CA1263866A - Process for the preparation of n-thienyl- chloroacetamides - Google Patents
Process for the preparation of n-thienyl- chloroacetamidesInfo
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Abstract
PROCESS FOR THE PREPARATION OF N-THIENYL-CHLOROACETAMIDES
Abstract of the Disclosure The invention provides compounds of formula I
I
wherein R is C1-4alkoxy-C2-4alkyl of which the C1-4alkoxy group is separated by at least 2 C-atoms from the N-atom to which R
is bound, each of R2 and R4 independently is CH3 or C2H5 and R5 is H or CH3, the preparation of such compounds and the use of such compounds for the preparation of N-(thien-3-yl)-chloroacetamides.
Abstract of the Disclosure The invention provides compounds of formula I
I
wherein R is C1-4alkoxy-C2-4alkyl of which the C1-4alkoxy group is separated by at least 2 C-atoms from the N-atom to which R
is bound, each of R2 and R4 independently is CH3 or C2H5 and R5 is H or CH3, the preparation of such compounds and the use of such compounds for the preparation of N-(thien-3-yl)-chloroacetamides.
Description
~ ~ti3 ~3~
-1- Case 130-3982 PROCESS FOR T~ PREPARATION OF N-THIENYL-CHLOROA~ETAMIDES
The present invention relates to novel tetrahydrothien-3-ylidenimines, their preparation and the use of such imines for the production of N-thienyl-chloroacetamides.
More specifically, the invention provides novel tetrahydrothiophen-imines of formula I R4 ~ NR
wherein R is Cl 4alkoxy-C2 4alkyl of which the Cl 4alkoxy group is separated by at least 2 C-atoms from the N-atom to which R is bound, each of R2 and R4 independently is CH3 or C2H5 and R5 is H or CH3.
It has been found that compounds of formula I can be readily dehydrogenated to compounds of formula II
R NH-R
4~ II
15 wherein R, R2, R4 and R5 are as defined above.
Compounds of formula II are known intermediates for the preparation of compounds of formula III R
R N ~
~ CO-CH2Cl III
R5 s 2 wherein R, R2, R4 and R5 are as defined above.
Compounds of formula III are known herbicides.
Compounds II and III are disclosed in UK Patent Specification
-1- Case 130-3982 PROCESS FOR T~ PREPARATION OF N-THIENYL-CHLOROA~ETAMIDES
The present invention relates to novel tetrahydrothien-3-ylidenimines, their preparation and the use of such imines for the production of N-thienyl-chloroacetamides.
More specifically, the invention provides novel tetrahydrothiophen-imines of formula I R4 ~ NR
wherein R is Cl 4alkoxy-C2 4alkyl of which the Cl 4alkoxy group is separated by at least 2 C-atoms from the N-atom to which R is bound, each of R2 and R4 independently is CH3 or C2H5 and R5 is H or CH3.
It has been found that compounds of formula I can be readily dehydrogenated to compounds of formula II
R NH-R
4~ II
15 wherein R, R2, R4 and R5 are as defined above.
Compounds of formula II are known intermediates for the preparation of compounds of formula III R
R N ~
~ CO-CH2Cl III
R5 s 2 wherein R, R2, R4 and R5 are as defined above.
Compounds of formula III are known herbicides.
Compounds II and III are disclosed in UK Patent Specification
2 114 566A. Said specification discloses several processes for the preparation of compounds of formula III, but none of the processes disclosed therein, or in other literature, allows the production of the compounds of formula III starting from readily available starting 25 materials.
i3 ~3~
The present invention discloses a very convenient route for the production of compounds of formula III.
One aspect of the invention is the preparation of a compound of formula II by dehydrogenation of a compound of formula I.
Said dehydrogenation may be effected catalytically or by oxydation with oxygen or with oxydation agents such as sulphur, sulphurylchloride and thionylchloride; it is preferably effected catalytically or with thionylchloride as oxydation agent. Particularly thionylchloride has been found surprisingly suitable for the dehydrogenation of csmpounds of formula I.
The catalytical dehydrogenation of a compound of formula I can be effected in the presence of any dehydrogenation catalyst. Examples of known dehydrogenation catalysts suitable for use in the dehydrogenation reaction of the invention are noble metals such as Pt or Pd, or other metals such as Cr203 or mixtures thereof with other metals such as CuO. The catalytical dehydrogenation can be carried out under the conditions known for such reactions. Where for example the catalyst is Pt, it is conveniently finely distributed on a carrier such as charcoal (e.g. 5% Pt/C~. The dehydrogenation reackion is then suitably carried out with heating, preferably at a temperature above 180C, e.g. at 220C or higher temperature, and under an inert gas atmosphere, such as a N2 blanket.
Compounds of formula I react - even below room temperature -with oxygen to form an intermediate product which decomposes on heating, usually at a temperature of ca. 100C or higher, to compounds of formula II. This conversion is conveniently performed in one step by oxydation above the decomposition point in a suitable solvent, e.g. an aromatic solvent such as toluene under reflux.
When applying an oxydation agent, the oxydation step is oonveniently effected in a solvent which is inert under the reaction conditions.
~X~;;3~ti~i
i3 ~3~
The present invention discloses a very convenient route for the production of compounds of formula III.
One aspect of the invention is the preparation of a compound of formula II by dehydrogenation of a compound of formula I.
Said dehydrogenation may be effected catalytically or by oxydation with oxygen or with oxydation agents such as sulphur, sulphurylchloride and thionylchloride; it is preferably effected catalytically or with thionylchloride as oxydation agent. Particularly thionylchloride has been found surprisingly suitable for the dehydrogenation of csmpounds of formula I.
The catalytical dehydrogenation of a compound of formula I can be effected in the presence of any dehydrogenation catalyst. Examples of known dehydrogenation catalysts suitable for use in the dehydrogenation reaction of the invention are noble metals such as Pt or Pd, or other metals such as Cr203 or mixtures thereof with other metals such as CuO. The catalytical dehydrogenation can be carried out under the conditions known for such reactions. Where for example the catalyst is Pt, it is conveniently finely distributed on a carrier such as charcoal (e.g. 5% Pt/C~. The dehydrogenation reackion is then suitably carried out with heating, preferably at a temperature above 180C, e.g. at 220C or higher temperature, and under an inert gas atmosphere, such as a N2 blanket.
Compounds of formula I react - even below room temperature -with oxygen to form an intermediate product which decomposes on heating, usually at a temperature of ca. 100C or higher, to compounds of formula II. This conversion is conveniently performed in one step by oxydation above the decomposition point in a suitable solvent, e.g. an aromatic solvent such as toluene under reflux.
When applying an oxydation agent, the oxydation step is oonveniently effected in a solvent which is inert under the reaction conditions.
~X~;;3~ti~i
-3- l30-3982 Examples of suitable solvents are chlorinated hydrocarbons, such as CH2Cl2 and hydrocarbons such as toluene or cyclohexane. Where the oxydation agent is sulphur, the oxydation reac~ion is suitably carried out with heating; where the oxydation agent is sulphuryl chloride or thionylchloride the reaction temperature is conveniently in the range of from -30C to +80C, e.g. at room temperature (about 20C
to 30C).
Thionylchloride is surprisingly suitable for use as oxydation agent in this reaction: the reaction can be carried out under mild reaction conditions and undesired side reactions (such as chlorination, further oxydation etc.) are not observed.
The thus obtained compounds of formula II are converted to compounds of formula III by N-chloroacetylation. Said N-chloroacetylation may be carried out according to procedures known for the preparation of chloroacetamides from the corresponding amines, e.g. under the condi-tions disclosed in UK Patent Specification 2 ll4 566~.
Where the compounds of formula I are oxydized with the aid of sulphurylchloride or thionylchloride, the compounds of formula II
will be obtained in the form of the hydrochloride acid addition salt.
Said hydrochloride can be reacted with chloroacetylchloride without prior isolation from the reaction mixture, and in the absence of a base, giving practically quantitative yields of compounds of formula III.
The compounds of formula I are readily obtained from the corres-ponding tetrahydrothiophen-3-ones of formula IV
R4 ~ IV
wherein R2, R4 and R5 are as defined above, by reaction with an amine of formula V
H2N-R (V) wherein R is as defined above.
~L~ 3 ~ 3
to 30C).
Thionylchloride is surprisingly suitable for use as oxydation agent in this reaction: the reaction can be carried out under mild reaction conditions and undesired side reactions (such as chlorination, further oxydation etc.) are not observed.
The thus obtained compounds of formula II are converted to compounds of formula III by N-chloroacetylation. Said N-chloroacetylation may be carried out according to procedures known for the preparation of chloroacetamides from the corresponding amines, e.g. under the condi-tions disclosed in UK Patent Specification 2 ll4 566~.
Where the compounds of formula I are oxydized with the aid of sulphurylchloride or thionylchloride, the compounds of formula II
will be obtained in the form of the hydrochloride acid addition salt.
Said hydrochloride can be reacted with chloroacetylchloride without prior isolation from the reaction mixture, and in the absence of a base, giving practically quantitative yields of compounds of formula III.
The compounds of formula I are readily obtained from the corres-ponding tetrahydrothiophen-3-ones of formula IV
R4 ~ IV
wherein R2, R4 and R5 are as defined above, by reaction with an amine of formula V
H2N-R (V) wherein R is as defined above.
~L~ 3 ~ 3
-4 l30-3982 Such condensakion reaction is conveniently effected in a solvent which is inert under the reaction conditions, such as cyclohexane or toluene. The reaction is preferably carried out with heating, e.g.
at reflux temperature. The reaction product is suitably dried e.g.
with the aid of a water trap or by an appropriate molecular sieve, e.g. of 5 A. This may be done continuously, by using a cooler, e.g.
a water cooler, and directing the condensate through a column comprising a molecular sieve, which is preferably protected by N2 to exclude atmospheric oxygen.
The above disclosed reaction route for the preparation of compounds of formula III from compounds of formula IV - via compounds of formula I and II may be effected in one and the same reaction vessel, i.e.
compounds of formula I and II may be obtained in good yields and need not be isolated from the reaction vessel for the next reaction step.
Compounds of formula IV are novel. They are readily obtained by cyclisation of compounds of formula VI
HOC0-CH(R2)-S-CH(R5~-CH(R4)COOH (VI) wherein R2, R4 and R5 are as defined above.
Such cyclisation can be carried out under the conditions of a Ruzicka cyclisation or modifications thereof.
The cyclisation is conveniently effected with heating; the presence of a condensation agent, such as 3a(0H)2, MnC03, Fe powder, acetates of Fe, CO(II) or Ni(II), acetic acid anhydride/LiCl or a tertiary amine e.g. a trialkylamine, promotes cyclisation. The use of Fe powder 2s or of acetates of Fe, CO(II) or Ni(II) as condensation agent is particularly advantageous.
The term acetates of Fe as used herein is intended to comprise Fe(II) and Fe(III) acetate compounds such as Fe(acetate)2 and Fe(OH)2-(acetate).
Compounds of Formula VI are also novel. They may be obtained from readily obtainable starting materials by addikion reaction of a compound of formula VII
~i3~
at reflux temperature. The reaction product is suitably dried e.g.
with the aid of a water trap or by an appropriate molecular sieve, e.g. of 5 A. This may be done continuously, by using a cooler, e.g.
a water cooler, and directing the condensate through a column comprising a molecular sieve, which is preferably protected by N2 to exclude atmospheric oxygen.
The above disclosed reaction route for the preparation of compounds of formula III from compounds of formula IV - via compounds of formula I and II may be effected in one and the same reaction vessel, i.e.
compounds of formula I and II may be obtained in good yields and need not be isolated from the reaction vessel for the next reaction step.
Compounds of formula IV are novel. They are readily obtained by cyclisation of compounds of formula VI
HOC0-CH(R2)-S-CH(R5~-CH(R4)COOH (VI) wherein R2, R4 and R5 are as defined above.
Such cyclisation can be carried out under the conditions of a Ruzicka cyclisation or modifications thereof.
The cyclisation is conveniently effected with heating; the presence of a condensation agent, such as 3a(0H)2, MnC03, Fe powder, acetates of Fe, CO(II) or Ni(II), acetic acid anhydride/LiCl or a tertiary amine e.g. a trialkylamine, promotes cyclisation. The use of Fe powder 2s or of acetates of Fe, CO(II) or Ni(II) as condensation agent is particularly advantageous.
The term acetates of Fe as used herein is intended to comprise Fe(II) and Fe(III) acetate compounds such as Fe(acetate)2 and Fe(OH)2-(acetate).
Compounds of Formula VI are also novel. They may be obtained from readily obtainable starting materials by addikion reaction of a compound of formula VII
~i3~
-5- l30-3982 H0-C0-CH(R2)-SH (VII) wherein R2 is as defined above, to a compound of formula VIII
R5-CH=C(R4)-COOH (VIII) wherein R4 and R5 are as defined above.
The addition of a compound of formula VII to a compound of formula VIII is conveniently effected under the conditions of a Michael addition or modifications thereof. The addition is conveniently effected with heating. The compound of formula VII may be used for example in its salt form (carboxylate salt), e.g. alkali metal salt form such as the Na carboxylate form. The compound of formula VII may however also be used in its free acid form, in which case the addition is conveniently effected in the presence of a tertiary amine, e.g. a trialkylamine such as tri(n-butyl)amine or of an acetate of Fe, CO(II) or Ni(II).
The latter process variante can be carried out in the absence of a solvent, the reaction proceeds fast with high yields, nonreacted starting material may be recovered and the compounds of formula VI may be cycli-sized to compounds of formula IV without necessitating the isolation of the compounds of formula VI.
R2 is preferably CH3. R4 is preferably CH3. R5 is preferably H. R signifies preferably CH(CH3)CH20CH3, CH2CH2-0-nC3H7 or CH2CH2-0-iC3H7, more preferably CH(CH3)-CH2-OCH3.
The following examples illustrate the invention. Temperatures are given in centigrade.
R5-CH=C(R4)-COOH (VIII) wherein R4 and R5 are as defined above.
The addition of a compound of formula VII to a compound of formula VIII is conveniently effected under the conditions of a Michael addition or modifications thereof. The addition is conveniently effected with heating. The compound of formula VII may be used for example in its salt form (carboxylate salt), e.g. alkali metal salt form such as the Na carboxylate form. The compound of formula VII may however also be used in its free acid form, in which case the addition is conveniently effected in the presence of a tertiary amine, e.g. a trialkylamine such as tri(n-butyl)amine or of an acetate of Fe, CO(II) or Ni(II).
The latter process variante can be carried out in the absence of a solvent, the reaction proceeds fast with high yields, nonreacted starting material may be recovered and the compounds of formula VI may be cycli-sized to compounds of formula IV without necessitating the isolation of the compounds of formula VI.
R2 is preferably CH3. R4 is preferably CH3. R5 is preferably H. R signifies preferably CH(CH3)CH20CH3, CH2CH2-0-nC3H7 or CH2CH2-0-iC3H7, more preferably CH(CH3)-CH2-OCH3.
The following examples illustrate the invention. Temperatures are given in centigrade.
-6- 130-3982 EXAMPLE 1 : N-(l-Methoxyprop-2-yl)-2,4-dimethyltetrahydrothien-3-yliden-imine A reaction flask is fitted with a thermometer, a water cooler and a column charged with 31 9 molecular sieve (5 ~).
A reaction flask is charged with a mixture of 0.2 mol of 2,4-di-methyltetrahydrothiophen-3-one, 0.225 mol of 1-methoxy-2-aminopropane and 50 ml of cyclohexane. The reaction flask is fitted with a thermometer a water cooler and a column charged with 31 9 molecular sieve (5 ~) in such a way, that the condensate of the boiling reaction mixture is directed continuously through the molecular sieve. The apparatus is protected by N2 to exclude atmospheric oxygen.
The reaction mixture is boiled during 9 hours. The title compounds is then vacuum distilled at 0.5 Torr at the boiling range of 65~0.
EXAMPLE 2: N-(l-Methoxyprop-2-yl)-2,4-dimethyl-3-aminothiophene 0.1 Mol thionylchloride dissolved in 20 ml toluene are added dropwise with stirring and cooling at 10-20 to a solution of 0.1 mol N-(l-methoxyprop-2-yl)-2,4-dimethyltetrahydrothien-3-ylidenimine in 80 ml.
The reaction mixture is stirred for 1 hour and then rendered alkaline with a conc. solution of caustic soda. The aqueous phase is separated off, the organic phase washed with water, dried and the toluene distilled off in vacuum. The residue is distilled at 0.2 Torr and yields the title cornpound, b.p. 70-72.
EXAMPLE 3: N-(-l-Methoxyprop-2-yl)-2,4-dimethylaminothiophene 0.01 Mol N-(l-methoxyprop-2-yl)-2,4-dimethyltetrahydrothien-3-yliden-imine are added dropwise, within 5 minutes to 0.013 mol sulphur powder in 2 ml boiling toluene (under reflux). The mixture is stirred under reflux for another 5 minutes and the crude residue distilled in a bulb tube, at 0.5 Torr and 150-170, whereby the title compound is obtained as a clear distillate.
~2~B~
A reaction flask is charged with a mixture of 0.2 mol of 2,4-di-methyltetrahydrothiophen-3-one, 0.225 mol of 1-methoxy-2-aminopropane and 50 ml of cyclohexane. The reaction flask is fitted with a thermometer a water cooler and a column charged with 31 9 molecular sieve (5 ~) in such a way, that the condensate of the boiling reaction mixture is directed continuously through the molecular sieve. The apparatus is protected by N2 to exclude atmospheric oxygen.
The reaction mixture is boiled during 9 hours. The title compounds is then vacuum distilled at 0.5 Torr at the boiling range of 65~0.
EXAMPLE 2: N-(l-Methoxyprop-2-yl)-2,4-dimethyl-3-aminothiophene 0.1 Mol thionylchloride dissolved in 20 ml toluene are added dropwise with stirring and cooling at 10-20 to a solution of 0.1 mol N-(l-methoxyprop-2-yl)-2,4-dimethyltetrahydrothien-3-ylidenimine in 80 ml.
The reaction mixture is stirred for 1 hour and then rendered alkaline with a conc. solution of caustic soda. The aqueous phase is separated off, the organic phase washed with water, dried and the toluene distilled off in vacuum. The residue is distilled at 0.2 Torr and yields the title cornpound, b.p. 70-72.
EXAMPLE 3: N-(-l-Methoxyprop-2-yl)-2,4-dimethylaminothiophene 0.01 Mol N-(l-methoxyprop-2-yl)-2,4-dimethyltetrahydrothien-3-yliden-imine are added dropwise, within 5 minutes to 0.013 mol sulphur powder in 2 ml boiling toluene (under reflux). The mixture is stirred under reflux for another 5 minutes and the crude residue distilled in a bulb tube, at 0.5 Torr and 150-170, whereby the title compound is obtained as a clear distillate.
~2~B~
-7- 130-3982 EXAMPLE 4 : N-(l-Methoxyprop-2-yl)-2,4-dimethylaminothiophene 0.1 Mol N-(l-methoxyprop-2-yl)-2,4-dimethyltetrahydrothien-3-yliden-imine are heated under N2 atmosphere with 2 9 5% Pt/charcoal at 200, during 11 hours. The catalyst is filtered off and the filtrate distilled at 0.1 Torr. The title compound is obtained at the boiling range of 68-71.
EXAMPLE S : N-(2,4-Dimethylthien-3-yl)-N-(l-methoxyprop-2-yl)-chloro acetamide a) Involving use of compound of formula II in salt form 0.02 Mol thionylchloride in 5 ml toluene are added dropwise, within 40 minutes, to 0.02 mol N-(l-methoxyprop-2-yl-)-2,4-dimethyltetra-hydrothien-3-ylidenimine, dissolved in 10 ml of toluene at 20. The reaction mixture is stirred for 2 hours whereby the hydrochloride of N-(-1-methoxyprop-2-yl)-2,4-dimethyl-3-aminothiophene is obtained.
Then are added 0.02 mol of chloroacetylchloride dissolved in 5 ml toluene. This mixture is heated during 1 hour at reflux, whereby HCl escapes. The title compound is obtained by column chromatography on silica gel with cyclohexane/ethyl acetate (8:2), b.p. 148-150/0.03 Torr.
b) Involving use of a compound of formula II in base form.
To a mixture of 315 9 (1.58 mol) N-(l-methyl-2-methoxy-ethyl)-2,4-dimethyl-3-aminothiophene in 1500 ml CH2Cl and 240 9 (1.75 mol) of K2C03 in 250 ml H20 are added dropwise, at room temperature, and while stirring vigorously, 200 9 (1.77 mol) of chloroacetylchloride.
After half an hour's reaction time at room temperature, the organic phase is separated off, washed with water (2 x 200 ml), dried over Na2S04 and concentrated by evaporation.
The title compounds is obtained by chromatography on silica gel with hexane/diethylether 85:15.Rf = 0.3 (silica gel; diethylether/hexane 2:1) b.p. 148-150/0.03 Torr.
~2~j38~
EXAMPLE S : N-(2,4-Dimethylthien-3-yl)-N-(l-methoxyprop-2-yl)-chloro acetamide a) Involving use of compound of formula II in salt form 0.02 Mol thionylchloride in 5 ml toluene are added dropwise, within 40 minutes, to 0.02 mol N-(l-methoxyprop-2-yl-)-2,4-dimethyltetra-hydrothien-3-ylidenimine, dissolved in 10 ml of toluene at 20. The reaction mixture is stirred for 2 hours whereby the hydrochloride of N-(-1-methoxyprop-2-yl)-2,4-dimethyl-3-aminothiophene is obtained.
Then are added 0.02 mol of chloroacetylchloride dissolved in 5 ml toluene. This mixture is heated during 1 hour at reflux, whereby HCl escapes. The title compound is obtained by column chromatography on silica gel with cyclohexane/ethyl acetate (8:2), b.p. 148-150/0.03 Torr.
b) Involving use of a compound of formula II in base form.
To a mixture of 315 9 (1.58 mol) N-(l-methyl-2-methoxy-ethyl)-2,4-dimethyl-3-aminothiophene in 1500 ml CH2Cl and 240 9 (1.75 mol) of K2C03 in 250 ml H20 are added dropwise, at room temperature, and while stirring vigorously, 200 9 (1.77 mol) of chloroacetylchloride.
After half an hour's reaction time at room temperature, the organic phase is separated off, washed with water (2 x 200 ml), dried over Na2S04 and concentrated by evaporation.
The title compounds is obtained by chromatography on silica gel with hexane/diethylether 85:15.Rf = 0.3 (silica gel; diethylether/hexane 2:1) b.p. 148-150/0.03 Torr.
~2~j38~
-8- 130-3982 EXAMPLE 6 : 2,4-Dimethyltetrahydrothiophen-3-one Cyclisation of 2,5-dimethyl-3-thiaadipic acid a) With Fe powder 100 Parts of 2,5-Dimethyl-3-thiaadipic acid are heated at 180-220 with 7.5 parts of iron powder. The thus obtained distillate is dissolved in CH2C12, washed with saturated aqueous NaHC03 solution, dried over Na2504. The title compound is distilled at 2 Torr, at a temperature of 39 40o.
b) With Ba (OH)2.
A mixture of 0.94 mol of 2,5-dimethyl-3-thiaadipic acid and 109 of Ba(OH)2 is heated during 24 hours in a distillation flask, at 230-250, with stirring. The distillate is extracted with diethylether, the ether solution dried (over MgS04) and distilled under reduced pressure b.p. 39-40 at 2 Torr.
c) With acetic acid anhydride.
0.5 Mol of 2,5-dimethyl-3-thiaadipic acid, 300 ml of acetic acid anhydride and 49 LiCl is stirred for 6 hours at 120. The crude mixture is poured onto ice, and 10 cm3 H2S04 conc. are added thereto. The mixture is then stirred overnight, rendered alkaline with conc. NaOH
solution, while cooling with pieces of ice, and extracted several times with diethylether. The ether phase is washed with water, dried over MgSO~ and concentrated by evaporation. The residue is distilled over a Vigreux column to give the title compound b.p. 81-88 at 20 Torr.
EXAMPLE 7 : 2,5-Dimethyl-3-thiaadipic acid To a solution of 320 9 (8 mol) NaOH in 1300 ml water are added within lS minutes, 424 g (4 mol) of thiolactic acid. After decay of the exother-mic reaction (35) are added 344 g (4 mol) of methacrylic acid and the reaction mixture is then stirred for 18 hours at 80.
The mixture is cooled to 50, poured onto a mixture of 3 kg of ice and 750 ml of concentrated HCl and extracted with 4 1000 ml portions ,6
b) With Ba (OH)2.
A mixture of 0.94 mol of 2,5-dimethyl-3-thiaadipic acid and 109 of Ba(OH)2 is heated during 24 hours in a distillation flask, at 230-250, with stirring. The distillate is extracted with diethylether, the ether solution dried (over MgS04) and distilled under reduced pressure b.p. 39-40 at 2 Torr.
c) With acetic acid anhydride.
0.5 Mol of 2,5-dimethyl-3-thiaadipic acid, 300 ml of acetic acid anhydride and 49 LiCl is stirred for 6 hours at 120. The crude mixture is poured onto ice, and 10 cm3 H2S04 conc. are added thereto. The mixture is then stirred overnight, rendered alkaline with conc. NaOH
solution, while cooling with pieces of ice, and extracted several times with diethylether. The ether phase is washed with water, dried over MgSO~ and concentrated by evaporation. The residue is distilled over a Vigreux column to give the title compound b.p. 81-88 at 20 Torr.
EXAMPLE 7 : 2,5-Dimethyl-3-thiaadipic acid To a solution of 320 9 (8 mol) NaOH in 1300 ml water are added within lS minutes, 424 g (4 mol) of thiolactic acid. After decay of the exother-mic reaction (35) are added 344 g (4 mol) of methacrylic acid and the reaction mixture is then stirred for 18 hours at 80.
The mixture is cooled to 50, poured onto a mixture of 3 kg of ice and 750 ml of concentrated HCl and extracted with 4 1000 ml portions ,6
-9- 130-3982 of CH2C12. The CH2C12 extracts are dried with Na2S04 and the organic phase then concentrated by rotary flash evaporation, yielding the title compound of m.p. 78-80 in the form of colourless crystals.
EXAMPLE 8 : 2,5-Dimethyltetrahydrothiophen-3-on a) With tertiary amine To a mixture of 0.2 mol thiolactic acid and 0.2 mol methacrylic acid are added dropwise 0.2 mol tributylamine, whereby the reaction temperature rises up to 60. The reaction mixture is then heated for 1 hour at 150-160 and thereafter at 210-220. Under these conditions distills a mixture of the title compound, water and tributylamine at 150-170 over, which is dissolved in ethyl acetate, diluted with water and neutralised with 10 % ~Cl. The organic phase is extracted with 2N NaOH, washed neutral, dried and concentrated by evaporation.
The residue is distilled at 15 Torr, yielding the title compound at the boiling range of 70-73.
b) With Fe(II) acetate A mixture of 85.9 9 thiolactic acid, 70.0 9 methacrylic acid and 0.8 9 Fe acetate is stirred and heated to 150-160 for 1 hour.
Then another 0.8 9 Fe acetate are added and the temperature is raised to 200-210C for 2 hours to yield 103.9 9 of a distillate. This is dissolved in 200 ml cyclohexane, made alkaline with sodium hydroxide and separated in a separation funnel. The aqueous phase is extracted with 100 ml cyclohexane. The combined organic layers are washed with water, dried over MgS04 and evaporated at 15 Torr to yield the title compound.
The aqueous layer is acidified with hydrochloric acid and extracted with methylenechloride. The extract is washed with water, dried with MgS04, evaporated at 15 Torr to yield 10.6 9 of a mixture of methacrylic acid and thiolactlc acid in the ratio 2:1.
-lo- 130-3982 EXAMPLE 9 : N^(l-methoxyprop-2-yl)-2,4dimethyl-3-aminothiophene A solution of 2 9 (0.01 mol) N-(l-methoxyprop-2-yl)-2,4-dimethyltetrahydrothien-3-ylidenimine in 3 9 carbon tetrachloride is stirred for 1 hour at room temperature under an atmosphere of oxygen.
200 ml of 2 are consumed. The NMR-spectrum of the solution shows no signals for aromatic protons. Then the product is distilled in a bulb tube at 0.2 Torr and 150-180 air temperature to yield the title compound.
EXAMPLE 8 : 2,5-Dimethyltetrahydrothiophen-3-on a) With tertiary amine To a mixture of 0.2 mol thiolactic acid and 0.2 mol methacrylic acid are added dropwise 0.2 mol tributylamine, whereby the reaction temperature rises up to 60. The reaction mixture is then heated for 1 hour at 150-160 and thereafter at 210-220. Under these conditions distills a mixture of the title compound, water and tributylamine at 150-170 over, which is dissolved in ethyl acetate, diluted with water and neutralised with 10 % ~Cl. The organic phase is extracted with 2N NaOH, washed neutral, dried and concentrated by evaporation.
The residue is distilled at 15 Torr, yielding the title compound at the boiling range of 70-73.
b) With Fe(II) acetate A mixture of 85.9 9 thiolactic acid, 70.0 9 methacrylic acid and 0.8 9 Fe acetate is stirred and heated to 150-160 for 1 hour.
Then another 0.8 9 Fe acetate are added and the temperature is raised to 200-210C for 2 hours to yield 103.9 9 of a distillate. This is dissolved in 200 ml cyclohexane, made alkaline with sodium hydroxide and separated in a separation funnel. The aqueous phase is extracted with 100 ml cyclohexane. The combined organic layers are washed with water, dried over MgS04 and evaporated at 15 Torr to yield the title compound.
The aqueous layer is acidified with hydrochloric acid and extracted with methylenechloride. The extract is washed with water, dried with MgS04, evaporated at 15 Torr to yield 10.6 9 of a mixture of methacrylic acid and thiolactlc acid in the ratio 2:1.
-lo- 130-3982 EXAMPLE 9 : N^(l-methoxyprop-2-yl)-2,4dimethyl-3-aminothiophene A solution of 2 9 (0.01 mol) N-(l-methoxyprop-2-yl)-2,4-dimethyltetrahydrothien-3-ylidenimine in 3 9 carbon tetrachloride is stirred for 1 hour at room temperature under an atmosphere of oxygen.
200 ml of 2 are consumed. The NMR-spectrum of the solution shows no signals for aromatic protons. Then the product is distilled in a bulb tube at 0.2 Torr and 150-180 air temperature to yield the title compound.
Claims (14)
1. Process for the preparation of a compound of formula II
II
wherein R is C1-4alkoxy-C2-4alkyl of which the C1-4alkoxy group is separated by at least 2 C-atoms from the N-atom to which R is bound, each of R2 and R4 independently is CH3 or C2H5 and R5 is H or CH3, which comprises dehydrogenating a compound of formula I
I
wherein R, R2, R4 and R5 are as defined in this claim.
II
wherein R is C1-4alkoxy-C2-4alkyl of which the C1-4alkoxy group is separated by at least 2 C-atoms from the N-atom to which R is bound, each of R2 and R4 independently is CH3 or C2H5 and R5 is H or CH3, which comprises dehydrogenating a compound of formula I
I
wherein R, R2, R4 and R5 are as defined in this claim.
2. Process according to Claim 1, for the preparation of a compound of formula III
III
wherein R, R2, R4 and R5 are as defined in Claim 1, which comprises dehydrogenating a compound of formula I to a compound of formula II and N-chloroacetylating the thus obtained compound of formula II.
III
wherein R, R2, R4 and R5 are as defined in Claim 1, which comprises dehydrogenating a compound of formula I to a compound of formula II and N-chloroacetylating the thus obtained compound of formula II.
3. Process according to Claim 1,wherein the compounds of formula I are obtained by reaction of tetrahydrothiophen-3-ones of formula IV
IV
wherein R2, R4 and R5 are as defined in Claim 1, with an amine of formula V
wherein R is as defined in Claim 1.
IV
wherein R2, R4 and R5 are as defined in Claim 1, with an amine of formula V
wherein R is as defined in Claim 1.
4. Process according to Claim 3, wherein the compounds of formula IV are obtained by cyclisation of a compound of formula VI
HO-CO-CH(R2)-S-CH(R5)-CH(R4)COOH VI
wherein R2, R4 and R5 are as defined in Claim 3.
HO-CO-CH(R2)-S-CH(R5)-CH(R4)COOH VI
wherein R2, R4 and R5 are as defined in Claim 3.
5. Processes according to Claim 4, wherein the compounds of formula VI are obtained by addition of a compound of formula VII
HO-CO-CH(R2)SH VII
wherein R2 is as defined in Claim 1, to a compound of formula VIII
R5-CH=C(R4)COOH VIII
wherein R4 and R5 are as defined in Claim 1.
HO-CO-CH(R2)SH VII
wherein R2 is as defined in Claim 1, to a compound of formula VIII
R5-CH=C(R4)COOH VIII
wherein R4 and R5 are as defined in Claim 1.
6. Process according to Claim 4, wherein the addition of a compound of formula VII to a compound of formula VIII, and the cyclisation of a compound of formula VI are carried out in the presence of a tert.
amine or of an acetate of Fe , Ni(II) or Co(II).
amine or of an acetate of Fe , Ni(II) or Co(II).
7. Process according to Claim 6, wherein the addition and cyclisation reaction are carried out in the presence of an acetate of Fe, Ni(II) or Co(II).
8. Process according to Claim 1, wherein the dehydrogenation of a compound of formula I is effected catalytically with O2 or with an oxydation agent.
9. Process according to Claim 8, wherein the dehydrogenation is effected catalytically.
Process according to Claim 8, wherein the dehydrogenation is effected with an oxydation agent.
11. Process according to Claim 10,wherein the oxydation agent is selected from sulphur, thionylchloride and sulphurylchloride.
12. Process according to Claim 11, wherein the oxydation agent is thionylchloride.
13. Process according to Claim 1, wherein the compound of formula II is chlorodcetylated in hydrochloride form.
14. Process according to Claim 1 for the preparation of N-(2,4-di-methylthien-3-yl)-N-(1-methoxyprop-2-yl)-chloroacetamide which comprises dehydrogenating N-(1-methoxyprop-2-yl)-2,4-dimethyltetrahydrothien-3-yli-denimine and N-chloroacetylating the thus obtained compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000487848A CA1263866A (en) | 1983-12-20 | 1985-07-31 | Process for the preparation of n-thienyl- chloroacetamides |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH6760/83A CH657129A5 (en) | 1983-12-20 | 1983-12-20 | Process for preparing N-thienylchloroacetamides |
| CA000487848A CA1263866A (en) | 1983-12-20 | 1985-07-31 | Process for the preparation of n-thienyl- chloroacetamides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1263866A true CA1263866A (en) | 1989-12-12 |
Family
ID=25670757
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000487848A Expired CA1263866A (en) | 1983-12-20 | 1985-07-31 | Process for the preparation of n-thienyl- chloroacetamides |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1263866A (en) |
-
1985
- 1985-07-31 CA CA000487848A patent/CA1263866A/en not_active Expired
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