Process for preparing a morphinan derivative

Details Process for preparing a morphinan derivative Process for preparing a morphinan derivative

2000-08-11

2001-06-05

Aulakh, C. S. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S229000, C546S042000, C546S048000

Reexamination Certificate

active

06242604

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the field of morphinans.
DESCRIPTION OF THE BACKGROUND ART
In 1954, Gates reported the first total synthesis of morphine 1 by an ingenious yet simple route, utilizing a &bgr;-dihydrothebainone-dihydrothebainone isomerization sequence in order to adjust the C
14
stereocenter. Since Gates's original approach, a total of 16 syntheses have been reported. The majority (nine of them), including the most recent one of Overman, proceed via 1-benzylisoquinoline intermediates, with the crucial step being C
12
-C
13
bond formation. These syntheses are formalized by intercepting Gates's dihydrothebainone (or &bgr;dihydrothebainone) or by producing the baine. The most efficient routes to date, those of Rice and Beyerman, have also used this strategy. Despite a number of attempts, only one successful synthesis (Evans) utilized a C
10
-C
11
closure late in the synthesis in order to complete the morphinan skeleton, followed by adjustment of stereochemistry at C
14
.
In 1994, Parker reported the full details of a radical cascade approach (published in a preliminary form in 1992)to racemic 1.
SUMMARY OF THE INVENTION
A process for preparing a morphinan derivative, by providing a dihydrofuranyl bridged tetracycle halide of the formula (19)
wherein X is halogen, R is an alkyl group of from 1 to about 10 carbon atoms, and R
1
is a protecting group; and converting the pentacycle halide into a morphinan derivative of formula (20)
wherein R is as defined above.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In accordance with one embodiment, the invention is directed to a process for preparing a morphinan derivative, comprising providing a dihydrofuranyl bridged tetracycle halide of the formula (19)
wherein X is halogen, R is an alkyl group of from 1 to about 10 carbon atoms, and R
1
is a protecting group; and converting said pentacycle halide into a morphinan derivative of formula (20)
wherein R is as defined above. In preferred embodiments, X is chlorine (Cl) and R is methyl. In further preferred embodiments, tetracycle halide is provided by converting a tetracycle of the formula (18)
wherein X is OH, and wherein R and R
1
are as defined above, into said tetracycle halide.
In preferred embodiments, said tetracycle is exposed to a methane sulfonyl halide and triethylamine, so as to convert said tetracycle to said tetracycle halide.
In further preferred embodiments, said tetracycle is provided by reducing a protected pentacycle of the formula (13)
wherein R and R
1
are as defined above, so as to form said tetracycle.
In preferred embodiments, said protected pentacycle is reduced with diisobutyl aluminum hydride in the presence of methylene chloride. In further preferred embodiments, said protected pentacycle is provided by cyclizing an aromatic halide of the formula (12)
wherein R and R
1
are as defined above, so as to form said protected pentacycle.
In preferred embodiments, said aromatic halide is cyclized in the presence of tributyltin hydride, azobisisobutyronitrile and benzene so as to convert said aromatic halide to said protected pentacycle. In further preferred embodiments, said aromatic halide is provided by protecting an acetonide of the formula (11a)
to form a diol of the formula (11a
1
)
and converting said diol into said aromatic halide by displacement of OH.
In preferred embodiments, said protected diol is reacted with the monomethyl ether of the bromocatechol of formula (4)
so as to convert the said protected diol to said aromatic halide of formula (12). In further preferred embodiments, said diol is provided utilizing a vinyl bromide of the formula (10)
wherein R is as defined above, so as to form said diol.
In preferred embodiments, said vinyl bromide is provided by converting a diol of the formula (7)
into said vinyl bromide. In further preferred embodiments, the method further includes the step of coupling to said diol an oxazolone of formula (5)
so as to convert said diol to said vinyl bromide.
In preferred embodiments, said diol is provided by reducing a diol of the formula (3)
so as to convert said diol of formula (3) to said diol of formula (7). In further preferred embodiments, said diol of formula (3) is provided by conversion of an aromatic compound of the formula (6)
so as to form said diol of formula (3).
In accordance with one embodiment, a morphinan precursor is prepared by providing a bromobenzene of the formula (6)
and converting said bromobenzene into a cylcohexadiene cis-diol of the formula (3)
The invention is further directed to compounds selected from the group consisting of a compound of the formula (10)
a compound of the formula (11a)
a compound of the formula (11b)
a compound of the formula (12)
a compound of the formula (13)
a compound of the formula (14)
a compound of the formula (15)
a compound of the formula (16)
a compound of the formula (18)
and a compound of the formula (20)
wherein R is an alkyl group of from 1 to about 10 carbon atoms, R
1
is a protecting group, and X═OH or halogen.
In accordance with one embodiment, the inventive compound is of the formulae (10), (12), (13), (14), (15), (16) or (20), and R is methyl.
In accordance with one embodiment, the inventive compound is of the formula (18), where R is methyl and X is OH.
In accordance with one embodiment, the inventive compound is of the formula (18), wherein R is methyl and X is Cl.


REFERENCES:
patent: 5912347 (1999-06-01), Hudlicky et al.
patent: 5952495 (1999-06-01), Huang et al.
Butora, G. et al. : Chemoenzymatic synthesis of the morphine skelton via radical cyclization and a C10-C11 closure. Tetrahed. Lett. vol. 37, pp. 8155-8158, Nov. 4, 1996.*
Arthur G.Schultz et al.Journal of Org.Chem.,vol. 50, pp. 217-231, 1985.*
Kathlyn A. Parker et al., “The Radical Cyclization Approach to Morphine, Models for Highly Oxygenated Ring-III Synthons”,J. Org. Chem., vol. 59, No. 14, 1994, pp. 3933-3938.

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