CA1071634A - Process for the preparation of tetrahydro-thieno (3, 2-c) - and (2, 3-c) pyridine derivatives - Google Patents
Process for the preparation of tetrahydro-thieno (3, 2-c) - and (2, 3-c) pyridine derivativesInfo
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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 (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:
(IIa) or a derivative of its isomer, tetrahydro[2,3-c]pyridine, with formaldehyde H-CHO and a phenol of the formula:
ABSTRACT OF THE DISCLOSURE
This invention relates to a process for the preparation of tetrahydro-thieno [3,2-c]pyridine derivatives of the formula (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:
(IIa) or a derivative of its isomer, tetrahydro[2,3-c]pyridine, with formaldehyde H-CHO and a phenol of the formula:
Description
~ ~ 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
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 ... . ... . ..
~(~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 .
.. ~ : . .. . .
.. . .
.
~ ,, -: .
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 ... . ... . ..
~(~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 .
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-.
. : . - . :
~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:
5-(2-Hydroxy-5-methoxy-benzyl)-4,5,697-tetrahydro-thieno~ ,2-~7-pyridine White crystals; M.p. = 90C
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.
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~
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.
5-(5-Fluoro-2-hydroxy-benzyl)-4,5,6,7-tet~ahydro-thieno~,2-c7-pyridine Pale yello~ crystals; M.p. _ 92C.
5-o-Hydroxybenzyl-4~5~6~7-tetrahydro-thieno~ ,2-~ pyridine, semi-oxalat~
White crystals; M.p. = 216C.
5-(2-~ydroxy-3-methyl-benzyl)~4,5,6,7-tetrahydro-thieno~ ,2ec7_ pyridine, semi-oxalate, semi-hydrate White crystals; M.p~ = 198C
5-(3-Acetamido-2-hydroxy-benzyl)-4,5,6,7-thieno~,2-c7pyridine White crystals; M.p. = 154C.
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.
6-(3~5-Dimethyl-4-hydroxy-benzyl)-4,5,6,7-tetrahydro-thieno~,3-c7py~idine Ivory crystals; M p. = 118C.
6-(2-Hydroxy-3-isopropyl-benzyl~-495,6~7-tetrahydro-thieno~ ,3-c7pyridine Very pale yellow crystals; M.p. = 101C.
.
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.
6-o-Hydroxybenzyl-4~5,697-tetrahydro-thieno~,3-c7pyridine Beige crystals; Mop~ = 98C.
..
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 _ ... : .
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-.
. : . - . :
~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:
5-(2-Hydroxy-5-methoxy-benzyl)-4,5,697-tetrahydro-thieno~ ,2-~7-pyridine White crystals; M.p. = 90C
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.
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~
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.
5-(5-Fluoro-2-hydroxy-benzyl)-4,5,6,7-tet~ahydro-thieno~,2-c7-pyridine Pale yello~ crystals; M.p. _ 92C.
5-o-Hydroxybenzyl-4~5~6~7-tetrahydro-thieno~ ,2-~ pyridine, semi-oxalat~
White crystals; M.p. = 216C.
5-(2-~ydroxy-3-methyl-benzyl)~4,5,6,7-tetrahydro-thieno~ ,2ec7_ pyridine, semi-oxalate, semi-hydrate White crystals; M.p~ = 198C
5-(3-Acetamido-2-hydroxy-benzyl)-4,5,6,7-thieno~,2-c7pyridine White crystals; M.p. = 154C.
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.
6-(3~5-Dimethyl-4-hydroxy-benzyl)-4,5,6,7-tetrahydro-thieno~,3-c7py~idine Ivory crystals; M p. = 118C.
6-(2-Hydroxy-3-isopropyl-benzyl~-495,6~7-tetrahydro-thieno~ ,3-c7pyridine Very pale yellow crystals; M.p. = 101C.
.
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.
6-o-Hydroxybenzyl-4~5,697-tetrahydro-thieno~,3-c7pyridine Beige crystals; Mop~ = 98C.
..
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 _ ... : .
Claims (6)
1. Process for the preparation of derivatives selected from the group consisting of the tetrahydro-thieno-[3,2-c]pyridine derivatives of the formula:
(Ia) and their isomeric pyridine derivatives of the formula:
(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:
(IIa) and their isomeric tetrahydrothieno [2,3-c]pyridine derivatives of the formula:
(IIb) in which R1 has the above-defined meanings, with formaldehyde H-CHO and a phenol of the formula:
(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).
(Ia) and their isomeric pyridine derivatives of the formula:
(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:
(IIa) and their isomeric tetrahydrothieno [2,3-c]pyridine derivatives of the formula:
(IIb) in which R1 has the above-defined meanings, with formaldehyde H-CHO and a phenol of the formula:
(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.
6. The tetrahydro-thieno [3,2-c]pyridine derivatives of the formula:
(Ia) and their isomeric pyridine derivatives of the formula:
(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.
(Ia) and their isomeric pyridine derivatives of the formula:
(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.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7521549A FR2317303A1 (en) | 1975-07-09 | 1975-07-09 | PROCESS FOR PREPARING TETRAHYDROTHIENO (3,2-C) AND (2,3-C) PYRIDINE DERIVATIVES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1071634A true CA1071634A (en) | 1980-02-12 |
Family
ID=9157715
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA254,573A Expired CA1071634A (en) | 1975-07-09 | 1976-06-10 | Process for the preparation of tetrahydro-thieno (3, 2-c) - and (2, 3-c) pyridine derivatives |
Country Status (26)
| Country | Link |
|---|---|
| JP (1) | JPS5236691A (en) |
| AR (1) | AR211019A1 (en) |
| AT (1) | AT348526B (en) |
| BE (1) | BE843822A (en) |
| CA (1) | CA1071634A (en) |
| CH (1) | CH609349A5 (en) |
| DD (1) | DD125081A5 (en) |
| DE (1) | DE2630474A1 (en) |
| DK (1) | DK141333B (en) |
| ES (1) | ES448404A1 (en) |
| FR (1) | FR2317303A1 (en) |
| GB (1) | GB1544093A (en) |
| GR (1) | GR59812B (en) |
| HU (1) | HU172280B (en) |
| IE (1) | IE42821B1 (en) |
| IL (1) | IL49641A (en) |
| LU (1) | LU74674A1 (en) |
| MX (1) | MX3224E (en) |
| NL (1) | NL7605362A (en) |
| PH (1) | PH12311A (en) |
| PL (1) | PL100685B1 (en) |
| PT (1) | PT65072B (en) |
| SE (1) | SE421699B (en) |
| SU (1) | SU628819A3 (en) |
| YU (1) | YU40137B (en) |
| ZA (1) | ZA763219B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5665315A (en) * | 1979-11-02 | 1981-06-03 | Nec Corp | Magnetic recording and inspecting system |
| DE3736664A1 (en) * | 1987-10-29 | 1989-05-11 | Boehringer Ingelheim Kg | TETRAHYDRO-FURO- AND -THIENO (2,3-C) PYRIDINE, THEIR USE AS A MEDICAMENT AND METHOD FOR THE PRODUCTION THEREOF |
| NZ233654A (en) * | 1989-05-18 | 1993-02-25 | Bristol Myers Squibb Co | 2-aminomethyl-5-aminophenol derivatives; hair dye compositions containing them |
-
1975
- 1975-07-09 FR FR7521549A patent/FR2317303A1/en active Granted
-
1976
- 1976-03-31 LU LU74674A patent/LU74674A1/xx unknown
- 1976-04-01 CH CH404576A patent/CH609349A5/en not_active IP Right Cessation
- 1976-04-21 GR GR50593A patent/GR59812B/en unknown
- 1976-04-23 YU YU1030/76A patent/YU40137B/en unknown
- 1976-05-06 PT PT65072A patent/PT65072B/en unknown
- 1976-05-19 NL NL7605362A patent/NL7605362A/en not_active Application Discontinuation
- 1976-05-21 IE IE1079/76A patent/IE42821B1/en unknown
- 1976-05-24 IL IL49641A patent/IL49641A/en unknown
- 1976-05-31 ES ES448404A patent/ES448404A1/en not_active Expired
- 1976-06-01 ZA ZA763219A patent/ZA763219B/en unknown
- 1976-06-03 AR AR263501A patent/AR211019A1/en active
- 1976-06-09 SU SU762366005A patent/SU628819A3/en active
- 1976-06-10 CA CA254,573A patent/CA1071634A/en not_active Expired
- 1976-06-16 MX MX000320U patent/MX3224E/en unknown
- 1976-07-01 DK DK297876AA patent/DK141333B/en not_active IP Right Cessation
- 1976-07-01 PH PH7618641A patent/PH12311A/en unknown
- 1976-07-05 AT AT489876A patent/AT348526B/en not_active IP Right Cessation
- 1976-07-06 BE BE168664A patent/BE843822A/en not_active IP Right Cessation
- 1976-07-07 DE DE19762630474 patent/DE2630474A1/en active Pending
- 1976-07-07 DD DD193745A patent/DD125081A5/xx unknown
- 1976-07-07 SE SE7607762A patent/SE421699B/en not_active IP Right Cessation
- 1976-07-08 JP JP51081441A patent/JPS5236691A/en active Granted
- 1976-07-08 GB GB28511/76A patent/GB1544093A/en not_active Expired
- 1976-07-08 PL PL1976191016A patent/PL100685B1/en unknown
- 1976-07-09 HU HU76PA00001255A patent/HU172280B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GB1544093A (en) | 1979-04-11 |
| PT65072A (en) | 1976-06-01 |
| JPS5310077B2 (en) | 1978-04-11 |
| LU74674A1 (en) | 1976-09-01 |
| GR59812B (en) | 1978-03-01 |
| SU628819A3 (en) | 1978-10-15 |
| NL7605362A (en) | 1977-01-11 |
| DE2630474A1 (en) | 1977-01-13 |
| HU172280B (en) | 1978-07-28 |
| MX3224E (en) | 1980-07-28 |
| IL49641A (en) | 1978-08-31 |
| IE42821L (en) | 1977-01-09 |
| YU103076A (en) | 1982-02-28 |
| DK141333B (en) | 1980-02-25 |
| CH609349A5 (en) | 1979-02-28 |
| ZA763219B (en) | 1977-05-25 |
| PT65072B (en) | 1977-09-13 |
| AU1568676A (en) | 1977-03-31 |
| IE42821B1 (en) | 1980-10-22 |
| SE421699B (en) | 1982-01-25 |
| PH12311A (en) | 1979-01-16 |
| FR2317303B1 (en) | 1977-12-16 |
| BE843822A (en) | 1977-01-06 |
| DD125081A5 (en) | 1977-03-30 |
| DK297876A (en) | 1977-01-10 |
| ES448404A1 (en) | 1977-07-01 |
| DK141333C (en) | 1980-08-25 |
| YU40137B (en) | 1985-08-31 |
| PL100685B1 (en) | 1978-10-31 |
| SE7607762L (en) | 1977-01-10 |
| JPS5236691A (en) | 1977-03-22 |
| FR2317303A1 (en) | 1977-02-04 |
| AT348526B (en) | 1979-02-26 |
| AR211019A1 (en) | 1977-10-14 |
| ATA489876A (en) | 1978-07-15 |
| IL49641A0 (en) | 1976-07-30 |
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