CA1055946A - Process for preparing pyridine derivatives with a fused carbocyclic ring - Google Patents
Process for preparing pyridine derivatives with a fused carbocyclic ringInfo
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Abstract
PROCESS FOR PREPARING
PYRIDINE DERIVATIVES
WITH A FUSED CARBOCYCLIC RING
ABSTRACT
The invention concerns a novel process for preparing 5,6,7,8-tetrahydroquinolines and related compounds substituted by a monosubstituted thioamide group in which a metal derivative of the 5,6,7,8,-tetrahydroquinoline or related compound is re-acted with an alkyl, aryl or aralkyl isothiocyanate and the product is treated with hydrogen ions. The compounds produced by the process of the invention are anti-ulcer agents.
PYRIDINE DERIVATIVES
WITH A FUSED CARBOCYCLIC RING
ABSTRACT
The invention concerns a novel process for preparing 5,6,7,8-tetrahydroquinolines and related compounds substituted by a monosubstituted thioamide group in which a metal derivative of the 5,6,7,8,-tetrahydroquinoline or related compound is re-acted with an alkyl, aryl or aralkyl isothiocyanate and the product is treated with hydrogen ions. The compounds produced by the process of the invention are anti-ulcer agents.
Description
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, 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
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
R --f=---__ ~ ~ (III) (CH~N J~ 1 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 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 ~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%.)
The process of the present invention relates to the preparation of novel compounds of formula I, 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
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
R --f=---__ ~ ~ (III) (CH~N J~ 1 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 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 ~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%.)
Claims (12)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of formula I
(I) 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 alkyl of 1-6 carbon atoms, m is 1, 2 or 3 and R4 is an alkyl radical of 1-6 carbon atoms, which process comprises treating a compound of formula II
(II) wherein R1, R2, R6, R7 and m are as defined in connection with formula I above and M is sodium, potassium, lithium, or MgHal where Hal is chlorine, bromine or iodine, with an isothiocyanate of formula R4NCS wherein R4 is as defined in connection with formula I and treating the product with hydrogen ions.
(I) 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 alkyl of 1-6 carbon atoms, m is 1, 2 or 3 and R4 is an alkyl radical of 1-6 carbon atoms, which process comprises treating a compound of formula II
(II) wherein R1, R2, R6, R7 and m are as defined in connection with formula I above and M is sodium, potassium, lithium, or MgHal where Hal is chlorine, bromine or iodine, with an isothiocyanate of formula R4NCS wherein R4 is as defined in connection with formula I and treating the product with hydrogen ions.
2. A process as claimed in Claim 1,wherein a compound of formula II in which M is lithium or MgBr is used.
3. A process as claimed in Claim 1, wherein the product after reaction with R4NCS is treated with an aqueous mineral acid.
4. A process as claimed in Claim 3, wherein the mineral acid is a hydrohalic acid.
5. A process as claimed in Claim 4, wherein the mineral acid is hydrochloric acid.
6. A process as claimed in Claim 1, characterised in that the isothiocyanate is one in which R4 is a lower alkyl radical.
7. A process as claimed in Claim 6, wherein the isothiocyanate is methylisothiocyanate.
8. A process as claimed in Claim 1 characterised in that the starting material of formula II is bicyclic.
9. A process as claimed in Claim 8, wherein the starting material of formula II is a 5,6,7,8-tetrahydro-quinoline.
10. A process as claimed in Claim 8, wherein the starting material of formula II is one in which R1, R2 and R6 are selected from hydrogen and lower alkyl and R7 is hydrogen.
11. A process as claimed in Claim 10, wherein the starting material of formula II is one in which R1, R2, and R6 are selected from hydrogen and methyl.
12. A process as claimed in claim 1, wherein the starting material of formula II is tricyclic and m and n are equal.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA251,040A CA1055946A (en) | 1976-04-22 | 1976-04-22 | Process for preparing pyridine derivatives with a fused carbocyclic ring |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA251,040A CA1055946A (en) | 1976-04-22 | 1976-04-22 | Process for preparing pyridine derivatives with a fused carbocyclic ring |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1055946A true CA1055946A (en) | 1979-06-05 |
Family
ID=4105782
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA251,040A Expired CA1055946A (en) | 1976-04-22 | 1976-04-22 | Process for preparing pyridine derivatives with a fused carbocyclic ring |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1055946A (en) |
-
1976
- 1976-04-22 CA CA251,040A patent/CA1055946A/en not_active Expired
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