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N-Demethylation of Morphine and Structurally Related Compounds With Chloroformate Esters - Journal of Medicinal Chemistry, 1972, 15(2), 208 - DOI: 10.1021/jm00272a025

N-Demethylation of Morphine and Structurally Related Compounds With Chloroformate Esters - Journal of Medicinal Chemistry, 1972, 15(2), 208 - DOI: 10.1021/jm00272a025

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Article title: N-Demethylation of Morphine and Structurally Related Compounds With Chloroformate Esters
Journal of Medicinal Chemistry, 1972, 15(2), 208
J. Med. Chem. 15(2), 208 (1972)
J Med Chem 15 (1972) 208
DOI: 10.1021/jm00272a025

structure-activity relationships, SARs, analgetics, acetylfentanyl, 3-methylfentanyl, 3MF, TMF, AMF, alphamethylfentanyl, Ohmefentanyl, beta-hydroxy, alpha-methyl, Mefentanyl, 4-methoxymethylcarbonyl, 4-methoxycarbonyl, 4-substituted piperidines, 4,4-disubstituted piperidines, 4-piperidines, 4-substituted, 4,4-disubstituted, fentanil, phentanyl, phentanil, N-phenylethyl-4-piperidones, piperid-4-ones, N-phenylethyl-4-piperidinones, piperidin-4-ones, NPP, ANPP, Sigfreid Sigfried fentanyl opioid opiate synthesis, mu u delta d Kappa K opioid receptor, opiate alkaloid, poppy alkaloids, subutex, suboxone, reducing agents, LiAlH4, lithium aluminum hydride, sodium borohydride, platinum oxide, catalytic hydrogenation, N-debenzylation, morphine-like, Paul A.J. PAJ Adrian Jan Janssen, Pharmaceuticals, pharma, Pharmacy, pharmacology, pharamcokinetics, P. Papaver somniferum, dipipanone, phenadoxone, 4-phenylpiperidines, organic synthesis, novel organic synthesis, 4-anilinopiperidine 4-propionanilinopiperidine 4-anilidopiperidine 4-propionanilidopiperidine chemistry, piperidine nitrogen chemistry, organic heterocyclic nitrogen compounds, opioid chemistry, opioid synthesis, chemical syntheses, pseudoephedrine, ephedra, phenylacetone, phenyl-2-propanone, P2P, methylamine, MDMA, MDA, methamphetamine amphetamine synthesis manufacture precursors, saffrole oil, methylenedioxymethamphetamne, ecstasy, x, XTC, ADAM, EVE, Alexander T. Shulgin, PiHKAL: A Chemical Love Story, TiHKAL, 2-CE, 2-CB, 2-CI, 2CE 2CI 2CB, PEA, phenylethylamines, psychoactive drugs, psychedelic, psychogenic, psychotropic, phenethylamines, Sympathomimetic amines, dopaminergic, serotonin, norepinephrine, noradrenaline, adrenaline, dopamine, catecholamines, central sympathetic parasympathetic nervous system, sympatholytics, parasympatholytics, anxiolytics, diuresis, diuretics, methyltestosterone, 5-alpha-reductase inhibitor, testosterone, dihydrotestosterone, PDE5, viagra, cialis, levitra, Sildenafil citrate, tadalafil, vardenafil, cGMP-specific phosphodiesterase type 5, BPH, benign prostate hyperplasia, avodart, Dutasteride CNS, SSRI, antidepressants, prozac, paxil, Zoloft, venlafaxine, fluoxetine, fluvoxamine, SNRI, Bupropion, Wellbutrin, Zyban, oxirane, MOR, DOR, KOR, naloxone, naltrexone, DXM, dextromethorphan, levorphanol, dextropropoxyphene, dextromoramide, phenacyl, arylmorphan, azabicyclo, azaprocin mixed partial agonist antagonist, binding affinity, EC50 ED50 IC50, concentration molarity osmolarity, molecules, molecular biology, biochemistry, drug substance abuse addiction potential dependency tolerance modulation, science, physics, levomethorphan, Alvimopan, Loperamide, Picenadol, oxycodone, oxycontin, hydromorphone, hydrocodone, darvocet, pethidine, meperidine, demerol, darvon, 6,7-benzomorphans, benzodiazepines, flunitrazepam, xanax, klonopin, clonazepam, alprazolam, diazepam, anticonvulsant, antidiuretic, diabetes, insulin, genetic engineering, formulations, tramadol, ultram, viminol, bromedol, Daniel Lednicer, Philip F. VonVoightlander, A.F. Casy, Parfitt, Opioid Analgesics: Chemistry and Receptors, narcotics, PCP, oxycodone, oxycontin, hydromorphone, hydrocodone, darvocet, pethidine, meperidine, demerol, darvon, Codeine-N-Oxide (Genocodeine) Dihydromorphine-6-glucuronide Hydromorphone-N-Oxide Heroin-7,8-Oxide Morphine-6-glucuronide, 6-Acetylmorphine Morphine-N-Oxide (Genomorphine) Naltrexol Norcodeine Normorphine, NSAIDs, tylenol, ibuprofen, controlled substance schedule I II III IV V 1 2 3 4 5, COX COX-2 COX-1 COX1 COX2 inhibitors, antipsychotic, DEA, DMT, DIPT, DBT, DET, harmine, dimethyltryptamine, DPT, LSD, Lysergic acid diethylamide, Albert Hofmann, UV-Vis, Raman IR infrared spectroscopy, organic microwave synthesis chemistry, e
Article title: N-Demethylation of Morphine and Structurally Related Compounds With Chloroformate Esters
Journal of Medicinal Chemistry, 1972, 15(2), 208
J. Med. Chem. 15(2), 208 (1972)
J Med Chem 15 (1972) 208
DOI: 10.1021/jm00272a025

structure-activity relationships, SARs, analgetics, acetylfentanyl, 3-methylfentanyl, 3MF, TMF, AMF, alphamethylfentanyl, Ohmefentanyl, beta-hydroxy, alpha-methyl, Mefentanyl, 4-methoxymethylcarbonyl, 4-methoxycarbonyl, 4-substituted piperidines, 4,4-disubstituted piperidines, 4-piperidines, 4-substituted, 4,4-disubstituted, fentanil, phentanyl, phentanil, N-phenylethyl-4-piperidones, piperid-4-ones, N-phenylethyl-4-piperidinones, piperidin-4-ones, NPP, ANPP, Sigfreid Sigfried fentanyl opioid opiate synthesis, mu u delta d Kappa K opioid receptor, opiate alkaloid, poppy alkaloids, subutex, suboxone, reducing agents, LiAlH4, lithium aluminum hydride, sodium borohydride, platinum oxide, catalytic hydrogenation, N-debenzylation, morphine-like, Paul A.J. PAJ Adrian Jan Janssen, Pharmaceuticals, pharma, Pharmacy, pharmacology, pharamcokinetics, P. Papaver somniferum, dipipanone, phenadoxone, 4-phenylpiperidines, organic synthesis, novel organic synthesis, 4-anilinopiperidine 4-propionanilinopiperidine 4-anilidopiperidine 4-propionanilidopiperidine chemistry, piperidine nitrogen chemistry, organic heterocyclic nitrogen compounds, opioid chemistry, opioid synthesis, chemical syntheses, pseudoephedrine, ephedra, phenylacetone, phenyl-2-propanone, P2P, methylamine, MDMA, MDA, methamphetamine amphetamine synthesis manufacture precursors, saffrole oil, methylenedioxymethamphetamne, ecstasy, x, XTC, ADAM, EVE, Alexander T. Shulgin, PiHKAL: A Chemical Love Story, TiHKAL, 2-CE, 2-CB, 2-CI, 2CE 2CI 2CB, PEA, phenylethylamines, psychoactive drugs, psychedelic, psychogenic, psychotropic, phenethylamines, Sympathomimetic amines, dopaminergic, serotonin, norepinephrine, noradrenaline, adrenaline, dopamine, catecholamines, central sympathetic parasympathetic nervous system, sympatholytics, parasympatholytics, anxiolytics, diuresis, diuretics, methyltestosterone, 5-alpha-reductase inhibitor, testosterone, dihydrotestosterone, PDE5, viagra, cialis, levitra, Sildenafil citrate, tadalafil, vardenafil, cGMP-specific phosphodiesterase type 5, BPH, benign prostate hyperplasia, avodart, Dutasteride CNS, SSRI, antidepressants, prozac, paxil, Zoloft, venlafaxine, fluoxetine, fluvoxamine, SNRI, Bupropion, Wellbutrin, Zyban, oxirane, MOR, DOR, KOR, naloxone, naltrexone, DXM, dextromethorphan, levorphanol, dextropropoxyphene, dextromoramide, phenacyl, arylmorphan, azabicyclo, azaprocin mixed partial agonist antagonist, binding affinity, EC50 ED50 IC50, concentration molarity osmolarity, molecules, molecular biology, biochemistry, drug substance abuse addiction potential dependency tolerance modulation, science, physics, levomethorphan, Alvimopan, Loperamide, Picenadol, oxycodone, oxycontin, hydromorphone, hydrocodone, darvocet, pethidine, meperidine, demerol, darvon, 6,7-benzomorphans, benzodiazepines, flunitrazepam, xanax, klonopin, clonazepam, alprazolam, diazepam, anticonvulsant, antidiuretic, diabetes, insulin, genetic engineering, formulations, tramadol, ultram, viminol, bromedol, Daniel Lednicer, Philip F. VonVoightlander, A.F. Casy, Parfitt, Opioid Analgesics: Chemistry and Receptors, narcotics, PCP, oxycodone, oxycontin, hydromorphone, hydrocodone, darvocet, pethidine, meperidine, demerol, darvon, Codeine-N-Oxide (Genocodeine) Dihydromorphine-6-glucuronide Hydromorphone-N-Oxide Heroin-7,8-Oxide Morphine-6-glucuronide, 6-Acetylmorphine Morphine-N-Oxide (Genomorphine) Naltrexol Norcodeine Normorphine, NSAIDs, tylenol, ibuprofen, controlled substance schedule I II III IV V 1 2 3 4 5, COX COX-2 COX-1 COX1 COX2 inhibitors, antipsychotic, DEA, DMT, DIPT, DBT, DET, harmine, dimethyltryptamine, DPT, LSD, Lysergic acid diethylamide, Albert Hofmann, UV-Vis, Raman IR infrared spectroscopy, organic microwave synthesis chemistry, e

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208
Journal
of
Medicinal Chemistry, 19
72,
Vol.
IS,
No.
2
Notes
?HIA
IB
ICIIA IIB IIC
Ar
=
3,6-Bis(trifluoromethyl)-9-phenanthryl
coupling constants observed in DMSO for the free bases andtheir protonated forms. Evidently, on protonation, the bulkof the solvated quaternary N in I
.
HCl is significantly in-creased by
H
bonding with DMSO. This would enhance thepopulation of IA at the expense of IB and IC. Similarly,protonation
of
I1 should increase the population of IIA witha concomitant decrease in IIB, due to the increased steric re-quirements of the solvated ammonium group.
a-(2-piperidyl)-3,6-bis(trifluoromethyl)-9-phenanthrene-
methanol were tested12 for antimalarial activity as theirHCl and TsOH salts and as their oxazolopyridine derivativesagainst Plasmodium berghei in mice and
P.
allinaceum inchicks by Dr. Leo Rane at the University of Miami. Thetest results, furnished to us through the Walter Reed ArmyInstitute of Research, show these materials to be highlyactive against
P.
berghei, giving
5
cures out of
5
nfectedmice at dosages of
40
mg/kg for the threo epimers and
5
cures at
80
mg/kg for the erythro compds.§
No
toxic deathswere reported up
to
dosages of
640
mg/kg. Against
P.
gal-Zinaceum, the minimum dosage showing activity was
20
and
160
mg/kg for the threo and erythro compds, respectively.To attempt
a
general correlation of epimer conformationwith antimalarial activity on the above limited data is pre-mature.Biological Data. The dl-erythro and dl-threo isomers ofExperimental Section#
dl-erythro-ol-(2-Piperidyl)-3,6-bis(trifluoromethyl)-9-phenan-
threnemethanol Hydrochloride (I HCI). H, was passed through amixt of
115
g
(0.275
mole) of
2-pyridyl3,6-bis(trifluoromethyl)-9-
phenanthryl ketone,
5.0
g of PtO, (Engelhard
85%), 4.2
1. of MeOH,and
40
ml of concd HCl for
16
hr. Darco was added and, after fil-tration, the filtrate was evapd
in
vacuo
to
10%
the original vol, pptga mass of white crystals. The solids were dissolved in MeOH (Darco)and again concd to
10%
he original vol to give
96.0 (82.3%)
ofI .HCl, mp
331-332"
dec.
Anal.
(C,,H,$JOF,. HC1) C, H, C1, N.methanol Hydrochloride
(I1
HCI). The mother liquors from theabove recryst were concd to dryness, treated with dil K,CO,
soln,
and dried. The mixt of I and 11
(15.0
,
35
mmoles)
in
200
ml ofMeOH was treated with
4.9 (25
mmobs) of TsOH
.
H,O, refluxed
dl-t
hreo-or-(2-Piperidyl)-3,6-bis(~uorome~yl)-9-ph~n~~ene-
§The synthesis
and
activity
of
I
'
HC1has
been previously reported
by
Nodiff,
et
al.'
#All
melting point (uncorr)
were
taken
01%
Buchi
apparatus.
In-
struments employed were: Beckman
IR-9
nfiared spectrophotom-
eter.
Varian Model
DP-60
igh-resolution nmr spectrophotometer
and
Beckman
DK-2
v
spectrophotometer. Elemental anal. werecorrect
(*0.3%)
and
were
performed
by
Galbraith Laboratories, Inc.,Knoxville,
Tenn.
for
5
min, and cooled to ppt I1
.
TsOH. Recrystn
(2x,
MeOH, Darco)gave an analytical material, mp
269-270".
nal.
(C,,H,,NO,F,S)C, H, N,
F.
I1
'
TsOH
(50
,
0.1
mole) was neutralized by stirring overnightwith
dil
aq NaOH
soh.
I1 was dissolved in anhyd Et,O and satdwith HCl
gas
to ppt 11. HCl. Refluxing with CCl, removed a yellowimpurity to leave 11. HC1 as a white powder, mp
284-285" (44.2
,
95%).
Anal.
(C,,H,,NOF,. HCl)
C,
H, N, C1.
I-
3,6-Bis(trifluoromethyl)-9-phenan~l]
exahydro-3H-o~-
azolo[3,46
pyridine. 111. A mixt
of
4.9
(1 1
mmoles) of I,
2
ml of(CH,O),
soln,
and
50
ml of MeOH was refluxed
8
r. Add1 (C%O),soh
(2
ml) was added, the reflux was contd overnight. The mixt wascooled and filtered, and the product was recrystd (EtOH, Darco) togive
3.0 (63%)
of I11 as white flakes, mp
167-168'.
Anal.
(C,J-L.NOF,) C, H,
N.
-
_I
IV. A scmilar reaction
of
I1 gave
4.5
g of crude product. Thesolid was dissolved in CHCl,, poured onto a silica gel H column
(75
g), and eluted with CHCl,. Recrystn (MeOH-H,O) gave
4.0 (84%)
of IV as a white powder, mp
181-182'.
Anal.
(C,,H,JVOF,) C, H, N.
Putnam for the nmr spectra.Acknowledgment. The author wishes to thank RoyReferences
(1)
D.
W.
Boykin, A. R. Patel,
R.
E. Lutz, and
A.
Burger,
J.
Hetero-cycl. Chem.,
4,459 (1967).(2)
A.
D.
Ainley and H. King,
Proc.
Roy.
Soc., Ser. B,
125,60(1938);
.
F.
Brown,
et al.,
J.
Amer. Chem. Soc.,
68, 2705(1946);
.
R.
uchman and
D.
R. Howton,
ibid.,
68,2718(1946);
. R. Buchman, H. Sargent, T. C. Meyers, and
D.
R.Howton,
ibid.,
68,2710 (1946);
E.
R. Buchman, H. Sargent,
T.
C. Meyers, and
J.
A. Seneker,
ibid.,
68,2697 (1946);
.
B.Koepfli, M.
M.
Rapport, A.
E.
Senear, and
J.
F.
Mead,
ibid.,
68,2697 (1946);
R.
. Lutz,
et
al.,
ibid.,
68, 813 (1946);
J.
F.
Mead, A.
E.
Senear, and
J.
B. Koepfli,
ibid.,
68,2708(1946);
.
A. Seibert, T. R. Norton, A. A. Benson, and
F.
W.
Bergstrom,
ibid.,
68,2721 (1946);
A.
E.
enear, H. Sargent,J.
F.
Mead, and J. B. Koepfli,
ibid.,
68, 2605 (1946);
.
Win-stein, T. L. Jacobs, E. F. Levy,
D.
Seymour,
G.
B. Linden, and
R.
B. Henderson,
ibid.,
68, 27 14 (1946).(3)
H. Sargent,
ibid.,
68,2688 (1946).(4)
F.
Y.
Wiselogle, "A Survey of Antimalarial Drugs,
1941-1945,"
.
W.
Edwards, Ann Arbor, Mich.,
1946.
(5)
E.
A. Nodiff, K. Tanabe, C. Seyfried,
S.
Matsuura,
Y.
Kondo,E. H. Chen, and
M.
P. Tyagi,
J. Med. Chem.,
14,921 (1971).(6)
T.
A. Crabb and R. F. Newton,
J. Heterocycl. Chem.,
3,418(1966).
(7)
A.
Dudas and
I.
Weisz,
Chem. Ber.,
94,412 (1960).(8)
. Kovar, J. Jay, andK.Blaha,
Collect. Czech. Chem. Com-
(9)
P.
S.
Portoghese,
J.
Med. Chem.,
10,
1057 (1967).
mun.,
28,2199 (1963).(10)
M.
E.
Munk,
M.
K. Meilahn, andP.Franklin,
J.
Org. Chem.,
33,3480 1968).
(11)
0.
. Chapman and R.
W.
King,
J. Amer. Chem. Soc.,
86,1256 (1964).(12)
T.
S.
Osdene, P. B. Russell, and L. Rane,
J. Med. Chem.,
10,
431 (1967).
N-Demethylation
of
Morphine and StructurallyRelated Compounds with Chloroformate Esterst
M.
M.
Abdel-Monem
and
P.
S.
Portoghese*
Department
of
Medicinal Chemistry, College
of
Pharmacy, University
of
Minnesota, Minneapolis, Minnesota
55455.
Received August
5,
I971
Hundreds
of
modifications of morphine and structurallyrelated compounds have been performed and the com-pounds tested in an effort
to
analyze the relationship be-tween structure and analgetic activity.ly2The most commonof these modifications is replacement
of
the Me groupattached
to
the basic
N
with some other substituent. Thus,
?This investigation was supported
by
NIH
Grant
NS
08738.
 
Notes
Journal of
Medicinal Chemistry,
1972,
Vol.
15,
No.
2
209
the secondary amine serves as an important intermediate inthe synthesis of such compounds. Although there are sev-eral methods reported"' for the demethylation of tertiaryamines, they suffer from the disadvantage of the toxicityof reagents employed and/or the low yields of demethyl-ated product.One approach to this problem which seemed worthwhileexploring involved demethylation of analgetics with achloroformate ester' followed by hydrolysis of the resultingcarbamate to the secondary amine as outlined below.Cleavage of tertiary amines with chloroformate esterswas first reported in 191
1.8
Gadamer and Knoch' studiedthe effect of ethyl chloroformate on a variety of cyclictertiary amines and observed that bulbocapnine, corydine,and laudanosine were converted to the corresponding ethylcarbamates, whereas compounds such as morphine, codeine,heroin, and tropine were not cleaved. Several examples ofthis reaction have been published since,'@l3 and in this re-gard, phenyl chloroformate was found to be superior toboth benzyl and ethyl chloroformate in the cleavage oftertiary amines.14 We wish to describe the utilization ofthis reaction as a means of conveniently demethylating, in
high
yield, structures related to morphine.the presence of KHC03 in boiling CHC13 and subsequenttreatment of the product
with
a mild base afforded, afterpurification, a nonbasic crystalline material which wasassigned structure
2,
based on its spectral properties. Thisassignment was confirmed further by
LAH
reduction of
2
to morphine and by its hydrolytic conversion to nor-morphine
(3)
with KOH. It is noteworthy that the reactionof morphine with phenyl chloroformate was unsuccessfulin the absence of base, possibly because esterification of the
3-
or 6-OH generates HCl which may protonate the basic
N
and hence diminish its reactivity.Codeine
(4)
was demethylated with ethyl chloroformatein a two-phase system containing aq KOH and CHC13. Thespectral characteristics of the neutral intermediate appearto be in harmony with
5.
The ethyl carbonate group of
5
could be hydrolyzed selectively to
6
which then was cleavedto norcodeine
(7)
under more vigorous conditions.Treatment of morphine
(1)
with phenyl chloroformate in
Ron
oR
1,
R
=
R'
=
H; R"
=
Me
2,
R
=
R'
=
H; R"
=
COOPh
3,
R=R'=R"=H
10.
R=Me:R'=H
8,
R
=
R'
=Me
9,
R
=
Me; R'
=
COOPh
4;
R=Me;R' =H;
R"
=Me
5,
R
=
Me;
R'
=
R"
=
COOEt
6,
R
=
Me; R'
=
H; R"
=
COOEt
7,
R
=
Me; R'
=
R"
=
H
Reaction of
3-methoxy-N-methylmorphinan
8)
withphenyl chloroformate at room temp afforded carbamateester
9.
The carbamate was obtained in crystalline form byselectively hydrolyzing the phenyl chloroformate contami-nant with aq K2C03. Structure
9
was corroborated by itsreconversion
to
8
with LAH. Hydrolysis
of
9
with
KOH
gave the desired secondary amine
(10).
Demethylation of
8
also was carried out with ethyl chloroformate. Hydrolysis
11;
R
=
Me: R'= COOEt
12,
R
=
R'
=
H
of this product
(1
1)
with HBr-HOAc afforded 3-hydroxy-morphinan
(12).
It is noteworthy that the present procedure also can beemployed as a convenient and relatively inexpensive methodfor introducing radioactivity into a N-Me group. Thus,[3H]LAH reduction of the carbamate intermediate ob-tained from the demethylation step would afford a 3H-labeled Me group.$ A 14C label may be incorporated by de-methylating with
[
'C]C1COOR followed by red~ction.'~Experimental Section!
N-Carbophenoxynormorphine
2).
A stirred suspension of 2.5g
(0.0088
mole) of morphine
(1)
and 15 g (0.15 mole) of KHCO,in CHCI, (250 ml) was treated with 11.5 g (0.077 mole) of phenylchloroformate and refluxed for 60
hr.
The mixt was treated withH,O (100 ml) and the CHCI, phase was sepd and concd
in
vacuo.The residue was dissolved in MeOH (150 ml), treated with an aqsoln (100 ml) contg 5.6 g of KOH and 10.0 g of KHCO,
,
and stirredunder N, for 24 hr. After the mixt was acidified
with
concd HCl, theMeOH was removed and the residue was dild
with
H,O and extd(Et,O). The Et,O was removed and the oily residue was chromatogdon a column of 45 g of silica gel (E. Merck AG, 70-325 mesh) andeluted with Et,O. Fractions 6-12
(50
ml each) were pooled, and thesolvent was removed
in
vacuo to afford 3.12 g of
2:
mp 127-130'(yield 91%); mass spec (70 eV)
m/e
391.
Anal.
(C,,H,,NO,) C, H, N.
LAH
Reduction
of
Carbophenoxynormorphe
(2).
A THF
soln
(50
ml) contgO.8 g (0.002 mole) of
2
was added slowly
to
a cooled,stirred suspension of LAH (0.2 g)
in
THF (150 ml). The mixt wasrefluxed under N, for 20
hr,
cooled, treated with EtOAc (15 ml),and refluxed for 30 min. The mixt was treated with 2
N
HCl(50ml) and sodium potassium tartrate (6 g) and refluxed for 4
hr.
Thiswas concd in vacuo to remove THF and extd with Et,O. The acidphase was adjusted to pH 8.5 and extd with a mixt of CHC1,-i-PrOH
(3:l).
The exts were concd in vacuo, and the residue was crystd from
50
ml of MeOH-H,O (1:4) to afford 0.45 g of morphine: mp 252-254" (reported 254-256")16 (yield 76%).Normorphine
(3).
A
soln
of
0.4
g (0.001 mole) of
2
in
a mixtof EtOH
(80
ml) and
50%
KOH (20 ml) was refluxed under N, for24 hr. The
soh
was treated with concd HCl(20 ml), the EtOH wasremoved in vacuo, and the residue was extd with Et,O. The Et,Oext contd some unreacted
2
as shown by tlc. The acid phase wasfiltered, adjusted to pH 8.5, and extd with CHC1,-i-PrOH (3:l).The solvent was removed
in
vaeuo to afford 0.12 g of
3:
mp 277'dec (reported 276-277");"
3.
HCl, mp 307"dec (reported 305'dec);I7 yield, 43.5%.(0.01
1
mole) of
8
and 2.0 g (0.013 mole) of phenyl chloroformatein CH,C1, (30 ml) was maintd at 25' for 24 hr. The CH,CI, was re-moved
in
vacuo, and the residue was suspended
in
1
N
HCl
(50
ml)and extd with Et,O. Basification of the aq
soln
afforded 0.86 g ofunreacted
8.
The Et,O
soln
was concd under reduced pressure andthe oily residue was dissolved in MeOH (60
ml)
nd treated with 2%aq K,CO, (40 ml). The mixt was maintd at room temp for 24
hr
and the MeOH removed in vacuo. Crystn (MeOH-H,O) afforded 2.7g (yield, 65%) of
9,
mp 100-102".
Anal.
(C,.,H,,NO,) C, H, N.
soln
(80
ml) contg 2.5 g (0.007 mole) of 9 was treated with
50%
aq KOH (20 ml) and the reaction mixt was refluxed under N, for 24
hr.
The
soln
was dild with HzO (20 ml) and the EtOH was partiallyremoved under reduced pressure. The aq suspension was extd withEt,O and the Et,O layer was extd with
1
N
HC1. Removal of Et20afforded
0.8
g of
9.
The
aq acid
soln
was filtered, basified, and extdwith Et,O. The Et,O was dried (MgSO,) and treated with ethanolicHC1 to give 1.45 g of crude
10.
HCl: yield, 74.5%; recrystd
10.
HCl(MeOH-EtOAc), mp 253.5-255'.
Anal.
(C]&$JO*HCl) C, H, N.
LAH
Reduction
of
9.
A
THF soln (100 ml) contg
0.8
g (0.002mole) of
9
was added slowly
to
a cooled, stirred suspension of 0.2 gof LAH
in
THF (100 ml). The mixt was refluxed under N, for 4
hr,
(+)-3-Methoxy-l7-carbophenoxymorphinan
9). A
soln
of 3.0 g(+)-3-Methoxymorphinan Hydrochloride
(10
HC1).
An EtOH
SA.
E. Takemori and
J.
Wang, Dept. of Pharmacology, University
of
Minnesota, have successfully prepared 'H-labeled morphine
by
employing a modification of our procedure.!Melting points were detd
in
open capillary tubes using a Thomas-Hoover melting point apparatus and are uncorrected. Microanalyseswere performed
by
M-H-W Laboratories, Garden City, Mich.
The
ir
spectra were obtd with a Perkin-Elmer
237B
pectrophotometerin CHCI, solution
or
KBr
disk. The nmr spectra were obtd with
a
Varian A-60D spectrometer (CDCl,, TMS). Mass spectra were obtdwith a Hitachi Perkin-Elmer
RMU-CD
mass spectrometer.

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