Note: Descriptions are shown in the official language in which they were submitted.
10559~6 H-153-f
The invention relates to processes for preparing
pyridine derivatives.
The process of the present invention relates to the
preparation of novel compounds of formula I,
R6
CSNHR4
and acid addition salts thereof, wherein R1 represents
hydrogen, alkyl of 1-6 carbon atoms, or phenyl, R2 represents
hydrogen or alkyl of 1-6 carbon atoms and R6 represents
hydrogen or alkyl of 1-6 carbon atoms, or R1 and R2 taken
together represent an alkylene chain -CH2(CH2)nCH2-
wherein n is 1, 2 or 3, R7 represents hydrogen or alkylof 1-6 carbon atoms, m is 1, 2 or 3 and R4 is an alkyl
radical of 1-6 carbon atoms.
Compouds of formula I, in which R4 is an alkyl
radical and including tricyclic compounds when m and n
are equal are described in our British Patent Specification
1 432 378.
These compounds and also corresponding tricyclic
compounds in ~hich m and n are different, are anti-ulcer
agents which display activity in the stress induced test
of Senay and Levine, Proc. Soc. Exp. Biol. Med. 124,
1221-3 (1967), and/or anti-secretory activity in the
~ 3
. ~ .
lO5S946 H-153-f
test of H. Shay, ~. Sun and H. Greenstein, Gastro-
enterology, 1954, 26, 903-13.
Accordingly the present invention provides a process
for preparing a compound of formula I as definsd above,
~hich process comprises treating a compound of formula II
R6
R7 ~ ~' (II)
where R1, R2, R6, R7 and m are as defined in ~onnection
with formula I above, and M is sodium, potassium, lithium,
or MgHal, where Hal is chlorine,bromine or iodine, with
a compound of formula R4NCS wherein R4 is as defined
in connection with formula I and treating the product
with hydrogen ions.
Preferably a starting material of formula II,
wherein M is lithium or MgHal e.g. MgBr is used.
Conveniently the product after reaction with R4NCS is
treated with acid, e.g. an aqueous mineral acid such as
a hydrohalic acid preferably hydrochloric acid. ;
Alternatively, any other proton source may be used
e.g. water or an alcohol e.g. a lower alkanol such as
methanol or ethanol, ~r acetic acid.
Starting materials of`formula II, wherein M is MgHal
may be prepared by treatment of a corresponding compound
of formula II ~here M is hydrogen with an alkyl magnesium
halide R5MgHal wherein R5 is an alkyl group, preferably
a lower alkyl group of 1-6 carbon atoms, and Hal is
chlorine, bromine or iodine, R5 may be a straight or
branched chain alkyl group, the isopropyl group being
presently preferred. The reaction is conducted in an
.~
.....
1055946 H-153-f
inert atmosphere. It has been found preferable to
conduct the above reaction with heat in the presence
of an inert solvent with a boiling point in the range
100-120C, e.g. toluene or dioxan, toluene baing the
preferred solvent. The reaction will take place in
the absence of a solvent but we have found that the
yields are generally lower, unless an excess of the
Grignard reagent e.g. 2:1 is used.
Starting materials of formula II where M is sodium,
potassium or lithium may be prepared by treating a
corresponding compound of formula II where M is hydrogen
with a metal alkyl e.g. MR3 where M is sodium, potassium
or lithium and R3 is an alkyl, aryl or aralkyl radical.
Preferably M is lithium and R3 is lower alkyl of 1-6
carbon atoms, butyl being preferred. Phenyl lithium
compounds are also useful.
~ hen a compound of formula II in which R1 is
methyl and R2, R6 and R7 are hydrogen and M is hydrogen
is treated with a metal alkyl MR3, the metal atom may
be inserted either at the desired position or in the
methyl group R1. This side reaction may also occur with
any compound containing an alkyl group R1 in which there
are one or two hydrogen atoms on the carbon atom adjacent
to the pyridine ring. These byproducts which contain a
metal atom, in any alkyl group R1 may react with the
isothiocyanate R4NCS giving a mixture of products ona
with the thioamide in the desired position replacing the
group M and the other in the alkyl group R1. Such mixture
may be separated by standard methods eO~g. by crystallisation
or chromatography.
~055~ H-153-E
Starting compounds of formula II ~here M is
hydrogen are either kno~n compounds or may be prepared
by methods kno~n for analogous compounds. Examples of
starting materials ara described in our U.K. Patent
Specification 1 432 378.
When any of R1, R2, R6 or R7 is an alkyl radical
it is prsferred that this is a lower alkyl radical ~hich
may be a straight or branched chain, having from 1 to 6
carbon atoms, e.g. methyl, ethyl, n-, and lso-propyl
and n-, s- and t-butyl, R7 may be a qem-dimethyl group.
The term alkyl radical is also intended to embrace cyclic
alkyl radicals e.g. cyclobutyl, cyclopentyl and cyclohexyl.
s
lO5S94f~ H- 1 53 f
Particularly preferred compounds are bicyclic
compounds especially those in which one of R1, R2 and
R6 is methyl, the others are hydrogen and R7 is hydrogen.
Tricyclic compounds may be a symmetrical (i.e. n and m
are equal) or unsymmetrical i.e. n and m are different.
In some instances where the starting compound is
tricyclic in which m and n are different, non-selectivity
of the reaction with the metal alkyl may lead to a
mixture of compounds of formula II, one ~ith the group M
in the desired ring and the other with the group M in
the other ring. When such a mixture is treated with
the compound of formula R4NCS a corresponding mixture
of products of formula I will be formed. This mixture
may be separated by standard techniques e.g. chromatography.
Preferably R1, R2 and R6 are selected from hydrogen
and lower alkyl and R is hydrogen. More preferably one
of R1, R2 and R6 is lower alkyl e.g. methyl and the
others are hydrogen and R7 is hydrogen. Preferab~y R4
is a lower alkyl radical with from 1 to 6 carbon atoms
1055~46 H-153-f
e.g. 1-4 carbon atoms.
It has been found that the desired compound of
formula I, may be accompanied by a bisthioamide of
formula III
R6
R2
R --f=---__ ~ ~ (III)
(CH~N J~ 1
CSNHR4 R
CgNHR4
h i R1 R2 R4 R6, R7 and m are as defined in
connection with formula I. Such bisthioamides can
usually be removed by fractional crystallisation.
The invention also includes a process for preparing
a compound of formula I as defined above which process
comprises treating a corresponding compound of formula II
as defined above, except that M i~ hydrogen, with a
compound of formula R MgHal where Hal is chlorine bromine
or iodine and R is an alkyl, aryl or aralkyl group or
a metal alkyl MR3 wherein M is sodium potassium or
lithium and R is alkyl, aryl or aralkyl, to obtain the
compound of formula ~, treating this compound with an
isothiocyanate of formula R4NCS wherein R4 is an alkyl,
aralkyl or aryl radical, and then treating the product
with hydrogen ions.
The following examples illustrate the invention,
temperatures are in C.
Example 1
3-Methyl-5.6,7,8-tetrahYdroquinoline-8-(N-methyl)-
thiocarboxamide
A 15% W/~ solution of n-butyl lithium in hexane
(26 ml, 0.06 m) was added dropwise to a stirred solution of
1055946 H-153-f
3-methyl-5,6,7,a-tetrahydroquinoline (7.39, 0.05m) in
anhydrous ether (50 ml) and in an atmosphere of dry
nitrogen. After 1 hour at 24C the reaction mixture
was cooled to 0C and treated dropwise with a solution
of methylisothiocyanate (3.89, 0.05m) in anhydrous ether
(10 ml) and allowed to stand for 4 hours at 24C. The
cooled reaction mixture ~as diluted ~ith 2N HCl and
the organic layer separated and discarded. The aqueous
solution was adjusted to pH 10.0 with sodium carbonate
and extracted with ether (3 x 50 ml). The combined
extracts ~ere washed with brine, dried (MgS04) and the
solvent removed. The residual oily solid was crystallised
from iso-propanol to give the title compound as pale yellow
; needIes (3.29) m.p.-159C. Found: C, 65.3; H, 7.2; N~ 12.5.
C12H16N2S requires: C, 65.4; H, 7.3; N, 12.7%.
ExamPle 2
3-Methyl-5t6,7,8-tetrahydroouinoline-8-(N-n-butYl)-
thiocarboxamide
A solution of 3-methyl-5,6,7,8-tetrahydroquinoline
(7.39, 0.05mol.) in anhydrous ether (50 ml.) ~as trsated
dropwise with stirring, cooling to 0C and in an atmosphere
of nitrogen with a 15% ~/W solution of n-butyl lithium in
hexane (26 ml. 0.06 m~l.) and the mixture stirred for a
further 30 minutes at room temperature. The mixture was
transferred to a dropping funnel and added dropuise ~ith
stirring, cooling and in an atmosphere of nitrogen to a
solution of n-butylisothiocyanate (6.959, 0.06mol.) in
anhydrous ether (50 ml.). The mixture was stirred at
room temperature for an additional 1 hour, diluted ~ith
water (50 ml.) and acidified with 2N HCl (50 ml.) and
the aqueous solution uas adjusted to pH 10.0 with sodium
H-153-f
1055946
carbonate and extracted with methylene chloride
(3 x 50 ml.). The combined extracts were washed with
brine, dried (MgS04) and the solvent removed in vacuo
to give a pale yellow oil which was dissolved in anhydrous
ether and treated with an excess of ether saturated with
HCl gas. The solid was filtered and recrystallised
from isopropanol to give the title compound as the
hydrochloride, colourless needles (11.59. 74%) m.p.
195C (dec.).
Found: C, 60.34; H, 7.79; N, 9.39%
C15H22N2S HCl requires: C, 60.30; H, 7.40; N, 9.3%.
Example 3
3-Methvl-5,6,7.8-tetrahydroquinoline-8-(N-methYl)-
thiocarboxamide
~-Methyl-5,6,7,8-tetrahydroquinoline (6.469, 0.044mol.)
was added portionwise to an ethereal solution of isopropyl-
magnesium bromide (prepared from magnesium (2.789, 0.1059.
atom), isopropylbromide (10.89, 0.088mol ) in ether
(20 ml.)) in an atmosphere of nitrogen. The reaction
mixture was heated to 90 and the ether removed by
distillation and toluene (5 ml.) added and the mixture
heated at 130 for 2 hours allowing 3 ml. of toluene to
distill. The residue (3-methyl-5,6,7,8-tetrahydroquinoline-
8-magnesium bromide) was cooled, diluted with ether
(30 ml.), decanted from unreacted magnesium and treated
dropwise, with cooling, with a solution of methyl-
isothiocyanate (6.46 9, 0.088 mol.) in ether (10 ml.).
The reaction mixture was stirred for an additional 1 hour
at room temperature, diluted with 2N HCl (200 ml.) and
the organic layer separàted and discarded. The aqueous
phase was adjusted to pH 10.0 with sodium carbonate and
1055946 H-153-f
extracted ~ith methylene chloride (2 x 100 ml.). The
combined extracts were washed with brine, dried and
the solvent removed in vacuo to give a pale yello~
oil, which was chromatographed on silica by elution
with chloroform to give the title compound as pale
yellow needles (29. 18%) after recrystallisation from
isopropanol m.p. 159C and identical to authentic
material.
Example 4
5,6,7,8-Tetrahydrocuinoline-8-(N-methyl)thiocarboxamide
and 5,6,7.8-tetrahydroquinoline-8,8-dir(N-methyl)thio-
carboxamidel
A solution of 5,6,7,8-tetrahydroquinoline (6.659,
0.05 mole) in ether (30 ml) was treated with 9% w/v n-
butyl lithium solution in hexane (39.5 ml, 0.055 mole) at
0C. The reaction mixture was stirred at this temperature
for 1 hour and a solution of methyl isothiocyanato
(4.01 9, 0.055 mole) in ether (5 ml) ~as added dropwise
and the stirring was continued for a further hour. Water
(5 ml.) was added and the mixture acidified with 2N HCl
solution. The acid layer ~as ~ashed ~ith ethyl acetate,
basified ~ith solid sodium carbonate and extracted with
chloroform (3 x 100 ml.). The chloroform extracts ~ere
dried with MgS04 filtered and evaporated. The residue
was triturated with hexane and the resulting solid was
recrystallised twice from isopropyl alcohol to give
5,6,7,8-tetrahydroquinoline-8,8-di[(N-methyl)thiocarboxamide]
(29) ~hich was converted into the hydrochloride in isopropyl
alcohol with ethereal HCl m.p. 217C decomp. (Found:
C, 48.7; H, 6.1; N, 12.5. C13H17N3S2 HCl. 1/4 H20 requires
C, 48.7; H, 5.8; N, 13.1). The mother liquors from the
isopropyl alcohol recrystallisations were combined and
evaporated to dryness and the residue was extracted with
hot hexane leaving a crystalline residue ~hich was
- 1L3 -
~055~46 H-153-f
recrystallised from isopropyl alcohol to give 5,6,7,8-
tetrahydroquinoline-8-(N-methyl)thiocarboxamide (3.59)
which was converted into the hydrochloride with ethereal
HCl and recrystallised from isopropyl alcohol m.p.
250C decomp. (Found: C, 54.5; H, 6.5; N, 11.5.
C11H14N2S.HCl requires C, 54.4; H, 6.2; N, 11.5%.)
