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Patent 1071634 Summary

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(12) Patent: (11) CA 1071634
(21) Application Number: 1071634
(54) English Title: PROCESS FOR THE PREPARATION OF TETRAHYDRO-THIENO (3, 2-C) - AND (2, 3-C) PYRIDINE DERIVATIVES
(54) French Title: PROCEDE POUR LA PREPARATION DE DERIVES TETRAHYDROTHIENO (3, 2-C) - ET (2, 3-C) PYRIDINE
Status: Term Expired - Post Grant Beyond Limit
Bibliographic Data
Abstracts

English Abstract


PROCESS FOR THE PREPARATION OF TETRAHYDRO-THIENO[3,2-C]-
AND [2,3-C]PYRIDINE DERIVATIVES.
ABSTRACT OF THE DISCLOSURE
This invention relates to a process for the preparation of
tetrahydro-thieno [3,2-c]pyridine derivatives of the formula
<IMG> (Ia)
and their isomeris tetrahydro-thieno [2,3-c]pyridine derivatives
in which R1 represents hydrogen, a lower alkyl or alkoxy radical,
an aryl radical or an aralkyl radical; R2 and R3 represent hydrogen,
halogen, a lower alkyl or alkoxy group, a di(loweralkyl)amino,
nitro, cyano or acetamido group or, together with the phenyl
nucleus to which they are attached, form a polycyclic aromatic
ring, comprising reacting a tetrahydrothieno[3,2-c]pyridine
derivative of the formula:
<IMG> (IIa)
or a derivative of its isomer, tetrahydro[2,3-c]pyridine, with
formaldehyde H-CHO and a phenol of the formula:
<IMG>
(III).
- 1 -


Claims

Note: Claims are shown in the official language in which they were submitted.


The embodiments of the invention in which an exclu-
sive property or privilege is claimed are defined as follows:
1. Process for the preparation of derivatives
selected from the group consisting of the tetrahydro-thieno-
[3,2-c]pyridine derivatives of the formula:
<IMG> (Ia)
and their isomeric pyridine derivatives of the formula:
<IMG>
(Ib)
in which the hydroxyl radical is at a position selected from
the 2- and 4-positions; R1 is selected from the group con-
sisting of hydrogen and a lower alkyl radical having 1 to 4
carbon atoms; R2 and R3, when taken individually, are each
selected from the group consisting of hydrogen, halogen, a
lower alkyl radical having 1 to 4 carbon atoms, a lower alkoxy
radical having 1 to 4 carbon atoms, a di(loweralkyl)amino
radical wherein the alkyl has 1 to 4 carbon atoms, nitro,
cyano and acetamido and R2 and R3 when taken together form a
fused benzene ring, R2 and R3 being at a position selected
from the 3-, 4-, 5- and 6-positions when OH is at 2-position
and being at the 3- and 5-positions and other than hydrogen
when OH is at 4-position, comprising heating a derivative
selected from the group consisting of the tetrahydro-thieno-
[3,2-c]pyridine derivatives of the formula:

<IMG> (IIa)
and their isomeric tetrahydrothieno [2,3-c]pyridine derivatives
of the formula:
<IMG> (IIb)
in which R1 has the above-defined meanings, with formaldehyde
H-CHO and a phenol of the formula:
<IMG> (III)
in which R2 and R3 have the above-defined meanings, to give the
desired derivative selected from the pyridine derivatives of
the formulae (Ia) and (Ib).
2. Process as claimed in claim 1, wherein the reaction is
effected within an organic solvent.
3. Process as claimed in claim 2, wherein said organic
solvent is selected from the group consisting of ethanol,
propanol and dioxan.
4. Process as claimed in claim 2, wherein the reaction is
effected at a temperature between 50°C and the boiling temperature
of the solvent.
5. Process as claimed in claim 2, wherein the reaction is
effected with stirring, during a period of time of 2-20 hours.
- 11 -

6. The tetrahydro-thieno [3,2-c]pyridine derivatives
of the formula:
<IMG>
(Ia)
and their isomeric pyridine derivatives of the formula:
<IMG>
(Ib)
in which the hydroxyl radical is at a position selected from
the 2- and 4-positions, R1 is selected from the group con-
sisting of hydrogen and a lower alkyl radical having 1 to 4
carbon atoms, R2 and R3, when taken individually, are each
selected from the group consisting of hydrogen, halogen, a
lower alkyl radical having 1 to 4 carbon atoms, a lower alkoxy
radical having 1 to 4 carbon atoms, a di(loweralkyl)amino
radical wherein the alkyl has 1 to 4 carbon atoms, nitro,
cyano and acetamido and R2 and R3 when taken together form a
fused benzene ring, R2 and R3 being at a position selected
from the 3-, 4-, 5- and 6-positions when OH is at 2-position
and being at the 3- and 5-positions and other than hydrogen
when OH is at 4-position, when prepared by the process defined
in Claim 1 or by an obvious chemical equivalent.
12

Description

Note: Descriptions are shown in the official language in which they were submitted.


~ ~ 7 ~ ~ ~ 4
This invention relates to a new process for the
preparation of tetrahydro-thieno ~,2- ~pyridine derivatives of
the formula:
OH
R1 ~ Rz (la)
and their isomers, tetrahydro-thieno ~,3- ~pyridine deriva-
tives of the formula:
~n CH2~ (1~)
in which the hydroxyl group OH is at 2- or 4-position; Rl
represents hydrogen, a lower alkyl or alkoxy radical, an aryl
; 10 radical or an aralkyl radical; R2 and R3 represent each hydro-
gen, halogen, a lower alkyl or alkoxy radical, a di-(lower-
alkyl)amino, nitro, cyano or acetamido radical or, together
with the phenyl nucleus to which they are attached, Form a
polycyclic aromatic ring, R2 and R3 being at 3-, 4-, 5- or 6-
position when OH is at 2-position and being at 3- and 5-
positions and other than hydrogen when OH is at 4-position.
Said compounds possess valuable therapeutic proper-
ties and, in addition, are useful intermediates in the prepa-
ration of derivatives used both in the chemical and pharma-
; 20 ceutical industries.
4,5,6,7-Tetrahydro-thieno ~,2- ~pyridine derivatives
have already been described, together with a process for their
preparation, in Canadian Patent 1,038,871 and its division
Canadian Patent 1,042,299. Said process comprises condensing
a compound of the forrnula:
B -
N
- 2

~ ~ 7 ~ ~ 3 ~
in which the radicals A and B represent each at least an atom
or
group selected from hydrogen, halogen, lower alkyl, lower
alkoxy, nitro and amino, with a halide of the formula Hal-R in
which Hal represents a halogen atom and R represents an
optionally substituted alkyl, aryl or aralkyl radical, to give
a pyridinium salt of the formula:
A
B ~ ~ - R, Hal~3
and subsequently hydrogenating said pyridinium salt to give a
derivative of the formula (I):
A
B ~ N - R
4,5,6,7-Tetrahydro-thieno ~ ,3- ~pyridine derivatives
have also been prepared by an analogous process (Canadian
Patent Appln. n 255,299, filed June 21, 1976, by Applicant).
This process, however, is expensive and delicate in
that it requires numerous difficult procedures.
In addition, use of this preparation process makes
it difficult to obtain derivatives having on the nitrogen atom
a benzyl radical carrying a hydroxyl group at 2- or 4-position.
Indeed, to obtain derivatives of such type according to said
process, ;t is necessary to proceed via the methoxylated
derivat;ve which is subsequently hydrolyzed.
Therefore, the object of the present invention is to
provide a simple process for the preparation, in good yields,
of derivatives of the formula (Ia) or their isomers of the
formula (Ib) in which the phenyl nucleus carries a hydroxy
group at 2- or 4-position.
The process of this invention comprises reacting a tetra-
~i ~
.
: , ' - ' ' ' . .,
' :. . ' ., , ' ' ', .: .

~ 7~63~
hydrothieno ~,2-c7pyridine derivative of the formula:
~ (IIa)
or a derivative of its isomer, tetrahydro~ ~3 _7pyridi~e, of the
formula: R1
~ ~ H ~IIb)
in which R1 has the above described meanings, with formaldehyde
. H-C~0 and a phenol of the formula
qH
~ R2 (III~
in which R2 and R3 have the above-defined meanings, to give the
desired derivative of the formula (Ia) or (Ib).
The (Mannich type) reaction occurs Q~ one of the ortho-
positions of the phenol, when it is free~ When both ortho-positions
are occupied, the reaction occurs at the para-position.
Thus~ in the case of phe~ols in which at least one of the
positions ortho to 0~ is free~ the Mannich reaction occurs at said
free ortho-positions
0~
N~ 2 ~ ~ N ~ n2
+ HCH0 + ~ ~~~ S R3
radicals R2 and R3 occupying optionally 3-9 4-~ 5- or 6-positions
in the derivative of the ~ormula (Ia) or (Ib).
The sa~e reaction occurs ~lith unsubstituted phenol~ and with
polycyclic phenols such a~ ~naphthol~ for example.
In the case of phenols carr~i~g both substituent~ R2 and R3
-- 4
... . ... . ..

~(~7~63~
at o~tho-position to the OH ~adical, the reaction occurs at
para-position:
~2
33 c~z ~oll
The condensation reaction o~ thi~ invention is advantageously
conducted within a medium consisting of an organic solvent such
as ethanol, propanol or dioxan. The reaction is advantageously
effected in the hot~ at a temperature bet~een 50C and the boiling
temperature of the solvent used, best results being obtained at
temperatures o~ about 80C.
It is preferred to effect the reaction with oonst~nt stirring,
during a period of time of 2-20 hours.
Formaldehyde or its different polymerization products9 such
as polyoxymethylene9 may be used for the reaction.
Purification of the desired deriYative is effected either by
recrystallization from an organic s-olvent, or after conversion to
a salt, by washing, drying and optionally recrystallization from
an organic solvent.
The following non-limiting Examples are give~ to illustrate
the p~esent invention.
EXA~LE 1
Preparation of 5-(3,5-dimethyl~4-hydroxy benzyl)-4,5~6,7-
tetrahydro thieno~ 92-_7pyridine
A mixture of 4~5,6,7-tetrahydro-thie~o~,2_~ pyridi~e (6~1 g;
44 mmoles)9 2,6-dimethyl-phenol (5~4 g; 44 mmoles)9 polyoxymethyle~e
(2.7 Bi 90 ~mole~) and dioxan (50 cc) is stirred at 80C duri~g 3
hours~ A~ter concentration in ~acuo, the residue is recrystallized
.
.. ~ : . .. . .
.. . .
.
~ ,, -: .

3~1
from ethanol-isopropanol (M.p. = 158C; yield: 4
EXAMPLE 2
.
Preparation o~ 5-(2~hydroxy-5~nitro-benzyl3-6-methyl-4,5,6~7_
tetrahydro--thie:no~,3 ~ 2--c7pyridine
A mixture of 6-methyl-4,5,6~7-tetrahydro-thieno~ ,2-c7_
pyridine (6.3 g; 41 mmoles), p-nitro-phenol (5.7 B; 41 mmoles) 7
polyoxymethylene (2D5 g; 83 mmoles) and dioxan (50 CC) iS sti~rPd
at 80C during 4 hours. After concentration in vacuo~ the residue
is dissolved in ether and then treated with 0.5 equivalent oxalic
acid in ethanol solution. The resulting semi-oxalate is filtered,
~ashed with boiling methanol-water (1:3)J filtered again and dried
(M.p. = 214C; yield: 27%).
EXA~
Preparation o~ 6-(2-hydroxy-5-chloro-benzyl3-7-methyl-475,6,7-
tetrahydro-thieno~3 -c7pyr i dinP
A mixture of 7-methyl-4,5,6,7--tetrahydro-thieno~ 73-_7-
pyridine (6~0 g; 39.2 mmoles), p-chlorophenol (5~05 g; 39~2 mmoles)~
polyoxymethylene (2.36 g; 78.5 mmoles) and dio~an (70 cc3 is
stirred at 80C during 15 hours~ After concentration in vacuo~
the resiaue is taken up into 2N hydrochloric acid~ The aqueous
phase is ext~acted with ether, made basic with concentrated ammonia
and again extracted with methylene chloride. The organic ext~acts
are washed With water~ dried o~er sodium sul~ate and concentrated
in Yacuo. The residue is treated with 0.5 equivalent oxalir acid
in ethanol solutionD The resulti~g semi-oxalate is fil-tered and
recrystallized ~rom ethanol-dimethyl ~ormamide (M~po = 170C;
yield: 38%)~
EXA~LE 4
Preparation of 6-(2-hydroxy--5-cyano~benzyl)-4,5,6,7-
- 6 -
.
. : . - . :

~7~63~
tetrahydro-thieno ~,3-_7pyridine
A mixture of 4,5,677-tetrahydro-thieno~93-~ py~idine (1 g;
7,2 mmoles)9 p-cyano-phenol (95% purity; 0.9 g; 7~2 mmoles)~
polyoxymethylene (0.43 g; 14.4 mmoles) and dioxan (20 oc) is
stirred at 80C during 4 hours. After concentration in vacuo, the
residue is taken up i~to 2N hydrochloric acid. The aqueous phase
is extracted with ether, made basie with concentrated ammonia and
again extracted with methylene chloride. The organic extracts are
washed with water, dried over sodium sul~ate and concentrated in
~acuo. The residue is recrystallized from isopropyl ether-
isopropanol (M.p. 134C; yield: 23~).
Using the proeedures described in the preceding Examples,
the following compounds are obtained:
EXAMPLE 5
5-(2-Hydroxy-5-methoxy-benzyl)-4,5,697-tetrahydro-thieno~ ,2-~7-
pyridine
White crystals; M.p. = 90C
EXAMPLE 6
5-(2-Hydroxy-5-nitro-benzyl)-4,5,6,7-tetrahydro-thieno~2-o7-
pyridine
Yellow cryst~ls; M p. = 160C.
EXA~LE 7
5-(2-Hydroxy-3-methoxy-benzyl)-4,596,7-tetrahydro-thieno~ ,2-~ _
pyridine
White crystals; M.p~ = 84C.
EXAMPLE 8
5-(5-Chloro-2-hydr~y-be~zyl)-495,6,7-tetrahydro-thieno~,2-c7_
pyridine
White erystals; M.p. _ 82_85C.
~ 7

l~t~
EXAMPLE 9
5-(5-Chloro-2~hydroxy-benzyl)-6-methyl-4, 5, 6,7-tetrahydro-
thienoL3~2-c7pyridine 7 se~i-oxalate
White c~ystals; M.p~ = 200C.
EXAMPLE 10
5-(5-Fluoro-2-hydroxy-benzyl)-4,5,6,7-tet~ahydro-thieno~,2-c7-
pyridine
Pale yello~ crystals; M.p. _ 92C.
EXAMPLE 11
5-o-Hydroxybenzyl-4~5~6~7-tetrahydro-thieno~ ,2-~ pyridine,
semi-oxalat~
White crystals; M.p. = 216C.
EXAMPLE 12
5-(2-~ydroxy-3-methyl-benzyl)~4,5,6,7-tetrahydro-thieno~ ,2ec7_
pyridine, semi-oxalate, semi-hydrate
White crystals; M.p~ = 198C
EXAMPLE 13
5-(3-Acetamido-2-hydroxy-benzyl)-4,5,6,7-thieno~,2-c7pyridine
White crystals; M.p. = 154C.
EXAMPLE 14
6-(S-Chloro-2-hydroxy-benzyl)-4,5,6,7-tetrahydro-thieno~ ,3__7_
pyridine
White crystals; M.p. = 222C.
EXA~LE 15
6-(3~4-Dichloro-2-hydroxy-benzyl)-495,6,7-tetrahydro-thieno~,3_~7_
pyridine
White crystals; M.p. = 153C~
: EXAMPLE 16
6-(2-Hydroxy-5-nitro-benzyl)-4,5~6~7-tetrahydro-~hieno~l3-c)-
~ 8 --
.

3~
pyridine
Iellow crystals; M.p. = 159C.
EXAMPLE 17
6-(3~5-Dimethyl-4-hydroxy-benzyl)-4,5,6,7-tetrahydro-
thieno~,3-c7py~idine
Ivory crystals; M p. = 118C.
EXAMPLE 18
6-(2-Hydroxy-3-isopropyl-benzyl~-495,6~7-tetrahydro-
thieno~ ,3-c7pyridine
Very pale yellow crystals; M.p. = 101C.
EXAMPLE 19
.
6-(2-Hydroxy-5-methyl-benzyl)~4,5~6,7-tetrahydro-
thieno~,3-_7pyridine~ semi-oxalate, æemi-hydrate
Very pale yellow crystals9 M.p. = 196C.
EXAMPLE _
6-(4-Dimethylami~o-2-hydroxy-benzyl)-4~596,7-tetrahydro-
thieno~ ,3-_7pyridine
Pink orystals; M.p. = 140C.
EXAMPLE 21
6-o-Hydroxybenzyl-4~5,697-tetrahydro-thieno~,3-c7pyridine
Beige crystals; Mop~ = 98C.
EXAMPLE 22
..
6~ ydroxynaphthyl-methyl)-4,5~6,7-tet~ahydro-thieno~,3-c7
pyridine
Pale yellow crystals; M~p~ = 150C
EXA~LE 23
5-(3,5-Dichloro-4-hydroxy~benzyl)-4~5~6,7-tetrahydro-
thieno~,2-c7pyridine
White crystals; M.p. = 170C.
_ g _
... : .

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Event History

Description Date
Inactive: Expired (old Act Patent) latest possible expiry date 1997-02-12
Grant by Issuance 1980-02-12

Abandonment History

There is no abandonment history.

Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
None
Past Owners on Record
None
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Abstract 1994-03-24 1 27
Cover Page 1994-03-24 1 24
Claims 1994-03-24 3 76
Drawings 1994-03-24 1 12
Descriptions 1994-03-24 8 244