Note: Descriptions are shown in the official language in which they were submitted.
~ ~0 7szsu
This application is a divisional of our copending Canadian Patent
Application Serial No. 216,313 flled December 18, 1974.
e present invention relates to sulphur-containing compounds~
According to the present in~ention there is provided a co~pound of
the general formula
~(GH2)n 5
R - C - Yl CO - N~(Z)m ~ R6 (I)
or an acid addition salt thereof,
or
X,--(CH2)n X
\ /
R - C Y T (II)
10 in which n stands for 2 or 3, X represents a sulphur atom, SO or S02, R
: represents a group of the formula
~1
R2
R3 ~ or
(a) (b)
in which Rl, R2 and R3 each represent a hydrogen or halogen atom or a lower
alkyl, lower alkoxy, aryl-(lower alkoxy), aryloxy, phenyl, nitro, trifluoro-
methyl, hydroxy, cyano, di(lower alkyl)amino or lower alkanoloxy group
or two adJacent Rl, R2 and R3 symbols together represent a methylenedioxy,
ethylenedioxy or butadien-1,3-ylene-1,4-group, R4 represents a hydrogen
atom or a lower alkyl group, R5, R6 and R7 each represent a hydrogen or
halogen atom or a lower aIkyl, lower alkoxy, hydroxy or benzyloxy group
~ ::
- 1 - ~
~ , .
~,~...
- . : . . .. : . - , . . . . , ~ . . . : . . . . . .
,' ' , ~ :", ~ , ,"", ~,,,,, ", ", ;,~ ,, ,",: "
1079Z90
or two ad~acent R5, R6 and R7 sy~bols together represent a methylenedioxy
or ethylenedioxy group, Yl represents:a straight-chain or branched-chain,
optlonally hydroxy-substituted, aliphatic group containing 1 - 7 carbon
atoms, of which 1 - 3 carbon ato~s are present in the chain, Z represents
a straight-chain or branched-chain, optionally hydroxy-substituted, aliphatic
group containing 1 - 8 carbon atoms, of which 1 - 4 carbon atoms are present
in the chain, m stands for zero or 1, Y represents a straight-chain, or
branched-chain, optionally hydroxy-substituted, aliphatic group containing
2 - 8 carbon atoms, of which 2 - 4 carbon atoms are present in the chàin
and T represents a group of the formula
8 (i)
A - (Z)m ~ (i~)
or
N H (iii)
in which A represents the group
R' - CO
- N
in which R4 represents a hydrogen atom or an aIkyl group containing 1 - 5
carbon atoms, R8 denotes a leaving atom or group and Z, m, R4, R5, R6 and R7
~'
~....; ~,
. .
~ .
, ' ' , .. : ~ .
.
..
. . . .. .
:` ~
. lQ79~g~
` have the above-mentioned meanings,
F or an acid addition salt of compound ~II3 in which T denotes the group
14
-N H (iii) -
and a process for its productlon.
e compounds of the present invention are precursors in the
production of sulphur-containing co~,pounds claimed in our copending C~nadian
Patent Application Serial No. 216,313 filed December 18, 1974 which possess
`~ coronary dilating properties.
As used in this description and in the accompanying claims, the
term "lower alkyl" means straight-chain or branched-chain aIkyl groups con-
taining 1 - 6 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-
butyl, isobutyl, tert-butyl, amyl, and hexyl). The term "lower alkoxy"
means lower aIkyl ether groups in which the "lower alkyl" moiety has the
aforementioned significance. me term "halogen" means fluorine, chlorine, -~
bromine and iodine. me term "lower alkanoyl" means alkanoyl groups con-
taining up to 6 carbon atoms (e.g. formyl, acetyl, pr~pionyl, and butyryl).
e term~"aryl" means unsubstituted or substituted phenyl, the substitutent(s)
being selected from halogen, lower alkyl, lower alkoxy, nitro and amino.
The term l'leaving atom or group" used hereinafter means known atoms and
groups such as, for example, halogen, preferably bromine or chlorine ary-
; sulphonyloxy such as tosyloxy, aIkylsulphonyloxy such as mesyloxy or an epoxy group and the like.
This invention also relates to a process in which the compounds of
fornLla (I) or (II) are prepared by either:
(a) when a compound of formula I is required,
- 3 -
~ ~,.
,
10792gl~
reacting an acid cf the general form~la
2)n~X
/ ~ (XVII)
R - C Yl C \
OH
in which R, X, Yl and _ have the same meanings as above with:an amine of the
general formula
R6 ,=j~
7 ~ (Z)m NH - R4 (VIIa)
wherein the various symbols are as defined above, and, if desired, the pro-
duct is converted to its acid addition salts; or
(b) when a compound of formula (II) is required, when T represents
a radical (i) reacting a compound of the general forn~la
O
R--- C--Y--R8 (XrV)
in which R and R8 have the same meanings as above, with a compound of the
general formula
~ HS - (CH2)n SH (V)
: in which n has the same meaning as above, and oxidising the product if X in
formula (II) is to:denote SO or S02, or when T represents a radical (ii),
acylating a compound of the general formula
X \ 2 / X H R~
R - C - Y - N (Z~m
l~
`~
's.'.......
.. .. .
,,: ' . - :
' . . ; ' . :
10'79Z90
in which R, X, Y, Z, R5, R6, R7, m and _ have the same meanings as above, to
introduce a formyl or (Cl-C5 alkyl) carbonyl group, or when T represents a
radical (iii), reacting a compound of the general formula
/ (CH2) ~
X\ /X
R C - Y - Cl (VIa)
in which R, Y, X and n have the same meanings as above, with an amine of the
general forn~la
R4 NH2 (XVI)
in which R4 has the same meaning as above, and if desired, converting the
product to its acid addition salt.
me compounds of formula II in which T represents radical (i) can
be prepared, for example, by reacting a compound of the general formula
O
,. - .
R C Y - R8 (XIV) :
in which R, R8 and Y have the significance given earlier, with a compound of
the general formula
HS (CH ) - SH (V)
in which n has the significance given earlier, and, if desired, converting
a thus obtained compound of formula (II) in which X represents a sulphur
atom into a compound of form~la II in which X represents S0 or S02 by
oxidation.
The reaction of a compound of formula XIV with a compound of formula
V can be carried out in a manner known per se. The reaction is expediently
-- 5 --
~ ~.,
-
~ .. .
. ... ,, ... , . , .... ,- . -, . : , . : . -: . -
1(~79Z9~
carried out in an organic solvent which is inert under the reaction
conditions, preferably in a polar solvent such as a halogenated hydrocarbon
(e.g. chloroform or methylene chloride or the like) or ethyleneglycol dimethyl
ether. The reaction is also expediently carried out in the presence of a
water-cleaying agent (e.g. sulphuric acid, a hydrohalic acid3 or phosphoric
acid) and at a temperature from 0C to the reflux temperature of the reaction
mixture, preferably at room temperature.
The conversion of a thus obtained said compound of formula II in
which X represents a sulphur atom into a compound of formula II in which X
represents SO or S02 can be carried out in a manner known per se; for exa~ple,
by oxidation with a peracid such as, for example, peracetic acid, perph-
thalic acid or m-chloroperbenzoic acid. Peracetic acid can, for example, be
formed in situ from glacial acetic acid and hydrogen peroxide.
The a~ides of formula II in which T represents radical (ii) can be
prepared in a m~nner known per se, for exa~,ple, by acylating a compound of
general formula
/(CH2)n~ 5
X \ / X H ~ R6
R _ C Y N- ( Z )m ~
R7
The acylation can be carried out, for example, using a halide of a lower car-
boxylic acid in a tertiary amine (e.g. pyridine) at a temperature of from 0C
to 30C, preferably at about room temperature.
The compounds of formula II in which T represents radical (ii~)
can be prepared, for example, by reacting a compound of the general formula
r~
.~
.... ~ ,
: ''~
10'79~9~
f (CH2)~
X~X
R C Y - Cl (VIa)
in which R, X, Y and _ have the significance given earlier, with an amine of
the general formula
R4 N~I2 (XVI)
in which R4 has the significance given earlier. Since, in carrying out this
reaction, hydrogen chloride is cleaved off, the reaction is expediently carri-
ed out in the presence of a base or using an excess of the amine of forn~la
XVI .
me com~ounds (XVI) are known. me compounds of form~la (VIa) can
be prepared in a manner analogous to the preparation of the compounds of
forn~la (II) in which T represents radical (i).
Amides of formula I can be prepared, for example, by reacting an
acid of the general formula
Xf (CH2)~X ' .
\/ D '
R C - Yl C \ (XVII)
OH
in which R, Yl, X and n have the sig~ificance given earlier, with an amine of
the general formula
R5
R6 ~ ( )m HN R4 (VIIa)
R7
in which R4 - R7, Z and m have the significance given earlier.
- 7 -
~ . .
~_........................................................... .
., - , '
,: .: ' ' '- ' ' - '
~ 1079Z90
me reaction can be expediently carried out in the presence of a
tertiary amine (e.g. triethylamine) and a halocarboxylic acid ester (e.g.
chloroformic acid isobutyl ester) mixed anhydride method) in an inert organic
solvent (e.g. tetrahydrofuran) and at a temperature of from 0C to 30C.
The acids of formula XVII can be prepared in a manner analogous to
that described hereinbefore for the preparation of co~lpounds of formula II
in ~hich T represents radical (i) starting from compounds of the general
formula
R C 1 OH (XVIII)
in which R and Yl have the significance given earlier. me compounds of
formula XVIII are known.
The ketones of formula I can be prepared in a manner known per se;
for example, by oxidising a corresponding alcohol. me oxidation can be car-
ried out, for example, using chromiwm trioxide/pyridine in pyridine at a tem-
perature of from -20C to about room temcerature, preferably at 0C.
me compounds of formula I and II in which T represents radical
(iii) can be converted into acid addition salts, for example by treatment
with an inorganic acid such as a hydroh~lic acid (e.g. hydrochloric acid
or hydrobromic acid), sulphuric acid, phosphoric acid or with an organic
acid such as oxalic acid, tartaric acid, citric acid or methanesulphonic
acid. Of the acid addition salts of the mentioned con~pounds, the pharma-
ceutically acceptable acid addition salts are preferred. If, in the course
of the process of this invention, an acid addition salt of a compound of
formula I or II is obtained, then such a salt can be converted into the
free base in a known manner (e.g. by treatment with alkali) and the free
.~
- - . . .
. , . ~ , '
' '.; , , ~
~ 10~9~90
base can, if desixed, be conYerted into another acid addition salt.
The following examples illustrate the process pro~ided by the
present invention:
Example 1
74.7gof3,4-dimethoxybenzaldehyde are dissolved in 1250 ml of
chloroform, treated with 50 ml of 1,3-propanedithiol and cooled at 0C with
stirring. 20 ml of boron trifluoride etherate are added and the mixture is
left to stand in a refrigerator for 18 hours. me mixture is then washed
three times successively with 500 ml of a 7% potassium hydroxide solution
and 500 ml of a 10% sodium chloride solution. The organic extracts are
combined, dried over magnesium sulphate and evaporated. The residue is re-
crystallised twice from ether. There are obtained 102.6 g of 2-(3,4-
dimethoxyphenyl)-m-dithiane of melting point 99 - 101C.
The following dithiane can be manufactured in an analogous manner:
2-phenyl-m-dithiane of melting point 72 - 73C (from methylene
chloride/isopropyl ether).
Exa~lple 2
60 g of 2-(3,4-dimethoxyphenyl)-m-dithiane (prepared as described
in Example 1) are dissolved in 470 ml of glacial acetic acid and treated at
room temperature with 235 ml of 30% h~drogen peroxide, the temperature of
the solution rising to ca 40C. m e solution is left to stand overnight
at room temperature. The solution is then heated for 2 hours at 100C.
After cooling to room temperature, the crystalline precipitate is filtered
off under a vacuum, washed with some glacial acetic acid, dried in vacuo
at 60C overnight and then recrystallised from acetonitrile. There are
obtained 57.1 g of 2-(3,4-dimethoxyphenyl)-m}dithiane-1,1,3,3-tetraoxide of
melting point 243 - 245C.
_ g _ ' .
, ,, , :
:.
1~7929~
~xample 3
292.5 g of N-methyl-homoveratrylamine are dissolved in 1000 ml of
dimethylformamide and treated with 415 g of anhydrous potassium carbonate.
The mixture is stirred at 5C, treated with 237 g of 1,3-bromochloropropane
in 500 ml of dimethylfornamide, stirred for a further 4 hours at room tem-
perature and then poured into 6 litres of water. The separated oil is ex-
tracted three times with 2 litres of ether each time. me organic extracts
are dried with magnesium sulphate and evaporated in vacuo. The residual oil
is distilled at between 60C and 70C with a mercury diffùsion pump at 0.005
Torr. There are obtained 206.7 g of N-(3-chloropropyl)-3,4-dimethoxy-N-
methylphenethylamine of boiling point 69 - 70C/0.005 Torr.
Example 4
500 g of polyphosphoric acid and 69 g of veratrol are added to a
1 litre round-bottom flask. To this are added 61 g of L~chlorobutyric acid
in one portion, the temperature rising steadily to 55C. After 1 hour, the
entire mixture is poured on to ice. The mixture is then extracted with a
mixture of ether/methylene chloride (3:1). The organic ~xtracts are extract-
ed with water, then with a saturated sodium bicarbonate solution and finally
again with water, dried over magnesium sulphate and evaporated in vacuo. me
residual crystal mass is recrystallised from ether. There are obtained 62.9
g of 3,4-din~thoxy-~-chlorobutyrophenone of melting point 91 - 92c.
10.9 g of 3,4-dimethoxy-~-chlorobutyrophenone are dissolved in 120
ml of chloroform and treated with 5 ml of 1,3-propanedithiol and 1 ml of boron
trifluoride etherate at room temperature. After 1 hour at room temperature,
the chloroform solution is washed three times with water, three times with
l-N sodium hydroxide and again three times with water. The organic phases
-- 10 --
~ .
, . ,
1~79Z91~
are dried over magnesium sulphate and evaporated in vacuo. The oily
residue is immediately dissolved in 500 ml of chloroform at 0 - 5C and
treated with 45/7 g of solid m-chloroperbenzoic acid in such a manner that
the temperature does not exceed 5C. me mdxture is subsequently left in
a refrigerator for 64 hours. The organic phase is washed three times with -
l-N sodium hydroxide and three times with water, dried over magnesium
sulphate and evaporated in vacuo. The residue is recrystallised from
methylene chloride/isopropyl ether. There is obtained 2-(3-chloropropyl)-2-
(3,4-dimethoxyphenyl)-m-dithiane-1,1,3,3-tetraoxide of melting point 183
- 184C.
Example 5
19.63 g of 2-phenyl-m-dithiane are dissolved in 300 ml of tetra-
hydrofuran. 43.5 ml of a solution of butyl lithium in hexane are slowly
added drop wise at -70C while gassing with argon. me mixture is stirred
for a total of 1.5 hours at -20C. me red solution obtained is added to a
solution of 15.74 g of 1,3-bromochloropropane in 250 ml of absolute
tetrahydrofuran at -70~C. me thus-obtained solution is left to stand for
1 hour at -20C and for 1 hour at room temperature. me solvent is evaporat-
ed in vacuo and the oily residue taken up in ether. me ethereal phase is
washed with l-N sodium hydroxide and with water, dried over magnesium sulphate
and evaporated in vacuo. m e thus-obtained 2-(3-chloropropyl)-2-phenyl-m-
dithiane is peroxidised at 0 - 5C with m-chloroperbenzoic acid in chloro-
form as described in the previous example. After recrystallisation from
ethyl acetate, there is obtained 2-(3-chloropropyl)-2-phenyl-m-dithiane-1,1,
3,3-tetraoxide of melting point 182C.
Example 6
9.6 g of 2-(3,4-dimethoxyphenyl)-m-dithiane-1,1,3,3-tetraoxide (pre-
-- 11 --
~..., ~,
, . ~ i . .
. .. '
,
.
1079ZgO
pared as described in Exa~lple 2) are dissolved in 35 ml of dimethylformamide
and, with stirring under argon, treated with 1,2 g of sodium hydride at
room temperature. The suspension is stirred at 40C for a further 0.5
hours, then cooled and treated with 2.8 g of epichlorohydrin. The mixture
is then heated at 100C for 16 hours. A~ter cooling to room temperature,
the suspension is poured on to water and the oily material extracted with
chloroform. After evaporation of the solvent, the residue is chromato-
graphed on silica gel with chloroform/ethanol (98:2). The 2-(3,4-dimethoxy-
phenyl)-2-(2,3-epoxypropyl)-m-dithiane-1,1,3,3-tetraox~de obtained is re-
crystallised from methylene chloride/ethanol and has a melting point of
175 - 176C.
Example 7
76.9 g of 2-(3,4-dimethoxyphenyl)-m}dithiane(prepared as described
in Exanple 1) are dissolved in 900 ml of absolute tetrahydrofuran, the
solution is cooled to -70C and treated with 128 ml of a butyl lithium
solution in such a manner that the temperature does not exceed -60C. me
mixture is then held for 2 hours at -20C, a precipitate forming. me
mixture is again cooled to -70C and 47.3 g of 1,3-bromochloropropane
in 750 ml of absolute tetrahydrofuran are added. The mixture is then held
for 1 hour at -20C and for 1 hour at room temperature. The tetrahydro-
furan is then evaporated, the residue taken up in ether and extracted. After
evaporation of the solvent, there is obtained 2-(3-chloropropyl)-2-(3,4-
dimethoxyphenyl)-m-dithiane.
me 2-(3,4-dimethoxyphenyl)-2-(2,3-epoxypropyl)-m-dithiane can be
prepared in an analogous manner starting from 2-(3,4-dimethoxyphenyl)-m-
dithiane (prepared as described in Example 1) using epichlorohydrin instead
of 1,3-bromochloropropane.
- 12 -
~' .
~.. ., ~,
'' ', '' : `
.
- . . . . .
- . : , . . ..
.
,,:: : ,,
.: :' , . . . :
1~92~1~
Example 8
50 g of 3-veratroylpropionic acid in 400 ml of chloroform and 22.7
g of 1,3-propanedithiol are treated with hydrogen chloride up to saturation
while stirring. After 3 hours at room temperature, the solution is evaporated
to 50 ml and diluted with ether. m e resultine solution is extracted three
times with 5% sodium carbonate. The basic phases are combined and made
acidic with concentrated hydrochloric acid. me precipitated product lS
extracted with ether/methylene chloride (1:3). me organic extracts are
dried and evaporated. The residue is recrystallised from ethanol, there
being obtained 2-(3,4-dimethoxypheny1)-m-dithiane-2-propionic acid Or melt-
ing point 134 - 135C.
13.2 g of 2-(3,4-dimethoxyphenyl)-m-dith~a~e-2-propionic acid, 4 g
of triethylamine and 180 ml of tetrahydrofuran are cooled to 0C and treated
dropwise within 10 minutes with ~.44 g of chloroformic acid isobutyl ester in
80 ml of tetrahydrofuran. me mixture is then held at room te~lperature for
3 hours and treated with 0C with 7.25 g of homoveratrylamine in 40 ml of
tetrahydrofuran. The suspension is left to stand at 3C for 48 hours, then
evaporated, treated with water and extracted with ether/methylene chloride
(3:1). me ethereal extracts are washed-with water, sodium bicarbonate sol-
2Q ution, l-N tartaric acid and water. m e organic phase is dried over
magnesium sulphate and evaporated. me residue is crystallised from methy-
lene chloride/ether at 0C. mere is obtained N-(3,4-dimethoxyphenethyl)-
2-(3,4-dimethoxyphenyl)-m-dithiane-2-propionamide of melting point 135 -
136C.
Example 9
3.95 g of 2-(3-chloropropyl~-2-(3,4-dimethoxyphenyl)-m-dithiane
- 13 -
~, '
. .- .- , , ~ : ' : .
.
-. , ' ~ :
'' " ' . . " ' ' ' ~" :, " ;', . ' ', . :' ,, : ' " ,' ': . "''' ; ' ' . ' . '
:~0~9290
1,1,3,3-tetraoxide are dissolYed~in sa nl of dimethylformamide. The solution
is cooled to 0C and treated with 15 g of methylamine. me mixture is heated
at 40C under pressure for 18 hours. The solution is then concentrated and
the crystalline residue recrystallised from a sm~ll amount of methanol.
mere is thus obtained the desired starting material of melting point 164C.
- 14 -
r
~ :
.. .. . . . .
