Note: Descriptions are shown in the official language in which they were submitted.
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NEW PROCESS FOR THE PREPARATION OF MORPHINANS
Field of the invention
s
The present invention is directed to a new process for the preparation of
14-alkoxyindolomorphinans and 14-alkoxybenzofuranomorphinans.
Background of the invention
io
Opioid antagonists have been indispensable as tools in opioid research. For
example, the
chief criterion for the classification of an agonist effect as being opioid
receptor mediated is
the ability of known opioid antagonists naioxone or naltrexone to reversibly
antagonize this
effect in a competitive fashion. The usefulness of naloxone and naltrexone for
this purpose
is stems from the fact that they are universal opioid antagonists; that is,
they are capable of
antagonizing the agonist effects mediated by multiple opioid receptor types.
In addition to their uses as pharmacological tools, selective, non-peptide
opioid antagonists
have been described as having potential clinical applications in the treatment
of a variety of
zo disorders where endogenous opioids play a modulatory role. These include
for instance
disorders of food intake, shock, constipation, mental disorders, CNS injury,
alcoholism, and
immune function (P.S. Portoghese at al., J. Med. Chem., Vol. 34: 1757-1762,
l991).
Non-peptide, competitive, S-selective opioid antagonists have been found to
have
zs immunosuppressive potency and less toxicity than the presently used
immunosuppressive
compound cyclosporin (EP 45b 833; EP 485 636; EP 614 898; K. Arakawa et al.,
Transplantation, Vol. 53: 951-953, l992; K. Arakawa et al., Transplant Proc.,
Vol. 24:
696-697, 1992; K. Arakawa et al., Transplant Proc., Vol. 25: 738-740, 1993).
Such
immunosuppressive agents can be used after organ transplantation to suppress
the rejection
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of the foreign organ and also in the treatment of autoimmune diseases (e.g.
rheumatoid
arthritis).
In US 5 223 507 and US 5 225 417 the synthesis of 14-O-substituted
indolomorphinans and
s benzofuranomorphinans have been disclosed. According to the process used for
preparing
the compounds claimed and disclosed in US 5 223 507, only a 3,14-dimethoxy
substituted
benzofuranomorphinan was prepared. According to the process used for preparing
compounds claimed and disclosed in US 5 225 417, two 14-O-alkyl substituted
benzofuranomorphinans have been prepared. According to the methods used for
preparing
~ o the compounds of both the two mentioned prior art documents, the 3-hydroxy
group was
protected by a methyl group which is not easily removed without having a loss
in yield.
According to the processes known from the prior art, the variations of the
substituents at
the oxygen in position 14 are very much limited when a 3-hydroxy group is
supposed to be
~ s present in the molecule. It is for instance not possible to prepare
compounds with a
substituent at the oxygen in 14-position, as this position is labile to the
conditions used for
the cleavage of the 3-methoxy group.
Thus, the object of the present invention was to find a new process which
would facilitate
2o the preparation of 14-O-substituted indolomorphinans and
benzofuranomorphinans.
The present patent application discloses a process whereby naloxone,
naltrexone or
oxymorphone is used as the starting material, whereby the 14-alkoxy group is
introduced
after the protection of the oxygen in 3-position with an easily removable
protecting group,
is preferably benzyl, methoxymethyl, ethoxymethyl, trityl or silyl, thereby
providing a process
enabling the synthesis of compounds involving 14-O-substitution.
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Outline of the invention
The present invention is directed to a new process for the preparation of
compounds of the
general formula (I)
s
wherein
R1 represents allyl, cyclopropylmethyl or methyl;
io
R2 represents C 1-C6 alkoxy, C 1-C6 alkenyloxy, C~-C 16 arylalkyloxy wherein
aryl is
C6-C ~ p aryl and alkyloxy is C ~ -C6 alkyloxy, C~-C I 6 arylalkenyloxy
wherein aryl is C6-C 1 p
aryl and alkenyloxy is C 1-C6 alkenyloxy, C 1-C6 alkanoyloxy, C~-C 16
arylalkanoyloxy
wherein aryl is C6-Clp aryl and alkanoyloxy is C1-C6 alkanoyloxy;
R3 represents hydroxy, C 1-C6 alkoxy) C~-C I 6 arylalkyloxy wherein aryl is C6-
C ~ p aryl and
alkyloxy is C ~ -C6 alkyloxy, C ~ -C6 alkenyloxy) C I -C6 alkanoyloxy, C~-C 16
arylalkanoyloxy
wherein the aryl is C6-C 1 p aryl and the alkanoyloxy is C 1-C6 alkanoyloxy,
C2-C ~ p
alkyloxyalkoxy wherein alkyloxy is C ~ -C4 alkyloxy and alkoxy is C 1-C6
alkoxy; and
X represents O, NH or NR4 wherein R4 is C 1-C6 alkoxy, C I -Cb alkenyloxy, C7-
C; 6
arylalkyloxy wherein aryl is C6-C 1 p aryl and alkyloxy is C 1-C6 alkyloxy, C~-
C 16
arylalkenyloxy wherein the aryl is C6-C 1 p aryl and alkenyloxy is C 1-C6
alkenyloxy, C 1-C6
alkanoyloxy, C~-C 16 arylalkanoyloxy wherein aryl is C6-C 1 p aryl and
alkanoyoloxy is
C1-C6 alkanoyloxy.
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The process for the preparation of the compounds of the general formula (I)
comprises the
following steps:
s (i) Naloxone (II), naltrexone (III} or oxymorphone (IIIa) of the formula
(ll): R = allyl
(III): R = cyclopropylmethyl
(111a): R = methyl
HL J
is reacted with phenylhydrazine hydrochloride in the presence of an acid,
preferably
to methanesulfonic acid, sulfuric acid or hydrochloric acid, giving
naloxindole (NLI))
naltrindole (NTI) or oxymorphindole (OMI), PS. Portoghese et al., J. Med.
Chem. Vol. 31:
281-282) l988) of the following formula:
NCR
OH NLI: R = allyl, X = NH
NTI: R = cyclopropylmethyl, X = NH
,,,~~~ , OMI: R = methyl, X = NH
or;
HO O
naloxone (II), naltrexone(III) or oxymorphone is reacted with O-phenyl-
hydroxyl amine
hydrochloride in the presence of an acid, preferably methanesulfonic acid,
sulfuric acid or
2o hydrochloric acid, giving the benzofurane derivatives NLB, naltriben (NTB;
P. S.
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.
Portoghese et al., J. Med. Chem., Vol. 34: 1715-1720, 1991 ) or OMB (US 5 223
507) of
the formula
NLB: R = allyl, X = O
NTB: R = cyclopropylmethyl, X = O
OMB: R = methyl, X = O
s (ii) the 3-hydroxy group is protected by alkylation with benzyl bromide,
methoxymethyl
bromide) ethoxymethyI bromide, trityl chloride or a silylating agent,
preferably dimethyl
isobutyl-silyl chloride, trimethylsilyl chloride, triethylsilyl chloride, t-
butyldimethylsilyl
chloride or tri-i-propylsilyl chloride, in a solvent, preferably N,N-
dimethylformamide,
dichloromethane or tetrahydrofurane, in the presence of a base which may not
be a weak
~ o base, preferably potassium carbonate, potassium hydroxide, sodium hydride,
sodium amide
or diisopropyl ethylamine, giving a compound of the formula (IV)
JiR~
OH
R20
~ s wherein
o~ uo> ,~~,
.,
R1 is allyl, cyclopropylmethyl or methyl;
R2 is benzyl, methoxymethyl, ethoxymethyl, trityl or silyl, preferably
dimethyl isobutyl silyl,
2o trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl;
and
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H(~ ,-
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X is NH, O, N-benzyl, N-methoxymethyl, N-ethoxymethyl, N-trityl or N-silyl,
preferably
dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl
or tri-i-propylsilyl;
(iii) the compound of the formula (IV ) is treated with C 1-C2 dialkyl
sulfates, C t -C~, alkyl
halides, C 1-C6 alkenyl halides, C~-C 16 aralkyl halides wherein the aryl is
C6-C 1 p aryl and
s the alkyl is C 1-C6 alkyl, C7-C 16 arylalkenyl halides wherein the aryl is
C6-C 1 p aryl and the
alkenyl is C2-C6 alkenyl, C2-C6 alkanoyl halides, C~-C ~ 6 arylalkanoyl
halides wherein the
aryl is C6-C ~ p aryl and the alkanoyl is C2-C~, aIkanoyl, in a solvent,
preferably N,N- -
dimethyl formamide or tetrahydrofurane, using a strong base, preferably sodium
hydride,
potassium hydride or sodium amide, giving a compound of the formula (V)
io
R1
o~ ,~o> ~~
R20
wherein
R ~ is allyl or cyclopropylmethyl;
is
R2 is benzyl, methoxymethyl, ethoxymethyl, trityl or silyl, preferably
dimethyl isobutyl silyl,
trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl; and
R3 is C 1-C6 alkyl, C I -C6 alkenyl; C~-C 16 arylalkyl wherein the aryl is C6-
C 1 p aryl and the
zo alkyl is C 1-C6 alkyl; C7-C ~ 6 arylalkenyl wherein the aryl C6-C 1 p aryl
and the alkenyl is C 1-
C6 alkenyl; C 1-C6 alkanoyl, C~-C 16 arylalkanoyl wherein the aryl is C6-C I p
aryl and the
alkyl is C t -C6 alkyl;
X is as defined in the formula (IV) above; and
is
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optionally the following step (iv) whereby
(iv) the compound of the formula (V) wherein X is NH, O, N-benzyl, N-
methoxymethyl, N
ethoxymethyl, N-trityl or silyl, preferably dimethyl isobutyl silyl,
trimethylsilyl, triethylsilyl,
s t-butyldimethylsilyl or tri-i-propylsilyl;
is hydrolized in diluted acids, preferably hydrochloric acid or sulfuric acid,
optionally in the
presence of a solvent, preferably an alcohol, and in particular methanol,
ethanol or n-
propanol, giving a compound of the formula (VI)
~n1
R3
o~ ,~o> ,~~,
HO \O ,,
wherein R ~ , and R3 are as defined above in formula ( V ), and X is NH, O ar
N-benzyl; and
is (v) the compound of the formula (VI) is alkylated or acylated, giving a
compound of the
formula (I).
Detailed description of the invention
2o The invention will now be described in more detail by the following
examples.
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EXAMPLES
Example 1
Synthesis of 17-(CycIopropylmethyl)-6,7-dehydro-4,5a-epoxy-14-hydroxy-3-
s (methoxymethoxy)-6,7-2',3'-benzo[b)furanomorphinan (compound 1).
Sodium hydride (426 mg, 17.7 mmol; obtained from 710 mg of sodium hydride
dispersion
in oil by washings with n-hexane) was added to a solution of naltriben
methanesulfonate
(2.0 g, 3.9 mmol) in 30 ml of anhydrous N,N-dimethyl formamide at 0~ C. The
resulting
i o mixture was stirred at 0~ C for 20 min and then at room temperature for
another 60 min.
After cooling to 0~ C, methoxymethyl bromide (653 pl, 8 mmol) was added and
stirnng was
continued for 15 min at 0~ C and then for additional 120 min at room
temperature. Excess
sodium hydride was destroyed by addition of methanol and H20. The resulting
mixture was
extracted with ethyl acetate (4 x 50 ml), the combined organic layers were
washed with
is H20 (2 x 50 ml) and brine, dried over Na2S04 and evaporated to give an oil
which was
crystallized from MeOH to yield 1.0 g (56%) of compound 1. M. p. l29-130~ C.
~ H-NMR (CDC13): S 7.45 (d, J = 8.3 Hz, I atom. H), 7.37 (d, J = 8.3 Hz, 1
atom. H), 7.25
(m, 1 arom.H), 7.l6 (m, 1 atom.), 6.86 (d, J = 8.3 Hz, 1 atom. H), 6.60 (d, J
= 8.3 Hz, I
2o atom. H), 5.63 (s, H-C(5)), 5.17 and 5.06 (2 d, J = 6.6, 6.6 Hz, OCH20),
3.42 {s, CH30).
Analysis calculated for C2gH29N05. 0.2 MeOH {465.95): C 72.69, H 6.45, N 3.01;
found:
72.58, H 6.28, N 3.00.
zs Example 2
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-14-hydroxy-3-
(methoxymethoxy)-6,7-2',3'-(N-methoxymethylindolo)morphinan (compound 2).
Sodium hydride (492 mg, 20.5 mmol; obtained from 820 mg of 60% dispersion in
oil by
3o washings with n-hexane) was added to a solution of naltrindole
hydrochloride ( 1.5 g, 3.3
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mmol) in 30 m1 of anhydrous N,N-dimethyl formamide at 0~ C. After stirring at
0~ C for 15
min and additional 30 min at room temperature, the mixture was cooled again to
0~ C and
methoxymethyl bromide ( 1.27 g) 10.2 mmol) was added. After stirring at 0~ C
for 30 min,
stirring was continued for another 120 min at room temperature. Methanol and
H20 were
s added to destroy excess of sodium hydride. The mixture was extracted with
ehtyl acetate (3
x 60 ml), the combined organic layers were washed with H20 (2 x 50 ml) and
brine (2 x 50
ml) and evaporated to give a yellowish oil which was purified by column
chromatography
(silica gel, elution with CH2C12/MeOH/conc. NH40H 245:10:1) to afford 500 mg
(30%)
pure compound 2 as a colorless foam.
~o
~H NMR (CDC13): S 7.44 (m, 2 arom. H), 7.20 (m, 1 arom. H), 7.07 (m, 1 arom.
H)) 6.82
(d, J = 8 Hz, 1 arom. H), 6.58 (J = 8 Hz), 5.81 (s, H-C(5)), 5.79 and 5.50 (2
d, J = 10.8,
10.8 Hz, NCH2O) 5.12 and 5.50 (2 d, J = 6.4, 6.4 Hz, OCH20), 3.41 and 3.33 (2
s,
CH30).
Analysis calculated for C3pH34N205 (502.61): C 7l.69, H 6.82, N 5.57; found: C
71.92, H
6.94, N 5.34.
Example 3
zo Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-14-(2',6'-
dichlorobenzyloxy)-4,5a
epoxy-3-(methoxymethoxy)-6,7-2',3'-benzo[b]furanomorphinan (compound 3).
Sodium hydride (36 mg, 1.5 mmol; obtained from 60 mg of 60% sodium hydride
dispersion
in oil by washings with n-hexane) was added to a solution of compound 1 (300
mg, 0.65
zs mmol) in 8 ml of anhydrous N,N-dimethylformamide at 0~ C. After stirring at
0~ C for 15
min, stirring was continued for another 30 min at room temperature and the
mixture was
cooled again to 0~ C. 2,6-Dichlorobenzyl bromide (240 g, 1 mmol) was added at
once and
stirring was continued for 15 min at 0~ C and then for 3 h at room
temperature. Excess
sodium hydride was destroyed with MeOH and H20 and the mixture was extracted
with
so ethyl acetate (3 x 30 ml). The combined organic layers were-washed with H20
(2 x 30 ml)
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and brine (2 x 30 ml), dried over Na2S04 and evaporated. The residue (400 mg
colorless
oil) was crystallized from MeOH to yield 300 mg (75%) of compound 3. M. p. l80-
182~ C.
1H NMR (CDC13): 8 7.41 (d, J = 8.3 Hz, 1 atom. H), 7.33 (d, J = 8.3 Hz, 1
atom. H), 7.23
s (m, 1 atom. H), 7.14 (m, 2 atom. H), 7.03 and 7.01 (2 d, J = 7.3, 7.3 Hz, 2
atom. H), 6.84
(d, J = 8.3 Hz, 1 atom. H), 6.59 (d, J = 8.3 Hz, 1 atom. H), 5.56 (s, H-C(5)},
5.32 and 4.68
(2 d, J = 8.7, 8.7 Hz, OCH2Ph), 5.16 and 5.05 (2 d, J = 6.6, 6.6 Hz, OCH20),
3.41 (s,
CH30).
~o Example 4
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-14-(2',6'-dichlorobenzyloxy)-
4,5a-
epoxy-3-hydroxy-6,7-2',3'-benzo[b]furanomorphinan (compound 4).
A solution of compound 3 ( 150 mg, 0.24 mmol) in MeOH (4 ml) and 1 N HCl (2
ml) was
i s refluxed for 1 h. After cooling, the solution was alkalized with cone.
NH40H, extracted
wiht ethyl acetate (3 x 15 ml), the combined organic layers were washed with
H20 (2 x 15
ml) and brine ( 10 ml), dried over Na2S04 and evaporated to give an oily
residue which was
crystallized from MeOH to yield 70 mg (51 %) of compound 4. M. p. l93-l95~ C
(dec.}.
1H NMR (CDC13): 8 7.42 (d, J = 8.3 Hz, 1 atom. H), 7.33 (d, J = 8 Hz, 1 atom.
H), 7.24
(m, 1 atom. H), 7.14 (m, 2 atom. H), 7.03 and 7.01 (2 d, J = 7.3 Hz, 1 atom.
H), 6.64 (d, J
= 8.1 Hz, 1 atom. H), 6.56 (d, J = 8.1 Hz, 1 atom. H), 5.58 (s, H-C(5)), 5.32
and 4.68 (2 d,
J = 8.6 Hz, OCH2Ph).
is Analysis calculated for C33H29C12N04 (574.51 ): C 68.79, H 5.09, N 2.44;
found: C 68.97,
HS.OS,N2.44.
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Example 5
Synthesis of 17-(Cyclopropylmethyl) -6,7-dehydro-4,5a-epoxy-3-(methoxymethoxy)-
14-
(3'-nitrobenzyloxy)-6,7-2',3'-benzojb]furanomorphinan (compound 5).
s Sodium hydride {36 mg, 1.5 mmol; obtained from 60 mg of 60~lo sodium hydride
dispersion
in oil by washings with n-hexane) was added to a solution of compound 1 (300
mg, 0.65
mmol) in 6 m1 of anhydrous N,N-dimethylformamide at 0~ C. The resulting
mixture was
stirred at 0~ C for 15 min and then at room temperature for another 30 min.
After cooling to
0~ C, 3-nitrobenzyl bromide (216 mg, 1 mmol) was added and stirring was
continued first
i o at 0~ C for 15 min and then at room temperature for 3 h. Excess sodium
hydride was
destroyed by addition of MeOH and H20. The resulting mixture was extracted
with ethyl
acetate (3 x 30 ml), the combined organic layers were washed with H20 (2 x 20
ml) and
brine (2 x 20 ml), dried over Na2S04 and evaporated to give 380 mg of a brown
oil which
was purified by column chromatography {silica gel, elution with
CH2Cl2/MeOH/conc.
~ s NH40H 240:10:1 ) to afford I00 mg (26% ) of compound 5 as colorless foam.
1H NMR (CDC13): b 8.25 (s, 1 arom. H), 7.99 (m, 1 arom. H), 7.55 (d, J = 7.8
Hz, 1 arom.
H), 7.47 (d) J = 8.3 Hz, 1 arom. H), 7.28 (m, 4 arom. H), 7.15 (m, 1 arom. H),
6.87 (d, J =
8.3 Hz, 1 arom. H), 6.62 (d, J = 8.3 Hz, 1 arom. H), 5.66 (s, H-C(5)), 5.17
and S.07 (2 d, J
20 = 6.6 Hz) OCH20, 4.92 and 4.44 (2 d, J = 11.5 Hz, OCH2Ph), 3.42 (s, CH30).
Example 6
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-(3'-
nitrobenzyloxy)-6,7-2',3'-benzojb]furanomorphinan Hydrochloride (compound 6).
zs
A solution of compound 5 (80 mg, 0.13 mmol) in MeOH (4 ml) and 1N HCl (2 ml)
was
refluxed for 1 h. After cooling, the solution was alkalized with conc. NH40H,
extracted
with ethyl acetate (3 x 20 ml), the combined organic layers were washed with
H20 (2 x 15
ml) and brine (15 ml), dried over Na2S04 and evaporated. The oily residue was
dissolved in
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acetone and transformed into the hydrochloride salt (compound 6) by addition
of ethereal
HCI. Yield 50 mg (66%). M. p. > 230~ C (dec.).
1 H NMR (DMSO-d6): S 9.40 (s, OH), 9.15 (broad s, +NH), 7.84 (s, 1 atom. H),
7.60 (d, J
s = 8.8 Hz, 1 atom. H), 7.53 (d, J = 7.6 Hz, 1 atom. H), 7.45 (d, J = 8 Hz, 1
atom. H), 7.23
(d, J = 7.6 Hz, 1 atom. H), 7.19 (d, J = 7.6 Hz, 1 atom. H), 6.98 (m, 1 atom.
H), 6.88 (d, J
= 7.6 Hz, 1 atom. H), 6.69 (d, J = 8.3 Hz, 1 atom. H), 6.66 (d, J = 8.3 Hz, 1
atom. H), 6.03
(s, H-C(5)), 4.98 and 4.87 (2 d, J = 14, 14 Hz, OCH2Ph).
~ o Analysis calculated for C33H3pN206 x HCl (587.08): C 67.52, H 5.32, N.
4.77; found: C
67.78, H 5.25, N 4. 76.
Example 7
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,Sa-epoxy-3-(methoxymethoxy)-
14-(2-
~ s naphthylmethoxy)-6,7-2',3'-benzo[b]furanomorphinan (compound 7).
Sodium hydride (36 mg, 1.5 mmol; obtained from 60 mg of sodium hydride
dispersion in oil
by washings with n-hexane) was added to a solution of compound 1 (300 mg, 0.65
mmol)
in 5 m1 of anhydrous N,N-dimethylformamide at 0~ C. The resulting mixture was
stirred at
20 0~ C for 15 min and then at room temperature for another 30 min. After
cooling to 0~ C, 2-
(bromomethyl)naphthalene (22l mg) 1 mmol) was added and stirring was continued
at first
at 0~ C for 1 S min and then at room temperature for 2 h. Excess sodium
hydride was
destroyed by addition of MeOH and H20. The resulting mixture was extracted
with ethyl
acetate (3 x 30 ml), the combined organic layers were washed with H20 (2 x 20
ml) and
2s brine (2 x 10 ml), dried over Na2S04 and evaporated to give a crystalline
residue which
was recrystallized to yield 285 mg (73%) of compound 7. M. p. 198-201~ C.
1H NMR (CDC13): 8 7.72-7.08 (m, 11 atom. H), 6.86 (d, J = 8.3 Hz, 1 atom. H),
6.62 (d, J
= 8.3 Hz, 1 atom. H), 5.68 (s, H-C(5)), 5.17 and 5.07 (2 d, J = 6.6, 6.6 Hz,
OCH20), 5.01
so and 4.57 (2 d, J = 11.2) 11.2 Hz, OCH2Ar), 3.42 (s, CH30):
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Analysis calculated for C39H3~N05 x 0.2 EtOAc (C4Hg02~ (617.35): C77.43, H
6.30, N
2.27; found: C 77.40, H 6.27, N 2.27.
s Example 8
Synthesis of 17-(Cyclopropyimethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-(2'-
naphthylmethoxy)-6,7-2',3'-benzo[b]furanomorphinan hydrochloride(compound 8).
A solution of compound 7 ( 180 mg, 0.3 mmol) in MeOH (5 ml) and 1N HCl (3 ml)
was
~ o refluxed for 30 min, cooled and kept in the refrigerator overnight. The
crystals formed were
isolated and washed with small amounts of MeOH and ether to yield 150 mg (84%)
of
compound 8. M. p. > 215~ C.
~ H NMR (DMSO-d6): 8 9.42 (s, OH), 9.00 (broad s, +NH), 7.68-6.85 (m, 11 arom.
H),
is 6.71 (d, J = 8 Hz, 1 arom. H), 6.67 (d, J = 8 Hz, 1 arom. H), 6.04 (s, H-
C(5)), 4.92 (s,
OCH2Ar).
Analysis calculated for C3~H33N04 x HCI. 0.3 MeOH (60l.75): C74.45, H 5.90, N
2.33;
found: C 74.47, H 5.76, N 2.3S.
2o Example 9
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,Sa-epoxy-14-(2'-
fluorobenzyloxy)-3-
(methoxymethoxy)-6,7-2',3'-benzo[b]furanomorphinan (compound 9}.
Sodium hydride (36 mg, 1.5 mmol; obtained from 60 mg of 60% sodium hydride
dispersion
2s in oil by washings with n-hexane) was added to a solution of compound 1
(300 mg, 0.65
mmol) in 5 ml of anhydrous N,N-dimethylformamide at 0~ C. The resulting
mixture was
stirred at 0~ C for 10 min and the at room temperature for another 30 min.
After cooling to
0~ C, 2-flourobenzyl bromide ( 120 ~.1, 1 mmol) was added and stirring was
continued at
first at 0~ C for 15 min and then at room temperature for 2 h. Excess sodium
hydride was
3o destroyed by addition of MeOH and H20. The resulting mixture was extracted
with ethyl
SUBSTITUTE SHEET (RULE 26)
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acetate (3 x 30 ml), the combined organic layers were washed with H20 (2 x 20
ml) and
brine (2 x 20 ml), dried over Na2S04 and evaporated to give an oil which
purified by
column chromatography (silica gel, elution with ethyl acetate/n-hexane 1 ) 1:3
2) 1:1 ) to
afford 215 mg (58%) of compound 9 as colorless foam.
s
io
I H NMR (DMSO-d6): b 7.56 (d, J = 8 Hz, 1 atom. H), 7.49 (d, J = 8 Hz, 1 atom.
H), 7.31
(m, 1 atom. H), 7.21 (m, 1 atom. H), 6.8l (d, J = 8.4 Hz, 1 atom. H), 6.67 (d,
J = 8.4 Hz),
5.72 (s, H-C(5}), 5.06 and 5.01 (2 d, J = 6.4, 6.4 Hz, OCH20), 4.89 and 4.57
(2 d, J =
11.6, 11.6 Hz, OCH2Ph), 3.33 (s, CH30).
Analysis calculated for C35H34NO5 (5b7.66): C 74.06, H 6.04, N 2.47; found: C
73.7l, H
5.92, N 2.42.
Example 10
is Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-14-(2'-
fluorobenzyloxy)-3-
hydroxy-6,7-2',3'-benzo[b)furanomorphinan Hydrochloride (compound 10).
A solution of compound 9 ( 160 mg, 0.28 mmol) in MeOH (3 ml) and 1 N HCI (3
ml) was
refluxed for 20 min, then cooled and kept in the refrigerator overnight. The
crystals formed
zo were isolated and washed with small amounts of MeOH and ether to yield 110
mg (70%) of
compound 10. M. p. > 215~ C.
1 H NMR (CDC13): 8 9.45 (s, OH), 9.04 (broad s, +IVH), 7.54 (d, J = 8.4 Hz, 1
atom. H,
7.31-6.73 (m, 7 atom. H), 6.71 (d, J = 8.2 Hz, 1 atom. H), 6.66 (d, J = 8.2
Hz, 1 atom. H),
zs 5.98 (s, H-C(5)), 4.81 and 4.84 (2 d, J = 12 Hz, OCH2Ph).
Analysis calculated for C33H3pFNO4 x HCI. 1.4 H20 (585.29): C 67.72, H 5.82, N
2.39;
found: C 67.63, H 5.56, N 2.51.
SUBSTITUTE SHEET (RULE 26)
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Example 11
Synthesis of 14-(Cinnamyloxy)-17-(cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-
(methoxymethoxy)-6,7-2',3'-benzo[b]furanomorphinan (compound 11 ).
s Sodium hydride {36 mg, 1.5 mmol; obtained from 60 mg of 60% sodium hydride
dispersion
in oil by washings with n-hexane) was added to a solution of compound 1 (300
mg, 0.65
mmol) in 5 mi of anhydrous N,N-dimethylformamide at 0~ C. The resulting
mixture was
stirred at 0~ C for 15 min and then at room temperature for another 30 min.
After cooling to
0~ C, cinnamyl bromide ( 197 mg, 1 mmol) was added and stirring was continued
first at 0~
i o C for I O min and then at room temperature for 2 h. Excess sodium hydride
was destroyed
by addition of MeOH and H20. The resulting mixture was extracted with ethyl
acetate (3 x
30 ml)> the combined organic layers were washed with H20 (2 x 20 ml) and brine
( I x 20
ml), dried over Na2S04 and evaporated to give a crystalline residue which was
treated with
boiling methanol to afford 200 mg (53%) of compound I I. M. p. I56-159~ C.
~s
zo
1H NMR (CDCl3): 8 7.47 (d, J = 8 Hz, I arom. H), 7.33 (d, J = 8 Hz, 1 arom.
H), 7.28-
7.07 (m, 7 arom. H), 6.84 (d, J, 8.4 Hz, 1 arom. H), 6.59 (d, J = 8.4 Hz, I
arom. H), 6.38
(d, 3 = 16 Hz, I olef. H), 6.13 (m, 1 olef. H), 5.68 (s, H-C(5)), 5.I6 and
5.06 (2 d, J = 6.4,
6.4 Hz) OCH20), 4.46 and 4.11 (2 m, CH20-C( 14)), 3.42 (s, CH30).
Analysis calculated for C3~H3~NOg. 0. I EtOAc (584.52): C 76.85, H 6.52, N
2.40; found:
C 76.70, H 6.48, N 2.41.
Example 12
is Synthesis of 14-(Cinnamyloxy)-17-(cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-
3-
hydroxy-6,7-2',3'-benzo[b]furanomorphinan Salicylate (compound 12).
A solution of compound 11 (160 mg, 0.28 mmol) in MeOH (3 ml) and 1N HCl (3 ml)
was
refluxed for 1 h. After cooling, the solution was alkalized with conc. NH40H,
extracted
3o with ethyl acetate (3 x 15 ml), the combined organic layers were washed
with H20 (2 x 15
SUBSTITUTE SHEET (RULE 26)
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ml) and brine ( 10 ml), dried over Na2S04 and evaporated to give a colorless
foam ( 100
mg). To a solution of this foam in a small amount of methanol 30 mg of
salicyclic acid were
added, the crystals formed collected and washed with cold methanol to yield
100 mg (53%)
~
of compound 12. M. p. > 170 C.
s
1 H NMR (CDCl3): 8 7.94 (d, J = 8 Hz, 1 arom. H), 7.35 (d, J = 8 Hz, 1 arom.
H), 7.30-
6.73 (m, 12 arom. H), 6.56 {d, J = 8 Hz, 1 arom. H), 5.96 (s, 2 olef. H), 5.55
(s, H-C(5)),
4.33-4.02 (m, CH20-C(14)).
io Analysis calculated for C35H33N0~. Salicyclic acid (C~H~03). I MeOH
(701.82): C 73.57,
H 6.18, N 2.00; found: C 73.56, H S.96, N 2.06.
Example 13
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-14-methoxy-3-
is (methoxymethoxy)-6,7-2',3'-benzo[b]furanomorphinan (compound 13).
Sodium hydride (36 mg, 1.5 mmol; obtained from 60 mg of 60% sodium hydride
dispersion
in oil by washings with n-hexane) was added to a solution of compound I (300
mg, 0.65
mmol) in 5 m1 of anhydrous N,N-dimethylformamide at 0~ C. The resulting
mixture was
2o stirred at 0~ C for 15 min and the at room temperature for another 30 min.
After cooling to
0~ C, dimethyl sulfate ( 100 ~.1, 1 mmol) was added and stirring was continued
at first at 0~
C for 15 min and then at room temperature for 2 h. Excess sodium hydride was
destroyed
by addition of MeOH and H20. The resulting mixture was extracted with ethyl
acetate (3 x
30 ml), the combined organic layers were washed with H20 (2 x 20 ml) and brine
(2 x 20
2s ml), dried over Na2S04 and evaporated to give a colorless foam (280 mg) of
compound 13
which was pure by TLC and NMR.
SUBSTITUTE SHEET (RULE 26)
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1H NMR (DMSO-d6): 8 7.56 (d, J = 8 Hz, 1 atom. H), 7.S2 (d, J = 8 Hz, 1 atom.
H), 7.32
(dd, J = 8, 8 Hz, 1 atom. H), 7.23 (dd, J = 8, 8 Hz, I atom. H), 6.79 (d, J =
8.2 Hz, I atom.
H), 6.64 (d, J = 8.2 Hz, 1 atom. H), 5.64 (s, H-C(5)), 5.05 and 5.00 (2 d, J =
6.4, 6.4 Hz,
OCH20), 3.32 (CH30).
s
Analysis calculated for C29H31 N05. 0.2 MeOH (479.98): C 73.07, H 6.68, N
2.92; found:
C 72.94, H 6.60, N 2.92.
Example 14
~o Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-
methoxy-6,7-
2',3'-benzo[b]furanomorphinan Hydrochloride (compound 14).
A solution of compound 13 ( 160 mg, 0.28 mmol) in MeOH (3 ml) and 1 N HCI (2
ml) was
refluxed for 20 min, then cooled and kept in the refrigerator overnight. The
crystals formed
i s were isolated and washed with small amounts of MeOH and ether to yield 70
mg (36%) of
compound 14. M. p. > 240~ C.
I H NMR (DMSO-db): 8 9.47 (s, OH), 9.17 (broad s, ~NH), 7.61 (d, J = 8 Hz, 1
atom. H),
7.53 (d, J = 8 Hz, 1 atom. H), 7.36 (dd, J = 8, 8 Hz, 1 atom. H), 7.27 (dd, J
= 8, 8 Hz, I
2o atom. H), 6.72 (d, J = 8.4 Hz, 1 atom. H), 6.65 (d, J = 8.4 Hz, 1 atom. H),
5.90 (s, H-
C(5)), 3.35 (s, CH30).
Analysis calculated for C2~H2~N04 x HCI. 1.5 HZO (493.00): C 65.78, H 6.34, N
2.84;
found: C 65.89, H 6.20, N 2.85.
SUBSTITUTE SHEET (RULE 26)
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Example 15
Synthesis of 17-(Cyclopropylmethyl)-14-(2'-chlorobenzyloxy}-6,7-dehydro-4,5a-
epoxy-3-
(methoxymethoxy)-6,7-2',3'-(N-methoxymethylindolo)morphinan (compound 15).
s Sodium hydride (36 mg, 1.5 mxnol; obtained from 60 mg of 60% sodium hydride
dispersion
in oil by washings with n-hexane) was added to a solution of compound 2 (327
mg, 0.65
mmol) in 5 m1 of anhydrous N,N-dimethylformamide at 0~ C. The resulting
mixture was
stirred at 0~ C for 1 S min and then at room temperature for another 30 min.
After cooling to
0~ C, 2-chlorobenzyl bromide (205 mg, 1 mmol) was added and stirring was
continued first
i o at 0~ C for 15 min and then at room temperature for 3 h. Excess sodium
hydride was
destroyed by addition of MeOH and H20. The resulting mixture was extracted
with ethyl
acetate (3 x 30 ml), the combined organic layers were washed with H20 (2 x 40
ml) and
brine (2 x 30 ml), dried over Na2S04 and evaporated to give 370 mg of compound
15 as
colorless foam which was pure by TLC and NMR.
is
1H NMR (CDC13): 8 7.56 (m, 1 arom. H), 7.44 (m, 1 arom. H), 7.37-7.17 (m, 3
arom. H),
7.01 (m, 1 arom. H), 6.9l (m, 1 arom. H), 6.83 (d, J = 8.2 Hz, 1 arom. H),
6.59 (d, J = 8.2
Hz, 1 arom. H), 5.90 (s, H-C(5)), 5.82 and 5.55 (2 d, J = 11.2, 11.2 Hz,
NCH20), 5.l3 and
5.03 (2 d, J = 6.4, 6.4 Hz, OCH20), 4.98 and 4.56 (2 d, J = 13, 13 Hz,
OCH2Ph), 3.40 and
zo 3.26 (2 s, 2 CH30).
Example 16
Synthesis of 17-(Cyclopropylmethyl)-14-(2'-chlorobenzyloxy)-6,7-dehydro-4,5a-
epoxy-3-
hydroxy-6,7-2',3'-indolomorphinan Hydrochloride (compound 16).
zs
A solution of compound 15 (300 mg, 0.48 mmol) in MeOH (5 ml) and IN HCl (3 ml)
was
refluxed for 1 h. After cooling, the solution was alkalized with conc. NH40H,
extracted
with ethyl acetate (3 x 20 ml), the combined organic layers were washed with
H20 (2 x 20
ml) and brine (20 ml), dried over Na2S04 and evaporated to give a colorless
oil. To a
so solution of this foam in a small amount of methanol ethereal HCl was added,
the crystals
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19
formed collected and washed with cold methanol to yield l20 mg (43%) of
compound 16.
M. p. > 250~ C (dec.).
1 H NMR (DMSO-d6): 8 11.38 (s, NH), 9.38 (s, OH), 8.76 (broad s, ~NH), 7.34-
6.85 (m, 8
s atom. H), 6.72 (d, J = 8 Hz, 1 atom. H), 6.64 (d, J = 8 Hz, I atom. H), 5.93
(s, H-C(5)),
4.80 and 4.67 (2 d, J = 13, 13 Hz, OCH2Ph).
Analysis calculated for C33H31N2O3 x HCI. (575.S4): C 68.87, H 5.60, N 4.87;
found: C
68.81, H 5.59, H 4.77.
io
Example 17
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-3,14-dimethoxy-4,5a-epoxy-6,7-
2',3'-
benzo[b]furanomorphinan (compound 17).
i s Sodium hydride ( l44 mg, 6 mmol; obtained from 240 mg of 60% sodium
hydride dispersion
in oil by washings with n-hexane) was added to a solution of naltriben methane-
sulfonate
(500 mg, 0.97 mmol) in 10 m1 of anhydrous N,N-dimethylformamide at 0~ C. The
resulting
mixture was stirred at 0~ C for 15 min and then at room temperature for
another 30 min.
After cooling to 0~ C, dimethyl sulfate (380 pl, 4 mmol) was added and
stirring was
2o continued first at 0~ C for 30 min and then at room temperature for 3 h.
Excess sodium
hydride was destroyed by addition of MeOH and H20. The resulting mixture was
extracted
with ethyl acetate (3 x 40 ml), the combined organic layers were washed with
H20 (2 x 30
ml) and brine (2 x 30 ml), dried over Na2SOq and evaporated to give a
crystalline residue
which was recrystallized from MeOH to afford 320 mg (74%) of compound 17. M.
p. 221-
zs 224~ C (dec.).
~H NMR (CDCI3): S 7.47-7.14 (m, 4 atom. H), 6.64 (d, J = 8.4 Hz, 1 atom. H),
6.S9 (d, J
= 8.4 Hz, 1 atom. H), 5.62 (s, H-C(5)), 3.78 (s, CH30-C(3)), 3.31 (s, CH30-C(
14)).
SUBSTITUTE SHEET (RULE 26)
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Analysis calculated for C2gH29N04. 0.3 MeOH (453.16): C 75.01, H 6.72, N 3.09;
found:
C 74.97, H 6.68) N 3.05.
Example 18
s Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-(3'-
chlorobenzyloxy)-6,7-2',3'-benzo[b]furanomorphinan Hydrochloride (compound
19).
To a stirred solution of naltriben methanesulfonate (256 mg, 0.5 mmol) in
anhydrous N,N-
dimethyl formamide ( 10 ml) was added sodium hydride (60% dispersion in oil,
60 mg, 1.5
~ o mmol) at 0~ C. The solution was stirred for 1 h at 20~ C and then cooled
to 0~ C prior to
addition of bromomethyl methyl ether ( 125 mg, 1.0 mmol). The mixture was
warmed up to
room temperature during 1 h and cooled again to 0~ C before sodium hydride
(60%
dispersion in oil, l00 mg, 2.5 mmol) was added. After 1 h, 3-chlorobenzyl
bromide (308
mg, 1.5 mmol) was added to the solution and the resulting mixture was stirred
for 4 h at 20~
~ s C, and then 5 m1 of methanol and 5 ml ethyl acetate were slowly added at
0~ C, followed by
addition of saturated aqueous NH4C1 solution (20 ml). The mixture was
extracted with
ethyl acetate (3 x 50 ml), the combined organic layers were washed with brine,
dried over
MgS04; and evaporated to give crude 17-(cyclopropylmethyl)-6,7-dehydro-4,5a-
epoxy-3-
(methoxymethoxy)-14-(3'-chlorobenzyloxy)-6,7-2', 3'-benzo[b]furanomorphinan
20 (compound 18). This crude product was dissolved in 5 m1 of ethanol and 1.5
ml of 1 N
hydrochloric acid and refluxed for 1 h. The reaction mixture was alkalized
with 1N aqueous
NH40H solution) extracted with ethyl acetate (3 x 50 ml), the combined organic
layers
were washed with brine, dried over MgS04, and concentrated to give a crude
product
which was purified by silica gel column chromatography (hexane: CHCl3
zs (75:25-Q50:50-~25:75~ l00:0) -~CHCI3:AcOEt {80:20-Q50:50--Q0:100) to afford
the title
compound as the free base (colorless oil; 232 mg, 86%). 1 H NMR (CDCl3): 8
7.50-7.05
(m, 8 arom. H), 6.69 (d, J = 8.4 Hz, 1 arom. H), 6.58 (d, J = 8.4 Hz, 1 arom.
H), 5.68 (s,
H-C(5)), 4.81 and 4.35 (2 d, J = 11.6, 11.6 Hz, OCH2(3'-CIPh)). A solution of
this free
base in anhydrous diethyl ether (5 ml) was treated with HCl/ether solution
(1M, 2 ml) at 0~
so C. Isolation of the precipitate provided the title compound 19 as a solid.
M. p. >230~ C
SUBSTITUTE SHEET (RULE 26)
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(dec.). IH NMR (DMSO-d6): 8 9.40 (s, OH), 8.59 (broad s, +NH), 7.53-6.90 (m, 8
atom.
H), 6.65 (s, 2 atom. H) 6.03 (s, H-C(5)), 4.74 and 4.62 (2 d, J = 13.6, l3.6
Hz, OCH2(3'-
C1PH)). Analysis calculated for C33H3pCIN04. HCI. 1.5 H20: C 65.67, H 5.68, N
2.32;
found: C 65.31, H 5.37, N 2.33.
Example 19
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-(2'-
chlorobenzyloxy)-6,7-2',3'-benzo[b]furanomorphinan Hydrochloride (compound
21).
i o To a stirred solution of naltriben methanesulfonate (256 mg, 0.5 mmol) in
anhydrous N,N-
dimethyl formamide ( 10 mI) was added sodium hydride (60% dispersion in oil,
I00 mg, 2.5
mmol) at 0~ C. The solution was stirred for 1 h at 20~ C and then cooled to 0~
C prior to
addition of bromomethyl methyl ether ( 125 mg, 1.0 mmol). The mixture was
warmed up to
room temperature during 1 h and cooled again to 0~ C before sodium hydride
(60%
i s dispersion in oil, 100 mg, 2.5 mmol) was added. After 1 h, 2-chlorobenzyl
bromide (205
mg, 1.0 mmol) was added to the solution and the resulting mixture was stirred
for 12 h at
20~ C, and then 5 m1 of methanol and 5 ml ethyl acetate were slowly added at
0~ C,
followed by addition of saturated aqueous NH4Cl solution (20 ml). The mixture
was
extracted with ethyl acetate (3 x 50 ml)) the combined organic layers were
washed with
2o brine, dried over MgS04, and concentrated to give crude 17-
(cyclopropylmethyl)-'6,7-
dehydro-4,5a-epoxy-3-(methoxymethoxy)-14-(2'-chlorobenzyloxy)-6,7-2', 3'-
benzo[b]furanomorphinan (compound 20). This crude product was dissolved in 5
m1 of
ethanol and 2 m1 of 1 N hydrochloric acid and refluxed for 2 h. The reaction
mixture was
alkalized with 1N aqueous NH40H solution, extracted with ethyl acetate (3 x 50
ml), the
is combined organic layers were washed with brine, dried over MgS04, and
evaporated to
give a crude product which was purified by silica gel column chromatography
(hexane:
CHC13 (75:25-~50:50~25:75--~ 100:0) to afford the title compound as the free
base
(colorless oil; 236 mg, 87%). 1H NMR (CDC13): 8 7.45-6.90 (m, 8 atom. H), 6.72
(d, J =
8.4 Hz, 1 atom. H), 6.68 (d, J = 8.4 Hz, 1 atom. H), 5.72 (s, H-C(5)), 4.96
and 4.55 (2 d, J
so = 11.6, 11.6 Hz, OCH2(2'-CIPh)). A solution of this free base in (5 ml) of
anhydrous
SUBSTITUTE SHEET (RULE 26)
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diethyl ether was treated with HC1/ether solution (1M, 2 ml) at 0~ C.
Isolation of the
precipitate provided the title compound as a solid. M. p. >220~ C.
IH NMR (DMSO-d6): 8 9.40 (s, OH), 8.59 (broad s, +NH), 7.56-6.90 (m, 8 arom.
H), 6.66
s (s, 2 arom. H) 6.03 (s, H-C(5)), 4.74 (s, OCH2(2'-CIPh)).
Analysis calculated for C33H3pC1NOq x HCI. 1.5 H20: C 65.67, H 5.68, N 2.32;
found: C
65.72, H 5.48, N 2.25.
i o Example 20
Synthesis of 14-Allyloxy-17-(cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-
hydroxy-I'-
allyl-6,7-2',3'-indolomorphinan Hydrochloride (compound 22).
Dimethyl isobutylsilyl chloride ( 114 mg, 0.75 mmol) was added at 0~ C to a
stirred solution
~ s of naltrindole methanesulfonate (255 mg, 0.5 mmol) and diisopropyl
ethylamine (260 mg,
2.0 mmol) in anhydrous N,N-dimethyl formamide ( 10 ml). The resulting solution
was stirred
at 20~ C for 1 h and then cooled to 0~ C prior to the addition of sodium
hydride (60%
dispersion in oil, l20 mg, 3.0 mmol). After I h, dimethyl isobutylsilyl
chloride ( 1 I 4 mg,
0.75 mmol) was added to the mixture. The resulting mixture was stirred for I h
at 20~ C
2o and then cooled to 0~ C before adding sodium hydride (60% dispersion in
oil, 120 mg, 3.00
mmol). After 1 h allyl bromide ( 1.51 mg, 1.25 mmol) was added. The reaction
mixture was
stirred for 2 h at 20~ C and then quenched with saturated aqueous NH4Cl
solution and
extracted with ethyl acetate (3 x 30 ml). The combined organic layers were
washed with
brine, dried over MgS04, and evaporated to give a yellow oil which was
dissolved in
2s methanol (6 ml) and 1 N hydrochloric acid (2 ml) and refluxed for 6 h. The
reaction mixture
was alkalized with 1N NH4OH solution, extracted with ethyl acetate (3 x 30
ml), the
combined organic layers were washed with brine, dried over MgS04, and
evaporated. This
crude product was purified by silica gel column chromatography (hexane: CHC13
(75:25-Q50:50) ~CHCI3:AcOEt-~ (75:25-Q50:50--~AcOEt) to give the title
compound as
so the free base (colorless oil; l06 mg).
SUBSTITUTE SHEET (RULE 2fi)
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1H NMR (CDC13): S 7.40 (d, J = 8.4 Hz, 1 arom. H), 7.24 (m, 1 arom. H), 7.15
(m, 1
arom. H), 7.03 (m, 1 arom. H), 6.S7 (d, J = 8.4 Hz, 1 arom. H), 6.50 (d,J =
8.4 Hz, 1 arom.
H), 6.08 (m, 1 olef. H), 5.76 (m, 1 olef. H), 5.72 (s, H-C(S)), 5.15-4.75 (m,
6 H, CH2N, 2
s CH2 = C), 4.24 and 3.92 (2 dd, J = 12.4, 4.8 Hz, CH20).
The free base was dissolved in diethyl ether (S ml) and treated with HCl/ether
solution ( 1M,
2 ml) at 0~ C. Isolation of the precipitate provided the title compound 22 as
a solid.
~ o Example 21
Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,Soc-epoxy-3-hydroxy-I4-
allyloxy-
6,7,2',3'-indolomorphinan Hydrochloride (compound 23)
To a stirred solution of naltrindole hydrochloride (220 mg, 0.5 mmol) in
anhydrous N,N-
i s dimethyl formamide ( 10 ml) was added sodium hydride (60% dispersion in
oil, l60 mg, 4.0
mmol) at 0~C. The solution was stirred for 1 h at 20~ C, and then cooled to 0~
C prior to
addition of bromomethyl methyl ether (2S0 mg, 2.0 mrnol). The mixture was
warmed up to
r.t. during one hour and cooled again to 0~ C before sodium hydride (60%, 100
mg, 2.5
mmol) was added. After 1 h allyl bromide (242 mg, 2.0 mmol) was added to the
solution
zo and the resulting mixture was stirred for 4 h at 20~ C, and then 5 ml
methanol and S ml
ethyl acetate were slowly added at 0~ C, followed by addition of saturated
aqueous NH4C1
solution (20 mI). The mixture was extracted with ethyl acetate (3x50 ml), the
combined
organic layers were washed with brine, dried over MgS04, and evaporated to
give crude
product, which was dissolved in 5 ml ethanol/1 ml 6N hydrochloric acid and
refluxed for 2
is hrs. The reaction mixture was alkalized with 1 N aqueous NH40H solution,
extracted with
ethyl acetate (3.50 ml), the combined organic layers were washed with brine)
dried over
MgS04, and concentrated to give a crude product, which was purified by silica
gel column
chromatography (Hexane: CHC13 {75:2S-Q50:50-Q25:75--Q0:100) ~CHCl3: AcOEt
(75:2S--Q50:50-Q0:100)) to afford compound 23 (S3 mg, 23%) as the free base
(colorless
SUBSTITUTE SHEET (RULE 26)
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24
oil). 1 H NMR (CDC13): 8 7.50-7.00 (m, 4 arom. H), 6.65-6.45 (m, 2 arom. H),
5.80 (m,
1 H, CH=C), 5.75 (s, H-C(5)), 5.18-4.85 (m, C=CH2), 4.25 & 3.95 (m, OCH2).
A solution of this free base (53 mg) in anhydrous ethyl ether (5 ml) was
treated with
s HCl/ether solution ( 1M, 1 ml) at 0~ C. Isolation of the precipitate
provided the title
compound 23 as a solid (hydrochloride salt). M.p. 270-28S~ C (dec.). IR (HCl
salt, KBr)
3087 (m), 2846 (m), 1623 (s), 1505 (s), l462 (s), l330 (s), 1166 (s), 922 (s)
cm 1.
Example 22
io Synthesis of 17-Cyclopropylmethyl-6,7-dehydro-4,5oc-epoxy-3-hydroxy-14-
benzyloxy-
6,7,2',3'-benzo[b]foranomorphinan Hydrochloride (compound 24):
To a stirred solution of naltriben methanesulfonate (256 mg, 0.5 mmol) and N,N-
diisopropylethylamine (260 mg, 2.0 mmol) in anhydrous N,N-dimethyl formamide (
10 ml)
is was added triisopropylsilyl chloride (l45 mg, 0.75 mmol) at 0~C. The
solution was stirred
for 1 h at 20~ C, and then cooled to 0~ C prior to addition of sodium hydride
(60%, 120
mg, 3.0 mmol) was added. After 1 h, benzyl bromide ( 171 mg, 1.0 mmol) was
dropwise
added to the solution. The resulting mixture was stirred for 2 h at 20~ C, and
then 5 m1
methanol and 5 ml ethyl acetate were slowly added at 0~ C. After 30 min the
mixture was
2o extracted with ethyl acetate (3x50 ml). The combined organic layers were
washed with
brine, dried over MgS04, and concentrated to a yellow oil, which was purified
by silica gel
column chromatography {Hexane: CHCl3 (75:25--Q60:40)--Hexane: AcOEt
(75:25-Q50:50)) to afford compound 24 (206 mg, 82%) as the free base
(colorless oil). 1 H
NMR (CDC13): S 7.60-7.05 (m, 9 arom. H), 6.80-6.60 (m, 2 arom. H), 5.72 (s, H-
C(5)),
is 4.95 and 4.52 (2 d, J=11.6) 11.6 Hz, OCH2Ph).
A solution of this free base in anhydrous ethyl ether (5 ml) was treated with
HCl/ether
solution (1M, 1 ml) at 0~ C. Isolation of the precipitate provided the title
compound 24 as a
solid (hydrochloride salt). M.p. 255-270~ C (dec.). IR (HCl salt, KBr) 3642
(m), 3l74 (s),
so 293b {s), 1616 (s), 1500 (s)) 1457 (s), 1309 (s), 1068 (s), 932 (s) cm 1.
Analysis calculated
SUBSTITUTE SHEET (RULE 26)
CA 02269910 1999-04-26
WO 98I22467 PCTlSE96/0149? _
_ 25
for C33H31 N04. HC1. 0.80 H20: C 71.23, H 6.09, N, 2.52. Found: C 71.32; H
5.78, N
2.35.
Example 23
s Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-
allyloxy-
6,7,2',3'-benzo(b]foranomorphinan Hydrochloride (compound 25)
To a stirred solution of naltriben methanesulfonate (256 mg, 0.5 mmol) and N,N-
diisopropylethylamine (260 mg, 2.0 mmol) in anhydrous N,N-dimethyl formamide (
10 ml)
~ o was added triisopropylsilyl chloride ( l45 mg, 0.75 mmol) at 0~C. The
solution was stirred
for 1 h at 20~ C) and then cooled to 0~ C prior to addition of sodium hydride
(60%, 120
mg, 3.0 mmol) was added. After 1 h, allyl bromide (363 mg, 3.0 mmol) was
dropwise added
to the solution. The resulting mixture was stirred for 2 h at 20~ C, and then
5 m1 methanol
and 5 ml ethyl acetate were slowly added at 0~ C. After 30 min the mixture was
extracted
i s with ethyl acetate (3x50 ml). The combined organic layers were washed with
brine, dried
over MgS04, and concentrated to a yellow oil, which was dissolved in MgSOq,
and
concentrated to a yellow oil, which was dissolved in 10 m1 ethanol/2.0 ml 1 N
hydrochloric
acid and refluxed for 5 hrs. The reaction mixture was alkalized with 1 N
aqueous NH40H
solution, extracted with ethyl acetate (3x50 ml). The combined organic layers
were washed
zo with brine) dried over MgSOq., and concentrated to give a crude product,
which was
purified by silica gel column chromatography (Hexane: CHC13 (75:2y50:50)-
~CHCl3:
AcOEt (75:25--Q50:50-~AcOEt)) to afford compound 25 ( 106 mg, 46%) as the free
base
(colorless oil). 1H NMR (CDCl3): 8 7.50-7.08 (m, 4 arom. H), 6.70-6.45 (m, 2
arom. H),
5.75 (m, 1 H, CH=C) 5.65 (s, H-C(5)), 5.18-4.82 (m, 2H), 4.81 (br s, OH), 4.25
and 3.90
2s (m, OCH2).
A solution of this free base in anhydrous ethyl ether (5 ml) was treated with
HCl/ether
solution ( 1M, 1 ml) at 0~ C. Isolation of the precipitate provided the title
compound 25 as a
solid (hydrochloride salt). M.p. 280-290~ C (dec.), IR (HCl salt, KBr) 3642
(m), 2948 (s),
SUBSTITUTE SHEET (RULE 26)
CA 02269910 1999-04-26
WO 98l22467 PCT/SE96/01497 - -
26
1641 (s), l500 (s), 1375 (s), 1315 (s), 996 (s) 920 (s) cm 1. Analysis
calculated for
C29H29N04~ HCI. 1.1 H20: C 68.05, H 6.34, N, 2.74. Found: C 67.94, H 5.95, N
2.S3.
Example 24
s Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-
crotyloxy-
6,7,2',3'-benzo[b]foranomorphinan Hydrochloride (compound 26)
To a stirred solution of naltriben methanesulfonate (256 mg, 0.5 mmol) and N,N-
diisopropylethylamine (260 mg, 2.0 mmol) in anhydrous N,N-dimethyl formamide (
10 ml)
io was added triisopropylsilyl chloride (145 mg, 0.75 mmol) at 0~C. The
solution was stirred
for 1 h at 20~ C, and then cooled to 0~ C prior to addition of sodium hydride
{60%, l20
mg, 3.0 mmol} was added. After 1 h, crotyl bromide (405 mg, 3.0 mmol) was
dropwise
added to the solution. The resulting mixture was stirred for 2 h at 20~ C, and
then 5 ml
methanol and 5 m1 ethyl acetate were slowly added at 0~ C. After 30 min the
mixture was
i 5 extracted with ethyl acetate (3x50 ml). The combined organic layers were
washed with
brine, dried over MgS04, and concentrated to a yellow oil, which was dissolved
in 10 m1
ethanol/2 ml 1 N hydrochloric acid and refluxed for 5 hrs. The reaction
mixture was
alkalized with 1 N aqueous NH40H solution, extracted with ethyl acetate (3x50
ml). The
combined organic layers were washed with brine, dried over MgS04, and
concentrated to
2o give a crude product, which was purified by silica gel column
chromatography (Hexane:
CHCl3 (75:25~50:50)~CHC13: AcOEt (75:2y50:50-~AcOEt)) to afford compound 26
(45 mg, 19%) as the free base (colorless oil). 1 H NMR (CDCl3): 8 7.48-7.08
(m, 4 arom.
H), 6.66-6.48 (m, 2 arom. H), 5.62 (s, H-C{5)), 5.40 (m, 2H, CH=CH), 4.20 and
3.82 (m,
OCH2), 1.48 & 1.52 (m, 3H, Me).
A solution of the free base in anhydrous ethyl ether (5 ml) was treated with
HCl/ether
solution (1M, 1 ml) at 0~ C. Isolation of the precipitate provided the title
compound 26 as a
~
solid in form of its hydrochloride salt. Mp. 245-260 C (dec.). IR (Hcl salt,
Kbr): 3642 {m),
3024 (s), l640 (s), l503 (s), 1325 (s), 927 (s) cm 1.
3a
SUBSTITUTE SHEET (RULE 26)
