Process for making 2-(methylthio)-5-(trifluoromethyl)-1,3,4-thiadiazole using methyldithiocarbazinate

Abstract

The invention relates to a process for the preparation of 2-(methylthio)-5-(trifluoromethyl)-1,3,4-thiadiazole. The process according to the invention consists in reacting methyl dithiocarbazinate with trifluoroacetic acid in the absence of phosphorus trichloride to produce a mixture of 2-(methylthio)-5-(trifluoromethyl)-1,3,4-thiadiazole and 2,5-bis(methylthio)-1,3,4-thiadiazole, and then selectively removing 2,5-bis(methylthio)-1,3,4-thiadiazole by acidifying the reaction mixture and subsequent phase separation. The acidification is carried out with a concentrated inorganic acid. The process according to the invention enables the reaction to be carried out effectively and efficiently even in the presence of water, and thus avoids the use of methyl dithiocarbazinate in powder form, which is extremely toxic in powder form. à

Description

The invention relates to the synthesis of thiadiazoles. More particularly, the invention relates to improved processes for the preparation of (2-methylthio)-5-(trifluoromethyl)-1,3,4-thiadiazole using trifluoroacetic acid and methyl dithiocarbazinate. 5 The current methods for the preparation of 2-(methylthio)-5-(trifluoromethyl)-1,3,4-thiadiazole are limited by the high cost of applying laboratory processes to industrial scale. Many known reports are based on laboratory studies, thus providing little information on how reaction temperatures and specific reagents affect product yield and purity. In addition, the methods and reactions developed in the laboratory are not directly applicable to industrial scale production, because such laboratory processes generally require the use of expensive reagents and expensive technological operations (e.g. separation and purification). U.S. Patent No. 3,562,284 discloses a process for the preparation of certain 2-(alkylthio)5-(haloalkyl)-1,3,4-thiadiazoles, such as 2-(methylthio)-5-(trifluoromethyl)-1,3,4-thiadiazole, by reacting methyl dithiocarbazinate with a carboxylic anhydride (e.g. trifluoroacetic anhydride) or a carboxylic acid (e.g. trifluoroacetic acid) in a solvent (e.g. toluene). This reaction can be carried out in the presence of phosphorus trichloride and pyridine with the addition of sulfuric acid (see German Patent No. DE-A-3,422,861), or with carbonyl chlorides (e.g. trifluoroacetyl chloride) and diethylene glycol dimethyl ether; and with pyridine and sulfuric acid (German Patent Specification DE-A-3 722 320). The first method is not very suitable for large-scale, industrial production because the reagents (anhydrides) are expensive and used in excess. In addition, when using anhydride, only half of the anhydride as a chemical unit is used in the reaction. Reactions with carboxylic acids, phosphorus trichloride, pyridine, sulfuric acid, and carbonyl chlorides involve a cumbersome workup procedure in which the pyridine is separated and regenerated. Furthermore, phosphorus trichloride only gives poorly soluble reaction products, which make mixing difficult and lead to an unacceptably large amount of waste. Finally, the yields achievable with these processes are unacceptably low. Another method for preparing 2-(Substituted)-5-(trifluoromethyl)-1,3,4-thiadiazoles is the reaction of a carboxylic acid (e.g. trifluoroacetic acid) and a dithiocarbazinic acid ester in the presence of phosphoryl chloride or polyphosphoric acid [see, for example, U.S. Patent No. 5,162,539 and Gyoefi and Csávássy, Acta Chim. Acad. Sci. Hung. 82, 55 91-97 (1974)]. The use of such phosphorus compounds results in an unacceptably large amount of phosphate-containing waste, thus posing an environmental hazard. In addition, this method requires the use of dry methyldithiocarbazinates (toxic, convulsant). In the dry state, this substance poses a serious industrial health problem. Accordingly, there is a need for an efficient, high-yielding, practical and safe industrial-scale process for the preparation of 2-(methylthio)-5-(trifluoromethyl)-1,3,4-thiadiazole. Such a process can be realized by the present invention. In the following, we briefly summarize our invention. The invention relates to a process for the preparation of 2-(methylthio)-5-(trifluoromethyl)-1,3,4-thiadiazole. The process comprises the following steps: methyl dithiocarbazinate is reacted with trifluoroacetic acid in the absence of phosphorus trichloride to obtain a mixture of 2-(methylthio)-5-(trifluoromethyl)-1,3,4-thiadiazole and 2,5bis(methylthio)-1,3,4-diadiazole, and then the 2,5-bis(methylthio)-1,3,4-thiadiazole (the “bis” by-product) is selectively removed by acidifying the mixture after removing the excess trifluoroacetic acid. The mixture is acidified with a concentrated inorganic acid, such as hydrochloric acid, sulfuric acid or nitric acid. Preferably, sulfuric acid is used. The concentration of sulfuric acid is in the range of about 55% to about 95%, preferably about 70%. When 70% sulfuric acid is used, the amount of sulfuric acid added to the reaction mixture is from about 2 moles to about 10 moles per mole of 2,5-bis(methylthio)-1,3,4-thiadiazole; preferably, an amount of sulfuric acid is used in the range of about 4 moles to about 7 moles per mole of 2,5-bis(methylthio)-1,3,4-thiadiazole. Acidification is generally carried out at a temperature of between about 10°C and about 60°C, preferably between about 10°C and about 40°C, more preferably between about 25°C and about 30°C. The reaction of methyl dithiocarbazinate with trifluoroacetic acid can also be carried out in the presence of a solvent. The solvent may be trifluoroacetic acid itself or an aromatic solvent such as toluene, xylene, cumene or mesitylene. Toluene is preferred. The methyldithiocarbazinate and trifluoroacetic acid may be used in any suitable ratio. Either reagent may be present in molar excess. Thus, the molar ratio of methyldithiocarbazinate to trifluoroacetic acid may range from about 4:1 to about 1:5. If the methyl dithiocarbazinate is present in molar excess, the preferred molar ratio of methyl dithiocarbazinate to trifluoroacetic acid is between about 2:1 and about 1.5:1. If the trifluoroacetic acid is present in molar excess, the preferred molar ratio of methyl dithiocarbazinate to trifluoroacetic acid is between about 1:1.25 and about 1:2. Below we describe our invention in detail. The invention provides a novel process for the preparation of 2-(methylthio)-5-(trifluoromethyl)-1,3,4-thiadiazole (TDA), which is an intermediate useful in the preparation of herbicides. The starting reagent in the novel process of the invention is HU 221 653 Bl We use methyl dithiocarbazinate (MDTC) and trifluoroacetic acid (TFA) as reagents. The new processes allow the production of TDA in high yields, with efficient removal of by-products and recycling of key reagents. 5 In one aspect of the process of the invention for the preparation of 2-(methylthio)-5-(trifluoromethyl)-1,3,4-thiadiazole, methyl dithiocarbazinate is reacted with an excess of trifluoroacetic acid in a solvent, and then the water and excess trifluoroacetic acid are removed. MDTC prepared by any method can be used in the process. A particularly preferred method for preparing MDTC is described in US Pat. No. 08,743,763, U.S. Patent Applications Nos. 743,764 and 08,743,775, filed November 7, 1996. The disclosures of these patent applications are incorporated herein by reference. TFA is commercially available. MDTC is reacted with a molar excess of TFA. As used herein, the term "molar excess" means that the molar amount of TFA in the reaction is in excess of the molar amount of MDTC. TFA is preferably present in a molar excess of 10-500% relative to MDTC. This means that the molar ratio of TFA to MDTC (TFA:MDTC) is from about 1.1:1 to about 5:1. More preferably, the molar ratio of TFA:MDTC is from about 1.25:1 to about 2.5:1, and more preferably from about 1.25:1 to about 2:1. It will be shown in the examples that by increasing the molar excess of TFA relative to MDTC, the yield of TDA can be significantly and substantially increased. The reaction is preferably carried out at a temperature range of about 30°C to about 150°C, more preferably about 30°C to about 140°C. When the temperature is between about 80°C and about 130°C, the reaction time is from about 1 hour to about 5 hours. 40 The MDTC used in the process according to the invention may contain water. The possibility of using "wet" MDTC is a fundamental advantage over the previous processes - which use only dry MDTC. MDTC is a known toxic substance 45 and its use in dry form is likely to result in contamination of processing plants with MDTC dust. This environmental pollution risk is greatly reduced if wet MDTC is used. When used in the process according to the invention 50 , the MDTC may contain up to about 10% by weight of water. In addition, unlike current processes, water can be added to the mixture as a separate reagent. The total amount of water in the reaction mixture is preferably less than about 30 g of water per 0.5 mol of MDTC. As shown in the examples below, The presence of water in an amount of 30 g or less per 0.5 mol of MDTC has no adverse effect on the formation of the product. However, if the amount of water is increased to 60 g or more, the yield of the TDA product decreases. The reaction of TFA and MDTC is carried out in the presence of a solvent. In one embodiment, trifluoroacetic acid itself serves as a solvent. However, it is preferred to use an aprotic aromatic cosolvent. Such cosolvents are well known in the art. Examples of such preferred cosolvents include toluene, xylene, cumene and mesitylene. Toluene is particularly preferred. The amount of cosolvent can vary widely, as can be readily determined by one skilled in the art. If a cosolvent is used, it is present in an amount of from about 0.5 moles to about 3.5 moles of toluene per mole of MDTC. Preferably, the amount of toluene is from about 1.5 moles to about 3.0 moles, more preferably from about 2.5 moles to about 3.0 moles, per mole of MDTC. The reaction can be carried out by mixing the desired total amount of MDTC and TFA. Any other method of addition can be used. A catalyst may optionally be added to the reaction mixture of MDTC and TFA. A preferred catalyst is, for example, p-toluenesulfonic acid. If toluenesulfonic acid is used, it is present in an amount of about 2.0 g per mole of MDTC. Water is formed as a reaction product of the reaction between TFA and MDTC. Additional water may be present due to recycle streams. The water is removed from the reaction mixture by azeotropic distillation. The azeotropic removal of water is easily achieved in the presence of the solvent, especially when toluene is used as a co-solvent. The temperature required for the complete reaction is suitable for the azeotropic removal of water and excess trifluoroacetic acid. No further work-up is therefore required. The removal of the bisthiadiazole product is described below. Another aspect of the invention provides a process for preparing TDA by reacting MDTC and TFA to obtain a mixture of TDA and 2,5-bis(methylthio)-1,3,4thiadiazole (bis by-product), and then selectively removing the bis by-product therefrom by acidifying the reaction mixture and separating the products. The reaction temperatures for MDTC and TFA are the same as those given above. MDTC and TFA can be used in any convenient ratio. Either reagent can be present in molar excess. Thus, the molar ratio of MDTC to TFA can be from about 4:1 to about 1:5. When MDTC is present in molar excess, the molar ratio of MDTC to TFA is preferably from about 2:1 to about 1.5:1; when TFA is present in molar excess, the molar ratio of MDTC to TFA is preferably from about 1:1.25 to about 1:2.0. HU 221 653 B1 is in the works. If the ratio of MDTC to TFA is reduced, the amount of bis-byproduct resulting from the reaction of MDTC and TFA is also reduced. As explained above, the reaction of MDTC and TFA is preferably carried out in the presence of a co-solvent. Preferred co-solvents are the same as those mentioned above. Most preferably, toluene can be used. The mixture is acidified with a concentrated inorganic acid, such as hydrochloric acid, sulfuric acid or nitric acid. The acid preferably has a pKa value of about 1 to about 4. Sulfuric acid is preferably used. The concentration of sulfuric acid is from about 55% to about 95%, preferably about 70%. When 70% sulfuric acid is used, the amount of sulfuric acid added to the reaction mixture is from about 2 moles of sulfuric acid to about 10 moles of sulfuric acid per mole of bis-by-product, preferably from about 4 moles to about 7 moles of sulfuric acid per mole of bis-by-product. Acidification is generally carried out at a temperature of between about 10°C and about 60°C, preferably between about 20°C and about 40°C, more preferably between about 25°C and about 30°C. The following examples illustrate preferred embodiments of the invention, but do not limit the scope of the invention in any way. Examples Example 1 Preparation of 2-(Methylthio)-5-(trifluoromethyl)-1,3,4-thiadiazole (TDA) using methyldithiocarbazinate (MDTC) and excess trifluoroacetic acid (TFA) A) General requirement 125 g of toluene are weighed into a flask, then 67.9 g (0.5 mol) of methyl dithiocarbazinate (MDTC) (active ingredient content 90%, 5% water and 5% impurities) are mixed in. To this mixture, while stirring, 114 g (1.0 mol) of TFA are added over 10-15 minutes without cooling. During the addition of TFA, the temperature of the mixture increases to approximately 38 °C. The mixture is heated to about 70°C and maintained at this temperature for about 3 hours. The reaction mixture is then heated to boiling point (about 115-116°C) and the water and distillable TFA are removed. This temperature is maintained for about 10 minutes, when no more aqueous phase separates from the condensate. The yield of TDA is about 90-93%. B) The effect of excess TFA The reaction of MDTC and TFA is carried out as described in A) above, except that the amount of TFA relative to MDTC is varied. The yield of TDA is determined for each amount of TFA. Our results are summarized in Table 1 below. Table 1 Effect of excess TFA on the yield of TDA (2.7 mol toluene / mol MDTC) TFA excess, mol% Pure yield, % Bis- byproduct, % (solvent-free) 0 70.4 9.8 10 81.5 9.4 20 88.2 6.2 30 90.2 5.5 40 91.0 4.3 50 91.1 3.8 100 92.2 1.9 200 92.8 1.2 It can be seen from the data in Table 1 that increasing the molar excess of TFA increases the yield of TDA. The largest increase in the yield of TDA is observed when the molar excess of TFA is increased from 10% to about 100%. Increasing the molar excess of TFA from about 100% to about 200% results in only a small increase in the yield of TDA. C) Effects of toluene as a solvent TDA is prepared as described in A) above, except that the amount of toluene in relation to MDTC is varied. In these experiments, 2 mol TFA is reacted with 1 mol MDTC. Our results are summarized in Table 2 below. Table 2 Effect of toluene on the yield of TDA (2.0 mol TFA / mol MDTC) Toluene, mol / MDTC, mol Net yield of TDA relative to MDTC, % 2.70 92.2 2.05 89.6 1.35 87.8 0.67 86.2 The data in Table 2 show that the yield of TDA increases with increasing toluene. The yield of TDA does not substantially improve when the amount of toluene is increased above about 2.7 moles per mole of MDTC. D) Effects of water volume In the primary reaction, water is expected from two main sources. On the one hand, the MDTC used in the reaction may contain up to about 10% by weight of water. Secondly, water can be added to the reaction mixture to increase the recovery of TFA. On this basis, we investigated the effect of water on the yield of TDA. For the purpose of our studies, 2.0 mol of TFA is reacted with 1 mol of MDTC. 2.1 mol of toluene is used per 1 mol of MDTC. The results of our studies are reported in Table 3 below. HU 221 653 Bl Table 3 Effect of water on TDA yield Added water (g) (0.5 mol batch) Net yield of TDA based on MDTC, % 0 92.0 10 91.8 20 91.9 30 91.6 35 89.2 40 88.7 50 83.7 The data in Table 3 show that the presence of up to 60 g of water per mole of MDTC in the reaction mixture does not adversely affect the net yield of TDA. However, when 1.5 mol of TFA is reacted with 1 mol of MDTC, the presence of 30-40 g of water per mole of MDTC significantly reduces the net yield of TDA (see Table 4). Table 4 Effect of water on TDA yield Net yield of TDA based on MDTC of added water (g) (0.5 mol batch), % 0 91.1 10 90.6 15 90.1 20 89.3 30 87.5 35 84.2 40 83.1 Example 2 Reducing the amount of bis-byproduct The major by-product from the reaction of MDTC and TFA is 2,5-bis(methylthio)-1,3,4-thiadiazole (the bis by-product). This bis by-product can be removed by acidification after phase separation. The effects of acidification on the removal of the bis-byproduct 5 and the yield of TDA are investigated as follows. After the reaction of TFA and MDTC, the reaction mixture is cooled to about 25-30 °C and treated with hydrochloric acid or sulfuric acid. The amount of bis-byproduct is then determined. The data in Table 1 above show that the formation of the bis by-product depends on the molar excess of TFA used in the initial reaction. The formation of the bis by-product decreases as the molar excess of TFA over MDTC is increased by 15. In the following studies, the molar ratio of TFA to MDTC is set to 1.5:1. The results in Tables 5 and 6 below demonstrate the effect of temperature and agitation on byproduct removal in relation to TDA recovery. Our studies have shown that up to 10 moles of 70% sulfuric acid per mole of bis-byproduct can be used for selective removal of the bis-byproduct at a temperature of 25-30 °C. For a solution containing about 40% TDA and 60% toluene, 5 moles of 70% sulfuric acid per mole of bis-byproduct reduces the amount of bis-byproduct to about 0.1% (based on solvent-free basis). For a solution containing about 60% TDA and 40% toluene, 4 moles of 70% sulfuric acid per mole of bis-byproduct reduces the amount of bis-byproduct to about 0.1% (based on solvent-free basis). In both cases, an additional 2-3 moles of 70% sulfuric acid 35 appeared to be necessary to reduce the amount of bis-byproduct to an undetectable range. However, these experiments resulted in TDA losses of 2-3%. Reducing the amount of bis-byproduct to less than about 0.1% is difficult even using 8-10 moles of 70% sulfuric acid per mole of bis-byproduct at 60-70°C; under such conditions, the TDA loss is 5-8%. Table 5 Series I Temperature, QC Moles of 70% sulfuric acid (moles of “bis-sulfide”) Solvent-free “bis-sulfide” before sulfuric acid treatment Solvent-free “bis-sulfide” after sulfuric acid treatment % yield of pure TDA Room temperature (25 °C) 6.0 2.21% 0.17% 99.5 40 °C 6.0 2.21% 0.22% 99.1 50 °C 6.5 2.21% 0.24% 98.9 60 °C 6.5 2.21% 0.31% 98.6 HU 221 653 Bl Series II Temperature, °C Moles of 70% sulfuric acid (moles of “bis-sulfide”) Solvent-free “bis-sulfide” before sulfuric acid treatment Solvent-free “bis-sulfide” after sulfuric acid treatment % yield of pure TDA 30 °C 6.0 2.16% 0.22% 99.6 50 °C 6.0 2.16% 0.29% 99.0 70 °C 6.0 2.16% 0.38% 98.3 Repeat at 70 °C 6.0 2.16% 0.39% 98.4 Table 6 Removal of bis-by-product from TDA / toluene solution (6 moles of sulfuric acid per mole of bis-by-product to be removed) Tempera- ture RPM (during mixing) Bisz,% (at time zero) Bisz,% after 5 minutes Bisz,% after 10 minutes Bisz,% after 15 minutes Bisz,% after 20 minutes Bisz,% after 25 minutes Bisz,% after 30 minutes Bisz,% after 35 minutes Bisz,% after 40 minutes 50 100 0.543 0.367 0.333 0.265 0.210 - 0.134 - 0.085 50 300 0.543 0.103 0.039 0.015 0.017 0.017 0.014 0.025 0.019 30 300 0.543 0.053 0.017 - n / a - n / a - n / a RPM: revolutions per minute Bis: bis by-product not measured nk: undetectable quantity Based on the above, the practical option is to reduce the amount of bis-byproduct to about 0.1% in solvent-free form by using about 4-5 moles of 70% sulfuric acid per mole of bis-byproduct at a temperature of about 25-30°C. Although the invention has been described in detail above for the purpose of illustration, it is apparent that such details are for illustrative purposes only and that many changes may be made to the invention by one skilled in the art without departing from the spirit and scope of the invention. 40

Claims

1. A process for the preparation of 2-(methylthio)-5-(trifluoromethyl)-1,3,4-thiadiazole, characterized in that (a) methyl dithiocarbazinate is reacted with trifluoroacetic acid in the absence of phosphorus trichloride to produce a mixture of 2-(methylthio)-5-(trifluoromethyl)-1,3,4-thiadiazole and 2,5bis(methylthio)-1,3,4-thiadiazole; and (b) 2,5-bis(methylthio)1,3,4-thiadiazole is selectively removed by acidifying the reaction mixture and then by subsequent phase separation.

2. The process according to claim 1, characterized in that the mixture is acidified with a concentrated inorganic acid.

3. The process according to claim 2, characterized in that hydrochloric acid, sulfuric acid or nitric acid is used as the concentrated inorganic acid.

4. The method according to claim 3, characterized in that the inorganic acid used is sulfuric acid with a concentration ranging from 55 percent to 95 percent.

5. The process according to claim 4, characterized in that the amount of sulfuric acid added to the reaction mixture ranges from 2 mol to 10 mol per 1 mol of 2,5-bis(methylthio)-1,3,4-thiadiazole.

6. The method according to claim 1, characterized in that the acidification is carried out in a temperature range from 20 °C to 60 °C.

7. The process according to claim 1, characterized in that the reaction is carried out in the presence of a solvent.

8. The process according to claim 7, characterized in that trifluoroacetic acid is used as the solvent.

9. The process of claim 7, wherein an aprotic aromatic cosolvent is used.

10. The process according to claim 1, characterized in that the methyl dithiocarbazinate is used in a molar ratio of 1:1 to 1:3 relative to the trifluoroacetic acid.