hydroxy-6-methoxy-6,14-ethanomorphinan-7-yl]ethanone (12). The
DielsꢀAlder adduct 11 (1.64 g; 4.01 mmol), tartaric acid (642 mg; 4.01
mmol), and Pd/C (450 mg; 10 wt %) were suspended in deionized water
(15 mL). The flask was then evacuated/refilled with H2 gas (four cycles)
and subjected to hydrogenation (1 atm.). The reaction mixture was then
stirred at 80 °C for 16 h under 1 atm of hydrogen. TLC (ethyl acetate)
analysis showed only traces of starting material (Rf = 0.5) and a majority of
12 (Rf = 0.4). The TLC sample was prepared by extraction of few drops of
reaction mixture between ethyl acetate (0.5 mL) and a satd solution of
NaHCO3 (0.5 mL). The hot reaction mixture was then filtered through a
0.7 cm pad of Celite which was then washed with hot deionized water
(70 °C, 2 ꢁ 2 mL). After the filtrate was cooled to room temperature, the
pH was adjusted to 6.60ꢀ6.70 (40% KOH; 930 μL) with vigorous stirring.
The resulting white precipitate was then filtered off and dried overnight
under vacuum at 50 °C to yield a porous white solid (1.52 g). 1H NMR
showed that this material contains ∼3% of starting 11 and ∼3% of corres-
ponding β-diastereomer. Chromatography (10 mL silica, hexane/ethyl
acetate 1:1) of 150 mg of this material afforded 135 mg of pure 12. It was
determined that the crude material contained ∼10% water and inorganic
impurities. The yield of 12 was estimated to be 1.37 g (83%).
12: mp 170ꢀ172 °C (EtOH), 166ꢀ168 °C (crude evaporated from
ethyl acetate); Rf = 0.4 (ethyl acetate); [R]20D ꢀ109.93° (c = 1, CHCl3);
IR (KBr, cmꢀ1) ν 3463, 3075, 2956, 2924, 2874, 2853, 2813, 2777, 1709,
1647, 1610, 1502, 1458, 1384, 1356, 1331, 1283, 1160, 1095, 1030, 958,
820, 702; 1H NMR (CDCl3, 300 MHz) δ 6.70 (d, J = 8.1 Hz, 1H), 6.53
(d, J = 8.1 Hz, 1H), 4.51 (d, J = 1.8 Hz, 1H), 3.43 (s, 3H), 3.10ꢀ3.04 (m,
2H), 2.97 (d, J = 18.3 Hz, 1H), 2.76 (ddd, J = 13.5, 11.4, 3.9 Hz, 1H),
2.65 (dd, J = 12.0, 5.1 Hz, 1H), 2.37ꢀ2.23 (m, 7H), 2.05 (ddd, J = 12.6,
12.6, 5.7 Hz, 1H), 1.74 (dd, J = 13.2, 6.3 Hz, 1H), 1.69ꢀ1.40 (m, 3H),
1.30 (ddd, J = 12.3, 12.3, 8.7 Hz, 1H), 0.83ꢀ0.64 (m, 2H), 0.54ꢀ0.40
(m, 2H), 0.15ꢀ0.05 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 210.9,
145.3, 137.4, 132.4, 128.2, 119.7, 116.5, 94.8, 77.8, 59.8, 58.4, 52.1, 49.5,
46.7, 43.8, 35.5, 35.2, 33.6, 30.5, 28.6, 22.8, 17.6, 9.4, 4.1, 3.4; MS (þEI)
m/z (%) 409 (6), 368 (5), 155 (2), 149 (4), 129 (5), 123 (4), 113 (7),
112 (9), 111 (6); HRMS (þEI) calcd for C25H31N1O4: 409.2253.
Found 409.2261; Anal. Calcd for C25H31N1O4: C, 73.32; H, 7.63.
Found C,73.22; H, 7.59.
[7r-Acetyl-17-(cyclopropylmethyl)-3-[(ethoxycarbonyl)oxy]-
6,14-endo(ethano)tetrahydronororipavine]. (1-[(5r,7r)-17-
(Cyclopropylmethyl)-4,5-epoxy-3-[(ethoxycarbonyl)oxy]-18,19-dihydro-
6-methoxy-6,14-ethenomorphinan-7-yl]ethanone (13). To a suspension
of 12 (0.5 g, ∼1.21 mmol; ∼90% purity;) in warm toluene (10 mL, 40 °C)
were added ethyl chloroformate (171 mg; 1.58 mmol) and triethylamine
(271 μL, 1.94 mmol). Upon addition of triethylamine, most of 12 was
dissolved and the reaction mixture turned a slight-yellow color followed by
red. TLC (ethyl acetate/hexane 1:1) analysis after 10 min showed disap-
pearance of starting material, a major spot corresponding to 13 (Rf =
0.3ꢀ0.4) and two spots of minor impurities (Rf = 0.4, 0.45). After being
stirred for an additional 30 min at room temperature, the reaction mixture
was filtered through a short pad of Celite, and triethylammonium hydro-
chloride and other inorganic material from the previous step were
removed. The filter cake was then washed with toluene (2 ꢁ 2.5 mL)
andthefiltrateconcentratedinvacuo.1H NMR of crude showedessentially
pure 13 and traces of toluene. The crude product (520 mg) was then
dissolvedin EtOH (2.5 mL) at 55°C and crystallized overnight in a freezer,
giving 320 mg (∼61%) of white crystals with slight yellow tinge. When
chromatography (30 mL silica, hexane/ethyl acetate 4:1) was used for
purification, the yield of 13 was 498 mg (95%).
mp 166ꢀ167 °C (methanol); [R]20 ꢀ168.60 (c = 1, CHCl3); IR
D
(KBr) ν 3445, 2908, 1630, 1458, 1234, 1046, 1016, 926, 868 cmꢀ1; 1H
NMR (600 MHz, CDCl3) δ 6.65 (d, J = 8.4 Hz, 1 H), 6.55 (d, J = 8.4
Hz, 1 H), 5.59 (d, J = 6.6 Hz, 1 H), 5.29 (s, 1 H), 5.07 (d, J = 6.6 Hz,
1 H), 4.02 (d, J = 6.6 Hz, 1 H), 3.61 (s, 3 H), 3.29 (d, J = 18.0 Hz, 1 H),
3.00 (dd, J = 12.6, 4.2 Hz, 1 H), 2.90 (m, 1 H), 2.76 (dd, J = 18.0, 7.2
Hz, 1 H), 2.55 (m, 2 H), 2.24 (m, 1 H), 1.71 (d, J = 11.4 Hz, 1 H), 0.97
(m, 1 H), 0.56 (d, J = 8.4 Hz, 2 H), 0.19 (d, J = 8.4 Hz, 2H); 13C NMR
(150 MHz, CDCl3) δ 152.2, 143.1, 138.8, 133.2, 132.6, 126.7, 119.7,
116.5, 112.1, 96.4, 89.4, 58.57, 58.55, 54.9, 46.9, 43.8, 36.2, 31.2, 9.2, 3.9
(2 ꢁ CH2); MS (þEI) m/z (%): 43 (100), 58(19), 84 (56), 227 (8),
282 (12), 337 (41); HRMS calcd for C21H23NO3 337.1678, found
337.1681.
[7r-Acetyl-17-(cyclopropylmethyl)-6,14-endo(etheno)tetra-
hydronororipavine]. 1-[(5r,7r)-17-(Cyclopropylmethyl)-4,5-epoxy-
3-hydroxy-6-methoxy-6,14-ethenomorphinan-7-yl]ethanone (11). Cy-
clopropylmethyl nororipavine 10 (157 mg; 0.53 mmol) was dissolved in
toluene (2.4 mL), and methylvinyl ketone (0.8 mL) was added. The
reaction mixture was stirred with a magnetic stirbar and heated to 80 °C.
After 12 h, TLC (ethyl acetate) analysis indicated no starting material (Rf =
0.05) but the presence of 11 (Rf = 0.5) and the adduct 18 (Rf = 0.4). The
reaction mixture was then concentrated in vacuo, and the resulting light
brown solid was crystallized from hot EtOH (0.4 mL), yielding 11 (182mg,
85%) as a white solid.
11: mp 211ꢀ214 °C(EtOH);Rf =0.5(ethylacetate);[R]20D ꢀ236.47°
(c = 1, CHCl3); IR (KBr, cmꢀ1) ν 3587, 3072, 3051, 3027, 3000, 2970,
2935, 2920, 2891, 2839, 2814, 2788, 1702, 1637, 1607, 1500, 1467, 1427,
1381, 1352, 1317, 1242, 1217, 1163, 1124, 1096, 1084, 1028, 932, 822, 786,
735; 1H NMR (CDCl3, 600 MHz) δ 6.62 (d, J = 7.8 Hz, 1H), 6.49 (d, J =
7.8 Hz, 1H), 5.87 (d, J = 9.0 Hz, 1H), 5.59 (d, J = 9.0 Hz, 1H), 4.62 (s, 1 H),
3.60ꢀ3.57 (m, 4H), 3.11 (d, J = 18.6 Hz, 1H), 3.03 (dd, J = 12.6, 10.2 Hz,
1H), 2.95 (dd, J = 9.0, 9.0 Hz, 1H), 2.73 (dd, J = 12.0, 4.8 Hz, 1H),
2.45ꢀ2.38 (m, 3H), 2.35 (dd, J= 12.6, 6.6 Hz, 1H), 2.16 (s, 3H), 1.98 (ddd,
J = 13.2, 13.2, 5.4 Hz, 1H), 1.86 (dd, J = 12.6, 2.4 Hz, 1H), 1.36 (dd, J = 12.6,
6.6 Hz, 1H), 0.85ꢀ0.83 (m, 1H), 0.56ꢀ0.49 (m, 2H), 0.17ꢀ0.12 (m, 2H);
13C NMR (CDCl3, 150 MHz) δ 209.3, 146.6, 137.4, 136.4, 134.1, 127.8,
125.7, 119.9, 116.3, 95.2, 81.3, 59.8, 57.1, 53.2, 50.7, 48.5, 44.0, 43.3, 33.5,
30.3, 30.0, 23.3, 9.5, 4.1, 3.5; MS (FABþ) m/z (%) 408 (18), 407 (13), 243
(22), 242 (100), 184 (11), 142 (19); HRMS (FABþ) calcd for C25H29-
N1O4: 407.2096. Found 407.2096.
[7r-Acetyl-17-(cyclopropylmethyl)-6,14-endo(etheno)tetra-
hydronororipavine]. 1-[(5r,7r)-17-(Cyclopropylmethyl)-4,5-epoxy-
3-(3-oxobutyl)-6-methoxy-6,14-ethenomorphinan-7-yl]ethanone (18).
This material was isolated by chromatography of combined filtrates left
after the crystallization of 11. First chromatography: hexane/ethyl acetate
4:1. Second chromatography: toluene/ethyl acetate 3:1.
18: Colorless oil. Rf = 0.5 (ethyl acetate); [R]20D ꢀ183.61° (c = 1,
CHCl3); IR (KBr, cmꢀ1) ν 3484, 3421, 3406, 3075, 2997, 2924, 2835,
2813, 2777, 1712, 1629, 1600, 1497, 1444, 1384, 1357, 1250, 1205, 1170,
1103, 1054, 937, 796; 1H NMR (CDCl3, 300 MHz) δ 6.64(d, J = 8.1 Hz,
1H), 6.51 (d, J = 8.1 Hz, 1H), 5.90 (d, J = 9.0 Hz, 1H), 5.60 (d, J = 9.0 Hz,
1H), 4.57 (s, 1 H), 4.40ꢀ4.20 (m, 2H), 3.61 (s, 3H), 3.58 (dd, J = 11.7,
6.3 Hz, 1H), 3.11 (d, J = 18.3 Hz, 1H), 3.08ꢀ2.90 (m, 2H), 2.87 (t, J =
6.6 Hz, 1H), 2.72 (dd, J = 11.7, 4.5 Hz, 1H), 2.48ꢀ2.28 (m, 4H), 2.22 (s,
3H), 2.16 (s, 3H), 1.98 (ddd, J = 12.0, 12.0, 5.1 Hz, 1H), 1.85 (dd, J =
12.9, 2.7 Hz, 1H), 1.37 (dd, J = 12.0, 5.7 Hz, 1H), 0.91ꢀ0.77 (m, 1H),
0.57ꢀ0.47 (m, 2H), 0.19ꢀ0.09 (m, 2H); 13C NMR (CDCl3, 75 MHz)
δ 209.3, 206.8, 148.6, 140.4, 136.4, 134.6, 129.2, 125.6, 119.6, 116.3,
95.6, 81.4, 65.2, 59.8, 56.9, 53.6, 50.8, 48.1, 43.9, 43.4, 43.2, 33.6, 30.60,
30.55, 29.9, 23.3, 9.5, 4.1, 3.4; MS (FABþ) m/z (%) 478 (100), 408 (26),
407 (16), 326 (14), 246 (28); HRMS from 408 fragment (FABþ) calcd
for C25H30N1O4: 408.2174. Found 408.2142.
13: mp 105ꢀ107 °C (MeOH); Rf = 0.3ꢀ0.4 (ethyl acetate/hexane
1:1); [R]20D ꢀ148.51° (c = 1, CHCl3); IR (KBr, cmꢀ1) ν 3077, 2965,
2930, 2837, 2812, 2778, 2745, 2255, 1764, 1711, 1614, 1492, 1451, 1384,
1369, 1356, 1259, 1243, 1200, 1163, 1130, 1095, 1063, 1024, 993, 958,
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The Journal of Organic Chemistry
ARTICLE
878, 781, 731; 1H NMR (CDCl3, 300 MHz) δ 6.88 (d, J = 8.1 Hz, 1H),
6.62 (d, J = 8.1 Hz, 1H), 4.51 (d, J = 1.5 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H)
3.38 (s, 3H), 3.09ꢀ2.98 (m, 3H), 2.74 (ddd, J = 13.5, 9.6, 3.9 Hz, 1H),
2.65 (dd, J = 12.0, 5.1 Hz, 1H), 2.37ꢀ2.23 (m, 7H), 2.05 (ddd, J = 12.6,
12.6, 5.4 Hz, 1H), 1.78ꢀ1.61 (m, 3H), 1.53 (dddd, J = 12.9, 12.9, ∼1,
∼1 Hz, 1H), 1.36 (t, J = 7.2 Hz, 3H), 1.29 (dd, J = 12.0, 6.0 Hz, 1H),
0.80ꢀ0.73 (m, 1H), 0.69ꢀ0.65 (m, 1H), 0.54ꢀ0.43 (m, 2H), 0.13ꢀ0.05
(m, 2H); 13C NMR (CDCl3, 75 MHz) δ 210.9, 153.2, 149.5, 134.6, 133.8,
131.9, 121.8, 119.3, 96.7, 77.6, 64.9, 59.8, 58.3, 52.4, 50.0, 46.1, 43.6, 35.4,
34.9, 33.9, 30.3, 28.6, 23.3, 16.6, 14.2, 9.4, 4.1, 3.4; MS (FABþ) m/z (%)
482 (100), 481 (78), 480 (2), 450 (21), 440 (25), HRMS (FABþ) calcd
for C28H36N1O6: 482.2542. Found 482.2507. Anal. Calcd for C28H35N1O6:
C, 69.83; H, 7.33. Found C, 69.53; H, 7.30.
Alternative Route. 17-(Cyclopropylmethyl)-3-[(ethoxycarbonyl)-
oxy]nororipavine (14). Cyclopropylmethylnororipavine (400 mg; 1.19
mmol) was suspended in ethyl acetate (4 mL) at room temperature, and
ethyl chloroformate (124 μL; 1.30 mmol) was added to suspension in one
portion followed by Et3N (215 μL; 1.54 mmol). The reaction mixture was
stirred at room temperature for 5 h, diluted with ethyl acetate (50 mL),
and washed with satd solution of NaHCO3 (10 mL). The aqueous
layer was re-extracted with ethyl acetate (10 mL), and the combined
organic layer was dried over MgSO4 and concentrated under vacuum.
Crystallization of crude product from acetone (3 mL) afforded white
crystals of 14 (316 mg, 65%). The mother liquor was concentrated and
crystallized from acetone/cyclohexane (0.5 mL, 1:1) giving an additional
15 mg (10%) of product. 14: mp 157ꢀ158 °C (EtOH); Rf 0.33 (ethyl
acetate þ20% methanol); [R]20D ꢀ97.80 (c = 1, CHCl3); IR (CHCl3)
ν 2997, 2933, 2837, 1761, 1608, 1446, 1370, 1261, 1023, 866 cmꢀ1; 1H
NMR (600 MHz, CDCl3) δ 6.86 (d, J = 8.1 Hz, 1H), 6.63 (d, J = 8.1 Hz,
1H), 5.59 (d, J = 6.4 Hz, 1H), 5.34 (s, 1H), 5.07 (d, J = 6.4 Hz, 1H), 4.33
(dq, J = 7.2, 0.9 Hz, 2H) 3.96 (d, J = 6.8 Hz, 1H), 3.62 (s, 3H), 3.28 (d, J =
18.1 Hz, 1H), 2.92 (dd, J = 13.0, 4.5 Hz, 1H), 2.81 (ddd, J = 12.7, 12.7, 3.0,
1H), 2.74 (dd, J = 18.1, 6.9 Hz, 1H), 2.50 (d, J = 6.4 Hz, 2H), 2.22 (ddd,
J = 12.6, 12.6, 5.1 Hz, 1H), 1.77 (dd, J = 12.6, 1.7 Hz, 1H), 1.38 (t, J = 7.2
Hz, 3H), 0.93 (m, 1H), 0.57 (m, 2H), 0.17 (dd, J = 9.7, 4.8 Hz, 2H); 13C
NMR (150 MHz, CDCl3) δ 153.2, 152.3, 147.5, 134.8, 133.5, 132.8,
132.3, 121.5, 119.3, 112.0, 96.3, 90.0, 64.9, 59.1, 58.4, 55.1, 46.5, 44.1, 36.6,
30.9, 14.2, 9.5, 3.9, 3.8; MS (þEI) m/z (%): 42 (23), 55 (45), 253 (25),
277 (41), 308 (23), 363 (100), 409 (14); HRMS calcd for C24H27NO5
409.1889, found 409.1889.
1099, 1062, 1023, 977, 780; 1H NMR (CDCl3, 300 MHz) δ 6.79 (d, J =
8.1 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 5.94 (d, J = 8.7 Hz, 1H), 5.60 (d, J =
9.0 Hz, 1H), 4.62 (s, 1 H), 4.28 (q, J = 7.2 Hz, 2H), 3.59ꢀ3.57 (m, 4H),
3.14 (d, J = 18.6 Hz, 1H), 3.00 (dd, J = 11.7, 9.6 Hz, 1H), 2.91 (dd, J =
9.3, 6.3 Hz, 1H), 2.73 (dd, J = 12.0, 4.5 Hz, 1H), 2.50ꢀ2.30 (m, 4H),
2.16 (s, 3H), 1.97 (ddd, J = 12.6, 12.6, 5.4 Hz, 1H), 1.90 (dd, J = 12.9, 2.7
Hz, 1H), 1.36 (t, J = 7.2 Hz, 3H), 0.83 (m, 1H), 0.54ꢀ0.50 (m, 2H),
0.17ꢀ0.11 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 209.2, 153.1, 150.8,
136.2, 135.5, 133.9, 131.9, 125.5, 121.4, 119.6, 97.1, 81.3, 77.5, 64.9, 59.8,
56.9, 53.9, 50.9, 48.2, 43.8, 43.2, 33.3, 30.8, 29.8, 23.7, 14.2, 9.5, 4.1, 3.4;
MS (FABþ) m/z (%) 480 (100), 436 (21), 328 (14), 246 (31); HRMS
(FABþ) calcd for C28H34N1O6: 480.2386. Found 480.2338.
Hydrogenation of 15 to 13: Carbonate 15 (135 mg; 0.28 mmol),
tartaric acid (42 mg; 0.28 mmol), and Pd/C (25 mg; 10 wt %) were
suspended in deionized water (2 mL). The flask was then evacuated/
refilled with H2 gas (four cycles) and subjected to hydrogenation
(1 atm). The reaction mixture was then stirred at 80 °C for 16 h. The
hot reaction mixture was then filtered through a 0.5 cm pad of Celite
which was then washed with hot deionized water (70 °C, 2 ꢁ 1 mL).
After being cooling to room temperature, the filtrate was washed
between ethyl acetate (15 mL) and has NaHCO3 solution (5 mL).
Organic layer was dried over MgSO4 and concentrated in vacuo.
Chromatography (8 mL silica, hexane/ethyl acetate 2:1) afforded 13
(113 mg, 75%) as a white solid, identical to the material obtained by
the previous route.
Buprenorphine (1). tert-Butylmagnesium chloride was prepared from
2 g of Mg turnings, 6.94 mL of THF, 9.8 g of t-BuCl, and 24.5 mL of
cyclohexane. An aliquot of Grignard reagent (∼1 mL) was dissolved in a
solution of 1,10-phenatroline monohydrate (1ꢀ2 mg) in 4 mL of THF
and titrated with a 1 M solution of menthol in THF until loss of purple
color from the magnesium/phenantroline complex. The Grignard
reagent was used as a slurry.
A solution of 13 (109 mg; 2.265 mmol) in toluene (1 mL) was added
dropwise to a vigorously stirred suspension of tert-butylmagnesium
chloride in hexane (2.3 mL; 1 M suspension) at room temperature. After
the mixture was stirred 35 min, TLC (hexane/ethyl acetate 1:1) analysis
showed the disappearance of all starting material and a major spot
corresponding to 16 (Rf = 0.8), traces of buprenorphine (Rf = 0.6), and a
byproduct (Rf = 0.1) not fully identified. This byproduct probably
resulted from the reduction of the ketone, as it appeared to be a mixture
of two diastereoisomers. The TLC sample was prepared by extraction of
few drops of reaction mixture between ethyl acetate (0.5 mL) and satd
NaHCO3 (0.5 mL). The reaction was then quenched by careful addition
of water (2 mL) to the reaction mixture at room temperature, which led
to a release of isobutane and heat (∼45 °C). The reaction mixture was
then diluted with ethyl acetate (30 mL) and extracted with satd NH4Cl
(4 mL). The aqueous layer (pH 7ꢀ8, paper) was then re-extracted with
ethyl acetate (2 ꢁ 10 mL). The combined organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The content of 16 (esti-
mated by 1H NMR) was 84%. The crude mixture was then dissolved in
MeOH (3 mL) and dichloromethane (2 mL), and 5% NaOH (0.91 mL;
5 equiv) was added dropwise. Immediately after addition of hydroxide,
the reaction turned to a brown-red color. After 10 min, TLC (hexane/
ethyl acetate 1:1) analysis showed complete hydrolysis of starting
material and a major spot of buprenorphine Rf = 0.6 acompanied by
two minor spots Rf = 0.65, 0.2. The reaction mixture was then diluted
with dichloromethane (50 mL) and washed with satd solution NH4Cl
(5 mL). The aqueous layer (pH 7ꢀ8, paper) was re-extracted with
dichloromethane (10 mL). The combined organic layer was dried with
MgSO4 and concentrated in vacuo. Chromatography (8 mL silica;
hexane/ethyl acetate 4:1f2:1) afforded buprenorphine (1) as slightly
yellow crystals (80 mg; 76%). mp 217ꢀ218 °C (MeOH); lit. mp
218.1 °C10 (no solvent given) or 216 °C (EtOH). Rf 0.23 (EtOAc:
[7r-Acetyl-17-(cyclopropylmethyl)-3-[(ethoxycarbonyl)-
oxy]-6,14-endo(etheno)tetrahydronororipavine]. 1-[(5r,7r)-
17-(Cyclopropylmethyl)-4,5-epoxy-3-[(ethoxycarbonyl)oxy]-6-methoxy-
6,14-ethenomorphinan-7-yl]ethanone (15). Diene 14 (243 mg; 0.59
mmol) was suspended in distilled water (1.5 mL) at room temperature,
and methylvinyl ketone (0.4 mL) was added. Sea sand (0.5 g) was added to
the mixture in order to have a better mixing regime, and the mixture was
stirred by magnetic stirring at 80 °C for 12 h. The mixture was then diluted
with EtOH (10 mL), sea sand was filtered off, and the filtrate was
concentrated in vacuo. Chromatography (11.5 mL silica, hexane/ethyl
acetate 5:1f4:1) afforded 261 mg (92%) of 15 as a white oil.
Carbonate 15 was also prepared from 11 by the following procedure:
The free phenol 11 (127 mg; 0.31 mmol) was suspended in ethyl acetate
(2 mL) at room temperature, and ethyl chloroformate (39 μL; 0.41 mmol)
was added to the suspension in one portion followed by Et3N (70 μL;
0.50 mmol). The reaction mixture was stirred at room temperature for
3 h, diluted with ethyl acetate (40 mL), and washed with satd solution of
NaHCO3 (8 mL). The aqueous layer was re-extracted with ethyl acetate
(8 mL), and the combined organic layer was dried over MgSO4 and
concentrated under vacuum. Chromatography (8 mL silica, hexane/
ethyl acetate 2:1) afforded 15 (135 mg, 90%) as a white oil.
15: Rf = 0.25 (hexane/ethyl acetate 3:1); [R]20 ꢀ200.85° (c = 1,
D
CHCl3); IR (KBr, cmꢀ1) ν 3448, 3431, 3076, 2995, 2933, 2834, 2813,
2777, 1765, 1704, 1614, 1492, 1451, 1384, 1370, 1358, 1241, 1201, 1167,
hexane/1:2); [R]20 ꢀ104.17 (c = 1, CHCl3); IR (CHCl3) ν 3583,
D
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The Journal of Organic Chemistry
ARTICLE
3389, 2982, 2952, 2815, 1633, 1503, 1370, 1132; 1H NMR (600 MHz,
CDCl3) δ 6.69 (d, J = 8.0 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 6.01 (s, 1H),
5.46 (bs, 1H), 4.47 (d, J = 1.2 Hz, 1H), 3.54 (s, 3H), 3.00 (bs, 1H), 2.99
(d, J = 13.4 Hz, 1H), 2.90 (m, 1H), 2.62 (dd, J = 11.9, 5.1 Hz, 1H), 2.37
(dd, J = 12.6, 6.0 Hz, 1H), 2.40ꢀ2.27 (m, 2H), 2.23 (dd, J = 18.3, 6.5 Hz,
1H), 2.17 (dd, J = 9.8, 9.8 Hz, 1H), 1.99 (ddd, J = 12.6, 12.6, 5.6 Hz,
1H), 1.85 (m, 1H), 1.77 (m, 1H), 1.69 (dd, J = 12.8, 2.5 Hz, 1H), 1.38
(s, 3H), 1.32 (dd, J = 18.9, 9.2 Hz, 1H), 1.08 (m, 1H), 1.05 (s, 9H),
’ ACKNOWLEDGMENT
The authors are grateful to the following agencies for financial
support of this work: Noramco, Inc.; Natural Sciences and
Engineering Research Council of Canada (NSERC) (Idea to
Innovation and Discovery Grants); Canada Research Chair Pro-
gram; Canada Foundation for Innovation (CFI); Research Corpo-
ration; TDC Research, Inc.; TDC Research Foundation; Brock
University.
0.81 (m, 1H), 0.72 (m, 1H), 0.52ꢀ0.45 (m, 2H), 0.13 (m, 2H); 13
C
NMR (150 MHz, CDCl3) δ 145.5, 137.3, 132.6, 128.3, 119.6, 116.4,
96.9, 80.9, 79.7, 59.5, 58.3, 52.6, 46.5, 43.72, 43.66, 40.4, 35.9, 35.7,
33.4, 29.6, 26.4, 22.9, 20.1, 18.2, 9.5, 4.2, 3.3; MS (þEI) m/z (%): 55
(100), 71 (64), 149 (26), 366 (21), 378 (92), 410 (31), 435 (20), 449
(23), 467 (25); HRMS calcd for C29H41NO4 467.3036, found
467.3043.
’ REFERENCES
(1) Reference to a patent for buprenorphine synthesis: Bentley,
K. W. US 3,433,791,1969.
(2) von Braun, J. Chem. Ber. 1900, 33, 1438.
(3) (a) Feutrill, G. I.; Mirrington, R. N. Tetrahedron Lett. 1970,
16, 1327–1328. (b) Thioethoxide undermicrowave irradiation: Cvengros,
J.; Neufeind, S.; Becker, A.; Schmaltz, H.-G. Synlett 2008, 1993–1998.
(4) (a) Lawson, J. A.; DeGraw, J. I. J. Med. Chem. 1977, 20, 165–166.
(b) Hutchins, C. W.; Cooper, G. K.; Purro, S.; Rapoport, H. J. Med.
Chem. 1981, 24, 773–777. (c) Michne, W. F. J. Med. Chem. 1978, 21,
1322–1324.
(2S)-2-[(ꢀ)-(5R,6R,7R,14S)-9R-Cyclopropylmethyl-4,5-epoxy-6,14-
ethano-3-[(ethoxycarbonyl)oxy]-6-methoxymorphinan-7-yl]-3,3-di-
methylbutan-2-ol (16). mp 125ꢀ128 °C (MeOH); Rf = 0.8 (ethyl
acetate/hexane 1:1); [R]20D ꢀ138.56° (c = 1, CHCl3); IR (KBr, cmꢀ1
)
ν 3443, 3077, 2979, 2954, 2928, 2878, 2846, 2812, 2777, 1763, 1614,
1491, 1451, 1402, 1384, 1370, 1338, 1303, 1247, 1201, 1164, 1134, 1077,
1021, 979, 877, 781, 731; 1H NMR (CDCl3, 300 MHz) δ 6.88 (d, J = 8.1
Hz, 1H), 6.61 (d, J = 8.1 Hz, 1H), 5.93 (s, 1H), 4.47 (d, J = 1.5 Hz, 1H),
4.27 (q, J = 7.2 Hz, 2H), 3.51 (s, 3H), 3.05 (d, J = 10.8 Hz, 1H), 3.01
(s, 1H), 2.90 (ddd, J = 13.5, 9.9, 3.6 Hz, 1H), 2.63 (dd, J = 11.7, 5.1 Hz,
1H), 2.40ꢀ2.17 (m, 4H), 2.14 (dd, J = 9.9, 9.9 Hz, 1H), 1.99 (ddd, J =
12.9, 12.9, 5.7 Hz, 1H), 1.93ꢀ1.77 (m, 2H), 1.73 (dd, J = 12.6, 2.4 Hz,
1H), 1.40ꢀ1.28 (m, 7H), 1.17ꢀ0.97 (m, 10H), 0.85ꢀ0.77 (m, 1H),
0.73ꢀ0.64 (m, 1H), 0.56ꢀ0.45 (m, 2H), 0.17ꢀ0.08 (m, 2H); 13C NMR
(CDCl3, 75 MHz) δ 153.2, 149.6, 134.8, 134.0, 131.9, 121.7, 119.3, 98.3,
80.7, 79.3, 64.9, 59.5, 58.1, 52.6, 46.3, 44.3, 43.5, 40.4, 35.9, 35.4, 33.4,
29.8, 26.4, 23.3, 19.9, 17.5, 14.19, 9.5, 4.2, 3.3; MS (FABþ) m/z (%)
538(69), 522(57), 482(37), 450(49), 438(17); HRMS (FABþ) calcd
for C32H45N1O6: 539.3246. Found 539.3263.
(5) Rice, K. C. J. Med. Chem. 1977, 20, 164.
(6) Sudo, Y.; Arai, S.; Nishida, A. Eur. J. Org. Chem. 2006, 752–758.
(7) Hudlicky, T.; Carroll, R.; Leisch, H.; Machara, A.; Werner, L.;
Adams, D. R. Processes for the preparation of morphinane and
morphinone compounds. PCT Int. Appl. CODEN: PIXXD2, WO
2010121369 A1 20101028 CAN 153:555396 AN 2010:1342585, 2010.
(8) (a) See reference 7 above. (b) Machara, A.; Werner, L.; Adams,
D.; Leisch, H.; Carroll, R.; Cox, D. P.; Hudlicky, T. Manuscript in
preparation.
(9) See for example: Manoharan, T. S.; Madyastha, K. M.; Bali Singh,
B.; Bhatnagar, S. P.; Weiss, U. Synthesis 1983, 809–812.
(10) Stinchcomb, A. L.; Dua, R.; Paliwal, A.; Woodard, R. W.; Flynn,
G. L. Pharm. Res. 1995, 12, 1526–1529.
17: mp 142ꢀ144 °C (MeOH); Rf = 0.9 (ethyl acetate/hexane 2:1);
[R]20D ꢀ151.478° (c = 1, CHCl3); IR (KBr, cmꢀ1) ν 3433, 3066, 2977,
2955, 2936, 2913, 2876, 2822, 2775, 1754, 1614, 1480, 1449, 1406, 1384,
1280, 1244, 1206, 1117, 1075, 1021, 960, 885, 783; 1H NMR (CDCl3,
300 MHz) δ 6.77 (d, J = 8.1 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 5.94
(s, 1H), 4.43 (d, J = 1.5 Hz, 1H), 3.47 (s, 3H), 3.04 (d, J = 12.3 Hz, 1H),
3.00 (s, 1H), 2.90 (ddd, J = 13.8, 10.8, 3.6 Hz, 1H), 2.63 (dd, J = 11.7, 4.8
Hz, 1H), 2.40ꢀ2.23 (m, 4H), 2.12 (dd, J = 9.9, 9.9 Hz, 1H), 1.98 (ddd,
J = 12.6, 12.6, 5.4 Hz, 1H), 1.94 (m, 1H), 1.82 (m, 1H), 1.72 (dd, J =
12.9, 2.4 Hz, 1H), 1.36 (s, 3H), 1.33 (s, 9H), 0.99 (s, 9H), 0.85ꢀ0.77 (m,
1H), 0.69 (dddd, J = 12.6, 12.6, 3.6, 3.6 Hz, 1H), 0.56ꢀ0.45 (m, 2H),
0.17ꢀ0.09 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 176.4, 149.9, 134.3,
133.7, 131.8, 121.9, 119.3, 98.2, 80.7, 79.2, 59.5, 58.2, 52.5, 46.3, 44.5,
43.6, 40.3, 38.9, 36.0, 35.4, 33.4, 29.8, 27.2, 26.4, 23.3, 19.9, 17.4, 9.5, 4.2,
3.3; MS (FABþ) m/z (%) 552 (39), 551 (37), 550 (75), 534 (65), 494
(45); HRMS (FABþ) calcd for C34H50N1O5: 552.3689. Found
552.3666; Anal. Calcd for C34H49N1O5: C, 74.01; H, 8.95. Found C,
74.24; H, 9.15.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra. This
S
b
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: thudlicky@brocku.ca.
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