Note: Descriptions are shown in the official language in which they were submitted.
.'`-``, lQ77478
~ .
The present invention relates to novel basic ethers, to a
, process for their preparation and to pharmaceutical compositions containing
i,; ~
them.
British Patent No. 1,35i,633 disclosed inter alia compounds of
the fo..~la ~
i
~'1 10
and salts theseof wherein Al is an alkylene group of 2-4 carbon atoms,
A2 is a hydrogen atom or Cl 4 alkyl group and A3 is a hydrogen atom or a
Cl 4 alkyl group. These compounds have been shown to possess a degree of
mood modifying activity. However it is now believed that the compounds of
he formula (I) are insufficiently potent. There has now been discovered a
group of compounds which have more potent mood modifying activity than the
` compounds of formula (I) and at higher doses have the additional utility of
supp~essing appetite.
Accordingly, in one aspect the invention provides compounds
,.
,' ~ 20 of the formula (II): -
'~ '! ~ . .
~ ' :',
~ '
i,~ l: .
};:'.~ ,
.'~', j~ :
: i'"1
.1 _ 2 -
. , ,
:i`
-I
~ . . ... ~ .. .
, .. :. . .... ..
. . ` . . - . .
, :. ~` :
.:. . ` - `
1~77478
.^;............................................. .
,
. ::
~'d'
~ ~O - X - ~R1~2 (II)
;; 5
and salts thereof wherein X is an alkylene group of 2-4 carbon atoms;
Y is an oxygen or sulphur atom or a CH2 group; R1 is a hydrogen atom or a
Cl 6 alkyl group; R2 is a hydrogen atom, a Cl_6 alkyl, phenyl, tolyl or
- benzyl group or R2 is linked to Rl so that the NR1R2 is a 5-, 6- or 7-
membered saturated ring; R3 is an aryl o~ aralkyl group; R4 is a hydrogen
~!i atom or a C1 4 alkyl group; and R5 is a hydrogen atom or a Cl_4 alkyl group.
~ When used herein, the term "alkylene" means a straight or
branched divalent alkyl group which produces a bridge at least two carbon
atoms long between the 0 and N atoms, When used herein the term 'laryl"
means phenyl, pyridyl, furyl, thienyl, pyrrolidyl or substituted phenyl
q~
;~ ~ group. When-used herein the term "aralkyl" means a CH2R6 or CH2CH2R6
i~ group wherein R6 is an aryl group. When used herein
".,, , '- '
~ 20
'"`i'" , ,
, ~.
",, ;
,~
- ' :
:'~
~j ~ 3 ~
!, '
.' `.J
.,
'''''',' ' ~ " , ' ' ,, ' ' ' , .
:-. ' '' ' , ' ' " ' '` ' '
'. ' . ' , ' ~ .. ' '
;~` `
i i,
1077478
the term "substituted phenyl group" means a phenyl group substituted by
one or two groups selected ~rom fluorine, chlorine or bromine atoms or
methoxyl, benzyloxyl, trifluoromethyl, methyl, nitro, acetoxyl, amino,
~` methylamino, ethylamino, dimethylamino, diethylamino, acetamido, hydroxyl,
~"
methoxycarbonyl, ethoxycarbonyl, carboxamido, sulphonamido, nitrile carboxy,
trifluoromethoxyl, trifluoromethylthio, methylsulphonyl, trifluoromethyl-
sulphonyl or methylthio groups.
Most suitably R4 and R5 are both methyl groups.
Suitably groups X include the -CH2-CH2-, -CH2-CH2-CH2-,
-CH2-CH2-CH2-CH2-~ -cH2-cH(cH3)-cH2- and -cH2-cu(cH3)2- group. Most
suitably X is a -CH2-CH2 group.
~X Suitable groups Rl lnclude the hydrogen atom and the methyl,
.
ethylj propyl and butyl groups. Suitable groups R2 include the hydrogen
atom and the methyl, ethyl and benzyl groups. Suitable cyclic groups
NRIR2 include pyrrolidino, piperidino, plperazinyl, N-methylpiperazinyl,
morpholino and like groups.
i,,.,~
~ ~ .
~' .
,~ .
~, 20
,'~" i ,
, ; ,
.,'
r, ~ 4--
., .
".';
.,"
',~,. ,, '
~r' . ~ : , :
~''~ ; , .
',:.' - : . '
:' ' ,
.
~` Particularly suitable groups XNRlR2 include the CH2CH2NHCH3
- and CH2CH2N(CH3)2 groups, the CH2CH2N(CH3)z group being preferred.
. , .
, Most suitably R3 is a phenyl or substituted phenyl group.
Preferably R3 is a trifluoromethylphenyl group.
:
A suitable value for Y is the sulphur atom. A particularly
suitable value for Y is a CH2 group. A preferred value for Y is the
,';~ oxygen atom.
`` One particularly suitable sub-group of compounds of the
formula (II) are those of the formula (III): /
~'~ 10 R
;, 3
' 3U ~ ~ - CU2 ~12 ' ~ 1 2
.:
and salts thereof when Z is an oxygen atom or a CH2 group and Rl, R2 and
`~', R3 are as defined in relation to formula (II).
...
,,
~ 20
~:"
. . .
~i,
;.,.~.~, : .
, ~ .
`:`1 .
;r;.,
., . .
1~
1 ~ 5 -
;
.
"~, .. .
.: . ., .. . . . . ; . .
~: , , . . . ~ : - :
' '' - - : ' ' ~ ': ': : ., ' ., .
~ . : . - ...
74~7B
~ . .
; ~
i~ Suitably Z is a methylene group. Preferably Z is an oxygen
atom.
` Suitably R3 is a phenyl or mono-substituted phenyl group.
A particularly suitable group R3 is the trifluoromethylphenyl group.
NRlR2 is suitably a methylamino or dimethylamino group,
preferably the dimethylamino group.
Another particularly suitable group of compounds of formula
(III) are those of the formula (IV):
~ 10 R7~8
~ ; H3C ~ 2 CN2 RRIR2
~ ' , '
and salts therein wherein Rl and R2 are as defined in relation to formula
(II); R7 i8 selected from a hydrogen, fluorine, chlorine or bromine atom or a
, '
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.;
., .
.
. ~ .
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.,
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.,. ~ .
.
-
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,........... . . . .
.
` 107'7478
trifluoromethyl, methyl, methoxyl, nitro, cyano hydroxyl, amino, dimethyl-
amino, carboxamido, trifluoromethyloxy, trifluoromethylthio or sulphonamido
group; and R8 is a hydrogen, fluorine or chlorine atom or a trifluoromethyl,
methoxyl, methyl or nitro group.
R7 is most suitably a hydrogen, fluorine or chlorine atom or
a methyl, methoxyl or trifluoromethyl group. R8 is most suitably a hydrogen,
fluorine or chlorine atom and is preferably a hydrogen atom.
Most suitably for the compounds of formula (IV) Rl is a
hydrogen atom or a methyl or ethyl group and R2 is a methyl or ethyl group.
Preferably both Rl and R2 are methyl groups.
A further particularly suitable group of compounds of the
formula (Il) are those of the formula (V):
~..
::,
i
Y ~7- ~ ~8
;., (V)
~`
3 ~ - CN2 - CN~ - N 3
~, ' .
",;.
. . .
.,.~.".
. ~
"..
, . .
~ ~ 7 -
~J ~
, . " ' ' '. ' "
~--, . . .
'"'"'.................. , '', ~ ' ', '
' - '' ' ' ,'. ,, "' ', ' ' '' ' , . ' ~ ' ' ' , ' ' " ' .
- ,
,: . . ' : ,, ' ., ,
:- , '. . - ' , . ' ' ' : - - :
. ' ' . , . :~ .,: . ' . ~ . :
` . ~:
1C~77478
, ~
. and salts thereof wherein Z is an oxygen atom or a CH2 group and R7 and R8
are as defined in relation to formula (IV).
.
~`. In compounds of the formula (V), Z is suitably a CH2 group.
In compounds of formula (V) Z is preferably an oxygen atom.
: Particularly favoured groups R7 and R8 are described in
relation to formula (IV).
It is considered that compounds particularly worthy of
:, .
. mention include those of the formula (VI):
....
:,
(VI)
U3C ~ ~ C~l2 ~ CR2 ~ nRIORII
, ................... .
- and salts thereof wherein P~9 is a hydrogen, fluorine, chlorine or bromine
.;
atom or a methyl, methoxyl or trlfluoromethyl group; Rlo is a hydrogen
atom or a methyl or ethyl group, and Rll is a methyl or ethyl gsoup or
~:; 20 is ~oined to Rlo so that the NRloRll group
:,.;.
..
,:.,
~ .
,.'.~ ; .
.. . .
':
.: 8 -
. . .,~ .
.. . . . : ,, . : .
`''' :: : ~ .. . . .
': ' ~ . : . : `: . : . : :
,.` . '' ~' . ' . ~ " ' . . . `~
`~:
77~8
~ , . .
.
~` group is a piperidino, pyrrolldlno, or morpholino, group.
Most suitably NR1oRl1 is not a cyclic group.
In certain particularly suitable compounds of the formula
, :~
i (VI) NR1oR11 is a methylamino group. In certain preferred compounds of
, . .
the formula (VI) NR1oR11 is a dimethylamino group.
... . .
: Particularly favoured compounds of the formula (VI) include
.'':'~
~ those wherein Rg is a meta- or para~ trifluoromethyl group.
.. ..
A further sub-group of compounds of this invention which
~: we believe are worthy of mention are those of the formula (VII):
~, 10
!, '.~
12
R4 ~ ~ ~ CR2 ~ C~2 ~ ~ (VII~
,.. . .
and wherein Rl, R2, R4 and R5 are defined in relation to formula (II) and
; R12 is a trifluoromethylphenyl group.
~1 .
3~
~ . ,
~ .
:,~;t `
s ~ 77~78
. .
A particularly suitable value for Rl in the compounds of
- formula (VII) is the methyl group. Particularly suitable values for R2
., .
ln the compounds of formula (VII) are the hydrogen atom and the methyl
group. Particularly suitable values for R4 and R5 in the compounds of
formula (VII) include the methyl group.
~, Since the compounds of this invention are nitrogenous bases
they are able to form acid addition salts in conventional manner. Normally,
~', such salts are those formed from pharmaceutically acceptable organic or
;-; .
~ inorganic acids such as citric, acetic, propionic, lactic, tartaric,
"
mandelic, succinic, fumaric, oleic, glutamic, gluconic, methanesulphonic,
toluenesulphonic, sulphuric, phosphoric, hydrobromic, hydrochloric or the
like acid. As will be recognized by those familiar with the fo~mulation
of pharmaceutical agents, the nature of the salting acid is relatively
unimportant as long aæ it forms a stable and preferably crystalline
pharmaceutically acceptable acid addition salts. Certain compounds
within this invention and their salts are able to form sol~ates such as
hydrates, for example, monohydrates.
,; . ,
Compounds within the formula (II) affect the
~ ' .
~ 20
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s~ . . ,
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: - , ~ .: . : . ~ : - -
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": . '
central nervous system. Thus depending on the dosage used, certain
compounds of the formula (II) are able to produce anorexic or mood
modifying effects in mammals.
,.....
Accordingly, in one o its aspects the present invention
provides pharmaceutical compositions which comprise a compound of this
~; invention as hereinbefore described together with a pharmaceutically
i:
~- acceptable carrier.
:~
,t,, Normally, the compositlons of this inventlon are adapted
. ,~. .
; for oral administratlon to humans although compositions adapted for
;~, ............... .
parenteral administration are also envlsaged.
The most suitable dosage forms are unlt dosage for~s
such as tablets, capsules, sachets and the like which contain a pre,
determlned quantity of active material.
Such unit dosage forms normally contain from 0.1 to 200 mg.
.7,. ~
of actlve materlal and may be taken once a day or several times a day
according to the dose desired. Generally a human adult will be
administered from 1 to 600 mgs. per day, for example, from 5 to 200 mgs.
,~ s~,
, ....
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~,
~,! y,
~' ~
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:';, ~ ' . . . : ':
'~ " ' ' ' " . ' ' ' ' ' ' '
,:
,
1~77478
. `, .
. ....
If the composition of this invention is intended for the
induction of anorexia the composition will normally be in the form of a
~; solid unit dosage form which contains from 1 mg. to 200 mg. of active
`; ingredient, for example, 2 mg. to 150 mg. of active ingredient.
If the composition of this invention is intended for mood-
modification such as anti-depressant effects, it is likely that it will
be used as a solid unit dosage form which contains from 0.1 mg. to 50 mg.
, of active ingredient, for example, 1 mg. to 25 mg. of active ingredient.
' In a further aspect this invention provides a method of
suppresslng appetite, which comprises administering an anorexically
,,
effective amount of a compound of this invention.
~ .:
In a further aspect this invention provides a method of
`- reducing depression, which comprises administering an anti-depressively
effective amount of a compound of this invention.
,
"
:.,
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.
'';
,:
, . .
,''~' ' :
~ 12 ~
.
,:
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, . '' : ~ ' ~ : '- ' ' - -
i~: 1077478
.
., The useul anorexic activity of compounds of this invention may
be determined by the oral admlnistration to hungry rats of the compound and
.~ ,,
"` measuring the reduction in their food intake. The results given in Table 1
;~............. were obtained for compounds of the formula (VIII):
"'` : ~R1 3
;,'.,- ~
;
~3C ~ ~ C~2 ~ CN2 3 3C1 (VIIL)
R14
~' .
i ~ TABLE l
Anorexic Activity of Some Compounds
-.of the Invention
. ~
, Approximate Dose
;,i 13 R14 Required to Reduce
. .Food Intake by 50%
. . . ...
3-Cl CH3 5
4-C1 CH3 0.6
. 4-CH30 CH3 3
3-CF3 CH3 23
4-CF3 CH3 10
, H CH3 4
~ 4-CF3 H 18
.`~ '.~ 3-CF3 32
~ - 13 -
~ .
'.; : -
.
: - : .
l: `
`
77478
;``.
..;
., .
` The useful mood-modifying activity of the compounds of this
-~ invention may be determined by standard tests such as the Reserpine Prevention
- test which demonstrates the ability of the compounds to prevent reserpine- -
;~:. induced hypothermia in mice. The results given in Table 2 were obtained
for compounds of the formula (IX):
. :,:
~ R
:: ~ 17 (IX)
, I .
; 1 18 ~ \ o CH
~j~ 19 2 2
,., R15
~ `T~BLE 2
'.~s. Dose at which`Certain Compounds of the Invention
,, are Active on the`Reserpine Prevention Test.
~; . ~pproximate
.~ R R16 Ri7 R18 R19 Z Dose Required
., mg/kg.
~:. . . __ . . _ _ . . :_ _ ~ . . ._ ____ .
,; CH3 . CH3 4-CF3 CH3 CH3 0 10 - -
.,; 20 CH3 CH3 4-F a H CH2
CH3 CH3 H CH3 CH3 CH2 4
` CH CH3 H CH3 CH3 0
.~, .
CH3 CH3 3-CF3 CH3 CH3 0 0.3
c~ C2H5 C2H5 H CH3 CH3 0 3
: ~ -- .
.. . .
~ .
': - 14 -
: ..,
,: .
''' '
;,~., ' . . : ' '' ' `
,~ ; : - . : ` :::-
.
~:, . ' -. : '
'.'' ` ' '. ' ' -" - ~,'
: 1~77478
,,.~ ,
The present invention also p~o~ides for the preparation of
.` compounds of the formula (II) as hereinbefore defined which processes
~' comprise:
~;i ( ) The reaction of a compound of the formula (X):
~3
R5 ~ Y ~ o~ (X~
.. .;
~ or a salt thereof wherein R3, R4, R5 and ~ are as defined in relation to
E 10 formula (II~, with either (i) compound of the formula (XI):
~ Ql ~ X - NRlR2 (XI)
..
or a salt thereof wherein X, Rl and R2 are as defined in relation to
. formula (II) and Ql is a group readily displaceable by a nucleophlle or
(ii) a compound of the formula (XII):
Ql ~ X Q2 (XII)
~' ' .
~ 20
., ~
,
., .
;' ,
.:
. ~ .
;,
~ . ~ 15 _
., .
: ;.. ~ ..
,: - .: . :- -
:: :. , .
~ ~ .
.,
i.
": .
.
~ .
` ` 1~77478
. .;
. wherein Ql and X are as defined ln relation to formula (XI) and Q2 is a group
` readily displaceable by a nucleophile, so as to form a compound of the
. formula (XIII):
- ~3
`- R4 ~3 O - X ~ Q2 (XIII)
;~ .
-~ and thereafter reacting the compound of the formula (XIII) with an amine
s : of the formula (XIV):
."....
: ,. ,' 1 0
. HNRlR2 (XIV)
:i wherein Rl and R2 are as defined in relation to formula (II).
'.~ (b) The reaction of a compound of the formula (XV):
. ~R3
j~ R4 3~o x NRIR2 ~xv~
.. .~
,
~ of a salt thereof wherein R1, R2, R3, R4, R5, X and Y are as defined in
:.,', relation to formula (II), with a reducing agent capable of reducing the
~ 20 vinylic double bond.
.,,"~ ~,
.' ' ' .
,.. .
., .
.
. . .
:,
, ' .
,. ~ .
_ 16
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. ' , .
' ~' '
''. :. ' '` . ' . ' ' "' ' . ' ' ' '
,'~ ;~. , .'. . . , ' , ' . ' .. ' ' '' . ' ' ' ' ' '
~''' ' ' .' ' ' ' ' . ' ,', ' ' ', ' " ''
' , ' ' . ' . ' '
. ' ' ' ' ~ ,' . ,
` ` 1077478
~'
~'
~: (c) The reaction of a compound o the formula (XVI):
5 ~b ~ xl co ~ N~IR~ (XVI)
where~n Rl, R2, R3, R4, R5 ~nd Y are as deflned in relation to for:ula (Il)
and X is a group such that X - CO is a group X as defined in relation to
formula (II), with a complex metal hydride capable of reducing amides to amines.
(d) For those compounds of the formula (II) wherein R1 is a hydrogen
1~ atom, by the hydrogenation of the corresponding compound of the formula (II)
wherein Rl is a group removable by hydrogenolysis.
~: (e) For those compounds o the formula (II) wherein Rl and/or R2
are alkyl groups, by the alkylation on a corresponding compound of the
formula (II) wherein Rl is a hydrogen atom and R2 is a hydrogen atom or
~- alkyl group.
(f) For those compounds o the ormula (II) wherein R4 and R5 are
both methyl groups and Y is an oxygen atom, by the dehydration of a compound
of the formula (XVII):
~,.; .~ R
: ,3
~3 ~ (YVII)
H3C OH HO - X - NRlR2
'' ? ~ ,
17 -
....
~-.~. :
: , ~
~: -~. : .. ,:
:. ..
1077478
wherein Rl, R2, R3 and X are as deflned in relation to formula (II).
(g) The reaction of a compound of the formula (XIII) as herein-
before defined with an amine of the formula (XIV) as hereinbefore defined.
The reaction of a compound of the formula (X) or its anion
with a compound of the formula ~XI) is normally carried out in an inert
solvent. Suitable sol~ents include hydrocarbons such as toluene or xylene,
ethers such as dimethoxyethane or dimethoxypropane, ketones such as acetone,
alcohols such as ethanol and other conventional solvents.
If desired the anion of the compound of the formula (X) may
:`
i 10 be produced before thè etherification reactIon or may be produced in situ
by reaction with a base such as NaH or the like.
Generally any non-extreme temperature is used, but the reaction
; is substantially complete in a conveniently short time if an elevated
` temperature is used. For example, the reactlon may be carried out at from
` about 0 - 180C, preferably in the region of 50 - 120C, for example,
. .
~ at about 70 - 100C.
;!, ~
.,
, ~ :
:
i~ .
. , :
... .
7',' -
.~.':
~ 18 ~
,.;, ~ ~, . : .
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- :. ~ : . -: . : : .
~; ~
j `:
1~77478
~. ,
Suitable groups Ql in the compound of the formula (XI) include
conventlonal good leaving groups such as chlorine, bromine or iodine atoms
r. or groups of the formula O.S02Rl or O.C02Rl where Rl is an inert organic
group such as a methyl, ethyl, phenyl, tolyl or like group. The group Q2
in the compounds of formulae (XII) and (XIII) may also have these values.
The reaction of a compound of the formula (X) with one of the
formula (XII) may take place under similar conditions to those outlined for
the reaction of the compound of the formula (X) with one of the formula (XI).
The reaction of the compound of the formula (XIII) with an
amine of the formula (XIV) will normally take place in an inert organic
solvent such as a lower alkanol such as methanol, ethanol or the like or
a halo-hydrocarbon such as methylene chloride or chloroform or the like.
~-~ Such reactions take place at non-extreme temperatures such as -20 - 140C,
~; and more usually at conventional temperatures such as 0 - 30 C, for example
~; at ambient temperature.
;,;
` The reduction of the compound of the formula (XV) is normally
, brought about by catalytic hydrogenation.
:~". ,~
~
~J 20
.,i -
~:.
~"~ ,
~ .i
~ -19 _
. .
~, .
,.
.~'. .'
."- t
'~'~ ' . ' ~ - .,
!
.,' , ' .
~` - 1C)77478
. .;
. .
Such hydrogenation reactions will generally take place in organic solvents
such as methanol, ethanol, methyl acetate, ethyl acetate or other
"
_~ conventional hydrogenation solvents using a low, ambient of elevated
:-.
pressure of hydrogen. Generally from 1 - 5 atmospheres of hydrogen
are used. Normally the reaction takes place at a non-extreme temperature
such as 0 - 100C, for example 12 - 80C.
The catalyst used in these reactions will normally be a
J'~, transition metal catalyst such as palladium. We have found 10-30% palladium
` on charcoal to be suitable.
The reduction of a compound of the formula (XVI) is normally
effected using a complex hydride such as lithium aluminium hydride. Such
reactions are carried out in an inert solvent medlum such as a dry ether
solvent, for example, in tetrahydrouran, dioxane, diethylether or the
' like. The reaction may be carried out at any non-extreme temperature,
for example, 0 - 120C and more suitably at an ambient or slightiy
elevated temperature, for example, at about 15 - 80C.
;~ The compounds o the formula (II) wherein Rl is a hydrogen
; atom are preparable from compounds o the formula (II) wherein XNR1R2 is
~ a group XNR2R20 wherein
'S 20
,.,,,.,. :
., .
~,
. . .
- 20 -
':
. ~ :- . , ,
-: : ' : ' ' . . - '.
~ -, . , . :
- . . . ~ . , .
:. . ` ~ ,-. : : : : i
.
~ 1~77478
, . .
. .A .
~'' ;,' .
R20 is an optionally substituted ben~yl group. Such groups include the
benzyl, benzhydride, trityl, methoxybenzyl, halobenzyl, dimethoxybenzhydride
or other equivalent group. Normally the removal of this group is effected
by catalytic hydrogenation, for example, using low, medium or high pressures
of hydrogen over a transition metal catalyst. ~e have found 1 - 5 atmospheres
of hydrogen to be suitable for use in conjunction with a palladium on
~,~,......................... .
charcoal catalyst. Normally the reaction is carried out at a non-extreme
~r~ temperature such as 0 - 100C, for example, 12 - 80C; in a conventional
~; - solvent such as methanol, ethanol, methyl acetate, ethyl acetate or the like.
The compounds of the formula (II) wherein Rl and/or R2 are
alkyl groups may be prepared by conventional methods of alkylation from
corresponding compounds. Reaction with compounds Rl ~1 or R2 ~1 under
conventional conditions may be employed but in general are not preferred ~ -
because they tend to lend to unacceptable side reactions. Particularly
suitable methods of alkalation include reductive alkylation using an
aldehyde in the presence of a reducing agent. For example, compounds of
the formula (II) wherein Rl and/or R2 are methyl groups and may be prepared
:~,;. .
^~ by reaction with formaldehyde in the presence of formic acid or by reaction
;` with formaldehyde in the presence of a reducing agent such as hydrogen
~ 20 and a transition metal catalyst. Such reactions normally
,,,j, .
~,. .
.', ,
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;.. , ' ' .
~ _ 21 -
, . . .
;,
. . ~ . . . . . . . . . .
: .:
."
. -- . . .
:: ~
` 1~77478
..
.,
take place at a non-extreme temperature such as -10 - 120C, for example,
10 - 60C and preferably at ambient temperature. Such reaction frequently
` takes place in a conventional organic solvent.
Dehydration of the compounds of the formula (XVII) may be
brought about by treatment with an acid catalyst and/or by heating.
Generally the reaction takes place ln a sol~ent which ls frequently a
~, hydrocarbon solvent. Suitable acld catalysts include mlneral acids or
. ,.
~'~ stronger organic acids such as toluenesulphonic acid. If the dehydration
is promoted by heating it is frequently suP1cient to warm the reaction
medium to 25 - 100C.
The reaction of a compound of the formula (XIII) with an
amine (XIV) occurs under conventional conditions as hereinbefore described.
'~ It will be appreciated that the compounds of the formulae
(X), (XIII), (XV), (XVI) and (XVII) are important intermediates and as such ` :
;.i
~ orm an important aspect of the present invention. The compounds of the
.. ..
;i,i, formulae (X) and (XV) represent particularly important intermediates for
:;;.,.
use in this invention. Especially useful intermediates include those
which may be converted into those compounds of formula (II) which have been
,, indicated as being especially suitable.
. ,.~
. .~.
.`;, ~
jl,
.... . .
~'
: ~ ,
~, - 22 -
' :
., ~ , . : ,- . . - : -
- , -,
: . . . , -. - - , , - : . , :, .
`;l`
\ ~
1~77478
~`'`' . .
;j~ Intermedia~ej--i of the formula ~X) may be prepared by the
~ detherification of a compound of the formula (XVIII):
, ~ ~ b C~12R21 (XVIII)
; wherein R21 is a hydrogen atom or phenyl group.
Demethylation of such a compound may be brought about by the action of a
...... .
strong acid such as hydrolodic acid or hydrobromic acid and debenzylation
may be brought about by catalytic hydrogenation in conventional manner.
'~' Compounds o~ the formula (XVIII) may be prepared by the
hydrogenation of the corresponding compound of the formula (xrx):
~ ~ ~ OCR2R21 (XIX)
,.~ .. .
wherein Y, R3, R4, R5 a~e as defined in relation to for~ula (IIj and R
is as defined in relation to formula (XXIV).
:'~ Such hydrogenation reactions may be carried out in ethanol
at ambient temperature using hydrogen at atmospheric pressure and a 10%
palladium on charcoal catalyst.
, . . .
" ~
~ 23 -
,~ ,
~, ,,.,, - .. . -:
'~ ' ' ' '' ' , :
, ~:
, . ~ . - .
~77~78
. .,
. ~
,
~`- The compounds of the fo~mula ~XIX) may be prepared by the
`; reaction of a compound of the formula (XX):
~ .
OCNzR21 (XX)
wherein Y, R4, R5 and R21 are defined in relation to formula (XIX) and a
` metal derivative of the formula R3M where M is Li, Na, Mgl, MgBr or MgCI
in conventional manner.
The compounds of the formula (XV) may be prepared by the
'. reaction in a conventional manner of the corresponding compound of the
formula (XXI):
\ 0 ~ X ~ XRIR2 (XXI~
.~.,;, :~ .
wherein Rl, R2, R4, R5, X and F are as de~ined in relation to formula (II)
: with a compound of the formula R3M where M is Li, Na, MgI, MgBr or MgCl,
followed by dehydration.
The initial step of such reaction takes place in aprotic media,
for example, in an ether solvent such as diethylether, tetrahydrofuran,
'!''~ dimethoxyethane or the like. The dehydratlon stage may conveniently be
carried out using an aqueous or alkanolic solution of an acid in conventional
''i.'
~ ~ manner.
: `
, . ~
~ . ~ 24 -
r .;
,, " ~
~ J
.~. ~.,
~, . . . . . .
`. , ` - . " ,
.-, ` ~ ~ - ,
, . , , . . ` .
.~ .. ~ , - ~ `
1077478
,,..~.`
~ ~,
The compound of the formula CXXI) may be prepared from the
corresponding compound of the formula (XXII):
R5 Y 0 Na (XXII)
~."' .
-'. by conventional methods oP ether Pormation such as by reaction of the
.: sodium salt with a compound such as Cl-X-NRlR2 at ambient temperature in
~ an alkanolic or similar solvent.
,:,:"
Compounds of the formula (XVII) may be prepared by the reaction
; - of CH3Li, CH3MgBr, CH3MgI, CH3MgCl or the chemical equivalent on a compound
of the formula (XXIII):
. ~3
0 ~0 ~ O ~ X ~ NRlR2 (XXIII)
.~ ~wherein Rl, R2, R3 and X are as defined in relation to Pormula (II). Such
~:.
:i reactions occur under conventlonal conditlons for Grignard reactions,
for example, in an ether solution in the absence of water. ~s previoufily
. 20
.~,,
,i ~.
. . . "
,; .
";~
. ,
.~:,
~ 25 ~
'. ~ ., .
.:,~,
,:
., t ,_" ,,~ ~.. ` `i
'"`,:' , . ' - ., . ' .. ' -:
"'" ........ ' , , ' '' ': ~ ,:. . ' ' ,, ' '
' ' . , ' .. '' :'' ''. ; ,-
`
` 1077478
ij .
~Y
'....
-;~ - indicated the resulting dlol frequently dehydrates spontaneously during
~,, work up to yield a chroman of the formula (II), especlally if heat or acid
is involved in the work up.
,; .
i Compounds of the formula (XXIII) may be prepared from the
.~ corresponding compound of the formula (XXIV):
0 ~ 0 Na
with a compound such as Cl-X-NRlR2 at amblent temperature in an alkanolic
~'f,'. or similar solvent.
. Compounds of the formula (II) wherein XNRlR2 is a CH2CH2NH2
group may also be prepared by a further process of the lnventlon whlch
:~, ,- .
comprises the reductlon of a corresponding compound wherein the XNRlR2
group is
... a CH2CN group which compound in turn may be prepared from,
... ,~ .
,; for example, a sodium salt off a compound of the formula (X) and compound
:~,i. such as Br CH2 CN.
. ~ The following Examples are illustrative of this invention.
f';'' .
.,~',": ~ .
.. ,~ ,
.,
!;~,
:,'"'~
~ _ 26 -
,,. ~
,~ -
,'i:
~_,_.. .. .. , -
.
~ - - . .
r, .. ' .. ' .
` ~ ~
`~ 1Ci77478
` ~
,.`;
~ ~
~ Example Group A.
.
R4 ~ ~3
R5 ~ X - N~ R2 R Y X ~ NRlR2
...... .
. .
Example 1
,`:
, 10 2,2- Dimethyl-7-dimethylaminoethyloxv-4-(3-
trifluoromethylphenyl) chroman hydrochloride
~', To a solution of 2,2-dlmethyl-7-dimethylaminoethyloxy-4-
. -ij .
~- , (3-trifluoromethylphenyl)-2H- chromene hydrochloride (4.96g) in ethanol
~ (75 ml) was added 10% palladium on charcoal. The mixture was hydrogenated
: ;i~. '
~'`;' under hydrogen (1 atmosphere pressure) at ambient temperature (about 18C)
;; until no further hydrogen was taken up. The mixture was filtered and the
;' solvent removed from the resulting filtrate under reduced pressure to
, .
~' yield the title compound (3.7g), m.p. 188 - 190C.
; L2~2-Dimethyl-7-dimethylamlnoethyloxy-4-(3-trifluoromethyl-
~, 20 phenyl)chroman and its pharmaceutically acceptable acid addition salts are
highly favoured compounds of this inventionl .
,,"' - '
,.; .
; .'.
.:"
,
:.,,
_ 27 -
'` -
;
: ,: . . .
:. ` , . ' ' . ~ . . ~ .
' :. ' ' ' :' ~- . ' '
~:. - , .
.
`- ` .' . . :
:
:
~`:
A
., `,, ~ ~
`.. 1C~77478
s` Example 2
~; Using a process strictly analogous to that of Example 1
if. '
~, - compounds of the formula
~ C32 ~ C3~ - ~(C}13)~. UCI
were prepared wherein R is as follows: -
~,...
R m.p. ( C)
; 3-chlorophenyl , 158
~4-chlorophenyl 195-8
4-methoxyphenyl 143-8
4-fluorophenyl 156-8
~'j 4-methylphenyl 201-2
4-trifluoromethylphenyl 201-3
3-methoxyphenyl 160
2-phenylethyl 96
4-chloro-3-trifluoromethylphenyl 211-2
2-methoxyphenyl 211-3
~' .
4-fluoro-3-trifluoromethylphenyl 196
' 2-f~uryl 188-193 (as ~ hydrate)
3,5-bistrifluoromethylphenyl 174-6
~, 2-methylphenyl 181-3
,i phenyl 165-7
;,~ (*catalyst used was platinum on charcoal).
.. .
.,: .
_ 28 -
,,,,~ .
",.~ , .
:,.,: - :
,,
'::
: :
,
"., ~:
~ .
,, . , ~
..
.~ , . . . .
~i 10774:78
` `
i`-`
~.`
~ Example 3
~ .
4-Benzyl-2,2-dimethyl-7-dimethylamlnoethyloxychroman
hydrochloride
~ ~ .
To 4-Benzylideno -2,2- dimethyl-7-dimethylaminoethyloxy-
chroman hydrochloride (3.5g) in ethanol (75 ml) was added 10% palladium
. on charcoal (0.3g). The mixture was hydrogenated as described in
Example 1 and filtered through kieselgurh and the resulting filtrate was
t.', evaporated under reduced pressure to yield the title compound (2.1g),
~ m.p. 150C (ex-ethyl acetate).
;:;
j10 A strictly analogous p~ocedure led to the production of
.~
2,2-dimethyl-7-dimethylaminoethyloxy-4-(3-trifluoromethylbenzyl)chroman
~; hydrochloride, m.p. 151-2C (ex-ethyl acetate).
.s.;;
",~"
;. .
. . :
:,.
. ,
.," . ~
:.
~, 20
;;:
,:.,
~',..
:': !
, .''
, . ~, .
i,''','' ' .
...
.....
~, .
i,~ .
>, ~ 29
::,
.,; j
"
,. .. .
.:,.,
, ~. . . ~: , ..
; .' ,, - - . ~. . :
,.: .:- .. ' - ,. . . . : ,
77478
.
' Example 4
j?,'~ ~ 2~2-Dimethyl-7-methylami~oethoxy-4-(4-t~ifluoromethylphenyl)-chroman
hydrochloride
7-(N-Benzyl-N -methylaminoethoxy)-2,2-dimethyl-4-(trifluoro-
methylphenyl)-2H-chromene hydrochloride (5.9g) was dissolved in ethanol
(100 ml) containing glacial acetic acid (3 drops). 10% Pd/C (0.6g) was
added and the mixture hydrogenated at ambient temperature (about 18C)
under 6 atmospheres of hydrogen until no further hydrogen was taken up.
The resulting mixture was filtered and the solvent removed under reduced
,~ lo pressure to yield the tltle compound (3g), m.p. 178-180C (ex-acetone).
~i.
A strictly analogous procedure led to the production of
2,2-dimethyl-7-methylaminoethyloxy-4-(3-trifluoromethylphenyl)-chroman
hydrochloride, m.p. 182-1&4C, to 2,2-dimethyl-7-methylaminoethyloxy-4-
(4-fluorophenyl)chroman hydrochloride, m.p. 222-224C, to 2,2-dimethyl-7-
;j~ methylaminoethyloxy-4-phenylchroman hydrochloride, m.p. 191-193C, and to
2,2-dimethyl-7-dimethylaminoethoxy-4-(3-fluorophenyl)-chroman hydrochloride,
,j m.p. 168-171.5 C.
,~ C2,2-Dimethyl-7-methylaminoethoxy-4-(4-trifluoromethylphenyl)-
chroman and 2,2-dimethyl-7!methylaminoethoxy-(3-trifluoromethylphenyl)-
; 20 chroman and their pharmaceutlcally acceptable salts are particularly
,., ~ .
' favoured compounds of this invention].
.' '
.,"
.~,. . .
'
' '
. . . .
.;
. - 30 -
... .
~s
; .
, ~. .. ~ . .
`; ~77~8
'.`'~'
- Example 5
. ~ ~
'. 3,3-Dimethyl~6-(2-dimethylamilioethoxy)-l-(3-triluoromethylphenyl)-l~2~3~4
tetrahydronaphthylene
.:
.:'.`'
A solution of 1-(3-trifluoromethylphenyl)-3,4-dihydro-3,3-
` dimethyl-6-(2-dimethylaminoethoxy)naphthylene(3.52g) in ethylacetate
' (50 ml) was hydrogenated at 1 atmosphere pressure in the presence of
10% palladium on charcoal (0.65g) until hydrogen uptake was complete.
After filtration the solvent was removed in vacuo to give the title
.
- compound as a colourless oll (3.3g) which on treatment with dry HCl inether followed by removal of the ether gave a hydrochloride salt (3.0g),
m.p. 206-208C (ex-acetone).
An analogous procedure yielded 3,3-dimethyl-6-(2-dimethyl-
aminoethoxy)-1-(4-trifluoromethylphenyl)-1,2,3,4-tetrahydronaphthylene
hydrochloride, m.p. 244.5-247C (ex-acetone).
,
.,~ ' ' ' ,
,'
. ~
i~
':~
':
,
- 31 -
'.'t ~
,, ~, ' ', '. .
''1':
~' ' : ' , ' ' . ' ' , . ' : ' ~
: ' ' - ' ' .
" '' ~ ,` . " " ' '. ' ' ' '
~ 1077478
Rxarple Group B R6
R5 ~ ~ OH B4 ~ 1 ~ \ . X N
Bxarple 6
- 7-N-Benzylmethylaminoethyloxy 2,2-dimethyl-4~(3-trifluoromethylphenyl)-
chro_an hydrochloride
N-benzylmethylaminoethyl chloride hydrochloride (1.37g) was
added to 2,2-dimethyl-4-(3-trifluoromethylphenyl)chroman-7-ol (2.0g),
potassium carbonate (5.16g) and potassium iodide (1.03g) in methyl ethyl
ketone (50 ml). The mixture was refluxed for 2 days and left to stand at
ambient temperature for a further 3 days. The mixture was filtered and
the solvent evaporated under reduced pressure. The resulting crude oil
was taken up ln water, and extracted into ether. The èther was dried
'~' .'1': : .
(MgS04) and the solvent was evaporated under reduced pressure to yield
an oil. This oil was dissolved in dry ether and passage of dry hydrogen
chloride through the solution yielded the title compound (l.Og) as a non-
crystalline foam which analysed as the monohydrate.
.~,.. ... .
. i.. . .
,..:
~:' r
- 32 ~
, ~.
~, . , , .
:, - . .
~, ` - '' . :,
. . .
:~ - :
- ' ~
-
1077478
..
`':"
Example 7
2~2-Dimethyl-7-dimethylaminoethyloxy~4~(~4-trifluoromethylphenyl)chroman
hydrochloride
`~ Dimethylaminoethylchloride hydrochloride (1.5g) was added to
2,2-dimethyl-4-(4-trifluoromethylphenylchroman-7-ol (l.Og), potassium
carbonate (4.0g) and potassium iodide (1.5g) in acetone (50 ml) and the
mixture refluxed for 2 days. The mixture was filtered and the acetone was
evaporated under reduced pressure. The resulting crude oil was chroma-
tographed on alumina. Elution with ether : petrol (1 : 1) gave a clear
oil which after dissolution in dry ether and passage of dry hydrogen
, chloride through the solution yielded the required chroman as the hydro-
~.
chloride salt (0.35g), m.p. 200-203 C.
~ 2,2-Dimethyl~7-dimethylaminoethyloxy-4-(4-tr if luoromethyl-
phenyl)chroman and its pharmaceutically acceptable acid addition salts are
highly favoured compounds of this inventionJ .
A strictly analogous procedure led to the preparation of
7-(N-benzyl-N -methylaminoethyloxy)-2,2-dimethyl-4-(3-trifluoromethylphenyl)-
2H-chromene hydrochloride, m.p. 138-140C.
,: .
.
,1,''; .
. .
~ ~ 33 ~
.,
:',
~ ~ '
.. . . . .
- . .. . . .
`: -' ~ ~ :' '
~` --
~i 1077478
,
~, "
`.~ Example 8
2,2-Dimethyl-7-dimethylaminoethyloxy-4-(2-thlenyl)chroman
hydrochloride
Sodium hydride (0.2g of a 60% dispersion in oil) was added
~' to 2,2-dimethyl-4-(2-thienyl) chroman -ol (O.lg) in dry toluene (20 ml).
;~ The solution was stirred for 10 minutes. Dimethylaminoethyl chloride
(0.5g) was added and the solution was refluxed for 3 hr. The solvent
: . .
was evaporated under reduced pressure. The oil was taken up in water
. and ether, the aqueous layer extracted with ether and the organic layers
"
dried over magnesium sulphate. Removal of the solvent under reduced
pressure gave a yellow oil. Dissolution in dry ether and passage of dry
hydrogen chloride through the solution gave the required chroman as the
hydrochloride salt (0.8g, 57~), m.p. 120-123C, (ethyl acetate).
~'"'
.,'~,'
":~,.................. .
.,,j
. :'~' '
:, .
.,
s~ 20
:; -
~' .
~ ;,
.,,:, ,
. .
. .,
... .
~ 34 -
.
. . ,
` .
.
'` ' ~ '
. .
.
.
: `~
` 1077478
.' ,
Example 9
1,2,3,4-Tetrahydro-2, 2-dlmethyl~7-(2-dimethyl-amino~ethoxy)-4-
, . .: . .
' phenylnaphthalene
A mixture of 1,2,3,4-tetrahydro-6-hydroxy-3,3-dimethyl-1-
phenylnaphthalene (3.72 g) sodlum hydride (0.53 g, 60% dlspersion in oil)
and 2-dimethylaminoethyl chloride (1.58 g) in toluene ~59 ml) was stirred
- and boiled under reflux for 6 hours. Water was added to the cooled
~- mixture and the organic layer was separated and extracted with 5N hydro-
.
, chloric acid (3 x 30 ml). The combined acid extract was basified,
extracted with ether and the ether extract dried (magnesium sulphate).
i,
Removal of the solvent gave 1,2,3,4-tetrahydro-2,2-dimethyl-7-(2-dimethyl-
` aminoethoxy)-4-phenylnaphthalene (3.0g) isolated as its hydrochloride salt,
.~ m.p. 212-214C.
,.......................................................................... .
',,`.'''~
`~:
. . .
;~I~,'.'i ' ' '
, ' . . .
~, 20
',......................................................................... .
~ .
`.; ~ : -
. .
'.'':,
,,
::, .
~ 35 ~
., - , :
~ ' ' ,.
. ~
.. -. ,.. . . . , . ~ , . :. :
.: ,. .. . - : : : :: . :
- - .
.': , . . , . .. , "- ~ : -
. ::.
:: : - , - : : , : , .
. - - :: . . - -
, . : . : ~ : :
1077478
! .....
.,
Example 10
Analogous procedures to that of Example 9 were used to prepare
-~ compounds of the formula
''` 1'; ~3~o x ~ 1 }ICI
; NRlR2 R3 R4 R5 ~ X m p C
phenyl H H CH2 CH2CH2 115-126
N(C2H5)2 phenyl CH3 CH3 0 CH2CH2 139-140
.:, 10N(CH3)2 3-trifluoro
~ phenyl CH3C2H5 CH2CH2 220-221.5
'" N(CH3)2 4-hhlolr 3 H3 CH2 2C 2 219-223.5
N(CH3)2 phenyl CH3 CH3 0 CH2CH2 165-167
N(CH3)2 3-trifluoro
phenyl CH3 CH3 0 CH2CH2 188-190
morpholino phenyl CH3 CH3 0 CH2CH2 187
pyrrolidino phenyl CH3 CH3 0 CH2CH2 162-164
piperidino phenyl CH3 CH3 0 CH2CH2 191
~ NH(CH3) phenyl CH3 CH3 0 CH2CH(CH3) 124
.,.~ 20( 3)2 phenyi CH3 CH3 0 (CH2)3 145-147
~ N(CH3)2 phenyl C2H5C2H5 0 CH2CH2 168-177
,~i *This compound was prepared as its hydrobromide salt
;'~
, ,;, , .
. .~ .
.. .
- 36 -
~,. -
~ ,
... ~, . . ..
, ' , ,
',~ . .~
., ~ . . .
~ `
` ~
1077478
; EXAMPLE GROUP C
3 R3
R X~-X-Q 4 ~b3\ O~X~NRI Zz
.: . '
~: EXAMPLE 11
: :.
- 2,2-Dimethyl-7-dimethylaminoethoxy-4(4-trifluoromethylphenyl)chroman
hvdrochloride
':i`~
;, 10 2,2 Dimethyl-7-(2-hydroxyethoxy)-4-(-4-trifluoromethylphenyl)
,~.,. "
chroman tosylate (0.65g) was dissolved in a solution of dimethylamine (excess)
containing a trace of sodium iodide and the mixture was heated in an auto-
clave at 120C for four hours and allowed to cool to room temperature over-
night. The solvents were then removed under reduced pressure. The resulting
dark oily solid was washed with dllute sodium blcarbonate and taken up into
ether. The ether solution was dried (MgS04) and the solvent evaporated
s under reduced pressure to yield an oil. The oil was redissolved in dry
ether and the passage of dry hydrogen chloride through the solution
;~~ yielded the title compound.
; 20
..... .
.;. ..
!'.~:~
.. . .
~,, .
~,"'' ' .
i :., - .
,'j.,"- ~ , .
~ 37 ~
,,`, :
. '':
... . .
. :.. . . , .. ~ , , - :
., , . - .
v - , . . ~ . ~ : ... .: -
.'. " . , : . . , . . . ' '~ , :: -
-~ . . - : -
ExAMpLE GROUP D 1077478
EXAMPLE 12
, .
?,2-Dimethyl-7-(2-dimethylamino-2-~ro~ylox~)-4-
phenylchroman hydrobromide.
~; 5 Sodium hydride (0,7g of an 80% dispersion in oil) was
added to a solution of 2,2-dimethyl-4-phenyl chroman-
7-oI (4.3g) in dry toluene (30 ml). Ethyl-2-bromo-
propionate (3.1g) was added and the solution refluxed
~,;; for 18 hours. The solvent was evaporated under reduced
; 10 pressure, the residue poured into water and extracted
with ether. The ether layers were dried ~MgS04).
Removal of the solvent under reduced pressure gave an
. .,
oil (5.5g) which was chromatographed on alumina. Elution
with ether : petrol (1 : 9) gave a colourless oil (1g)
whose spectroscopic properties were consistant with
2,2-dimethyl-7-(ethyl-2-oxypropionate)-l+-phenylchroman.
is was dissolved in ethanol (30 ml) and a 33% solution
~ of dimethylamine in ethanol (20 ml) added. The reaction
,~ mixture was heated at 120 for 7 hours. Removal of the
solvent under reduced pressure gave an oil which was
~hromatographed on alumina (100g). Elution with ether :
petrol (1 : 1) gave a yellow oil (0.3g) whose spectroscopic
I
~; properties were consistent with 2,2-dimethyl-7-(2-oxy-
propionamide)-4-phenylchroman. The amide (0.17g) was
dissolved in dry ether and lithium aluminium hydride (0.4g)
: . . .
:, ~ .
l - 38 -
.
,.. .
,.~ I
., ` ,
...
.. . ~..... . . .
.", . . ..
.
~ . .
1(~77478
added. The mixture was filtered, washed with ether and
the filtrate dried (MgS04). Removal of the solvent under
~.
reduced pressure gave a clear oil which on dissolution
in ether and passage of hydrogen bromide through the
~: 5 solution gave the required chroman hydrobromide (0.09g)
~` m.p. 122-129 (after initial softening at 114).
,........................................................................... .
;~
, ...
~,
:.. . . .
,- ,.
:' .,
.
.. ,; '
' 1
':
:
. .1 ,
:.;
,.. .
,, .
,~:,
..,
. ,
:
~ .
. .
':',
~ "
. .;,
, . .
''.' '
,~ - 39 ~
.. ~ .
:.''
. :. - , . . .
. -
:,;, - , - :
~,., . : .
~ .
.. . . .
'; ' '' ' :
, .
~ . . .
~' m7747s
~`
~; EXAMPLE 13
. ,.~,
~: 2~2-Dimethyl-7-dimethylaminoethoXy-4-(4~trifluoromethylphenyl)chroman
~ . ,.
s ~ The tltle compound may be prepared by the method of R.N. Icke,
.~ V.B. Wisegarber and G.A. Alles, Organic Synthesis, Collected Volume 3,
page 723 from 2,2-dimethyl-7-methylaminoethoxy-4-(4-trifluoromethylphenyl)
chroman or from 2,2-dimethyl-7-amlnoethoxy-4-(4-trifluoromethylphenyl)
chroman. The corresponding 4-(3-trlfluoromethylphenyl) compound may be
prepared in an analogous manner.
~,~,; .
2,2-Dimethyl-7-dimethylaminoethoxy-4-~3-trifluoromethylphenyl) chroman.
Formaldehyde (30 ml of a 35% aqueous solution) was added to 7-aminoethyloxy-
,;.: .
2,2-dimethyl-4-(3-trlfluoromethylphenyl) chroman (1 g) in ethanol (30 ml)
and the mixture was hydrogenated over 10% palladium of charcoal (0.1 g) at
4 atmospheres. The catalyst was removed by filtration and the filtrate
. , ,~, .
evaporated under reduced pressure to give an oil which was taken up in
~-~ water and extracted with ether. The ethereal extracts were evaporated
, ..:
~:~ to give an oil which contained the title compound.
... .
, .. .
.. . .
".,;
. :. .
.~:
~ .
.,; ~,
:,. .
~;,
;,:,;
.. ~ .
., ' .
.
:"',
~ . .
. . .
;:; .
; - 40 ~
. .
; .,:
. .
. .
~; ~ .
f
~ .
.'.
,',. .
,.'" ' ' ~ .
~ .
, .
,
.''
1077478
.":
~ EXAMPLE 14
~ .:, . .
2,2-Dimethyl-7-methylaminoethoxy-4-~4-tri~luoromethylphenyl)chroman
~; hydrochloride.
7-(N-Benzyl~N-methylaminoethoxy)-2,2-dimethyl-4-(trifluoro-
-~ methylphenyl)chroman hydrochloride (6g) was hydrogenated as described in
~. o
. Example 4 to yield the title compound (3g), m.p. 178 - 180 C (ex-acetone).
A strictly analogous procedure led to the production of
~' the corresponding 4-(3-trifluoromethylphenyl) compound, m.p. 182 - 184C.
The above reactions may also be carried out using starting
,,
compounds in which the N-benzyl group is replaced by a N-(4-methoxybenzyl)
or N-(4-chlorobenzyl) group.
~,
.: :
,:
:
..
. ~
.,
:' '
;, 20
;;~ ,,
;'.;
~:`
,
.~.:. .
.... .
,, .
- : .
, - 41 ~
. .
,`~
~. ~
, .--
;, ~ : . - .
;;~" ' '' ' " '
~' '
!, ' ' : , .
; . : .
1{~77~78
..
.
Example Group E
.,,
Preparation of`Intermediates
,~.
Example 15
2~2-Dimethyl-4-(3-trifluoromethylphenyl)chroman-7-ol
` 7-Benzyloxy-2,2-dimethyl-4-(3-trifluoromethylphenyl)-2H-
..,
chromene (lO.Og) was dissolved in ethanol (100 ml) and 10% Pd/C (1 g) added.
This was hydrogenated at 60 and 5 atmospheres pressure for 18 hrs.
Filtration through Kieselguhr and evaporation of the solvent under reduced
pressure gave an oil which solidified on addition of carbon tetrachloride.
Recrystallisation from carbon tetrachloride gave the title compound (7.7g),
m.p. 63 - 68C, (analysing as compound plus 1 mole of carbon tetrachloride).
An analogous procedure was used to prepare 2,2-dimethyl-4-
phenyl-2H-chroman-7-ol, m.p. 103 - 109C (ex ether-petrol).
An analogous procedure in which the reduction was carried
out at 18C at atmospheric pressure yielded 2,2-dimethyl-4-(4-trifluoro-
methylphenyl)chroman-7-ol.
...
;~,
... .
~ 20
,:,'.~
.
,'''-.'
,
,'.~ , .
,ij, .
- 42 ~
":
""' ` '
~`
.,
,
i , - :
, : : - .
. . :
'
107 7478
~ Example 16
'I
~ 7-Benzyloxy-2,2-dimethyl-4-(4-trifluoromethylphenyl)-2H-
. ., . _ chromene.
~,' n-Butyl-lithium (142 ml of a 2.4M solution)
was added under dry nitrogen to a solution of 4-bromo-
,t,, benzotrifluoride (76.5g) in dry ether at -50C. The
..
`,, mixture was left to stir for 2 hours. 7-Benzyloxy-2,2-
~^j dimethylchroman-4-one (64g) in dry ether was added drop-
wise. Water was added and the ether layer washed with
5N.Hel (2 x 100 ml), and dried (MgS04). Removal of the
.. ;~, ~ .
~olvent under reduced pressure gave an oil (84g) which
'~ was chromatographed on alumina. Elution with petrol-
ether (1 : 1) gave the title compound (52g).
~,", ~
- :t ~ .:
'''', ~ ~
., ,~ .
~'
.
.
~ ' .
'~ l
.
~' .
~r' . t ~
..~, ~:
','.~
j - 43 -
,ii ~;,
i .......................................... . . :
, i,
t
.'.': . . '
,, ,~, ' - .
~'' .' ' : ' . ' '
' ~: ., , ' ' ' , . . ' ' , . ., ' , . ' ', : ' -
' ' ' ' . .' ,, ' ' , . ..
'
` c 1077478
~............... ~e~
`.:...
~`, 2,2-Dimethyl-4-phenyl-2H-chromene-7-ol
~;'
~, Bromobenzene (141.3g) in dry tethyd-ofuran
~',`,'~ (300 ml) was added to magnesium ~3.7g) in dry tetra-
~ hydrofuran (100 ml). 2,2-Dimethylchroman-4-one-7-ol
'~''t (34.5g) in dry tetrahydrofuran (250 ml) was then added
~, and the solution refluxed for 48 hours. The mixture
::
~i''l was poured into ammonium chloride solution, the tetra-
. .
hydrofuran layer was separated and evaporated under
reduced pressure. The aqu,eous layer was extracted with
ethyl acetate and the organic layer and the residue from
the tetrahydrofuran layer was shaken with 10% sodil~
hydroxide solution. me basic layer was acidi~ied and
re-extracted with ethyl acetate. The organic layers
were dried (MgS04). Removal of the solvent, under reduced
pressure gave an oil (26g) which was chrom~tographed on
silica. Elution with ether - petrol (? : 1) gave the
title compound (14g).
., ~
,. t:
"'''1
;~
.',1
4~ ~
. . .
1 ``J'
.:,
.. I
.. ~ .. ; . . ... ~ - . .
. ~ . , . . .. .. .. , .. , ., - . . . .
1077 478
~ Exam~le 18
. ,
~ 3-Bromobenzotrifluoride (61g) in dry ether (100 ml)
,:,
was added to magnesium (6.6g) in ether (50 ml). 2,2-
~ Dimethylchroman-4-one-7-ol (17.4g) suspended in ether
- (~00 ml) was added and the mixture refluxed for 16 hourss.
The reaction mixture was poured into ammonium chloride
solution and extracted with ether. The combined ether
,,,. j .
layers were washed with 2N HCl (2 x 100 ml) and dried
(MgS04). Removal of the solvent under reduced pressure
gave the ti~le compound (25g), m.p. 102-106C.
~i: ' . -
~' '' . '
~ 45 -
. j, . - . . . . .
~: ., . . . . .. : .
?
` 1077478
::
.
'` Example_19
2,2-Dimethyl-7-dimethylaminoethyloXy~4-(3-trifluoromethylphenyl)-2H-
`-- chromene hydrochloride.
- 4-Bromobenzotri~luoramide (38.4g) in dry ether (70 ml) was
~ added dropwise to magnesium (4.16g) in dry ether (30 ml). The Grignandreagent was stirred and refluxed for ~ hr. after addition of the halide.
, 2,2-Dimethyl-7-dimethylaminoethyloxychroman-4-one (15.0g) in dry ether
(150 ml) was added dropwise. The mixture was poured into ammonium
`~ chloride solution and extracted with ether. The ethereal layers were
combined and washed with 5N.HCl (3 x 100 ml). The acid layers were
combined, basified and extracted with ether. The ether layers were
dried (MgSO4). Removal of the solvent under reduced pressure gave an
;` oil which was chromatographed on alumina (600g). ~lution with ether :
,.:
petrol (1 : 1) gave a white solid (16.0g). Dissolution in dry ether and
passage of dry hydrogen chloride through the solution gave the required
: chromene as the hydrochloride salt (15.7g) m.p. 181-184C.
i The following compounds were prepared using the same method.
......
R
~ ~
: 3 ~ \ 0cH2cH2N(cH3)2~ HCl
.' "; ,
, . .
,.'
, .
.;
. :
.':
.
::,
. .
- :. ' : - : ' :~ ::: : . : : :` : ., . ~ . "
.: : - ~ ... . . . .
.. . .
~ ` ~ \
~77478
` R m.p. C.
;
~' phenyl 186-187
3-chlorophenyl 193
4-chlorophenyl 187-190
4-methoxyphenyl 171
;,~ 4-f].uorophenyl 154
~' 1-naphthyl 192
.~,
4-me~hylphenyl 161
2-methoxyphenyl 191-3
, 3-thienyl 203-6
-~ 3-methoxyphenyl 146
. ,,
2-methylphenyl 212-4
4-fluoro-~trifluoromethyl-
t~ - phenyl
phenylethyl 144
4-chioro-3-trifluoromethyl-
phenyl 207
Also prepared by this method were 7 (N-benzyl-
~I~ methylaminoethyloxy)-2,2-dimethyl-~(4-trifluorometnyl-
phenyl)-2H -chromene hydrochloride m.p. 170-174 and
7-(N-benzylmethylaminoethyl)-2,2-dimethyl-4 (3-trifluoro-
~j~ methylphenyl)-2H chromene hydrochloride m.p. 138-140.
-
~: '
` ' `.
~ 47 -
?:~1 `
~,-; . ' ~ . - - . - :
. ~ . , ,
.
. , . ~ . : ~ .
. . - . ~ - : - ~:
1077478
Example ~0
'
4-Benzylideno-2,?-dimethyl-7=dimethylaminoeth~
c~lroman hydrochloride.
` Benzyl bromide (27g) in dry ether was added
: dropwise to magnesium (2.8g) in dry ether. The solution
. .
was refluxed for ~ hr. 2,2-dimethyl-7-dimetllylamino-
ethyloxy chroman-4-one (15.0g) in ether was added drop-
,. ,
wise and the mixture refluxed 1 hour. The reaction
mixture was ~Jorked up in the conventional manner to give
the benzylideno-chroman hydrochloride (10.6g), m.p. 224-
225 (ethanol) containing less than 10% of the 2H chromene
isomer
Similarly prepared were 2,2-dimethyl-7-dimethyl-
aminoethyloxy~4-(3-trifluoromethylbenzylideno)chroman
hydrochloride which was obtained as an 87% pure isomer
, . .
', after fractiollal recrystallization from ethyl acetate; and
2,2-dimethyl-7-diemethylaminoethyloxy-4-(3-triflu~rometh~Jtl-
benzyl)-2H-chromene hydrochloride also 87% pure after
fractional recrystallisation from ethyl acetate~
,, ', . .
~,,.
,:,,
.,1 .
. ,i ,1 .
l - 48 -
,
. .,
.
,
''., .
, '.
. . ~ . . . .
: : . : . . .
... . . . ~ . .
.~ ' . ': . : .
, . .
1077478
` -
~ Exampfle 21
~ . . .
~ 2H-chromene hydrochloride.
... .
~; n-Butyl-lithium (28.6 ml of a 2.4M solution)
.....
was added dropwise under dry nitrogen to a solution of
.,?,', dibromobenzene (13.5g) in dry ether at~30C, 2,2-fdimethyl-
-7~dimethylaminoethyloxychroman-4-one (10.0g) in dry ether
~ ,:
.~ was added dropwise and the solution was allowed to stir for
2 hours and then left to stand for 16 hours. Water (50 ml)
~, was added and the mixture was extracted with 5N.HCl (3 x
i~'s~l 100 ml). The acid layers were basified, the basic solution
,f,~
tf;~l extracted with ether and the ether layers dried (MgS04).
~i Removal of the solvent under reduf_ed pressure gave an
or~nge oil (14g) which was chromatographed on alumina
(420g). Elution with petrol - ether (1 : 1) gave the
required chromene (9.1g). Dissolution of this in dry ether
and passage of hydrogen chloride through the solution gave
the title compo~nd (9.35g), m.p~ 182-186C (ex acetone).
~', Similarly ~repared were
' ~ H3C ~ OCH2CH~(CH3)2. HCl.
R m.p. C.
~i; 4-trifluoromethylphenyl 197-199
3,5-bistrifluoromethylphenyl sublimes from 154
,~ 2-trifluoromethylphenyl 198-200
, : .;
- 49 -
;,., ,. , , . . . . _ . _
. ~ . . : ~ . , : .
; ' ,- ' . '. ' ' , ' '. , '' ~, ~ ..
. .. . . . . .
, . . . . .
`i ~,
` 1077478
~J Example 22
'''2'. 2!2-Dimethyl-7-dimethylaminoethyloxy-4-(2-furyl)-2H-
~`; ; chromene hydrochloride.
~, ~
- n-Butyl-lithium (56 ml o~ a 2N solution) was
added under dry nitrogen to a solution o~ furan (10 ml)
in dry ether (15 ml) at room temperature and the solution
~` was refluxed for 1 hour. 2,2-Dimethyl-7-dimethylaminoethyl-
oxychroman-4-one (10.0g) in dry ether (40 ml) was added
~' dropwise and the solution was refluxed for 1 hour. Water
:
(50 ml) was added and the mixture extracted with 2N.HCl
(3 x 100 ml~ The acid layers were basified and the basic
solution extracted with ether and the organic layers dried
(MgS04). Removal of the solvent under reduced pressure
gave an oil (12c5g) which was chromatographed on alumina
(375g). Elution with ether : petrol (1 : 1) gave an oil
(11.5g) which on dissolution in dry ether and passage of
hydrogen chloride through the solution gave the title
compound as the hydroch]oride salt ( 8g), m.p. 189-191C
(ex-ethyl acetate).
: ........................................ . . ..
r 1 ~ ~
I~ - 50 -
.; .,
1`' '
,', " ~ . .
'i,,:,~ ~
,', .,' . .. ' " ', '' .' ' ' : '' ' ' , '.~; :' '' ' .:' .''. ' '.
.
` `` - 1C~77478
:`
EXAMPI~_
.
- 1,2-Dih~ro-7-methox~-2,_2-dimeth~l-4-~henYlnaphthalene
. ,
.
To a stirred solution of phenylmagnesium bromide Cfrom
bromobenzene (36.8g) and magnesium (6.4g) in dry tetra-
hydrofuran (90 ml)3 was added 6-methoxy-3, 3-dimethyl-1-
tetralone (8g) in dry THF (90 ml) and the resulting
solution was boiled under reflux for 2 weeks~ The cooled
~- reaction mixture was decomposed with 2.5 N hydrochloric
acid and the organic layer separated and dried (magnesium
sulphate). Removal of the solvent gave a yellow oil which
t, was chromatographed on silica in 3% ether - 97% light
petroleum ~b.p. 60-80) to give 1,2-dihydro-7-methoxy-2,
2,dimethyl-4-phenylnaphthalene (5.47g) as a colourless
.,.! . Solid-
Analogous procedures yielded 1-(4-chlorophenyl)-3,4-
dihydro-6-methoxy-3,3-dimethylnaphthalene as a colourless
oil; 2,2-dimethyl-7-~2~imethylaminoetho~y)-4-phenyl-2H-
chromene as an oil (which on conversion to hydrochloride
salt, m.p. 186.5 - 187.5C); 1-(4-fluorophenyl)-3,4-
dihydro-6-methoxynaphthalene as a colourless solid;
1-(4-fluorophenyl)-3,4-dihydro-6-methoxy-3,3-dimethyl-
naphth~ene as a colourless oil; 7-(2-N-benzyl-~-methyl-
, aminoethoxy)-4-(4-fluorophenyl)-2~2-dimethyl-2H=chromene
as a colourless oil.
i i
i... .
... . . .
~ 1 .
,,
- 5l -
~.'
: , :
.~,. ~ . . '
. ~ .
. . .
~.
.`;: ``` 1077478
.;`;
... .
`:` EX~MPL.~` 24
:~; na~hthalene.
.
~ ~ A solution of 1,2-dihydro-7-methoxy-2, 2-dimethyl-4-
;,.. ~
~ 5 phenylnaphthalene (10.0g) in ethanol (150 ml) was
.~:
hydrogenated at atmospheric pressure and ambient
temperatv.re in the presence of 10% palladium on charcoal
. (1.0g). When hydrogen uptake had ceased the catalyst
was removed. by filtration through kieselguhr and the
resulting filtrate was evaporated in vacuo to give
.~. 1,2,3,4-tetrahydro-6-methoxy-3, 3-dimethyl-1-phenyl-
, . -
naphthalene as a colourless oil (8.4g) which later solidi~ed.
An analogous procedure yielded 1-(4-chlorophenyl)-1,2,3,4-
tetrahydro-6-methoxy-3,3-dimethylnaphthalene as a
il~ 15 colourless oil; 1-(4-fluorophenyl)-3,4-dihydro-6-methoxy-
naphthalene as a colourless oil; 1-(4-fluorophenyl)-1t2,
r.~l ~ 3,4-tetrahydro-6-methoxy-3,3-dimethylnaphthalene as a
colourless oil;
,
..!,~
` i
'. ~ .
~C;., `` -
.S !' ',;
,j~................................................. .
. ., .
! I
'.'`
` ` - 52-
",`';j .
,',.i .
.~,'', .
` ~ '' ' . - ., . -
~; - ' . ~ .: .
: ` . ` ., : .. ' ' .
,'.:. . . : ~ . ~ .
., . .. .. . . , - . . ... -: :
.. . . ... ~ ~ . : . ~ :
`r 107'7478
,i,~
112?~3,4-Tetrahydro-6-h~droxy-3, 3-dimethyl-1-phenyl-
, .,~
na~hthalene.
~ . .
A mixture of 1,2,3,4-tetrahydro-6-methoxy-3~ 3-dimethyl-
~i 5 1 phenylnaphthalene (1.3g), 48% hydrobromic acid (3 ml)
and glacial acetic acid (6 ml) was boiled under reflux
;,
for 17 hours. The cooled mixture was poured into water,
basified with solid sodium bicarbonate and extracted into
ether. The ether extract was dried (ma~lesium sulphate)
and the solvent removed in vacuo to give 1,2,3,4-tetra-
hydro-6-hydroxy-3, 3-dimethyl-1-phenylnaphthalene (0.96g)
," ,1
as a red oil.
Analogous procecedures yielded 1-(4-chlorophenyl)-1,2,3,4-
tetrahyd~o-6-hydroxy-3,3-dimethylnaphthalene; 1-(4-
fluorophenyl)-1,2,3,4-tetrahydro-6-hydroxynaphthlene as
, a yellow oil;
~, 1
. .,1
~1' `'
.'', j , .
., ' ' ' ' .
, ~. .
., ,
. ' '
,'',1.~
~i - 53 -
;, i
.
, ~
,i, .~....
.. ..
.
. . . -,
.
; ~ .
107747~
. `,
. .
~ EXAMPLE 26
.` - .
,' 2.2-Dimethyl-4-(2-thienyl)chroman-7-ol
'.,,
a 7-Hydrox~-4-(2-thienvl) dihYdrocoumarin.
2-Thienylacrylic acid (5g) and resorcinol (~.6g) were
'~ 5 dissolved in concentrated hydrochloric acid (100 ml)
~,~ and the mixture refluxed for 1 hour with passage of
~"~ gaseous hydrogen chloride through the reaction mixture.
'',', Tne hydrochloric acid was decanted off and the residue
" ' washed with saturated sodium bicarbonate solution.
,, 10 Filtration afforded the dihydrocoumarin as a buff-coloured
~-,
,', solid (6.72g). -~
. .
' ~ b. 2,2-~im,ethyl-4-(2-thienyl)chroman-7-ol.
,', Methyl-lithium (150 ml of a 2N solution) was added under
.. ; i, .
`', dry N2 to a solution of 7-hydroxy-4-(2-thienyl) dihydro-
15, coumarin ~14.8g) in dry ether (120 ml) and the mixture
, allowed to stand for 3 days. Water (500 ml) was added
,i
'l and the ether layer discarded. The aqueous layer was
''' , acidified, extracted with ether and the combined ether
.. . .
layers dried (MgS04). Removal of the solvent under
re~uced pressure ga~e a black oil which was then dissolved
'''I, in dry benzene (100 ml) containing a trace of ~-toluene
'''`, sulphonic acid. The mixture was heated under reflux for
,',~ 3 hours in a Dean & Stark apparatus. ~emoval of the solvent
under reduced pressure and chromatography on silica gave
the required phenol (7g).
. i.",
~~ - 54 -
~ ................ .
'I .
.:. . . . .
.. ,. . ,. , . . . , .: :
.
: -:: - . , . , .: -
. .
, .- .. , , : :, . . - - -
-- ~ , :: . . -. . ~- .
~ 1~77478
'`.:
;,, 1;
EXAMPLE 27
7-(N-Benzyl-N-methylaminoethyloxy)-2,2 dimethylchroman-
~, 4-one.
~;
N-Benzylmethylaminoethylchloride hydrochloride (14.98g)
was added to a mixture of potassium carbonate (86.28g),
potassium iodide (17.28g) and 2,2-dimethylchroman-4-one-
,~ 7-ol (20g) and the reaction mixture refluxed in acetone
for two days. Filtration and removal of the solvent under
'- reduced pressure gave an oil which was taken up in ether
~: 10 and washed with 1M sodium hydroxide and then with water.
The ether layer was dried (MgS04) and evaporated under
reduced pressure to give the title compound as an oil
~ (19.9g).
'' 'I
s: -
~i! `
.;:1
.,, I . .
,.
...
~.
,,, :
.~,.. ...1
!
,. .. ~
'.'.1 ,
- 55 -
;
;.
,,
, , , "
.,~ ,. . . . . .
,. . .
. ~
`` :` 1~)77478
'`':^
; EXAMPIE 28
`: ~
1-(3-Trifluoromethylphenyl)-3~4-dihvdro-3~3-dimethyl-
6-(2-dimethylaminoethoxy)naphthalene.
. .,
'`".!~, To a solution of 3-trifluoromethylphenylmagnesium bromide
[originally prepared from 3-bromobenzotrifluoride ~33.7g,
~ 5 eq.) in tetrahydrofuran (70 ml) and magnesium (3.84g.
`3.':,: 5.3 eq.) in tetrahydrofuran (30 ml)] was added dropwise,
with stirring, a solution of 3,3-dimethyl-6-(2-dimethyl-
:
J~ l aminoethoxy)-1-tetralcne (7.83g.) in tetrahydrofuran
(20 ml). The resulting solution was stirred under reflux
i~ for 60 hours then poured into ammonium chloride solution.
l The tetrahydrofuran layer was separated, evaporated in vac!lo
l and the resulting residue di~solved in ether and extracted
... .
, with 5N hydroch1oric acid (3 x 100 ml). The acid layer
;~ 15 was neutralized and extrac~ed into ether. A~ter being
washed with water and dried (magnesium sulphate) the ether
was evaporated in vacuo to give a brown oil (8.26g) which
-~ was shown by both tlc and nmr to be a mixture of starting
material and products. Chromatography on al~mina (240g)
'~ 20 in 25% ether - 75,6 light petroleum (b.p. 60 - 80C) gave
the title compound (3.74g) as a colourless solid, m.p. 57-
59 (hydrochloride salt~ m.p. 207-208). [Elution of the
alumina column with 50% ether - ~0/0 light petroleum gave
`,". .
starting tetralone (2.48g)].
,;.. : .
~ The corresponding 4-trifluoromethylphenyl compound was
`¦~ made by a strictly analogous process.
~.1 .. ,
.~ - 56 -
; ' ' . ''.''., . '' : ' ' '' ~ ~ ' -
'.`` .' ' . ` ' ' ' ' ' .' ' , , - ' '
.:-.. , .. : . . . , , . - : - .
- : . : . . ., . --
1~77478
~ EX.~IPL~ 29
~. ~
~ 3,3-Dimeth~l-6-(2-dimethylaminoethoxy)-1-tetralone
. ,. ~ . ta) 6-~Iydroxv-3~3=dimeth~ tetralone
A mixture of 6-methoxy-3,3-dimethyl-1-tetralone (20 g),
49% hydrobromic acid (50 ml) and glacial acetic acid
(50 ml) was stirred under reflux for 16 hours then
cooled, poured into water and extracted with ethyl
acetate. The organic layer was washed several times with
water then aqueous sodi~m bicarbonate solution and dried
(magnesium sulphate). Removal of the solvent gave
6~hydrox~-3,3-dimethyl-1-tetralone (19 g) as a pale
brown so'id in quantitative yield. A portion was
crystallised from ethyl acetate to give buff needles,
m.p. 149.5 - 151C.
(b) 3,3-Dim _ hvl-6-~2-dimeth~laminoethoxy)-1-tetralone
To a hot s~lution of 6~ ydroxy-3,3-dimethyl-1-tetralone
(19 g) in sodium dry toluene (200 ml) was added sodium
t.', .' : ~ , .
; ~ ~ hydride (4.5 , 1.5 eq. , 80% dispersion in oil). The
~ ~ stirred so]ution was brought to reflux and 2dimethyl-
ti~ aminoethyl chloride (11.82 g. , 1.1 eq.) in dry toluene
(20 ml) was added dropwise over 0.5 hours. After being
~l stirred under reflux for 5 hours the reaction mixture
~f~ was cooled, decomposed with water and the toluene layer
~eparated and evaporated in vacuo. The residue was
~'"~
57 -
., :,, :.,
,.,.~j.,
.. . .. _. ....
,. , ~, .
,,:.~ - :
;: . , . -
.,~ . - -
~.'
.. . .
i~ `
;i' ";
1~377478
dissolved in ether and extracted with three portions
t100 ml each) of 5 N hydrochloric acid. The combined
acid extracts ~ere basi~ied, extrac-ted into ether and
the ether extract washed with water and dried (magnesiun
sulphate). Removal o~ -the solvent gave 3,3-dimethyl-6-
(2-dimethylaminoethoxy)-2--tetralone ~19.55 g.), as
a yellow solid. A portion WclS converted to the hydro-
chloride salt, m.p. 207 - 209C.
;~.,
.... .
i .
~;
,-,,,~
, .
:~ !
: ,.
,~'~ . . ..
,.1 .
,. . I
~-,i,` . I
~;j !
,.. ;. . . I
.,.i 1
.
.~.. . .
.. ,, i . , -
. .
...
- .. 1 , .
.'~1 .
' 4
. ~. .
''{`,
. ''~, .
. ~ ,1
~ '1 .
. ', ' ' .
. ., , . , ' : - ', . , ' ',
'... . .' , ' . , ' ' ` ' ~".,' . '' ' :. ' ~ ' ' ` ` ' ' ` '' . `, '' . : `
1077478
~
2-Ethyl-4-(3-trifluoromethylphenyl)-7-hydroxy-2-methYl-
chroman
(a) 2-Ethyl-4-(~-trifluoromethylPhenyl)-7-hydroxy-2-
methyl-2H-chromene.
2-Ethyl-7-hydroxy-2-methyl-4-chromanone, m.p. 109 - 110.5C,
was prepared by condensing resorcinol with 3-methyl-2-
pentanoic acid in the presence of boron trifluoride diethyl
etherate. Reaction of the chromanone with 3-trifluoromethyl-
phenyl magnesium bromide as described in Example 28 gave
the title chromene as a golden yellow oil.
(b) 2-EthYl-4-(3-trifluoromethylphenYl~-7-hydroxy-2-meth~l-
chroman.
Hydrogenation of the chromine as described in Example 24
yieided the title chromane as a pale yellow oil.
~,
~,,,i~,,,l
,..;j,
,,~." I .
~1
.... ~ .
.~. ~ ~ , ...
.I . - 59 -
.. ,.. ,, ~ '
. ~ .~
. " .
.~ ,
.
.. : - , ~ ~
. , - ~ . :
'
~ 1077478
.~` .
. . .
~' EXAMPLE 31
7-Aminoethyloxy-2,2-dimethyl-4~(3-trifluoromethylphenyl)chroman
"
hydrobromide
A solution of 7-cyanomethyloxy-2,2-dimethyl-4-(3-tri-
fluoromethylphenyl) chroman (5.4g) and 10% palladium on charcoal (0.5g)
` in ethanol (75 ml) was hydrogenated at atmospheric pressure. The catalyst
was removed by filtration and the filtrate evaporated under reduced
~: pressure to give an oil which was treated with ethereal hydrogen bromide
to give the title compound (4 g) as a very hygroscopic non-crystalline
compound.
'''.' .
~',, '
. r:
JA
;$,
,
,.. . . .
:, ~
..
:
"~ :
,
!.~
,., i:.
~ .
.` `
, ',' .
., .
.' -
1,~
- 60 -
:' ~
.~ . .: .
,
.. . - , ~ . : , . - .
, . . . ..
: . . . - . , .
``~
1077478
....
?~
' EXAMPLE 32
:, . .
`~ 7-Cyanomethyloxy-2,2-dlmethyl-4-(3-trifluoromethylphenyl) chroman
Sodium hydride (0.93g, 80~ dispersion in oil) was added to
a solution of 2,2-dimethyl-4-(3-trifluoromethylphenyl) chroman-7-ol
(containing I mole of carbon tetrachloride of crystallisation) (7.5g) in
dimethylformamide (25 ml). Chloroacetonitrile (1.76g) was added and the
mixture heated at 60 C for 3 hours. The solvent was removed under
~.. ~ !
i reduced pressure and the resulting oil was poured into water. The
. . .
j, aqueous solution was extracted with ether and tXe ethereal extracts were
,:.,
dried (Mg S04) and evaporated under reduced pressure to yield an oil.
~x~ Chromatography on alumina with ether - petrol (40-60C), 1:3 as eluate
~- gave the title compound which crystallised on standing.:t,
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EXAMPLE 33
^-'' ' .
2,2-Dimethylamino -7- (2-hyd~oxyethyloxy)-4-(4-trifluoromethylphenyl)
-- chroman
.`:
`~r Sodium hydride (0.6g, 80% dispersion in oil) was added to
2,2-dimethyl-4-(4-trifluoromethylphenyl) chroman -7~ of (containing 1 mole
of carbon tetrachloride of crystallisatio~) (6g) in dry toluene (20 ml)
and the suspension was stirred and boiled under reflux for 30 minutes.
~; . !
`; Ethylbromo acetate (2.lg) in toluene (5ml) was added and the suspension
. . .
~',, boiled under reflux for a further 9 hours. The solvents were removed
~: .
under reduced pressure and the residue was taken up in ether. The
ethereal solution was washed with water and dried (MgS04). ~emoval of
the solvent under reduced pressure gave an oll (5.4g) which was identified
.... . .
:- by its spectrophometric properties as 2,2-dimethyl-7-(carbethoxymethyleneoxy)-
~, 4-(4-trifluoromethylphenyl) chroman. Lithium aluminium hydride (0.2g)
, was added to the above ester (lg) in dry ether (30 ml) and the mixture boiled
`~ under reflux for 15 minutes. Water (1 ml), lM sodium hydroxide (1 ml)
and further water (3 ml) were added and the suspension was extracted with
ether (2x25 ml). The combined ethereal extracts were dried (MgS04) and
evaporated under reduced pressure to give a clear oil (0.79g) which was
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; identified by its spectrophotomet~ic properties as the title compound.
EXAMPLE 34
7-Dimethylaminoethoxy-2-methyl-4-phenyl-2-H-chromene hydrochloride
Phenyl-lithium (8 ml of a 2N solution ln ether-benzene) was added under
. nitrogen to a solution of 7-dimethylaminoethoxy-2-methyl chroman-4-one
(1 g) in dry ether (25 ml) at -78C. The solution was left to stir for
; half an hour and then allowed to warm to room temperature. Water was
,. .
~ added and the solution was made acidic with 5N hydrochloric acid and
., .
extracted with ether. The ethereal extracts were washed with 5N hydro-
,, 10 chloric acid (2 x 50 ml) and the acid washings basified with sodium
is~
~ hydroxide solution and extracted with ether. The combined ether extracts
;~A'. were dried (MgS04) and evaporated under reduced pressure to give a yellow
~` oil which was chromatographed on alumina (60 g) using ether-petrol
(40 - 60), 3:1 as eluant. The eluate was evaporated to a clear oil
;i -
,',! ' ' which on treatment with ethereal hydrogen chloride gave the title compound,
~t' m.p. 135 - 145C.
, EXAMPLE 35
7-Dimethylaminoethoxy-2-methyl-4-phenyl chroman hydrochloride. To 8
solution of 7-dimethylaminoethoxy-2-methyl-4-phenyl-2-H-chromene hydro-
:.
chloride (0.5 g) in ethanol was added 10% palladlum on charcoal (0.1 g).
The mixture was hydrogenated at 1 atmosphere pressure until reaction
:; `
was complete and the catalyst removed by filtration through Kieselguhr.
."
The filtrate was evaporated under reduced pressure to give the title
compound, m.p. 189 - 192C (ethyl acetate-acetone).
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` 1077478
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EXAMPLE 36
7-Dimethylaminoethoxy-4-phenyl chroman hydrochloride.
~m~ Sodium hydride (0.16 g, 80% dispersion in oil) was added to a solution
`'. of 4-phenyl chroman-7-ol (0.65 g) in dry toluene (20 ml). Dimethyl-
aminoethyl chloride (0.31 g) was added and the mixture heated under
~` reflux for 19 hours. The solvent was removed under reduced pressure
.:
~ and the residue was taken up in water and extracted with ether. The
.,; ",
ethereal extract was dried (MgS04) and evaporated to give an oil which
~~ was chromatographed on alumina (30 g) using ether-petrol (40 - 60),
1:1 as eluant. The eluate was evaporated and treated with ethereal
; hydrogen chloride to give the title compound, m.p. 175 - 180C
^ ; (ethyl acetate-acetone).
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