CA1228073A - Method for the synthesis of 5-thio-1,2,3- thiadiazole - Google Patents
Method for the synthesis of 5-thio-1,2,3- thiadiazoleInfo
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Abstract
ABSTRACT OF THE DISCLOSURE
This disclosure describes a novel process for the syn-thesis of 5-mercapto-1,2,3-thiadiazoles which are useful as intermediates in the preparation of antibacterial agents.
Case No. 28,725 DIV I
This disclosure describes a novel process for the syn-thesis of 5-mercapto-1,2,3-thiadiazoles which are useful as intermediates in the preparation of antibacterial agents.
Case No. 28,725 DIV I
Description
~8~713 This application is a divisional application from Canadian Patent ~pplication 437,550, filed September 26, 1983.
BRIEF SUl~RY OF THE INVENTION
.
This invention relates to a novel method for the preparation of 5-mercapto-1,2,3-thiadiazoles and, more particu-larly, is concerned with a synthetic process as set forth by the following reaction scheme:
~2~ 3 Rl-NH-NH2 + R2-C-CH2-X
(I) (II) \ / R2 Rl-NH-] ~=C-CH2-X + M-$-cH2cH2co2R3 - -- -(III) (IV~
Rl-NH-NH2 + R2-c-cH2-s-cH2cH2co2R3 (I) ~ (VII) (VI) --Rl-NH-N=C ~CH2-S-CH2CH2C02R3,~ .~. . ..
(V) N~ ,C - S-CH2CH2C02R3 (Vl I I ) ~ I X ) 7;~
wherein Rl is para-toluenesulfonyl, carbamoyl or car-boalkoxy having from two to four carbon atoms; R2 is hy-drogen or methyl; R3 is alkyl having up to three carbon atoms; X ;s chloro, bromo or iodo; and M is sodium or potassium. In àccordance with the above reaction scheme;
an appropriately substituted hydrazine (I) is condensed with an appropriately substituted ~-haloacetaldehyde (II) to provide the corresponding ~-haloacetaldehyde hydrazone (III). This condensation is readily carried out in a~ueous solution in the presence of sodium acetate at ambient temperatures for a period of several hours. The hydrazone (III) is then reacted with an alkyl thiopro-panoate salt (IV) in a lower alkanol as solvent at the reflux temperature thereof for several hours whereby the corresponding alkyl 3-(formylmethylthio)propanoate hydra-zone (V) is obtained.
Alternatively, an alkyl 3-thiopropanoate sodium salt of the formula Na-S-CH2CH2CO2R3 is condensed with a l,l-dialkoxyethyl bromide of the formula (R30)2CR2C~2Br in a solvent such as methanol at the reflux temperature for several hours to provide the corresponding alkyl 3--[(2-dialkoxyethyl)thio]propanoate (VI~. Removal of the solvent and extraction into ethyl aceta~e provides the purified derivative (VI) which is then hydrolyzed in dilute (l~/o) hydrochloric acid at ambient temperatures to provide the corresponding alXyl 3-1(2-oxoethyl)thio]-propanote (VII). Condensation of (VII) with an appropri-ately substituted hydrazine (I) under nitrogen for several hours in ethanol at the reflux temperature~ followed by extraction in ethyl acetate and purification by column chromatography on silica gel using ethyl acetate:hexane as eluant provides the corresponding alkyl 3--(formylmethylthio~propanoate hydrazone (~
Cyclization of (V) is accomplished with thionyl chloride and triethylamine in methylene chloride for a few hours at ambIent temperatures. Purification by chroma-tography on silica gel using the system hexane:ethyl acetate (4:1) provides the corresponding 5-alkoxy car-bonylethylthio-1,2,3-thiadiazole (VIII). Treatment of (VIII) with sodium or potassium methoxide in methanol at ambient temperatures for an hour or so follos~ed by pre-cipitation with diethyl ether provides the 5-mercapto--1,2,3-thiadiazole alkali metal salt (IX).
The 5-mercapto-1,~,3-thiadiazole potassium salt is disclosed in J. Heterocyclic Chemistry 15, 1298 (1978).
Its utility is disclosed in J. ~ed. Chem. 22, 1214 ~1979) where it is employed to form a derivative of 7-amino-cephalosporanic acid having activity as an antibacterial agent. The presently disclosed method provides a means of making the 1,2,3-thiadiazoles in higher yield and by a more convenient method which does not use diazomethane and thiophosgene and also does not give the isomeric 1,3,4-thiadiazole.
The invention will be described in greater detail in conjunction with the following specific examples.
Example 1 Methyl 3-(2-dietnoxyethylthio)propanoate A 12.05 g. portion of methyl 3-thiopropanoate is dissolved in 50 ml. of methanoi. A 5.4 g. portion of sodium methoxide is added in portions with stirring. A
19.7 g. portion of l,l-diethoxyethyl bromide is added dropwise, then the solution is refluxed for 3 hours during which time a precipitate forms. The suspension is con-centrated in vacuo until the methanol is removed and then the residue is distributed between 50 ml. each of water and ethyl acetate. The aqueous layer is extracted again with ethyl acetate and the combined organic extracts are dried and concentrated to an oily residue which is dis-tilled in vacuo, [b.p. 109-112C. (0.6-0.7 mm. Hg.)]
giving 12.3 g. of the desired compound.
Examele 2 Chloroacetaldehyde semicarbazone _ A 34.9 g. portion of a 45% aqueous solution of chloroacetaldehyde is diluted with 100 ml. of water and then filtered. The filtrate is added to a solution of 22.2 g. of semicarbazide hydrochloride and 30 g. of sodium acetate trihydrate in 100 ml. of water. The mixture is stirred and then allowed to stand overnight. The solid is collected, washed with water, dried and recrystallized from ethanol giving the desired compound, m.p. 133-135C.
(dec.).
Example 3 M hyl 3-(formylmethylthio~ro~anoate semicarbazone A mixture of 1.08 g. of sodium methoxide, 2.4 g.
of methylthiopropanoate and 2.72 g. of chloroacetaldehy~e semicarbazone in 40 ml. of methanol is stirred and re-fluxed for 4-5 hours. The mixture is filte,ed and the filtrate concentrated to an oil .~hich .s puriC ed by chromatography on silica gel, givin~ the desired compound.
3~ 3 Example 4 Methyl 3-(formylmethylthio)-propanoate A mixture of 13.2 g. of methyl 3-[(2-diethoxy-ethyl~thio~-propanoate and 200 ml. of 1% hydrochloric acid is stirred, under nitrogen, for 4 hours. The solution is decanted from a small amount of insoluble oil, adjuste~
to pH 4.5 with sodium acetate and extracted with four lO0 ml. portions of ethyl acetate. The combined extracts are dried over magnes;um sulfate and then evaporated, giving 8.2 g. of the desired compound as a colorless oil.
Example 5 Methyl 3-(formylmethYlthio)-propanoate semicarbazone A mixture of 6.7 g. of semicarbazide hydro-chloride and 6.7 g. of sodium acetate in 50 ml. of ethanol is refluxed for lO minutes, then filtered while ho~ and 10.6 g. of methyl 3-(formylmethylthio)-propanoate is added to the filtrate. This solution is refluxed for one hour, then cooled and diluted with 200 ml. of water. The mix-ture is extracted with three 100 ml. of portions of ethyl acetate. The organic extracts are combined~ washed with brine, dried over magnesium sulfate and eYaporated, giving 11.8 g. of the desired compound as an amber oil.
Example 6 Meth 1 (3-form lmeth lthio) ro anoate ethox carbonvl-Y . Y Y P P Y
hydrazone A 100 ml. portion of 1% hydrochloric acid is purged with nitrogen for lO minutes and then added to 4.73 g. of methyl 3-(2-diethoxyethylthio)propanoate.
Nitrogen is bubbled into this mixture for 5 minutes then the flask is stoppered and stirred for 17 hours. Tne pH
of the solution is raised to 4.2 with saturated aqueous sodium acetate and 7..08 g. of ethyl carbazate in 8 ml. of water is added. The solution is briefly flushed with nitrogen~ then stoppered and stirred for 2 hours and then extracted with two 100 ml. portions of ethyl acetate. The combined extracts are dried and evaporated to 5.09 g. of ~ ~28~3~3 an oil. This oil is chromatographed on a 200 g. silica gel column using ethyl acetate:hexane (1:1) as eluant and collecting fractions of 100 ml. each. Fractions 8-13, containing the desired component are combined and evapor-ated, giving 1.8 g. of an oil which crystallizes on standing.
Certain variations of the above procedure may be used to derive the desired product.
A) Hydrolysis of 5.9 g. of methyl 3-(2-di-ethoxyethylthio)propanoate is carried out for 3 hours, under nitrogen in 100 ml. of 1% hydrochloric acid. Re-moval by pipette of a small quantity of un~issolved oil, followed by reaction of the solution with 2.6 g. of ethyl carbazate for 2 hours gives, after workup as described above, 6.11 g. of crude product.
B) The syrup from workup of a 10 mmole run is treated with ether to precipitate some of the undesired lower Rf component and the residue is chromatographed as described above.
Example 7 Methyl 3-(formylmethylthio)-propanoate p-toluenesulfonyl hydrazone A mixture of 8.2 g. of methyl 3-(formyl-methylthio)-propanoate and 9.4 g. of p-toluenesulfonyl-hydrazide in 75 ml. of ethanol is refluxed for 2 hours, ~hen chilled and the desired compound is collected by filtration giving 5.4 g., m.p. 94-96C.
Example 8 5-Methoxycarbonylethylthio-1,2,3-thiadiazole A 0.5 g. portion of methyl 3-(formylmethylthio)--propanoate p-toluenesulfonyl hydrazone is added to 4 ml.
of thionyl chloride and allowed to react for 30 minutes.
The mixture is evaporated to dryness, the residue dis-solved in methylene chloride and again evaporated. This crude product is purified by thick layer chrQmatography giving 18~ mg. of the desired compound.
~73 Example _ 5-Methoxycarbonylethylthio-1,2,3-thiadiazole A solution of 2.40 ml. of thionyl chloride in 3 ml. o~ methylene chloride is added rapidly, dropwise to a stirred solution of 8.23 g. of methyl (3-formylmethyl-thio)propanoate ethoxycarbonylhydrazone and 9.25 ml. oftriethylamine in 25 ml. of methylene chloride. After 30 minutes, 2.4 ml. of thionyl chloride is added rapidly, dropwise. After 60 minutes, 2.4 ml. of thionyl chloride îs again added as above. After a total reaction time of 1~ 2 hours, the mixture is evaporated at reduced pressure and with mild heat. Ether is added to the residue which is then filtered. The filtrate is evaporated to a residue which is chromatographed on 500 g. of silica gel using hexane:ethyl acetate (4:1) and collecting Eractions of 50 ml. each. Fractions 10-21 are collected, pooled and evaporated, giving 3.13 g. of the desired compound as an oil.
It is also possible to perform this reaction with another inert solvent such as eoluene or without a solvent. Also, the triethylamine can be omitted and the molar equivalents of thionyl chloride can be reduced, but yields will be less.
Example 10 5-Methoxycarbonylethylthio-1,2,3-thiadia~ole 2i A 177.5 g. porcion or methyl 3-(formylmethyl-thio)-propanoate semicarbazone is diluted with 100 ml. of dry methylene chloride and this is added, fairly rapidlv.
using a dropping funnel, ~o 875 ml. of thionyl chloride with rapid stirring which is continued for 2 hours after addition is complete. The thionyl chloride is then re-moved under reduced pressure and two portions of methylene chloride are added and removed under reduced press re.
The residue is dissolved in ethyl acetate, filtered and the filtrate washed first with saturated aqeuous sodium bicarbonate and then with brine. The solu~ion is dried over ~a~nesium sulfate, an e~ual volume of hexane is added ~f~8~3 and the solution is filtered through a silica gel pad topped with diatomaceous earth. The pad is washed with a 1:1 solution of ethyl acetate and hexane and this wash is concentrated under reduced pressure to an oil. The oil is dissolved in 100 ml. of a 20% ethyl acetate in hexane solution. One half of this solution is injected onto a Waters Prep 500 HPLC, using two prepacked columns and eluted with a solution of 12.5% ethyl acetate in hexane containing 1% methanol. After 2.5 liters of solvent has been eluted (one liter being the void volume), fractions 3-7 (containing approximately 3 liters of eluent) are combined and concentrated under reduced pressure. This procedure is repeated-with the other half of the solution of the product. Total yield is 57.8 g. of the desired compound.
Example 11 Sodium 1,2,3-thiadiazole-5-thiolate A solution of 756 mg. of sodium methoxide in 20 ml. of methanol is added to a solution of 3.13 g. of S-methoxycarbonylethylthio-1,2,3,-thiadiazole in 30 ml. of methanol. After 45 minutes, the reaction solution is evaporated in vacuo to about S ml. A 3 ml. portion of methanol is added and then about 15 ml. of ether causing precipitation of a solid. This solid is collected, washed with ether, dried and recrystallized from methanol-ether, giving 1.94 g. of the desired product.
BRIEF SUl~RY OF THE INVENTION
.
This invention relates to a novel method for the preparation of 5-mercapto-1,2,3-thiadiazoles and, more particu-larly, is concerned with a synthetic process as set forth by the following reaction scheme:
~2~ 3 Rl-NH-NH2 + R2-C-CH2-X
(I) (II) \ / R2 Rl-NH-] ~=C-CH2-X + M-$-cH2cH2co2R3 - -- -(III) (IV~
Rl-NH-NH2 + R2-c-cH2-s-cH2cH2co2R3 (I) ~ (VII) (VI) --Rl-NH-N=C ~CH2-S-CH2CH2C02R3,~ .~. . ..
(V) N~ ,C - S-CH2CH2C02R3 (Vl I I ) ~ I X ) 7;~
wherein Rl is para-toluenesulfonyl, carbamoyl or car-boalkoxy having from two to four carbon atoms; R2 is hy-drogen or methyl; R3 is alkyl having up to three carbon atoms; X ;s chloro, bromo or iodo; and M is sodium or potassium. In àccordance with the above reaction scheme;
an appropriately substituted hydrazine (I) is condensed with an appropriately substituted ~-haloacetaldehyde (II) to provide the corresponding ~-haloacetaldehyde hydrazone (III). This condensation is readily carried out in a~ueous solution in the presence of sodium acetate at ambient temperatures for a period of several hours. The hydrazone (III) is then reacted with an alkyl thiopro-panoate salt (IV) in a lower alkanol as solvent at the reflux temperature thereof for several hours whereby the corresponding alkyl 3-(formylmethylthio)propanoate hydra-zone (V) is obtained.
Alternatively, an alkyl 3-thiopropanoate sodium salt of the formula Na-S-CH2CH2CO2R3 is condensed with a l,l-dialkoxyethyl bromide of the formula (R30)2CR2C~2Br in a solvent such as methanol at the reflux temperature for several hours to provide the corresponding alkyl 3--[(2-dialkoxyethyl)thio]propanoate (VI~. Removal of the solvent and extraction into ethyl aceta~e provides the purified derivative (VI) which is then hydrolyzed in dilute (l~/o) hydrochloric acid at ambient temperatures to provide the corresponding alXyl 3-1(2-oxoethyl)thio]-propanote (VII). Condensation of (VII) with an appropri-ately substituted hydrazine (I) under nitrogen for several hours in ethanol at the reflux temperature~ followed by extraction in ethyl acetate and purification by column chromatography on silica gel using ethyl acetate:hexane as eluant provides the corresponding alkyl 3--(formylmethylthio~propanoate hydrazone (~
Cyclization of (V) is accomplished with thionyl chloride and triethylamine in methylene chloride for a few hours at ambIent temperatures. Purification by chroma-tography on silica gel using the system hexane:ethyl acetate (4:1) provides the corresponding 5-alkoxy car-bonylethylthio-1,2,3-thiadiazole (VIII). Treatment of (VIII) with sodium or potassium methoxide in methanol at ambient temperatures for an hour or so follos~ed by pre-cipitation with diethyl ether provides the 5-mercapto--1,2,3-thiadiazole alkali metal salt (IX).
The 5-mercapto-1,~,3-thiadiazole potassium salt is disclosed in J. Heterocyclic Chemistry 15, 1298 (1978).
Its utility is disclosed in J. ~ed. Chem. 22, 1214 ~1979) where it is employed to form a derivative of 7-amino-cephalosporanic acid having activity as an antibacterial agent. The presently disclosed method provides a means of making the 1,2,3-thiadiazoles in higher yield and by a more convenient method which does not use diazomethane and thiophosgene and also does not give the isomeric 1,3,4-thiadiazole.
The invention will be described in greater detail in conjunction with the following specific examples.
Example 1 Methyl 3-(2-dietnoxyethylthio)propanoate A 12.05 g. portion of methyl 3-thiopropanoate is dissolved in 50 ml. of methanoi. A 5.4 g. portion of sodium methoxide is added in portions with stirring. A
19.7 g. portion of l,l-diethoxyethyl bromide is added dropwise, then the solution is refluxed for 3 hours during which time a precipitate forms. The suspension is con-centrated in vacuo until the methanol is removed and then the residue is distributed between 50 ml. each of water and ethyl acetate. The aqueous layer is extracted again with ethyl acetate and the combined organic extracts are dried and concentrated to an oily residue which is dis-tilled in vacuo, [b.p. 109-112C. (0.6-0.7 mm. Hg.)]
giving 12.3 g. of the desired compound.
Examele 2 Chloroacetaldehyde semicarbazone _ A 34.9 g. portion of a 45% aqueous solution of chloroacetaldehyde is diluted with 100 ml. of water and then filtered. The filtrate is added to a solution of 22.2 g. of semicarbazide hydrochloride and 30 g. of sodium acetate trihydrate in 100 ml. of water. The mixture is stirred and then allowed to stand overnight. The solid is collected, washed with water, dried and recrystallized from ethanol giving the desired compound, m.p. 133-135C.
(dec.).
Example 3 M hyl 3-(formylmethylthio~ro~anoate semicarbazone A mixture of 1.08 g. of sodium methoxide, 2.4 g.
of methylthiopropanoate and 2.72 g. of chloroacetaldehy~e semicarbazone in 40 ml. of methanol is stirred and re-fluxed for 4-5 hours. The mixture is filte,ed and the filtrate concentrated to an oil .~hich .s puriC ed by chromatography on silica gel, givin~ the desired compound.
3~ 3 Example 4 Methyl 3-(formylmethylthio)-propanoate A mixture of 13.2 g. of methyl 3-[(2-diethoxy-ethyl~thio~-propanoate and 200 ml. of 1% hydrochloric acid is stirred, under nitrogen, for 4 hours. The solution is decanted from a small amount of insoluble oil, adjuste~
to pH 4.5 with sodium acetate and extracted with four lO0 ml. portions of ethyl acetate. The combined extracts are dried over magnes;um sulfate and then evaporated, giving 8.2 g. of the desired compound as a colorless oil.
Example 5 Methyl 3-(formylmethYlthio)-propanoate semicarbazone A mixture of 6.7 g. of semicarbazide hydro-chloride and 6.7 g. of sodium acetate in 50 ml. of ethanol is refluxed for lO minutes, then filtered while ho~ and 10.6 g. of methyl 3-(formylmethylthio)-propanoate is added to the filtrate. This solution is refluxed for one hour, then cooled and diluted with 200 ml. of water. The mix-ture is extracted with three 100 ml. of portions of ethyl acetate. The organic extracts are combined~ washed with brine, dried over magnesium sulfate and eYaporated, giving 11.8 g. of the desired compound as an amber oil.
Example 6 Meth 1 (3-form lmeth lthio) ro anoate ethox carbonvl-Y . Y Y P P Y
hydrazone A 100 ml. portion of 1% hydrochloric acid is purged with nitrogen for lO minutes and then added to 4.73 g. of methyl 3-(2-diethoxyethylthio)propanoate.
Nitrogen is bubbled into this mixture for 5 minutes then the flask is stoppered and stirred for 17 hours. Tne pH
of the solution is raised to 4.2 with saturated aqueous sodium acetate and 7..08 g. of ethyl carbazate in 8 ml. of water is added. The solution is briefly flushed with nitrogen~ then stoppered and stirred for 2 hours and then extracted with two 100 ml. portions of ethyl acetate. The combined extracts are dried and evaporated to 5.09 g. of ~ ~28~3~3 an oil. This oil is chromatographed on a 200 g. silica gel column using ethyl acetate:hexane (1:1) as eluant and collecting fractions of 100 ml. each. Fractions 8-13, containing the desired component are combined and evapor-ated, giving 1.8 g. of an oil which crystallizes on standing.
Certain variations of the above procedure may be used to derive the desired product.
A) Hydrolysis of 5.9 g. of methyl 3-(2-di-ethoxyethylthio)propanoate is carried out for 3 hours, under nitrogen in 100 ml. of 1% hydrochloric acid. Re-moval by pipette of a small quantity of un~issolved oil, followed by reaction of the solution with 2.6 g. of ethyl carbazate for 2 hours gives, after workup as described above, 6.11 g. of crude product.
B) The syrup from workup of a 10 mmole run is treated with ether to precipitate some of the undesired lower Rf component and the residue is chromatographed as described above.
Example 7 Methyl 3-(formylmethylthio)-propanoate p-toluenesulfonyl hydrazone A mixture of 8.2 g. of methyl 3-(formyl-methylthio)-propanoate and 9.4 g. of p-toluenesulfonyl-hydrazide in 75 ml. of ethanol is refluxed for 2 hours, ~hen chilled and the desired compound is collected by filtration giving 5.4 g., m.p. 94-96C.
Example 8 5-Methoxycarbonylethylthio-1,2,3-thiadiazole A 0.5 g. portion of methyl 3-(formylmethylthio)--propanoate p-toluenesulfonyl hydrazone is added to 4 ml.
of thionyl chloride and allowed to react for 30 minutes.
The mixture is evaporated to dryness, the residue dis-solved in methylene chloride and again evaporated. This crude product is purified by thick layer chrQmatography giving 18~ mg. of the desired compound.
~73 Example _ 5-Methoxycarbonylethylthio-1,2,3-thiadiazole A solution of 2.40 ml. of thionyl chloride in 3 ml. o~ methylene chloride is added rapidly, dropwise to a stirred solution of 8.23 g. of methyl (3-formylmethyl-thio)propanoate ethoxycarbonylhydrazone and 9.25 ml. oftriethylamine in 25 ml. of methylene chloride. After 30 minutes, 2.4 ml. of thionyl chloride is added rapidly, dropwise. After 60 minutes, 2.4 ml. of thionyl chloride îs again added as above. After a total reaction time of 1~ 2 hours, the mixture is evaporated at reduced pressure and with mild heat. Ether is added to the residue which is then filtered. The filtrate is evaporated to a residue which is chromatographed on 500 g. of silica gel using hexane:ethyl acetate (4:1) and collecting Eractions of 50 ml. each. Fractions 10-21 are collected, pooled and evaporated, giving 3.13 g. of the desired compound as an oil.
It is also possible to perform this reaction with another inert solvent such as eoluene or without a solvent. Also, the triethylamine can be omitted and the molar equivalents of thionyl chloride can be reduced, but yields will be less.
Example 10 5-Methoxycarbonylethylthio-1,2,3-thiadia~ole 2i A 177.5 g. porcion or methyl 3-(formylmethyl-thio)-propanoate semicarbazone is diluted with 100 ml. of dry methylene chloride and this is added, fairly rapidlv.
using a dropping funnel, ~o 875 ml. of thionyl chloride with rapid stirring which is continued for 2 hours after addition is complete. The thionyl chloride is then re-moved under reduced pressure and two portions of methylene chloride are added and removed under reduced press re.
The residue is dissolved in ethyl acetate, filtered and the filtrate washed first with saturated aqeuous sodium bicarbonate and then with brine. The solu~ion is dried over ~a~nesium sulfate, an e~ual volume of hexane is added ~f~8~3 and the solution is filtered through a silica gel pad topped with diatomaceous earth. The pad is washed with a 1:1 solution of ethyl acetate and hexane and this wash is concentrated under reduced pressure to an oil. The oil is dissolved in 100 ml. of a 20% ethyl acetate in hexane solution. One half of this solution is injected onto a Waters Prep 500 HPLC, using two prepacked columns and eluted with a solution of 12.5% ethyl acetate in hexane containing 1% methanol. After 2.5 liters of solvent has been eluted (one liter being the void volume), fractions 3-7 (containing approximately 3 liters of eluent) are combined and concentrated under reduced pressure. This procedure is repeated-with the other half of the solution of the product. Total yield is 57.8 g. of the desired compound.
Example 11 Sodium 1,2,3-thiadiazole-5-thiolate A solution of 756 mg. of sodium methoxide in 20 ml. of methanol is added to a solution of 3.13 g. of S-methoxycarbonylethylthio-1,2,3,-thiadiazole in 30 ml. of methanol. After 45 minutes, the reaction solution is evaporated in vacuo to about S ml. A 3 ml. portion of methanol is added and then about 15 ml. of ether causing precipitation of a solid. This solid is collected, washed with ether, dried and recrystallized from methanol-ether, giving 1.94 g. of the desired product.
Claims (4)
1. A process for producing a compound of the formula:
wherein R2 is hydrogen or methyl and M is sodium or po-tassium which comprises cyclizing a compound of the formula:
wherein R1 is p-toluenesulfonyl, carbamoyl or carboalkoxy having 2 4 carbon atoms and R3 is alkyl having up to 3 carbon atoms with thionyl chloride in the presence of triethylamine in methylene chloride as solvent at a tem-perature of 15°-55°C. for 0.5-4.0 hours whereby there is obtained the intermediate of the formula:
and treating the intermediate with sodium or potassium methoxide in methanol as solvent at a temperature of 15°-55°C. for 0.5-4.0 hours.
wherein R2 is hydrogen or methyl and M is sodium or po-tassium which comprises cyclizing a compound of the formula:
wherein R1 is p-toluenesulfonyl, carbamoyl or carboalkoxy having 2 4 carbon atoms and R3 is alkyl having up to 3 carbon atoms with thionyl chloride in the presence of triethylamine in methylene chloride as solvent at a tem-perature of 15°-55°C. for 0.5-4.0 hours whereby there is obtained the intermediate of the formula:
and treating the intermediate with sodium or potassium methoxide in methanol as solvent at a temperature of 15°-55°C. for 0.5-4.0 hours.
2. The process according to Claim 1 wherein R1 is p-toluenesulfonyl, R2 is hydrogen, R3 is methyl, and M is sodium.
3. The process according to Claim 1 wherein R1 is carbamoyl, R2 is hydrogen, R3 is methyl, and M is sodium.
4. The process according to Claim 1 wherein R1 is carbethoxy, R2 is hydrogen, R3 is methyl, and M is sodium.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000524600A CA1228073A (en) | 1982-09-27 | 1986-12-04 | Method for the synthesis of 5-thio-1,2,3- thiadiazole |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/424,825 US4454336A (en) | 1982-09-27 | 1982-09-27 | Derivatives of 3-(formylmethylthio)-propanoate |
| US424,825 | 1982-09-27 | ||
| CA000437550A CA1229619A (en) | 1982-09-27 | 1983-09-26 | Method for the synthesis of 5-thio-1,2,3-thiadiazole |
| CA000524600A CA1228073A (en) | 1982-09-27 | 1986-12-04 | Method for the synthesis of 5-thio-1,2,3- thiadiazole |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000437550A Division CA1229619A (en) | 1982-09-27 | 1983-09-26 | Method for the synthesis of 5-thio-1,2,3-thiadiazole |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1228073A true CA1228073A (en) | 1987-10-13 |
Family
ID=25670162
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000524600A Expired CA1228073A (en) | 1982-09-27 | 1986-12-04 | Method for the synthesis of 5-thio-1,2,3- thiadiazole |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1228073A (en) |
-
1986
- 1986-12-04 CA CA000524600A patent/CA1228073A/en not_active Expired
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