Note: Descriptions are shown in the official language in which they were submitted.
104~ 5;~;
This invention relates to novel chemical compounds
and processes of producing the same. More particularly,
this invention is concerned with novel benzopyrans and the
use of such compounds, particularly those having pharma-
cological activity.
According to one aspect of the subject invention
there is provided novel 1,2,3,4-tetrahydrocyclopenta[c][l]
benzopyrans of the formula
R Rl
~ OH
R2 ~ R3 ~ormu1a 1
wherein R is a lower alkyl having 1 to 5 carbons and Rl
is hydrogen or a lower alkyl group having 1 to 5 carbons,
and when R and Rl are both lower alkyl such groups can be
on the same or different carbon atoms in the cyclopenta or
c-ring moiety, R2 is a lower alkyl group and R3 is an alkyl
group having 1 to 20 carbon atoms, a phenyl-lower alkyl
group or a cycloalkyl-lower alkyl group, and novel inter-
mediates useful in making such compounds. When R and Rl
are both in the l-position on the ring system, generally
only one of such groups will be alkyl and the other will
be hydrogen.
As used herein, the term "lower-alkyl" means
saturated, monovalent aliphatic-radicals, including
straight and branched-chain radicals of from one to six
. ~ , , ~ - ,
1041SZ~;
carbon atoms, as illustrated by, but not limited to methyl,
ethyl, propyl, isopropyl, butyl, sec.-butyl, amyl, hexyl
and the like.
As used herein, the term "alkyl" means saturated,
monovalent aliphatic radicals, including straight and
branched chain radicals of from one to twenty carbon atoms,
as illustrated by, but not limited to methyl, n-amyl,
n-hexyl, 2-heptyl, n-heptyl, 3-methyl-2-octyl, n-octyl,
2-nonyl, 2-tetradecyl, n-hexadecyl, 2-eicosanyl, and the -
like.
As used herein, the term "cycloalkyl" means
cyclic, saturated aliphatic-radicals of from three to
eight carbon atoms, as illustrated by, but not limited
to cyclopropyl, cyclobutyl, 2-methylcyclobutyl, cyclohexyl, -
4-methylcyclohexyl, cyclooctyl, and the like.
As used herein, the term "phenyl-lower alkyl",
means a monovalent radical consisting of a phenyl nucleus
bonded to the rest of the molecule, respectively, through ~-
a divalent lower-alkylene radical of from one to six carbon
atoms as illustrated by, but not limited to methylene,
l,l-ethylene, 1,2-ethylene, 1,3-propylene, 1,2-propylene,
1,4-butylene, and the like. Here and elsewhere throughout ;
this specification, it will be understood the benzene or
phenyl ring can bear any number and kind of substituents
such as would occur to the man skilled in organic chemistry. ~
Solely for illustration, and without limitation, such -
substituents include lower-alkyl, lower-alkoxy, halo
(chloro, bromo, iodo or fluoro), nitro, lower-alkylmercapto,
and the like.
- - ,: , , .
- : . : - . . . . . . ..
1041SZ~;
The compounds of Formula 1 can be prepared by
reacting a 5-substituted resorcinol of Formula 2
OH
HO R3 Formula 2
wherein R3 has the previously assigned significance, with
a 2-carbo-lower alkoxy-cyclopentanone of Formula 3
R R1
COOR4 Formula 3
wherein R4 represents a lower alkyl group, to produce a
4-oxo-1,2,3,4-tetrahydrocyclopenta[c]ll]benzopyran of
Formula 4
R R~
~R3 Formula 4
which can then be reacted with a lower alkyl magnesium
halide to produce a compound of Formula 5
1 1
R2~LR3
R2 Formula 5
~041S26
which is then reacted with an acid such as hydrochloric
acid or ~-toluene sulfonic acid to dehydrate it to produce
a 4,4-dialkyl-9-hydroxy-7-R3-1,2,3,4-tetrahydrocyclopenta
[c]ll]benzopyran of Formula 1, wherein in Formulas 2 to 5
the substituents and symbols have the meanings assigned as
with respect to Formula 1.
Some of the 5-substituted resorcinols which can
be used in the process are 5-(3-methyl-2-octyl) resorcinol,
5-pentylresorcinol, 5-benzylresorcinol, 5-(3-phenylpropyl)
resorcinol, 5-[2-(p-fluorophenyl)ethyl]resorcinol,
5-cyclopentylmethyl resorcinol and 5-(3-cyclohexylpropyl)
resorcinol. The resorcinol starting materials are dis-
closed in the chemical literature and many are commercially
available.
Some of the 2-carbo-lower alkoxy-cyclopentanone
starting materials of Formula 3 which can be used in the
process are 2-carbethoxy-4,4-dimethyl-cyclopentanone,
2-carboethoxy-5-methyl-cyclopentanone, 2-carboethoxy-4-
methyl cyclopentanone and 2-carboethoxy-S-ethyl cyclopentanone.
Some of the starting materials which can be used are dis-
closed in J. Org. Chem. 29, 2782 (1964); 33, 4067 (1968) and
35, 3204 (1970) and others can be prepared by following -~
the procedures disclosed in this and other chemical
literature.
The first step of the process in which the
5-substituted resorcinol is reacted with a 2-carbo-lower ~ -
alkoxy cyclopentanone of Formula 3 is readily effected
by bringing the reactants together in a suitable liquid
- 4 - ~-
:,
1041S~;
reaction medium in the presence of an acid catalyst.
Hydrochloric acid dissolved in ethanol is suitable for
conducting the reaction. The reaction can be carried out
also in a mixture of concentrated sulfuric acid and
phosphorous oxychloride, or in phosphorus oxychloride
either alone or in an organic solvent, for example benzene
or toluene. The product can be recovered from the reaction
mixture by conventional means.
Some of the products produced by the described
reaction which come within the scope of Formula 4 are
l-methyl-4-oxo-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-
tetrahydrocyclopenta[c][l]benzopyran, 2-methyl-4-oxo-
9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-tetrahydrocyclopenta
[c][l]benzopyran, 9-hydroxy-7-(3-methyl-2-octyl)-2,2-
dimethyl-4-oxo-1,2,3,4-tetrahydrocyclopenta[c][l]benzopyran,
l-ethyl-4-oxo-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-tetra-
hydrocyclopenta[c][l]benzopyran, l-methyl-4-oxo-9-hydroxy-
7-n-pentyl-1,2,3,4-tetrahydrocyclopenta[c][l]benzopyran,
2-methyl-4-oxo-9-hydroxy-7-n-pentyl-1,2,3,4-tetrahydro-
cyclopenta[c][l]benzopyran, l-methyl-4-oxo-9-hydroxy-7-
(3-p-fluorophenylpropyl)-1,2,3,4-tetrahydrocyclopenta[c][l]
benzopyran, and 2-methyl-4-oxo-9-hydroxy-7-(2-cyclohexylethyl)-
1,2,3,4-tetrahydrocyclopenta[c][l]benzopyran.
The compounds of Formula 4 can be converted to
the compounds of Formula 5 by reacting a compound of
Formula 4 with an alkyl magnesium halide such as methyl
magnesium chloride, ethyl magnesium iodide or propyl
magnesium chloride. The reaction can be effected by
1041526
bringing the reactants together in a suitable inert
liquid reaction medium such as diethyl ether, dibutyl
ether, tetrahydrofuran, anisole and pyridine. The reaction
proceeds rapidly at reflux temperature. Although the
desired product of Formula 5 can be isolated from the
reaction mixture by standard methods after the reaction - -
is terminated, it is generally not advantageous to isolate
the triol. Instead, the triol of Formula 5 can be
treated, without isolation, with an acid to convert it to
a compound of Formula 1.
Some of the compounds of Formula 1 which can
be produced as described are 9-hydroxy-7-(3-methyl-2-
octyl)-1,4,4-trimethyl-1,2,3,4-tetrahydrocyclopenta
[c][l]benzopyran, 9-hydroxy-7-(3-methyl-2-octyl)-2,4,4-
trimethyl-1,2,3,4-tetrahydrocyclopenta[c][l~benzopyran,
9-hydroxy-7-(3-methyl-2-octyl)-2,2,4,4-tetramethyl-
1,2,3,4-tetrahydrocyclopenta[c][l]benzopyran, l-ethyl-
4,4-dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-
tetrahydrocyclopenta[c][l]benzopyran, 9-hydroxy-7-
n-pentyl-1,4,4-trimethyl-1,2,3,4-tetrahydrocyclopenta[c]
[l]benzopyran, 9-hydroxy-7-n-pentyl-2,4,4-trimethyl-
1,2,3,4-tetrahydrocyclopenta[c][l]benzopyran, 9-hydroxy-
7-(3-~-fluorophenylpropyl)-1,4,4-trimethyl-1,2,3,4-tetra-
hydrocyclopenta[c][l]benzopyran, and 9-hydroxy-7-(2-cyclo-
hexylethyl)-2,4,4-trimethyl-1,2,3,4-tetrahydrocyclopenta
[c][l]benzopyran.
- 6 -
.
,
~ ' , .
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:.
,
10415Z~
The compounds of this invention have antihypertensive,
antidepressant, analgesic, anticonvulsant, tranquilizing and/or
anti-anxiety activity in animals and such activities indicates
potential human use for the compounds as drugs.
The pharmacological activity for the compounds
having the nuclear alkyl substitutents in the _-ring of this
invention is surprisingly different from the activity of
the prior art related compound 4,4-dimethyl-9-hydroxy-7-
(3-methyl-2-octyl)-1,2,3,4-tetrahydrocyclopenta[c]~l]benzo-
pyran (SP-7) disclosed in United States patent No. 3,639,426
issued February 1, 1972 which does not have an alkyl group
in the _-ring. This will be seen from the following
summaries of the pharmacological activity of SP-7 and
specific compounds provided by this invention. The data
reported in the summaries was obtained using test procedures
reported in the literature as follows:
1. Antihypertensive test using hypertensive rats:
Tabei et al., Clinical Pharmacology and Therapeutics, 11,
No. 2, p. 269 (1970).
2. Mouse modified DOPA potentiation test for
antidepressant activity. Everett, G.M., Proc. First Internat.
Sympos. Antidepressant Drugs, Excerpta Med. Int. Cong. Ser.
No. 122, 1966.
3. Audiogenic seizure test for anticonvulsant
activity: Plotnikoff, N.P., J. Pharmacol. Exp. Therap. 119,
294 (1957).
1041S'~
4. Mouse fighting test for tranquilizing activity:
Tedeschi, R.E. et al., J. Pharmacol. Exp. Therap., 125,
28 (1959) with modifications; response to footshock measured.
5. Acetic acid induced writhing test for analgesic
activity: Brit. J. Pharmacol, 22, 296 (1964).
6. Rat tail flick test for analgesic activity:
J. Pharmacol. Exper. Therap.,72, 74 (1941). ;~
7. Hot plate test for analgesic activity:
J. Pharmacol. Exper. Therap., 80, 300 (1944). -
..
. . .
8. Jewett and Norton, Experimental Neurology, 15,
463-474 (1966),with modifications.
SP-7 administered orally in a dose of 10 mg./kg.,
reduced the systolic blood pressure of genetically hypertensive
rats. In an oral dose of 10 mg./kg., it showed marked activity
in the mouse modified DOPA potentiation test. In the audio-
genic seizure test, SP-7 in oral doses of 10 and 30 mg./kg.,
protected 25~ and 65~i of the mice, respectively, from the ;-
convulsions. At oral doses of 5 and 10 mg./kg., SP-7 caused
.~, .
56% and 65% reductions in fighting behavior, respectively, --
in the mouse fighting test. SP-7 had moderate activity in the ~ -
hot plate (ED50 = 45.1 mg./kg., p.o.) and the acetic acid
induced writhing test in mice (ED50 = 25.3 mg./kg., p.o.).
SP-7 at an oral dose of 0.5 mg./kg., caused an
increase of 59 minutes in total sleep time in EEG (sedative-
hypnotic) studies in cats. This increase was a result of -~
an increase of 32 minutes in the slow wave stage of sleep, ~ -
no change in the spindle sleep, and an increase of 27 minutes
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.
: ' . ;~ ' . - -~' ~;- ' ,
- :,- ~ j. ~ : .
~041SZ6
in the rapid eye movement (REM) stage. At an oral dose of
1.0 mg./kg., SP-7 caused an increase of 65 minutes in total
sleep time. This increase was a result of an increase of
65 minutes in the slow wave stage of sleep, a decrease of
12 minutes in the spindle stage, and an increase of 12
minutes in the REM stage of sleep.
9-Hydroxy-7-(3-methyl-2-octyl)-2,2,4,4-tetramethyl-
1,2,3,4-tetrahydrocyclopenta[c][l]benzopyran (SPA-4) was not
tested in genetically hypertensive rats. At an oral dose
of 10 mg./kg., it showed marked activity in the mouse
modified DOPA potentiation test. In the audiogenic seizure
test, SPA-4 in an oral dose of 30 mg./kg., protected 20% of
the mice from the convulsions. At an oral dose of 10
mg./kg., SPA-4 caused a 56~ reduction in fighting behavior
in the mouse fighting test. SPA-4 had no analgesic activity
at the doses employed. SPA-4 is useful as an antidepressant
or an anti-anxiety agent.
9-Hydroxy-7-(3-methyl-2-octyl)-2,4,4-trimethyl-
1,2,3,4-tetrahydrocyclopenta~c][l]benzopyran (SPA-47) admin-
istered orally at doses of 0.3 and 1.0 mg./kg., showed
no reduction in the systolic blood pressure of genetically
hypertensive rats. At an oral dose of 20 mg./kg., it showed
marked activity in the mouse modified DOPA potentiation test.
In the audiogenic seizure test, SPA-47 at an oral dose of
30 mg./kg., afforded no protection to the mice from the
convulsions. At an oral dose of 10 mg./kg., SPA-47 caused
a 19~ reduction in fighting behavior in the mouse fighting
test. SPA-47 had moderate activity in the acetic acid induced
writhing test in mice (ED50, 22.6 mg./kg., p.o,) SPA-47 is
useful as an antidepressant or analgesic agent.
1041SZ6
9-Hydroxy-7-(3-methyl-2-octyl)-1,4,4-trimethyl-
1,2,3,4-tetrahydrocyclopenta[c][l]benzopyran (SPA-90)
administered orally at doses of 1 and 10 mg./kg., reduced
the systolic blood pressure of genetically hypertensive rats.
In oral doses of 5, 10 and 20 mg./kg., it was essentially
inactive in the mouse modified DOPA potentiation test. In
the audiogenic seizure test, SPA-90 in oral doses of 10
and 30 mg./kg., protected 80% and 100% of the mice,
respectively, from the convulsions. At an oral dose of 10 -~
mg./kg., SPA-90 caused an 87% reduction in fighting behavior ~
in the mouse fighting test. SPA-90 had marked activity in -
the acetic acid induced writhing test in mice (ED50, 13.3
mg./kg., p.o.). SPA-90 at an oral dose of 0.5 mg./kg., caused
an increase of 58 minutes in total sleep time in EEG (sedative-
hypnotic) studies in cats. This increase was a result of
an increase of 38 minutes in the slow wave stage of sleep,
an increase of 30 minutes in the spindle stage, and a decrease
of 10 minutes in the REM stage of sleep. SPA-90 is useful as
an anticonvulsant, anti-anxiety, analgesic agent or sedative-
hypnotic agent.
.
Summary -
SPA-4 is approximately comparable in potency to
SP-7 as both an antidepressant and an anti-anxiety agent.
However, SPA-4 is less potent than SP-7 as an anticonvulsant
agent, and the analgesic properties have been greatly reduced
or eliminated. SPA-4 is thus a more selective drug in its
activity than is SP-7.
SPA-47 is comparable in potency to SP-7 as an anal-
gesic agent. SPA-47 is somewhat less potent than SP-7 as an
-- 10 --
,-
.;:
,,; , . .
~041S26
antidepressant, while the anticonvulsant, anti-anxiety,
and antihypertensive properties have been greatly reduced
or eliminated. The range of activity of SPA-47 is thus more
selective than for SP-7.
SPA-90 is more potent than SP-7 in anticonvulsant,
anti-anxiety, and analgesic properties. However, the anti-
depressant activity in SP-7 has been greatly reduced or
eliminated in SPA-90 indicating a selective activity not
possessed by SP-7. The sedative-hypnotic potencies of SP-7
and SPA-90 are approximately the same.
The amount of active ingredient administered
may be varied; however, it is necessary that the amount of
active ingredient be such that a suitable dosage is given.
The selected dosage depends upon the desired therapeutic
effect, on the route of administration and on the duration
of treatment. Dosages of from 0.1 to 25 mg./kg. of body
weight daily, preferably in divided doses, i.e., three to
four times daily, can be administered.
The active agents of this invention can be
administered to animals, including humans, as pure
compounds. It is advisable, however, to first combine
one or more of the compounds with a suitable pharmaceutical
carrier to attain a satisfactory size to dosage relation-
ship and thereby obtain a pharmaceutical composition.
Pharmaceutical carriers which are liquid or
solid can be used. Solid carriers such as starch, sugar,
talc and the like can be used to form powders. The powders
can be used for direct administration or they may be used
-- 11 --
. . . ~ . . . -~.
- . . . .
1041S;~
to make tablets or to fill gelatin capsules. Suitable
lubricants like magnesium stearate, binders such as gelatin,
and disintegrating agents like sodium carbonate in combina-
tion with citric acid can be used to form tablets. Sweeten-
ing and flavoring agents can also be included.
Unit dosage forms such as tablets and capsules
can contain any suitable predetermined amount of one or
more of the active agents, and they may be administered one
or more at a time at regular intervals. Such unit dosage
forms, however, should generally contain a concentration of
0.1 to 50 percent by weight of one or more of the active
compounds. Unit dosage forms, such as tablets and capsules,
can contain about 2 to 300 mg. of active agent.
A typical tablet can have the composition: -
~ '.
Active agent (1) 100 ~-
Starch U.S.P. 57
Lactose U.S.P. 73
Talc. U.S.P. 9 ;; -
Stearic acid 12
(1) 9-hydroxy-7-(3-methyl-2-octyl)-1,4,4-trimethyl-1,2,3,4-
tetrahydrocyclopenta[c][l]benzopyran.
The compounds of this invention exhibit both oral
and parenteral activity and accordingly can be formulated in
dosage forms for either oral or parenteral administration to
a patient.
Solid dosaqe forms for oral administration include
capsules, tablets, pills, powders, granules and the like.
- 12 -
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.. . - . -: - ., . . : ~ . :
10415Z6
Liquid dosage forms for oral administration include
emulsions, solutions, suspensions, syrups and the like, con-
taining diluents commonly used in the art such as water.
Besides inert diluents, such preparations can also include
adjuvants such as wetting agents, emulsifying and suspending
agents and sweetening, flavoring and perfuming agents.
Preparations for parenteral administration include
sterile aqueous or non-aqueous solutions. Examples of non-
aqueous solvents or vehicles are propylene glycol, poly-
ethylene glycol, vegetable oils such as olive oil and inject-
able organic esters such as ethyl oleate. The parenteral
preparations are sterilized by conventional methods.
The following examples are presented to further
illustrate the invention.
Example 1
9-Hydroxy-7-(3-methyl-2-oatyl)-1,4,4-trimethyl-1,2,3,4-
tetrahydrocyclopenta[c~[l]benzopyran
To 60 ml. of benzene and 4.3 ml. of phosphorous
oxychloride was added 14 g. of 5-(3-methyl-2-octyl)-resorcinol
and 11 g. of 5-methyl-2-carbethoxycyclopentanone [J. Org.
Chem. 29, 2782 (1964)]. The solution was refluxed 13 hours
and let stand at room temperature for 10 hours. Dilute
sodium carbonate was then added with stirring. The reaction
mixture was extracted with ether, the ether solution was
dried over magnesium sulfate and then concentrated to a
dark oil. The dark oil was extracted twice with pentane
leaving 10.4 g. of 1-methyl-4-oxo-9-hydroxy-7-(3-methyl-2-
octyl)-1,2,3,4-tetrahydrocyclopenta~c][l]benzopyran.
:
- 13 - ~
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.
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1~)415~;
A methyl magnesium bromide solution was prepared
by adding a solution of 175 g. of methylbromide in 450 ml.
of ether dropwise to 40 g. of magnesium in 150 ml. of ether.
To the solution was added 53 g. of 1-methyl-4-oxo-9-hydroxy-
7-(3-methyl-2-octyl)-1,2,3,4-tetrahydrocyclopenta[c][l]
benzopyran in 90 ml. of benzene and 90 ml. of ether. The
mixture was refluxed for 18 hours. The mixture was cooled
and then 800 ml. of saturated aqueous ammonium chloride was
added very slowly. The organic phase was separated, dried
over magnesium sulfate and concentrated to a residue.
The residue was dissolved in 900 ml. of benzene and 0.1 g.
of ~-toluene-sulfonic acid was added. The mixture was refluxed
for 2.5 hours, then cooled and shaken with aqueous potassium
bicarbonate. The solyent was removed by evaporation.
Petroleum ether and activated charcoal were added, the
solution was filtered and then concentrated to give 45 g. ;
of crude oil. The product was purified by chromatography
on magnesium silicate using 95/5 petroleum ether/ether
as the eluating solvent giving 25 g. of 9-hydroxy-
7-(3-methyl-2-octyl)-1,4,4-trimethyl-1,2,3,4-tetrahydro-
cyclopenta~c][l]benzopyran.
Example 2
9-Hydroxy-7-(3-methyl-2-octyl)-2,4,4-trimethyl-1,2,3,4- ^~
tetrahydrocyclopenta[c][l]benzopyran
To 300 ml. of benzene was added 26 g. of sodium
hydride with stirring under nitrogen. The sodium hydride
settled and 220 ml. of benzene was withdrawn. Then 300
- 14 -
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1041~
ml. of fresh benzene was added. The reaction mixture was
refluxed and to it was added 47 g. of the diethyl ester of
3-methyladipic acid in S0 ml. of benzene dropwise. After
1/4 of the ester was added, 75 ml. of benzene was distilled
off at atmospheric pressure to induce reaction. The
reaction then proceeded quickly. The rest of the diester
was added dropwise and 150 ml. of benzene was added and
the mixture was cooled in ice. After the addition of 45
ml. of acetic acid, the resulting pasty mass was treated
with 100 ml. of water. The aqueous layer was extracted
with benzene, dried and the combined organic layers were
distilled under vacuum to give 32.1 g. of 2-carboethoxy-4-
methyl cyclopentanone.
To 70 ml. of benzene was added 15 g. of 5-(3-methyl-
2-octyl)-resorcinol, 14 g. of 2-carboethoxy-4-methyl
cyclopentanone and 10 g. of phosphorous oxychloride followed
by refluxing for 8.5 hours. After standing for 8 hours at
room temperature the red solution was poured into cold dilute
sodium carbonate solution and then extracted with ether.
The ether layer was dried and concentrated and then tri-
turated with pentane to give a gummy blue solid. This
material was recrystallized from acetonitrile to give 7.5 g.
of 2-methyl-4-oxo-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-
tetrahydrocyclopenta[c][l]benzopyran as a light blue solid,
m.p. 176-178C.
A solution of 45 g. of methylbromide in 180 ml.
of ether was added dropwise to 10 g. of magnesium in 70 ml.
of ether over a period of 40 minutes followed by refluxing
1041SZ~
for 0.5 hours. 50 ml. of ether was distilled off and to
the remaining solution was added dropwise a suspension of 12.6
g. of 2-methyl-4-oxo-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-
tetrahydrocyclopenta~c][l]benzopyran in 60 ml. of ether and
60 ml. of benzene. The mixture was refluxed for 20 hours
and 250 ml. of saturated aqueous ammonium chloride was
added dropwise very slowly. The reaction mixture was
extracted with ether, dried over magnesium sulfate and
evaporated to a residue. The residue was dissolved in
300 ml. of benzene, 0.05 g. of p-toluenesulfonic acid was
added and the mixture was refluxed for 2 hours. The
mixture was cooled, shaken with sodium bicarbonate, and
dried over magnesium sulfate. The mixture was added to
petroleum ether and treated with charcoal. After evapora- ~
tion of the solvents, the residue was chromatographed using `
95/5 petroleum ether/ether for elution and the product of
9-hydroxy-7-(3-methyl-2-octyl)-2,4,4-trimethyl-1,2,3,4-
tetrahydrocyclopenta[c][l]benzopyran was obtained as 10.95
g. of yellow oil.
Example 3
9-Hydroxy-7-(3-methyl-2-octyl)-2,2,4,4-tetramethyl-1,2,3,4-
tetrahydrocyclopenta[c][l]benzopyran
To 13.5 g. of 5-(3-methyl-2-octyl)-resorcinol
and 10.5 g. of 4,4-dimethyl-2-carboethoxycyclopentanone -
[Canadian J. of Chem. 47, 1982-1988 (1969)] in 59 ml. of
benzene was added 4.3 ml. of phosphorous oxychloride with
:
- 16 -
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,
1041SZ~;
stirring and refluxing for 6 hours. After the red solutionwas allowed to stand at room temperature for 8 hours, it
was added to an ice and sodium carbonate solution. The
colorless mixture was extracted with ether, dried over
magnesium sulfate and concentrated. The mixture was
extracted with cold pentane and the pentane was discarded.
The residue [9-hydroxy-7-(3-methyl-2-octyl)-2,2,-dimethyl-
4-oxo-1,2,3,4-tetrahydrocyclopenta[c][l]benzopyran] was
obtained as a gummy solid.
22 grams of magnesium was added to 100 ml. of
ether and to the mixture was added dropwise a solution of
124 g. of methyliodide in 100 ml. of ether. The mixture
was refluxed for 0.5 hour and then the crude 9-hydroxy-7-
(3-methyl-2-octyl)-2,2,-dimethyl-4-oxo-1,2,3,4-tetrahydro-
cyclopenta[c][l]benzopyran in 130 ml. of benzene was added
over 20 minutes. The mixture was refluxed and stirred for
18 hours and, after cooling, 50 ml. of water was added drop- ~
wise under nitrogen. After the addition of 35 ml. of sulfuric - -
acid and 150 mI. of water, the ether layer was separated,
dried over magnesium sulfate and concentrated to a residue
which was dissolved in 200 ml. of benzene. Then 250 mg.
of _-toluene sulfonic acid was added followed by refluxing
for 1 hour. The solvent was removed and the residue was
dissolved in pentane. The solution was treated with char-
coal, filtered and concentrated to 13.5 g. of 9-hydroxy-7-
(3-methyl-2-octyl)-2,2,4,4-tetramethyl-1,2,3,4-tetrahydro-
cyclopenta[c~[l]benzopyran as a dark oil. The product ~;
- 17 - ~ -
~, .. . ,. . . . ~ , . -
104~5;~
was purified by column chromatography to give 10.4 g. of
pure product.
Example 4
l-Ethyl-4,4-dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-
tetrahydrocyclopenta[c][l]benzopyran
The general procedure of Example 1 is followed
in the following reactions.
2-Carboethoxycyclopentanone is reacted with ethyl
iodide in the presence of sodium hydride to produce
2-carboethoxy-2-ethyl-cyclopentanone.
2-Carboethoxy-2-ethyl-cyclopentanone is reacted
with sodium ethoxide to produce 5-ethyl-2-carboethoxy-
cyclopentanone. (J. Org. Chem. 29, 2782 (1964))
5-Ethyl-2-carboethoxycyclopentanone is reacted -
with 5-(3-methyl-2-octyl)-resorcinol to produce l-ethyl-
4-oxo-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-tetrahydro-
cyclopenta[c][l]benzopyran.
A solution of 40.1 g. (0.112 mole) of 1-ethyl-4- ;
oxo-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-tetrahydro-
cyclopenta[c][l]benzopyran in 300 ml. of ether was added
dropwise to a stirred solution of 1.12 mole of methyl
magnesium bromide in 340 ml. of ether. The resulting
solution was stirred and refluxed for 19 hours. The -~ ;
reaction mixture was cooled to room temperature and to
the mixture was added dropwise with stirring an ammonium
chloride solution (120 g. in 350 ml. of water). The
mixture was filtered to remove the inorganic salts which
- 18 -
. . - , ~ ' ~ .
' . ' ' ~ ~ : ' ''
- , ~ '
104;~
were well washed with benzene. The filtrate was concentrated
to dryness to give a dark viscous oil which was taken up
in 200 ml. of benzene. A few crystals of ~-toluenesulfonic
acid monohydrate were added and the mixture was refluxed 2
hours. The solvents were removed giving l-ethyl-4,4-dimethyl-
9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-tetrahyd~ocyclopenta
[c][l]benzopyran as a dark viscous oil. The product was
chromatographed on a magnesium silicate column and eluted
with 96/4 petroleum ether/diethyl ether. After rechromato-
graphy there was obtained 8.1 g. of product. The nuclear
magnetic resonance and infrared analysis of the product
showed it to be the expected compound.
Analysis Calcd. for C25H38O2: C, 81.03; H, 10.34; O, 8.63
Found: C, 80.48; H, 10.36; O, 9.4
The foregoing detailed description has been
given for clearness of understanding only, and no unneces-
sary limitations should be understood therefrom, as
modifications will be obvious to those skilled in the art.
-- 19 --
:
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