HK1021898A - A process for producing 2-(methylthio)-5-(trifluoromethyl)-1,3,4-thiadiazole - Google Patents

Description

Preparation method of 2- (methylthio) -5- (trifluoromethyl) -1,3, 4-thiadiazole

The field of the invention is the synthesis of thiadiazoles. More particularly, the present invention relates to an improved process for preparing 2- (methylthio) -5- (trifluoromethyl) -1,3, 4-thiadiazole using trifluoroacetic acid and methyldithiocarbazinate.

The current process for the preparation of 2- (methylthio) -5- (trifluoromethyl) -1,3, 4-thiadiazole is limited by the excessive cost of applying the laboratory process to an industrial scale. Many of the current reports have been made based on laboratory studies and, therefore, little information has been provided regarding the reaction conditions, particularly the reactants, which will affect the yield and purity of the product. In addition, the methods and reactions developed in the laboratory cannot be directly applied to industrial scale production, since such laboratory methods typically involve the use of expensive reactants and/or expensive techniques (e.g., separation and purification methods).

U.S. Pat. No. 3,562,284 discloses a process for preparing certain 2- (alkylthio) -5- (haloalkyl) -1,3, 4-thiadiazoles such as 2- (methylthio) -5- (trifluoromethyl) -1,3, 4-thiadiazole by reacting methyldithiocarbazinate with a carboxylic acid anhydride (e.g., trifluoroacetic anhydride) or carboxylic acid (e.g., trifluoroacetic acid) in a solvent (e.g., toluene). The reaction can be carried out in the presence of phosphorus trichloride and pyridine with addition of sulfuric acid (DE-A-3,422,861) or using phosgene, for example trifluoroacetyl chloride, and diethylene glycol dimethyl ether, and pyridine and sulfuric acid (DE-A-3,722,320).

The first method described above is not suitable for industrial mass production because the reactants (anhydrides) are expensive and they are used in excess. In addition, only half of the reacted portion is used due to the use of anhydride. The reaction with carboxylic acids, phosphorous trichloride, pyridine, sulfuric acid and phosgene requires an extended finishing step in which the pyridine is separated and recovered. In addition, phosphorus trichloride forms a reaction product which is only sparingly soluble, which makes the mixing operation difficult and generates unacceptably large amounts of waste. Finally, the yields obtained with such processes are unacceptably low.

Other processes for the preparation of 2- (substituent) -5- (trifluoromethyl) -1,3, 4-thiadiazoles include reacting a carboxylic acid (e.g., trifluoroacetic acid) with a dithiocarbazate (dithiocarbazic ester) in the presence of phosphorus oxychloride or polyphosphoric acid, see, for example, US5,162,539 and Gyoefi and Cssaviasy, Hungary academy of sciences Chemicals (Acta Chimica academia scientific Hungarica), Vol.82 (1):91-97,1974 ]. The use of such phosphorus compounds results in the formation of a waste product containing unacceptably high levels of phosphate, thus creating an environmentally hazardous problem. Furthermore, the method requires the use of dry methyl dithiocarbazinate (a spasmodic agent). In the dry state, this material presents a serious industrial hygiene problem.

Therefore, there is a need in the art for an efficient, high yield, practical and safe process for the industrial large scale production of 2- (methylthio) -5- (trifluoromethyl) -1,3, 4-thiadiazole. The present invention provides such a method.

The present invention provides a process for preparing 2- (methylthio) -5- (trifluoromethyl) -1,3, 4-thiadiazole. The process comprises the steps of reacting methyldithiocarbazinate with excess trifluoroacetic acid in a solvent and removing water and excess trifluoroacetic acid.

Trifluoroacetic acid is preferably present in a 10 to 500 mole% excess relative to methyldithiocarbazinate. That is, the molar ratio of trifluoroacetic acid to methyldithiocarbazinate is from about 1.1: 1 to about 5: 1. More preferably, the molar ratio of trifluoroacetic acid to methyldithiocarbazinate is from about 1.25: 1 to about 3.5: 1, and particularly preferably from 1.25: 1 to about 2.0: 1.

The reaction temperature is preferably from about 30 ℃ to about 150 ℃, more preferably from about 30 ℃ to about 140 ℃. When the temperature is from about 80 ℃ to about 130 ℃, the reaction time is from about 1 to about 5 hours.

The methyldithiocarbazinate used in the present process may contain up to about 50% by weight water. The total amount of water in the reaction mixture is preferably less than 30g of water present for 0.5mol of methyl dithiocarbazinate.

The reaction of trifluoroacetic acid with methyldithiocarbazinate is carried out in the presence of a solvent. In one embodiment, trifluoroacetic acid itself functions as the solvent. However, the solvent is preferably an aromatic co-solvent, such as toluene, xylene, cumene or 1,3, 5-trimethylbenzene. Among them, toluene is particularly preferred.

The use of a co-solvent allows for a reduction in the amount of trifluoroacetic acid used as compared to reactions without a co-solvent. The co-solvent is used in an amount of at least about 0.5 moles, preferably from about 1.5 to about 3.0 moles, more preferably from about 2.5 to about 3.0 moles, per 1 mole of methyl dithiocarbazinate.

In the present process, water is a by-product. Water and excess trifluoroacetic acid can be azeotropically removed from the reaction mixture by distillation.

Detailed description of the invention I

The present 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 novel process of the present invention uses Methyldithiocarbazinate (MDTC) and trifluoroacetic acid (TFA) as the primary reactants. The process allows production of TDA in high yield while efficiently removing by-products and recovering the main reactants. Method of using excess trifluoroacetic acid

In one aspect, the process of the invention for preparing 2- (methylthio) -5- (trifluoromethyl) -1,3, 4-thiadiazole includes reacting methyldithiocarbazinate with an excess of trifluoroacetic acid, optionally in the presence of a co-solvent, and removing the water produced and the excess trifluoroacetic acid.

MDTC prepared by any method can be used in the process of the invention. Particularly preferred methods for preparing MDTC are disclosed in U.S. patent application Ser. Nos. 08/743,763, 08/743,764, and 08/743,755, all of which were filed 11/7/1996. The disclosure of all of these inventions is incorporated herein by reference. TFA is commercially available.

The TFA is preferably present in an excess of 10 to 500 mol% relative to the MDTC. That is, 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 to MDTC is from about 1.25: 1 to about 3.5: 1, and more preferably from about 1.25: 1 to about 2.0: 1. As shown in the examples below, increasing the molar excess of TFA relative to MDTC improves the yield of TDA as shown in Table 1.

The reaction temperature for the reaction is preferably from about 30 ℃ to about 150 ℃, more preferably from about 30 ℃ to about 140 ℃. The reaction time depends on the temperature. When the temperature is from about 80 ℃ to about 130 ℃, the reaction time is from about 1 to about 5 hours.

The MDTC used in the present invention may contain water. The use of "wet" MDTC provides significant advantages over prior methods that use only MDTC. MDTC is known as a toxic substance, which causes pollution of air in a treatment plant due to generation of MDTC dust when it is used in a dry state. This environmental hazard is greatly reduced if the use of wet MDTC is allowed. When used in the process of the present invention, MDTC allows for up to about 50 weight percent water.

Unlike prior art processes, water can be introduced into the reaction via a recycle stream. The total amount of water in the reaction mixture is preferably less than about 30g of water per 0.5mol of MDTC. As shown in the examples below, the presence of water in an amount of 30g or less per 0.5mol of MDTC has no adverse effect on the product formation. Increasing the moisture to 40g or more results in a decrease in the yield of the product (TDA).

The reaction of TFA with MDTC is carried out in the presence of a solvent. In one embodiment, trifluoroacetic acid itself functions as the solvent. However, it is preferred to use an aprotic aromatic co-solvent. Such co-solvents are well known in the art. Preferred examples of such co-solvents are toluene, xylene, cumene and 1,3, 5-trimethylbenzene. Among them, toluene is particularly preferred.

The amount of co-solvent used can vary over a wide range and can be readily determined by one skilled in the art. When a co-solvent is used, it should be used in an amount of at least about 0.5 moles, preferably from about 1.5 to about 3.0 moles, more preferably from about 2.5 to about 3.0 moles, per 1 mole of MDTC. The reaction can be carried out by mixing all the required amounts of MDTC and TFA. All other ways of addition are also applicable.

The reaction mixture of MDTC and TFA may optionally contain a catalyst. Examples of catalysts are p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid. When the catalyst is used, it is used in an amount of about 2.0g per 1mol of MDTC.

Water is formed as the reaction product of the reaction of MDTC with TFA. Additional water may also be present due to the recycle stream. Water may be removed from the reaction mixture by azeotropic distillation. Azeotropic removal of water can be easily accomplished in the presence of a solvent, particularly where toluene is used as a co-solvent. Where a co-solvent is used, water may be removed from the condensate as a separate phase. The temperature used to complete the reaction is sufficient to remove the water and excess trifluoroacetic acid by distillation. No additional processing steps are therefore required. Variation of stoichiometric proportions of reactants

Any suitable ratio of MDTC to TFA may be used. Either reactant may be present in molar excess. Thus, the molar ratio of MDTC to TFA can range from about 4: 1 to about 1: 5. When MDTC is present in molar excess, the preferred molar ratio of MDTC to TFA is from about 2: 1 to about 1.5: 1. When TFA is present in molar excess, the preferred molar ratio of MDTC to TFA is from about 1: 1.25 to about 1: 3.50. The amount of 2, 5-bis (methylthio) -1,3, 4-thiadiazole formed by the reaction of MDTC and TFA decreases as the ratio of MDTC to TFA decreases.

As mentioned above, the reaction of MDTC with TFA is preferably carried out in the presence of a co-solvent. Preferred co-solvents are the same as described above. The most preferred of these is toluene.

The following examples are intended to illustrate preferred embodiments of the invention, but are in no way intended to limit the specification or the claims. Example 1

Preparation of 2- (methylthio) -5- (trifluoromethyl) -1,3, 4-Thiadiazole (TDA) A using MDTC and excess TFA general procedure

Toluene (125g) was added to a flask. To the flask was added 67.9g (0.5mol) of Methyl Dithiocarbazinate (MDTC) (90% a.i., 5% water and 5% impurities) to form a slurry. Trifluoroacetic acid (TFA) (114g,1.0mol) was added to the slurry and stirred without cooling for 10-15 minutes. The temperature of the mixture rose to about 38 ℃ upon addition of TFA. The mixture was heated to about 70 ℃ and maintained at that temperature for about 3 hours. The mixture was then heated to reflux (about 115 ℃ C. to 116 ℃ C.) to remove water and any distillable TFA. The temperature was maintained for about 10 minutes until no aqueous phase separated from the condensate. The yield of TDA was about 90% to 93%. B. Effect of excess TFA

The reaction of MDTC and TFA was carried out according to the procedure described in (A) above, except that the amount of TFA relative to MDTC was varied. TDA yield was determined for each TFA amount. The results obtained are summarized in table 1 below.

TABLE 1 influence of TFA excess on TDA yield (2.7mol toluene/mol MDTC)

TFA excess, based on	Net yield%	% two by-products (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

As can be seen from the data in table 1, the yield of TDA increased with increasing molar excess of TFA. The greatest improvement in TDA yield occurred when the molar excess of TFA was increased from 10% to about 100%. While there was only a small increase in TDA yield when the molar excess of TFA was increased from about 100% to about 200%. C. Influence of toluene as solvent

TDA was prepared by following the procedure described in (A) above except that the amount of toluene was varied with respect to the amount of MDTC. In these studies, 2mol TFA was reacted with 1mol MDTC. The results obtained are summarized in Table 2 below.

TABLE 2 influence of toluene on the TDA yield (2.0mol TFA/mol MDTC)

Toluene moles/MDTC moles	Net yield of TDA based on 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 usage. When the amount of toluene used exceeds about 2.7mol per 1mol of MDTC, the TDA yield is not substantially increased. D. Influence of Water content

It is anticipated that the water in the initial reaction comes from two major sources. First, the MDTC used in the reaction may contain water. Second, water may be added to increase TFA recovery. The effect of water on TDA recovery was therefore investigated. In these studies, 2.0mol TFA were reacted with 1mol MDTC. 2.1mol of toluene were used per 1mol of MDTC. The results of these studies are shown in table 3 below.

TABLE 3 Effect of Water on TDA yield

Added water, g, (0.5M 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 60g of water per 1mol of MDTC in the reaction medium has no adverse effect on the net yield of TDA. However, when 1mol of MDTC was reacted with 1.5mol of TFA, the net yield of TDA was significantly reduced in the presence of 30-40 g of water per 1mol of MDTC (see Table 4).

TABLE 4 Effect of Water on TDA yield

Added water, g (0.5M batch)	Net yield of TDA based on MDTC%
		0	91.1
10	90.6
		15	90.1
20	89.3
		30	87.5
35	84.2
		40	83.1

Although the foregoing description has been described in detail for the purpose of illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be limited by the claims.

Claims (10)

1. A process for preparing 2- (methylthio) -5- (trifluoromethyl) -1,3, 4-thiadiazole comprising the steps of:

(a) reacting methyldithiocarbazinate with an excess of trifluoroacetic acid; and

(b) water and excess trifluoroacetic acid were removed.

2. The method of claim 1 wherein the methyldithiocarbazinate contains up to about 50% by weight water.

3. The process of claim 1 wherein the molar ratio of trifluoroacetic acid to methyldithiocarbazinate is from about 1.1: 1 to about 5: 1.

4. The process of claim 1 wherein said reaction is carried out at a temperature of from about 30 ℃ to about 150 ℃.

5. The process of claim 1 wherein said reaction is carried out in the presence of a solvent.

6. The process of claim 5 wherein the solvent is trifluoroacetic acid.

7. The process of claim 5, wherein an aprotic aromatic co-solvent is used.

8. The process of claim 7 wherein the co-solvent is toluene, xylene, cumene or 1,3, 5-trimethylbenzene.

9. The process of claim 8 wherein the co-solvent is toluene and the amount of toluene used is at least about 0.5 mole per 1 mole of methyldithiocarbazinate.

10. The process of claim 1 wherein the water and excess trifluoroacetic acid are removed by distillation.