CA1086723A - Process for the preparation of 14-hydroxymorphinan derivatives - Google Patents
Process for the preparation of 14-hydroxymorphinan derivativesInfo
- Publication number
- CA1086723A CA1086723A CA274,241A CA274241A CA1086723A CA 1086723 A CA1086723 A CA 1086723A CA 274241 A CA274241 A CA 274241A CA 1086723 A CA1086723 A CA 1086723A
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- Prior art keywords
- compound
- boron
- formula
- borane
- acid
- Prior art date
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
- C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/28—Morphinans
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- Pain & Pain Management (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
N-substituted -14-hydroxy-3-substituted-morphinan derivatives have been found to possess potent narcotic agonist or antagonist activity. In particular, the compound N-Cyclo-butylmethyl-3,14-dihydroxymorpinan has been found to possess potent agonist/antagonist activity as a non-narcotic analgesic.
An improved total synthesis of these compounds is described herein from the starting material 2-(p-methoxybenzyl)-1,2,3,4, 5,6,7,8-octahydroisoquinoline. A preferred feature of the process involves borane reduction of 2-cyclobutylcarbonyl-9,10-dihydroxy-1-(p-methoxybenzyl) perhydroisoquinoline (Va) to provide the corresponding cyclobutylmethyl derivative complexed with borane which is converted directly to N-cyclobutylmethyl-14.beta.-hydroxy-3-methoxymorphinan (LVa) by treating with acid.
N-substituted -14-hydroxy-3-substituted-morphinan derivatives have been found to possess potent narcotic agonist or antagonist activity. In particular, the compound N-Cyclo-butylmethyl-3,14-dihydroxymorpinan has been found to possess potent agonist/antagonist activity as a non-narcotic analgesic.
An improved total synthesis of these compounds is described herein from the starting material 2-(p-methoxybenzyl)-1,2,3,4, 5,6,7,8-octahydroisoquinoline. A preferred feature of the process involves borane reduction of 2-cyclobutylcarbonyl-9,10-dihydroxy-1-(p-methoxybenzyl) perhydroisoquinoline (Va) to provide the corresponding cyclobutylmethyl derivative complexed with borane which is converted directly to N-cyclobutylmethyl-14.beta.-hydroxy-3-methoxymorphinan (LVa) by treating with acid.
Description
IMPROVED PROCESS FOR T~IE PREPARATION
This invention relates to a new and novel synthesis of N-substituted-14-hydroxy-3-substituted-morphinans having :
the formula ~ -R .
/H
R o J
.
in which R2 is H or (lower)alkyl and R is cyclobutylmethyl or cyclopropylmethyl. :
.. . . .
Drug abuse by thrill-seeking youth or by people .. . :.
looking for an escape from the realities of everyday li~e 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 i9 because of the ;:.
high addictive potential of these agents that much time and . ~.
money are being expended by the pharmaceutical industry and by .
governments to try to discover and develop new non-addicting ~
analgetics and/or narcotic antagonists. . . ;
, .
It was an ob]ect of the present invention to develop a method of synthesis for the above-described compounds char~
acterized by Formula ~ that would not be dependent upon opium :.
alkaloids as starting materials and yet would be commercially .. :
feasible.
~ The object~ves of the:present inventlon have~been 30 achieved by the process of prepar mg the compounds of Formula L by their total synthesis:from readily available 2-(p-alkoxy-benzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline starting material , ' .".',: '` :''- " " ~,~ " ;,~i;" ,~"~ ,", ,, ,~
l~B67Z3 such as 2-(methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline.
The compounds prepared by the instant invention have the basic morphinan nucleus which is numbered and represented by the following plane formula:
10/~\7 17 ' '' 3~148 ~.. ,~ .
5~
~ ``',:,',, Although there are three asymetric carbons (asterisks) in the morphinan molecule, only two diastereisomeric (racemic) -forms are possible, because the iminoethano system, attached to position 9 and 13, is geometrica]ly constrained to a cis-(1,3-diazial)-fusion. These racemates can, therefore, differ only at the junction of rings B and C--in other words, in the con~iguration of carbon 14. The only variable will be the cis and trans relationship 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 "morphin-ans". The use of a graphic representation of a "morphinan" is meant to include the dl racemic mixture and the resolved d and 1 isomers thereof. -~
The "morphinan" compounds of the present lnventlon characterized by Formula L can each exist as two optical iso-.
mers, the levorotatory and dextrorotatory isomers. The optical isomers can be graphlcally illustratèid as~
This invention relates to a new and novel synthesis of N-substituted-14-hydroxy-3-substituted-morphinans having :
the formula ~ -R .
/H
R o J
.
in which R2 is H or (lower)alkyl and R is cyclobutylmethyl or cyclopropylmethyl. :
.. . . .
Drug abuse by thrill-seeking youth or by people .. . :.
looking for an escape from the realities of everyday li~e 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 i9 because of the ;:.
high addictive potential of these agents that much time and . ~.
money are being expended by the pharmaceutical industry and by .
governments to try to discover and develop new non-addicting ~
analgetics and/or narcotic antagonists. . . ;
, .
It was an ob]ect of the present invention to develop a method of synthesis for the above-described compounds char~
acterized by Formula ~ that would not be dependent upon opium :.
alkaloids as starting materials and yet would be commercially .. :
feasible.
~ The object~ves of the:present inventlon have~been 30 achieved by the process of prepar mg the compounds of Formula L by their total synthesis:from readily available 2-(p-alkoxy-benzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline starting material , ' .".',: '` :''- " " ~,~ " ;,~i;" ,~"~ ,", ,, ,~
l~B67Z3 such as 2-(methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline.
The compounds prepared by the instant invention have the basic morphinan nucleus which is numbered and represented by the following plane formula:
10/~\7 17 ' '' 3~148 ~.. ,~ .
5~
~ ``',:,',, Although there are three asymetric carbons (asterisks) in the morphinan molecule, only two diastereisomeric (racemic) -forms are possible, because the iminoethano system, attached to position 9 and 13, is geometrica]ly constrained to a cis-(1,3-diazial)-fusion. These racemates can, therefore, differ only at the junction of rings B and C--in other words, in the con~iguration of carbon 14. The only variable will be the cis and trans relationship 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 "morphin-ans". The use of a graphic representation of a "morphinan" is meant to include the dl racemic mixture and the resolved d and 1 isomers thereof. -~
The "morphinan" compounds of the present lnventlon characterized by Formula L can each exist as two optical iso-.
mers, the levorotatory and dextrorotatory isomers. The optical isomers can be graphlcally illustratèid as~
- 2 -'.
:
-MORPEIINANS -R2~ R20~ OR
and ~ -The present invention embodies the preparation of all of the morphinan isomers including the optical isomers in their ~`t resolved form.
The optical isomers can be separated and isolated by Practional crystallization of the diastereoisomeric salts formed, for instance, with d- or l-tartaric acid or D-(+)-a-bromocamphor sulfonic acid. The levorotatory isomers of the -~ ~-compounds of the present 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 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, etc. The term "pharmaceutically acceptable acid addition salk" is defined to include all those inorganic and organic acid salts of the compounds of the instant inven- ~
tion, which salts are commonly used to produce nontoxic salts ~ ;
o~ medicinal agents containing amine functions. Illustrative cxamples would be those salts formed by mixing the compounds o~ Foxmula L with hydrochloric, sulfuric, nitric, phosphoric, phosphorous, hydrobromic, maleic, malic, ascorbic, citric or ~-tartaric, pamoic, lauric, stearic, palmitic; oleic, myrlstic, ~ 30 lauryl sulfuricj naphthalenesulfoni~c, linoleic or linolenic ; acid, and the like.
6 ~ :
The morphinan compounds L~ (wherein~R is cyclopropyl .:
.
-- 3 -- .:
or cyclobutyl and R2 is (lower)alkyl) and LX (wherein R is cyclopropyl or cyclobutyl) of the inStant inVention are pre- ~
pared by a total synthesis comprising 4-6 steps. The synthesis : .
is efficient and appears ~ommercially feasible. Chart I il-lustrates the process for the prepara-tion of N-cyclobutyl- :
methyl-3,14-dihydroxymorphinan (LXa) utilizing N-cyclobutyl-methyl-14-hydroxy-3-methoxymorphinan (LVa).
~ N-CH2-R ~ -CH -R
~ ~ ~ ~ 2 :- ' LU LX
:
' .
- ' .: - 3a - ~
: - ,:
".' ':.'-,, 67;~3 C~ART I
C~, ~ C~O ~
Ia ~
xample 2 / IIa C O
` C
IIIa 1 Example 3 IVa ~ , _ _ . .
O . O
CH.
ya ~Ia:
~ , GH~ ]
~IIa ~ LVa Exa Ple 1~ ~ /\
~; J~
,.
LXa ~ ' _ 4 : .
In opening the 9,10-epoxide group of compounds such as IIIa and IVa according to the procedure of Example 3, there are obtained 9,10-diol compounds capable of existing in con-formations illustrated by the following planer formulas (and the four optical isomers thereof) wherein R is cyclobutyl or cyclopropyl and R is (lower)alkyl.
OH OH
(~}`l--C--R l~N-C-R
HO~ oR2 ~O~ oR2 VI' (cis-diol) ~trans-diol) OH OM
C~N C_R ~\~N-C--R
~IO ~oR2 ~ oR2 (cis-diol) V' (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 possesses the trans-9~,lOa-diol relationship of compound Va .
(and its corresponding mirror image) with only a trace of the .
less desirable diol VIa.
.~:
- ~0~;7Z3 Thus, the instant invention includes the novel inter~
mediates of the formula : :
X :'" ' . ' /1 N-C--R :
OH
~:, in which X is carbonyl (=O) or H2 ~ R is cyclopropyl or cyclo-butyl and R2 is (lower) alkyl, preferably methyl. ~ ~ ;
A preferred embodiment of the present invention is the process for preparation of compounds having the formula A :
' ~ L
~1 J :-... . ..
wherein R is cyclobutyl or cycIopropyl and R2 is H or (lower)-alkyl comprising the consecutive steps of ~ : .
(a) reducing the compound having the formula V
.. .. .. . .
R20 ~ V
~HO
:
-MORPEIINANS -R2~ R20~ OR
and ~ -The present invention embodies the preparation of all of the morphinan isomers including the optical isomers in their ~`t resolved form.
The optical isomers can be separated and isolated by Practional crystallization of the diastereoisomeric salts formed, for instance, with d- or l-tartaric acid or D-(+)-a-bromocamphor sulfonic acid. The levorotatory isomers of the -~ ~-compounds of the present 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 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, etc. The term "pharmaceutically acceptable acid addition salk" is defined to include all those inorganic and organic acid salts of the compounds of the instant inven- ~
tion, which salts are commonly used to produce nontoxic salts ~ ;
o~ medicinal agents containing amine functions. Illustrative cxamples would be those salts formed by mixing the compounds o~ Foxmula L with hydrochloric, sulfuric, nitric, phosphoric, phosphorous, hydrobromic, maleic, malic, ascorbic, citric or ~-tartaric, pamoic, lauric, stearic, palmitic; oleic, myrlstic, ~ 30 lauryl sulfuricj naphthalenesulfoni~c, linoleic or linolenic ; acid, and the like.
6 ~ :
The morphinan compounds L~ (wherein~R is cyclopropyl .:
.
-- 3 -- .:
or cyclobutyl and R2 is (lower)alkyl) and LX (wherein R is cyclopropyl or cyclobutyl) of the inStant inVention are pre- ~
pared by a total synthesis comprising 4-6 steps. The synthesis : .
is efficient and appears ~ommercially feasible. Chart I il-lustrates the process for the prepara-tion of N-cyclobutyl- :
methyl-3,14-dihydroxymorphinan (LXa) utilizing N-cyclobutyl-methyl-14-hydroxy-3-methoxymorphinan (LVa).
~ N-CH2-R ~ -CH -R
~ ~ ~ ~ 2 :- ' LU LX
:
' .
- ' .: - 3a - ~
: - ,:
".' ':.'-,, 67;~3 C~ART I
C~, ~ C~O ~
Ia ~
xample 2 / IIa C O
` C
IIIa 1 Example 3 IVa ~ , _ _ . .
O . O
CH.
ya ~Ia:
~ , GH~ ]
~IIa ~ LVa Exa Ple 1~ ~ /\
~; J~
,.
LXa ~ ' _ 4 : .
In opening the 9,10-epoxide group of compounds such as IIIa and IVa according to the procedure of Example 3, there are obtained 9,10-diol compounds capable of existing in con-formations illustrated by the following planer formulas (and the four optical isomers thereof) wherein R is cyclobutyl or cyclopropyl and R is (lower)alkyl.
OH OH
(~}`l--C--R l~N-C-R
HO~ oR2 ~O~ oR2 VI' (cis-diol) ~trans-diol) OH OM
C~N C_R ~\~N-C--R
~IO ~oR2 ~ oR2 (cis-diol) V' (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 possesses the trans-9~,lOa-diol relationship of compound Va .
(and its corresponding mirror image) with only a trace of the .
less desirable diol VIa.
.~:
- ~0~;7Z3 Thus, the instant invention includes the novel inter~
mediates of the formula : :
X :'" ' . ' /1 N-C--R :
OH
~:, in which X is carbonyl (=O) or H2 ~ R is cyclopropyl or cyclo-butyl and R2 is (lower) alkyl, preferably methyl. ~ ~ ;
A preferred embodiment of the present invention is the process for preparation of compounds having the formula A :
' ~ L
~1 J :-... . ..
wherein R is cyclobutyl or cycIopropyl and R2 is H or (lower)-alkyl comprising the consecutive steps of ~ : .
(a) reducing the compound having the formula V
.. .. .. . .
R20 ~ V
~HO
3 ;: .
.. ... - .: .
, ~ ~ - 6 - :- .
! ~:: :
.' . ',.
in which R is cyclobu~yl or cyclopropyl and R is (lower)alkyl with borane or a source of borane in an inert organic solvent to produce a boron complex of the compound having the formula VI I
R2 ~ ~ OH VII
Ho' in which R is cyclobutyl or cyclopropyl and R2 is (lower)alkyl;
(b) treating the boron complex of compound VII with acid to produce the compound having the formula LV
"' .
R20 ~ LV
J
~ in which R is cyclobutyl or cyclopropyl and R2 is (lower)alkyl;
: and, when desired, (c) cleaving the R O-ether function of compound LV ~:~
by treating with NaSC2H5, hydrobromic acid, boron tribromide .~
or pyridine hydrochloride to produce the compound having the ;
Eormula LX
HO J~HO
, ~'., '~ ' ' .' ' - 7 - . ~
,~i ~ 6723 in which R is cyclopropyl or cyclobutyl.
Preferred embodiments o the oregoing process for preparation 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;
' ' .
,.' ' ;,' ., ~ ~ ' .. ,'' , .
.: . . ," '"' ' ~ ' ' ' . ' '~ , '.
. '' .
, ;' ~ ' ' ' ~`'~ ,"' .
~;`,` .''' ' ' ` . ' "'' ~`~
~ 7a -.~ .
~3~ in step (a), the formula V compound is reduced wlth borane generating ln sit~l by reacting sod~um boro-hydride with a compound selected from the group.of boron-trifluoride, boron-trifluoride tetrahydrofuran complex9 or boron-trlfluorlde alkyletherate;
~4) in step ta) borane i9 employed in the ratio of about 1 mole of compound V to 1.33~to 2.0 moles of borane;
~5) ln step ta) borane ls employed in the ratio of about 1 mole of compound V to 1.6 to 1.9 mole~ of borane;
~6) in step (a~ borane i5 employed in the ratio of a~out 1 mole of compound ~ to 1.75 moles of borane;
~7) step ta) is carried out with the ald~or heat in the range of about 50-115C.
- ~8) step ~a) is carried out in refluxing toluene; : :
~9~ in step tb) the boron comple~ of compound VII is :treated wlth an acid selected ~rom~the group consisti.ng of phosphoric, orthophosphorlc, pyrophosphoric, and I polyphosphoric; ~ ~
1 ~10) in step ~b) the boro~ complex of compound VII is treated with anhydrous phosphorlc acid and pho3phorous pentoxide;
~11) in step ~b) the boron co~plex of compound VII is i ~reated ~ith a large e~cess of anhyd~ous phospho-ic acld and phosphorous pentoxide;
(12~ step tb) ls carried out at a temperature in the range of 50-100C.;
~: ~ tl3)~ step~tb);is:carried out~at~a ~emperature in the range of~70-7SC.;
,, .
l ':
. : ~
, .
;723 ~14) s~ep (b) io ca,ried out at a temperature ln the range o 70~75C. with anhydrous phosphoric acid and pho~~
phorous pentoxide.
Another preferred embodiment of the prese~t ~v~r.tion is the process ~or the preparation of compounds having the formula ~ -CH~R
R~ L ¦:
J
, wherein R is cyclobu~yl or cyclopropyl snd Rl is H or ~lower)alkyl ; comprising the consecutive steps o~
~a) reducing the compound having the ormula .
' ./1 ~ : ~
-C-R
' in which R is cyclobutyl or cyclopropyl`and R~ is ~lower)a1kyl wlt~
boxane or a saurce a barane in an inert organic solvent to produce a boron complex of the compo~nd having the formula VII
..
-CHa-R ~ : .
. V~
R ~ "
~ 9~
ln which R 1~ cyclobutyl or cyclopropyl. and R~ i3 (lower)alk~l;
bydrolyzing thP boror. complex of compound VII wl~h a~u~ous acld to provlde compound VII;
(c~ treating compound VII w~th an acid selected from th~
' group consisting of pho5phoric, orthophosphoric, pyropho3phoric, and polyphosphoric until cycti~a~ion is essentially complete to ~roduce the compound having the for~.ula ~V .
. ~j ~ ~ ) ~J
in which R is cyclobutyl or cyclopropyl and R~ is (lower)a;lcyl; and, when desired, ~ d) cleavlng the R10-ether function of compound L~J by trqating with ~aSC ~5, hydrobromic acld~ boron-tribro~aide: nr pyrldine . hydrochlorlde to produce the compound havlng::the formula L~
' -~,_L
in whlc~ cyclobutyl or cyclopropyl.
: , ... .. . ..
: Alternatively, step ~c) can be carried out in a separate st.~p ; by~tr;eating compound;VII~with borane followed by an acid catalyst as : ~ described àbove.~
Pre~erred embodiments of the a~ove proc ss for the preparation of ~corpounds char~c-e~ized bl:Formula L are~those whereln:
. ~ ~
..
~, ::
i :
:-~ ~ ~
Ei7;~3 llj step ~c~ is carr'~' out aL a temp2ratur~ in the range of 70-90C.; and ~2) step ~c) is carried out with anhydrous phosphoric acid at a temperature in the range of 80-85C.
The most preferred embodiment of the present invention is a process for the preparation of the compound having the formula L' R~O~[~-Cl~
wherein R~ is hydrogen or methyl comprising the consecuti~e steps of ~a) reducing the compoun~ having the formula Va . . O
C~i.OJ~ '1~1 wit~ borane in a molar ration of about 1.75 mole ~Ç borane to about 1 mole o~ compound Ya in ~oluene with the aid of heat i3 the range of about 5~-115~C. to produce a boron complex of the compound . having the ormula~VI}a :
,, : ~, i723 ~0 H ~tII8 ' ~~ I I
~/
~ b) treating the boron complex of compound VIIa with a large excess of a 6.4:1 ~ixtUre of anhydrous phosphoric acid:phosphorous pentoxide With the aid of heat in the range of about 70-75C. unt11 cyclization i9 essentially complete tO produce ~he compound having the formula LVa Cd~0 ' and~ when desired ~ d) demethylating compound J.Va With NaSC~H~ hydrobromic acid, boron-tribromide or pyridine hydrochloride to produce. the compound havin~ the formula LXa ' `' : :: : ~
i723 and, when desired td) con~erting compound L~a into a nontoxic yha~maceutically accept~ble acid additiou salt thereof by methods known ~n the art.
The compounds N-cyclopropylmethyl-14~-hydroxy-3-methoxy-morphinan, N-cyclobutyl~ethyl-14~-hydroxy-3-methoxymorphinan, N-cyrlo-propyl~ethyl-3,14~-dihyroxymorphinan and N-cyclobutylmethyl-3,14~-dihydroxymorphanln are known and descr~bed in U.S. Patent 3,819,635 '~
~ or the purpose of this disciosure thë têrm "lnertorganic solvent" means an organlc solvent that does no~ participaee $n the reaction to the extent that it Pmerges unchanged rom the reactio~ Such solvenes are methylene cnloride, chloroform, dichlor-ethane, tetrachloromethane, benzene,~toluene, e~her, ethyl acetate, ~ylene, tetrahydrofuraD dioxane, dimethylacetamide, and the like ExperimeDtal All temperatures are expressed in degrees centigr2de~
VPC means vapor phase chromatography IR means in~rared s~ectru~
N~ _ ans ~uclear ~-gne~ic r~sonsance sp~c~rum ' ' `.
:
:;
` ~
: :
:
7;23 Examole I
2-Cyclobutylcarbonyl-l-tp-methoxybenzyl)~
l,2,3~4,5,6,7,8-octahydroisoquinollne (IIa) Trlethylamine ~22.2 g., 0.~2 mole~ 15 slowly added to l-~p-methoxybenzyl)-1,2,3~4,5,6,7,8-octahydroisoquinoline hydrochloride Ia (29.4 g~, 0.1 mole~ dissolved in 200 ml. of me~hyle~e 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 stirring to the mixture while maintaining a temperatur_ of 0 to 5C. After stlrring the reaction mlxture for 1 hr. at room temperature, lO0 ml. of water is added, the ~ixture acidified by addi~g 50 ml. of 10% sulfurlc acid, and the methylene~chlorlde layer separated. If desired, the methylene ch;oride: solution containlng IIa can be used for the next step direct~ly or concentrated to give an oll whlch solidlfies upon standing.~ Recrystalllzatlon of a samFle of the salidified material fro~ acetone provides crystalline product IIa, m.p. 89-91. ~ ~
Various organic tertlary amines com~only e~.ployed as proton acceptors in-acylation reactlons may be substituted or triethylamlne in the above procedure. Such amines are trl(lower)-alkylamine8, e.g., trimethylamine~ triethylamine and the llke pyridine, dimethylaniline, N-methylpiperidine, and the like.
Examplé 2 2-CyclobutylcarboDyl-9,10-epoxy-l-(p-methoxy-~en ~ ;perhydrolsoquinollne ~IIIa and na~) Method A - Peracetic~acid oxidation ~ To: a solution of 2-cyciobutylcarbonyl-1-~-methoxybenzyl~-1,2,3,4~5,6,~7~,8-octahydroisoqulnoline (IIa) (0.1 mole) in 230 ml. of methylene chlorlde~is a~ded peracetlc~acid (40%, Z3.8 g., 0.12 mole) :
.
at such a rate so as to keep the temperature at 30-35C. After stirring the resulting solution at room temperature for 1 hr., 200 ml. of water is added and the excess peracetic acid destroy-ed by adding 100 ml. of 10~ sodium bisulfite solution. The methylene chloride phase is separated and concentrated under reduced pressure to give an oily residue comprised of the iso-meric epoxides trans IIIa and cis IVa in ratio of 23:78 accord- -~
ing to vapor phase chromato~raphy analysis (VPC). The two -epo~ides can be separated, if desired, by column chromatography using alumina or silica column (eluting with diethylether).
The minor epoxide (IIIa), m.p. 118, has the "trans- -coniguration" and the major epoxide (IVa), m.p. 82-84, has the "cis configuration" with respect to steric relationship of the p-methoxybenzyl group and the oxirane group.
Method B - Pertrifluoroacetic acid oxidation To a solution of 2-cyclobutylcarbonyl-1-(p-methoxy-benzyl)-1,2,3,4,S,6,7,8-octahydroisoquinoline (IIa) (0.05 mole) in 125 ml. of methylene chloride is added sodium carbonate ~ -, (20 g., 0.19 mole) and the mixture cooled to 0C. A solution of pertri1uoroacetic acid is prepared by mixing tri1uoro- `;~
acetic anhydride (16.6 g., 0.077 mole) and 90% hydrogen per-.
oxide (2.94 g., 0.077 mole) in 35 ml. of methylene 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 0 to 5. After completing the addition, the xeaction mixture is stirred for a period of 0.5 hr. at O to 5C. and excess peracid then destroyed by addition of 10% sodium bisulite solution with agitation until the evaluation of CO2 ceased. The methylene chloride phase is washed with water, ' dried over anhydrous sodium sulfate and concentrated under reduced pressure to an oily residue comprised of the . '' ~: ' .
j7;~3 l~omeric epoxldes IIIa and IVa in a trans:ci~ ratio of 35:65 sccording ~o vPC.
xample 3 2-C~clobutylcarbonyl-9, 10-d~hydroxy 1-(p-m oxybenzyl)perhydroisoquilloline (Va and VIa) ~ he m~xture of isomeric epoxides IIIa and IVa from peracetic acid oxidation of Example 2 is dissolved in 300 ml. of acetone and cooled to 0. To this solution is first added 30 ml. o~ water and then 30 ml. of concentrated sulfuric acid at such a rate as to k~.ep the temperature below 25. After stirring the reaction mixeure for a period of 1.5 hr. at 25, a 150 ml. portion of wàter and a 300 ml.
portion of toluene are added. The resuIting two phase ~ixture is made baslc with sodium hydroxide soLution and the toluene iayer separated and concentrated to a residue oil. This oil, stirred with 300 ml. of cyclohexane, provides a suspension of whlte solid which i6 collected on a filter. The white solid consists principally of the de~ired trans diol Va contaminated with the isomerie trans diol , VIa as indicated by VPC. The yield oÇ Va calculated from the s~arting amine Ia is 75~. The cyclohexane fi].trate is retreated with sulf~ric acid to give another 10% yield of trans diol. Fur~her purification of t~he white solid is carried out by crystallization from acetonitrile to provide material with m.p. 145-147. In place of the concentrated . .
sulfuric acid used abovel other acids such as nitrlc, hydrochlorlc, hydrobromic or strong organlc acids~such as alkylsulfonic, trlfluo~o-acetic and the like may be~employcd.
Hydrolysis of the pure minor crans epoxide IIIa accordlng to thc above procedure gl~es only ~the~deslred tran5 dlol Vs ~hlle hydrolysl:
of the ma~or cis epoxide I~a glvss ths deslred trans dlol Va -~ltn sone of the lsomeric trans dlol YIa in s Va:VIa ratio of 86:14~
~ . ~ :: :
j7Z3 Exan:~le 4 2-Cyclobutylmethyl-g,lO-dlhydroxy-l-(p-methoxyben~yl)perhydroisoquinoline ~VIIa) To a 601ution of 2-cyclobutylcarbonyl-9,10-dihyd~oxy-1-~mathoxybenzyl)perhydroiso~uinoline Va t30 g., 0.08 mole) in 300 ml. of tetrahydrofuran is added borane dimethylsul1de neat solutlon ~14 ml~, 0.14 mole) through a syrlnge needle under nitrogen atmosphere. The resulting mixture is heated to rerlux for 2 hr.
and then concentrated under reduced pressure to remove the 301ve~.
The resulting borane complex of the cyolobutylmethyl ~lne VIIa can be used directly for the next reaction or it can be hydrolyzed with aqueous acid such as hydrochloric acid to provlde VIaa, m.p. 120-12~C. Reduction of the trans dlol Va amido function with the ollowing borane sources als,o provides VIIa.
1) Borane-tetrahydrofuran complex.
2) In ~sltu~ generated borane in tetrahydrofuran using sodlum borohydride and borDn trifluoride gas ~or boron tri1uoride tetrahydrofuran complex or ~oron-trifluoride ; alkyletherate.
Example S
N-CYclobutylmethyl-14~-hydroxy-3-methoxymorphinan~(LVa) Method A. CYcllzation~with boran complex To the borane complex residue from borane reduction reaction ~0.08 mole) o~ Example 4 is added 320 g. of anhydrous phosphoric acid tprepared ~ro~ 85% phosphoric scid and phosphorous pento~lde) ant 5~ g. o~ phosphorous pentoxide. The mixture is stirred at - room temperature for 0.5 hr. and then at 70-75 for a period o~
.. ... - .: .
, ~ ~ - 6 - :- .
! ~:: :
.' . ',.
in which R is cyclobu~yl or cyclopropyl and R is (lower)alkyl with borane or a source of borane in an inert organic solvent to produce a boron complex of the compound having the formula VI I
R2 ~ ~ OH VII
Ho' in which R is cyclobutyl or cyclopropyl and R2 is (lower)alkyl;
(b) treating the boron complex of compound VII with acid to produce the compound having the formula LV
"' .
R20 ~ LV
J
~ in which R is cyclobutyl or cyclopropyl and R2 is (lower)alkyl;
: and, when desired, (c) cleaving the R O-ether function of compound LV ~:~
by treating with NaSC2H5, hydrobromic acid, boron tribromide .~
or pyridine hydrochloride to produce the compound having the ;
Eormula LX
HO J~HO
, ~'., '~ ' ' .' ' - 7 - . ~
,~i ~ 6723 in which R is cyclopropyl or cyclobutyl.
Preferred embodiments o the oregoing process for preparation 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;
' ' .
,.' ' ;,' ., ~ ~ ' .. ,'' , .
.: . . ," '"' ' ~ ' ' ' . ' '~ , '.
. '' .
, ;' ~ ' ' ' ~`'~ ,"' .
~;`,` .''' ' ' ` . ' "'' ~`~
~ 7a -.~ .
~3~ in step (a), the formula V compound is reduced wlth borane generating ln sit~l by reacting sod~um boro-hydride with a compound selected from the group.of boron-trifluoride, boron-trifluoride tetrahydrofuran complex9 or boron-trlfluorlde alkyletherate;
~4) in step ta) borane i9 employed in the ratio of about 1 mole of compound V to 1.33~to 2.0 moles of borane;
~5) ln step ta) borane ls employed in the ratio of about 1 mole of compound V to 1.6 to 1.9 mole~ of borane;
~6) in step (a~ borane i5 employed in the ratio of a~out 1 mole of compound ~ to 1.75 moles of borane;
~7) step ta) is carried out with the ald~or heat in the range of about 50-115C.
- ~8) step ~a) is carried out in refluxing toluene; : :
~9~ in step tb) the boron comple~ of compound VII is :treated wlth an acid selected ~rom~the group consisti.ng of phosphoric, orthophosphorlc, pyrophosphoric, and I polyphosphoric; ~ ~
1 ~10) in step ~b) the boro~ complex of compound VII is treated with anhydrous phosphorlc acid and pho3phorous pentoxide;
~11) in step ~b) the boron co~plex of compound VII is i ~reated ~ith a large e~cess of anhyd~ous phospho-ic acld and phosphorous pentoxide;
(12~ step tb) ls carried out at a temperature in the range of 50-100C.;
~: ~ tl3)~ step~tb);is:carried out~at~a ~emperature in the range of~70-7SC.;
,, .
l ':
. : ~
, .
;723 ~14) s~ep (b) io ca,ried out at a temperature ln the range o 70~75C. with anhydrous phosphoric acid and pho~~
phorous pentoxide.
Another preferred embodiment of the prese~t ~v~r.tion is the process ~or the preparation of compounds having the formula ~ -CH~R
R~ L ¦:
J
, wherein R is cyclobu~yl or cyclopropyl snd Rl is H or ~lower)alkyl ; comprising the consecutive steps o~
~a) reducing the compound having the ormula .
' ./1 ~ : ~
-C-R
' in which R is cyclobutyl or cyclopropyl`and R~ is ~lower)a1kyl wlt~
boxane or a saurce a barane in an inert organic solvent to produce a boron complex of the compo~nd having the formula VII
..
-CHa-R ~ : .
. V~
R ~ "
~ 9~
ln which R 1~ cyclobutyl or cyclopropyl. and R~ i3 (lower)alk~l;
bydrolyzing thP boror. complex of compound VII wl~h a~u~ous acld to provlde compound VII;
(c~ treating compound VII w~th an acid selected from th~
' group consisting of pho5phoric, orthophosphoric, pyropho3phoric, and polyphosphoric until cycti~a~ion is essentially complete to ~roduce the compound having the for~.ula ~V .
. ~j ~ ~ ) ~J
in which R is cyclobutyl or cyclopropyl and R~ is (lower)a;lcyl; and, when desired, ~ d) cleavlng the R10-ether function of compound L~J by trqating with ~aSC ~5, hydrobromic acld~ boron-tribro~aide: nr pyrldine . hydrochlorlde to produce the compound havlng::the formula L~
' -~,_L
in whlc~ cyclobutyl or cyclopropyl.
: , ... .. . ..
: Alternatively, step ~c) can be carried out in a separate st.~p ; by~tr;eating compound;VII~with borane followed by an acid catalyst as : ~ described àbove.~
Pre~erred embodiments of the a~ove proc ss for the preparation of ~corpounds char~c-e~ized bl:Formula L are~those whereln:
. ~ ~
..
~, ::
i :
:-~ ~ ~
Ei7;~3 llj step ~c~ is carr'~' out aL a temp2ratur~ in the range of 70-90C.; and ~2) step ~c) is carried out with anhydrous phosphoric acid at a temperature in the range of 80-85C.
The most preferred embodiment of the present invention is a process for the preparation of the compound having the formula L' R~O~[~-Cl~
wherein R~ is hydrogen or methyl comprising the consecuti~e steps of ~a) reducing the compoun~ having the formula Va . . O
C~i.OJ~ '1~1 wit~ borane in a molar ration of about 1.75 mole ~Ç borane to about 1 mole o~ compound Ya in ~oluene with the aid of heat i3 the range of about 5~-115~C. to produce a boron complex of the compound . having the ormula~VI}a :
,, : ~, i723 ~0 H ~tII8 ' ~~ I I
~/
~ b) treating the boron complex of compound VIIa with a large excess of a 6.4:1 ~ixtUre of anhydrous phosphoric acid:phosphorous pentoxide With the aid of heat in the range of about 70-75C. unt11 cyclization i9 essentially complete tO produce ~he compound having the formula LVa Cd~0 ' and~ when desired ~ d) demethylating compound J.Va With NaSC~H~ hydrobromic acid, boron-tribromide or pyridine hydrochloride to produce. the compound havin~ the formula LXa ' `' : :: : ~
i723 and, when desired td) con~erting compound L~a into a nontoxic yha~maceutically accept~ble acid additiou salt thereof by methods known ~n the art.
The compounds N-cyclopropylmethyl-14~-hydroxy-3-methoxy-morphinan, N-cyclobutyl~ethyl-14~-hydroxy-3-methoxymorphinan, N-cyrlo-propyl~ethyl-3,14~-dihyroxymorphinan and N-cyclobutylmethyl-3,14~-dihydroxymorphanln are known and descr~bed in U.S. Patent 3,819,635 '~
~ or the purpose of this disciosure thë têrm "lnertorganic solvent" means an organlc solvent that does no~ participaee $n the reaction to the extent that it Pmerges unchanged rom the reactio~ Such solvenes are methylene cnloride, chloroform, dichlor-ethane, tetrachloromethane, benzene,~toluene, e~her, ethyl acetate, ~ylene, tetrahydrofuraD dioxane, dimethylacetamide, and the like ExperimeDtal All temperatures are expressed in degrees centigr2de~
VPC means vapor phase chromatography IR means in~rared s~ectru~
N~ _ ans ~uclear ~-gne~ic r~sonsance sp~c~rum ' ' `.
:
:;
` ~
: :
:
7;23 Examole I
2-Cyclobutylcarbonyl-l-tp-methoxybenzyl)~
l,2,3~4,5,6,7,8-octahydroisoquinollne (IIa) Trlethylamine ~22.2 g., 0.~2 mole~ 15 slowly added to l-~p-methoxybenzyl)-1,2,3~4,5,6,7,8-octahydroisoquinoline hydrochloride Ia (29.4 g~, 0.1 mole~ dissolved in 200 ml. of me~hyle~e 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 stirring to the mixture while maintaining a temperatur_ of 0 to 5C. After stlrring the reaction mlxture for 1 hr. at room temperature, lO0 ml. of water is added, the ~ixture acidified by addi~g 50 ml. of 10% sulfurlc acid, and the methylene~chlorlde layer separated. If desired, the methylene ch;oride: solution containlng IIa can be used for the next step direct~ly or concentrated to give an oll whlch solidlfies upon standing.~ Recrystalllzatlon of a samFle of the salidified material fro~ acetone provides crystalline product IIa, m.p. 89-91. ~ ~
Various organic tertlary amines com~only e~.ployed as proton acceptors in-acylation reactlons may be substituted or triethylamlne in the above procedure. Such amines are trl(lower)-alkylamine8, e.g., trimethylamine~ triethylamine and the llke pyridine, dimethylaniline, N-methylpiperidine, and the like.
Examplé 2 2-CyclobutylcarboDyl-9,10-epoxy-l-(p-methoxy-~en ~ ;perhydrolsoquinollne ~IIIa and na~) Method A - Peracetic~acid oxidation ~ To: a solution of 2-cyciobutylcarbonyl-1-~-methoxybenzyl~-1,2,3,4~5,6,~7~,8-octahydroisoqulnoline (IIa) (0.1 mole) in 230 ml. of methylene chlorlde~is a~ded peracetlc~acid (40%, Z3.8 g., 0.12 mole) :
.
at such a rate so as to keep the temperature at 30-35C. After stirring the resulting solution at room temperature for 1 hr., 200 ml. of water is added and the excess peracetic acid destroy-ed by adding 100 ml. of 10~ sodium bisulfite solution. The methylene chloride phase is separated and concentrated under reduced pressure to give an oily residue comprised of the iso-meric epoxides trans IIIa and cis IVa in ratio of 23:78 accord- -~
ing to vapor phase chromato~raphy analysis (VPC). The two -epo~ides can be separated, if desired, by column chromatography using alumina or silica column (eluting with diethylether).
The minor epoxide (IIIa), m.p. 118, has the "trans- -coniguration" and the major epoxide (IVa), m.p. 82-84, has the "cis configuration" with respect to steric relationship of the p-methoxybenzyl group and the oxirane group.
Method B - Pertrifluoroacetic acid oxidation To a solution of 2-cyclobutylcarbonyl-1-(p-methoxy-benzyl)-1,2,3,4,S,6,7,8-octahydroisoquinoline (IIa) (0.05 mole) in 125 ml. of methylene chloride is added sodium carbonate ~ -, (20 g., 0.19 mole) and the mixture cooled to 0C. A solution of pertri1uoroacetic acid is prepared by mixing tri1uoro- `;~
acetic anhydride (16.6 g., 0.077 mole) and 90% hydrogen per-.
oxide (2.94 g., 0.077 mole) in 35 ml. of methylene 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 0 to 5. After completing the addition, the xeaction mixture is stirred for a period of 0.5 hr. at O to 5C. and excess peracid then destroyed by addition of 10% sodium bisulite solution with agitation until the evaluation of CO2 ceased. The methylene chloride phase is washed with water, ' dried over anhydrous sodium sulfate and concentrated under reduced pressure to an oily residue comprised of the . '' ~: ' .
j7;~3 l~omeric epoxldes IIIa and IVa in a trans:ci~ ratio of 35:65 sccording ~o vPC.
xample 3 2-C~clobutylcarbonyl-9, 10-d~hydroxy 1-(p-m oxybenzyl)perhydroisoquilloline (Va and VIa) ~ he m~xture of isomeric epoxides IIIa and IVa from peracetic acid oxidation of Example 2 is dissolved in 300 ml. of acetone and cooled to 0. To this solution is first added 30 ml. o~ water and then 30 ml. of concentrated sulfuric acid at such a rate as to k~.ep the temperature below 25. After stirring the reaction mixeure for a period of 1.5 hr. at 25, a 150 ml. portion of wàter and a 300 ml.
portion of toluene are added. The resuIting two phase ~ixture is made baslc with sodium hydroxide soLution and the toluene iayer separated and concentrated to a residue oil. This oil, stirred with 300 ml. of cyclohexane, provides a suspension of whlte solid which i6 collected on a filter. The white solid consists principally of the de~ired trans diol Va contaminated with the isomerie trans diol , VIa as indicated by VPC. The yield oÇ Va calculated from the s~arting amine Ia is 75~. The cyclohexane fi].trate is retreated with sulf~ric acid to give another 10% yield of trans diol. Fur~her purification of t~he white solid is carried out by crystallization from acetonitrile to provide material with m.p. 145-147. In place of the concentrated . .
sulfuric acid used abovel other acids such as nitrlc, hydrochlorlc, hydrobromic or strong organlc acids~such as alkylsulfonic, trlfluo~o-acetic and the like may be~employcd.
Hydrolysis of the pure minor crans epoxide IIIa accordlng to thc above procedure gl~es only ~the~deslred tran5 dlol Vs ~hlle hydrolysl:
of the ma~or cis epoxide I~a glvss ths deslred trans dlol Va -~ltn sone of the lsomeric trans dlol YIa in s Va:VIa ratio of 86:14~
~ . ~ :: :
j7Z3 Exan:~le 4 2-Cyclobutylmethyl-g,lO-dlhydroxy-l-(p-methoxyben~yl)perhydroisoquinoline ~VIIa) To a 601ution of 2-cyclobutylcarbonyl-9,10-dihyd~oxy-1-~mathoxybenzyl)perhydroiso~uinoline Va t30 g., 0.08 mole) in 300 ml. of tetrahydrofuran is added borane dimethylsul1de neat solutlon ~14 ml~, 0.14 mole) through a syrlnge needle under nitrogen atmosphere. The resulting mixture is heated to rerlux for 2 hr.
and then concentrated under reduced pressure to remove the 301ve~.
The resulting borane complex of the cyolobutylmethyl ~lne VIIa can be used directly for the next reaction or it can be hydrolyzed with aqueous acid such as hydrochloric acid to provlde VIaa, m.p. 120-12~C. Reduction of the trans dlol Va amido function with the ollowing borane sources als,o provides VIIa.
1) Borane-tetrahydrofuran complex.
2) In ~sltu~ generated borane in tetrahydrofuran using sodlum borohydride and borDn trifluoride gas ~or boron tri1uoride tetrahydrofuran complex or ~oron-trifluoride ; alkyletherate.
Example S
N-CYclobutylmethyl-14~-hydroxy-3-methoxymorphinan~(LVa) Method A. CYcllzation~with boran complex To the borane complex residue from borane reduction reaction ~0.08 mole) o~ Example 4 is added 320 g. of anhydrous phosphoric acid tprepared ~ro~ 85% phosphoric scid and phosphorous pento~lde) ant 5~ g. o~ phosphorous pentoxide. The mixture is stirred at - room temperature for 0.5 hr. and then at 70-75 for a period o~
4 hr. The reaction m~xeure i~ dilùted wlth 200~1. of water , ~ - 17 - ~
7~:3 and then poured ~nto a mlxture of 600 ml. of concentrated ammonium hydroxlde and 1 liter of crushed ice. Thz mixtu~e i~
extracted wlth 400 ml. of heptane and the hep~ane extract dried over sodium sulfate. Concentration of the dried heptane extract ~rovlde~
~3.1 ~. of oil ~85~ yield) of product LVa. This oil is dissolved in acetone and treated wlth anhydrous hydrogen chlorlde gas to afford erystalline hydrochloride salt of product LVa, m.p. 248 250.
Method B. Cyclization without boron complex of any kind 1.5 g. of 2-Cyclobutylmethyl-9~10-dihydroxy-1-(p-methoxy-ben7yl)perhydroisoquinoline ~IIa and 16.0 g. of 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 mlxture of ~ce and 35 ml. of concentrated ammonium hydroxide. The mixture is extracted with 40 ml. of methylene chloride and the methylene chloride extract eoneentrated to give 1.15 g. of oil. According to vapor p~ase ehromatography-~ass spectrometry analysls, the oil contained 57~ of the desired N-cyclobutylmethyl-14~-hydroxy-3-methoxymorphinan L~a, 27~ of a dehydrated by-product and 15% of uncycli~ad VIIa starting materlal.
Example 6 ~~1~2S~ y-N-Cyclobutylmethyl-14~-hvdroxv-3-methoxYmorphinan ~Va t)~
Substitution in the procedure of Example 1 of dextrorotator~-~ -methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline hydrochlorlde for racemic ~a and se~uentially applying the procedures o~ Examples 2-5 provides the levorotatory product LVa'.
Tha procedures of Examples 4 and 5 are carri2d out as follows. To a solutio~ of ~ o}~ LL-2'cyclobutylcarDonyl-9,10-. .
i7Z3 dlhydroxy 2~ methoxybenzyl)perhydroisoquinoline ~10 8-- 0.0267 ~ole) ir. lO0 ~1. of toluene i9 added borane dimethylsulflde neat solution (6 ml., 0.057 mole) through a syringe needle under nitrogen atmos-phere. ~le re3ulting solution is refluxed for 3 hr.) concentrated under reduced pressure to remove approximately 40 ml. of solvent and the borane complex of levor_tatory cyclobutylmethyl amine VIIa' is used directly iXI the cyclization reaction.
Cyclization of the levorotatory-cyclobutylmethyl amine VIIa' is carried out by adding the above toluene-borane complex mixture portionwise to 200 g. of anhydrous phosphorio acid and 35 g.
of phosphorus pentoxide with stirring while maintaining a temperature range of 0-25C. After the addition is complete, the mixture is heated and stirred for a period of 5 hr. at 70C. and then poured into a mixture o 400 ml. of concentrated ammonium hydroxide ~ith sufficient ice to maintain a temperature of approximately 25~C.
The mixture is extracted with toluene, the toluene extr2ct washed with water and then concentrated under reduced pressure to provide levorotatory-N-cyclobutylmethyl-14~-hydroxy-3-methoxy-morphinan ~LVa~) base. The oily base is converted to the sulfate salt by treating with sulfur1c acid to accord 7.2 g. ~61% yield? of levorotatorY--N-cyclobutylmethyl-l4~-hydroxy-3-methoxy-morphinan~
m.p. 232-237C. ~dec.~, Ea~d-5s.4C. (C = 0.56, CHjOH~.
~ , .
' .. . . .
!
:
.
.
2:~
am~le 7 2-Cyclopropylcarbonyl-l-(p-methoxybenzyl)-l,2,3~4,5,6,798-octahydroisoqulnoline ~
Substitution in the procedure of Example 1 for the cyclobu~ylcarbonyl chlorlde used therein of an equimolar quantity of cyclopropylcarbonyl chloride produces the title material IIb.
Example 8 2-Cyclopropylcarbonyl-9,10-epoxy-l~(p-methoxy- -ben~yl)perhydroisoquinolines ~IIIb and IVb~
Substitution in the procedure of Example 2 ror the ~acemic IIa used therein of an equimolar quantity of TIb prod~ces the title compounds IIIb and IVb.
Example 9 2-Cyclopropylcarb~nyl-9,10-dihydroxy~l-(p-methox~benzyl)perhydrolsoquinoline (Vb, VIb) Substitution in the procedure of ExampIe 3 for.the .
racemic IIIa and IVb used therein of an equimolar quanti~y of IIIb and IVb produces the title compounds Vb and VIb.
Example 10 .
2-Cyclopropylmethyl-9,10-dihydroxy-1-(p-_thoxybenzYl~perhydroisoquinoline (VIIb) Substitution in the procedure of Example 4 for the racemlc ~a used therein of an equimolar quantity of Vb produces the title eompound Vllb.
, . : Example 11 ~-Cyclopropylmethy~-14~-hYdroxy-3-methoxy~orphinan (LVb) !Sub~titution in the procedure of Exampl.e 5 for the racemic VIIa used therein of an equlmolar quantity of VIIb produces the title produet LVb. ~
;
' ' ~ .
~ - 20 -~
.; :
7;23 Exam~le 1z N-Cyclobutylmethyl-3,14-dihydroxymorphinan (LXa) A mixture of N-cyclobutylmethyl-14~ hydroxy-3-methoxymoryhinan (LVa) (1.0 g., 2.58 m mole) and 10 ml. of 48% Hsr is refluxed under a nitrogen atmosphere for a period of five minutev. After cooling, the reactlon mixture is diluted with water and made basic with aqueous ammonium hydro~ide. The a~ueous basic mixture is extracted with se~eral portions of chloroform and the combined chloroform extracts dried over anhydrous sodium sulfate. AEter evaporating ~he solvent, the residua~
oil (730 mg.) i~ taken up in dry ether and the resulting solutlon filtered through diatomaceous earth-charcoal. The filtrate is ~reated with a saturated solution of hydrogen chlor1de in dry ether and the hydrochloride salt thus obtained is collected and crystallized from methanol-acetone to afford 565 mg. t56.5%) of N-cyclobutylmethyl-3,14-dihydroxymorphinan hydrochloride (LXa), m.p. 272-274 ~dsc.). The IR and NMR spectra were consistent with the structure.
~ -- Calcd.~for C~1H~N0,-HCl~2CH30H ~percent): C, 67.97;
H, 8,49; N, 3.49. Found ~percent~: C, 68.10; H, 8il4; N, 3.80.
Acidification of the filtered dry ether solution referred to above with appropriate acids provides varlous "pharmaceutically acceptable acid addition salts" of LXa.
The 3-methoxy ether function of N-cycIobutylmethyl-14~-hydroxy-3-methoxymorphinan may also be cleaved by treatment with ether cleaving agents such as NaSC1H" boron tribromide, or pyridine hydro-chloride to produce the deslred demethylaeed product LXa.
~ ' . ' ' .; ~ .
~ 21 ~
7~:3 and then poured ~nto a mlxture of 600 ml. of concentrated ammonium hydroxlde and 1 liter of crushed ice. Thz mixtu~e i~
extracted wlth 400 ml. of heptane and the hep~ane extract dried over sodium sulfate. Concentration of the dried heptane extract ~rovlde~
~3.1 ~. of oil ~85~ yield) of product LVa. This oil is dissolved in acetone and treated wlth anhydrous hydrogen chlorlde gas to afford erystalline hydrochloride salt of product LVa, m.p. 248 250.
Method B. Cyclization without boron complex of any kind 1.5 g. of 2-Cyclobutylmethyl-9~10-dihydroxy-1-(p-methoxy-ben7yl)perhydroisoquinoline ~IIa and 16.0 g. of 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 mlxture of ~ce and 35 ml. of concentrated ammonium hydroxide. The mixture is extracted with 40 ml. of methylene chloride and the methylene chloride extract eoneentrated to give 1.15 g. of oil. According to vapor p~ase ehromatography-~ass spectrometry analysls, the oil contained 57~ of the desired N-cyclobutylmethyl-14~-hydroxy-3-methoxymorphinan L~a, 27~ of a dehydrated by-product and 15% of uncycli~ad VIIa starting materlal.
Example 6 ~~1~2S~ y-N-Cyclobutylmethyl-14~-hvdroxv-3-methoxYmorphinan ~Va t)~
Substitution in the procedure of Example 1 of dextrorotator~-~ -methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline hydrochlorlde for racemic ~a and se~uentially applying the procedures o~ Examples 2-5 provides the levorotatory product LVa'.
Tha procedures of Examples 4 and 5 are carri2d out as follows. To a solutio~ of ~ o}~ LL-2'cyclobutylcarDonyl-9,10-. .
i7Z3 dlhydroxy 2~ methoxybenzyl)perhydroisoquinoline ~10 8-- 0.0267 ~ole) ir. lO0 ~1. of toluene i9 added borane dimethylsulflde neat solution (6 ml., 0.057 mole) through a syringe needle under nitrogen atmos-phere. ~le re3ulting solution is refluxed for 3 hr.) concentrated under reduced pressure to remove approximately 40 ml. of solvent and the borane complex of levor_tatory cyclobutylmethyl amine VIIa' is used directly iXI the cyclization reaction.
Cyclization of the levorotatory-cyclobutylmethyl amine VIIa' is carried out by adding the above toluene-borane complex mixture portionwise to 200 g. of anhydrous phosphorio acid and 35 g.
of phosphorus pentoxide with stirring while maintaining a temperature range of 0-25C. After the addition is complete, the mixture is heated and stirred for a period of 5 hr. at 70C. and then poured into a mixture o 400 ml. of concentrated ammonium hydroxide ~ith sufficient ice to maintain a temperature of approximately 25~C.
The mixture is extracted with toluene, the toluene extr2ct washed with water and then concentrated under reduced pressure to provide levorotatory-N-cyclobutylmethyl-14~-hydroxy-3-methoxy-morphinan ~LVa~) base. The oily base is converted to the sulfate salt by treating with sulfur1c acid to accord 7.2 g. ~61% yield? of levorotatorY--N-cyclobutylmethyl-l4~-hydroxy-3-methoxy-morphinan~
m.p. 232-237C. ~dec.~, Ea~d-5s.4C. (C = 0.56, CHjOH~.
~ , .
' .. . . .
!
:
.
.
2:~
am~le 7 2-Cyclopropylcarbonyl-l-(p-methoxybenzyl)-l,2,3~4,5,6,798-octahydroisoqulnoline ~
Substitution in the procedure of Example 1 for the cyclobu~ylcarbonyl chlorlde used therein of an equimolar quantity of cyclopropylcarbonyl chloride produces the title material IIb.
Example 8 2-Cyclopropylcarbonyl-9,10-epoxy-l~(p-methoxy- -ben~yl)perhydroisoquinolines ~IIIb and IVb~
Substitution in the procedure of Example 2 ror the ~acemic IIa used therein of an equimolar quantity of TIb prod~ces the title compounds IIIb and IVb.
Example 9 2-Cyclopropylcarb~nyl-9,10-dihydroxy~l-(p-methox~benzyl)perhydrolsoquinoline (Vb, VIb) Substitution in the procedure of ExampIe 3 for.the .
racemic IIIa and IVb used therein of an equimolar quanti~y of IIIb and IVb produces the title compounds Vb and VIb.
Example 10 .
2-Cyclopropylmethyl-9,10-dihydroxy-1-(p-_thoxybenzYl~perhydroisoquinoline (VIIb) Substitution in the procedure of Example 4 for the racemlc ~a used therein of an equimolar quantity of Vb produces the title eompound Vllb.
, . : Example 11 ~-Cyclopropylmethy~-14~-hYdroxy-3-methoxy~orphinan (LVb) !Sub~titution in the procedure of Exampl.e 5 for the racemic VIIa used therein of an equlmolar quantity of VIIb produces the title produet LVb. ~
;
' ' ~ .
~ - 20 -~
.; :
7;23 Exam~le 1z N-Cyclobutylmethyl-3,14-dihydroxymorphinan (LXa) A mixture of N-cyclobutylmethyl-14~ hydroxy-3-methoxymoryhinan (LVa) (1.0 g., 2.58 m mole) and 10 ml. of 48% Hsr is refluxed under a nitrogen atmosphere for a period of five minutev. After cooling, the reactlon mixture is diluted with water and made basic with aqueous ammonium hydro~ide. The a~ueous basic mixture is extracted with se~eral portions of chloroform and the combined chloroform extracts dried over anhydrous sodium sulfate. AEter evaporating ~he solvent, the residua~
oil (730 mg.) i~ taken up in dry ether and the resulting solutlon filtered through diatomaceous earth-charcoal. The filtrate is ~reated with a saturated solution of hydrogen chlor1de in dry ether and the hydrochloride salt thus obtained is collected and crystallized from methanol-acetone to afford 565 mg. t56.5%) of N-cyclobutylmethyl-3,14-dihydroxymorphinan hydrochloride (LXa), m.p. 272-274 ~dsc.). The IR and NMR spectra were consistent with the structure.
~ -- Calcd.~for C~1H~N0,-HCl~2CH30H ~percent): C, 67.97;
H, 8,49; N, 3.49. Found ~percent~: C, 68.10; H, 8il4; N, 3.80.
Acidification of the filtered dry ether solution referred to above with appropriate acids provides varlous "pharmaceutically acceptable acid addition salts" of LXa.
The 3-methoxy ether function of N-cycIobutylmethyl-14~-hydroxy-3-methoxymorphinan may also be cleaved by treatment with ether cleaving agents such as NaSC1H" boron tribromide, or pyridine hydro-chloride to produce the deslred demethylaeed product LXa.
~ ' . ' ' .; ~ .
~ 21 ~
Claims (9)
1. A process for the preparation of compounds having the formula L
wherein R is cyclobutyl or cyclopropyl and R2 is H or (lower)alkyl comprising the consecutive steps of (a) reducing the compound having the formula V
V
in which R is cyclobutyl or cyclopropyl and R2 is (lower) alkyl with borane in an inert organic solvent to produce a boron complex the compound having the formula VII
VII
in which R is cyclobutyl or cyclopropyl and R2 is (lower) alkyl;
(b) treating the boron complex of compound VII with acid to produce the compound having the formula LV
LV
in which R is cyclobutyl or cyclopropyl and R2 is (lower) alkyl; and, when desired, (c) cleaving the R2O-ether function of compound LV by treating with NaSC2H5, hydrobromic acid, boron tribromide or pyridine hydrochloride to produce the compound having the formula LX
LX
in which R is cyclobutyl or cyclopropyl.
wherein R is cyclobutyl or cyclopropyl and R2 is H or (lower)alkyl comprising the consecutive steps of (a) reducing the compound having the formula V
V
in which R is cyclobutyl or cyclopropyl and R2 is (lower) alkyl with borane in an inert organic solvent to produce a boron complex the compound having the formula VII
VII
in which R is cyclobutyl or cyclopropyl and R2 is (lower) alkyl;
(b) treating the boron complex of compound VII with acid to produce the compound having the formula LV
LV
in which R is cyclobutyl or cyclopropyl and R2 is (lower) alkyl; and, when desired, (c) cleaving the R2O-ether function of compound LV by treating with NaSC2H5, hydrobromic acid, boron tribromide or pyridine hydrochloride to produce the compound having the formula LX
LX
in which R is cyclobutyl or cyclopropyl.
2. The process of Claim 1 wherein in step (a) the formula V compound is reduced with borane dimethylsulfide.
3. The process of Claim 1 wherein in step (a) the formula V compound is reduced with boron generated in situ by reacting sodium borohydride and boron trifluoride or sodium borohydride and boron-trifluoride tetrahydrofuran complex or sodium borohydride and boron-trifluoride alkyletherate.
4. The process of any of Claims 1-3 wherein in step (a) borane is employed in a ratio of about 1 mole or compound V to 1.33 to 2.0 moles of borane.
5. The process of any of Claims 1-3 wherein step (a) is carried out with the aid of heat in the range of about 50 to 115° C.
6. The process of any of Claims 1-3 wherein in step (b) the boron complex of compound VII is treated with an acid selected from the group consisting of phosphoric, orthophosphoric, pyrophosphoric, and polyphosphoric.
7. The process of any of Claims 1-3 wherein in step (b) the boron complex of compound VII is treated with anhydrous phosphoric acid and phosphorous pentoxide.
8. The process of any of Claims 1-3 wherein step (b) is carried out at a temperature in the range of 50 to 100° C.
9. A process according to any of Claims 1-3 wherein subsequent to the reduction step (a), the boron complex of compound VII
is hydrolyzed with aqueous acid prior to the cyclization step (c).
is hydrolyzed with aqueous acid prior to the cyclization step (c).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA339,989A CA1091675A (en) | 1976-03-23 | 1979-11-16 | 2-cycloalkylmethyl-9,10-dihydroxy-1-(p- methoxybenzyl)perhydroisoquinoline compounds |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US669,795 | 1976-03-23 | ||
| US05/669,795 US4058531A (en) | 1976-03-23 | 1976-03-23 | Process for the preparation of 14-hydroxymorphinan derivatives |
| US05/769,808 US4139534A (en) | 1977-02-17 | 1977-02-17 | Process for the preparation of 14-hydroxymorphinan derivatives |
| US769,808 | 1977-02-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1086723A true CA1086723A (en) | 1980-09-30 |
Family
ID=27100195
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA274,241A Expired CA1086723A (en) | 1976-03-23 | 1977-03-18 | Process for the preparation of 14-hydroxymorphinan derivatives |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS52136176A (en) |
| CA (1) | CA1086723A (en) |
| CH (1) | CH629783A5 (en) |
| DK (2) | DK155322C (en) |
| FI (1) | FI61486C (en) |
| LU (1) | LU77000A1 (en) |
| NL (2) | NL189846C (en) |
| SE (1) | SE431749B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0373510U (en) * | 1989-11-15 | 1991-07-24 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3634429A (en) * | 1969-09-30 | 1972-01-11 | Hoffmann La Roche | Morphinan derivatives and preparation thereof |
| CA919668A (en) * | 1970-06-20 | 1973-01-23 | Murakami Masuo | Morphinan derivatives |
| BE788478A (en) * | 1971-09-08 | 1973-03-06 | Bristol Myers Co | PROCESS FOR PREPARING ANALGESIC COMPOUNDS |
| US3775414A (en) * | 1972-05-10 | 1973-11-27 | Bristol Myers Co | Process for the preparation of 14-hydroxymorphinan derivatives |
-
1977
- 1977-03-17 JP JP2871277A patent/JPS52136176A/en active Granted
- 1977-03-18 CA CA274,241A patent/CA1086723A/en not_active Expired
- 1977-03-18 FI FI770865A patent/FI61486C/en not_active IP Right Cessation
- 1977-03-18 NL NLAANVRAGE7703000,A patent/NL189846C/en active Protection Beyond IP Right Term
- 1977-03-21 DK DK123877A patent/DK155322C/en not_active IP Right Cessation
- 1977-03-21 SE SE7703236A patent/SE431749B/en not_active IP Right Cessation
- 1977-03-22 CH CH358077A patent/CH629783A5/en not_active IP Right Cessation
- 1977-03-23 LU LU77000A patent/LU77000A1/xx unknown
-
1988
- 1988-10-27 DK DK597188A patent/DK160987C/en active
-
1996
- 1996-09-16 NL NL960022C patent/NL960022I1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NL960022I1 (en) | 1996-12-02 |
| DK155322B (en) | 1989-03-28 |
| SE7703236L (en) | 1977-09-24 |
| SE431749B (en) | 1984-02-27 |
| DK160987B (en) | 1991-05-13 |
| DK597188D0 (en) | 1988-10-27 |
| DK155322C (en) | 1989-09-11 |
| NL189846B (en) | 1993-03-16 |
| JPS52136176A (en) | 1977-11-14 |
| DK160987C (en) | 1991-11-11 |
| FI770865A (en) | 1977-09-24 |
| CH629783A5 (en) | 1982-05-14 |
| JPS6139938B2 (en) | 1986-09-06 |
| DK123877A (en) | 1977-09-24 |
| FI61486B (en) | 1982-04-30 |
| LU77000A1 (en) | 1977-10-03 |
| DK597188A (en) | 1988-10-27 |
| FI61486C (en) | 1982-08-10 |
| NL7703000A (en) | 1977-09-27 |
| NL189846C (en) | 1993-08-16 |
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