Note: Descriptions are shown in the official language in which they were submitted.
lO~O~iZ
This invention provides a process for preparing
5-isopropylidene-2,7-dihydroxy-9-substituted-2,6-methano-
3,4,5,6-tetrahydro-2H-l-benzoxocins, which process is char-
acterized by reacting a 5-(substituted)resorcinol with a
1-alkoxy-4-(1-hydroxy-1-methylethyl)-1,4-cyclohexadiene in
the presence of stannic chloride for from 1 to 15 minutes.
The benzoxocin derivatives are useful in the synthesis of
certain dibenzo[b,d]pyran-9-ones, valuable as anti-anxiety,
analgesic, and anti-depressant drugs.
The present invention pertains to 5-isopropylidene-
2,7-dihydroxy-9-substituted-2,6-methano-3,4,5,6-tetrahydro-
2H-l-benzoxocins. Certain benzoxocin derivatives are known
in the art. 2-Methyl-5-isopropenyl-7-hydroxy-9-n-pentyl-
2,6-methano-3,4,5,6-tetrahydro-2H-l-benzoxocin has been
prepared by reaction of boron trifluoride etherate with
2-(3-methyl-6-isopropenyl-2-cyclohexenyl)-5-n-pentylresorcinol,
commonly referred to as cannabidiol; see Gaoni and Mechoulam,
Tetrahedron, 22, 1481 (1966), and J. Am. Chem. Soc., 93, 217
(1971). Razdan and Zitko reported that the above named
isopropenyl benzoxocin derivative can be converted to the
corresponding isopropylidene benzoxocin derivative by
reaction with ~-toluenesulfonic acid. These authors addi-
tionally suggested that 2-methyl-5-isopropylidene-7-
hydroxy-9-n-pentyl-2,6-methano-3,4,5,6-tetrahydro-2H-l-
benzoxocin can be converted to l-hydroxy-3-_-pentyl-
6,6,9-trimethyl-6a,7,8,10a-tetrahydrodibenzo[b,d]pyran under
acidic conditions; see Tetrahedron Letters, No. 56, 4947
(1969). Recently, Razdan et al. reported the preparation of
X-4585
" 109S062
2-methyl-5-isoprop~iidene-7-nydroxy-9-n-pentyl-2,6-methano-
3,4,5,6-tetrahydro-2H-l-benzoxocin by reaction of 5-~-
pentylresorcinol with l-hydroxy-l-methyl-4-isopropenyl-2-
cyclohexene; J. Am. Chem. Soc~, 96, 5860 (1974).
The compounds described by formula I below have
been described before, such as in Belgian Patent 856,409.
In that patent it is explained that the compounds of formula
I are useful as intermediates for the preparation of dibenzo-
[b,d]pyran-9-ones, which are now known to be of great
importance as antl-depressant and anti-anxiety drugs. This
invention provides a particularly ~uick and efficient
process for preparing such intermediate benzoxocins.
The present invention provides a process for
preparing 5-isopropylidene-2,7-dihydroxy-9-substituted-
2,6-methano-3,4,5,6-tetrahydro-2H-l-benzoxocins of the
formula
CH3
H3C--~ ~H
/5 /~
2 o I CH~ 0 L
o
OH
1 C5 C10 alkyl, C5-C10 alkenyl, C5-C cyclo-
alkyl, or C5-C8 cycloalkenyl; which process is characterized
by reacting a l-alkoxy-4-(1-hydroxy-1-methylethyl)-1,4-
cyclohexadiene of the formula
X-4585J ~3~
X~
~L09~6~:
10-R3
I I III
~/
HO - C - CH
CH3
wherein R3 is Cl-C4 alkyl, with a 5-substituted resorcinol
of the formula
Il()\ ~ ~ /OH
I ~ II
~t/
~,
in an organic solvent in the presence of stannic chloride
for from 1 to 15 minutes at a temperature from -40C. to
ambient temperature.
Any of a number of 5-substituted resorcinols can
be utilized in the condensation, in which the 5-substituent
of the resorcinol is defined by Rl in the above formula.
Representative examples of C5-C10 alkyl groups include
n-pentyl, n-hexyl, l-methylpentyl, isoheptyl, l,l-dimethyl-
heptyl, 1,2,3-trimethylheptyl, isodecyl, l-ethylheptyl,
l,l-diethylpentyl and 1,2-dimethyloctyl.
Examples of C5-C10 alkenyl groups include 2-
pentenyl, 3-hexenyl, 1,2-dimethyl-1-heptenyl, 4-octenyl,
1,1-dimethyl-2-heptenyl, 1-ethyl-2-methyl-2-pentenyl,
1,2,3-trimethyl-3-heptenyl, and related groups.
X-4585J -4-
~ ~950~2
Typical C5-C8 cycloalkyl groups include cyclo-
pentyl, cyclohexyl, cycloheptyl and cyclooctyl. Similarly,
typical C5-C8 cycloalkenyl groups include 1-cyclopentenyl,
2-cyclohexenyl, 3-cyclohexenyl, l-cycloheptenyl, and 1-
cyclooctenyl.
Examples of 5-substituted resorcinols of formula
II routinely reacted with the aforementioned l-alkoxy-
4-(1-hydroxy-1-methylethyl)-1,4-cyclohexadiene to provide
the compounds of formula r include 5-_-pentylresorcinol,
5-(1,1-dimethylheptyl)resorcinol, 5-(1,2-dimethyl-1-hept-
enyl)resorcinol, 5-(1-ethylhexyl)resorcinol, 5-(3-hexenyl)-
resorcinol, 5-cycloheptylresorcinol, 5-cyclooctylresorcinol,
5-(1-cyclohexenyl)resorcinol, 5-(2-cycloheptenyl)resorcinol,
and related resorcinols.
In accordance with this invention, approximately
equimolar quantities of a 5-substituted resorcinol and a 1-
alkoxy-4-(1-hydroxy-1-methylethyl)-1,4-cyclohexadiene are
commingled in the presence of stannic chloride and in an
organic solvent, at a temperature generally from -40C. to
ambient temperature.
The above-described reactions to prepare compounds
of formula I are carried out in an organic solvent. Commonly
used solvents include halogenated hydrocarbons such as
dichloromethane, chloroform, l,l-dichloroethane, 1,2-
dichloroethane, bromomethane, 1,2-dibromoethane, l-bromo-
2-chloroethane, l-bromopropane, l,l-dibromoethane, 2-
chloropropane, l-iodopropane, 1-bromo-2-chloroethane,
bromobenzene, and 1,2-dichlorobenzene; and aromatic solvents
such as benzene~ chlorobenzene, toluene, and xylene.
X-4585J -5-
1~950G2
Small amounts of water in the reaction mixture
tend to improve the process, and the addition of water is a
preferred technique. The preferred amount of water is about
one mole per mole of product to be prepared.
The process of this invention is complete in very
short reaction times from 1 to 15 minutes. The preferred
reaction time is from 1 to 10 minutes. As is made clear by
the following examples, it is desirable to carry out this
process very quickly, and to quench the reaction mixture as
soon as the additions are complete.
The preferred method for carrying out the process
of this invention is to to combine the compounds of formulae
II and III, to cool the reaction mixture to relatively low
temperature toward the bottom of the temperature range, and
to then add the stannic chloride in a fine stream or
dropwise over a period of a few minutes, allowing the
reaction mixture to warm somewhat as the addition is carried
on.
Of course, the reaction will commence as soon as
the compounds of formulae II and III and the catalyst are
all present in the reaction mixture. Accordingly, the order
of addition may be any which may be convenient in the
circumstances, so long as the temperature is controlled
during the addition of the last item to the reaction
mixture, and so long as the reaction is properly quenched
so that the period of time during which all of the necessary
ingredients are present in the reaction mixture does not
exceed the specified time periods.
X-4585J -6~
....
S0~2
Upon completion of the reaction, isolation of the
benzoxocin derivative normally is a simple procedure and can
usually be accomplished by washing the reaction mixture with
water and a dilute aqueous base, evaporating the reaction
solvent, and crystallizing the residual product from common,
relatively nonpolar solvents such as hexane or methylcyclo-
hexane.
Examples of typical benzoxocins of formula I which
can routinely be prepared and which are provided in accord-
ance with the present invention are as follows:
2,7-dihydroxy-5-isopropylidene-9-n-pentyl-2,6-
methano-3,4,5,6-tetrahydro-2H-l-benzoxocin;
2,7-dihydroxy-5-isopropylidene-9-(1,2-dimethyl-
heptyl)-2,6-methano-3,4,5,6-tetrahydro-2H-l-benzoxocin;
2,7-dihydroxy-5-isopropylidene-9-(2-hexenyl)-
2,6-methano-3,4,5,6-tetrahydro-2H-l-benzoxocin;
2,7-dihydroxy-5-isopropylidene-9-(1-ethyl-2-
methyl-2-butenyl) 2,6-methano-3,4,5,6-tetrahydro-2H-l-
benzoxocin;
202,7-dihydroxy-5-isopropylidene-9-cyclohexyl-
2,6-methano-3,4,5,6-tetrahydro-2H-l-benzoxocin;
2,7-dihydroxy-5-isopropylidene-9-(n-decyl)-2,6-
methano-3,4,5,6-tetrahydro-2H-l-benzoxocin;
2,7-dihydroxy-5-isopropylidene-9-(n-heptyl)-
2,6-methano-3,4,5,6-tetrahydro-2H-1-benzoxocin;
2,7-dihydroxy-5-isopropylidene-9-(1-methylheptyl)-
2,6-methano-3,4,5,6-tetrahydro-2H-l-benzoxocin;
2,7-dihydroxy-5-isopropylidene-9-~1-cycloheptenyl)-
2,6-methano-3,4,5,6-tetrahydro-2H-l-benzoxocin; and
X-458CJ -7-
10~5062
2,7-dihydroxy-5-isopropylidene-9-(2-cyclooctenyl)-
2,6-methano-3,4,5,6-tetrahydro-2H-l-benzoxocin.
The l-alkoxy-4-(1-hydroxy-1-methylethyl)-1,4-
cyclohexadienes which are required as starting materials for
preparing the benzoxocin derivatives of the present in-
vention can readily be prepared by reducing p-alkoxy-
a,a-dimethylbenzyl alcohols. Typically, the reduction is
accomplished by reaction of the benzyl alcohol derivative
with a metal such as lithium in the presence of liquid
ammonia and a proton source such as ethyl alcohol. Such
reaction is carried out according to the standard Birch
reduction conditions. See Belgian Patent 856409. The
resorcinol starting compounds are readily available; see,
for example, Adams _ al., J. Am. Chem. Soc. 70, 664 (1948)._ _ _ _
The benzoxocin derivatives of formula I are useful
as intermediates in the synthesis of hexahydrodibenzopyranones.
The compounds of formula I are converted, upon treatment
with an aluminum halide such as aluminum chloride, to the
corresponding dl-trans-l-hydroxy-3-substituted-6,6-dimethyl-
20 6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one. For
example, reaction of a 2-hydroxybenzoxocin of this invention,
such as 2,7-dihydroxy-5-isopropylidene-9-(1,2-dimethyl-
heptyl)-2,6-methano-3,4,5,6-tetrahydro-2H-l-benzoxocin, with
about a 2 to 4 molar excess of aluminum chloride in a
solvent such as dichloromethane effects rearrangement to
provide dl-trans-l-hydroxy-3-(1,2-dimethylheptyl)-6,6-
dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d~pyran-9-
one. Such dl-trans-hexahydrodibenzopyranones are useful in
the treatment of anxiety and depression, and are also
sedatives and analgesics.
X-4585J -8-
109SO~Z
The 2-hydroxybenzoxocins of formula I can also
be converted to the corresponding dl-cis-hexahydrodibenzo-
pyranone by additional treatment with stannic chloride. For
example, reaction of 5-isopropylidene-2,7-dihydroxy-9-
n-pentyl-2,6-methano-3,4,5,6-tetrahydro-2H-l-benzoxocin with
about an equimolar quantity or an excess of stannic chloride
in a solvent such as benzene effects rearrangement to
provide dl-cis-l-hydroxy-3-n-pentyl-6,6-dimethyl-6,6a,7,-
8,10,10a-hexahydro-9H-dibenzo[b,d]pyran 9-one. Such cis-
hexahydrodibenzopyranones, while pharmacologically active inthe treatment of anxiety and depression, are somewhat less
active than the corresponding trans-isomer. However,
treatment of such cls-hexahydrodibenzopyranones with an
aluminum halide such as aluminum chloride effects epimeriza-
tion to provide the corresponding pharmacologically more
active trans-hexahydrodibenzopyranone. For example,
reaction of dl-cis-1-hydroxy-3-n-pentyl-6,6-dimethyl-
6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one with
aluminum chloride in dichloromethane effects epimerization
to provide the corresponding dl-trans-hexahydrodibenzo-
pyranone.
Example 1
2,7-Dihydroxy-5-isopropylidene-9-(1,1-dimethylheptyl)-2,6-
methano-3,4,5,6-tetrahydro-2~ benzoxocin
A solution of 11.8 g. of 5-(1,1-dimethylheptyl)-
resorcinol, 12.0 g. of 1-methoxy-4-(1-hydroxy-1-methyl-
ethyl)-1,4-cyclohexadiene and 0.9 ml. of water in 100 ml. of
dichloromethane stabilized with cyclohexane (ie. commercial
grade dichloromethane) was stirred and cooled to -20C. in a
dry ice-acetone bath. To the cold stirred solution was
X-4585J -9-
..
~so~z
added 13 ml. o~ stannic chloride dropwise at a rapid rate
over three minutes, during which time the temperature of the
reaction mixture increased to -11C. Immediately following
complete addition of the stannic chloride to the reaction
mixture, the mixture was poured into 2C0 9. of ice, and
50 ml. of water was added to the ice mixture. The organic
layer was separated, washed twice with 200 ml. portions of
1~ sodium hydroxide and th~n with 250 ml. of water. The
organic layer next was dried, and the solvent was removed by
evaporation under reduced pressure to provide 20.5 g. of the
product as a solid. The solid thus formed was recrystal-
lized from'n-hexane to afford 16.2 g. (87 percent yield) of
2,7-dihydroxy-5-isopropylidene-9-(1,1-dimethylheptyl)-2,6-
methano-3,4,5,6-tetrahydro-2H-l-benzoxocin. M.P. 148-152C.
Example 2
2,7-Dihydroxy-5-isopropylidene-9-~1,1-dimethylheptyl)-2,6-
methano-3,4,5,6-tetrahydro-2H-l-benzoxocin
A mixture of 11.8 g. of 5-(1,1-dimethylheptyl)-
resorcinol, 12.0 g. of l-methoxy-4-(l-hydroxy-l-methylethyl)
1,4-cyclohexadiene, 0.9 ml. of water and 100 ml. of di-
chloromethane was cooled to 0C. The mixture was stirred
while 13 ml. of stannic chloride was added dropwise over a
10 minute period, holding the temperature of the reaction
mixture between 0C. and 10C. The reaction mixture was
immediately worked up as described in Example 1, to obtain
15.5 y. of 2,7-dihydroxy-5-isopropylidene-9-(1,1-dimethyl-
heptyl)-2,6-methano-3,4,5,6 tetrahydro-2H-l-ben~oxocin, M.P.
145~148C., yield 83~.
X-~585 J -10-
~,
. ~ J~!
~ 95f)6~:
Example 3
2,7-Dihydroxy-5-isopropylidene-9-(1,1-dimethylheptyl)-2,6-
methano-3,4,5,6-tetrahydro-2H-l-benzoxocin
The process of Example 2 was carried out again,
except that the initial temperature of the reaction mixture
was -20C., and the stannic chloride was added over a time
of 2-3 minutes, while the reaction mixture was allowed to
warm to 9C. The mixture was worked up as described in
Example 1 to obtain 16.0 g. of 2,7-dihydroxy-5-isopropylidene-
9-(1,1-dimethylheptyl)-2,6-methano-3,4,5,6-tetrahydro-
2H-l-benzoxocin, M.P. 151-153C., yield 87~.
Examp~e 4
2,7-Dihydroxy-5-isopropylidene-9-(1,1-dimethylheptyl)-2,6-
methano-3,4,5,6-tetrahydro-2H-l-benzoxocin
The same process as Examples 2-3 was used in this
example, except that the initial temperature of the reaction
mixture was -40C. The stannic chloride was added in 1
minute, and the temperature of the reaction rose to -11C.
The same procedure of work up was used, to obtain a yield of
14.2 g. of 2,7-dihydroxy-5-isopropylidene-9-(1,1-dimethyl-
heptyl)-2,6-methano-3,4,5,6 tetrahydro-2H-l-benzoxocin, M.P.
153-155C., yield 78%.
Exam~le 5
2,7-Dihydroxy-5-isopropylidene-9-(1,1-dimethylheptyl)-2,6-
methano-3,4,5,6-tetrahydro-2H-l-benzoxocin
A 2.36 g. portion of 5-(1,1-dimethylheptyl)-
resorcinol and a 2.0 g. portion of 1-methoxy-4-(1-hydroxy~
l-methylethyl)-1,4-cyclohexadiene were combined in 25 ml. of
toluene, the solution was cooled to -20C., an 0.18 ml.
portion of water was added, and then 2.6 ml. of stannic
chloride was added in a period of 2 minutes, while the
X-4585J -11-
~)9506Z
temperature rose to -4C. The reaction mixture was im-
mediately worked up as described in Example 1 to obtain
1.47 g. of 2,7-dihydroxy-5-isopropylidene-9-(1,1-dimethyl-
heptyl)-2,6~methano-3,4,5,6-tetrahydro-2H-l-benzoxocin, M.P.
156-158C., yield 40%~
Preparation 1
dl-trans-l-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-
6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one
A solution of 100 mg. of 2,7-dihydroxy-5-iso-
propylidene-9-(1~1-dimethylheptyl)-2,6-methano-3,4,5,6-
tetrahydro-2H-l-benzoxocin in 5 ml. of dichloromethane was
stirred at about 24C. while 100 mg. of aluminum chloride
was added in one portion. The reaction mixture was stirred
at 24C. for six hours, and was then washed with lN hydro-
chloric acid solution, with water, and dried. Removal of
the solvent by evaporation under reduced pressure provided a
solid residue, which was recrystallized from hexane to
provide dl-trans-l-hydroxy-3-(1,1-dimethylheptyl)-6,6-
dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-
one. M.P. 160-161C.
X-4585J -12-
