U.S. patent number RE29,943 [Application Number 05/826,683] was granted by the patent office on 1979-03-20 for aminomethanobenzazocine intermediates.
This patent grant is currently assigned to Sterling Drug Inc.. Invention is credited to Noel F. Albertson, Mark P. Wentland.
United States Patent |
RE29,943 |
Wentland , et al. |
March 20, 1979 |
**Please see images for:
( Certificate of Correction ) ** |
Aminomethanobenzazocine intermediates
Abstract
N-Alkylated-8-aminated-2,6-methano-3-benzazocines, useful as
strong analgesics, are prepared by one route comprising reduction
of 8-nitro intermediates or by another route comprising Birch type
reduction of 8-methoxy intermediates followed by
dehydration-rearrangement of the oximes of the resulting 8-oxo
intermediates.
Inventors: |
Wentland; Mark P. (North
Greenbush, NY), Albertson; Noel F. (Schodack, NY) |
Assignee: |
Sterling Drug Inc. (New York,
NY)
|
Family
ID: |
24543442 |
Appl.
No.: |
05/826,683 |
Filed: |
August 22, 1977 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
507965 |
Sep 20, 1974 |
3957793 |
|
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Reissue of: |
634355 |
Nov 24, 1975 |
04032529 |
Jun 28, 1977 |
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Current U.S.
Class: |
546/97 |
Current CPC
Class: |
C07D
221/22 (20130101) |
Current International
Class: |
C07D
221/22 (20060101); C07D 221/00 (20060101); C07D
221/26 () |
Field of
Search: |
;260/293.54,DIG.13 |
References Cited
[Referenced By]
U.S. Patent Documents
|
|
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3632591 |
January 1972 |
Albertson et al. |
3764606 |
October 1973 |
Akkerman et al. |
3853889 |
December 1974 |
Monkovic et al. |
4009171 |
February 1977 |
Albertson |
|
Primary Examiner: Trousof; Natalie
Assistant Examiner: Schwartz; Richard A.
Attorney, Agent or Firm: Miller; Theodore C. Wyatt; B.
Woodrow
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATION
This application is a division of copending application Ser. No.
507,965, filed Sept. 20, 1974 now U.S. Pat. No. .[.3,957,973.].
.Iadd.3,957,793. .Iaddend.
Claims
We claim: .[.1.
1,2,3,4,5,6-Hexahydro-3-Q'-8RR"N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazoc
ine having the formula ##STR11## wherein: Q' is hydrogen, benzyl,
propyl, isobutyl, neopentyl, allyl, 2-methyl-2-propenyl,
2-chloro-2-propenyl, cis-3-chloro-2-propenyl,
cis-3-chloro-2-butenyl, trans-3-chloro-2-butenyl, propargyl,
cyclopropylmethyl or (2,2-dichlorocyclopropyl)methyl;
R is hydrogen or methyl;
R" is formyl, acetyl, propionyl, butyryl, isobutyryl, benzoyl or
cyclopropanecarbonyl;
X is hydrogen, methyl or ethyl;
Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;
Z is hydrogen, methyl, ethyl or hydroxy; and
Z' is hydrogen, methyl or ethyl; or an acid addition salt
thereof..].
.[. A compound according to claim 1 wherein X is hydrogen and Z is
hydrogen or an acid addition salt thereof.]. .[.3. A compound
according to claim 2 wherein Y is methyl and Z' is methyl or an
acid addition salt
thereof..]. .[.4. A compound according to claim 3 wherein R is
hydrogen or an acid addition salt thereof..]. .[.5. A compound
according to claim 4 wherein Q' is cyclopropylmethyl or an acid
addition salt thereof..]. .[.6. A compound according to claim 5
wherein R" is formyl or an acid addition salt thereof..]. .[.7. A
compound according to claim 5 wherein R" is acetyl or an acid
addition salt thereof..]. .[.8. A compound according to claim 5
wherein R" is propionyl or an acid addition salt thereof..]. .[.9.
A compound according to claim 5 wherein R" is butyryl or an acid
addition
salt thereof..]. 10.
1,2,3,4,5,6-Hexahydro-3-Q"-8RR"N-5X-6-Y-11-Z-11Z'-2,6-methano-3-benzaz
ocine having the formula ##STR12## wherein: Q" is formyl, acetyl or
Q* wherein Q* is propionyl, isobutyryl, pivaloyl, acryloyl,
2-methylacryloyl, 2-chloroacryloyl, cis-3-chloroacryloyl,
cis-3-chlorocrotonoyl, trans-3-chlorocrotonoyl, propiolyl,
cyclopropanecarbonyl or 2,2-dichlorocyclopropanecarbonyl;
R is hydrogen or methyl;
R" is formyl, acetyl, propionyl, butyryl, isobutyryl, benzoyl or
cyclopropanecarbonyl;
X is hydrogen, methyl or ethyl;
Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;
Z is hydrogen, methyl, .[.ethyl or hydroxy.]..Iadd.or ethyl;
.Iaddend.and
Z' is hydrogen, methyl or ethyl. 11. A compound according to claim
10
wherein X is hydrogen and Z is hydrogen. 12. A compound according
to claim
11 wherein Y is methyl and Z' is methyl. 13. A compound according
to claim
12 wherein R is hydrogen. 14. A compound according to claim 13
wherein Q"
is cyclopropanecarbonyl. 15. A compound according to claim 14
wherein R"
is cyclopropanecarbonyl. 16. A compound according to claim 13
wherein Q"
is acetyl. 17. A compound according to claim 16 wherein R" is
acetyl.
18. A compound according to claim 13 wherein Q" is isobutyryl. 19.
A
compound according to claim 18 wherein R" is isobutyryl. 20. A
compound
according to claim 13 wherein Q" is propionyl. 21. A compound
according to claim 20 wherein R" is propionyl.
Description
SUMMARY OF THE INVENTION
This invention relates to intermediates and processes useful in the
preparation N-alkylated-8-aminated-2,6-methano-3-benzazocines,
which are useful as strong analgesics and which are more
particularly defined as
1,2,3,4,5,6-hexahydro-3-Q-8-RR'N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazoc
ines having the formula ##STR1## wherein: Q is propyl, isobutyl,
neopentyl, allyl, 2-methyl-2-propenyl, 2-chloro-2-propenyl,
cis-3-chloro-2-butenyl, trans-3-chloro-2-butenyl, propargyl,
cyclopropylmethyl or (2,2-dichlorocyclopropyl)methyl;
R is hydrogen or methyl;
R' is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, benzyl or cyclopropylmethyl;
X is hydrogen, methyl or ethyl;
Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;
Z is hydrogen, methyl, ethyl or hydroxy; and
Z' is hydrogen, methyl or ethyl; and acid addition salts
thereof.
In addition to being useful as strong analgesics some of the
compounds of Formula I are also useful as intermediates for
preparing other compounds of Formula I and are thus one related
intermediate aspect of the invention.
Another related intermediate aspect of the invention sought to be
patented is
1,2,3,4,5,6-hexahydro-3-Q'-8-nitro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzaz
ocine having the formula ##STR2## wherein: Q' is hydrogen, benzyl,
propyl, isobutyl, neopentyl, allyl, 2-methyl-2-propenyl,
2-chloro-2-propenyl, cis-3-chloro-2-propenyl,
cis-3-chloro-2-butenyl, trans-3-chloro-2-butenyl, propargyl,
cyclopropylmethyl or (2,2-dichlorocyclopropyl)methyl;
X is hydrogen, methyl or ethyl;
Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;
Z is hydrogen, methyl, ethyl or hydroxy; and
Z' is hydrogen, methyl or ethyl; or an acid addition salt
thereof.
Still another related intermediate aspect of the invention sought
to be patented is
1,2,3,4,5,6,7,8,9,10-decahydro-3-Q'-8-oxo-5-X-6-Y-11-Z-11-Z'-2,6-methano-3
-benzazocine having the formula ##STR3## wherein: Q' is hydrogen,
benzyl, propyl, isobutyl, neopentyl, allyl, 2-methyl-2-propenyl,
2-chloro-2-propenyl, cis-3-chloro-2-propenyl,
cis-3-chloro-2-butenyl, trans-3-chloro-2-butenyl, propargyl,
cyclopropylmethyl or (2,2-dichlorocyclopropyl)methyl;
X is hydrogen, methyl or ethyl;
Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;
Z is hydrogen, methyl, ethyl or hydroxy; and
Z' is hydrogen, methyl or ethyl; or an acid addition salt
thereof.
One related process aspect of the invention sought to be patented
is the process which comprises reducing
1,2,3,4,5,6-hexahydro-3-Q'-8-nitro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzaz
ocine of Formula II by a method effective in reducing 8-nitro to
8-amino without otherwise reducing or transforming the molecule to
produce
1,2,3,4,5,6-hexahydro-3-Q'-8-amino-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzaz
ocine wherein:
Q' is hydrogen, benzyl, propyl, isobutyl, neopentyl, allyl,
2-methyl-2-propenyl, 2-chloro-2-propenyl, cis-3-chloro-2-propenyl,
cis-3-chloro-2-butenyl, trans-3-chloro-2-butenyl, propargyl,
cyclopropylmethyl or (2,2-dichloropropyl)methyl;
X is hydrogen, methyl or ethyl;
Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;
Z is hydrogen, methyl, ethyl or hydroxy; and
Z' is hydrogen, methyl or ethyl.
Another related process aspect of the invention sought to be
patented is the process which comprises nitrating
1,2,3,4,5,6-hexahydro-3-Q'-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocine
to produce
1,2,3,4,5,6-hexahydro-3-Q'-8-nitro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzaz
ocine of Formula II wherein:
Q' is hydrogen, benzyl, propyl, isobutyl, neopentyl, allyl,
2-methyl-2-propenyl, 2-chloro-2-propenyl, cis-3-chloro-2-propenyl,
cis-3-chloro-2-butenyl, trans-3-chloro-2-butenyl, propargyl,
cyclopropylmethyl of (2,2-dichlorocyclopropyl)methyl;
X is hydrogen, methyl or ethyl;
Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;
Z is hydrogen, methyl, ethyl or hydroxy; and
Z' is hydrogen, methyl or ethyl.
Still another related process aspect of the invention sought to be
patented is the process which comprises reducing
1,2,3,4,5,6-hexahydro-3-Q'-8-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benz
azocine by a reduction of the Birch type to produce
1,2,3,4,5,6,7,8,9,10-decahydro-3-Q'-8-oxo-5-X-6-Y-11-Z-11-Z'-2,6-methano-3
-benzazocine of Formula III wherein:
Q' is hydrogen, benzyl, propyl, isobutyl, neopentyl, allyl,
2-methyl-2-propenyl, 2-chloro-2-propenyl, cis-3-chloro-2-propenyl,
cis-3-chloro-2-butenyl, trans-3-chloro-2-butenyl, propargyl,
cyclopropylmethyl or (2,2-dichlorocyclopropyl)methyl;
X is hydrogen, methyl or ethyl;
Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;
Z is hydrogen, methyl, ethyl or hydroxy; and
Z' is hydrogen, methyl or ethyl.
One intermediate aspect of the invention sought to be patented is
1,2,3,4,5,6,7,8,9,10-decahydro-3-Q'-8-hydroxyimino-5-X-6-Y-11-Z-11-Z'-2,6-
methano-3-benzazocine having the formula ##STR4## wherein: Q' is
hydrogen, benzyl, propyl, isobutyl, neopentyl, allyl,
2-methyl-2-propenyl, 2-chloro-2-propenyl, cis(3-chloro-2-propenyl,
cis-3-chloro-2-butenyl, trans-3-chloro-2-butenyl, propargyl,
cyclopropylmethyl or (2,2-dichlorocyclopropyl)methyl;
X is hydrogen, methyl or ethyl;
Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;
Z is hydrogen, methyl, ethyl or hydroxy; and
Z' is hydrogen, methyl or ethyl; or an acid addition salt
thereof.
Another intermediate aspect of the invention sought to be patented
is
1,2,3,4,5,6-hexahydro-3-Q.degree.-8-RR'N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-
benzazocine having the formula ##STR5## wherein: Q.degree. is
hyrogen or benzyl;
R is hydrogen or methyl;
R' is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, benzyl or cyclopropylmethyl;
X is hydrogen, methyl or ethyl;
X is hydrogen, methyl, ethyl, propyl, allyl or phenyl;
Z is hydrogen, methyl, ethyl or hydroxy; and
Z' is hydrogen, methyl or ethyl; or an acid addition salt
thereof.
Still another intermediate aspect of the invention sought to be
patented is
1,2,3,4,5,6-hexahydro-3-Q'-8-RR'N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazo
cine having the formula ##STR6## wherein: Q" is formyl, acetyl or
Q* wherein Q* is propionyl, isobutryl, pivaloyl, acryloyl,
2-methylacryloyl, 2-chloroacryloyl, cis-3-chloroacryloyl,
cis-3-chlorocrotonyl, trans-3-chlorocrotonoyl, propiolyl,
cyclopropanecarbonyl or 2,2-dichlorocyclopropanecarbonyl;
R is hydrogen or methyl;
R' is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, benzyl or cyclopropylmethyl;
X is hydrogen, methyl or ethyl;
Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;
Z is hydrogen, methyl, ethyl or hydroxy; and
Z' is hydrogen, methyl or ethyl; or an acid addition salt
thereof.
Yet another intermediate aspect of the invention sought to be
patented is
1,2,3,4,5,6-hexahydro-3-Q"-8-nitro-5-X-6-11-Z'-2,6-methano-3-benzazocine
having the formula ##STR7## wherein: Q" is formyl, acetyl or Q*
wherein Q* is propionyl, isobutyryl, pivaloyl, acryloyl,
2-methylacryloyl, 2-chloroacryloyl, cis-3-chloroacryloyl,
cis-3-chlorocrotonoyl, trans-3-chlorocrotonoyl, propiolyl,
cyclopropanecarbonyl or 2,2-dichlorocyclopropanecarbonyl;
X is hydrogen, methyl or ethyl;
Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;
Z is hydrogen, methyl, ethyl or hydroxy; and
Z' is hydrogen, methyl or ethyl.
Even another intermediate aspect of the invention sought to be
patented is
1,2,3,4,5,6-hexahydro-3-Q'-8-RR"N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazo
cine having the formula ##STR8## wherein: Q' is .[.hydrogen,.].
benzyl, propyl, isobutyl, neopentyl, allyl, 2-methyl-2-propenyl,
2-chloro-2-propenyl, cis-3-chloro-2-propenyl,
cis-3-chloro-2-butenyl, trans-3-chloro-2-butenyl, propargyl,
cyclopropylmethyl or (2,2-dichlorocyclopropyl)methyl;
R is a hydrogen or methyl;
R" is formyl, acetyl, propionyl, butyryl, isobutyryl, benzoyl or
cyclopropanecarbonyl;
X is hydrogen, methyl or ethyl;
is hydrogen, methyl, ethyl, propyl, allyl or phenyl;
Z is hydrogen, methyl, ethyl or hydroxy; and
Z' is hydrogen, methyl or ethyl; or an acid addition salt
thereof.
Finally another intermediate aspect of the invention sought to be
patented is
1,2,3,4,5,6-hexahydro-3-Q"-8-RR"N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazo
cine having the formula ##STR9## wherein: Q" is formyl, acetyl or
Q* wherein Q* is propionyl, isobutyryl, pivaloyl, acryloyl,
2-methylacryloyl, 2-chloroacryloyl, cis-3-chloroacryloyl,
cis-3-chlorocrotonoyl, trans-3-chlorocrotonoyl, propiolyl,
cyclopropanecarbonyl or 2,2-dichlorocyclopropanecarbonyl;
R is hydrogen or methyl;
R" is formyl, acetyl, propionyl, butyryl, isobutyryl, benzoyl or
cyclopropanecarbonyl;
X is hydrogen, methyl or ethyl;
Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;
Z is hydrogen, methyl, ethyl or hydroxy; and
Z' is hyrogen, methyl or ethyl.
The compounds of Formulas II-IX are useful as intermediates for
preparing compounds of Formula I.
A process aspect of the invention sought to be patented is the
process which comprises dehydrating and rearranging
1,2,3,4,5,6,7,8,9,10-decahydro-3-Q'-8-hydroxyimino-5-X-6-Y-11-Z-11-Z'-2,6-
methano-3-benzazocine of Formula IV to produce
1,2,3,4,5,6-hexahydro-3-Q'-8-amino-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzaz
ocine wherein:
Q' is hydrogen, benzyl, propyl, isobutyl, neopentyl, allyl,
2-methyl-2-propenyl, 2-chloro-2-propenyl, cis-3-chloro-2-propenyl,
cis-3-propenyl, cis-3-chloro-2-butenyl, trans-3-chloro-2-butenyl,
propargyl, cyclopropylmethyl or
(2,2-dichlorocyclopropyl)methyl;
X is hydrogen, methyl or ethyl;
Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;
Z is hydrogen, methyl, ethyl or hydroxy; and
Z' is hydrogen, methyl or ethyl.
Another process aspect of the invention sought to be patented is
the process which comprises selectively hydrolyzing
1,2,3,4,5,6-hexahydro-3-Q"-8-RR"N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazo
cine of Formula IX by a method effective in removing R" without
removing Q" to produce
1,2,3,4,5,6-hexahydro-3-Q"-8-RHN-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazoc
ine wherein:
Q" is formyl, acetyl or Q* wherein Q* is propionyl, isobutyryl,
pivaloyl, acryloyl, 2-methylacryloyl, 2-chloroacryloyl,
cis-3-chloroacryloyl, cis-3-chlorocrotonoyl,
trans-3-chlorocrotonoyl, propiolyl, cyclopropanecarbonyl or
2,2-dichlorocyclopropanecarbonyl;
R is hydrogen or methyl;
R" is formyl, acetyl, propionyl, butyryl, isobutyryl, benzoyl or
cyclopropanecarbonyl;
X is hydrogen, methyl or ethyl;
Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;
Z is hydrogen, methyl, ethyl or hydroxy; and
Z' is hydrogen, methyl or ethyl.
Still another process aspect of the invention sought to be patented
is the process which comprises reducing
1,2,3,4,5,6-hexahydro-3-Q"-8-nitro-5-X-6-Y-11-Z'-2,6-methano-3-benzazocine
of Formula VII by a method effective in reducing 8-nitro to 8-amino
without otherwise reducing or transforming the molecule to produce
1,2,3,4,5,6-hexahydro-3-Q40
-8-amino-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocine wherein:
Q" is formyl, acetyl or Q* wherein Q* is propionyl, isobutyryl,
pivalolyl, acryloyl, 2-methylacryloyl, 2-chloroacryloyl,
cis-3-chloroacryloyl, cis-3-chlorocrotonoyl,
trans-3-chlorocrotonoyl, propiolyl, cyclopropanecarbonyl or
2,2-dichlorocyclopropanecarbonyl;
X is hydrogen, methyl or ethyl;
Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;
Z is hydrogen, methyl, ethyl or hydroxy; and
Z' is hydrogen, methyl or ethyl.
Yet another process aspect of the invention sought to be patented
is the process which comprises reducing 1,2,3,4,5,6-hexahydro-3-Q*
8-RR'N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocine of Formula VI
by a method effective in reducing 3Q* to 3Q without otherwise
reducing or transforming the molecule to produce
1,2,3,4,5,6-hexahydro-3-Q-8-RR'-N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazo
cine of Formula I wherein:
Q is propyl, isobutyl, neopentyl, allyl, 2-methyl-2-propenyl,
2-chloro-2-propenyl, cis-3-chloro-2-propenyl,
cis-3-chloro-2-butenyl, trans-3-chloro-2-butenyl, propargyl,
cyclopropylmethyl or (2,2-dichlorocyclopropyl)methyl; *L6 Q* is
propionyl, isobutyryl, pivaloyl, acryloyl, 2-methylacryloyl,
2-chloroacryloyl, cis-3-chloroacryloyl, cis-3-chlorocrotonoyl,
trans-3-chlorocrotonoyl, propiolyl, cyclopropanecarbonyl or
2,2-dichlorocyclopropanecarbonyl;
R is hydrogen or methyl;
R' is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, benzyl or cyclopropylmethyl;
X is hydrogen, methyl or ethyl;
Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;
Z is hydrogen, methyl, ethyl or hydroxy; and
Z' is hydrogen, methyl or ethyl.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of Formulas I-IX can each exist as one or the other
optical isomer or a mixture thereof. The features ##STR10## and C.
. Z' represent bonds oriented below the plane of the page if the
plane of the tetralin moiety is considered to be in the plane of
the page. When Z is methyl, ethyl or hydroxy, it is referred to as
equatorial (eq) with respect to the tetralin moiety and trans with
respect to Y. When Z is hydroxy, the 11-carbon atom is SR in
chirality and the compound is in the .alpha.-series of
benzomorphans as designated by May and coworkers (see Nathan B.
Eddy and Everette L. May, Synthetic Analgesics, Part IIB of Parts
IIA and IIB, Pergamon Press, Oxford, 1966, pp. 117-137). When Z' is
methyl or ethyl, it is referred to as axial (ax) with respect to
the tetralin moiety and cis with respect to Y. When X is methyl or
ethyl, it is referred to as equatorial with respect to the
hexahydrobenzazocine moiety and trans with respects to Y.
The compounds of Formulas I-VI and VIII are amino bases and react
with organic and inorganic acids to form acid addition salts. Due
to the presence of the basic amino grouping, the free base forms
represented by the formulas react with organic and inorganic acids
to form acid addition salts. The acid addition salt forms are
prepared from any organic or inorganic acid. They are obtained in
conventional fashion, for instance either by direct mixing of the
base with the acid or, when this is not appropriate, by dissolving
either or both of the base and the acid separately in water or an
organic solvent and mixing the two solutions, or by dissolving both
the base and the acid together in a solvent. The resulting acid
addition salt is isolated by filtration, if it is insoluble in the
reaction medium, or by evaporation of the reaction medium to leave
the acid addition salt as a residue. The acid moieties or anions in
these salt forms are in themselves neither novel nor critical and
therefore can be any acid anion or acid-like substance capable of
salt formation with the base.
Representative acids for the formation of the acid-addition salts
include formic acid, acetic acid, isobutyric acid,
alpha-mercaptopropionic acid, trifluoroacetic acid, malic acid,
fumaric acid, succinic acid, succinamic acid, tannic acid, glutamic
acid, tartaric acid, oxalic acid, pyromucic acid, citric acid,
lactic acid, glycolic acid, gluconic acid, saccharic acid, ascorbic
acid, penicillin, benzoic acid, phthalic acid, salicylic acid,
3,5-dinitrobenzoic acid, anthranilic acid, cholic acid,
2-pyridinecarboxylic acid, pamoic acid, 3-hydroxy-2-naphthoic acid,
picric acid, quinic acid, tropic acid, 3-indoleacetic acid,
barbituric acidm sulfamic acid, methanesulfonic acid,
ethanesulfonic acid, isethionic acid, benzenesulfonic acid,
p-toluenesulfonic acid, butylarsonic acid, methanephosphonic acid,
acidic resins, hydrofluoric acid, hydrochloric acid, hydrobromic
acid, hydriodic acid, perchloric acid, nitric acid, sulfuric acid,
phosphoric acid, arsenic acid, and the like. All of the acid
addition salts are useful as sources of the free bases by reaction
with a stronger base. Thus, if one or more characteristics such as
solubility, molecular weight, physical appearance, toxicity or the
like or a given base or acid addition salt thereof render that form
unsuitable for the purpose at hand, it can be readily converted to
another, more suitable form. For pharmaceutical purposes, acid
addition salts of relatively non-toxic, pharmaceutically-acceptable
acids, for example hydrochloric acid, lactic acid, tartaric acid,
and the like, are of course employed. Either the free bases or the
acid addition salts thereof may crystallize as crystalline solvates
with solvent of crystallization in integral or fractional amounts,
for example, as the hydrate sesquihydrate or ethanolate.
The manner and process of making and using the invention and the
best mode of carrying it out will now be described so as to enable
any person skilled in the art to which it pertains to make and use
it.
The process which comprises reducing
1,2,3,4,5,6-hexahydro-3-Q'-8-nitro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzaz
ocine of Formula II is carried out by any method effective in
reducing 8-nitro to 8-amino without otherwise reducing or
transforming the molecule, for example, by the use of iron and
aqueous hydrochloric acid. A cosolvent, for example, ethanol can be
used. A buffering agent, for example, sodium acetate, can also be
used. The rate of the reduction can be controlled by heating or
cooling. The process which comprises reducing
1,2,3,4,5,6-hexahydro-3-Q"-8-nitro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzaz
ocine of Formula VII is carried out similarly.
The process which comprises dehydrating and rearranging
1,2,3,4,5,6,7,8,9,10-decahydro-3-Q'-8-hydroxyimino-5-X-6-Y-11-Z-11-Z'-2,6-
methano-3-benzazocine of Formula IV is effectively an aromatization
process and is carried out by any method effective in dehydrating
the oxime without otherwise dehydrating or transforming the
molecule, for example, by the use of hydrochloric acid and acetic
anhydride. A solvent, for example, acetic acid, can be used. The
rate of the aromatization can be controlled by heating or cooling.
The use of hydrochloric acid and acetic anhydride on the compounds
of Formula IV produces the corresponding compounds of Formula VII
wherein R is hydrogen and R" is acetyl and the corresponding
compounds of Formula IX wherein R is hydrogen and Q" and R" are
both acetyl, which can be isolated or can be hydrolyzed without
isolation to remove acetyl.
The 8-nitro reductions and the 8-hydroxyimino
dehydration-rearrangement-hydrolysis sequence are alternative
processes and produce only the corresponding compounds of Formula
I, V and VI wherein R and R' are both hydrogen, which can be used
as intermediates for preparing the remaining compounds of Formulas
I, V and VI wherein R is methyl and R' is methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, benzyl or cyclopropylmethyl,
which are prepared either by alkylation or by an
acylation-reduction sequence. The alkylation is accomplished using,
for example, dimethyl sulfate, ethyl iodide, propyl bromide,
isopropyl bromide, butyl methanesulfonate, isobutyl bromide,
sec-butyl bromide, benzyl chloride or cyclopropylmethyl bromide.
Dimethylation is preferably accomplished by catalytic hydrogenative
methylation using formaldehyde and palladium-on-carbon as catalyst
or, alternatively, by reductive methylation using formaldehyde and
formic acid. Monobenzylation is preferably accomplished by
reductive benzylation using benzaldehyde and sodium borohydride.
The acylation step of the acylation reduction sequence affords the
corresponding compounds of Formulas VIII and IX and is accomplished
using, for example, formic-acetic anhydride, acetic anhydride,
propionic anhydride, butyric anhydride, isobutyryl chloride,
benzoyl chloride or cyclopropanecarbonyl chloride. The reduction
step of the acylation-reduction sequence is accomplished using, for
example, diborane or lithium aluminum hydride and results in the
simultaneous reduction of Q* in the compounds of Formula IX to the
corresponding Q in the compounds of Formula I.
A third alternative process for preparing the compounds of Formula
I is the process which comprises reducing the corresponding
1,2,3,4,5,6-hexahydro-3-Q*-8-RR'N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazo
cine of Formula VI, which is also accomplished using, for example,
lithium aluminum hydride.
Producing the desired combination Q, R and R' in the compounds of
Formula I may require the use of protecting groups during
N-alkylation or N-acylation. Benzyl is such a protecting group in
the compounds of Formula VIII wherein Q' is benzyl and can be
removed, for example, by catalytic hydrogenation using palladium as
catalyst. Formyl and acetyl are such protecting groups in the
compounds of Formula VI wherein Q" is formyl or acetyl and can be
removed, for example, by hydrolysis.
In the compounds of Formula IX R" is selectively removed without
removing Q" in the process which comprises selectively hydrolyzing
1,2,3,4,5,6-hexahydro-3-Q"-8-RR"N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazo
cine of Formula IX, which is accomplished using, for example,
dilute hydrochloric acid. The rate of the selective hydrolysis can
be controlled by heating or cooling.
The process which comprises nitrating
1,2,3,4,5,6-hexahydro-3-Q'-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocine
to produce
1,2,3,4,5,6-hexahydro-3-Q'-8-nitro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzaz
ocine of Formula II is carried out by any method effective in
substituting nitro for hydrogen at the 8-position of the aromatic
ring without otherwise transforming the molecule, for example, by
the use of nitric acid. A solvent is preferably used, for example,
acetic acid. The rate of the nitration can be controlled by heating
or cooling.
1,2,3,4,5,6-Hexahydro-3-Q"-8-nitro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzaz
ocine of Formula VII is similarly obtained by nitrating
1,2,3,4,5,6-hexahydro-3-Q"-5-X-6Y-11-Z-11-Z'-2,6-methano-3-benzazocine.
The process which comprises reducing
1,2,3,4,5,6-hexahydro-3-Q'-8-methoxy-5-X-6Y-11-Z-11-Z'-2,6-methano-3-benza
zocine is carried out by a reduction of the Birch type (The Merck
Index, Eighth Edition, Merck & Co., Rahway, N.J., 1968, p.
1146) using, for example, sodium and liquid ammonia. A cosolvent,
for example, a mixture of tetrahydrofuran and isopropyl alcohol can
be used.
1,2,3,4,5,6,7,10-Octahydro-3-Q'-8-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methano-3
-benzazocine is the immediate product and is easily hydrolyzed
using, for example, dilute hydrochloric acid to produce
1,2,3,4,5,6,7,8,9,10-decahydro-3-Q'-8-oxo-5-X-6-Y-11-Z-11-Z'-2,6-methano-3
-benzazocine of Formula III. If Q' is benzylic or allylic, it is
removed by the reduction, but can be replaced by one of the methods
described below.
The compounds of Formula IV are prepared from the corresponding
compounds of Formula III using hydroxylamine or an acid addition
salt thereof, for example, hydroxylamine hydrochloride.
In the compounds of Formulas VI, VII and IX Q" is introduced by
acylation of the corresponding compounds of Formula V wherein
Q.degree.is hydrogen, the compounds of Formula II wherein Q'is
hydrogen and the compounds of Formula VIII wherein Q' is hydrogen,
respectively, using, for example, formic-acetic anhydride, acetic
anhydride, propionyl chloride, isobutyryl chloride, pivaloyl
chloride, 2-methylacryloyl chloride, 2-chloroacryloyl chloride,
cis-3-chloroacryloyl chloride, cis-3-chlorocrotonoyl chloride,
trans-3-chlorocrotonoyl chloride, propiolyl chloride,
cyclopropanecarbonyl chloride or 2,2-dichlorocyclopropanecarbonyl
chloride. Alternatively, Q" is built into the compounds of Formula
VII by first acylating the corresponding
1,2,3,4,5,6-hexahydro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocine
and then nitrating the resulting
1,2,3,4,5,6-hexahydro-3-Q"-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocine
as described above.
Thus, Q can be built into the compounds of Formula I by an
acylation-reduction sequence through the corresponding Q*, which
appears in the compounds of Formulas VI, VII and IX, as described
above, or, alternatively, by alkylation in the corresponding
compounds of Formulas II, III and VIII wherein Q" is hydrogen, the
corresponding
1,2,3,4,5,6-hexahydro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocines
prior to 8-nitration or the corresponding
1,2,3,4,5,6-hexahydro-8-methoxy-5-X-6-Y-11-Z-11-Z'-4,6-methano-3-benzazoci
nes prior to the Birch reduction using, for example, propyl
bromide, isobutyl bromide, neopentyl bromide, allyl chloride,
2-methyl-2-propenyl chloride, 2-chloro-2-propenyl chloride,
cis-3-chloro-2-propenyl chloride, cis-3-chloro-2-butenyl chloride,
trans-3-chloro-2-butenyl chloride, propargyl bromide,
cyclopropylmethyl bromide or (2,2-dichlorocyclopropyl)methyl
bromide.
Some of the
1,2,3,4,5,6-hexahydro-3-Q'-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocines,
1,2,3,4,5,6-hexahydro-3-Q'-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzaz
ocines,
1,2,3,4,5,6-hexahydro-3-Q"-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocines
and
1,2,3,4,5,6-hexahydro-3-Q"-8-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benz
azocines are known; those which are not known are prepared from the
corresponding
1,2,3,4,5,6-hexahydro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocines
and
1,2,3,4,5,6-hexahydro-8-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazoci
nes by the methods described above. Some of the
1,2,3,4,5,6-hexahydro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocines
and
1,2,3,4,5,6-hexahydro-8-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methoxy-3-benzazoci
nes are known; those which are not known are prepared, for example,
from the corresponding
1,2,3,4,5,6-hydrohydro-3-methyl-5-X-6-Y-11-Z-11-Z'
-2,6-methano-3-benzazocines and
1,2,3,4,5,6-hexahydro-3-methyl-8-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-
benzazocines, for example, by cyanogenation with cyanogen bromide
followed by hydrolysis of the resulting
1,2,3,4,5,6-hexahydro-3-cyano-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocine
s and
1,2,3,4,5,6-hexahydro-3-cyano-8-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-b
enzazocines. Those
1,2,3,4,5,6-hexahydro-3-methyl-8-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-
benzazocines which are not known are prepared from the
corresponding
1,2,3,4,5,6-hexahydro-3-methyl-8-hydroxy-5X-6-Y-11-Z-11-Z'-2,6-methano-3-b
enzazocines by O-methylation using, for example, diazomethane.
The various combinations of the Z-, Y-, Z- and Z'-substituents in
the
1,2,3,4,5,6-hexahydro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocines
and
1,2,3,4,5,6-hexahydro-8-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazoci
nes are known or are prepared by known methods. See, for example,
Eddy and May (reference cited above) Parfitt and Walters (J. Med.
Chem., Vol. 14, No. 7, 1971, pp. 565-568), May and co-workers (J.
Med. Chem., Vol. 12, No. 2, 1969, pp. 405.408), U.S. Pat. No.
3,320,265, British Pat. Nos. 1,299,699 and 1,299,700 and
Netherlands Application No. 73/14758.
The following examples illustrate the invention. Structures of
compounds are inferred from reaction types. Confirmations of
structures are made by analyses of the elements, ultraviolet
spectra, infrared spectra, nuclear magnetic resonance spectra
and/or mass spectra. Courses of reactions and homogeneities of
products are ascertained by thin layer chromatography and/or
gas-liquid chromatography. Melting and boiling points or ranges are
uncorrected unless otherwise indicated.
EXAMPLE 1
A. A solution of
3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-
3-benzazocine (Example 1 of U.S. Pat. No. 3,382,249, 11.0 g.) in
acetic acid (50 ml.) was added with stirring and cooling (at
2.5.degree.-5.degree. C.) to a solution of red fuming nitric acid
(155 ml.) and acetic acid (90 ml.). The temperature was allowed to
rise slowly to room temperature. After being allowed to stand
overnight the solution was purged with a stream of air, then
partially evaporated (at 55.degree.-60.degree. C.) under reduced
pressure to a yellow liquid (148 g.), to which was added a solution
of sodium hydroxide (85 g.) in water. A solution of the resulting
product in chloroform was washed with water, dried and
concentrated, affording a red syrup (11.6 g.). A solution of the
red syrup in ether was filtered. Addition of ethereal hydrochloric
acid to the filtrate and recrystallization of the product (10.3 g.)
from ethanol afforded off-white crystals of
3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-8-nitro-2,6-
methano-3-benzazocine hydrochloride (7.2 g., m.p.
283.degree.-284.degree. C.). The free base obtained as an orange
syrup from the salt using sodium hydroxide and is the compound of
Formula II wherein Q' is cyclopropylmethyl, X is hydrogen, Y is
methyl, Z is hydrogen and Z' is methyl.
B. Iron powder (13.2 g.) was added portionwise to a solution of
3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-8-nitro-2,6-
methano-3-benzazocine (the free base product of part (A) of this
example, 11.6 g.) water (35 ml.), ethanol (60 ml.) and concentrated
hydrochloric acid (3.66 ml.) and the mixture was stirred under
reflux. Sodium bicarbonate (5 g.) was added, the resulting mixture
was filtered and the filtrate was concentrated under reduced
pressure. Ether and ethanol were added to the residual yellow
syrup, the resulting mixture was filtered and the filtrate was
concentrated. Hydrogen chloride was added to a solution of part
(5.47 g.) of the resulting red syrup (10.4 g.) in ethanol.
Recrystallization of the product (m.r. 303.degree.-306.degree. C.)
from methanol-ether afforded off-white crystals of
8-amino-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-
methano-3-benzazocine dihydrochloride (2.71 g., m.p.
314.degree.-316.degree. C.), the free base of which is the compound
of Formula I wherein Q is cyclopropylmethyl, R is hydrogen, R' is
hydrogen, X is hydrogen, Y is methyl, Z is hydrogen and Z' is
methyl.
C. A solution of the
1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine
(the free base of which is the compound described as
5,9-dimethyl-6,7-benzomorphan picrate and hydrochloride at J. Org.
Chem., 24, 117 (1959); 40.4 g.) in acetic acid (320 ml.) was added
to a solution of nitric acid (90%, 600 ml.) and acetic acid (400
ml.) with cooling (to 5.degree..+-.1.degree.C.) and stirring. The
resulting mixture was allowed to warm to room temperature, poured
onto ice (4500 ml.), basified with sodium hydroxide solution (35%)
and extracted with ether. The ether extracts were dried and
concentrated, affording a syrup (40.0 g.). Hydrogen chloride was
added to a solution of the syrup in acetone. Recrystallization of
the product (27.5 g., m.p. 252.degree.-255.degree. C.) from ethanol
afforded as a white powder
1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-nitro-2,6-methano-3-benzazoc
ine hydrochloride (16.9 g., m.p. 266.degree.-268.degree. C.), the
free base of which is the compound of Formula II wherein Q' is
hydrogen, X is hydrogen, Y is methyl, Z is hydrogen and Z' is
methyl.
D. Acylation of 1,2,3,4,5,6-hexahydro-6(eq),
11(ax)-dimethyl-8-nitro-2,6-methano-3-benzazocine (the free base of
the product of part (C) of this example) with cyclopropanecarbonyl
chloride provides
1,2,3,4,5,6-hexahydro-3-cyclopropanecarbonyl-8-nitro-6(eq),11-(ax)-dimethy
l-2,6-methano-3-benzazocine, the compound of Formula VII wherein Q"
is cyclopropanecarbonyl, X is hydrogen, Y is methyl, Z is hydrogen
and Z' is methyl.
E. Reduction of
1,2,3,4,5,6-hexahydro-3-cyclopropanecarbonyl-8-nitro-6(eq),11(ax)-dimethyl
-2,6-methano-3-benzazocine (the product of part (D) of this
example) using iron and hydrochloric acid provides
1,2,3,4,5,6-hexahydro-3-cyclopropanecarbonyl-8-amino-6(eq),11(ax)-dimethyl
-2,6-methano-3-benzazocine, the compound of Formula VI wherein Q"
is cyclopropanecarbonyl, R is hydrogen, R' is hydrogen, X is
hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.
F. Reduction of
1,2,3,4,5,6-hexahydro-3-cyclopropanecarbonyl-8-amino-6(eq),11(ax)-dimethyl
-2,6-methano-3-benzazocine (the product of part (E) of this
example) using lithium aluminum hydride provides
8-amino-3-cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-m
ethano-3-benzazocine, which is identical with the free base product
of part B of this example.
G. A solution of
3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-8-methoxy-6-(eq),11(ax)-dimeth
yl-2,6-methano-3-benzazocine (the free base product of part (A) of
Example 20 of U.S. Pat. No. 3,372,165, 50.0 g.), tetrahydrofuran
(500 ml.) and isopropyl alcohol (500 ml.) was added with stirring
to liquid ammonia (about 1.51.) under reflux. Sodium (69.5 g.) was
then added in small (about 1 g.) pieces with continued stirring
(during 1/2 hr.). After the blue color of the solution had
disappeared (about 1 hr. more), methanol (200 ml.) was added, the
condenser was removed and the ammonia was allowed to evaporate
overnight. The residual cloudy solution was diluted with water and
extracted with ether (three 300 -ml. portions). The ether extracts
were washed with water and brine, dried and concentrated, affording
3-(cyclopropylmethyl)-1,2,3,4,5,6,7,10-octahydro-8-methoxy-6(eq),11(ax)-di
methyl-2,6-methano-3-benzazocine (45.4 g.), part (10- and 20-g.
portions) of which was converted into the hydrochloride salt using
ethereal hydrogen chloride and concurrently hydrolyzed. Three
recrystallizations of the combined salt portions from
benzene-methanol afforded white fine crystals of
3-(cyclopropylmethyl)-1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl-8-o
xo-2,6-methano-3-benzazocine hydrochloride (about 8.5 g., m.p.
206.degree.-208.degree. C.), the free base of which is the compound
of Formula III wherein Q' is cyclopropylmethyl, X is hydrogen, Y is
methyl, Z is hydrogen and Z' is methyl.
H. A mixture of
3-(cyclopropylmethyl)-1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl-8-o
xo-2,6-methano-3-benzazocine hydrochloride (the product of part G
of this example, 1.0 g.), hydroxylamine hydrochloride (0.24 g.),
ethanol (5 ml.) and pyridine (5 ml.) was refluxed (for 3 hr.),
diluted with water, basified with sodium bicarbonate and extracted
with cloroform. The chloroform extracts were dried and
concentrated. Recrystallization of the residue from ethanol
afforded
3-(cyclopropylmethyl)-1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl-2,6
-methano-3-benzazocine-8-one oxime, the compound of Formula IV
wherein Q' is cyclopropylmethyl, X is hydrogen, Y is methyl, Z is
hydrogen and Z' is methyl. On larger scale the product was obtained
as off-white crystals (m.p. 190.degree.-193.degree. C.).
I. Acetic anhydride (1.02 g.) was added to a solution of
3-(cyclopropylmethyl)-1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl-2,6
-methano-3-benzazocine-8-oxime (the product of part (H) of this
example, 2.2 g.) in acetic acid (20 ml.). Gaseous hydrogen chloride
was bubbled through the solution, which was then refluxed (for 1
hr.) and stripped of solvents. Dilute hydrochloric acid (2N) was
added to the residue and the mixture was heated on the steam bath
(for 2 hr.), basified with aqueous ammonia and extracted with
chloroform. The chloroform extracts were dried and concentrated.
Ethereal hydrogen chloride was added to a solution of the residue
in methanol, affording
8-amino-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-
methano-3-benzazocine dihydrochloride, the infrared spectrum of
which showed that it was identical with the salt product of part
(B) of this example.
EXAMPLE 2
A. A solution of
1,2,3,4,5,6-hexahydro-8-methoxy-cis-6,11-dimethyl-2,6-methano-3-benzazocin
e (described as 2'-methoxy-5,9-dimethyl-6,7-benzomorphan at J. Org.
Chem., 25, 986 (1960); 9.25 g.), tetrahydrofuran (130 ml.) and
isopropyl alcohol (130 ml.) was added with stirring to liquid
ammonia (about 400 ml.) under reflux. Sodium was then added in
pieces (about 15) with continued stirring (during 1/2 hr.). After
further stirring and disappearance of the blue color (about 4 hr.
more), methanol (40 ml.) was added and the mixture was warmed to
room temperature and allowed to stand overnight. The residual
colorless, cloudy solution was diluted with water (600 ml.) and
extracted with ether (two 400-ml. portions). The ether extracts
were washed with saturated salt solution, dried and concentrated,
affording
1,2,3,4,5,6,7,10-octahydro-8-methoxy-6(eq),11(ax)-dimethyl-2,6-methano-3-b
enzazocine (9.3 g.) as a yellow-brown oil.
Concentrated hydrochloric acid (8 ml. was added to a solution of
1,2,3,4,5,6,7,10-octahydro-8-methoxy-6(eq),-11-(ax)-dimethyl-2,6-methano-3
-benzazocine (21 g.) in acetone (50 ml.) and the mixture was kept
cold (0.degree. C.) for 5 days. The crystalline product was
collected in two corps. Each crop was separately recrystallized
from acetone-water and the products were combined, affording
off-white crystals of
1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl-2,6-methano-3-benzazocine
-8-one hydrochloride (11 g., 198.degree.-201.degree. C.), the free
base of which is the compound of Formula III wherein Q' is
hydrogen, X is hydrogen, Y is methyl, Z is hydrogen and Z' is
methyl.
B. A solution of
1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl-2,6-methano-3-benzazocine
-8-one hydrochloride (the product of part (A) of this example, 2.0
g.), hydroxylamine hydrochloride (0.6 g.), pyridine (10 ml.) and
ethanol (20 ml.) was refluxed (for 2 hr.), then concentrated. The
product was triturated with isopropyl alcohol and dried, affording
off-white crystals of
1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl-2,6-methano-3-benzazocine
-8-one oxime hydrochloride (1.8 g., m.p. 237.degree.-240.degree.
C.), the free base of which is the compound of Formula IV wherein
Q' is hydrogen, X is hydrogen, Y is methyl, Z is hydrogen and Z' is
methyl.
C. Gaseous hydrogen chloride was bubbled through a mixture of
1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl-2,6-methano-3-benzazocin-
8-one oxime hydrochloride (the product of part (B) of this example,
4.0 g.), acetic anhydride (2.0 g.) and acetic acid (15 ml.). The
resulting red solution was heated to reflux; the hydrogen chloride
stream was stopped; and the solution was refluxed (for 3 hrs.),
then concentrated. A solution of the residual red syrup in dilute
hydrochloric acid (6N, 50 ml.) was heated on a steam bath (for 1
hr.) and concentrated. Recrystallization of the resulting purple
crystals from aqueous alcohol afforded light orchid crystals of
8-amino-1,2,3,4,5,6,-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine
dihydrochloride hydrate (4 g., m.p.>280.degree. C.), the free
base of which is the compound of Formula V wherein Q.degree. is
hydrogen, R is hydrogen, R' is hydrogen, X is hydrogen, Y is
methyl, Z is hydrogen and Z' is methyl.
D. A mixture of
8-amino-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine
dihydrochloride hydrate (the product of part (C) of this example, 2
g.), cyclopropanecarbonyl chloride (3 g.), saturated sodium
bicarbonate solution (20 ml.) and chloroform (30 ml.) was stirred
at ice temperature (for 1 hr.) and then at room temperature (for 1
hr.). The chloroform layer was washed with saturated sodium
bicarbonate solution and concentrated, affording as a yellow oil
N-(3-cyclopropanecarbonyl)-1,2,3,4,5,6-hexahydro-6-(eq),11(ax)-dimethyl-2,
6-methano-3-benzazocin-8-yl)cyclopropanecarboxamide (3.2 g.), the
compound of Formula IX wherein Q' is cyclopropanecarbonyl, R is
hydrogen, R" is cyclopropanecarbonyl, X is hydrogen, Y is methyl, Z
is hydrogen and Z' is methyl.
E. A solution of
N-(3-(cyclopropanecarbonyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,
6-methano-3-benzazocine-8-yl)cyclopropanecarboxamide (the product
of part (D) of this example, 3.8 g.) in tetrahydrofuran (30 ml.)
was added to a solution of diborane in tetrahydrofuran (1M as
BH.sub.3, 50 ml.) with cooling at ice temperature, then the mixture
was heated under reflux (for 2 hr.) Dilute hydrochloric acid (5N,
100 ml.) was added cautiously and the clear solution was
concentrated under reduced pressure. The aqueous residue was washed
with ether, basified with sodium hydroxide solution (35%) and
extracted with chloroform. The chloroform extracts were dried and
concentrated to a red oil (3.2 g.). A similar reduction of
N-[3-(cyclopropanecarbonyl)-1,2,3,4,5,6-hexahydro-6-(eq),11(ax)-dimethyl-2
,6-methano-3-benzazocine-8-yl]cyclopropanecarboxamide (5.8 g.) also
afforded a red oil (5 g.) Crystallization of the red oil from
isopropyl acetate afforded white crystals of
3-(cyclopropylmethyl)-8-(cyclopropylmethylamino)-1,2,3,4,5,6-hexahydro-cis
-6,11-dimethyl-2,6-methano-3-benzazocine hydrochloride (m.p.
229.degree.-232.degree. C), the free base of which is the compound
of Formula I wherein Q is cyclopropylmethyl, R is hydrogen, R' is
cyclopropylmethyl, X is hydrogen, Y is methyl, Z is hydrogen and Z'
is methyl.
EXAMPLE 3
A. Formic acid (10 ml.) was added dropwise with cooling (to
0.degree. C.) to acetic anhydride (20 ml.) and the resulting
solution was heated (to 50.degree. C. for 1/4 hr.). A solution of
8-amino-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-
methano-3-benzazocine (the free base product of part (B) of Example
1, 6.7 g.) in formic acid (20 ml.) was added dropwise with cooling
(to 0.degree. C.). The resulting mixture was refrigerated overnight
and stripped of solvents. The residue was basified with sodium
bicarbonate, then with concentrated aqueous ammonia, and extracted
with ether. The ether extracts were dried and stripped of ether,
affording N-(3-cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6(eq),
11(ax)-dimethyl-2,6-methano-3-benzazocin-8-yl)-formamide (5 g.),
the compound of Formula VIII wherein Q' is cyclopropylmethyl R is
hydrogen, R" is formyl, X is hydrogen, Y is methyl, Z is hydrogen
and Z' is methyl.
B. A mixture of
N-(3-cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-me
thano-3-benzazocin-8-yl)formamide (the product of part (A) of this
example, 5 g.) and a solution of diborane in tetrahydrofuran (1 M
as BH.sub.3, 80 ml.) was refluxed (for 3 hr.), acidified with
dilute hydrochloric acid (6N) and stripped of tetrahydrofuran. The
aqueous residue was washed with ether, basified with sodium
hydroxide and extracted with ether. The ether extracts were dried
and stripped of ether. Ethereal hydrogen chloride was added to a
solution of the product (3.5 g.) in ethanol, affording off-white
crystals of
3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-8-(methylami
no)-2,6-methano-3-benzazocine dihydrochloride ethanolate hydrate
(m.p. > 250.degree. C.), the free base of which is the compound
of Formula I wherein Q is cyclopropylmethyl), R is hydrogen, R' is
methyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is
methyl.
EXAMPLE 4
A. A mixture of
8-amino-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine
dihydrochloride hydrate (the product of part (C) of Example 2, 10
g.), acetic anhydride (20 ml.) and pyridine (100 ml.) was heated on
a steam bath (for 4 hr.) and stripped of solvents, affording
N-(3-acetyl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benz
azocin-8-yl)acetamide, the compound of Example IX wherein Q" is
acetyl, R is hydrogen, R" is acetyl, X is hydrogen, Y is methyl, Z
is hydrogen and Z' is methyl.
B. A mixture of the entire product of part A of this example and
dilute hydrochloric acid (2N) ethanol (1:1) was heated on a steam
bath (for 2 hr.), stripped of ethanol, cooled, basified with
ammonia and extracted with ether. The ether extracts were dried.
The product crystallized from the ether solution and was
recrystallized from ethyl acetate, affording off-white crystals of
3-acetyl-8-amino-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-ben
zazocine (m.p. 208.degree.-209.degree. C.), the compound of Formula
VI wherein Q" is acetyl, R is hydrogen, R' is hydrogen, X is
hydrogen, Y is methyl, Z is hydrogen and Z' is hydrogen.
C. A mixture of
3-acetyl-8-amino-1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-methano-3-benzazo
cine (the product of part (B) of this example, 20 g.), formalin
(35-40%, 25 ml.), ethanol (180 ml.) and a catalytic amount of
palladium-on-carbon (10%) was hydrogenated on a Parr apparatus (at
55.degree. C.), then filtered. The filtrate was concentrated and
the residue was dissolved in ether. The ether solution was dried
and stripped of ether, affording as an oil
3-acetyl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-(dimethylamino)-2,6
-methano-3-benzazocine (17.7 g.), the compound of Formula VI
wherein Q" is acetyl, R is methyl, R' is methyl, X is hydrogen, Y
is methyl, Z is hydrogen and Z' is methyl.
D. A mixture of
3-acetyl-1,2,3,4,5,6-hexahydro-6(eq),-88(ax)-dimethyl-8-(dimethylamino)-2,
5-methano-3-benzazocine (the product of part (C) of this example,
17 g.) and concentrated hydrochloric acid (200 ml.) was reflixed
(for 30 hr.), then concentrated. A mixture of the residue and water
was basified with concentrated aqueous ammonia and extracted with
chloroform. The chloroform extracts were dried and concentrated.
The picrate salt of the product was recrystallized from aqueous
ethanol and freed of picric acid. The oxalate salt of the product
was recrystallized three times from absolute ethanol and freed of
oxalic acid, affording as an oil
1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-(dimethylamino)-2,6-methano-
3-benzazocine, the compound of Formula V wherein Q' is hydrogen, R
is methyl, R' is methyl, X is hydrogen, Y is methyl, Z is hydrogen
and Z' is methyl.
e. cyclopropanecarbonyl chloride (4ml.) was added dropwise with
stirring and cooling to ice temperature to a mixture of
1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-(dimethylamino)-2,6-methano-
3-benzazocine oxalate (the oxalate salt product of part (D) of this
example, 3.5 g.), chloroform (100 ml.) and dilute sodium hydroxide
solution (1N, 100 ml.). Stirring was continued at room temperature
(for 3 hr.) and the mixture was basified with sodium hydroxide. The
chloroform layer was washed with saturated sodium bicarbonate
solution, dried and stripped of chloroform, affording
3-(cyclopropanecarbonyl)-1,2,3,4,5,6-hexahydro-6(eq),
11(ax)-dimethyl-8-dimethylamino)-2,6-methano-3-benzazocine (4g.),
the compound of Formula VI wherein Q" is cyclopropanecarbonyl, R is
methyl, R' is methyl, X is hydrogen, Y is methyl, Z is hydrogen and
Z' is methyl.
F. A solution of
3-(cyclopropanecarbonyl)-1,2,3,4,5,6-hexahydro-6(eq.),11(ax)-dimethyl-8-(d
imethylamino)-2,6-methano-3-benzazocine (the product of part (E) of
this example, 4 g.) in tetrahydrofuran (20 ml.) was added dropwise
with stirring to a slurry of lithium aluminum hydride (2 g.) in
tetrahydrofuran (70 ml.). The mixture was refluxed (for 3 hr.),
then cooled. Saturated sodium potassium tartrate solution was added
and the tetrahydrofuran layer was decanted and concentrated. A
solution of the residue in ether was washed with water, dried and
concentrated. Treatment of the residue with hydrogen chloride and
two recrystallization of the product from ethanol afforded as an
off-white powder
3-cyclopropylmethyl-8-dimethylamino-cis-6,11-dimethyl-1,2,3,4,5,6-hexahydr
o-2,6-methano-3-benzazocine dihydrochloride (m.p.
243.degree.-246.degree. C.), the free base of which is the compound
of Formula I wherein Q is cyclopropylmethyl, R is methyl, R' is
methyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is
hydrogen and Z' is methyl.
G. A mixture of 1,2,3,4,5,6-hexahydro-6(eq,11
11(ax)-dimethyl-8-nitro-2,6-methano-3-benzazocine hydrochloride
(the product of part (C) of Example 1, 14.2 g), sodium bicarbonate
(9.5 g.), benzyl chloride (5.8 ml.) and N,N-dimethylformamide (90
ml.) was refluxed (for 4 hr.), the filtered, and the filtrate was
concentrated. A solution of the residual syrup in ether was
filtered and acidified with ethereal hydrogen chloride. Two
recrystallizations of the product (18.2 g.) from ethanol afforded
as an off-white powder
1,2,3,4,5,6-hexahydro-3-benzyl-6(eq),11(ax)-dimethyl-8-nitro-3-benzazocine
hydrochloride (257.+-.258.degree. C.), the free base of which is
the compound of Formula II wherein Q' is benzyl, X is hydrogen, Y
is methyl, Z is hydrogen and Z' is methyl.
H. Reduction of
1,2,3,4,5,6-hexahydro-3-benzyl-6(eq),-11-(ax)-dimethyl-8-nitro-3-benzazoci
ne hydrochloride (the product of part (G) of this example) using
iron and hydrochloric acid provides
8-amino-3-benzyl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3
-benzazocine, the compound of Formula V wherein Q.degree. is
benzyl, R is hydrogen, R' is hydrogen, X is hydrogen, Y is methyl,
Z is hydrogen and Z' is methyl.
I. Reductive methylsation of
8-amino-3-benzyl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3
-benzazocine (the product of part (H) of this example) using
formaldehyde and formic acid provides
3-benzyl-1,2,3,4,5,6-hexahydro-6(eq),
11(ax)-dimethyl-8-(dimethylamino)-2,6-methano-3-benzazocine, the
compound of Formula V wherein Q' is benzyl, R is methyl, R' is
methyl, X is hydrogen, Y is methyl, Y is methyl, Z is hydrogen and
Z' is methyl.
J. Debenzylation of
3-benzyl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-(dimethylamino)-2,6
-methano-3-benzazocine (the product of part I of this example) by
catalytic hydrogenation using palladium as catalyst provides
1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-(dimethylamino)-2,6-methano-
3-benzazocine, which is identical with the product of part D of
this example.
K. Acylation of
1,2,3,4,5,6-hexahydro-6-(eq),11(ax)-dimethyl-8-(dimethylamino)-2,6-methano
-3-benzazocine (the product of part (D) of this example) with
cyclopropanecarbonyl chloride provides
3-(cyclopropanecarbonyl)-1,2,3,4,5,6-hexahydro-6-(eq),
11(ax)-dimethyl-8-(dimethylamino)-2,6-methano-3-benzazocine, which
is identical with the product of part (E) of this example.
EXAMPLE 5
A. Isobutyryl chloride (8 ml.) was added dropwise to a solution of
8-amino-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine
(the free base of the product of part (C) of Example 2, 4 g.) and
chloroform. Saturated sodium bicarbonate solution (50 ml.) was
added and the mixture was refluxed (for 2 hr.). The chloroform
layer was washed was saturated sodium bicarbonate solution, dried
and concentrated, affording as a red oil
N-(3-isobutyryl-1,2,3,4,5,6-hexahydro-6-(eq),11(ax)-dimethyl-2,6-methano-3
-benzazocin-8-yl)isobutyramide, the compound of Formula IX wherein
Q" is isobutyryl, R is hydrogen, R" is isobutyryl, X is hydrogen, Y
is methyl, Z is hydrogen and Z' is methyl.
B. A solution of
N-(3-isobutyryl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-
benzazocin-8-yl)isobutyramide (the product of part (A) of this
example, 5 g.), dilute hydrochloric acid (6N, 200 ml.) and ethanol
(100 ml.) was heated on a steam bath (for 3 hr.), stripped of
ethaol, washed with ether, basified with sodium hydroxide and
extracted with ether. The ether extracts were dried and
concentrated, affording
8-amino-3-isobutyryl-1,2,3,4,5,6-hexahydro-6(eq),
11(ax)-dimethyl-2,6-methano-3-benzazocine (about 4 g.), the
compound of Formula VI wherein Q" is isobutyryl, R is hydrogen, R'
is hydrogen, X is hydrogen, Y is methyl, Z is hydrogen and Z' is
methyl.
C. A solution of
8-amino-3-isobutyryl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-metha
no-3-benzazocine (the product of part (B) of this example, 4 g.) in
tetrahydrofuran (50 ml.) was added with stirring to a slurry of
lithium aluminum hydride (2.5 g.) in tetrahydrofuran (100 ml.).
Stirring was continued and the mixture was refluxed (for 3 hr.),
the cooled. Saturated sodium potassium bitartrate solution was
added and the tetrahydrofuran layer was decanted and concentrated.
Ethereal hydrogen chloride was added to a solution of the residue
in ethanol. Recrystallization of the resulting solid from
ethanol-ether and then from aqueous ethanol containing concentrated
hydrochloric acid afforded as an off-white powder
8-amino-1,2,3,4,5,6-hexahydro-3-isobutyl-cis-6,11-dimethyl-2,6-methano-3-b
enzazocine dihydrochloride (m.p.> 300.degree. C.), the free base
of which is the compound of Formula I wherein Q is isobutyl, R is
hydrogen, R' is hydrogen, X is hydrogen, Y is methyl, Z is hydrogen
and Z' is methyl.
EXAMPLE 6
A. A mixture of
8-amino-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine
(the free base of the product of part (C) of Example 2, 3g.),
chloroform (80 ml.), saturated sodium bicarbonate solution (80 ml.)
and propionyl chloride (5 ml.) was stirred at room temperature (for
2 hr.). The chloroform layer was dried and concentrated, affording
as a red oil
N-(3-propionyl-1,2,3,4,5,6-hexahydro-6-(eq),11(ax)-dimethyl-2,6-methano-3-
benzazocin-8-yl)-propionamide (4.2 g.), the compound of Formula IX
wherein Q" is propionyl, R is hydrogen, R" is propionyl, X is
hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.
B. A mixture of the entire product of part (A) of this example,
ethanol (50 ml.) and dilute hydrochloric acid (5N, 25 ml.) was
heated on a steam bath (for 1 hr.), then diluted with water. The
resulting mixture was washed with ether, basified with ammonia and
extracted with ether. The ether extracts were washed with brine,
dried and concentrated, affording as a red oil
8-amino-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-3-propionyl-2,6-methan
o-3-benzazocine (3 g.), the compound of Formula VI wherein Q" is
propionyl, R is hydrogen, R' is hydrogen, X is hydrogen, Y is
methyl, Z is hydrogen and Z' is methyl.
C. A solution of the entire product of part (B) of this example in
tetrahydrofuran was added with stirring to a slurry of lithium
aluminum hydride (0.6 g.) in tetrahydrofuran (about 50 ml. in all).
The mixture was stirred under reflux (for 1 hr.), then cooled.
Saturated potassium sodium tartrate solution was added and the
mixture was filtered. The filtrate was concentrated. Treatment of
the residual red oil with hydrogen chloride and recrystallization
of the product from methanol-ether afforded as an off-white powder
8-amino-cis-6,11-dimethyl-1,2,3,4,5,6-hexahydro-3-propyl-2,6-methano-3-ben
zazocine dihydrochloride sesquihydrate (m.r.
202.degree.-207.degree. C.), the free base of which is the compound
of Formula I wherein Q is propyl, R is hydrogen, R' is hydrogen, X
is hydrogen, Y is methyl, Z is hydrogen and Z' is hydrogen.
EXAMPLE 7
A solution of
8-amino-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-meth
ano-3-benzazocine (the free base product of part (B) of Example 1,
4.4 g.), benzaldehyde (3.2 g.) and ethanol (100 ml.) was refluxed
(for 2.5 hr.), then cooled. Sodium borohydride (1.0 g.) was added
and the resulting solution was stirred at room temperature (for 2
hr.), then concentrated. The residue was diluted with hydrochloric
acid (6%), washed with ether, basified with sodium hydroxide and
extracted with ether. The ether extracts were washed with brine,
dried and concentrated. Treatment of the residual red oil (5.2 g.)
with hydrogen chloride and recrystallization of the product from
ethanol afforded as a white powder
3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-8-benzylamino-2,
6-methano-3-benzazocine dihydrochloride (m.r.
233.degree.-237.degree. C.), the free base of which is the compound
of Formula I wherein Q is cyclopropylmethyl, R is hydrogen, R' is
benzyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is
methyl.
EXAMPLE 8
A. A mixture of
1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethy-2,6-methano-3-benzazocin-8
-one hydrochloride (the product of part (A) of Example 2, 5.12 g.),
allyl bromide (2.42 g.), sodium bicarbonate (3.36 g. ) and
N,N-dimethylformamide (about 50 ml.) was heated (at 140.degree. C.)
with stirring under nitrogen (for 1 hr.), then concentrated. The
residue was mixed with water, ether and saturated sodium
bicarbonate solution. The ether layer was dried, treated with
charcoal and concentrated. Addition of ethereal hydrogen chloride
to a solution of the residue in ethaol and recrystallization of the
product from ethanol-ether afforded
3-allyl-1,2,3,4,5,6,7,8,9,10-decahydro-6(eq),11-(ax)-dimethyl-2,6-methano-
3-benzazocin-8-one hydrochloride (4 g.), the free base of which is
the compound of Formula III wherein Q' is allyl, X is hydrogen, Y
is methyl, Z is hydrogen and Z' is methyl.
B. A mixture of
3-allyl-1,2,3,4,5,6,7,8,9,10-decahydro-6-(eq),11(ax)-dimethyl-2,6-methano-
3-benzazocin-8-one hydrochloride (the product of part (A) of this
example, 1.7 g.), hydroxylamine hydrochloride (0.4 g.) pyridine
(about 10 ml.) and ethanol (about 20 ml.) was refluxed (for 2 hr.),
the concentrated. Recrystallization of the residue from ethanol
afforded
3-allyl-1,2,3,4,5,6,7,8,9,10-decahydro-6-(eq),11(ax)-dimethyl-2,6-methano-
3-benzazocin-8-one oxime hydrochloride, the free base of which is
the compound of Formula IV wherein Q' is allyl, X is hydrogen, Y is
methyl, Z is hydrogen and Z' is methyl.
C. A refluxing mixture of
3-allyl-1,2,3,4,5,6,7,8,9,10-decahydro-6(eq),11(ax)-dimethyl-2,6-methano-3
-benzaocin-8one oxime hydrochloride (the product of part (B) of
this example, 2.1 g.), acetic anhydride (0.7 g.) and acetic acid
(about 30 ml.) was saturated with gaseous hydrogen chloride. The
resulting red solution was stirred under reflux (for 2 hr.) then
concentrated. A mixture of the residue and dilute hydrochloride
acid (2N, 40 ml.) was heated on a steam bath (for 1 hr.), then
concentrated. Crystallization of the residue from ethanol and
recrystallization of the product from ethanol afforded as an
off-white powder
8-amino-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-3(2-propenyl)-2,6-methano-
3-benzazocine dihydrochloride (m.p. >270.degree. C.), the free
base of which is the compound of Formula I wherein Q is allyl, R is
hydrogen, R' is hydrogen, X is hydrogen, Y is methyl, Z is hydrogen
and Z' is methyl.
EXAMPLE 9
A. Acetic anhydride (20 ml.) and pyridine (10 ml.) were added to a
slurry of
8-amino-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2
,6-methano-3-benzazocine dihydrochloride (the product of part (B)
of Example 1, 3 g.) in chloroform (100 ml.) with cooling at ice
temperature. The resulting solution was stirred with continued
cooling (for 1 hr.), washed with sodium bicarbonate solution, dried
and concentrated, affording as a red oil
N-(3-cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-me
thano-3-benzazocin-8-yl)acetamide, the compound of Formula VIII
wherein Q' is cyclopropylmethyl, R is hydrogen, R" is acetyl, X is
hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.
B. Lithium aluminum hydride (0.5 g.) was added to a solution of
N-(3-cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-me
thano-3-benzazocin-8yl)acetamide (the product of part (A) of this
example, about 3 g.) in tetrahydrofuran (50 ml.). The slurry was
refluxed (for 2 then cooled. Saturated sodium potassium tartrate
solution was added, the mixture was filtered and the filtrate was
concentrated. An ether solution of the residue was washed with
water, dried and concentrated. Distillation of the residual red oil
afforded as a yellow viscous oil
3-(cyclopropylmethyl)-8-(ethylamino)-1,2,3,4,5,6-hexahydro-cis-6,11-dimeth
yl-2,6-methano-3-benzazocine (700 mg., b.r. 155.degree.-160.degree.
C./0.03 mm.), the compound of Formula I wherein Q is
cyclopropylmethyl, R is hydrogen, R' is ethyl, X is hydrogen, Y is
methyl, Z is hydrogen and Z' is methyl.
EXAMPLE 10
A. A mixture of
8-amino-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-
methano-3-benzazocine dihydrochloride (the product of part (B) of
Example 1, 4 g.), propionic anhydride (4 ml.), pyridine (8 ml.) and
chloroform (80 ml.) was stirred overnight at room temperature. The
resulting solution was washed with sodium bicarbonate solution,
dried and concentrated, affording as a yellow oil
N-(3-cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6(eq),11-(ax)-dimethyl-2,6-m
ethano-3-benzazocin-8-yl)propionamide (3.8 g.), the compound of
Formula VIII wherein Q' is cyclopropylmethyl, R is hydrogen, R" is
propionyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is
methyl.
B. Lithium aluminum hydride (0.75 g.) was added slowly with cooling
at ice temperature to a solution of
N-(3-cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-me
thano-3-benzazocin-8-yl)propionamide (the product of part (A) of
this example, 3.8 g.) in tetrahydrofuran (70 ml.) and the resulting
mixture was refluxed (for 1 hr.). Saturated sodium potassium
tartrate solution was cautiously added, the slurry was filtered and
the filtrate was concentrated. Distillation of the residual oil
afforded as an amber oil
3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-8(propylamin
o)-2,6-methano-3-benzazocine (2.0 g., b.r. 155.degree.-160.degree.
C./0.05 mm.), the compound of Formula I wherein Q is
cyclopropylmethyl, R is hydrogen, R' is propyl, X is hydrogen, Y is
methyl, Z is hydrogen and Z' is methyl.
EXAMPLE 11
A mixture of
8-amino-3-(cyanopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-
methano-3-benzazocine dihydrochloride (the product of part (B) of
Example 1, 4 g.), butyric anhydride (4 ml.), pyridine (5 ml.) and
chloroform (80 ml.) was stirred at ice temperature (for 2 hr.). The
resulting solution was washed with sodium bicarbonate solution and
concentrated, affording as a yellow oil
N-(3-cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6-(eq),11(ax)-dimethyl-2,6-m
ethano-3-benzazocin-8-yl)butyramide (3.5 g.), the compound of
Formula VIII wherein Q' is cyclopropylmethyl, R is hydrogen, R' is
butyryl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is
methyl.
B. Lithium aluminum hydride (0.75 g.) was added cautiously with
cooling at ice temperature to a solution of
N-(3-cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-me
thano-3-benzazocin-8-yl)butyramide (the product of part (A) of this
example, 3.5 g.) in tetrahydrofuran (100 ml.) and the resulting
mixture was refluxed (for 3 hr.), then cooled. Saturated sodium
potassium tartrate solution was added, the slurry was filtered and
the filtrate was concentrated. Distillation of the residual oil
afforded as an amber viscous liquid
8-(butylamino)-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-(dimet
hyl-2-methano-3-benzazocine (2.0 g., b.r. 161.degree.-165.degree.
C./0.07 mm.), the compound of Formula I wherein Q is
cyclopropylmethyl, R is hydrogen, R' is butyl, X is hydrogen, Y is
methyl, Z is hydrogen and Z' is methyl.
EXAMPLE 12
A. Benzyl chloride (250 g.) was added dropwise to a solution of
3,4-diethylpyridine (262 g., Beilsteins Handbuch der Organischen
Chemie, Vierte Auflage, Julius Springer, Berlin, 1935 p. 253) in
isopropyl alcohol (700 ml.). The resulting solution was refluxed
(for 2 hr.), then concentrated under water pump vacuum. Benzene
(250 ml.) was added to the residue and the solution was
concentrated again. The process was repeated with two further
portions (250 ml. and 500 ml.) of benzene. The residue began to
crystallize. Benzene (2250 ml.) was added, affording a thick slurry
of 1-benzyl-3,4-diethylpyridinium chloride.
B. A Grignard reagent prepared from magnesium (85.5 g.), benzyl
chloride (407 g.) and ether (3020 ml.) was added to the slurry
product of part (A) os this example. Refluxing was maintained by
the heat of reaction during the addition and was continued by
applied heat after the addition (for 1.5 hr.). The reaction mixture
was quenched in ice-water containing ammonium chloride (453 g.) and
the quench was basified with aqueous ammonia. The ether layer was
washed with water and stripped of ether, affording
1,2-dibenzyl-3,4-diethyl-1,2-dihydropyridine (712 g.).
C. A solution of sodium borohydride (52 g.) in water (260 ml.) was
added to a solution of the entire product of part (B) of this
example in ethanol (2.1). The mixture was stirred (for 3.5 hr.) and
allowed to stand overnight at room temperature, then filtered.
Water and ether were added to the filtrate. The ether layer was
washed with water, dried and concentrated. Vacuum distillation of
the residue (714 g.) produced two fractions (408.2 g. and 109.5 g.)
which appeared to be only partially reduced. Therefore, dry sodium
borohydride (42 g.) was added portionwise to a solution of most
(515 g.) of the combined two fractions in absolute ethanol (11.).
The mixture was stirred at room temperature (for 6 hr.), then
concentrated. Water and ether were added to the residue. The ether
layer was washed with water, dried and concentrated. Since the
product still appeared incompletely reduced, dry sodium borohydride
(40 g.) was added to a solution of it in N,N-dimethylformamide
(11.). The mixture was allowed to stand overnight, diluted with
water (21.) and extracted with ether. The ether extracts were
washed with water, dried and concentrated. Vacuum distillation of
the residue afforded as a yellow liquid
1,2-dibenzyl-3,4-diethyl-1,2,5,6-tetrahydropyridine (Fraction II:
b.r. 148.degree. C./0.2 mm.-170.degree. C./0.1 m.,203 g.; Fraction
III: b.r. 154.degree.-178.degree. C./0.1 mm., mostly at 174.degree.
C., 172 g.).
D. A mixture of 1,2-dibenzyl-3,4-diethyl-1,2,5,6-tetrahydropyridine
(Fraction III of part (C) of this example), hydrobromic acid (48%,
1350 ml.) and acetic acid (50 ml.) was refluxed (for 22 hr.), then
concentrated. The residue was treated with sodium hydroxide (35%)
and extracted with benzene with warming and stirring. The benzene
extract was washed with water, dried and concentrated. Vacuum
distillation of the residue (155 g.) afforded an orange syrup
(Fraction I: b.r. 140.degree. C./0.3 mm.-164.degree. C./0.05 mm.,
54.5 g., Fraction II: b.r. 150.degree.-184.degree. C./0.05 mm.,
72.3 g.). Oxalic acid (25 g.) was added to a solution of Fraction I
of the orange syrup in ethanol (250 ml.), affording the oxalate
salt (9.4 g., m.p. 213.degree.-215.degree. C.). Oxalic acid (32 g.)
was added to a solution of Fraction II of the orange syrup in
ethanol (250 ml.), also affording the oxalate salt (24.9 g., m.p.
216.degree.-221.5.degree. C.). A mixture of most (29.9 g.) of the
combined oxalate salts, dilute sodium hydroxide (10%, 400 ml.) and
toluene was swirled, then filtered. Concentration of the toluene
layer afforded the free base as a yellow syrup (22.6 g.). Treatment
of the free base with hydrogen chloride afforded the hydrochloride
salt as a white solid (23.8 g., m.r. 202.degree.-205.degree. C).
Recrystallization of part (2.5 g.) of the hydrochloride salt from
ethyl acetate afforded
cis-6,11-diethyl-1,2,3,4,5,6-hexahydro-3-benzyl-2,6-methano-3-benzazocine
hydrochloride (m.p. 210.degree.-212.5.degree. C.).
E. A mixture of
cis-6,11-diethyl-1,2,3,4,5,6-hexahydro-3-benzyl-2,6-methano-3-benzazocine
hydrochloride (the hydrochloride salt product of part (D) of this
example, 8.9 g.), ethanol (100 ml.) and palladium-on-carbon (10%,
0.4 g.) was hydrogenated with heating (at 50.degree. C.) on a Parr
apparatus, then filtered. Concentration of the filtrate and
trituration of the residue with ether afforded a white solid (6.0
g., m.r. 204.degree.-211.degree. C.). Recrystallization of part
(all but 2.65 g.) of the white solid first from isopropyl
alcohol-ether and then from isopropyl alcohol afforded
cis-6,11-diethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine
hydrochloride (m.r. 208.5.degree.-211.degree. C., about 3 g.). This
hydrochloride salt preparation was combined with two (14.5 g. and
15.4 g.) similar preparations. The combined preparations were
shaken with aqueous sodium hydroxide and toluene, and the toluene
layer was concentrated. Vacuum distillation of the residue afforded
the free base in three fractions (Fraction I: b.r.
78.degree.-90.degree. C./0.03 mm., 3.29 g., Fraction II: b.r.
90.degree.-98.degree. C./0.03 mm., 14.32 g.; Fraction III; b.p.
98.degree. C./0.03 mm., 9.69 g.).
F. Nitric acid (90%, 70 ml.) was added (during 1 hr.) to a solution
of cis-6,11-diethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine
(the free base product of part (E) of this example, 22.66 g.) in
acetic acid (75 ml.) cooled to ice temperature, then the mixture
was allowed to stand overnight at room temperature. Ice (200 g.)
water (50 ml.) and sodium hydroxide solution (35%, 125 ml.) were
added. The resulting oil solidified, affording in two crops a
nitrate salt (31.3 g., m.r. 210.degree.-214.degree. C.; 0.8 g.,
m.r. 225.degree.-230.degree. C.). Part (21.8 g.) of the nitrate
salt was shaken with sodium hydroxide solution (35%), with water
and ether. The ether layer was washed with water, dried and
concentrated. Ethereal hydrogen chloride was added to a solution of
the resulting red syrup (16.4 g.) in ethanol (200 ml.).
Recrystallization of the resulting first crop (11.0 g., m.r.
285.degree.-286.degree. C.) of crystals from isopropyl alcohol
afforded in two crops
cis-6,11-diethyl-1,2,3,4,5,6-hexahydro-8-nitro-2,6-methano-3-benzazocine
hydrochloride (1.7 g., m.r. 293.degree.-294.degree. C; 7.1 g., m.r.
288.degree.-289.degree. C.), the free base of which is the compound
of Formula II wherein Q' is hydrogen, X is hydrogen, Y is ethyl, Z
is hydrogen and Z' is ethyl.
G. A mixture of
cis-6,11-diethyl-1,2,3,4,5,6-hexahydro-8-nitro-2,6-methano-3-benzazocine
hydrochloride (the product of part (F) of this example, 3.11 g.),
sodium bicarbonate (2.0 g.), N,N-dimethylformamide (25 ml.) and
cyclopropylmethylbromide (1.60 g.) was refluxed (for 1.5 hr.), then
filtered. The solid washed with ethanol and the filtrate was
concentrated. The residue was shaken with water and ether. The
ether layer was washed with water, treated with charcoal and
concentrated. Ethereal hydrogen chloride was added to a solution of
the residue (3.0 g.) in ethanol (15 ml.), affording crystalline
3-(cyclopropylmethyl)-6-(eq),11-(ax)-diethyl-1,2,3,4,5,6-hexahydro-8-nitro
-2,6-methano-3-benzazocine hydrochloride (2.4 g., m.r.
243.degree.-245.degree. C.), the free base of which is the compound
of Formula II wherein Q' is cyclopropylmethyl, X is hydrogen, Y is
ethyl, Z is hydrogen and Z' is ethyl.
H. A mixture of
3-(cyclopropylmethyl)-6-(eq),11-(ax)-diethyl-1,2,3,4,5,6-hexahydro-8-nitro
-2,6-methano-3-benzazocine hydrochloride (the product of part (G)
of this example, 2.4 g.), water (6 ml.), ethanol (11 ml.), iron
filings (2.3 g.) and concentrated hydrochloric acid (2 drops) was
heated on a steam bath with stirring (for 7 hr.). Sodium
bicarbonate (1.5 g.) was added and the mixture was filtered. The
solid was washed with ethanol and the filtrate was concentrated.
The residue was partitioned between water and chloroform and the
chloroform layer was concentrated. trituration of the resulting
syrup (3.6 g.) with ether afforded a yellow powder. Addition of
ethereal hydrogen chloride to a solution of the yellow powder in
ethanol afforded crystals in two crops (0.9 g., m.p. 237.degree.
C.; 0.9 g., m.r. 226.degree.-234.degree. C.). Combination and
recrystallization of the two crops from aqueous acetone afforded
also in two crops white crystals of
8-amino-3-(cyclopropylmethyl)-cis-6,11-diethyl-1,2,3,4,5,6-hexahydro-2,6-m
ethano-3-benzazocine dihydrochloride (m.r. 290.degree.- 292.degree.
C. and m.r. 287.degree.-290.degree. C., total of 1.04 g.), the free
base of which is the compond of Formula I wherein Q is
cyclopropylmethyl, X is hydrogen, Y is ethyl, Z is hydrogen and Z'
is ethyl.
As stated above the compounds of Formula I are useful as strong
analgesics, which can be demonstrated by standard pharmacological
procedures readily carried out by technicians having ordinary skill
in pharmacological test procedures. Thus, the test results for a
particular compound can be determined without extensive
experimentation.
All of the compounds of Formula I of the examples were tested and
determined to be active in the acetylcholine writhing test, a
primary screening test for analgesia. In this test the ability of
test compounds to prevent acetylcholine-induced writhing in mice is
determined. The following is an adaptation of the method of Collier
and co-workers (Brit. J. Pharmacol. Chemother., 32, 295(1968) by
Anne K. Pierson. An intraperitoneal injection of acetyl-choline
(3.2 mg/kg.) causes mice to exhibit writhing, which is a abdominal
constriction, and sometimes twisting, followed by extension of the
hind limbs. The mice are dosed with the test compound plus vehicle
or vehicle alone (controls) 20 minutes prior to, and are observed
for 2 minutes after, the acetylchloine injection. During the
2-minute observation period mice not responding by writhing are
scored protected and mice responding by writhing one or more times
are scored not protected. The mice are dosed orally (usually at
150-200 mg./kg.) or subcutaneously (usually at 75-100 mg./kg.).
Fifteen mice per does level are used. Ed.sub.50 values for active
compounds are calculated by probit analysis (C. I. Bliss, The
Statistics of Bioassay, Academic Press, New York, 1952) of quantal
scores of tests at four or more appropriate dose levels. The
following subcutaneous ED.sub.50 values for the compounds of
Formula I of the examples were determined.
______________________________________ Compound of ED.sub.50 Value
(mg./kg.) ______________________________________ Example 1B 0.80
Example 2E 0.70 Example 3B 0.44 Example 4F 0.79 Example 5C 1.5
Example 6C 5.6 Example 7 1.6 Example 8C 2.5 Example 9B 1.3 Example
10B 1.2 Example 11B 1.0 Example 12H 1.3
______________________________________
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