Process for preparation of substituted thiophenesulfonyl isocyanate

Abstract

The present invention relates to a process for preparing 2, 4-di substituted thiophene-3- sulfonyl isocyanate compound of Formula (I), by reacting with the compound of Formula (II) with phosgene in the presence of a catalyst, and a mixture of a non-polar solvent and an organosulfur co-solvent, and optionally in the presence of a base.

Description

[0001] PROCESS FOR PREPARATION OF SUBSTITUTED THIOPHENE SULFONYL

[0002] ISOCYANATE

[0003] Field of the Invention:

[0004] The invention relates to a novel process for the preparation of 2,4-disubstituted thiophene-3- sulfonyl isocyanate compound of Formula (I) and uses thereof, especially used for the preparation of herbicidal active compound of Formula (X).

[0005] Background of the Invention:

[0006] 2, 4-di substituted thiophene-3 -sulfonyl isocyanate are useful as intermediates in the preparation of agrochemical compound.

[0007] U.S. 4,481,029 patent discloses a process for the synthesis of substituted sulfonyl isocyanates, the method involves a reaction of 2-alkoxy carbonyl-3 -thiophene sulfonamide with phosgene, butyl isocyanate and l,4-diaza[2.2.2]bicyclooctane (DABCO) in xylene or other inert solvent with sufficiently high boiling point.

[0008] The problem associated with the process of the above patent is that it is difficult to achieve a high conversion of 2-alkoxycarbonyl-3 -thiophene sulfonamide to substituted thiophene sulfonyl isocyanate in relatively low polar and high boiling solvents. Moreover, the low solubility of substituted thiophene sulfonyl isocyanate in such low polar solvents at room temperature makes their use in the next step of herbicide production challenging due to crystallization during storage and delivery. Moreover, most of the polar solvents that usually improve solubility when added as co-solvents, such as alcohols, amines, and amides, cannot be used because they react both with phosgene and with isocyanates, producing chloroformates, carbonates, carbamates, carbamoyl chlorides, urea, etc.

[0009] Therefore, there is an unfelt need to overcome the limitations of conventional processes and to make more efficient and economical the conversion process of 2, 4-di substituted thiophene- 3-sulfonyl amides to 2, 4-di substituted thiophene-3-sulfonyl isocyanate compounds and their use for herbicide synthesis.

[0010] Hence, there is a need to develop an economically efficient and robust process for the preparation of 2, 4-di substituted thiophene-3 -sulfonyl isocyanate compounds and uses thereof.

[0011] Summary of the Invention:

[0012] The present invention provides a process for the preparation of a compound of Formula (I): in which

[0013] R1is alkoxy having from 1 to 4 carbon atoms, and

[0014] R2is alkyl having from 1 to 4 carbon atoms, comprising reacting a compound of Formula (II) with phosgene or phosgene substitute in the presence of a catalyst, and a mixture of a nonpolar solvent and an organosulfur co-solvent, and optionally in the presence of a base.

[0015] In an aspect, the process for the preparation of the compound of Formula (I) is carried out at a temperature from 100 °C to 150 °C.

[0016] In another aspect, the process of the present invention provides that the phosgene substitute is selected from the group comprising tri chloromethyl chloroformate (diphosgene) or bis(trichloromethyl) carbonate (triphosgene).

[0017] In yet another aspect, the amount of phosgene equivalents that are added as a phosgene or phosgene substitute for 1 mol of the compound of Formula (II) is from about 1.5 to 10 equivalents, more preferably from 2 to 3 equivalents.

[0018] In a further aspect, the process of the present invention, that may take place with and without the base, provides that the base is an organic base selected from the group comprising 1,4- diaza[2.2.2]bicyclooctane (DABCO), N,N-dimethylethylamine, N-methyl-pyrrolidine, or triethylamine.

[0019] In an aspect, the molar ratio of the base and the compound of Formula (II) is from about 0.001 : 1 to 0.1 : 1.

[0020] In another aspect, the process of the present invention provides that the non-polar solvent is an aromatic hydrocarbon solvent selected from the group comprising toluene, chlorobenzene, dichlorobenzene, xylene and mixtures thereof.

[0021] In yet another aspect, the process of the present invention provides that the organosulfur cosolvent is sulfolane.

[0022] In a further aspect, the molar ratio of the organosulfur solvent and the compound of Formula (II) is from about 0.2: 1 to 3: 1, preferably about 0.4: 1 to 0.8: 1, more preferably about 0.5: 1 to 0.7: 1.

[0023] In an aspect, the process of the present invention provides that the catalyst is an alkyl C2-C6 isocyanate selected from the group comprising butyl isocyanate or pentyl isocyanate, preferably butyl isocyanate.

[0024] In another aspect, the molar ratio of the catalyst and the compound of Formula (II) is from about 1 : 5 to 1 : 20, preferably 1 : 10. In a further aspect, the compound of Formula (I) is methyl 4-isocyanatosulfonyl-5- methy Ithi ophene-3 -carb oxy 1 ate .

[0025] In an aspect, the compound of Formula (II) is methyl 5-methyl-4-sulfamoylthiophene-3- carboxylate.

[0026] In another aspect, the present invention provides a process for the preparation of a compound of Formula (X) comprising the preparation of the compound of Formula (I) as mentioned above and the compound of Formula (I) in the mixture of the non-polar solvent and the organosulfur cosolvent is reacted with a triazole compound to obtain a compound of Formula (X).

[0027] In yet another aspect, the triazole compound used for the preparation of the compound of Formula (X) is 5-methoxy-4-methyl-2,4-dihydro-3 / / - l ,2,4-triazol-3-one.

[0028] In an aspect, the present invention provides the process for the preparation of methyl 4- isocyanatosulfonyl-5-methylthiophene-3-carboxylate comprises reaction of methyl 5-methyl- 4-sulfamoylthiophene-3-carboxylate with phosgene or phosgene substitute in the presence of a base, catalyst and a mixture of a non-polar solvent and organosulfur solvent.

[0029] In another aspect, the present invention provides the process for the preparation of methyl 4- isocyanatosulfonyl-5-methylthiophene-3-carboxylate comprises reaction of methyl 5-methyl- 4-sulfamoylthi ophene-3 -carboxylate with bis(tri chloromethyl) carbonate in the presence of l,4-diaza[2.2.2]bicyclooctane, butyl isocyanate and a mixture of a non-polar solvent and sulfolane.

[0030] In a further aspect, the present invention provides the process for the preparation of methyl 4- isocyanatosulfonyl-5-methylthiophene-3-carboxylate comprises reaction of methyl 5-methyl- 4-sulfamoylthiophene-3-carboxylate with phosgene in the presence of butyl isocyanate and a mixture of a non-polar solvent and sulfolane. In a preferred aspect, the present invention provides the process for the preparation of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate comprises reaction of methyl 5- methyl-4-sulfamoylthiophene-3 -carboxylate with phosgene in the presence of 1,4- diaza[2.2.2]bicyclooctane, butyl isocyanate and a mixture of a non-polar solvent and sulfolane.

[0031] In another preferred aspect, the present invention provides the process for the preparation of the compound of Formula (X) by reacting methyl 5-methyl-4-sulfamoylthiophene-3- carboxylate with phosgene in the presence of l,4-diaza[2.2.2]bicyclooctane, butyl isocyanate and a mixture of a non-polar solvent and sulfolane to obtain methyl 4-isocyanatosulfonyl-5- methylthiophene-3 -carboxylate, followed by reacting with 5-methoxy-4-methyl-2,4-dihydro- 3J / -l,2,4-triazol-3-one in the mixture of chlorobenzene and sulfolane solvent to obtain the compound of Formula (X).

[0032] In a further preferred aspect, the present invention provides the process for the preparation of the compound of Formula (X) by reacting methyl 5-methyl-4-sulfamoylthiophene-3- carboxylate with phosgene in the presence of butyl isocyanate and a mixture of a non-polar solvent and sulfolane to obtain methyl 4-isocyanatosulfonyl-5-methylthiophene-3- carboxylate, followed by reacting with 5-methoxy-4-methyl-2,4-dihydro-3J / -l,2,4-triazol-3- one in the mixture of chlorobenzene and sulfolane solvent to obtain the compound of Formula (X).

[0033] Description of the Invention:

[0034] For the sake of clarity, specific terminology is resorted to in describing the embodiments of the invention. However, it is not intended that the invention be limited to the specific terms so selected, and it is to be understood that each specific term includes all technical equivalents that operate in a similar manner to accomplish a similar purpose.

[0035] It will be understood that the terminology used herein is for the purpose of describing embodiments only and is not intended to be limiting. As used in this specification, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, the reference to “a compound” includes one or more of such compounds. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one ordinarily skilled in the art to which the invention pertains. Although other methods and materials similar to or equivalent to those described herein can be used in the practise of the present invention, the preferred materials and methods are described herein.

[0036] As used herein, the term “or” means “and / or”. It will be further understood that the terms “comprises”, “comprising”, “includes”, “including”, or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition or a method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such a method.

[0037] Throughout the application, descriptions of various embodiments use the term “comprising”. However, it will be understood by one of skill in the art that in some specific instances, an embodiment can alternatively be described using the language “consisting essentially of’ or “consisting of.”

[0038] As used herein the term “mol” or “molar” refers to the quantity of a substance that reacts with an arbitrary quantity (usually one mole) of another substance in a particular chemical reaction.

[0039] As used herein the term “mmol” or “millimolar” refers to the quantity of a substance that reacts with an arbitrary quantity (usually one millimole) of another substance in a particular chemical reaction.

[0040] Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed considering the number of reported significant digits and by applying ordinary rounding techniques.

[0041] In addition, the endpoints of all ranges directed to the same component or property herein are inclusive of the endpoints, are independently combinable, and include all intermediate points and ranges. As used herein, the term “alkyl” refers to straight or branched chain, saturated alkyl groups having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, butyl and the like.

[0042] As used herein, the term “alkoxy” refers to saturated straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, and the like.

[0043] As used herein, the term “phosgene” or “phosgene substitute” can be used for any substitute of phosgene such as phosgene gas, trichloromethyl chloroformate (diphosgene) or bis(trichloromethyl) carbonate (triphosgene).

[0044] As used herein, the term “base” refers to a substance which acts as a base yet whose strength or activity as a base and the base herein in include the “organic base”. Non-limiting examples of organic base include l,4-diaza[2.2.2]bicyclooctane (DABCO), N,N-dimethylethylamine, N-methyl-pyrrolidine, or triethylamine.

[0045] As used herein, the term “non-polar solvent” refers to a solvent without significant partial charges on any atoms or a solvent where polar bonds are arranged in such a way that the effect of their partial charges cancel out. Non-limiting examples of non-polar solvents include but not limited to an aromatic hydrocarbon solvent such as toluene, chlorobenzene, dichlorobenzene or xylene and mixtures thereof.

[0046] As used herein, the term “organosulfur co-solvent” refers to a co-solvent which does not react with phosgene or phosgene substitute, and with the compound of Formula (I).

[0047] As used herein, the term “catalyst” refers to a substance that participates in a reaction, improves the rate of the process, but generally remains unchanged at the end of the reaction.

[0048] As used herein the term “about” refers to and includes the values shown and the range before and after those values. In certain embodiments, the term “about” refers to ± 10%, ± 5%, or ± 1% of the values shown.

[0049] As used herein, the term “process” refers to “batch process” as well as “multistep batch process”.

[0050] As used herein, the term “batch process” refers to a chemical process that involves a series of operations on a separate, identifiable item or parcel of material, in which the product comes out in groups and not continuously. As used herein, the term “multistep batch process” refers to a chemical process that involves a process carried out by telescopic manner without isolation of intermediates produced during the synthesis.

[0051] All ranges are inclusive. As used throughout the specification, the following abbreviations are applied: °C = Centigrade or min.= minute(s) or h = hour(s).

[0052] Thiophenesulfonyl isocyanate compounds are useful as intermediates in the preparation of agrochemical compounds such as the compound of Formula (X). The compound of Formula (X) is used for pre-emergence control of grassy and broad-leaved weeds.

[0053] The present invention provides a process for the preparation of the compound of Formula (I): in which

[0054] R1is alkoxy having from 1 to 4 carbon atoms, and

[0055] R2is alkyl having from 1 to 4 carbon atoms, comprising reacting a compound of Formula (II) with phosgene or phosgene substitute in the presence of a catalyst, and a mixture of a nonpolar solvent and an organosulfur co-solvent, and optionally in the presence of a base.

[0056] In a preferred embodiment, the present invention provides a process for the preparation of the compound of Formula (I): in which

[0057] R1is alkoxy having from 1 to 4 carbon atoms, and

[0058] R2is alkyl having from 1 to 4 carbon atoms, comprising reacting a compound of Formula (II) with phosgene or phosgene substitute in the presence of a base, catalyst and a mixture of a non-polar solvent and an organosulfur co-solvent.

[0059] In an embodiment, the process of the present invention is a multistep batch process for the preparation of the compound of Formula (X) that is carried out by telescopic manner without isolation of intermediates such as the compound of Formula (I) produced during the synthesis.

[0060] In another embodiment, the process of the present invention is a batch process for the preparation of the compound of Formula (X) that is carried out by isolation of the intermediate such as the compound of Formula (I) produced during the synthesis.

[0061] In a further embodiment, the compound of Formula (I) is methyl 4-isocyanatosulfonyl-5- methy Ithi ophene-3 -carb oxy 1 ate .

[0062] In yet another embodiment, the compound of Formula (II) is methyl 5-methyl-4- sulfamoylthiophene-3-carboxylate.

[0063] When carrying out the process of the present invention for the preparation of the compound of Formula (I), the reaction temperature can be varied within a relatively wide range. The temperature chosen will depend on the nature of the solvent and the catalyst, for example on their boiling point and / or their effectiveness for promoting the desired reaction, and on the speed at which the reaction is to be carried out. In general, the reaction may be carried out at a temperature of from 100 °C to 150 °C. In an embodiment, the process for the preparation of the compound of Formula (I) is carried out at a temperature from 110 °C to 140 °C, more preferably between 125 °C and 135 °C.

[0064] In the process of the present invention the reaction of sulfonamides with phosgene or phosgene substitute, the reaction times are generally between 4 to 20 hours, preferably between 6 to 9 hours.

[0065] In another embodiment, the phosgene substitute selected from the group comprising trichloromethyl chloroformate (diphosgene) or bis(trichloromethyl) carbonate (triphosgene). The process of the present invention provides the same results on slow feeding of the phosgene gas as obtained with the use of diphosgene or triphosgene.

[0066] The process of the present invention of the compound of Formula (I) are prepared preferably by using the reagent in an equimolar amount or in excess. In an embodiment, the amount of phosgene equivalents that are added as a phosgene or phosgene substitute for 1 mol of compound of Formula (II) is from about 1.5 to 10 equivalents, more preferably from 2 to 3 equivalents. However, greater excesses of phosgene may also be used in accordance with the invention.

[0067] The process of the present invention may take place with and without the base, provides that the base is an organic base selected from the group comprising l,4-diaza[2.2.2]bicyclooctane (DABCO), N,N-dimethylethylamine, N-methyl-pyrrolidine, or triethylamine.

[0068] DABCO (l,4-diazabicyclo[2.2.2]octane) is environmentally friendly, reactive, low-toxic base and strong nucleophile that is used often as an organic catalyst. l,4-diaza[2.2.2]bicyclooctane (DABCO) is a preferred organic base for the process of the present invention.

[0069] In an embodiment, the molar ratio of the base and the compound of Formula (II) is from about 0.001 : 1 to 0.1 : 1. However, the amount of base depends on the compound of Formula (II) used in the process of the present invention.

[0070] In an embodiment, the reaction of the compound of Formula (II) with the phosgene equivalents that are added as phosgene or phosgene substitute in the presence of a catalyst and optionally in the presence of a base carried out in a mixture of non-polar solvent and organosulfur co-solvent. Non-polar solvent is used in the process of the present invention as a high boiling and inert solvent under reaction conditions and suitable for batch process as well as telescopic process for the synthesis of the compound of Formula (I), synthesis and separation of the final compound of the Formula (X).

[0071] In an embodiment, the process of the present invention provides that the non-polar solvent is an aromatic hydrocarbon solvent selected from the group comprising toluene, chlorobenzene, dichlorobenzene, xylene and mixtures thereof.

[0072] In another embodiment, the process of the present invention provides that the organosulfur co-solvent is sulfolane.

[0073] Sulfolane is a polar solvent with high boiling point and stable under reaction conditions. It does not react with phosgene, phosgene substitutes and isocyanates like most of other polar solvents, for example protic solvents such as alcohols, amines, and amides react both with phosgene and with isocyanates to form chloroformates, carbonates, carbamates, carbamoyl chlorides, ureas, etc., aprotic solvents such as tri ethylamine and pyridine react with phosgene to form acyl onium salts that are decomposed at high temperature, amides solvents such as dimethylformamide, dimethyl acetamide, N-methyl-2-pyrrolidone react with phosgene to form Vilsmeier reagent.

[0074] In a further embodiment, the molar ratio of the organosulfur solvent and the compound of Formula (II) is from about 0.2: 1 to 3: 1, preferably about 0.4: 1 to 0.8: 1, more preferably about 0.5: 1 to 0.7: 1.

[0075] The process of the present invention carried out in the presence of a catalyst. The catalyst is an alkyl C2-C6 isocyanate selected from the group comprising butyl isocyanate or pentyl isocyanate, preferably butyl isocyanate.

[0076] In another embodiment, the molar ratio of catalyst and the compound of Formula (II) is from about 1 : 5 to 1 : 20, preferably 1 : 10.

[0077] In a further embodiment, the present invention provides a process for the preparation of a compound of Formula (X) comprising the preparation of the compound of Formula (I) as mentioned above and the compound of Formula (I) in the mixture of the non-polar solvent and the organosulfur cosolvent is reacted with a triazole compound to obtain a compound of Formula (X).

[0078] In yet another embodiment, the triazole compound used for the preparation of the compound of Formula (X) is 5-methoxy-4-methyl-2,4-dihydro-3 / / - l ,2,4-triazol-3-one.

[0079] In an embodiment, the present invention provides the process for the preparation of methyl 4- isocyanatosulfonyl-5-methylthiophene-3-carboxylate comprises reaction of methyl 5-methyl-

[0080] 4-sulfamoylthiophene-3-carboxylate with phosgene or phosgene substitute in the presence of a base, catalyst and a mixture of a non-polar solvent and organosulfur solvent.

[0081] In another embodiment, the present invention provides the process for the preparation of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate comprises reaction of methyl

[0082] 5-methyl-4-sulfamoylthiophene-3-carboxylate with bis(trichloromethyl) carbonate in the presence of l,4-diaza[2.2.2]bicyclooctane, butyl isocyanate and a mixture of a non-polar solvent and sulfolane.

[0083] In a further embodiment, the present invention provides the process for the preparation of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate comprises reaction of methyl 5-methyl-4-sulfamoylthiophene-3-carboxylate with phosgene in the presence of butyl isocyanate and a mixture of a non-polar solvent and sulfolane.

[0084] In a preferred embodiment, the present invention provides the process for the preparation of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate comprises reaction of methyl 5-methyl-4-sulfamoylthiophene-3-carboxylate with phosgene in the presence of 1,4- diaza[2.2.2]bicyclooctane, butyl isocyanate and a mixture of a non-polar solvent and sulfolane.

[0085] In another preferred embodiment, the present invention provides the process for the preparation of the compound of Formula (X) by reacting methyl 5-methyl-4- sulfamoylthiophene-3 -carboxylate with phosgene in the presence of 1,4- diaza[2.2.2]bicyclooctane, butyl isocyanate and a mixture of a non-polar solvent and sulfolane to obtain methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate, followed by reacting with 5-methoxy-4-methyl-2,4-dihydro-3J / -l,2,4-triazol-3-one in the mixture of chlorobenzene and sulfolane solvent to obtain the compound of Formula (X).

[0086] In a further preferred embodiment, the present invention provides the process for the preparation of the compound of Formula (X) by reacting methyl 5-methyl-4- sulfamoylthiophene-3 -carboxylate with phosgene in the presence of butyl isocyanate and a mixture of a non-polar solvent and sulfolane to obtain methyl 4-isocyanatosulfonyl-5- methylthiophene-3 -carboxylate, followed by reacting with 5-methoxy-4-methyl-2,4-dihydro- 3J / -l,2,4-triazol-3-one in the mixture of chlorobenzene and sulfolane solvent to obtain the compound of Formula (X).

[0087] The process according to the present invention is generally carried out under atmospheric pressure. However, it is also possible to carry out the process according to the invention under elevated or reduced pressure. In an embodiment, the process for preparing 2,4- disubstituted thiophene-3 -sulfonyl isocyanate compound of Formula (I) may be conducted at a pressure from about 1 bar to about 10 bar. In another embodiment, the process may be conducted at a pressure from about 1 bar to about 5 bar. In yet another embodiment, the process for 2, 4-di substituted thiophene-3 -sulfonyl isocyanate compound of Formula (I) may be conducted at atmospheric pressure. In a further embodiment, the process may be conducted at about 10 bar. In certain embodiments, it may be preferred that the process is conducted at pressures less than atmospheric pressure. For example, the process may be carried out at 0.7 bar, 0.75 bar, 0.8 bar, 0.9 bar or 0.95 bar.

[0088] The progress of the reaction of synthesis of the compound of Formula (I) and the compound of Formula (X) can be monitored using any suitable method, which can include, for example, chromatographic methods such as, e.g., high performance liquid chromatography (HPLC), thin layer chromatography (TLC), and the like. In yet another embodiment, the compound of Formula (I) or compound of Formula (X) can be isolated from the reaction mixture by any conventional technique well-known in the art. Such isolation techniques can be selected, without limitation, from the group consisting of extraction, crystallization, or precipitation by concentration, cooling or antisolvent addition; filtration; centrifugation, and a combination thereof, followed by drying. In yet another embodiment, the compound of Formula (I) and the compound of Formula (X) can be optionally purified by any conventional technique well-known in the art. Such purification techniques can be selected, without limitation, from the group consisting of precipitation, crystallization, extraction, slurrying, washing in a suitable solvent, filtration through a packed-bed column, dissolution in an appropriate solvent, re-precipitation by addition of a second solvent in which the compound is insoluble, and a combination thereof.

[0089] The process of the present invention is advantageous in that it is significantly easier for industrial implementation because the compound of Formula (I) does not crystallize in the mixture of non-polar solvent and organosulfur co-solvent at a concentration up to 24% at the temperature down to 0 °C which is an essential requirement for industrial scale production of the compound of Formula (X). In addition to it, presence of the organosulfur co-solvent makes possible to achieve higher conversion of the compound of Formula (II) to the compound of Formula (I) and, accordingly, to improve the yield both of the intermediate compound of Formula (I) and of the final compound of Formula (X).

[0090] The following examples illustrate the practice of the present invention in some of its embodiments but should not be construed as limiting the scope of the present invention. From consideration of the specification and examples, other embodiments will be apparent to one skilled in the art. It is intended that the specification, including the examples, be considered exemplary only without limiting the scope and spirit of the present invention.

[0091] An exemplary experimental procedure for producing 2,4-disubstituted thiophene-3 -sulfonyl isocyanate compound of Formula (I) is described as follows:

[0092] Example 1:

[0093] Step 1: Synthesis of methyl 4-(isocyanatosulfonyl)-5-methylthiophene-3-carboxylate:

[0094] Triphosgene, DABCO n-butyl isocyanate Solvent - Chlorobenzene methyl 5-methyl-4- + Sulfolane methyl 4-(isocyanatosulfonyl)- sulfamoylthiophene-3-carboxylate 5-methylthiophene-3-carboxylate 600 g of chlorobenzene, 100 g of sulfolane, 288 g (1.2 mol) of methyl 5-methyl-4- sulfamoylthiophene-3-carboxylate and 0.7 g (6 mmol) l,4-diazabicyclo[2.2.2]octane (DABCO) were added to a four-necked flask. The mixture was dried by azeotropic distillation under reduced pressure until no water droplets were seen in the distilled solvent (vacuum: -0.09Mpa, reactor temperature: 70 °C to 80 °C).

[0095] The vacuum was broken with nitrogen and 12 g (0.12 mol) of n-butyl isocyanate was added into the mixture at 70 °C to 80 °C. The mixture was heated to 128 °C to 133 °C and solution of 200 g (0.67 mol) of bi s(tri chloromethyl) carbonate (triphosgene) in 300 g of chlorobenzene were added dropwise into the mixture within 9 hours at 128 °C to 133 °C.

[0096] The reaction mixture was cooled below 70 °C and about 300 g of chlorobenzene together with n-butyl isocyanate and traces of phosgene were distilled out under reduced pressure (vacuum: -0.09Mpa, reactor temperature: 70 °C to 80 °C). The vacuum was broken with nitrogen, the residue was analyzed and about 400g of dry chlorobenzene were added to it in order to obtain solution of methyl 4-(isocyanatosulfonyl)-5-methylthiophene-3-carboxylate with concentration 22 % to 24 %.

[0097] The mixture was cooled to room temperature and filtrated from insoluble impurities. The yield of methyl 4-(isocyanatosulfonyl)-5-methylthiophene-3-carboxylate product was 88%. The solution of methyl 4-(isocyanatosulfonyl)-5-methylthiophene-3-carboxylate in the mixture of chlorobenzene and sulfolane was delivered to the Step-2 for the synthesis of methyl 4-{[(4,5-dihydro-3-methoxy-4-methyl-5-oxo-17 / -l,2,4-triazol-l- yl)carbonyl]sulfamoyl}-5-methylthiophene-3-carboxylate.

[0098] Step 2: Synthesis of methyl 4-{[(4,5-dihydro-3-methoxy-4-methyl-5-oxo-LH-l,2,4- triazol-l-yl)carbonyl]sulfamoyl}-5-methylthiophene-3-carboxylate: methyl 4-(isocyanatosulfonyl)- Solvent - Chlorobenzene methyl 4-{[(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1 methylthiophene-3-carboxylate + Sulf H- 5- olane 1,2,4-triazol-1-yl)carbonyl]sulfamoyl}- 5-methylthiophene-3-carboxylate 290 g of chlorobenzene and 145 g (1.11 mol) of 5-methoxy -4-methyl-2,4-dihydro-3JT- 1,2,4- triazol-3-one were added to a four-necked flask. The mixture was dried by azeotropic distillation under reduced pressure until no water droplets were seen in the distilled solvent (vacuum: -0.09Mpa, reactor temperature: 70 °C to 80 °C).

[0099] The vacuum was broken with nitrogen and solution of methyl 4-(isocyanatosulfonyl)-5- m ethylthiophene-3 -carboxylate in the mixture of chlorobenzene and sulfolane from Step- Iwas added dropwise into the mixture within 0.5 hour at 70 °C to 75 °C. The mixture was stirred at the same temperature for additional 0.5 h.

[0100] 580 g of chlorobenzene were added to the reaction mixture and suspension was heated to 125 °C to 130 °C until the solid was dissolved.

[0101] The mixture was cooled to 0 °C to 5 °C, the solid was filtered and the cake was rinsed with 145 g of cooled chlorobenzene. Methyl 4-{[(4,5-dihydro-3-methoxy-4-methyl-5-oxo-17T- l,2,4-triazol-l-yl)carbonyl]sulfamoyl}-5-methylthiophene-3-carboxylate was dried at 60 °C to 65 °C. The yield of the product was 83.5 % based on methyl 5-methyl-4- sulfamoylthiophene-3-carboxylate.

[0102] Comparative Example 1:

[0103] Step 1: Synthesis of methyl 4-(isocyanatosulfonyl)-5-methylthiophene-3-carboxylate:

[0104] Triphosgene, DABCO n-butyl isocyanate Solvent - Chlorobenzene methyl 5-methyl-4- methyl 4-(isocyanatosulfonyl)- sulfamoylthiophene-3-carboxylate 5-methylthiophene-3-carboxylate

[0105] 990 g of chlorobenzene, 495 g (2 mol) of methyl 5-methyl-4-sulfamoylthiophene-3- carboxylate, and 1.1 g (10 mmol) of l,4-diazabicyclo[2.2.2]octane (DABCO) were added to a four-necked flask. The mixture was dried by azeotropic distillation under reduced pressure until no water droplets were seen in the distilled solvent (vacuum: -0.09Mpa, reactor temperature: 70 °C to 80 °C).

[0106] The vacuum was broken with nitrogen and 20 g (0.2 mol) of n-butyl isocyanate was added into the mixture at 70 °C to 80 °C. The mixture was heated to 128 °C to 133 °C and solution of 329 g (1.1 mol) of bis(trichloromethyl) carbonate (triphosgene) in 495 g of chlorobenzene were added dropwise into the mixture within 10 h at 128-133 °C.

[0107] The reaction mixture was cooled below 70 °C and about 500 g of chlorobenzene together with n-butyl isocyanate and traces of phosgene were distilled out under reduced pressure (vacuum: -0.09Mpa, reactor temperature: 70 °C to 80 °C). The vacuum was broken with nitrogen, the residue was analyzed and about 500 g of dry chlorobenzene were added to it in order to obtain solution of methyl 4-(isocyanatosulfonyl)-5-methylthiophene-3-carboxylate with concentration 22% to 24 %.

[0108] The mixture was filtrated from insoluble impurities at the temperature 80 °C and kept at 60 °C to 65 °C to prevent crystallization of methyl 4-(isocyanatosulfonyl)-5-methylthiophene-3- carboxylate. The yield of methyl 4-(isocyanatosulfonyl)-5-methylthiophene-3-carboxylate product was 85%.

[0109] Step 2: Synthesis of methyl 4-{[(4,5-dihydro-3-methoxy-4-methyl-5-oxo-LH-l,2,4- triazol-l-yl)carbonyl]sulfamoyl}-5-methylthiophene-3-carboxylate:

[0110] 5-methoxy-4-methyl-2,4-dihydro -3H-1 ,2,4-triazol-3-one methyl 4-(isocyanatosulfonyl)- Solvent - Chlorobenzene methyl 4-{[(4,5-dihydro-3-methoxy-4-methyl-5-oxo-1 H- 5-methylthiophene-3-carboxylate 1,2,4-triazol-1-yl)carbonyl]sulfamoyl}-

[0111] 5-methylthiophene-3-carboxylate

[0112] 476 g of chlorobenzene and 238 g (1.81 mol) of 5-methoxy-4-methyl-2,4-dihydro-3J / -l,2,4- triazol-3-one were added to a four-necked flask. The mixture was dried by azeotropic distillation under reduced pressure until no water droplets were seen in the distilled solvent (vacuum: -0.09Mpa, reactor temperature: 70 °C to 80 °C).

[0113] The vacuum was broken with nitrogen and hot solution of methyl 4-(isocyanatosulfonyl)-5- methylthiophene-3 -carboxylate were added dropwise into the mixture within 0.5 hour at 70 °C to 80 °C. The mixture was stirred at the same temperature for additional 1 h.

[0114] 950 g of chlorobenzene was added to the reaction mixture and the suspension was heated to 130 °C to 135 °C until the solid was dissolved. The mixture was cooled to 20 °C to 25 °C, the solid was filtered and the cake was rinsed with 245 g of chlorobenzene. Methyl 4-{[(4,5- dihydro-3-methoxy-4-methyl-5-oxo-lJ / -l,2,4-triazol-l-yl)carbonyl]sulfamoyl}-5- methylthiophene-3 -carboxylate was dried at 60 °C to 65 °C. The yield of the product was 80% based on methyl 5-methyl-4-sulfamoylthiophene-3-carboxylate.

Claims

We claim:

1. A process for the preparation of a compound of Formula (I):in whichR1is alkoxy having from 1 to 4 carbon atoms, andR2is alkyl having from 1 to 4 carbon atoms, comprising reacting a compound of Formula (II)with a phosgene or phosgene substitute in the presence of a catalyst, and a mixture of a non-polar solvent and an organosulfur co-solvent, and optionally in the presence of a base.

2. The process as claimed in claim 1, wherein the reaction is carried out at a temperature from 100 °C to 150 °C.

3. The process as claimed in claim 1, wherein the phosgene substitute is selected from the group comprising tri chloromethyl chloroformate or bis(trichloromethyl) carbonate.

4. The process as claimed in claim 1, wherein the amount of phosgene or phosgene substitute and compound of Formula (II) is from about 1.5: 1 to 10: 1.

5. The process as claimed in claim 1, wherein the base is an organic base.

6. The process as claimed in claim 5, wherein the organic base is selected from the group comprising l,4-diaza[2.2.2]bicyclooctane, N,N-dimethylethylamine, N-methyl- pyrrolidine, or triethylamine.

7. The process as claimed in claim 5, wherein the molar ratio of the base and the compound of Formula (II) is from about 0.001 : 1 to 0.1 : 1.

8. The process as claimed in claim 1, wherein the non-polar solvent is an aromatic hydrocarbon solvent.

9. The process as claimed in claim 8, wherein the aromatic hydrocarbon solvent is selected from the group comprising toluene, chlorobenzene, di chlorobenzene, xylene and mixtures thereof.

10. The process as claimed in claim 1, wherein the organosulfur co-solvent is sulfolane.

11. The process as claimed in claim 10, wherein the molar ratio of organosulfur solvent and the compound of Formula (II) is from about 0.2: 1 to 3: 1.

12. The process as claimed in claim 1, wherein the catalyst is an alkyl C2-C6 isocyanate.

13. The process as claimed in claim 12, wherein the alkyl C2-C6 isocyanate is selected from the group comprising butyl isocyanate or pentyl isocyanate.

14. The process as claimed in claim 12, wherein the molar ratio of the catalyst and compound of Formula (II) is from about 1 : 5 to 1 : 20.

15. The process as claimed in claim 1, wherein the compound of Formula (I) is methyl 4- isocyanatosulfonyl-5-methylthiophene-3-carboxylate.

16. The process as claimed in claim 1, wherein the compound of Formula (II) is methyl 5- methyl-4-sulfamoylthiophene-3-carboxylate.

17. The process as claimed in claim 1, wherein the mixture of compound of Formula (I) in the non-polar solvent and the organosulfur co-solvent is reacted with a triazole compound to obtain a compound of Formula (X).

18. The process as claimed in claim 17, wherein the triazole compound is 5-methoxy-4- methyl-2,4-dihydro-3J / -l,2,4-triazol-3-one.

19. A process for the preparation of a compound of Formula (X)comprising the preparation of compound of Formula (I) as claimed in claim 1 and the compound of Formula (I) in the mixture of the non-polar solvent and the organosulfur co-solvent is reacted with a triazole compound to obtain a compound of Formula (X).

20. The process as claimed in claim 19, wherein the triazole compound is 5-methoxy-4- methyl-2,4-dihydro-3J / -l,2,4-triazol-3-one.

21. The process as claimed in claim 19, wherein the non-polar solvent is an aromatic hydrocarbon solvent.

22. The process as claimed in claim 21, wherein the aromatic hydrocarbon solvent is selected from the group comprising toluene, chlorobenzene, di chlorobenzene, xylene and mixtures thereof.

23. The process as claimed in claim 19, wherein the organosulfur co-solvent is sulfolane.