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Morphine Alkaloids CXVIIInvestigation of the Azidolysis of Tertiary Alcohols of Thebaine Derivatives with Bridged Ring C.

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313
Morphine Alkaloids
Morphine Alkaloids, CXVII'):
Investigation of the Azidolysis of Tertiary Alcohols of Thebaine
Derivatives with Bridged Ring C
Agnes Sepsis), Sandor BerCnyib),Sandor Makleitb)*,and Zoltan Totha)
a)
Alkaloida Chemical Factory, H-4440 Tiszavasvari, Hungary
h,
Department of Organic Chemistry, Lajos Kossuth University, H-4010 Debrecen, P.O.B. 20, Hungary
Received March 16, 1992; revised form received May 11, 1992
-
Morphin-Alkaloide, 117. Mitt.:
Untersuchung der Azidolyse von tertiaren Alkoholen bei ThebainDerivaten mit iiberbriicktem Ring C
Replacement of the C-19 tertiary hydroxyl group of some thebdine and oripavine derivatives with bridged ring C (so-called Benfley's compounds)
for an azido group has been performed with hydrazoic acid. In case the
hydroxyl group was connected to a centre of chirality, substitution resulted
in the formation of diastereomeric mixture of azides and elimination took
place a5 well, the extent of which was dependent mainly on steric factors.
Configuration of the C-19 has been determined by 'H-NMR spectra and
calculated proton-proton distances of amines 13a and 13b obtained by the
reduction of JOc followed by separation.
Tertiary alcohols, e.g. ethorphine and buprenorphine, obtained from the
Diels-Alder- adducts of thebaine (J), possess considerable analgesic activity. According to our experiences, azidolysis of the secondary hydroxyl
group (C-6-OH) of morphine derivatives resulted in favourable alteration
of the analgesic, antitussive'), antagonistic2), and anorexogenic3) activities.
In our present paper synthesis of tertiary azides obtained
from thebaine and oripavine derivatives with bridged ring C
is reported.
Recently we reported the azidolysis of tosylates of primary alcohol prepared from the Diefs-Alder-adduct of thebaine and secondary alcohols
obtained from thebdine and its Ci6 modified derivatives4,'). Compounds
prepared were not suitable for ph
acological tests since the isolated azides were converted into azatetracyc odecane derivatives with nitrogen loss
on heating. Such a conversion was obtained even on standing at room
temp.
To our knowledge, morphine derivatives with a tertiary azide group
have not yet been described. To investigate the possibility of the tertiary
hydroxyl and azide replacement methylthevinol (3) obtained easily from
thevinone (2)6)was used as model compound. We failed to convert the tertiary hydroxyl group into the appropriate alkyl or aryl sulfonyl ester.
Methylthevinol (3) gave olefin 49) on treatment with P Q 8 ) (Scheme I).
For the preparation of the tertiary azide benzene or toluene solutions of
hydrazoic acid and BF,-etherate proved to be convenient"). The azido
derivative 5 obtained from methylthevinol (3) with the above-mentioned
reagent gave the cyclic compound 6 on heating at 100°C for 48 h in dimethylformamide solution or at room temp. with nitrogen loss and yielded a
new derivative of the azatetracyclodecane ring system described earlier by
us'). Crude azide 5 afforded the amino derivative 7 on reduction. To avoid
"T
+)
For part CXVI of this series see ref. 20
Arch. Pharm. (Weinheim) 326,313-317 (1993)
Es wurde der Austausch der tertiaren Hydroxylgruppe an C-19 einiger
Thebain- und Oripavinderivate mit iiberbriicktem Ring C (sog.
Bentley'sche Verbindungen) gegen eine Azidogruppe mit Hilfe van
Azoimid untersucht. 1st die Hydroxylgruppe an ein chirales C-Atom
gebunden, liefert die Substitution ein Gemisch diastereomerer Azide und
die Umsetzung wird von einer Eliminierung begleitet, deren Ausmall vermutlich vorrangig sterisch bedingt ist. Die Konfigurationsverhlltnisse der
an C-19 diastereomeren Azide liel3en sich aus dem Protonenspektrum der
durch Trennung der aus dem Gemisch JOc mittels Reduktion gewonnenen
Amine 13a,b, weiterhin anhand der durch Computer berechneten durchschnittlichen Proton-Proton-Entfernungenbestimmen.
the ring closure reaction our further studies have been performed with tertiary alcohols obtained from dihydrothevinone (8)" (Scheme 2).
Tertiary azide 10a was obtained in 61% yield by azidolysis of dihydromethylthevinol 9a7).In the case of tertiary
alcohols 9b-9d7) possessing a centre of chirality at C-19
diastereomeric mixtures of azides lob-10d were obtained
and the substitution was accompanied by elimination (llbl l d ) . Our efforts to separate the diastereomeric mixtures of
azides were unsuccessful. The diastereomeric ratio was
estimated from the integral intensity values of the 'H signals of C-SPH, C-6-OMe, and C-19-Me which were 4:1 for
lob, 3:1 for lOc, and 1:l for 10d. For the determination of
the relative configuration of C - 19 of the diastereomers
attempts were made to separate the amines prepared by the
reduction of the azide mixtures. This was successful only in
the case of amines 13a and 13b obtained from 1Oc. j@H19-Me = +8.5% NOE value was measured for the main
component of the amine mixture. On this basis and on the
calculated (ALCHEMY) proton-proton distances (C- 19-S
r8aH-19-Me = 0.273 nm, C-19-R r8aH-19-Me = 0.326 nm)
it appears that the C-19-S diastereomer is the major product. No azide derivative was prepared on the azidolysis of
compound 9e7).The two products formed were the known
1211)as the major one and olefin l l e as the minor component.
On the basis of the results of the substitution and elimination reactions and from the ratio of the diastereomeric azi-
0VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1993 0365-6233/93/0606-0313 $5.00 + ,2510
314
Makleit and coworkers
Me
Me
I
1st
I
=0
Me-g-OH
1
thebaine
=CH2
Me --C
y
-
OMe
-6
4
3
-
f
Me
Me
I
Me
-5
-N3
5
-
Scheme 1
des it appears that steric factors are more important than
electronic ones concerning the reaction mechanism.
To prepare the oripavin derivative 10f corresponding to
10a, 9a was 0-demethylated with KOH in ethylene glyTable 1: Analgesic Activity
~-
-
-
~~
GPI
Compound
IC,,,nM/I
HP
R
K,,nM/I
EDsn m&g
1.1
1.2
1.4
1.2
6.0
0.32
0.59
~
morphine
9f orvinol
10f azido-
68
3.2
7.0
22.1
10.1
orvinol
The test compounds as their bases were dissolved in 5% H,PO,, pH of the
solution was adjusted to 6 with 10%NaOH.
is the concentration of the opiate causing 50% inhibition of the contraction elicited by low frequency (0.1 Hz) field stimulationlh,")
R:
i s the ICso ratio (ICso of normorphine/lCsOof the drug)
Kch: is the equilibrium dissociation constant of naloxone against examined agonist, calculated from the equation KeN= naloxone/CR -1'6.'9)
CR: is the concentration ratio of the agonist required to depress the
twitch to the same extent in the presence or absence of a given concentration of the antagonist, naxolone.
EDS,,: is the effective dose at which the mice showed 50% of the maximal
analgesic effect, determined from the dose-response curve.
lCio:
coil2), then the phenolic OH-group was selectively acetylated (9g) by the method of Welsh")). Compound log obtained by azidolysis was deacetylated with hydroxylamine
hydrochloride to afford 10f.
Pharmacological results
Compounds 9f and 10f were evaluated in vitro for opioid
agonist properties in the isolated guinea-pig ileal longitudinal muscle preparation (GPI)'5,16)and in vivo in the hotplate assay (HP)17,'8)in mice (Table 1): Compound 10f
exhibits p opioid agonism as judged by the equilibrium dissociation constant value of naxolone.
According to our studies replacement of the tertiary
hydroxyl by an azide group resulted in no increase in the
bioactivity.
This work was supported by Alkaloida Chemical Factory (Tiszavasvari,
Hungary) and the Hungarian Academy of Sciences (OTKA I/2 reg. number: 848/88).
Experimental Part
Melting points: Electrothermal 8103 apparatus, uncorrected.. TLC: Kieselgel60 F254 (Merck 5562), benzene:methanol = 8:2 (v/v) and ethyl aceta-
Arch. Pharm. (Weinheim)326,313-317 (1993)
315
Morphine Alkaloids
R'
I
$-<-OH
Me
I
c= 0
R'
I
R~-c_-N~
R1
R2
R3
a
Me
Mc
Mc
b
Mc
Et
Mc
c
Mc
n-Pr
Mc
c
d
Mc
Ph
Mc
d
c
Mc
LDu
Mc
R2
a
Mc
Me
Me
b
Mc
Et
Et
Me
Mc
Me
,
M c n-Pr
n-Pr M
e
Mc
Ph
Ph
Mc
gMe6 - e
Mc
II
f
Me
Me
H
g
Mc
Mc
hc
g
Mc
Me
hc
Me Me
I
,,J
,,,,f
-
R*-E-NH~
OMc
/N
Me
,,O'
%,
0
%
/N
Me
0
OMe
OMe
13
12
11
R1
R'
I
I
M e - E --C - M \e
0
Mc
Mc
Mc
20 19
0
Me
Me
f
R~-HC=C_-R'
Me
/N
R3
R1
R2
R1
R2
b
Me
Me
a
Me
nPr
(19s)
c
Me
Et
b
nPr
Me
(19R)
d
Ph
H
e
tBu
H
Scheme 2
te:methanol:NH40H= 8:21 (vtv). Detection: DragendorfSs reagent.- 'HNMR spectra: Varian-Gemini 200 spectrometer at 200 MHz. For diastereomeric mixtures only those n.m.r. data are given which were used for the
determination of the ratio of the components.- IR spectra: Digilab FTS 40.Mass spectra: VG-TRIO-2.
Method B: Reduction of the azides
Method A: Azidolysis of tertiary alcohols
A mixture of tertiary azide (5.0 mmol), ethanol (40 ml), Raney nickel
(2.0 g, Fluka 50% aqueous suspension) and 98% hydrazine hydrate (40.0
mmol) was refluxed for 30 min, then cooled and filtered. The solvent was
evaporated, the residue dissolved in 5% HCI, the pH was adjusted to 8
with NaHC03, and the mixture was extracted with benzene (3 x 20 ml).
The aqueous solution was basified (pH 12) with Na2C03and extracted
with chloroform (3 x 30 ml), the org. phase was dried with MgS04 and the
solvent evaporated.
(I .2 ml, 10.0 mmol) were added under stirring at room temp. The mixture
was stirred for further 4 h, then 20 ml of water were added to dissolve the
precipitate. The pH was adjusted to 8 with Na2C03 and the org. phase was
separated. The aqueous phase was extracted with chloroform (3 x 20 ml),
the solution washed with water, dried with MgS04, and the solvent evaporated to afford an oily product.
5 was prepared from 37)according to method A. The crude product was
subjected to ring closure (6) or reduced to amine 7 without purification.
Yield 62%.- 'H-NMR (CDC13): 6 (ppm) = 1.15 (s, 3H, 19-Me); 1.32 (s,
3H, 19-Me); 2.40 (s, 3H, N-Me); 3.65 (s, 3H, 6-OMe); 3.83 (s, 3H, 3OMe); 4.58 (s, lH, 5P-H); 5.40 (d, lH, 17-H); 5.80 (d, lH, 18-H); 6.60
(AB, J = 8 Hz, 2H, Ar-H).
General procedures
Arch. Pharm. (Weinheim)326,313-317 (1993)
316
Iha,7rw.I4a)-2',2' -Dinirthyl-S'$6'.6.7-teii-uiiydi-o-2'H ,KH- I ' 5' .6',14-dicy(.lopyrido[.3'.4':7,6]thcbuine (6)
Crude azide 5 (0.5 g, 1.18 mmol) was dissolved in dimethylformamide
(0.5 mlj and the solution was stirred at 100°C for 40 h, then poured into
water (50 ml) and extracted with chloroform (3 x 15 ml). The org. phase
was washed with water, dried, the solvent evaporated and the residue purified by column chromatography on Kieselgel40 (benzene:methanol = 8:2)
to afford 0.3 g (64%) oily product.- MS: m/z 394 (M+', 200/).- 'H-NMR
(CDCI?): 6 (ppmj = 1.15 (d, J = 6 Hz, IH, S'-H), 1.35 (s, 3H, 2'-Me): 1.45
(s- 3H, 2'-Mej; 2.15 (d. J = 6 Hz, IH, 6'-H), 2.35 (s, 3H, N-Me); 3.48 (s,
3H, 6-OMe); 3.88 (s, 3H. 3-OMe): 4.98 (s. IH, 5P-H); 6.65 (AB. J = 7.6
Hz. 2H, Ar).
7 was prepared from the crude azide 5 according to method H. Yield
8:3%, imp. 149-153°C.- CLIH1203N2(396.5) Calcd. C 72.6 H 8.12 N 7.0
Found C 72.0 H 8.05 N 6.8.- MS: m/z 396 (M", 20%): [a],:-182.4" (c =
0.2. CHCI,).. 'H-NMR (CDCI,): 6 (ppm) = 1.00 (s, 3H, 19-Me); 1.08 (s,
311, I9-Me); 2.40 (s, 3H. N-Me): 3.71 (s, 3H, 6-OMe); 3.82 (s, 3H, 3OMe); 4.58 (s, IH, 5P-H); 5.41 (d, J = 8 HL, IH, 17-H); 5.90 (d, J = 8 Hz,
IH, 18-H): 6.60 (AB, J = 8 HL, 2H. Ar).
. ~ - O - A ~ ~ e i ~ l - d i ~ i y r l , . o n i e f / i(9g)
~l~~~i~i~iol
Acetic anhydride (6.0 ml) was added 10 a stirred mixture of dihydromethylorvinol (9f)".'4' (1.0 g, 2.6 mniol), NaHC03 (10.0 g) and water (100
ml) at room temp. The mixture was stirred for further 30 min at ambient
temp., then extracred with chloroform ( 3 x 30 ml). The org. phase was
washed with 5%1 NaOH and water, dried with MgSOI, and the solvent was
evaporated. The residue was cvystallized from methanol to afford 0.92 g
(83%), 9s. m.p. 146-147°C.- CZSH?TNO?(427.5) Cdkd. C 70.2 H 7.77 N
3.3 Found C 70.3 H 8.0 N 3.5.- MS: m/z 427 (M+', 95%): [all,:-164" (c =
0.2. CHCI?).. 'H-NMR (CDCI,): 8 (pprn) = 1.17 (s, 3H, 19-Me); 1.35 (s,
3H, 19-Me): 2.25 (s, 3H, 3-OAc): 2.32 (s, 3H, N-Me); 2.65 (m, IH, 9a-H);
3.12 ((1, J = 20 H i , IH, 10P-H); 3.45 (s, 3H. 6-OMe); 4.40 (s, IH, 5P-H):
5.OX (s, IH, 19-OH): 6.70 (AB. J = 8.2 Hz, 2H, Ar).
Makleit and coworkers
Ilb: Yield 13%: MS: m/z 395 (M", 90%): 'H-NMR (CDCI,): 6 (ppm)
= 1.60 (d, J = 7.2 Hz, 3H, 20-Me); 1.75 (s, 3H. 19-Me); 2.3 (s, 3H, N-Me);
3.1 (d. J = 18 Hz, IH, IOP-H); 3.35 (s, 3H, 6-OMej; 3.88 (s, 3H, 3-OMe);
4.50 (s, IH, 5P-H); 5.40 (d, J = 7.2 Hz, IH, 20-H); 6.65 (AB, J = 8 Hz, 2H,
Ar).
7a-(I -Azido- I -mrthylhutyl)-h,14-endo-eihonotet~uh~d~~~t~i~~huine
(loci
und 7u41-methyl-1-hutenpl~-h.l4-enrlo-erhun~~tetruhydr-olrbuine
(1lc)
These compounds were prepared from 9c7' according to method A and
separated by column chromatography using Kieselgel 40; to1uene:methano1 = 9: 1.
1Oc: Yield 4476.- 1R (KBrj: 2095 c m ~ (N3j.'
MS: m/z 452 (M+', 60%);
410 ((M - 42)+, l00%).- 'H-NMR (CDCI,): 6 (pprn) = 1.44 and 1.48 (2s.
IH, 19-Me); 3.42 and 3.50 (2s, 3H, 6-OMe); 4.39 and 4.42 (2s. IH, 50-H).
l l c : Yield 6%. m.p. 186-IX7"C.-95.4" (c = 0.2, CHCI,).C2hH35N03(409.5) Calcd. C 76.2 H 8.60 N 3.4 Found C 76.8 H 8.7 N
3.6.- MS: m/z 409 (M+', 30%); 394 ((M - IS)+, l00%).- 'H-NMR
(CDCI,): 6 (pprn) = 0.98 (t, J = 7 Hz, 3H, C-Me); 1.75 (s. 3H, 19-Me);
2.30 (s, 3H, N-Me); 3.35 (s, 3H, 6-OMe); 3.88 (s, 3H, 3-OMe); 4.51 (s,
IH, 5P-H); 5.30 (t, J = 7 Hz, IH, 20-H); 6.64 (AB, J = 8 Hz, 2H, Arj.
7ff-(l-A~ido-l-phenyl-ethyl)-6,14-end~~-ethunoietruhydr~~thebuine
(IOdJ
7 ~ ~-pheiiyl-etheiiyl)-h,14-e~id~-ethan~tet~uhyd~otlichuine
41
(1 Id)
ut7d
These compounds were prepared from 9d7) according to method A and
separated by column chromatography using Kieselgel 40; toluencmethano1 = 19.1.
1Od: Yield 40%.- 1R (KBr): 2095 cm-' (N3j.- MS: m/z 486 (M+', 20%);
458 ((M - 28)". 30%): 'H-NMR (CDCI,): F (ppm) = 1.90 and 1.95 (2s,
3H, 19-Me); 2.28 and 2.35 (25, 3H, N-Me): 2.98 and 3.26 (2s, 3H, 6OMe): 4.35 and 4.4 (2s, IH, 5P-H).
l l d : Yield 5 % , m.p. 170-171°C.- [a],:-146.9" (c = 0.2, CHCI,)..
C ~ , ) H ? T N(443.6)
O~
Calcd. C 78.5 H 7.49 N 5.2 Found C 79.1 H 7.51 N
5.3.- MS: m/z 443 (M+*, 65%); 428 ((M - IS)+, 100%).- 'H-NMR
(CDCI,): 6 (ppm) = 2.30 (s, 3H, N-Me); 3.00 (s, 3H, 6-OMe); 3.88 (s, 3H.
3-OMe): 4.54 (s, IH, 5P-Hj; 5.35 (s, 2H, 20-H): 6.62 (AB, J = 7.2 Hz, 2H,
Ar); 7.30 (m, SH, 19-Ar).
7 n - ( l - , 4 ~ i d o - l - r i 1 ~ t l 1 ~ l ~ ~ t h y l ) - 6 , 1 4 - i ~ i i d ~ ~ - i ~ ~ ~ i u n ~ ~(IOa)
f~~ti~u/iydi-~~thi~bairie
IOa was prepared from 9a" according to method A and purified by
column chromatography using Kieselgel 40 and benzenemethanol = 9: 1 to
obtain an oily product (61941. m.p. of its hydrochloride 225-228°C.C2,H32N403,HCI(460.9) Calcd. N 12.2 CI 7.9 Found N 12.4 CI 8.2.- IR
(KBrj: 2100 c m ~(N&'
MS: m/z 424 (M+', 40%), 382 ((M - 42)+, 70%);
'H-NMR (CDC13j: 6 (pprn) = 1.44 (s, 3H, 19-Me): 1.46 (s, 3H, 19-Me);
2.25 (s, 3H, N-Me): 2.75 (m, IH, 9a-H), 3.15 (d, J = 16 Hz, IH, IOP-H);
3.42 (s, 3H, 6-OMe); 3.88 (s. 3H. 3-OMe): 4.40 (s, IH, 5P-H); 6.62 (AB, J
= 7.2 Hz. 2H. Ar).
7~x41
-Aiido-I -methylethyl)-6.14-en~o-~~thuno-~-O-u~et~ltetruhyd~~~o~ipui'inc (log)
1Og was prepared from 9g according to method A and purified by
column chromatography on Kieselgel 40; to1uene:methanol = 9: 1. Yield
35%. oily product.. IR (KBrj: 2098 (N3): 1770 cm-' (C=O).- MS: m/z 452
(M+-, 40%); 410 ((M - 42)+, 60%): 'H-NMR (CDCI,): 6 (ppm) = 1 .I8 (s,
3H, 19-Me); 1.35 (s, 3H, 19-Me); 2.28 (s, 3H, 3-OAc); 2.32 (s, 3H, NMe); 3.15 (d, J = IX Hz, IH, IOP-H); 3.38 (s, 3H, 6-OMe); 4.38 (s, IH, 5pH); 5.08 (s, IH, OH); 6.70 (AB, J = 8.4 Hz, 2H, Arj.
7a-(I -Aziilo- I -inethyl-I -pi-op~~)-6,14-c~ndo-ethunot~tr~uhyd~otIiehuine
(lOfJ
und 7a-(I -nirthyl-l- ~ ~ i - o ~ ~ c n ~ I J - 6 , 1 4 - e n ~ i ~ ~ - e t h u n o t e t ~ u h ~ ~7a-(I-A.-ido-l-niethylethyl)-6.14-endo-ethano-tetrahydroo~~puv~ne
d~othehainc
(lib)
A mixture of 1Og (0.7 g, 1.54 mmol), H,NOH.HCI (0.16 g, 2.3 mmol),
ethanol (20 ml), and water (4.0 ml) was stirred at 50°C for 30 min. The
These compounds were prepared from 9b7' according to method A and
solvent was evaporated, the residue dissolved in water (40 ml), the pH was
separated by column chromatography using Kieselgel 40; to1uene:methaadjusted to 8 with Na2C03 solution, and the mixture extracted with chlorono1 = 19.1.
form. The org. phase was washed with water, dried with MgS04, and the
lob: Yield 35%: IR (KBr): 2100 cm-' (N& MS: m/z 438 (M+', 60%);
solvent was evaporated. The residue was crystallized from ethanol to
396 ( ( M - 42)+. 100%).- 'H-NMR (CDCI,): 6 (pprn) = 1.43 and 1.48 (2s,
obtain 0.5 g (79%) lOf, m.p. 101-103°C.- C,,H,,,N403 (410.5) Calcd. C
3H, 19-Me): 3.42 and 3.50 (2s. 3H, 6-OMe); 4.38 and 4.42 (2s, IH, 50-H).
( 1Oh)
Arch. Pharm. {Weinheim)326,313-317 (1993)
3 17
Morphine Alkaloids
67.2 H 7.35 N 13.6 Found c 66.8 H 7.21 N 13.3.- IR (KBr): 2099 cm-1
(N&- MS: m/z 410 (M+', 30%); 368 ((M - 42)+, 100%): [aID: -120' (c =
0.2, CHC13).- 'H-NMR (CDC13): 6 (ppm) = 1.45 (s, 3H, 19-Me); 1.48 (s,
3H, 19-Me); 1.6-2.1 (m, 8H, CH,); 2.30 (s, 3H, N-Me); 2.71 (m, lH, 9 a H); 3.1 (d, J = 20 Hz, IH, 10P-H); 3.45 (s, 3H, 6-OMe); 4.42 (s, IH, 5PH); 4.90 (s, lH, 3-OH); 6.65 (AB, J = 8.2 Hz, 2H, Ar).
7ff-(l-tert-Butyl-ethenyl)-6,14-endo-etha~~otetrahydrothebai~e
( l l e ) and
6,14-endo-ethano-2',3' ,4',5'
,7,8-hexahydro-4' 5',5'-trimethyl-jurano[2',3',6,7]-codide(12)"'
l l e : Yield 22%, m.p. 137-138°C (ether).- [a],,:
-124.3" (c = 0.2,
CHC13).- C27H37N03 (423.6) Calcd. C 76.5 H 8.74 N 3.3 Found C 76.6 H
8.82 N 3.5.- MS: m/z 423 (M", 50%); 408 (M - 15)+, 60%).- 'H-NMR
(CDCI,): 6 (pprn) = 1.10(s, 9H, 19-tBu); 2.30 (s, 3H, N-Me); 2.70 (m,lH,
9a-H); 3.15 (d, J = 20 Hz, lH, IOP-H); 3.35 (s, 3H, 6-OMe); 3.90 (s, 3H,
3-OMe); 4.35 (s, IH, 5P-H); 5.10 (d, J = 26 Hz, 2H, 20-H); 6.62 (AB, J =
8 Hz,2H, Ar).
12: Yield 35%, m.p. 157-159°C.-Lit.: m.p. 156-157°C").
References
1
3
4
5
6
8
9
10
11
12
7a-[(IS)-I -Amino-l -methylhuryl]-6,14-endo-ethanotetrahydro-thehaine
(13a) and 7a-[(IR)-l-amino-1-methylbutyl]-6,14-endo-ethano-tetrahydro-thehaine (13b)
13
14
15
These compounds were prepared from 10c according to method B and
separated by column chromatography using Kieselgel 40, ethyl
acetate:methanol:NH,OH = 8:2:0.5.
13a: Yield 58%.- 'H-NMR (CDC13): 6 (ppm) = 0.75 (m,lH, 8P-H);
0.95 (t, 3H, 21-Me); 1.28 (s, 3H, 19-Me); 3.20 (s, 3H, N-Me); 3.50 (s, 3H,
6-OMe); 3.88 (s, 3H, 3-OMe); 4.45 (s, lH, 5P-H); 6.60 (AB, J = 8.4 Hz,
2H, Ar).
13b: Yield 18%.- 'H-NMR (CDCI,): 6 (pprn) = 0.75 (m, IH, 80-H);
0.95 (t, J = 7 Hz, 3H, 21-Me); 1.10 (s, 3H, 19-Me); 2.30 (s, 3H, N-Me);
3.50 (s, 3H, 6-OMe); 3.88 (s, 3H, 3-OMe); 4.42 (s, lH, 5P-H); 6.60 (AB, J
= 8.2 Hz, 2H, Ar).
16
Arch. Pharm. IWeinheim) 326,313-317 (1993)
17
18
19
20
J. Knoll, S. Makleit, T. Friedmann, L.G. Harsing, Jr., P. HadhBzy,
Arch. In(. Pharmacodyn. Ther. 1974,210,241-249.
J. Knoll, S. Furst, S. Makleit, Arch. Int. Pharmacodyn. Ther. 1977,
228,268-292.
S. BerCnyi, S. Makleit, S. Hosztafi, S. Furst, T. Friedmann, J. Knoll,
Med. Chem. Res. 1991,1, 185-190.
S . Berenyi, Gy. Gulyas, Gy. Batta, S. Makleit, Org. Prep. Proced. Int.
1991.23, 11 1-1 13.
S. Berknyi, Gy. GulyBs, Gy. Batta, T. Gunda, S. Makleit, J . Chem.
Soc. Perkin Trans. 11991, 1139.1142.
K.W. Bentley, D.G. Hardy, J . Am. Chem. Soc. 1967,89, 3267-3273.
K.W. Bentley, D.G. Hardy, B. Meek, J . Am. Chem. Soc. 1967, 89,
3273-3280.
J.A. Miller, Tetrahedron Lett. 1975,2959-2960.
K.W. Bentley, D.G. Hardy, B. Meek, J . Am. Chem. Soc. 1967, 89,
3293-3303.
A. Pancrazi, Q. Khuong-Huu, Tetrahedron 1974,30,2337-2343.
K.W. Bentley, D.G. Hardy, B. Meek, J.B. Taylor, J.J. Brown, G.O.
Morton, J . Chem. Soc. (C) 1969,2229-2232.
K.W. Bentley, D.G. Hardy, B. Meek, J . Am. Chem. Soc. 1967, 89,
3281-3292.
L.H. Welsh, J . Am. Chem. Soc. 1952,74,4967-4968.
J.W. Lewis, M.J. Readhead, J . Med. Chem. 1970,13,525-527.
E.A. Gyang, H.W. Kosterlitz, Br. J . Pharmac. Chemother. 1966, 27,
5 14-527.
H.W. Kosterlitz, A.J. Watt, Br. J . Pharmac. Chemother. 1968, 33,
266-272.
G. Woolfe, A.D. McDonald, J . Pharmacol. Exp. Ther. 1944,80, 300307.
D. Calcagnetti, S.G. Holtzman, Pharmacol. Biochem. Behaviour
1991,38, 185-190.
H.W. Kosterlitz, A.A. Waterfield, V. Berthoud, in Advances in Biochem. Psychopharm. (Ed.: M.C. Braude), Vol. 8, Raven Press, New
York, 1974, p. 319-334.
S . Hosztafi, Cs. Simon, S. Makleit, Synth. Comrnun., 1992, 22, 16731682.
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