Note: Descriptions are shown in the official language in which they were submitted.
IMPROVED PROCESS FOR THE PREPARA~ION
OF 14--HYDROXYMORPHINAN DERIVATIVES
This invention relates to a new and novel synthesis of
N-substituted-14-hydrox~-3-substituted-morphinans having the
formula
A
R2O ~ \ ~ ~ L
in which R2 is H or (lower)alkyl and R is cyclobutylmethyl or cyclo
propylmethyl.
Drug abuse by thrill-seeking youth or by people looking for
an escape from the realities of everyday life has become more and
more commonplace in our present society. One class of widely
abused drugs are the narcotic analgetics such as codeine, morphine,
meperidine, etc. It is because of the high addictive potential of
these agents that much time and mone~ are ~eing expended ~y the
pharmaceutical industry and by governments to try to discover and
develop new~-non-addicting analgetics and~or narcotic antagonists.
It was an object of the present invention to develop a
method of synthesis for the above-described compounds characterized
by Formula L that would not be dependent upon opium alkaloids as
starting materials and yet would be commercially feasihle.
The objectives of~the present invention have heen achieved
by the process of preparing the compounds of Formula L by their
total synthesis from readily available 2-tp-alkoxybenzyl)-1,2,3,4,
5,6,7,8-octahydroisoquinoline starting material such as 2-~methox-
benzy~ 1,2,3,4,5,6,7,8-octahydroisoquinoline.
- 1 - `'~
The compounds prepared by the instant invention have the
basic morphinan nucleus which i5 num~ered and represented by the
~ollowing plane ~ormula:
--N~l 7
3 e~
Although there are three asymetric carbons (asterisks~ in
the morphinan molecule, only two diastereoisomé~ic(racemic) forms
are possible, because the iminoethano system, attached to position
9 and 13, is geometrically constrained to a cis-tl,3-diaxial)-
fusion. These racemates can, therefore, differ only at the junc-
tion of rings B and C--in other words, in the configuration of
carbon 14. The only variable will be the cis and trans relation-
ship between the 5 (13~ and 8 (14~ bonds (Analgetics. Ed. George
de Stevens, Academic Press, New York, p. 137 (1965~. When the
5 (13) and 8 (14) bonds are cis to each other, the compounds are
commonly designated as "morphinans". The use of a graphic repre-
sentation of a "morphinan" is meant to include the dl racemic
mixture and the resolved d and 1 isomers thereo~.
The "morphinan" compounds of the present invention charac-
terized by Formula L can each exist as two optical isomers, the
levorotatory and dextrorotatory isomers. The optical isomers can
be graphically illustrated as:
M0 8HIN~NS ~ R
and
-- 2 --
l~t3 1.~ 7rj
The present invention embodies the preparation of all of the
morphinan isomers including the optical ;somers in their resolved
form.
The optical isomers can be separated and isolated by frac-
tional crystalliza~ion oE the diaskereoisomeric salts ~ormed, for
instance, with d- or l-tartaric acid or D~ bromocamphor sul-
fonic acid. The levorotatory isomers of the compounds of the pre-
sent invention are the most preferred embodiments.
For the purpose of this disclosure, the term "(lower~alkyl"
is defined as an alkyl radical containing 1 to 6 carhon atoms,
e.g., methyl, ethyl, propyl, isopropyl, _-butyl, iso-butyl, sec-
butyl, etc. The term "pharmaceutically acceptable acid addition
salt" is defined to include all those inorganic and organic acid
salts of the compounds of the instant invention, which salts are
commonly used to produce nontoxic salts of medicinal agents con-
taining amine functions. Illustrative examples would be those
salts-fo ~ ~rby'mixing-,~ e~cc ~ un-dsl~iF.o ~ ulatL~with hydrochl`ortic'~ s~ uric,
nitric,:phosphoric,,phosphorous,-hydrobromic,L;ma~leic,!mali~-, asc~rbic, citric,
or tartaric, pam~ic;-liauric, stearic, pa~mitic, oleic,~myristic, lauryl sul-
furic,~naphthalenésulfoDic,!linoleicror linolenic-acid,-and the llke.~
The morphinan compounds LV ~wherein R is cyclopropyl or
cyclobutyl and R is (lower)alkyl) and LX (wherein R is cyclo-
propyl or cyclobutyl) of the instant invention are prepared by a
total synthesis comprising 4-6 steps. The synthesis is efficient
and appears commercially feasible. Chart I illustrates the pro-
ce~s for the preparation of N-cyclobutylmethyl-3,14-dihydroxy-
morphinan (LXa) utilizing N-cyclobutylmethyl-14-hydroxy-3-
methoxymorphinan (LVa).
R2O ~ 0H HO ~ C~2-R
J i~J
_ 3 _ LX
3~ 7~fj
C~IART I
A~
. Ia ExamPle 2 / I~a
,, ,~ O
CY,~ Cd,O
~ IVa
IIIa 1Exam~le 3
O . . O
- ~d.~"~ C~i~
- ya - VIa
Exam~le 4
~ ~ ~d
VIla LYa
~r Example 1~ ! /\
~C~
, ,
l~a
- 4 -
In opening the 9,10-epoxide ~roup o~ compounds such as
IIIa and IVa according to the procedure of Example 3, there are
obtained 9,10-diol compounds capa~le of existing in conformations
illustrated by the following planer formulas (.and the four optical
isomers thereof~ wherein R is cyclo~utyl or cyclopropyl and R2 is
(lower)alkyl.
OH
OH
N-C-R ~ "
" _~' ~ ~ N-C-R
\~0~ DR2 ~oR2
VI'
(cis-dioll ~,trans-diol~
OH
~-C-R C~-C--R
HO j~ oR2 V
(cis-diol) ~trans-diol)
According to the process of the instant invention, it is
thought that substantially all of the product obtained by the
opening of the 9,10 epoxide group of compounds IIIa and IVa
posses~es the trans-9~,10a-diol relationship of compound Va ~and
its corresponding mirror image) with only a trace of the less
desirable diol VIa.
Thus, the instant invention includes the novel intermediates
of the formula
-- 5 --
,IX
R20 ~ / -C-R
HO'''U
in which X is carbonyl (-O) or H2~ R is cyclopropyl or cyclobutyl
and R2 is (lower) alkyl, pre~erably methyl.
In this divisional specification the invention is the pro-
cess for pr~paration of intermediates VII for making compounds
having the formula L:
/N-CH2R
R20 [~U
J
wherein R is cyclobutyl or cyclopropyl and R2 is H or Clower~alkyl
comprising the step of
(a) reducing the compound having the formula V
o
/1 "
~ ~ -C-R V
U
in which R is cyclobutyl or cyclopropyl and R2 is tlower)alkyl
with borane or a source of borane in an inert organic solvent to
produce a boron complex of the compound having the formula VII
/~-`CH2'-R
Ho ~ V~I
in which R is cyclobutyl or cyclopropyl and R2 is (lower)alkyl.
hisr~in-termediat~e compound(V~ m~ay b~ ~urther processed by
~ b~-~.treati~3~h~-boron complex ofi~.ompound vII w.ith
acid to produce the compound having the formula LV
R20 ~ CH2-R LV
J
in which R is cyclobutyl or cyclopropyl and R2 is (lower)alkyl;
and, when desired,
(c) cleaving the R20-ether function of compound LV by
treating with Nasc2H5~ hydrobromic acid, boron tribromide or
pyridine hydrochloride to produce the compound having the formula
LX
/ \ l:,X
in which R is cyclopropyl or cyclobutyl.
Preferred embodiments of the foregoing process for pre-
paration of compounds characterized by Formula L are those
wherein:
(1) step (a) is carried out in tetrahydrofuran, toluene
or benzene;
~2) in step (a~, the formula V compound is reduced with
borane dimethylsulfide;
.ti~
(3) in step (al, the formula V compound is reduced with
borane generatin~ in situ ~y reacting sodium boro-
hydride with a compound selected fro~ the group of
boron-trifluoride, boron-trifluoride tetrahydrofuran
complex, or boron-trifluoride alkyletherate;
(4) in step (a) borane is employed in the ratio of about
1 mole of compound V to 1.33 to 2.0 moles o~ boranei
(5] in step (a) borane is employed in the ratio of about
1 mole of compound V to 1.6 to l.9 moles of borane;
(6) in step (a) borane is employed in the ratio of about
1 mole of compound V to 1.75 moles of borane;
(7) step (a~ is carried out with the aid of heat in the
range of about 50-115C.
(8) step (a1 is carried out in refluxing toluene;
(9~ in step (b~ the boron complex of compound V~I is
treated with an acid selected from the ~roup consisting
of phosphoric, orthophosphoric, pyrophosphoric, and
polyphosphoric;
(10~ in step (b~ the boron complex of compound VII is
treated with anhydrous phosphoric acid and phosphorous
pentoxide;
(11) in step (b~ the boron complex of compound VII is
treated with a large excess of anhydrous phosphoric
acid and phosphorous pentoxide;
(12~ step (b~ i9 carried out at a temperature in the range
of 50-100C.;
(131 step (b) is carried out at a temperature in the range
of 70-75C.;
.fi~;
step (b) is carried out at a temperature in the range
of 70-75C. with anhydrous phosphoric acid and phos-
phorous pentoxid~.
Another em~odiment oE the overall process is the process for
the preparation of compounds having the formula
/\
/ ~-CH2R L
R20 ~U
wherein R is cyclobutyl or cyclopropyl and R2 is H or ~lowerlalkyl
comprising the consecutive steps of
(b) hydrolyzing the ~oron complex of compound VII with
aqueous acid to provide compound VII;
(c) treating compound VII with an acid selected from the
group consisting of phosphoric, orthophosphoric, pyrophosphoric, and
polyphosphoric until cyclization is essentially complete to produce
the compound having the formula LV
R20 ~ LV
in which R is cyclobutyl or cyclopropyl and R2 is (lower)alkyl; and,
when desired,
~ d~ cleaving the R~O-ether ~unction o~ compound LV ~y
treating with NaSC2H5, hydro~romic acid, ~oron-tri~romide or pyridine
hydrochloride to produce the compound having the formula LX
_ g _
/ ~-CH2~R
H LX
HO , J
in which R is cyclobutyl or cyclopropyl.
Alternatively step (c) can be carried out in a separate
step by treating compound VII with borane followed by an acid
catalyst as described above.
Preferred embodiments of the above process for the prepara-
tion of compounds characterized by Formula L are those wherein:
(1) step (c~ is carried out at a temperature in the
range of 70-90C.; and
(2~ step (c) is carried out with anhydrous phosphoric
acid at a temperature in the range of 80-85 C.
The most preferred embodiment of the present invention is
a process for the preparation of an intermediate VIIa for making
the compound having the formula L'
R2O ~ N~2 ~ L'
wherein R is hydrogen or methyl comprising the step of
i~i'J.~ L~'75
(a~ reducin~ the compound having the formula Va
CH3~ Va
H0
with borane in a molar ratio of about 1.75 mole o~ borane to a-
bout 1 mole of compound Va in toluene ~ith the aid of heat in
the range of about 50-115C. to produce a boron complex of the
compound having the formula VIIa
~ N ~
CH30 ,~ ~ VIIa
H0
This intermediate compound V~Ia may be further processed
by:
(b) treating the boron complex of compound V~Ia with a
large excess of a 6.4:1 mixture of anhydrous phosphoric acid:
phosphorous pentoxide with the aid of heat in the range of
about 70-75C. until cyclization is essentially complete to pro-
duce the compound having the formula LVa
~ LVa
-- 11 --
~ 3~ 7.~j
and, when desired
~ d~ demethylatin~ compound LVa ~ith NaSC2H5, hydrobromic
acid, boron-tri~romide or pyridine hydrochloride to produce the
compound having the ~ormula LXa
~ 2 ~ ~Xa
and, when desired
(d~ converting compound LXa into a nontoxic pharmaceutically
acceptable acid addition salt thereof by methods known in the art.
The compounds N-cyclopropylmethyl-14~-hydroxy-3-methoxy-
morphinan, N-cyclobutylmethyl-14~-hydroxy-3-methoxymorphinan, N-
cyclopropylmethyl-3,14~-dihydroxymorphinan and N-cyclo~utylmethyl-3,
14~-dihydroxymorphinan are known and described in U.S. Patent
3,819,`635.
For the purpose of this disclosure the term "inert organic
solvent" means an organic solvent that does not participate in
the reaction to the extent that it emerges unchanged from the
reaction. Such solvents are methylene chloride, chloroform,
dichlorethane, tetrachloromethane, henzene, toluene, ether, ethyl
acetate, xylene, tetrahydrofuran dioxane, dimethylacetamide, and
the like.
Experimental
All temperatures are expressed in degrees centrigrade,VPC
means vapor phase chromatography. IR means in~rared spectrum.
NMR means nuclear magnetic resonance spectrum.
ti7~5
Exam~'le 1
2~C clo~utylcarbonyl~ methox benz 1~-
1!2,~,4,5,6,7~,8-oct~ah~dro~'s'o'q'uin'o~'in'e'~I'I'a)
Triethylamine ~22.2 g., 0.22 mole~ is 510wly added io 1
(~-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroiso~uinoline hydro-
chloride Ia (29.~ g., 0.1 mole) dissolved in 200 ml. of methylene
chloride with stirring and ice-bath cooling. Cyclobutylcarbonyl
chloride (13 g., 0.107 mole~ in 30 ml. of methylene chloride is
then added dropwise with stirrin~ to the mixture while maintain-
ing a temperature of 0 to 5C. After stirring the reaction mix-
ture for 1 hr. at room temperature, lQQ ml. of water is added,the mixture acidified by adding sn ml. of 10% sulfuric acid,
and the methylene chloride layer separated. If desired, the
methylene chloride solution containing Ira can be used for the
next step directly or concentrated to give an oil which solidi-
fies upon standing. Recrystallization of a sample of the soli~-
fie-ae-l material from acetone provides crystalline product IIa,
m.p. 89-91~.
Various organic tertiary amines commonly employed as
proton acceptors in acylation reactions may ~e substituted for
triethylamine in the above procedure. Such amines are tritlower)
alkylamines, e.g., trimethylamine, triethylamine and the like,
pyridine, dimethylaniline, N-methylpiperidine, and the like.
Example 2
2-Cyclobutylcarbonyl-9,10-epoxy-1-tp-methoxy-
benzyl)perhydroisoquinoline-s tIIIa and IVa~
Method A - Peracetic acid oxidation
To a solution of 2-cyclobutylcarbonyl~ -methoxybenzyl)-
1,2,3,4,5,6,7,8-octahydroisoquinoline (IIa) ~0.1 mole1 in 230 ml.
of methylene chloride is added peracetic acid ~40%, 23.8 g., 0.12
mole) at such a rate so as to keep the temperature at 30-35 C.
After stirring the resulting solution at room temperature for 1
hr., 200 ml. of water is added and the excess peracetic acid
:~i3~ aki~7~
destroyed by adding lQ0 ml. of 10~ sodium bisulfite solution.
The methylene chloride phase is separated and concentrated under
reduced pressure to give an oily re~idue comprised o~ the
isomeric epoxides trans IlIa and c IVa in ratio of 23:78
according to vapor phase chromatography analysis (VPC~. The
two epoxides can be separated, if desired, ~y column chroma-
tography using alumina or s;lica column (eluting with diethyl-
ether).
The minor epoxide (IIIa1, m.p. 118, has the-"tran~-
configuration" and the major epoxide (IVa~ m.p. 82-84, has
the"cls configuration" with respect to steric relationship of
the ~-methoxybenzyl group and the oxirane group.
Method B - Pertrifluoroacetic acid oxidation
To a solution of 2-cyclobutylcar onyl-l-C~methoxy~enzyl~-
1,2,3,4,5,6,7,8-octahydroisoquinoline tI~a) C~.Q5 mole~ in
125 ml. of methylene chloride is added sodium car~onate t2Q g.,~
0.19 mole) and the mixture cooled to a. A solution of pertri-
fluoroacetic acid is prepared by mixing trifluoroacetic anhy-
dride (16.6 g., Q.~77 mole~ and 9Q% hydrogen peroxide ~2.94 g.,
0-077 mole1 in 35 ml. of mRthylene chloride at 0. The peracid
solution is added to the reaction mixture of IIa dropwise at
such a rate so as to maintain the reaction temperature at Q
to 5. After completing the addition, the reaction mixture is
stirred for a period of Q.5 hr. at ~ to 5C. and excess peracid
then destroyed by addition of 10% sodium bisulfite solution
with agitation until the evaluation of C02 ceased. The methy-
lene chloride phaoe iæ washed with water, dried over anhydrous
sodium sulfate and concentrated under reduced pressure to an
oily residue co~prised of the isomeric epoxides rIIa and IVa
in a trans:cis ratio of 35:65 according to VPC.
- 14 -
~ '7
Example 3
2-Cyclobutylcar~onyl-9,10-dihydroXy-l-t ~
methoxybenæyl~perhydroisoquinollne tVa anX VIa)
The mixture of isomeric epoxides IIIa and IVa ~rom peracetic
acid oxidation of Example ~ is dissolved in 3~0 ml. of acetone
and cooled to 0. To this solution is first added 30 ml. of
water and then 30 ml. of concentrated sulfuric acid at such a
rate as to keep the temperature below 25. After stirring the
reaction mixture for a period of 1.5 hr. at 25, a 150 ml. por-
tion of water and a 300 ml. portion of toluene are added. The10
resulting two phase mixture is made basic with sodium hydroxide
solution and the toluene layer separated and concentrated to a
residue oil. This oil~ stirred ~ith 300 ml. of cyclohexane,
provides a suspension of white solid which is collected on a
filter. The ~hite solid consists principally of the desired
trans diol Va contaminated with the isomeric trans diol VIa as
indicated by VPC. The yield of Va calculated from the starting
amine Ia is 75~. The cyclohexane filtrate is retreated with
sulfuric acid to give another 10~ yield of-trans diol. Further
~0
purification of the white solid is carried out by crystalliæation
from acetonitrile to provide material ~ith m.p. 145-147. In
place of the concentrated sulfuric acid used a~ove, other acids
such as nitric, hydrochloric hydro~romic or stron~ organic acids
such as alkylsulfonic, trifluoroacetic and the like ma~ ~e
employed.
Hydrolysis of the pure minor trans epoxide IIIa accordin~
to the above procedure gives only the desired-trans diol Va
while hydrolysis of the major cis epoxide IVa gives the desired
trans diol Va with some of the isomeric trans diol VIa in a
Va:VIa ratio of 86:14.
-- 15 --
Example 4
2-Cyclobutylmethyl-g,10-dihydroxy-1-~p-
methoxy~enzyl~perhYdroisoquinoline (VIIa)
To a solution o 2-cyclobutylcarbonyl-9,10-dihydroxy-1-
(~-methoxybenzyl)perhydroisoquinoline Va t30 g., 0.08 mole~ in
300 ml. of tetrahydrofuran is added ~orane dimethylsulfide neat
solution ~14 ml., 0.14 mole) through a syrinye needle under
nitrogen atmosphere. The resulting mixture is heated to reflux
for 2 hr. and then concentrated under reduced pressure to remove
the solvent. The resulting borane com~lex of the cyclo~utylmethyl
amine VIIa can be used directly for the next reaction or it can
by hydrolyzed with a~ueous acid such as hydrochloric acid to pro-
vide VIaa, m.p. 120-122C. Reduction of the trans diol Va amido
function with the following ~orane sources also provides VIIa.
1~ Borane-tetrahydrofuran complex.
2) In 'situ' generated borane in tetrahydrofuran using
sodium borohydride and ~oron trifluoride gas or ~oron
trifluoride tetrahydrofuran complex or ~oron-
trifluoride alkyletherate.
Example 5
N-Cyclobutylmethyl-14~-hyaroxy-3:-methoxymorphinan ~Va~
Method A. Cyclization with borane complex
To the borane complex residue from ~orane reduction reac-
tion (0.08 mole) of Example 4 is added 32a g. of anhydrous
phosphoric acid (prepared from 85~ phosphoric acid and phosphor-
ous pentoxide) and 50 g. of phosphorous pentoxide. The mixture
is stirred at room temperature for 0.5 hr. and then at 70-75
for a period of 4 hr. The reaction mixture is diluted with 200
ml. of water and then poured into a mixture of 600 ml. of con-
centrated ammonium hydroxide and 1 liter of crushed ice. The
mixture is extracted with 4Qa ml. of heptane and the heptane
- 16 -
jr7 ~
extract dried over sodium sul~ate, Concentration o~ the dried
heptane extract provides 23.1 y. of oil (85~ yield~ of product
LVa. This oil is dissolved in acetone and treated with anhydrous
hydrogen chloride gas to af~ord crystalline hydrochloride salt
of product LVa, m.p. 2~8-250.
Method B. Cyclization without bo'ro'n 'com'plex''o~ an~ kind
1.5 g. o~ 2-Cyclo~utylmethyl-~,lO-dihydroxy~ -methoxy-
benzyl)perhydroisoquinoline VIIa and 16.0 g. o~ anhydrous
phosphoric acid are stirred at 80-85 for 23 hr. The reaction
mixture is diluted with 20 ml. of water and poured into a mix-
ture of ice and 35 ml. of concentrated ammonium hydroxide. The
mixture is extracted with 40 ml. of methylene chloride and
the methylene chloride extract concentrated to give 1.15 g. of
oil. According to vapor phase chromatography-mass spectrometry
analysis, the oil contained 57% of the desired N-c~clo~utylmethyl-
14~-hydroxy-3-methoxymorphinan LVa, 27% o~ a dehydrated by-product
and 15% of uncyclized VIIa starting material.
EXample 6
Levorotatory-N-Cyclobutylmethyl-14~-h~droxY-3'-metho'xYmorphinan
(LVa'~
Substitution in the procedure of Example l o~ deXtrorotatory-
l-(_-methoxybenzyl~-1,2,3,4,5,6,7,8-octahydroisoquinoline
hydrochloride for racemic Ia and sequentially applying the pro-
cedures of Examples 2 5 provides the levorotatory product LVa'.
The pro~ed~res of Examples ~ and 5 are carried out as
follows. To a solution of levorotatory-2-cyclobutylcar~onyl-9,
lO-dihydroxy-2-(p-methoxybenzyl~perhydroisoquinoline ClO g.,
0.0267 mole~ in lO0 ml. of toluene is added borane dimethyl-
sulfide neat solution (6 ml., 0.057 mole~ through a syring~
needle under nitrogen atmosphere. The resulting solution is
refluxed for 3 hr., concentrated under reduced pressure to
remove approximately 4Q ml. of solvent and the borane complex of
- 17 -
,it7.5
levorotatory cyclobutylmethyl amine VII,a' is used directly in the
cyclization reaction.
Cyclization of the le~o~otatory-cyclobutylmethyl amine VIIa'
is carried out by adding the a~ove toluene-borane complex mixture
portionwise to 200 g. o~ anhydrous phosphoric acid and 35 g. of
phosphorus pentoxide with stirring while maintaininy a temperature
range of 0-25C. A~ter the addition is complete, the mixture is
heated and stirred for a period of 5 hr. at 70C. and then poured
into a mixture of 40Q ml. of concentrated ammonium hydroxide
with sufficient ice to maintain a temperature o~ approximately
25C. ~he mixture is extracted ~ith toluene, the toluene
extract washed with water and then concentrated under reduced
pressure to provide levorotatory-N-cyclobut~lmethyl-14~-hydroxy-
3-methoxy-morphinan (LVa') base. The oily base is con~erted to
the sulfate salt by treating with sulfuric acid to accord 7.2 g.
(61% yield) of levorotatory-N-cyclobutylme,thyl-14~-hydroxy-3-
methoxy-morphinan, m.p. 232-237~C. tdec.l, L~J d-55.4?C~
(C = 0.56, CH30H~.
Example 7
2-Cyclopropylcarbonyl-l-~p-methoxybenæyl~-
1,2,3,4,5,6,7,8-octahydroisoquinol-ine tIIb)
Substitution in the procedure of Example 1 for the
cyclobutylcarbonyl chloride used therein of an equimolar quanti-
ty of cyclopropylcarbonyl chloride produces the title material
IIb.
Example 8
2-cyclopropylcarbonyl-g~lo-epoxy-~tp-meth
benz~l)perh~roisoquinol'ine's' tIrIb and'rV~1
Substitution in the procedure of Example 2 for the racemic
IIa used therein of an equimolar quantity of IIb produces the
title compounds IIIb and IVb.
- 18 -
Example' 9
2-Cyclopropylcarbonyl-9~l~-dihydr
ethoxybenzylJperhydroisoquinoline (V~', VIb~
Substitution in the procedure o~ Example 3 for the racemic
IIIa and IVb used therein of an equimolar quantity of I-IIb and
IVb produces the title compounds Vb and VIb.
Example 10
2-Cycloprop lmethyl-9,l~-dihydroxy-l~cP
methoxy~enzy~lperhydroisoquinoline '(VI'I J
Substitution in the procedure of Example 4 for the racemic
Va used therein of an equimolar quantity of Vb produces the
title compound VIIb.
EXample 11
7- ~ clopropylmethyl-14~-hydroxy--3--methoxymorp~inan
5ubstitution in the procedure of Example 5 for the
racemic VIIa used therein of an equimolar quantity of VIIb
produces the title product LVb.
Example 12
N-CYclobutvlmethyl-'3,14'-dihydr'oxymo'r'phin'an '~L'Xa~
A mixture of N-cyclobutylmethyl-14~-hydroxy-3-methoxymor-
phinan (LVa) (1.0 g., 2.58 m mole~ and 10 ml. of 48~ HBr is
refluxed under a nitrogen atmosphere for a period of five
minutes. After cooling, the reaction mixture is diluted with
water and mad~ basic with aqueous ammonium hydroxide. The
aqueous basic mixture is extracted with several portions of
chloroform and the combined chloroform extracts dried over
anhydrous sodium sulfate. After evaporating the solvent, the
residual ~il t730 mg.~ is taken up in dry ether and the result-
ing solution filtered through diatomaceous earth-charcoal. The
filtrate is treated ~ith a saturated solution of hydrogen
chloride in dry ether and the hydrochloride salt thus ohtained
is collected and crystallized from methanol-acetone to afford
565 mg. (56.5%~ of N-cyclobutylmethyl-3,14-dihydroxymorphinan
-- 19 --
;7~
hydrochloride (LXa), m.p. 272-274 (dec.). The IR and NMR
spectra were consistent with the structure.
Ana'l'y's'is - Calc'd. ~or C21H'2gN02 HCl ~CH'30H ~percent~:
C, 67.~7; ~, 8.4~; N, 3.49. Found (percent~: C, 68.10; H,
8.14; N, 3.80.
Acidi~ication of the filtered dry ether solution re~erred
to ahove with appropriate acids provides various "pharmaceutical-
ly acceptable acid addition salts" of LXa.
The 3-methoxy ether function of N-cyclobutylmeth,yl-14~-
hydroxy-3-methoxymorphinan may also ~e cleaved hy treatment
with ether cieaving agents such as NaSC2~'3, horon tri~romide,
or pyridine hydrochloride to produce the desired demethylated
product LXa.
- 2a
