Synthesis and opioid receptor binding affinities of 2-substituted and 3-aminomorphinans: Ligands for μ, κ, and δ opioid receptors

Article abstract of DOI:10.1021/jm9013482

The phenolic group of the potent μ and κ opioid morphinan agonist/antagonists cyclorphan and butorphan was replaced by phenylamino and benzylamino groups including compounds with parasubstituents in the benzene ring. These compounds are highly potent μ and κ ligands, e.g., p-methoxyphenylaminocyclorphan showing a K_i of 0.026 nMat the μ receptor and a K_i of 0.03 nM at the κ receptor. Phenyl carbamates and phenylureas were synthesized and investigated. Selective o-formylation of butorphan and levorphanol was achieved. This reaction opened the way to a large set of 2-substituted 3-hydroxymorphinans, including 2-hydroxymethyl-, 2-aminomethyl-, and N-substituted 2-aminomethyl-3- hydroxymorphinans. Bivalent ligands bridged in the 2-position were also synthesized and connected with secondary and tertiary aminomethyl groups, amide bonds, and hydroxymethylene groups, respectively. Although most of the 2-substituted morphinans showed considerably lower affinities compared to their parent compounds, the bivalent ligand approach led to significantly higher affinities compared to the univalent 2-substituted morphinans. 2009 American Chemical Society.

Full text of DOI:10.1021/jm9013482

402 J. Med. Chem. 2010, 53, 402–418
DOI: 10.1021/jm9013482
Synthesis and Opioid Receptor Binding Affinities of 2-Substituted and 3-Aminomorphinans: Ligands
for μ, K, and δ Opioid Receptors
Michael Decker,† Yu-Gui Si,† Brian I. Knapp,‡ Jean M. Bidlack,‡ and John L. Neumeyer*,†
†Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, Massachusetts 02478-9106 and
‡Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642
Received September 10, 2009
The phenolic group of the potent μ and κ opioid morphinan agonist/antagonists cyclorphan and
butorphan was replaced by phenylamino and benzylamino groups including compounds with para-
substituents in the benzene ring. These compounds are highly potent μ and κ ligands, e.g., p-methoxy-
phenylaminocyclorphan showing a Ki of 0.026 nM at the μ receptor and a Ki of 0.03 nM at the κ receptor.
Phenyl carbamates and phenylureas were synthesized and investigated. Selective o-formylation of
butorphan and levorphanol was achieved. This reaction opened the way to a large set of 2-substituted
3-hydroxymorphinans, including 2-hydroxymethyl-, 2-aminomethyl-, and N-substituted 2-amino-
methyl-3-hydroxymorphinans. Bivalent ligands bridged in the 2-position were also synthesized and
connected with secondary and tertiary aminomethyl groups, amide bonds, and hydroxymethylene
groups, respectively. Although most of the 2-substituted morphinans showed considerably lower
affinities compared to their parent compounds, the bivalent ligand approach led to significantly higher
affinities compared to the univalent 2-substituted morphinans.
Introduction
neously but equipotent when administered orally. The phe-
nylamine and benzylamine compounds showed subnano-
molar affinity at κ and μ receptors, respectively.9
Within the group of opioid ligands with a morphinan
structure the phenolic group in the 3-position is historically
regarded as a requirement for high affinity interactions with a
respective H-bond accepting site of the opioid receptor.1,2
Others have shown that replacing the phenolic group in the
opioid antagonist naltrindole3 and in morphine4 with alkyl or
aryl groups greatly reduces affinity.
Hepatic first-pass metabolism after oral administration by
O-glucoronidation of the phenolic group is a common feature
of these opioid ligands and determines their pharmacokinetic
behavior, bioavailability, and therapeutic application.5,6
Morphine administered orally, for example, has only approxi-
mately one-quarter the bioavailability compared to a parent-
erally administered dose.6
We have previously shown that a 2-aminothiazole moiety
can replace the phenolic group bioisosterically yielding com-
pounds showing high potencies.7 Wentland’s group has also
shown that the phenolic group in certain opioids (morphine,
cyclazocine) can be replaced by primary or secondary amino
groups to yield compounds with good affinities.8,9 Substitut-
ing morphine’s OH group with NH2, CH3NH, phenyl-NH, or
benzyl-NH yielded compounds with decreased affinities com-
pared to morphine, with two-digit nanomolar affinities at the
μ receptor subtype.8 Wentland prepared amino derivatives
of the potent opioid cyclazocine, which showed subnanomo-
lar affinities for κ and/or μ receptor subtypes.9 The primary
amino derivative of cyclazocine was 5-fold less potent in a
rodent antinociception model when administered subcuta-
There are several findings that show that additional aro-
matic moieties aretoleratedoreven beneficialatthe3-position
of morphinans. This may be due to the presence of three
phenylalanine residues in the μ receptor, information derived
from a homology model of the receptor interacting with the
antagonist norBNI.10 Wehave previously reported carbamate
derivatives of levorphanol (1), butorphan (3b), and cyclor-
phan (3a).11 Carboxamido analogues of cyclazocine and
ethylketocyclazocine bearing a biphenyl unit also showed
subnanomolar affinities at both μ and δ receptors.12 These
findings suggest that the introduction of an additional aro-
matic moiety connected at the 3-position can lead to active
compounds without the necessity of the phenolic group.
The highly potent benzyl and especially phenyl carba-
mates11 of 3a/3b suggest a promising lead for the development
of SPECT ligands (123I for SPECT). The κ receptor has been
implicated as a primary target for the development for
pharmacotherapies for the treatment of cocaine depen-
dence,13-15 Thus p-iodophenyl carbamates were synthesized
and evaluated for their affinity and selectivity profiles. Since
primary urea derivatives of the 3-aminomorphinans showed
similar high affinities to their parent amino compounds,16 the
phenylureas and p-iodophenylureas were also synthesized and
evaluated (Figure 1).
High affinity opioid ligands bearing a 3-phenylamino or a
3-benzylamino group were also synthesized and evaluated
pharmacologically (Figure 1).
We also report here the synthesis of a series of 2-substituted
analogues of1 and 3b using a regioselective ortho-formylation
method as the key step. The salicylaldehydes obtained by this
*To whom correspondence should be addressed. Phone: 617-855-
3388. Fax: 617-855-2519. E-mail: jneumeyer@mclean.harvard.edu.
r
pubs.acs.org/jmc
Published on Web 11/23/2009
2009 American Chemical Society

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 403
Figure 1. Structures of ligands related to levorphanol (1), cyclorphan (3a), and butorphan (3b).
3-imines (5a,b). These catalytic conditions enable working
method provide a structural prototype for the preparation of
2-substituted analogues of 1 and represent a useful starting
point for the preparation of bivalent compounds connected at
the 2-position, keeping the basic nitrogen and the phenol
moiety as important pharmacophoric elements unchanged.
We present preliminary information concerning the SAR of
such bivalent ligands bridged at the 2-position. Bivalent
ligands containing an aminomethyl group in the 2-position
could be synthesized with different spacer lengths containing
either secondary amino groups (therefore bearing both hydro-
gen bond accepting and donating properties) or tertiary
amino groups (showing only H-bond accepting properties
and being sterically more demanding). Furthermore, it was
possible to connect two 2-aminomethylbutorphan molecules
as diamides lacking any basicity of the N atoms and bivalent
ligands without N atoms in the spacer but bearing two
hydroxy groups (Figure 1).
in a far less oxygen-sensitive reaction environment. Subse-
quent cleavage with hydroxylamine hydrochloride leads to
the 3-aminomorphinans (6a,b; Scheme 1).20,21 Alkylation
with 1-(bromomethyl)-4-iodobenzene yielded the p-iodo-
benzylmorphinans (7a,b) in moderate yield, while some
formation of dialkylated product (7e) could be observed. In
case of the cyclobutylmethyl compound, this dialkylated
derivative (7e) was isolated. When using 1-(bromomethyl)-
4-methoxybenzene to obtain the respective p-methoxy
compound, the desired product 7c was obtained in very
low yields. The dialkylated product 7d was formed pre-
dominantly, with monoalkylation being the less favored
reaction.
For the synthesisofthe 4-iodophenylcarbamates,1, 3a, and
3b were treated with 4-iodophenyl isocyanate, yielding the
novel 4-iodophenyl carbamates in 61-80% yield (9a-c,
Scheme 2; the unsubstituted phenyl carbamates have been
described previously11). For the respective urea compounds,
the 3-aminomorphinans 6a,b and the 3-amino derivative
of 17a (6c, 17-methylmorphinan-3-amine) were treated with
phenyl isocyanate and 4-iodophenyl isocyanate, respectively,
to yield the ureas 10a-e in 61-70% yield (Scheme 2; the
unsubstituted urea of 3b was not synthesized because of the
comparatively low affinities of compounds).
Ortho-formylation of 1 was first carried out as previously
described for aporphines using a MeMgBr/HMPA (hexa-
methylphosphoramide) and paraformaldehyde reaction sys-
tem.22 The salicylaldehyde derivative was obtained in 46%
yield; however, when the reaction was scaled up under these
conditions, it was difficult to remove the HMPA completely
from the product. When ortho-formylation of 1 was con-
ducted using MgCl2-Et3N base system and paraformalde-
hyde,23 ortho-formylation occurred exclusively at the 2-posi-
tion. By use of these reaction conditions, ortho-formylation of
1 and 3b yielded aldehydes 11 and 12 (Scheme 3). Further
reduction gave the alcohols 13 and 14 (Scheme 3). The
salicylaldehyde derivative 11 was also condensed with ben-
zylamine followed by reduction to N-benzylsalicylamine 16
Chemistry
The starting material for the synthesis of all target com-
pounds is the commercially available (-)-3-hydroxy-N-methyl-
morphinan (levorphanol) tartrate, which after conversion to
its free base (1) could be demethylated to norlevorphanol (2)
and alkylated with either (bromomethyl)cyclopropane or
(bromomethyl)cyclobutane to yield 3a and 3b, respectively
(Scheme 1).17 In the presence of pyridine, the triflates (4a,b)
were formed, whichcouldbecoupledin aBuchwald-Hartwig
reaction,18 in this case using tris(dibenzylideneacetone)-
dipalladium(0) [Pd2(dba)3] as Pd catalyst, bis(diphenylphos-
phino)ferrocene (dppf) as ligand, and sodium tert-butoxide
as a strong base, to yield the benzyl (8a,d), p-methoxyphenyl
(8b,e) and phenyl compounds (8c,f) directly, albeit in moder-
ately low yields (Scheme 1).18,19
For the preparation of the p-iodobenzylaminomorphinans
(7a,b) the triflates of 3a (4a) and 3b (4b), respectively, were
converted to their 3-aminomorphinans (6a,b) through Pd
catalysis (Pd(OAc)2 and rac-BINAP as ligand). Coupling to
benzophenone imine in the presence of cesium carbonate
resulted in the formation of (diphenylmethylene)morphinan-

404 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1
Decker et al.
Scheme 1a
a Reagents and conditions: (i) Tf2O, pyridine, CHCl3; (ii) (rac)-BINAP, Pd(OAc)2, Cs2CO3, THF; (iii) NaOAc, H2NOH HCl; (iv) K2CO3, EtOH; (v)
3
Pd2(dba)3, dppf, sodium tert-butoxide, toluene, 80 °C.
Scheme 2a
amine followed by reduction to obtain the N-n-propyl amine
21. The bivalent ligands 22a-c were prepared by condensa-
tion of the aldehyde12withdiamines, yielding diimines21a-c
followed by reduction with NaBH4 (Scheme 4). The bivalent
ligands 24a and 24b bearing an additional ethyl group at the
amine function were prepared by the reaction of 22a,b with
excess acetyl chloride followed by reduction with LiAlH4
(Scheme 4; here only the spacer lengths with 8 and 10 atoms
were realized).
Furthermore, the aldehyde 12 was treated with EtMgBr to
obtain 25 (Scheme 5). When the aldehyde 12 was treated with
Grignard reagent prepared from 1,4-dibromobutane, the
bivalent ligand 26a and the univalent ligand 27a were ob-
tained. Similarly, 12 was treated with the Grignard reagent
from 1,10-dibromodecane. The bivalent ligand 26b and the
univalent ligands 27b and 28 were obtained (Scheme 5).
Reacting 2-aminomethylbutorphan 19 with adipic acid
yielded a bivalent ligand bridged in position 2 (29) without
the basic nitrogen atoms in the linking chain.
a Reagents and conditions: (i) NEt3, CH2Cl2.
Results and Discussion
All the novel univalent and bivalent ligands were examined
for their affinity and selectivity for μ, κ, and δ opioid receptors
with Chinese hamster ovary (CHO) cells stably expressing one
of the human opioid receptors. The data are shown in Table 1.
It is noted that the lead compounds 3a and 3b already
represent extremely potent compounds with subnanomolar
(Scheme 3). Compound 16 could also be converted into the
fused cyclic compound 17 (Scheme 3).
The aldehyde 12 was also condensed with hydroxylamine to
yield its oxime 18, which could be reduced with hydrogen over
Pd/C in acidic medium to give the 2-aminomethylbutorphan
19 (Scheme 4).24 Compound 12 was condensed with n-propyl-

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 405
Scheme 3a
a Reagents and conditions: (i) MgCl2 anhydrous, NEt3, (HCHO)n, THF, reflux; (ii) NaBH4, MeOH; (iii) BnNH2, MeOH; (iv) NaBH4, MeOH;
(v) (HCHO)n, MeOH, reflux.
Scheme 4a
a Reagents and conditions: (i) H2NOH HCl, MeOH; (ii) H2, Pd/C, HCl; (iii) n-PrNH2, MeOH; (iv) NaBH4, MeOH; (v) 1,4-diaminobutane (or 1,6-
diaminohexane or 1,8-diaminooctane), MeOH; (vi) excess acetyl chloride, NEt3, CH2Cl2; (vii) LiAlH4, THF.
3
affinities at μ and κ receptors. Concerning the 3-aminomor-
phinans, a number of highly potent compounds could be
identified: If the phenol is replaced by a benzylamino group
(8a and 8d), a roughly 10-fold decrease in affinity at μ and κ

406 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1
Decker et al.
Scheme 5a
a Reagents and conditions: (i) 1,4-dibromobutane or 1,10-dibromodecane, Mg, THF; (ii) EtMgBr, THF; (iii) (1) (COCl)2, cat. DMF, NEt3, CH2Cl2;
(2) 2-(aminomethyl)-3-hydroxy-17-N-cyclobutylmethylmorphinan (19), NEt3, CH2Cl2.
receptors is observed and at the δ receptor a 76-fold and 112-
fold decrease in affinity are observed. Substitution in para-
position (7c, -OCH3) does not significantly alter binding
affinities, and an iodine atom in para-position (7a and 7b)
leads only to a minor decrease in binding affinities.
Since the 3-phenolic group is generally considered as an
important pharmacophore in morphinans, it is of interest to
note that a benzylamino group can replace the phenolic group
to yield compounds with decreased, albeit still high, affinities.
In this regard it is also noteworthy that compounds 7d and 7e,
in which tertiary dibenzylamino groups replace the phenolic
group, retain nanomolar affinity. These compounds no longer
bear an H-bond donor and are sterically hindered.
The morphinans with phenylamino groups in position 3 are
even more potent ligands (8b,c,e,f). Although the CBM
compound 8f shows lower affinities than butorphan at μ
and κ, the CPM compound 8c has an affinity of 0.080 nM
at μ and 0.047 nM at κ with 70-fold selectivity δ/μ. Substitu-
tion with a p-methoxy group further increases affinities with
0.61 nM at μ and 0.59 nM at κ for the CBM compound 8e and
0.026 nM at μ and 0.030 nM at κ for the CPM compound 8b
with 65-fold selectivity δ/μ. Compound 8b is thus the most
potent compound synthesized in this 3-aminomorphinan
series, exceeding butorphan and cyclorphan in terms of
affinity and selectivity.
For the phenylurea derivates the affinities range from the
low nanomolar range (10b) to the higher nanomolar range
(10c and 10e). For the CPM phenylurea compound 10b, its
p-iodo derivate 10d shows roughly 10-fold decrease in affinity.
The carbamates 9a,b show high affinities in the subnanomolar
range at μ and κ receptors, again with the CPM compound
showing higher affinities. Interestingly, the p-iodo-substituted
carbamate of 1 (9a) shows a remarkable 470-fold selectivity
of δ/μ being the most selective compound in the series of
compounds described in this study. Compared with the un-
substituted carbamates described previously,11 the p-iodo
compounds show lower affinities.
The 2-substituted compounds generally had lower affinities
when compared to the highly potent 3b and 3a. The
2-hydroxymethyl analogues 13 (-NCH3) and 14 (-N-CBM)
show lower affinities at all receptors. The 2-oxime 18 is the
most potent compound in the series of 2-substituted com-
poundssynthesized with an affinity of 3.8 nMatthe μ receptor
and 0.62 nM at the κ receptor. The 2-aminomethyl compound
(19) and the monobenzylated (16) and monopropylated (21)
derivatives have only submicromolar affinities at κ and μ
receptors. Bivalent ligands bridged at secondary amines
(24a-c) are only moderately active, albeit less active than
bivalent ligands bridged at the 3-position.25 When the sec-
ondary amine functions in the spacer are ethylated (24a with
8 spacer atoms and 24b with 10 spacer atoms), affinities
significantly decrease further. The univalent compounds 25,
27a, and 28 show comparatively low affinities. Concerning all
compounds with 1-hydroxyalkyl substituents in position 2
(25, 26a,b, 27a,b, 28), the most potent is the 1-hydroxypentyl
compound (27a) with 17 and 13 nM at μ and κ and the least
potent is the 1-hydroxypropyl compound (25) with 180 and
72 nM at μ and κ, respectively. Obviously, a longer alkyl chain
considerably increases affinities. The respective bivalent com-
pounds 26a,b do not show significantly higher affinities. The
only amide-bridged bivalent ligand 29 shows affinities of
36 nM at μ and 30 nM at κ.

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 407
Table 1. Ki Values for the Inhibition of μ, δ, and κ Opioid Binding to CHO Membranes

408 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1
Table 1. Continued
Decker et al.

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 409
Table 1. Continued

410 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1
Table 1. Continued
Decker et al.
a Reference 7a.
Conclusion
3-Aminobenzyland 3-aminophenylderivativesof3aand 3b
were synthesized, and it was demonstrated that these phar-
macophores could replace the phenolic group to yield high
affinity opioid ligands. 3-Phenylureas and carbamates were

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 411
synthesized with the 3-phenyl carbamates being nano- and
subnanomolar ligands at μ and κ receptors.
General Procedure for the Synthesis of N-Benzyl-, N-Phenyl-,
and N-(4-Methoxyphenyl)-17-cyclopropylmethyl/cyclobutylme-
thyl)morphinan-3-amines (8a-f) by Buchwald-Hartwig Coupl-
ing. A three-necked flask was equipped with an N2 balloon, a
septum, and a stopper. Through the neck the flask was charged
under a mild N2 stream with 1.4 mmol (2 equiv to triflate) of
aniline (for preparation of 8c,f)/benzylamine (for 8a,d)/4-meth-
oxyaniline (for 8b,e), 81 mg (0.84 mmol, 1.2 equiv to triflate) of
sodium tert-butoxide, 32 mg (0.035 mmol, 0.05 equiv to triflate)
of tris(dibenzylideneacetone)dipalladium(0), and 58 mg (0.105
mmol, 0.15 equiv to triflate) of bis(diphenylphosphino)ferro-
cene. Nitrogen was flushed for 5 min over the solids. After this
time, an amount of 5 mL of toluene, which had been degassed in
a Schlenk flask prior to addition, was added via the septum.
Under vigorous stirring the mixture was warmed to 80 °C. A
solution of 0.7 mmol of cyclorphan triflate (3-trifluoromethyl-
(sulfonyl)oxy-N-cyclopropylmethylmorphinan, for the prepar-
ation of 8a-c) or butorphan triflate (3-trifluoromethyl(sulf-
onyl)oxy-N-cyclobutylmethylmorphinan, for the preparation
of 8d-f) in 2 mL of degassed toluene was added dropwise over
1 h. The mixture was heated under vigorous stirring overnight at
80 °C until TLC control (hexane/EtOAc/NEt3, 10/10/1) showed
complete consumption of the triflate. The mixture was filtered
over a small pad of silica and the residue washed twice with
hexane/EtOAc/NEt3, 10/10/1 (column eluent system). The sol-
vents were evaporated, and the residue was further dried under
high vacuum to remove excess primary amine. The residue was
purified by column chromatography first using methylene
chloride/methanol, 10/1, followed by hexane/EtOAc/NEt3,
10/10/1, to yield the respective product.
Experimental Section
General Synthetic Methods. 1H (and 13C NMR) spectra were
recorded at 300 MHz (75 MHz) using CDCl3 as solvent on a
Varian Mercury 300 spectrometer. Chemical shifts are given as δ
value (ppm) downfield from tetramethylsilane as an internal
reference. Melting points were determined on a Thomas-Hoover
capillary tube apparatus and are reported uncorrected. Elemen-
tal analyses, performed by Atlantic Microlabs, Atlanta, GA,
were within (0.4% of theoretical values. Analytical thin-layer
chromatography (TLC) was carried out on 0.2 micrometer
Kieselgel 60F-254 silica gel plastic sheets (EM Science, Newark,
NJ). Flash chromatography was used for the routine purifica-
tion of reaction products. Eluent systems are described for the
individual compounds.
Synthesis of 17-(Cyclopropylmethyl)morphinan-3-ol (cyclo-
rphan, 3a) and 17-(Cyclobutylmethyl)morphinan-3-ol (buto-
rphan, 3b). 3a and 3b were prepared as described,17 and spec-
tral/physical data are in accordance with literature data.17
Synthesis of 17-(Cyclopropyl/cyclobutylmethyl)morphinan-
3-yl Trifluoromethanesulfonate (Cyclorphan/Butorphan Triflate,
4a,b). To a suspension of 4 mmol of 3a or 3b, respectively, in
25 mL of anhydrous chloroform was added 1.26 g (1.32 mL,
16 mmol) of pyridine, and a clear solution was formed. The
mixture was put into an ice bath, and under N2 an amount of
2.26 g (1.35 mL, 8 mmol) of trifluoromethane sulfonic anhy-
dride (triflate anhydride) was added under ice-cooling. The
mixture was allowed to reach room temperature, and stirring
was continued overnight. TLC control (after microworkup)
showed that no 3a/3b remained. The organic phase was diluted
with methylene chloride and washed with brine. The organic
phase was dried over anhydrous sodium sulfate and the solvent
evaporated. Heating under high vacuum was applied to remove
excess pyridine. The residue was purified by column chroma-
tography (EtOAc/NEt3, 20/1) to yield the product as viscous
oils. Spectral data were in accordance with literature data.26
17-(Cyclopropylmethyl)morphinan-3-yl Trifluoromethanesul-
fonate (4a). Colorless oil (47%). 13C NMR (CDCl3): 144.7,
140.0, 134.9, 125.7, 114.6, 114.5, 56.4, 51.7, 41.8, 41.0, 38.1,
N-Benzyl-17-(cyclopropylmethyl)morphinan-3-amine (8a). Color-
less oil (16%). 13C NMR (CDCl3): 147.0, 141.7, 140.1, 129.0, 128.7,
128.1, 127.6, 127.5, 111.1, 110.2, 60.4, 56.3, 49.2, 46.3, 45.8, 42.4,
38.2, 37.1, 27.3, 27.1, 24.2, 22.7, 9.9, 4.5, 4.0 ppm. 1H NMR
(CDCl3): 7.25-7.38 (m, 5 H), 6.91 (d, J = 8 Hz, 1H), 6.49 (d,
J = 2.4 Hz, 1H), 6.48 (dd, J = 8, 2.4 Hz, 1H), 4.3 (s, 2H), 3.87 (bs,
1H), 3.05 (m, 1H), 2.84 (d, J = 18 Hz, 1H), 2.46-2.58 (m, 2H),
2.23-2.34 (m, 2H), 2.01 (m, 1H), 1.61-1.85(m, 3H), 1.17-1.46(m,
7H), 0.87 (m, 1H), 0.51 (m, 2H), 0.11 (m, 2H) ppm. Anal.
1
(C27H34N2 /10EtOAc) C, H, N.
3
17-(Cyclopropylmethyl)-N-(4-methoxyphenyl)morphinan-3-
amine (8b). Brown solid (13%). Mp: 60-62 °C. 13C NMR (CD-
Cl3): 154.4, 142.7, 141.5, 136.9, 129.6, 128.38, 120.4, 114.6,
114.3, 113.7, 60.0, 55.8, 55.5, 45.8 45.2, 41.9, 37.7, 36.6, 26.93,
1
34.6, 32.9, 23.1, 22.8, 20.7, 18.3, 5.8 ppm. H NMR (CDCl3):
7.17 (d, J = 9 Hz, 1H), 7.13 (d, J = 2.1 Hz, 1H), 7.00 (dd, J = 9,
2 Hz, 1H), 3.1 (m, 1H), 2.92 (d, J = 18 Hz, 1H), 2.31-2.88 (m,
4H), 1.81-2.05 (m, 3H), 1.57-1.68 (m, 2H), 1.08-1.42 (m, 7H),
0.86 (m, 1H), 0.51 (m, 2H), 0.10 (m, 2H) ppm.
1
26.6, 23.9, 22.3, 9.4, 4.1, 3.6 ppm. H NMR (CDCl3): 7.02 (d,
J = 2 Hz, 2H), 6.99 (d, J = 2 Hz, 1H), 6.82-6.98 (m, 3H), 6.75
(dd, J = 8, 2 Hz, 1H), 3.78 (s, 3H), 3.08 (m, 1H), 2.87 (d, J = 18
Hz, 1H), 2.46-2.69 (m, 2H), 2.25-2.34 (m, 2H), 2.04 (m, 1H),
1.62-1.86 (m, 3H), 1.26-1.50 (m, 7H), 0.87 (m, 1H), 0.50
17-(Cyclobutylmethyl)morphinan-3-yl Trifluoromethanesulfo-
nate (4b). Light-brown viscous oil (76%). 13C NMR (CDCl3):
148.3, 143.6, 138.6, 129.3, 120.9, 118.24, 118.1, 61.4, 55.6, 45.4,
44.6, 41.7, 38.0, 36.4, 34.8. 27.9, 27.7, 26.7, 26.4, 24.5, 21.9, 18.8
ppm. 1H NMR (CDCl3): 7.17 (d, J = 9 Hz, 1H), 7.10 (d, J = 2.1
Hz, 1H), 7.00 (dd, J = 9, 2.1 Hz, 1H), 3.1 (d, J = 18 Hz, 1H),
2.84 (m, 1H), 1.53-2.63 (m, 18H), 1.04-1.45 (m, 5H) ppm.
Synthesis of 17-(Cyclopropylmethyl/cyclobutylmethyl)mor-
phinan-3-amine (6a,b). The 3-amino derivatives of cyclorphan
and butorphan were prepared from the triflates (4a,b) in two
steps as recently described.7a Spectral data are in accordance
with the literature data.7a
1
(m, 2H), 0.12 (m, 2H) ppm. Anal. (C27H34N2O /10EtOAc)
3
C, H, N.
17-(Cyclopropylmethyl)-N-phenylmorphinan-3-amine
(8c).
White solid (18%). Mp: 63-65 °C. 13C NMR (CDCl3): 144.6,
142.1, 141.1, 131.7, 129.7, 128.8, 120.3, 117.0, 116.8, 116.4, 60.4,
56.2, 46.2, 45.7, 42.4, 38.2, 37.0, 27.3, 27.1, 24.5, 22.7, 9.9, 4.5,
4.0 ppm. 1H NMR (CDCl3): 7.23 (t, J = 15 Hz, 2 H), 6.99 (d,
J = 8.4 Hz, 4H), 6.83-6.89 (m, 2H), 5.63 (bs, 1H), 3.1 (m, 1H),
2.89 (d, J = 18 Hz, 1H), 2.46-2.70 (m, 2H), 2.28-2.35 (m, 2H),
2.02 (m, 1H), 1.53-1.88 (m, 3H), 1.26-1.46 (m, 7H), 0.87 (m,
17-(Cyclopropylmethyl)morphinan-3-amine (6a). 1H NMR
(CDCl3): 6.86 (d, J = 8 Hz, 1H), 6.61 (d, J = 2.4 Hz, 1H),
6.48 (dd, J = 8, 2.4 Hz, 1H), 3.5 (bs, 2H), 3.05 (m, 1H), 2.83 (d,
J = 18 Hz, 1H), 2.47-2.57 (m, 2H), 2.23-2.34 (m, 2H), 2.00 (m,
2H), 1.63-1.85 (m, 3H), 1.15-1.43 (m, 7H), 0.86 (m, 1H), 0.50
(m, 2H), 0.11 (m, 2H) ppm.
1
1H), 0.50 (m, 2H), 0.13 (m, 2H) ppm. Anal. (C26H32N2 /10-
EtOAc) C, H, N.
3
N-Benzyl-17-(cyclobutylmethyl)morphinan-3-amine (8d). Light-
yellow oil (9%). 13C NMR (CDCl3): 146.6, 141.3, 139.7, 128.6,
128.3, 127.7, 127.2, 110.8, 109.8, 61.5, 56.1, 48.9, 46.1, 45.3, 41.9,
37.6, 36.7, 35.0, 28.0, 26.9, 26.6, 24.0, 22.3, 18.9 ppm. 1H NMR
(CDCl3): 7.23-7.37 (m, 5 H), 6.91 (d, J = 8 Hz, 1 H), 6.53 (d, J =
2.4 Hz, 1H), 6.48 (dd, J = 8, 2.4 Hz, 1H), 4.3 (s, 2H), 3.85 (bs, 1H),
2.90 (d, J = 18 Hz, 1H), 2.78 (bs, 1H), 2.40-2.58 (m, 5H),
2.21-2.25 (m, 1H), 1.59-2.12 (m, 10H), 1.12-1.44 (m, 7H) ppm.
Anal. (C28H36N2 2HCl H2O) C, H, N.
17-(Cyclobutylmethyl)morphinan-3-amine (6b). 1H NMR
(CDCl3): 6.88 (d, J = 8 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H),
6.49 (dd, J = 8, 2.4 Hz, 1H), 3.5 (bs, 2H), 2.90 (d, J = 18 Hz,
1H), 2.78 (bs, 1H), 2.40-2.56 (m, 5H), 2.21-2.25 (m, 1H),
1.63-2.15 (m, 10H), 1.12-1.48 (m, 7H) ppm.
3
3

412 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1
Decker et al.
17-(Cyclobutylmethyl)-N-(4-methoxyphenyl)morphinan-3-
amine (8e). Brown glassy solid (26%). Mp: 70-74 °C. 13C NMR
(CDCl3): 154.5, 142.8, 141.3, 136.8, 128.4, 120.5, 114.6, 114.4,
113.6, 61.3, 56.1, 55.6, 46.0, 44.8, 41.6, 37.5, 36.5, 34.7, 27.9,
26.8, 26.5, 24.2, 22.2, 18.8 ppm. 1H NMR (CDCl3): 6.86-7.03
(m, 3H), 6.82-6.86 (m, 3H), 6.75 (dd, J = 8, 2.4 Hz, 1H), 5.42
(bs, 1H), 3.79 (s, 3H), 2.94 (d, J = 18 Hz, 1H), 2.86 (bs, 1H),
2.42-2.64 (m, 5H), 2.20-2.25 (m, 1H), 1.64-2.13 (m, 10H),
(s, 4H, 2 ꢀ Bn-CH2), 3.78 (s, 6H, 2 ꢀ OCH3), 3.77 (s, 2H), 3.30
(bs, 1H), 2.61-2.87 (m, 4H), 2.57 (m, 1H), 2.23 (m, 1H),
1.88-2.23 (m, 3H), 1.57 (m, 1H), 1.12-1.43 (m, 7H), 1.05 (m,
1H), 0.59 (m, 2H), 0.24 (m, 2H) ppm. Anal. (C28H36N2O 1/2-
3
CH3OH) C, H, N.
17-(Cyclopropylmethyl)-N,N-bis(4-methoxybenzyl)morphinan-
3-amine (7d). Brown glassy solid (22%). Mp: 64-66 °C. 13C
NMR (CDCl3): 158.8, 146.7, 141.1, 131.6, 129.0, 128.3, 113.9,
110.8, 109.7, 59.8, 56.0, 55.3, 48.2, 46.0, 44.9, 41.7, 37.6, 36.6,
31.4, 26.8, 26.6, 23.8, 22.2, 9.1, 4.1, 3.7 ppm. 1H NMR (CDCl3):
7.29 (d, J = 8 Hz, 2H), 6.82-6.89 (m, 3H), 6.56 (d, J = 2 Hz,
1H), 6.48 (dd, J = 8, 2 Hz, 1H), 4.21 (s, 2H, Bn-CH2), 3.78 (s,
3H, OCH3), 3.77 (s, 2H), 3.30 (bs, 1H), 2.49-2.87 (m, 4H),
2.24-2.41 (m, 2H), 2.09 (m, 1H), 1.75-2.13 (m, 2H), 1.64 (m,
1H), 1.12-1.47 (m, 7H), 0.91 (m, 1H), 0.51 (m, 2H), 0.13 (m, 2H)
1.12-1.51 (m, 7H) ppm. Anal. (C28H36N2O 0.4EtOAc)
3
C, H, N.
17-(Cyclobutylmethyl)-N-phenylmorphinan-3-amine (8f). Light-
yellow solid (14%). Mp: 53-55 °C. 13C NMR (CDCl3): 144.6,
142.1, 141.1, 131.7, 129.7, 128.8, 120.3, 117.0, 116.8, 116.4, 60.4,
56.2, 46.2, 45.7, 42.4, 38.2, 37.0, 27.3, 27.1, 24.5, 22.7, 9.9, 4.5, 4.0
ppm. 1H NMR (CDCl3): 7.23 (t, J = 15 Hz, 2 H), 6.99 (d, J = 8.4
Hz, 4H), 6.83-6.89 (m, 2H), 5.63 (bs, 1H), 3.1 (m, 1H), 2.89 (d,
J = 18 Hz, 1H), 2.46-2.70 (m, 2H), 2.28-2.35 (m, 2H), 2.02 (m,
1H), 1.53-1.88 (m, 3H), 1.26-1.46 (m, 7H), 0.87 (m, 1H), 0.50
ppm. Anal. (C36H44N2O2 0.5CH2Cl2) C, H, N.
3
17-(Cyclobutylmethyl)-N,N-bis(4-iodobenzyl)morphinan-3-
amine (7e). White crystals (12%). Mp: 75-77 °C. 13C NMR (free
base, CDCl3): 147.3, 140.7, 138.7, 137.6, 129.0, 128.5, 111.4,
110.3, 92.1, 61.0, 56.2, 54.8, 46.1, 44.6, 41.2, 37.4, 36.5, 28.0,
27.8, 26.7, 26.4, 23.9, 21.9, 18.8 ppm. 1H NMR (free base,
CDCl3): 7.60 (d, J = 8 Hz, 4H), 7.11 (d, J = 8 Hz, 4H), 6.88
(d, J = 8 Hz, 1H), 6.51 (dd, J = 8, 2 Hz, 1H), 6.46 (d, J = 2 Hz,
1H), 4.46 (d, J = 6 Hz, 2H), 2.87 (m, 2H), 2.50-2.65 (m, 5H),
1.52-2.05 (m, 11H), 0.88-1.34 (m, 7H) ppm. Anal. (C35H40-
I2N2) C, H, N.
1
(m, 2H), 0.13 (m, 2H) ppm. Anal. (C27H34N2 /10EtOAc)
3
C, H, N.
General Procedure for the Synthesis of 17-(Cyclopropyl-
methyl/cyclobutylmethyl)-N-(4-methoxybenzyl/4-iodobenzyl)mor-
phinan-3-amines (7a-c) and N-Dibenzylated Compounds (7d,e).
To a solution of 0.18 mmol of 17-(cyclopropylmethyl)mor-
phinan-3-amine (6a) or 17-(cyclopropylmethyl)morphinan-3-
amine (6b), respectively, in 3 mL of ethanol was added 53 mg
(0.18 mmol) of 4-iodobenzyl bromide (to yield compounds 7a,b,
e) or 4-methoxybenzyl bromide (to yield compounds 7c,d). To
the clear solution an amount of 50 mg (0.35 mmol, 2 equiv) of
well triturated potassium carbonate was added, and the mixture
was vigorously stirred at room temperature overnight. TLC
control (EtOAc/NEt3, 20/1) showed that only small amounts of
starting material were left. The solids were filtered off and
washed twice with methylene chloride. After evaporation of
solvents, the residue was purified by column chromatography
using CH2Cl2/MeOH, 9/1, and then hexane/EtOAc/NEt3,
10/10/1.
General Procedure for the Synthesis of 17-(Methyl/cyclopro-
pylmethyl/cyclobutylmethyl)morphinan-3-yl 4-Iodophenyl Car-
bamates (9a-c). In an N2 atmosphere, 0.58 mmol (59 mg, 1.5
equiv) of NEt3 and 0.39 mmol of 4-iodophenyl isocyanate were
added to a suspension of 0.389 mmol of 1, 3a, or 3b, respectively,
in 10 mL of CH2Cl2. The resulting mixture was stirred at room
temperature overnight. The solvent was evaporated in vacuo,
and the residue was purified by column chromatography over a
short column of silica gel eluting with CH2Cl2/MeOH, 100/1.
The carbamates were obtained as white solids. The free bases
were converted into their hydrochlorides using 1 N HCl in
diethyl ether.
17-(Cyclopropylmethyl)-N-(4-iodobenzyl)morphinan-3-amine
(7a). After the first column two spots with very similar Rf values
could be observed on TLC, which could be separated into
compounds 7a and 7e by applying a second column using
EtOAc/NEt3, 9/1, as eluent system. White solid (42%). Mp:
170-173 °C. 13C NMR (CDCl3): 146.4, 141.6, 139.8, 137.8,
129.8, 128.6, 111.0, 110.1, 92.5, 61.8, 56.2, 48.5, 46.2, 45.5, 42.2,
37.8, 37.0, 35.3, 28.2, 28.2, 27.2, 26.9, 24.2, 22.5, 22.4, 19.1 ppm.
1H NMR (CDCl3): 7.63 (d, J = 8 Hz, 2H), 7.11 (d, J = 8 Hz,
2H), 6.88 (d, J = 8 Hz, 1H), 6.46 (d, J = 2 Hz, 1H), 6.41 (dd, J =
8, 2.4 Hz, 1H), 4.22 (s, 2H), 3.86 (bs, 1H), 3.15 (bs, 1H), 2.88 (d,
J = 18 Hz, 1H), 2.74 (bs, 1H), 2.38-2.55 (m, 5H), 2.15-2.19 (m,
1H), 1.56-2.07 (m, 10H), 1.07-1.42 (m, 7H) ppm. Anal.
17-Methylmorphinan-3-yl 4-Iodophenyl Carbamate (9a).
White solid (74%). Mp (free base): 160-162 °C (dec). Mp
(HCl salt): 223-225 °C (dec). 13C NMR (base, CDCl3): δ
151.7, 149.0, 141.7, 137.9, 137.3, 134.8, 128.6, 120.6, 118.7,
118.2, 86.7, 57.7, 46.9, 44.6, 42.4, 41.4, 37.1, 36.3, 26.5, 26.3,
23.7, 22.0 ppm. 1H NMR (base, CDCl3): δ 7.60 (d, J = 8.4 Hz,
2H), 7.22 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 1H), 7.03 (d,
J = 2.4 Hz, 1H), 6.94 (dd, J = 8.4 and 2.4 Hz, 1H), 3.03 (d, J =
18.6 Hz, 1H), 2.89 (m, 1H), 2.67 (dd, J = 18.6 and 5.4 Hz, 1H),
2.51 (dd, J = 12.3 and 2.7 Hz, 1H), 2.42 (s, 3H), 2.30 (d, J = 12.3
Hz, 1H), 2.10 (m, 1H), 1.91-1.73 (m, 2H), 1.61 (m, 1H), 1.50 (m,
1H), 1.43-1.23 (m, 5H), 1.10 (m, 1H) ppm. Anal. (C24H27-
IN2O2 HCl 1.5H2O) C, H, N.
1
(C27H33IN2 /10EtOAc) C, H, N.
3
3
3
17-(Cyclopropylmethyl)morphinan-3-yl 4-Iodophenyl Carba-
mate (9b). White solid (71%). Mp (free base): 189-191 °C
(dec). Mp (HCl salt): 238-240 °C (dec). 13C NMR (base,
CDCl3): δ 151.7, 148.9, 142.0, 137.9, 137.4, 135.1, 128.5,
120.6, 118.6, 118.2, 86.7, 59.8, 55.6, 45.5, 44.6, 41.5, 37.8, 36.4,
26.6 26.4, 24.1, 22.0, 9.1, 4.0, 3.6 ppm. 1H NMR (base, CDCl3):
δ 7.58 (d, J = 8.8 Hz, 2H), 7.37 (br, 1H), 7.21 (d, J = 8.8 Hz,
2H), 7.10 (d, J = 8.2 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.92 (dd,
J = 8.2 and 2.4 Hz, 1H), 3.14 (m, 1H), 2.94 (d, J = 18.6 Hz, 1H),
2.72 (dd, J = 9.3 and 3.0 Hz, 1H), 2.63 (dd, J = 18.6 and 5.7 Hz,
1H), 2.50 (dd, J = 12.6 and 6.3 Hz, 1H), 2.37-2.27 (m, 2H),
2.05-1.70 (m, 3H), 1.63 (d, J = 10.9 Hz, 1H), 1.51 (d, J = 10.9
Hz, 1H), 1.43-1.23 (m, 5H), 1.10 (m, 1H), 0.89 (m, 1H), 0.516
(m, 2H), 0.12 (m, 2 H) ppm. MS (ESIþ): m/z 543 (M þ H)þ.
17-(Cyclopropylmethyl)-N-(4-iodobenzyl)morphinan-3-amine
(7b). White crystals (24%). Mp: 67-69 °C. 13C NMR (CDCl3):
146.6, 141.3, 139.7, 137.8, 129.7, 128.6, 111.1, 110.0, 92.5, 60.0,
56.2, 48.4, 46.2, 45.0, 41.8, 37.8, 36.8, 27.0, 26.8, 24.1, 22.4, 9.3,
4.4, 4.0 ppm. 1H NMR (CDCl3): 7.62 (dd, J = 8, 2 Hz, 2H), 7.13
(d, J = 8 Hz, 2H), 6.88 (d, J = 8 Hz, 1H), 6.50 (d, J = 2 Hz, 1H),
6.43 (dd, J = 8, 2 Hz, 1H), 4.25 (s, 2H), 3.91 (bs, 1H), 3.15 (bs,
1H), 2.51-2.81 (m, 4H), 2.01-2.39 (m, 3H), 1.75-1.90 (m, 2H),
1.63 (m, 1H), 1.11-1.46 (m, 7H), 0.97 (m, 1H), 0.53 (m, 2H),
0.15 (m, 2H) ppm. Anal. (C28H35IN2) C, H, N.
17-(Cyclopropylmethyl)-N-(4-methoxybenzyl)morphinan-3-
amine (7c). After the first column two spots with very similar Rf
values could be observed on TLC, which could be separated into
compounds 7c and 7d by applying a second column using
CH2Cl2/MeOH, 9/1, as eluent system. White solid (5%). Mp:
38 °C. 13C NMR (CDCl3): 158.5, 148.0, 130.9, 128.1, 128.0,
113.9, 111.47, 110.1, 59.3, 56.2, 55.2, 54.2, 46.1, 40.7, 37.3, 36.2,
26.5, 26.2, 23.7, 21.8, 8.2, 4.2, 4.0 ppm. 1H NMR (CDCl3): 7.17
(dd, J = 8 Hz, 4H), 6.83-6.90 (m, 5H), 6.57-6.63 (m, 2H), 4.50
Anal. (C27H31IN2O2 1HCl) C, H, N.
3
17-(Cyclobutylmethyl)morphinan-3-yl 4-Iodophenyl Carba-
mate (9c). White solid (85%). Mp (HCl salt): 203-205 °C
(dec). 13C NMR (base, CDCl3): δ 151.5, 149.8, 139.9, 137.8,
137.4, 131.5, 128.8, 120.7, 119.9, 118.6, 86.8, 59.5, 56.7, 46.2,

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 413
41.5, 38.9, 36.6, 35.3, 31.7, 27.7, 27.6, 25.9, 25.6, 24.4, 21.5, 18.6
ppm. 1H NMR (base, CDCl3): δ 7.69 (br, 1H), 7.59 (d, J = 8.5
Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.4 Hz, 1H), 7.05
(d, J = 2.4 Hz, 1H), 7.02 (dd, J = 8.4 and 2.4 Hz, 1H), 3.33 (m,
1H), 2.95 (m, 6H), 2.29 (m 2H), 2,14 (m, 3H), 1.96-1.81 (m, 4H),
1.65-1.32 (m, 6H), 1.25 (m, 2H), 1.02 (m, 1H) ppm. MS (ESIþ):
m/z 557 (M þ H)þ. Anal. (C28H33IN2O2 HCl H2O) C, H, N.
8.7 Hz, 2H), 7.16 (dd, J = 8.1 and 1.5 Hz, 1H), 6.98 (d, J = 8.1
Hz, 1H), 2.87 (m, 1H), 2.71 (m, 1H), 2.45-2.23 (m, 5H),
1.95-1.14 (m, 17H), 0.99 (m, 1H) ppm. Anal. (C28H34IN3O
3
HCl H2O) C, H, N.
3
General Procedure for the Formylation of 3-Hydroxymorphi-
nans. Method A (MeMgBr/HMPA System). Under nitrogen at
room temperature, MeMgBr (1.0 mL, 3.0 M solution in ether)
was added into the suspension of 1.0 mmol of starting material
(levorphanol or butorphan) in benzene (25 mL). The resulting
mixture was stirred for 30 min. HMPA (3.0 mmol) was added
and the clear mixture stirred for 15 min. Paraformaldehyde
(300 mg, 10 mmol) was added in one portion. The resulting
mixture was heated under reflux for 4 h. The mixture was poured
into ice-water and stirred for 15 min. The mixture was extracted
with CH2Cl2/MeOH, 10:1 (50 mL ꢀ 3). The combined organic
layers were washed with brine and dried over Na2SO4. The
solvent was removed in vacuo and the residue was purified on
silica gel column, eluting with CH3OH/CH2Cl2, 1:50 to 1:20, to
obtain the products in 40-50% yield.
3
3
General Procedure for the Synthesis of N-[17-(Methyl/cyclo-
propylmethyl/cyclobutylmethyl)morphinan-3-yl]-N0-phenylureas
(10a-e). In an N2 atmosphere, 1.5 equiv of triethylamine and
1.0 equiv of phenyl isocyanate (for preparation of compounds
10a,b) or 4-iodophenyl isocyanate (for preparation of 10c-e)
were added to a suspension of 1.0 equiv of the respective 3-
aminomorphinan (6a-c) in 10 mL of CH2Cl2. The resulting
mixture was stirred at room temperature overnight. The solvent
was evaporated under reduced pressure, and the residue was
purified by column chromatography over a short column of
silica gel eluting with EtOAc/Et3N, 50/1. The ureas were ob-
tained in 61-70% yield. The free bases were converted into their
hydrochlorides using 1 N HCl in diethyl ether.
Method B (MgCl2/Et3N System). To a solution (10 mL) of 1
or 3b (1.0 mmol) in anhydrous THF (distilled freshly from
benzophenone ketyl radical), anhydrous magnesium chloride
(190 mg, 2.0 mmol, beads, 10 mesh, 99.9% purity, from Aldrich
used directly without further drying), and triethylamine
(0.28 mL, 2.0 mmol), paraformaldehyde (90 mg, 3.0 mmol)
was added. The reaction mixture was heated to reflux under
nitrogen atmosphere for 2 days. The reaction was monitored
with TLC (CH3OH/CH2Cl2, 1:10). After evaporation of sol-
vent, water (50 mL) was added and the reaction mixture was
extracted with CH2Cl2 (50 mL ꢀ 3). The combined organic
layers were washed with brine and dried over anhydrous sodium
sulfate and the crude product was purified on silica gel column,
eluting with CH3OH/CH2Cl2, 1:50 to 1:20, to obtain the pro-
ducts in 40-75% yield.
N-(17-Methylmorphinan-3-yl)-N0-phenylurea (10a). White
solid (75%). Mp (HCl salt): 158-160 °C (dec). 13C NMR
(base, DMSO-d6): δ 152.6, 139.9, 139.8, 137.9, 130.7, 128.7,
127.8, 121.6, 118.0, 116.1, 114.7, 57.1, 46.6, 44.3, 42.2, 41.3, 36.5,
35.9, 26.1, 25.9, 23.1, 21.8 ppm. 1H NMR (base, DMSO-d6): δ
8.64 (s, 1H), 8.61 (s, 1H), 7.42 (d, J = 7.8 Hz, 2H), 7.31-7.18 (m,
4H), 7.01 (d, J = 8.4 Hz, 1H), 6.93 (t, J = 7.2 Hz, 1H), 2.92 (d,
J = 18.6 Hz, 1H), 2.74 (m, 1H), 2.38-2.26 (m, 2H), 2.29 (s, 3H),
2.02-1.94 (m, 2H), 1.75-1.15 (m, 8H), 1.02 (m, 1H), 0.97 (t, J =
7.5 Hz, 1H) ppm. Anal. (C24H29N3O HCl 1.1H2O) C, H, N.
3
3
N-[17-(Cyclopropylmethyl)morphinan-3-yl]-N0-phenylurea (10b).
White solid (73%). Mp (free base): 88-90 °C (dec). Mp (HCl salt):
>250 °C (dec). 13C NMR (base, CDCl3): δ 178.8, 153.8, 139.5,
139.2, 138.3, 128.8, 128.2, 122.5, 119.2, 117.9, 116.2, 58.6, 56.0,
45.7, 42.6, 37.0, 35.8, 26.2, 26.0, 24.8, 21.8, 10.3, 7.4, 4.2, 4.1 ppm.
1H NMR (base, CDCl3): δ 8.64 (s, 1H), 8.54 (s, 1H), 7.39 (d, J =
7.8 Hz, 2H), 7.32-7.16 (m, 4H), 6.94 (t, J = 7.8 Hz, 2H), 3.40
(s, 1H), 2.91-2.84 (m 2H), 2.74-2.58 (m, 2H), 2.31-1.85 (m, 5H),
1.59-1.02 (m, 9H), 0.57 (m, 2H), 0.22 (m, 2H) ppm. Anal.
(C27H33N3O HCl 1.5H2O) C, H, N.
2-Formyl-3-hydroxymorphinan (11). 1H NMR (base, 300
MHz, CDCl3): δ 10.13 (s, br, 1H), 9.84 (s, 1H), 7.30 (s, 1H),
6.92 (s, 1H), 3.06 (d, J = 18.3 Hz, 1H), 2.91 (m, 1H), 2.68 (dd,
J = 18.3 and 5.7 Hz, 1H), 2.54-2.33 (m, 2H), 2.43 (s, 3H), 2.05
(m, 1H), 1.93-1.77 (m, 2H), 1.68-1.01 (m, 8H) ppm. 13C NMR
(base, 75 MHz, CDCl3): δ 195.7, 159.7, 151.8, 132.1, 129.0,
118.9, 113.9, 57.4, 46.8, 44.4, 42.4, 41.4, 38.0, 36.4, 26.8, 26.1,
23.0, 22.0 ppm.
3
3
N-(4-Iodophenyl)-N0-(17-methylmorphinan-3-yl)urea (10c).
White solid (70%). Mp (HCl salt) >250 °C (dec). 13C NMR
(base, DMSO-d6): δ 152.4, 139.8, 139.7, 137.8, 137.2, 130.5,
127.9, 120.3, 116.2, 114.8, 84.3, 57.2, 46.6, 44.0, 42.0, 41.0,
36.4, 35.8, 33.2, 26.5, 25.9, 23.2, 21.8, 14.7 ppm. 1H NMR
(base, DMSO-d6): δ 8.87 (s, 1H), 8.73 (s, 1H), 7.56 (d, J = 8.4
Hz, 2H), 7.33 (d, J = 1.5 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H),
7.18 (dd, J = 8.1 and 1.5 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H),
3.04-2.82 (m, 2H), 2.59-2.25 (m, 3H), 2.05-1.94 (m, 1H),
2-Formyl-3-hydroxy-17-N-cyclobutylmethylmorphinan (12).
1H NMR (base, 300 MHz, CDCl3): δ 10.53 (s, br, 1H), 9.83 (s,
1H), 7.28 (s, 1H), 6.91 (s, 1H), 3.03 (d, J = 18.3 Hz, 1H), 2.88 (m,
1H), 2.68-2.48 (m, 5H), 2.33 (m, 1H), 2.09-1.99 (m, 3H),
1.91-1.63 (m, 7H), 1.54 (m, 1H), 1.45-1.01 (m, 6H) ppm. 13
C
NMR (base, 75 MHz, CDCl3): δ 195.9, 159.7, 152.2, 132.2,
129.3, 118.9, 114.0, 61.2, 55.5, 45.6, 44.2, 41.3, 38.6, 36.5, 34.4,
27.7, 27.0, 26.2, 23.7, 22.1, 18.7 ppm.
1.74-1.21 (m, 9H), 1.07-0.95 (m, 2H) ppm. Anal. (C24H28
-
General Procedure for the Preparation of 2-Hydroxymethyl-3-
hydroxymorphinans. At room temperature, an amount of 2.4
equiv of NaBH4 was added into a solution of the aldehyde 11
derived from 1 or compound 12 derived from 3b in MeOH
(8.0 mL). The mixture was stirred for 1 h at room temperature.
Then the mixture was poured into ice-water (50 mL). Then
the mixture was stirred for 15 min and evaporated in vacuo
to remove MeOH. The residue was extracted with CH2Cl2
(50 mL ꢀ 4). The combined organic layers were washed with
brine and dried over Na2SO4. The solvent was removed in vacuo
and the residue was purified on silica gel column, eluting with
CH3OH/CH2Cl2, 1:1 to 10:1, to obtain the products in 90-95%
yield. The free base was converted to its HCl salt with 1.0 M HCl
in diethyl ether.
2-Hydroxymethyl-3-hydroxymorphinan (13). Mp (HCl salt):
>250 °C (dec). 1H NMR (base, 300 MHz, CDCl3): δ 7.13 (s, br,
1H), 6.76 (s, 1H), 6.69 (s, 1H), 4.76 (ab, J = 13.2 and 5.4 Hz,
2H), 2.87 (d, J = 18.3 Hz, 1H), 2.77 (m, 1H), 2.58 (dd??, J = 18.3
and 5.1 Hz, 1H), 2.33 (s, 3H), 2.25 (m, 1H), 2.05 (m, 1H), 1.78
(m, 1H), 1.68-1.05 (m, 8H) ppm. 13C NMR (base, 75 MHz,
IN3O HCl 0.4H2O) C, H, N.
3
3
N-[17-(Cyclopropylmethyl)morphinan-3-yl]-N0-(4-iodophenyl)-
urea (10d). White solid (75%). Mp (HCl salt): >250 °C (dec).
13C NMR (base, DMSO-d6): δ 152.4, 140.2, 139.8, 137.6, 137.2,
131.1, 127.8, 120.3, 116.1, 114.9, 84.3, 59.0, 55.1, 45.0, 44.4, 41.4,
1
37.2, 36.0, 26.3, 26.0, 23.7, 21.8, 9.2, 3.8, 3.4 ppm. H NMR
(base, DMSO-d6): δ 8.79 (s, 1H), 8.66 (s, 1H), 7.56 (d, J = 9.0
Hz, 2H), 7.31 (d, J = 1.8 Hz, 1H), 7.28 (d, J = 9.0 Hz, 2H), 7.16
(dd, J = 8.1 and 1.8 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 2.98 (m,
1H), 2.83 (d, J = 18.3 Hz, 1H), 2.60-2.42 (m, 2H), 2.40-2.20
(m, 2H), 1.96-1.86 (m, 2H), 1.75-0.95 (m, 11H), 0.78 (m,1H),
0.43-0.49 (m, 2H), 0.11-0.04 (m, 2H) ppm. Anal. (C27H32-
IN3O HCl) C, H, N.
3
N-[17-(Cyclobutylmethyl)morphinan-3-yl]-N0-(4-iodophenyl)-
urea (10e). White solid (86%). Mp (HCl salt): 245-247 °C (dec).
13C NMR (base, DMSO-d6): δ 152.4, 140.2, 139.8, 137.6, 137.2,
131.2, 127.7, 120.3, 116.1, 114.9, 84.3, 60.6, 55.5, 45.1, 44.5, 41.6,
37.1, 36.0, 33.6, 26.7, 26.6, 26.3, 26.0, 23.9, 21.8, 18.3 ppm. 1H
NMR (base, 300 MHz, DMSO-d6): δ 8.73 (s, 1H), 8.60 (s, 1H),
7.56 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 1.5 Hz, 1H), 7.28 (d, J =

414 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1
Decker et al.
CDCl3): δ 155.1, 140.5, 127.4, 126.6, 123.7, 112.7, 63.7, 57.9,
46.9, 44.0, 42.1, 40.9, 36.6, 36.3, 26.5, 26.3, 23.5, 22.0 ppm. Anal.
(C18H25NO2 HCl H2O) C, H, N.
41.9, 36.9, 36.5, 26.7, 26.5, 23.3, 22.2 ppm. Anal. (C26H32-
N2O 2HCl H2O) C, H, N.
3
3
17-N-(Cyclobutylmethyl)-3-hydroxymorphinan-2-carbaldehyde
Oxime (18). To a solution of 2-formyl-3-hydroxy-N-cyclobu-
tylmethylmorphinan 12 (434 mg, 1.28 mmol) in methanol
(3 mL) were added hydroxylamine hydrochloride (175 mg,
2.56 mmol) and anhydrous sodium acetate (210 mg, 2.56 mmol).
Under stirring a clear solution was formed. The solution was
stirred overnight at room temperature. The methanol was
evaporated under reduced pressure and water (50 mL) added.
The water phase was extracted with methylene chloride (50 mL
ꢀ 3). The combined organic phases were dried over Na2SO4, and
solvent was evaporated. The crude oxime was column chroma-
tographed using CH2Cl2/MeOH/NEt3, 50/50/1, as eluent sys-
tem to yield 436 mg (96%) of a fluffy white solid. Mp (free base):
214-216 °C; mp (HCl salt, dec): 216-218 °C. 1H NMR (base,
300 MHz, CDCl3): δ 9.90 (bs, 1H), 8.18 (s, 1H), 6.90 (d, J = 10
Hz, 2H), 2.92-3.02 (m, 2H), 2.51-2.68 (m, 5H), 2.24 (d, J = 12
Hz, 1H), 2.08 (m, 3H), 1.62-1.94 (m, 7H), 1.26-1.54 (m, 6H),
1.12 (m, 1H) ppm. 13C NMR (base, 75 MHz, CDCl3): δ 155.8,
151.8, 143.9, 129.2, 128.3, 115.0, 113.1, 61.2, 55.5, 46.0, 44.1,
41.1, 37.8, 36.4, 34.3, 28.2, 28.1, 27.0, 26.4, 23.7, 22.2, 18.8 ppm.
Anal. (C22H30N2O2 HCl 0.8H2O) C, H, N.
3
3
2-Hydroxymethyl-3-hydroxy-17-N-cyclobutylmethylmorphi-
nan (14). Mp (HCl salt): 218-220 °C (dec). 1H NMR (base, 300
MHz, CDCl3): δ 6.76 (s, 1H), 6.70 (s, 1H), 4.78 (ab, J = 13.8 Hz,
2H), 2.88 (d, J = 18.0 Hz, 1H), 2.78 (m, 1H), 2.57-2.47 (m, 4H),
2.36 (m, 1H), 2.21 (m, 3H), 2.06-1.98 (m, 3H), 1.91-1.59 (m,
7H), 1.43-1.04 (m, 7H) ppm. 13C NMR (base, 75 MHz,
CDCl3): δ 154.8, 141.2, 128.2, 126.7, 123.1, 112.7, 64.0, 61.1,
55.6, 45.8, 44.1, 41.1, 37.2, 36.4, 34.5, 28.2, 28.1, 26.8, 26.4, 23.9,
22.1, 18.8 ppm; Anal. (C22H31NO2 HCl H2O) C, H, N.
3
3
2-Benzylaminomethyl-3-hydroxymorphinan (16). At room
temperature, benzylamine (51 mg, 0.48 mmol) was added into
the solution of salicylaldehyde 11 (125 mg, 0.43 mmol) in MeOH
(10.0 mL). The mixture was stirred overnight at room tempera-
ture. The reaction was monitored by TLC (CH3OH/CH2Cl2,
1:10). After complete consumption of salicylaldehyde and eva-
poration of solvent, the reaction mixture was directly loaded on
silica gel column and eluted with CH3OH/CH2Cl2, 1:10 to 1:1,
to obtain the bright-yellow aldimine 15 (80 mg) in 50% yield.
To the solution of aldimine 15 (80 mg, 0.21 mmol) in MeOH
(8 mL) was added NaBH4 (10 mg, 0.25 mmol), and the mixture
was stirred at room temperature overnight. The reaction was
monitored by TLC (CH3OH/CH2Cl2, 1:1). After complete
consumption of the aldimine, the pH of the mixture was
adjusted to 2-3 with 1 N HCl to decompose the excess of
NaBH4 and then to 9-10 with saturated KHCO3 aqueous
solution. After evaporation of solvent, water was added to the
residue and extracted with CH2Cl2 (50 mL ꢀ 3). The combined
organic layers were washed with brine and dried over Na2SO4.
The solvent was removed in vacuo and the residue was purified
on silica gel column, eluting with CH3OH/CH2Cl2/Et3N,
50:50:1, to obtain a colorless oil in 88% yield. The free base
was converted to its HCl salt as a white solid with 1 N HCl in
diethyl ether.
3
3
2-(Aminomethyl)-3-hydroxy-17-N-cyclobutylmethylmorphinan
(19). Concentrated HCl (1.0 mL) was added to a solution of
17-(cyclobutylmethyl)-3-hydroxymorphinan-2-carbaldehyde
oxime 18 (336 mg, 0.95 mmol) in ethanol (5.0 mL). To this
mixture was added 10 wt % palladium on charcoal (40 mg).
Under a hydrogen atmosphere (1 atm) the suspension was
vigorously stirred until TLC (CH2Cl2/MeOH/NEt3, 50/50/1)
showed the complete consumption of the oxime (∼36 h). The
Pd/C was filtered off through Celite and washed with methanol
(30 mL ꢀ 3). After removal of the methanol, water (50 mL) was
added and the mixture was extracted with methylene chloride
(50 mL ꢀ 3). The combined organic phases were dried over
Na2SO4, and solvent was evaporated. The crude product was
column-chromatographed using CH2Cl2/MeOH/NEt3, 50/50/
1, as eluent system to yield 125 mg (39%) of white foam. The
foam was repeatedly dissolved in CH2Cl2/MeOH, 5/1, and
solvents were evaporated to remove residual NEt3. Mp (HCl
salt): >270 °C (dec). 1H (base, 300 MHz, CDCl3): δ 6.67 (d, J =
9 Hz, 2H), 4.03 (bs, 2H), 2.85 (d, J = 18 Hz, 1H), 2.76 (m, 1H),
2.26-2.50 (m, 6H), 1.96-2.26 (m, 3H), 1.58-1.86 (m, 7H),
1.23-1.45 (m, 6H), 1.09 (m, 1H) ppm. 13C NMR (base, 75 MHz,
CDCl3): δ 156.7, 141.2, 128.3, 127.2, 121.9, 113.3, 61.7, 56.2,
46.2, 45.3, 45.2, 42.0, 37.7, 36.8, 35.1, 28.2, 27.2, 26.8, 24.1, 22.5,
19.1 ppm. Anal. (C22H32N2O 2HCl H2O) C, H, N.
Aldimine 15. 1H NMR (base, 300 MHz, CDCl3): δ 13.01 (s, br,
1H), 8.38 (s, 1H), 7.37-7.24 (m, 5H), 7.01 (s, 1H), 6.89 (s, 1H),
4.79 (s, 2H), 2.99 (d, J = 18.3 Hz, 1H), 2.83 (dd, J = 5.1 and 3.3
Hz, 1H), 2.60 (dd, J = 18.3 and 6.0 Hz, 1H), 2.48-2.34 (m, 3H),
2.40 (s, 3H), 2.08 (dt, J = 12.6 and 3.3 Hz, 1H), 1.86-1.62
(m, 3H), 1.53-1.25 (m, 5H), 1.11 (m, 1H) ppm. 13C NMR (base,
75 MHz, CDCl3): δ 165.2, 159.1, 146.0, 138.3, 130.1, 128.5,
127.8, 127.6, 127.2, 116.9, 113.3, 63.2, 57.8, 47.1, 45.0, 42.7, 41.8,
37.5, 36.5, 26.9, 26.4, 23.0, 22.2 ppm.
2-Benzylaminomethyl-3-hydroxymorphinan (16). Mp (HCl
salt): 188-190 °C. 1H NMR (base, 300 MHz, CDCl3): δ
7.37-7.25 (m, 5H), 6.74 (s, 1H), 6.70 (s, 1H), 3.95 (s, 2H), 3.83
(s, 2H), 2.90 (d, J = 18.3 Hz, 1H), 2.80 (m, 1H), 2.54 (dd, J =
17.7 and 5.4 Hz, 1H), 2.47-2.30 (m, 2H), 2.39 (s, 3H), 2.09 (dt,
J = 12.3 and 3.0 Hz, 1H), 1.82-1.61 (m, 3H), 1.41-1.26 (m,
6H), 1.11 (m, 1H) ppm. 13C NMR (base, 75 MHz, CDCl3): δ
156.2, 140.8, 138.4, 128.5, 128.2, 127.7, 127.4, 119.9, 112.7, 58.0,
52.8, 51.6, 47.2, 45.0, 42.6, 41.7, 36.8, 36.5, 26.7, 26.5, 23.2, 22.1
ppm. Anal. (C25H32N2O 2HCl 1.5H2O) C, H, N.
3
3
2-(N-n-Propyl)aminomethyl-3-hydroxy-17-N-cyclobutylmethyl-
morphinan (21). At room temperature, n-propylamine (19 mg,
0.33 mmol) was added into a solution of salicylaldehyde com-
pound 12 derived from 3b (75 mg, 0.22 mmol) in MeOH
(8.0 mL). The mixture was stirred overnight at room tempera-
ture. The reaction was monitored with TLC (CH3OH/CH2Cl2,
1:10). After complete consumption of the salicylaldehyde and
evaporation of solvent, the reaction mixture was directly loaded
to the silica gel column and eluted with CH3OH/CH2Cl2, 1:10 to
1:1, to obtain the bright-yellow aldimine 20 (64 mg) in 77%
yield. To the solution of this aldimine (64 mg, 0.168 mmol) in
MeOH (10 mL) was added NaBH4 (10 mg, 0.26 mmol), and the
mixture was stirred at room temperature overnight. The reac-
tion was monitored with TLC (CH3OH/CH2Cl2, 1:1). After
complete consumption of the aldimine, the pH of the mixture
was adjusted to 2-3 with 1 N HCl to decompose the excess
NaBH4 and then to 9-10 with saturated KHCO3 aqueous
solution. After evaporation of the solvent, water (50 mL) was
added to the residue and extracted with CH2Cl2 (50 mL ꢀ 3).
The combined organic layers were washed with brine and dried
over Na2SO4. The solvent was removed in vacuo and the residue
was purified on silica gel column, eluting with CH3OH/CH2Cl2/
Et3N, 100:100:1, to obtain a colorless oil (60 mg) in 93% yield.
3
3
3-Benzyl-3,4-dihydro-2H-benzo[e][1,3]oxazinemorphinan (17).
Under nitrogen, a mixture of 2-(N-benzylaminomethyl)-3-hydro-
xymorphinan 16 (30 mg, 0.08 mmol) and paraformaldehyde
(5 mg, 0.16 mmol) in MeOH (10 mL) was refluxed overnight.
After removal of solvent, the residue was loaded on the silica gel
column, eluting with CH3OH/CH2Cl2/Et3N, 50:50:1, to obtain a
colorless oil (23 mg) in 74% yield. The free base was converted
into HCl salt as a white solid with 1 N HCl in diethyl ether. Mp
1
(HCl salt): 208-210 °C. H NMR (base, 300 MHz, CDCl3): δ
7.39-7.26 (m, 5H), 6.70 (s, 1H), 6.65 (s, 1H), 4.83 (s, 2H), 3.93 (s,
4H), 2.93 (d, J = 18.0 Hz, 1H), 2.83 (m, 1H), 2.60-2.30 (m, 3H),
2.41 (s, 3H), 2.14 (dt, J = 12.3 and 3.0 Hz, 1H), 1.85-1.65 (m,
3H), 1.51-1.25 (m, 6H), 1.16 (m, 1H) ppm. 13C NMR (base, 75
MHz, CDCl3): δ 152.5, 139.9, 138.2, 129.5, 128.8, 128.6, 128.3,
127.2, 126.3, 117.5, 112.7, 82.1, 58.0, 55.7, 49.5, 47.2, 45.0, 42.6,

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 415
The free base was converted to its HCl salt as a white solid with
1 N HCl in diethyl ether.
1,4-N,N-Bis(17-N-cyclobutylmethyl-3-hydroxymorphinan-2-
methylamino)butane-1,4-diamine (22a). Yield: 81%. Mp: 250-
265 °C (dec). Mp (HCl salt): 250-253 °C. 1H NMR (base, 300
MHz, CD3OD): δ 7.15 (s, 2H), 6.86 (s, 2H), 4.02 (m, 4H), 3.45
(m, 2H), 2.91- 3.22 (m, 14H), 2.79 (qui, J = 7 Hz, 2H), 2.57 (m,
2H), 2.40 (d, J = 14 Hz, 2H), 1.79-2.20 (m, 20H), 1.20-1.65 (m,
14H), 1.02-1.18 (m, 2H) ppm. 13C NMR (base, 75 MHz,
CD3OD): δ 156.9, 141.6, 132.0, 126.7, 120.1, 113.0, 60.4, 59.1,
47.9, 43.1, 40.0, 37.7, 36.7, 33.1, 28.4, 28.3, 27.2, 27.1, 26.2, 25.2,
23.0, 19.5 ppm. Anal. (C48H70N4O2 4HCl 3.5H2O) C, H, N.
1,6-N,N-Bis(17-N-cyclobutylmethyl-3-hydroxymorphinan-2-
methylamino)hexane-1,6-diamine (22b). Yield: 85%. Mp: 210-
215 °C (dec). Mp (HCl salt): 245-249 °C. 1H NMR (base, 300
MHz, CD3OD): δ 7.11 (s, 2H), 6.83 (s, 2H), 4.07 (s, 4H), 3.26 (m,
2H), 2.68-3.13 (m, 16H), 2.36-2.41 (m, 4H), 2.12-2.17 (m,
4H), 1.25-2.02 (m, 34 H), 1.04-1.16 (m, 2H) ppm. 13C NMR
(base, 75 MHz, CD3OD): δ 157.1, 142.3, 131.6, 127.5, 119.4,
112.0, 61.0, 58.4, 47.4, 44.0, 40.8, 38.0, 37.0, 34.0, 28.6, 28.5,
Aldimine 20. 1H NMR (base, 300 MHz, CDCl3): δ 13.23 (s, br,
1H), 8.26 (s, 1H), 6.95 (s, 1H), 6.85 (s, 1H), 3.52 (t, J = 6.9 Hz,
2H), 2.95 (d, J = 17.7 Hz, 1H), 2.83 (m, 1H), 2.62-2.42 (m, 5H),
2.34 (d, J = 11.7 Hz, 1H), 2.08-2.00 (m, 3H), 1.95-1.63 (m,
9H), 1.62 (m, 1H), 1.48-1.28 (m, 5H), 1.09 (m, 1H), 0.95 (t, J =
7.2 Hz, 3H) ppm. 13C NMR (base, 75 MHz, CDCl3): δ 164.0,
159.2, 145.6, 129.7, 127.5, 116.8, 113.2, 61.4, 61.2, 55.8, 45.7,
44.5, 41.5, 37.9, 36.5, 34.6, 27.7, 26.9, 26.4, 24.0, 23.7, 22.1, 18.7,
11.6 ppm.
3
3
2-(N-n-Propyl)aminomethyl-3-hydroxy-17-N-cyclobutylmethyl-
morphinan (21). Mp (HCl salt): >198-200 °C. 1H NMR (base,
300 MHz, CDCl3): δ 6.69 (s, 1H), 6.68 (s, 1H), 3.91 (ab, J = 15.6
and 14.1 Hz, 2H), 2.86 (d, J = 17.7 Hz, 1H), 2.76 (m, 1H), 2.65
(t, J = 6.9 Hz, 2H), 2.56-2.38 (m, 5H), 2.30 (d, J = 9.6 Hz, 1H),
2.06-1.98 (m, 3H), 1.94-1.51 (m, 9H), 1.46 (m, 1H), 1.40-1.25
(m, 5H), 1.11 (m, 1H), 0.94 (t, J = 7.2 Hz, 3H) ppm. 13C NMR
(base, 75 MHz, CDCl3): δ 156.3, 140.8, 127.9, 127.0, 120.1,
112.6, 61.4, 55.9, 52.4, 50.6, 45.9, 44.9, 41.7, 37.3, 36.5, 34.9,
27.8, 26.8, 26.5, 23.9, 22.6, 22.2, 18.7, 11.5 ppm. Anal.
(C25H38N2O 2HCl H2O) C, H, N.
27.8, 27.5, 27.4, 27.3, 25.0, 23.2, 19.6 ppm. Anal. (C50H74N4O2
4 HCl 3.5H2O) C, H, N.
3
3
1,8-N,N-Bis(17-N-cyclobutylmethyl-3-hydroxymorphinan-2-
methylamino)octane-1,8-diamine (22c). Yield: 90%. Mp (free
3
3
1
General Procedure for the Condensation of Aldehyde 12 with
Diamine. At room temperature, the appropriate diamine (0.28
mmol) was added into a solution of salicylaldehyde 12 (190 mg,
0.56 mmol) in MeOH (8.0 mL). The mixture was stirred over-
night at room temperature. The reaction was monitored with
TLC (CH3OH/CH2Cl2, 1:10). After complete consumption of
the salicylaldehyde and evaporation of the solvent, the reaction
mixture was directly loaded to the silica gel column and eluted
with CH3OH/CH2Cl2, 1:10 to 1:1, to obtain the bright-yellow
aldimines in 42-62% yield. To the solution of the respective
aldimine (0.137 mmol) in MeOH (10 mL) was added NaBH4
(13 mg, 0.32 mmol), and the mixture was stirred at room
temperature overnight. The reaction was monitored by TLC
(CH3OH/CH2Cl2, 1:1). After complete consumption of the
aldimine, the pH of the mixture was adjusted to 2-3 with 1 N
HCl to decompose the excess NaBH4 and then to 9-10 with
saturated KHCO3 aqueous solution. After evaporation of the
solvent, water was added to the residue and extracted with
CH2Cl2 (50 mL ꢀ 3). The combined organic layers were washed
with brine and dried over Na2SO4. The solvent was removed in
vacuo and the residue was purified on silica gel column, eluting
with CH3OH/CH2Cl2/Et3N, 50:50:1, to obtain the product as
white foam in 81-90% yield. The free base was converted to its
HCl salt as a white solid with 1 N HCl in diethyl ether.
base): 182-184 °C. Mp (HCl salt): >250 °C. H NMR (base,
300 MHz, CD3OD): δ 6.90 (s, 2H), 6.70 (s, 2H), 3.88 (s, 4H), 2.96
(d, J = 18.3 Hz, 2H), 2.89 (m, 2H), 2.73-2.46 (m, 14H), 2.33 (d,
J = 11.7 Hz, 2H), 2.12-2.05 (m, 6H), 1.93 (m, 2H), 1.82-1.52
(m, 18H), 1.41-1.25 (m, 18H), 1.12 (m, 2H) ppm. 13C NMR
(base, 75 MHz, CD3OD): δ 157.0, 141.9, 130.2, 128.5, 121.5,
112.9, 62.0, 57.3, 50.5, 49.2, 47.2, 45.3, 42.1, 38.3, 37.5, 35.3,
30.2, 29.3, 29.0, 28.8, 27.9, 27.6, 24.8, 23.3, 19.6 ppm. Anal.
(C52H78N4O2 4HCl 2H2O) C, H, N .
3
3
General Procedure for the Synthesis of Bivalent Ligands Con-
taining Spacers with Tertiary Amine Groups (24a,b). In a one-
neck flask 0.068 mmol of the corresponding secondary diamine
(22a or 22b) and 8 equiv (0.55 mmol) of triethylamine were
dissolved in CH2Cl2 (10 mL). At room temperature, an amount
of 8 equiv (43 mg, 0.55 mmol) of acetyl chloride was added
dropwise. The solution was stirred overnight under N2 at room
temperature. Additional methylene chloride (50 mL) was added
and the organic phase washed with NaHCO3 solution and brine
(50 mL). The organic phase was dried over Na2SO4, and solvent
was evaporated. The crude product was purified by silica gel
column chromatography, eluting with CH2Cl2/MeOH/NEt3
(50/50/1). Proton NMR showed that both the secondary amine
group and the phenolic hydroxy group were acetylated (the
latter only partially). Without further characterization the
acetylated compound (23a,b) was dissolved in anhydrous THF
(20 mL), and LiAlH4 (30 mg, 0.75 mmol) was added to the
solution under nitrogen atmosphere. The mixture was stirred
under N2 at room temperature overnight. Aqueous ammonia
solution (50 mL) was added dropwise to decompose excess
LiAlH4, and the white suspension was stirred for further 15 min.
The aqueous phase was extracted with CH2Cl2/MeOH, 5/1
(30 mL ꢀ 4). The combined organic phases were dried over
Na2SO4, and solvents were evaporated. The crude product was
purified by silica gel column chromatography, eluting with
EtOAc/hexane/NEt3, 10/10/1, to yield a colorless foam that
was repeatedly dissolved in CH2Cl2/MeOH, 5/1, and solvents
were evaporated to remove residual NEt3.
1
Aldimine 21a. Bright-yellow oil (59%). H NMR (base, 300
MHz, CDCl3): δ 13.09 (bs, 2 H), 8.28 (s, 2 H), 6.97 (s, 2H), 6.87
(s, 2H), 3.62 (bs, 4H), 2.95 (d, J = 18 Hz, 2 H), 2.80 (m, 2H),
2.33-2.59 (m, 12 H), 1.29-2.09 (m, 36 H), 1.03-1.26 (m, 2H)
ppm. 13C NMR (base, 75 MHz, CDCl3): δ 164.5, 159.1, 146.1,
129.9, 128.1, 116.8, 113.3, 61.6, 59.5, 55.8, 45.8, 45.0, 41.9, 38.2,
36.7, 35.0, 28.6, 27.8, 27.1, 26.6, 23.8, 22.3, 18.9 ppm.
1
Aldimine 21b. Bright-yellow oil (62%). H (base, 300 MHz,
CDCl3): δ 13.12 (bs, 2 H), 8.25 (s, 2 H), 6.94 (s, 2H), 6.84
(s, 2H), 3.56 (t, J = 7 Hz, 4H), 2.92 (d, J = 18 Hz, 2 H), 2.77
(m, 2H), 2.30-2.57 (m, 12 H), 1.26-2.05 (m, 40 H), 1.04-1.23
(m, 2H) ppm. 13C NMR (base, 75 MHz, CDCl3): δ 164.2,
159.2, 146.0, 129.8, 128.0, 116.9, 113.3, 61.6, 59.6, 55.8, 45.8,
45.0, 41.9, 38.1, 36.7, 35.0, 30.8, 27.9, 27.1, 26.9, 26.6, 23.8, 22.3,
18.9 ppm.
1,4-N,N-Diethyl-1,4-N,N-bis(17-N-cyclobutylmethyl-3-hydroxy-
morphinan-2-methylamino)butane-1,4-diamine (24a). Yield: 26
mg (48% over both steps). Colorless solid. Mp: 248-255 °C
(HCl salt). 1H NMR (base, 300 MHz, CDCl3): δ 6.63 (d, J = 6
Hz, 4H), 3.62 (m, 4H), 2.84 (d, J = 18 Hz, 2H), 2.73 (m, 2H),
2.26-2.57 (m, 21H), 2.01 (m, 6H), 1.52-1.97 (m, 21H),
1.11-1.34 (m, 10H), 1.03-1.10 (m, 6H) ppm. 13C NMR (base,
75 MHz, CDCl3): δ 156.1, 140.8, 128.1, 127.3, 119.4, 112.3, 61.6,
57.3, 56.0, 52.5, 46.8, 46.0, 45.1, 41.8, 37.5, 36.6, 35.0, 27.9, 27.0,
1
Aldimine 21c. Bright-yellow oil (42%). H NMR (base, 300
MHz, CDCl3) δ 13.25 (s, br, 2H), 8.26 (s, 2H), 6.97 (s, 2H), 6.86
(s, 2H), 3.55 (t, J = 6.9 Hz, 4H), 2.96 (d, J = 18.0 Hz, 2H), 2.84
(m, 2H), 2.63-2.45 (m, 10H), 2.34 (d, J = 11.7 Hz, 2H),
2.08-2.00 (m, 6H), 1.93-1.60 (m, 18H), 1.51 (m, 2H),
1.41-1.25 (m, 18H), 1.10 (m, 2H) ppm. 13C NMR (base, 75
MHz, CDCl3): δ 164.0, 159.2, 145.6, 129.7, 127.6, 116.9,
113.261.3, 59.6, 55.8, 45.8, 44.5, 41.6, 37.9, 36.5, 34.6, 30.8,
29.2, 27.8, 27.0, 26.9, 26.4, 23.8, 22.2, 18.7 ppm.
26.7, 24.3, 24.0, 22.3, 18.9, 11.1 ppm. Anal. (C52H78N4O2
4HCl 3H2O) C, H, N.
3
3

416 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1
Decker et al.
1,6-N,N-Diethyl-1,6-N,N-bis(17-N-cyclobutylmethyl-3-hydroxy-
morphinan-2-methylamino)hexane-1,6-diamine (24b). Yield: 40
mg (74% over both steps). Colorless solid. Mp: 227-235 °C
(HCl salt). 1H NMR (base, 300 MHz, CDCl3): δ 6.63 (d, J = 6
Hz, 4H), 3.63 (m, 4H), 2.84 (d, J = 18 Hz, 2H), 2.75 (m, 2H),
2.26-2.58 (m, 21H), 2.02 (m, 6H), 1.44-1.90 (m, 21H),
1.24-1.35 (m, 14H), 1.03-1.11 (m, 6H) ppm. 13C NMR (base,
75 MHz, CDCl3): δ 156.4, 141.0, 128.2, 127.5, 119.7, 112.5, 61.8,
57.5, 56.3, 53.0, 46.9, 46.3, 45.4, 42.1, 37.7, 36.9, 35.3, 28.2, 27.5,
1H), 2.90 (d, J = 5.7 Hz, 1H), 2.77 (m, 1H), 2.52-2.30 (m, 5H),
2.21 (d, J = 12.9 Hz, 1H), 2.10-1.98 (m, 3H), 1.94-1.50 (m,
9H), 1.42-1.03 (m, 11H), 0.92 (t, J = 6.6 Hz, 3H). 13C NMR
(base, 75 MHz, CDCl3): δ 154.2, 140.1, 127.6, 126.5, 125.8,
113.0, 75.0, 61.0, 55.5, 45.9, 43.9, 40.9, 37.4, 37.0, 36.3, 34.4,
28.2, 28.1, 26.7, 26.3, 23.7, 22.5, 22.0, 18.7, 14.0. Anal.
(C26H39NO2 HCl 0.25H2O) C, H, N.
3
3
(rac)-1,12-Bis(17-N-cyclobutylmethyl-3-hydroxymorphinan-
2-yl)dodecane-1,12-diol (26b), (rac)-2-(1-Hydroxydodecyl)-3-
hydroxy-17-N-cyclobutylmethylmorphinan (27b), and (rac)-
1-(17-N-Cyclobutylmethyl-3-hydroxymorphinan-2-yl)dodecane-
1,12-diol (28). The same procedure was followed as described for
compounds 26a and 27a, using magnesium turnings (144 mg,
6.0 mmol), 1,10-dibromodecane (360 mg, 1.2 mmol), and
2-formyl-3-hydroxy-17-N-cyclobutylmethylmorphinan 12 (339
mg, 1.0 mmol). The residue was purified by silica gel column
chromatography, eluting with CH3OH/CH2Cl2, 1:10, obtaining
the following product: 50 mg of (rac)-1,12-bis(17-N-cyclobutyl-
methyl-3-hydroxymorphinan-2-yl)dodecane-1,12-diol 26b in
6.0% yield as a colorless oil, 44 mg of (rac)-2-(1-hydro-
xyundecyl)-3-hydroxy-17-N-cyclobutylmethylmorphinan 27b
in 9.1% yield as a colorless oil, and 16.5 mg of (rac)-1-(17-N-
cyclobutylmethyl-3-hydroxymorphinan-2-yl)undecane-1,11-
diol 28 in 3.3% yield as a white foam. The free bases were
converted to HCl salts with 1 N HCl in diethyl ether.
27.2, 26.9, 26.7, 24.2, 22.6, 19.1, 11.2 ppm. Anal. (C54H82N4O2
4HCl 4H2O) C, H, N.
3
3
(rac)-2-(1-Hydroxypropyl)-3-hydroxy-17-N-cyclobutylmethyl-
morphinan (25). Under nitrogen, EtMgBr (2.5 mL, 1.0 M in
MeOtBu) was added slowly by syringe to the solution of
2-formyl-3-hydroxy-17-N-cyclobutylmethylmorphinan 12 (84
mg, 0.25 mmol) in THF (10 mL) at -78 °C. The mixture was
warmed to room temperature slowly and stirred overnight. The
reaction was quenched with saturated NH4Cl, and the pH of the
mixture was adjusted to 9-10 with saturated KHCO3 aqueous.
The mixture was extracted with CH2Cl2 (50 mL ꢀ 3). The
combined organic layers were washed with brine and dried over
Na2SO4. The solvent was removed in vacuo and the residue was
purified by silica gel column chromatography, eluting with
CH3OH/CH2Cl2, 1:10, to obtain a white foam (60 mg) in 65%
1
yield. Mp: 113-115 °C. H NMR (base, 300 MHz, CDCl3): δ
6.69 (s, 1H), 6.68 (s, 1H), 4.63 (t, J = 2.7 Hz, 1H), 2.91 (m, 1H),
2.83 (m, 1H), 2.55-2.38 (m, 5H), 2.21 (d, J = 12.0 Hz, 1H),
2.10-1.98 (m, 3H), 1.95-1.50 (m, 9H), 1.42 (m, 1H), 1.34-1.06
(m, 6H), 0.98 (t, J = 7.5 Hz, 3H) ppm. 13C NMR (base, 75 MHz,
CDCl3): δ 154.2, 140.3, 127.5, 126.0, 125.7, 113.2, 60.9, 55.8,
46.0, 43.8, 40.9, 37.1, 36.3, 34.3, 30.4, 28.1, 28.0, 26.7, 26.3, 24.0,
(rac)-1,12-Bis(17-N-cyclobutylmethyl-3-hydroxymorphinan-2-yl)-
dodecane-1,12-diol (26b). Mp (HCl salt): 235-238 °C. 1H NMR
(300 MHz, CDCl3, a drop of CD3OD): δ 6.72 (s, 2H), 6.69 (s,
2H), 4.71 (t, J = 6.9 Hz, 2H), 2.89 (d, J = 18.0 Hz, 2H), 2.86 (m,
2H), 2.58-2.44 (m, 10H), 2.26 (d, J = 8.1 Hz, 2H), 2.10-2.00
(m, 6H), 1.93-1.61 (m, 18H), 1.47 (m, 4H), 1.40-1.20 (m, 24H),
1.08 (t, J = 12.3 Hz, 2H) ppm. 13C NMR (base, 75 MHz,
CDCl3, a drop of CD3OD): δ 153.6, 139.7, 127.4, 126.4, 125.9,
112.6, 74.0, 60.7, 55.4, 45.8, 43.7, 40.6, 37.2, 36.9, 36.2, 33.9,
29.3, 29.2, 28.0, 27.8, 26.5, 26.2, 25.7, 23.7, 21.9, 18.6 ppm. Anal.
(C54H80N2O4 2HCl 3H2O) C, H, N.
23.9, 22.1, 18.8, 10.4 ppm. Anal. (C24H35NO2 0.8H2O) C, H, N.
3
(rac)-1,6-Bis(17-N-cyclobutylmethyl-3-hydroxymorphinan-2-yl)-
hexane-1,6-diol (26a) and (rac)-2-(1-Hydroxypentyl)-3-hydroxy-
17-N-cyclobutylmethylmorphinan (27a). Magnesium turnings
(175 mg, 7.3 mmol) were weighed into a dry flask containing
freshly dried and distilled tetrahydrofuran (10 mL). To the
mixture a solution of 1,4-dibromobutane (473 mg, 2.2 mmol)
in freshly distilled tetrahydrofuran (5 mL) was added dropwise
via syringe. The resulting mixture was heated at reflux for 3 h.
The mixture was cooled to room temperature. Under nitrogen
atmosphere, this Grignard reagent solution was added dropwise
via syringe to a solution of 2-formyl-3-hydroxy-17-N-cyclobu-
tylmethylmorphinan 12 (250 mg, 0.73 mmol) in anhydrous
tetrahydrofuran (20 mL). The resulting mixture was stirred at
room temperature overnight. The mixture was cooled to 0 °C,
and saturated aqueous ammonium chloride solution (50 mL)
was added very slowly. The aqueous layer was extracted with
ethyl acetate (50 mL ꢀ 3). The combined organic layers were
dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by silica gel column chromatography,
eluting with CH3OH/CH2Cl2, 1:20, obtaining 25 mg of (rac)-
1,6-bis(N-cyclobutylmethyl-3-hydroxymorphinan-2-yl)hexane-
1,6-diol 26a in 4.6% yield as a white foam and 40 mg of
(rac)-2-(1-hydroxypentyl)-3-hydroxy-17-N-cyclobutylmethylmor-
phinan 27a in 14% yield. The free bases were converted to HCl
salts with 1 N HCl in diethyl ether obtaining white solids.
(rac)-1,6-Bis(17-N-cyclobutylmethyl-3-hydroxymorphinan-2-yl)-
hexane-1,6-diol (26a). Mp (HCl salt): >250 °C. 1H NMR (300
MHz, CDCl3, a drop of CD3OD): δ 6.67 (s, 4H), 4.70 (m, 2H),
2.87 (d, J = 18.0 Hz, 2H), 2.78 (s, 2H), 2.60-2.50 (m, 8H), 2.37
(d, J = 9.0 Hz, 2H), 2.24 (d, J = 9.0 Hz, 2H), 2.04-1.59 (m,
26H), 1.43-1.12 (m, 14H), 1.10 (m, 2H) ppm. 13C NMR (base,
75 MHz, CDCl3, a drop of CD3OD): δ 153.7, 140.2, 127.9,
126.2, 125.9, 112.9, 74.3, 61.0, 55.4, 45.8, 43.9, 37.3, 37.1, 36.3,
34.4, 28.1, 28.0, 27.9, 26.7, 26.3, 25.6, 23.8, 22.0, 18.7 ppm. Anal.
3
3
(rac)-2-(1-Hydroxyundecyl)-3-hydroxy-17-N-cyclobutylmethyl-
1
morphinan (27b). Mp (HCl salt): 115-118 °C. H NMR (300
MHz, CDCl3, a drop of CD3OD): δ 6.68 (s, 2H), 4.69 (t, J = 5.7
Hz, 1H), 2.90 (d, J = 17.4 Hz, 1H), 2.86 (m, 1H), 2.59-2.40 (m,
4H), 2.22 (d, J = 11.1 Hz, 1H), 2.10-2.00 (m, 3H), 1.95-1.60
(m, 8H), 1.58-1.40 (m, 3H), 1.39-1.18 (m, 22H), 1.06 (t, J =
12.3 Hz, 1H), 0.87 (t, J = 6.3 Hz, 3H) ppm. 13C NMR (base, 75
MHz, CDCl3, a drop of CD3OD): δ 154.1, 139.6, 126.8, 126.5,
125.8, 112.9, 74.6, 60.6, 55.7, 46.0, 43.5, 40.5, 37.4, 37.4, 36.8,
36.1, 33.8, 31.7, 29.5, 29.5, 29.3, 29.2, 28.1, 27.9, 26.5, 26.2, 25.9,
23.7, 22.5, 21.9, 18.6, 14.0 ppm. Anal. (C32H51NO2 HCl)
C, H, N.
3
(rac)-1-(17-N-Cyclobutylmethyl-3-hydroxymorphinan-2-yl)-
undecane-1,11-diol (28). Mp (HCl salt): 143-145 °C. 1H NMR
(300 MHz, CDCl3): δ 6.68 (s, 1H), 6.65 (s, 1H), 4.69 (t, J = 5.4
Hz, 1H), 3.62 (t, J = 6.9 Hz, 2H), 2.87 (d, J = 18.3 Hz, 1H), 2.77
(m, 1H), 2.58-2.30 (m, 5H), 2.21 (d, J = 11.4 Hz, 1H),
2.06-1.94 (m, 3H), 1.90-1.66 (m, 8H), 1.60-1.53 (m, 4H),
1.41-1.07 (m, 20H) ppm. 13C NMR (base, 75 MHz, CDCl3): δ
154.0, 140.4, 127.9, 126.1, 125.9, 113.1, 75.0, 62.9, 61.1, 55.5,
45.9, 44.2, 41.1, 37.4, 37.2, 36.3, 34.5, 32.7, 29.5, 29.4, 29.3, 28.1,
28.0, 26.7, 26.4, 25.9, 25.6, 23.9, 22.1, 18.8 ppm. Anal.
(C32H51NO3 HCl) C, H, N.
3
Hexanedioic Acid Bis(17-N-cyclobutylmethyl-3-hydroxymor-
phinan-2-methyl)amide (29). To a suspension of adipic acid (12.0
mg, 0.08 mmol) in anhydrous methylene chloride (1.0 mL) were
added 2 drops of DMF, followed by dropwise addition of
oxalylchloride (41 mg, 0.03 mL, 0.32 mmol) under N2 atmo-
sphere. The mixture was stirred at room temperature overnight.
The solvent was removed under reduced pressure, and excess
oxalyl chloride was removed under high vacuum. The residual
acid chloride was dissolved in anhydrous methylene chloride
(1.0 mL), and a solution of 2-(aminomethyl)-3-hydroxy-17-
N-(cyclobutylmethyl)morphinan 19 (55 mg, 0.16 mmol) in
(C48H68N2O4 2HCl) C, H, N.
3
(rac)-2-(1-Hydroxypentyl)-3-hydroxy-17-N-cyclobutylmethyl-
1
morphinan (27a). Mp (HCl salt) 180-182 °C. H NMR (300
MHz, CDCl3): δ 6.68 (s, 1H), 6.66 (s, 1H), 4.70 (t, J = 2.7 Hz,

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 417
methylene chloride (1.0 mL) was added. To the mixture was
added triethylamine (65 mg, 0.09 mL, 0.64 mmol). The mixture
was stirred at room temperature overnight. Additional methy-
lene chloride (20 mL) was added, and the organic phase was
washed with NaHCO3 solution. The organic phase was dried
over Na2SO4, and solvent removed under reduced pressure. The
residual oil was purified by silica gel column chromatography,
eluting with CH2Cl2/MeOH/NEt3, 50/50/1, to yield 30 mg
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1
(47%) of a white solid. Mp (HCl salt): 240-245 °C (dec). H
NMR (base, 300 MHz, CDCl3): δ 7.46 (bs, 2H), 6.23-6.84 (m,
4H), 4.16-4.33 (m, 4H), 2.89 (m, 4H), 2.46-2.75 (m, 10H),
2.04-2.24 (m, 12H), 1.40-1.88 (m, 20H), 1.08-1.38 (m, 12H),
1.08 (m, 2H) ppm. 13C NMR (base, 75 MHz, CDCl3): δ 175.0,
154.2, 141.6, 130.0, 127.8, 122.3, 113.9, 60.7, 59.1, 56.2, 45.6,
40.1, 37.2, 36.3, 35.3, 33.9, 29.7, 27.8, 26.6, 26.4, 24.8, 24.6, 22.0,
18.8 ppm. Anal. (C50H70N4O4 2HCl 3H2O) C, H, N.
3
3
To prove unambiguously that only the diamide formed with-
out formation of ester, LC-MS (performed on an Agilent 6210
time-of-flight spectrometer using an ESI source with the LC
being performed on an Agilent 1200 series system with an
autosampler and the mobile phases A (H2O with 0.1% formic
acid) and B (acetonitrile with 0.1% formic acid)) showed the
presence of only one compound, the NMR data of which are in
accordance with the diamide structure. MS (TOF ESI-): m/z
(% rel intens) = 791 ([M - 2H]2-, 100).
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Acknowledgment. This work was supported in part by
NIH Grants R01-DA14251 (J.L.N.) and K05-DA 00360
(J.M.B.) and a research fellowship to M.D. from the
“Deutsche Akademie der Naturforscher Leopoldina”
(Grant BMBF-LPD 9901/8-147). Levorphanol tartrate was
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Supporting Information Available: Results from elemental
analysis. This material is available free of charge via the Internet
at http://pubs.acs.org.
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