Title of Invention	"PROCESS FOR THE PREPARATION OF 5-SUBSTITUTED-1,3,4-OXADIAZOLE-2-THIOLS AS NEW UREASE AND NITRIFICATION INHIBITORS"
Abstract	5-Substituted-l,3,4-oxadiazole-2-thiols of formula, 1, as urease and nitrication inhibitors and an environment benign process for the preparation of the same by reacting carboxylic acid hydrazide, RCONHNH2, with carbon disulphide, CS2, in an energy transfer medium under microwave irradiation (MW1); wherein R is C\| to Cis saturated or unsaturated alkyl, unsubstituted or substituted by halogen, nitro, OR' - R' = CHs, C2Hs and or hydroxy; CG to €20 aralkyl or aryl, unsubstituted or substituted by C1 to C4 alkyl, halogen, nitro, OR' - R' = CH3, C2H5 and or hydroxy; heterocyclyl, heterocycloalkyi and the like, are described. Following simple laboratory conditions, near quantitative yields of the resultant derivatives have been reported. Methods of the using the materials along with the various nitrogenous fertili/crs arc described.

Title of Invention

"PROCESS FOR THE PREPARATION OF 5-SUBSTITUTED-1,3,4-OXADIAZOLE-2-THIOLS AS NEW UREASE AND NITRIFICATION INHIBITORS"

Abstract

5-Substituted-l,3,4-oxadiazole-2-thiols of formula, 1, as urease and nitrication inhibitors and an environment benign process for the preparation of the same by reacting carboxylic acid hydrazide, RCONHNH2, with carbon disulphide, CS2, in an energy transfer medium under microwave irradiation (MW1); wherein R is C| to Cis saturated or unsaturated alkyl, unsubstituted or substituted by halogen, nitro, OR' - R' = CHs, C2Hs and or hydroxy; CG to €20 aralkyl or aryl, unsubstituted or substituted by C1 to C4 alkyl, halogen, nitro, OR' - R' = CH3, C2H5 and or hydroxy; heterocyclyl, heterocycloalkyi and the like, are described. Following simple laboratory conditions, near quantitative yields of the resultant derivatives have been reported. Methods of the using the materials along with the various nitrogenous fertili/crs arc described.

Full Text	3. Preamble to the description "The following specification particularly describes the invention and the manner in which it is to be performed. This invention relates to a new process tor the preparation of 5-substituted-1,3,4- oxadiazole-2-thiols (1) and their new use as ureasc and nitrification inhibitors.This invention relention to a new srooess for the preparation of 5- Substituulid-1,2,3-okdiaeole-2 this is (1) and their new use as usease and nitracation in histers,(Formula Removed) R is C1 to C15 saturated or unsaturated alky!, unsubstituted or substituted by halogen, nitro, OR' - R' = CH3, C2H5 and or hydroxy; C6 to C2o aralkyl or aryl, unsubstituted or substituted by C1 to C4 alkyl, halogen, nitro, OR' - R' = CH3, C2H5 and or hydroxy; heterocyclyl, heterocycloalkyl and the like. Background 5-Substituted-l,3,4-oxadiazole-2-thiols are important biologically active compounds. These l,3,4-oxadiazole-2-thiols are reportedly useful as tone improvers in photography (US Patent No 3,173,789) and also as side chain of well-known cephalosporin antibiotics (US Patent No 4,020,060). 5-Substituted-l,3,4-oxadizoles are also known to exhibit antimalarial, nematocidal, antimicrobial activities and have other important medicinal properties. 5-substituted-l,3,4-oxadiazole-2-thiols have not been known to act as urease and nitrification inhibitors. There is, thus, scope tor developing a new environmentally benign, tast, high yielding and atom efficient process for the preparation ol"5-substituted-l,3,4-oxadiazole-2-thiols and to tind their new use as urease and nitrification inhibitors. Prior Art Several procedures are available to produce 5-substituted-l,3,4-oxadiazole-2- thiols. J. Chem. Soc. 4811-4817 (1952), J. Am. Chcm. Soc. 78, 4475-4478 (1956) and Main Group Metal Chemistry 20(6), 367-372 (1997); each discloses a process tor preparing 5-substituted-l,3,4-oxadiazole-2-thiols from carboxylic acid hydrazide following its reaction with carbon disulphide in the presence of potassium hydroxide in alcohol. These processes suffer from the disadvantages of longer reaction time, from hours to days, low atom economy or atom utilization and low yields. J. Am. Chem. Soc. 77, 400-403 (1955) and Synthetic Communications 32(1), 111-114 (2002) disclose processes for preparing 5-substituted-l,3,4-oxadiazole-2-thiols from acyl dithiocarbazate salts. Its reaction produces good yields in less reaction time, but requires the isolation of acyl dithiocarbazate salts prepared by the reaction of carboxylic acid hydrazide with carbon disulphide. In order to make available to plants the nitrogen needed by them, they are fertilized, as is known, with ammonium compounds, which are micro bially oxidized / nitrified to nitrate in the soil in relatively short time. The nitrate is leached from soil more easily than ammonium and the leached portion, besides being non available for plant nutrition and also contributes to health and environmental hazards through contamination of ground water as well as by denitrification. Therefore, rapid nitrification is undesirable. In order that the tertilizer is utilized well, nitrification inhibitors are added to the soil. These inhibitors keep nitrogen in ammonium form and thus regulate its oxidation, thereby extending the availability to plants. This also enables a check on nitrogen losses, thereby improving nitrogen utiliztion efficiency. Several nitrification inhibitors are being reported from time to time and those reported recently are the pyrazole derivatives (US Pat No 3,635,690; US Pat No 4,969,946; US Pat No 5,972,064; US Pat No 6,488,734 131; US Pat No 6,802,882 B2). Most of the known nitritication inhibitors are not still fully satisfactory as they have one or more of the following disadvantages: Complex synthetic process High volatility Low stability Requirement of further modifications of the active molecule Addition of other compounds High cost 5-substituted-l,3,4-oxadiazole-2-thiols have not been known to act as nitrification inhibitors. The present invention reports the use of such derivatives as effective urease and nitrification inhibitors and a process of obtaining such derivatives. Statement of the invention This invention relates to 5-substituted-l,3,4-oxadiazole-2-thiols of formula 1 as urease and nitrification inhibitors and an environment benign process tor the preparation of the same by reacting carboxylic acid hydrazide RCONHNH2., with carbon disulphide, CS2, in an energy transfer medium under microwave irradiation as follows (Formula Removed) R = C1 to C15 saturated or unsaturated alkyl, unsubstituted or substituted by halogen, nitro, OR' - R' = CH3, C2H5 and or hydroxy; C6 to C2o aralkyl or aryl, unsubstituted or substituted by Ci to C4 alkyl, halogen, nitro, OR' - R' = CH3, O2H5 and or hydroxy; heterocyclyl, heterocycloalkyl and the like. The molar ratio of carboxylic acid hydrazide to carbon disulphide is generally from 0.1:1 to 2:1. The reaction is carried out in an energy transfer medium which is selected from amongst alcohols, glycols, organic acids, sulphoxides, amides, azines and the like, preferably pyridine, dimethyl sulphoxide, N,N-dimethyl amides, more preterably, dimethyl sulphoxide, N,N-dimethyltbrmamide, N,N-dimethyl acetamide. The reaction is carried out in a microwave oven at 90-900 watts for a period of instantaneous to 20 minutes, preterably 20 seconds to 10 minutes; more preterably 30 seconds to 5 minutes. The reaction product is subsequently worked up, following the usual prescribed methods. This process is fast, high yielding and environment friendly. As the reaction does not require any base such as potassium hydroxide under MW1; this process has higher atom economy as compared to earlier reported methods, that is, more number of atoms present in reactants are utilized to yield the product. Besides this, reaction rates were also fast with better yields. The invention also describes the use of l,3,4-oxadiazole-2-thiols as urease and nitrification inhibitors either through on the spot physical admixture or applied otherwise jointly or separately with the nitrogen fertilizers or as ready to use preparations of the fertilizer and the inhibitor. The application of inhibitor at 1-20% levels, preterably 5-10% level of the nitrogen level of the fertilizer has been found to be effective. 4. Description Detailed description of the invention I Process • t An environment benign method of producing 5-substituted-l,3,4-oxadiazole-2-thiols has been developed. The process has higher atom utilization, higher yield, less reaction time and simple work up procedure. This objective has been accomplished by reacting carboxylic acid hydrazide, RCONHNH2, with carbon disulphide, CS2, in a suitable energy transfer medium under microwave irradiation (MW1). The molar ratio of carboxylic acid hydrazide to carbon disulphide is generally from 0.1:1 to 2:1, preferably from 0.2:1 to 1.5:1, more preferably from 0.3:1 to l:land most preferably from 0.5:1 to 0.8:1. Suitable energy transfer medium means a solvent, which absorbs microwave energy efficiently and is therefore heated rapidly under microwave irradiation. It also has a boiling point that is at least 20-30 °C higher than the desired reaction temperature. Such suitable energy transfer medium may be any solvent having high dielectric constant and high boiling point. Suitable solvents arc generally alcohols, glycols, water, organic acids, sulphoxides, amides, azines, preferably pyridine, dimethyl sulphoxide, N,N-dimethyl amides, particularly dimethyl sulphoxide, N,N-dimethyl formamide, N,N-dimethy lacetamide. The amount of solvent used is generally from 0.3 to 20 ml per gram of carboxylic acid hydrazide, preferably from 1 to 15 ml per gram of carboxylic acid hydrazide, more preferably from 1 to 10 ml per gram of carboxylic acid hydrazide and most preferably from 2 to 8 ml per gram of carboxylic acid hydrazide. The power levels of microwave oven at which reaction was irradiated were generally from 90 to 900 watts, preferably rrom 270 to 900 watts, more preferably rrom 360 to 900 watts and most preferably from 540 to 900 watts. The time of microwave irradiation varied generally from 10 seconds to 20 minutes, preferably from 20 seconds to 10 minutes, more preferably from 30 seconds to 8 minutes, and most preferably from 30 seconds to 5 minutes. I'he work up procedure is simple. 'I'he reaction mixture is taken out from oven, cooled to room temperature; water added and the separated product filtered, dried and recrystallised. The amount of water added was generally from 1 to 200 ml per gram of carboxylic acid hydrazide taken initially, preferably from 5 to 100 ml per gram of carboxylic acid hydrazide taken initially, more preferably from 10 to 80 mi per gram of carboxylic acid hydrazide taken initially, and most preferably from 10 to 50 ml per gram of carboxylic acid hydrazide taken initially. In case the product remains miscible after addition of water; it was extracted with ether. Organic layer was separated, passed through anhydrous sodium sulphate and the solvent removed to get the product. Examples 1. Preparation Example 1 In a 250 ml conical flask fitted with a gas outlet tube, 0.68 g (0.5 millimole) of benzoic acid hydrazide, 0.57 g (0.75 millimole) of carbon disulphide and 2 ml of dimethyl sulphoxide were taken and irradiated under microwaves tor 70 seconds at 900 watts.T'he reaction product was taken out from microwave oven, cooled and 20 ml water added to it. The resulting suspension was filtered off, giving 0.77 g of 5-phenyl-1,3,4,-oxadiazole-2-thiol. The yield was 87 per cent. Example 2 In a 250 ml conical flask fitted with a gas outlet tube, 0.68 g (0.5 millimole) of benzoic acid hydrazide, 0.57 g (0.75 millimole) of carbon disulphide and 1 ml of dimethyl sulphoxide were taken and irradiated under microwaves for 120 seconds at 540 watts. The resultant reaction product was taken out from microwave oven, cooled and 15 ml water added to it. The resulting suspension was filtered off, giving 0.72 g of 5-phenyl-l,3,4,-oxadiazolc-2-thiol. The yield was 81 per cent. Example 3 In a 250 ml conical tlask fitted with a gas outlet tube, 0.68 g (0.5 millimole) of benzoic acid hydrazide, 0.57 g (0.75 millimole) of carbon disulphide and 2 ml of dimethyl formamide were taken and irradiated under microwaves for 120 seconds at 900 watts. The resultant reaction product was taken out from microwave oven, cooled and 25 ml water added to it. The resulting suspension was filtered off, giving 0.67 g of 5-phenyl-l,3,4,-oxadiazole-2-thiol. The yield was 75 per cent. Example 4 In a 250 ml conical tlask fitted with a gas outlet tube, 0.63 g (0.5 millimole) of furoic acid hydrazide, 0.57 g (0.75 millimole) of carbon disulphide and 2 ml of dimethyl sulphoxide were taken and irradiated under microwaves tor 75 seconds at 900 watts. The resultant reaction product was taken out from microwave oven, cooled and 20 ml water added to it. The resulting suspension was filtered off, giving 0.632 g of 5-furyl-1,3,4,-oxadiazole-2-thiol. The yield was 70 per cent. Example 5 In a 250 ml conical flask fitted with a gas outlet tube, 0.44 g (0.5 millimole) of propanoic acid hydrazide, 0.57 g (0.75 millimole) of carbon disulphide and f 'ml of dimethyl sulphoxide were taken and irradiated under microwaves for 80 seconds at 900 watts. The resultant reaction product was taken out from microwave oven, cooled and 20 ml water added to it. The resulting suspension was filtered off, giving 0.468 g of 5-ethyl-l,3,4,-oxadiazole-2-thiol. The yield was 72.8 per cent. 11. Nitrification inhibition Compounds suitable ibr use as nitrification inhibitors are 5-substituted-l,3,4-oxadiazole-2-thioIs of general formula 1 (Formula Removed) in which R is generally C1 to C15, saturated or unsaturated alkyl, unsubstituted or substituted by halogen, nitro, OR' - R' = CH3, C2H5 and or hydroxy; C6 to C2o aralkyl or aryl, unsubstituted or substituted by C1 to C4 alkyl, halogen, nitro, OR' - R' = CH3, C2H5 and or hydroxy; heterocyclyl, heterocycloalkyl etc. '1'he 5-substituted-l,3,4-oxadiazole-2-thiols of formula 1 preferably contain units which are derived from acetic acid hydrazide, propanoic acid hydrazide, butanoic acid hydrazide, pentanoic acid hydrazide, octanoic acid hydrazide, decanoic acid hydrazide, dodecanoic acid hydrazide, benzoic acid hydrazide, furoic acid hydrazide and the like. The rate of application of 5-substituted-l,3,4-oxadiazole-2-thiols is generally from 0.01 to 30% of urea nitrogen, preierably 1 to 20% of urea nitrogen, and more preferably from 5 to 10% of urea nitrogen. The 5-substituted-l,3,4-oxadiazole-2-thiols of formula 1 which can be prepared in a simple manner from cost effective starting materials are especially distinguished in their use as nitrification inhibitors in that they effectively inhibit the nitrification of ammonium nitrogen in the soil over a long period of time. Example 6 Nitrification inhibitory activity: The test chemicals were evaluated in a sandy loam soil \|lnceptisol\| at 10% of applied urea-N, with urea alone as control. The experiments were laid following complete randomised design. One hundred gram of air dried, finely ground and sieved (10 mesh) soil was taken in 250 ml beakers and mixed with calculated amount of solutions of the test chemical followed by addition of 20 mg of urea-N in aqueous solution in each treatment. Nitrapyrin and DCL), Uicyandiamide, were employed as reference inhibitors at 5% of applied urea-N. The experiment was conducted in triplicate. The contents of beakers were mixed and incubated at 30 °C maintaining moisture at 50 per cent of water holding capacity of the soil throughout the study. The moisture level was maintained by adding the required amount of distilled water every alternate day. Samples were withdrawn at 14, 28, 42 and 56 days of incubation; extracted with 1M sodium sulphate solution and estimated for ammonium, nitrite and nitrate nitrogen The percentage nitrification inhibition was calculated as follows {disclosed in Plant Soil 55, 487-490 (1980)}. Nitrification rate = {(NO3'-N + NO2"-N) x 100} / {(NH4'-N + NO3"-N + NO2"-N)} Percentage nitrification inhibition = {(Nitrification rate in control - Nitrification rate in sample) 100} / {Nitrification rate in control} As an example 5-furyI-l,3,4-oxadiazole-2-thiol, 9, showed 60.6 and 45.4% nitrification inhibition on 28th and 42nd day of incubation as compared to 58.4 & 13% nitrification inhibition by dicyandiamide on respective days (Table 1). Table 1 Nitrification inhibitory activity of sonic l,3,4-oxadiazole-2-thiols (1-11) (Table Removed) US Patent references cited James R King and James R Moran. Method and composition for inhibiting silver'sludge in thiosulfate monobaths. 1965, 3,173,789. Jeffrey D Griffith. Soil treating method and composition for conserving nitrogen in soil by addition ofapyrazole thereto. 1972, 3,635,690. Raymond C Erickson and Ronald E Bambury. 7-la-Amino-ε(3,4-methylenedioxy phenyl)acylamidojcephalosporanic acid derivatives. 1977, 4,020,060. Kim E Arndt and Ronald W McCormick. Soil treating method and composition for conserving nitrogen in naturally alkaline soil. 1972, 4,969,946. Stefan Rittinger, Norbert Rieber, Randall Evan Gold and Jurgen Dressel. Use of low- volatlity pyrazole derivatives having hydrophilic groups as nitrification inhibitors. 1999, 5,972,064. Thomas Barth, Norbert Rieber, Randall Evan Gold, Jurgen Uressel, Klaus Erhardt, Klaus Horchler von Locquengh, Edgar Leibold and Stefan Rittinger. Nitrification inhibitors, and the use of poly acids which contain a nitrification inhibitor Jor the treatment of inorganic fertilizers. 2002, 6,488,734 Bl. I'homas Barth, Norbert Rieber, Randall Evan Gold, Jurgen Dressel, Klaus Erhardt, Klaus Horchler von Locquengh, Edgar Leibold and Stetan Rittinger. Nitrification inhibitors, and the use ofpolyacids which contain a nitrification inhibitor for the treatment of inorganic fertilizers. 2004, 6,802,882 B2. Other references cited E 1 loggarth. 1952. Journal of Chemical Society. 4811 -4817. R W young and K H Wood. 1955. Journal of American Chemical Society. 77: 400-403. C Ainsworth. 1956. Journal of American Chemical Society. 78: 4475-4478. S Joshi and A V Karnik. 2002. Synthetic Communications, 32( 1): 111 -114. M Kidwai. Rajcsh Kumar and Y Goel. 1997. Main Groiip Metal Chemistry 20(6): 367- 372. KL Sahrawat. 1980. Plant Soil 55: 487-490. Claims We claim: 1. 5-Substituted-l,3,4-oxadiazole-2-thiols of formula 1 as urease and nitrification inhibitors and an environment benign process for the preparation of the same by reacting carboxylic acid hydrazide, RCONHNH2, with carbon disulphide, CS2, in an energy transier medium under microwave irradiation, (Formula Removed) 1 MW1, wherein R in formula 1 is C1 to C15 saturated or unsaturated alkyl, unsubstituted or substituted by halogen, nitro, OR' - R' = CH3, C2H5 and or hydroxy; C6, to C2o aralkyl or aryl, unsubstituted or substituted by C1 to C'4 alkyl, halogen, nitro, OR' - R' = CH3, Calls and or hydroxy; heterocyclyl, heterocycloalkyl and the like. 2. A process as claimed in claim 1, wherein the molar ratio of carboxylic acid hydrazide to carbon disulphide is generally Irom 0.1:1 to 2:1, preterably trom 0.2:1 to 1.5:1, more preferably trom 0.3:1 to l:land most preferably from 0.5:1 to 0.8:1. 3. A process as claimed in claim 1, wherein the energy transler medium may be a solvent belonging to the group of alcohols, glycols, organic acids, sulphoxidcs, amides, azines and the like, preterably pyridine, dimethyl sulphoxide, N,N-dimethyl amides, more preferably dimethyl sulphoxide, N,N-dimethyl tbrrnamide and N,N-dimethylacetamide. 4. A process as claimed in claim 1, wherein the amount of solvent used is generally from 0.3 to 20 ml per gram of carboxylic acid hydrazide, preferably from 1 to 15 ml per gram of carboxylic acid hydrazide, more preferably from 1 to 10 ml per gram of carboxylic acid hydrazide and most preferably from 2 to 8 ml per gram of carboxylic acid hydrazide. 5. A process as claimed in claim 1, wherein the power levels of microwave oven range generally from 90 to 900 watts, preferably from 270 to 900 watts, more preferably from 360 to 900 watts and most preferably from 540 to 900 watts. 6. A process as claimed in claim 1, wherein the time of microwave irradiation is generally from instantaneous to 20 minutes, preferably from 20 seconds to 10 minutes, more preferably from 30 seconds to 8 minutes, and most preferably from 30 seconds to 5 minutes. 7. 5-Substitutcd-l,3,4-oxadiazole-2-thiols of claim 1-6 for use as urease and nitrification inhibitors in compositions along with the nitrogenous materials such as urea, ammonium sulphate, calcium ammonium nitrate and the like made through their addition either separately or in combinations prepared at the time of application or manufactured as ready to use materials. 8. 5-Substituted-l,3,4-oxadiazole-2-thiols and the compositions based on them as claimed in claims 1-7 wherein the nitrification inhibitors of are used at 0.01-30% of nitrogen level of the fertilizer, preferably from 1 to 20% and more preferably from 5-10% level. 9. 5-Substituted-l,3,4-oxadiazole-2-thiols and the various compositions as claimed in any of the above claims and as described in the body of the application, for use as effective use situations in the basic and "applied agriculture.

Full Text

3. Preamble to the description
"The following specification particularly describes the invention and the manner in which it is to be performed.
This invention relates to a new process tor the preparation of 5-substituted-1,3,4-
oxadiazole-2-thiols (1) and their new use as ureasc and nitrification inhibitors.This invention relention to a new srooess for the preparation of 5- Substituulid-1,2,3-okdiaeole-2 this is (1) and their new use as usease and nitracation in histers,(Formula Removed)

R is C1 to C15 saturated or unsaturated alky!, unsubstituted or substituted by halogen, nitro, OR' - R' = CH3, C2H5 and or hydroxy; C6 to C2o aralkyl or aryl, unsubstituted or substituted by C1 to C4 alkyl, halogen, nitro, OR' - R' = CH3, C2H5 and or hydroxy; heterocyclyl, heterocycloalkyl and the like. Background
5-Substituted-l,3,4-oxadiazole-2-thiols are important biologically active compounds. These l,3,4-oxadiazole-2-thiols are reportedly useful as tone improvers in photography (US Patent No 3,173,789) and also as side chain of well-known cephalosporin antibiotics (US Patent No 4,020,060). 5-Substituted-l,3,4-oxadizoles are also known to exhibit antimalarial, nematocidal, antimicrobial activities and have other important medicinal properties. 5-substituted-l,3,4-oxadiazole-2-thiols have not been known to act as urease and nitrification inhibitors. There is, thus, scope tor developing a new environmentally benign, tast, high yielding and atom efficient process for the preparation ol"5-substituted-l,3,4-oxadiazole-2-thiols and to tind their new use as urease and nitrification inhibitors.
Prior Art
Several procedures are available to produce 5-substituted-l,3,4-oxadiazole-2-
thiols. J. Chem. Soc. 4811-4817 (1952), J. Am. Chcm. Soc. 78, 4475-4478 (1956) and
Main Group Metal Chemistry 20(6), 367-372 (1997); each discloses a process tor preparing 5-substituted-l,3,4-oxadiazole-2-thiols from carboxylic acid hydrazide
following its reaction with carbon disulphide in the presence of potassium hydroxide in alcohol. These processes suffer from the disadvantages of longer reaction time, from hours to days, low atom economy or atom utilization and low yields.
J. Am. Chem. Soc. 77, 400-403 (1955) and Synthetic Communications 32(1), 111-114 (2002) disclose processes for preparing 5-substituted-l,3,4-oxadiazole-2-thiols from acyl dithiocarbazate salts. Its reaction produces good yields in less reaction time, but requires the isolation of acyl dithiocarbazate salts prepared by the reaction of carboxylic acid hydrazide with carbon disulphide.
In order to make available to plants the nitrogen needed by them, they are fertilized, as is known, with ammonium compounds, which are micro bially oxidized / nitrified to nitrate in the soil in relatively short time.
The nitrate is leached from soil more easily than ammonium and the leached portion, besides being non available for plant nutrition and also contributes to health and environmental hazards through contamination of ground water as well as by denitrification. Therefore, rapid nitrification is undesirable. In order that the tertilizer is utilized well, nitrification inhibitors are added to the soil. These inhibitors keep nitrogen in ammonium form and thus regulate its oxidation, thereby extending the availability to plants. This also enables a check on nitrogen losses, thereby improving nitrogen utiliztion efficiency.
Several nitrification inhibitors are being reported from time to time and those reported recently are the pyrazole derivatives (US Pat No 3,635,690; US Pat No 4,969,946; US Pat
No 5,972,064; US Pat No 6,488,734 131; US Pat No 6,802,882 B2). Most of the known nitritication inhibitors are not still fully satisfactory as they have one or more of the following disadvantages:
Complex synthetic process High volatility Low stability
Requirement of further modifications of the active molecule Addition of other compounds High cost
5-substituted-l,3,4-oxadiazole-2-thiols have not been known to act as nitrification inhibitors. The present invention reports the use of such derivatives as effective urease and nitrification inhibitors and a process of obtaining such derivatives.
Statement of the invention
This invention relates to 5-substituted-l,3,4-oxadiazole-2-thiols of formula 1 as urease
and nitrification inhibitors and an environment benign process tor the preparation of the same by reacting carboxylic acid hydrazide RCONHNH2., with carbon disulphide, CS2, in an energy transfer medium under microwave irradiation as follows
(Formula Removed)
R = C1 to C15 saturated or unsaturated alkyl, unsubstituted or substituted by halogen, nitro, OR' - R' = CH3, C2H5 and or hydroxy; C6 to C2o aralkyl or aryl, unsubstituted or substituted by Ci to C4 alkyl, halogen, nitro, OR' - R' = CH3, O2H5 and or hydroxy; heterocyclyl, heterocycloalkyl and the like.
The molar ratio of carboxylic acid hydrazide to carbon disulphide is generally from 0.1:1 to 2:1.
The reaction is carried out in an energy transfer medium which is selected from amongst alcohols, glycols, organic acids, sulphoxides, amides, azines and the like, preferably pyridine, dimethyl sulphoxide, N,N-dimethyl amides, more preterably, dimethyl sulphoxide, N,N-dimethyltbrmamide, N,N-dimethyl acetamide. The reaction is carried out in a microwave oven at 90-900 watts for a period of instantaneous to 20 minutes, preterably 20 seconds to 10 minutes; more preterably 30 seconds to 5 minutes. The reaction product is subsequently worked up, following the usual prescribed methods. This process is fast, high yielding and environment friendly. As the reaction does not require any base such as potassium hydroxide under MW1; this process has higher atom economy as compared to earlier reported methods, that is, more number of atoms present in reactants are utilized to yield the product. Besides this, reaction rates were also fast with better yields.
The invention also describes the use of l,3,4-oxadiazole-2-thiols as urease and nitrification inhibitors either through on the spot physical admixture or applied otherwise jointly or separately with the nitrogen fertilizers or as ready to use preparations of the fertilizer and the inhibitor. The application of inhibitor at 1-20% levels, preterably 5-10% level of the nitrogen level of the fertilizer has been found to be effective.
4. Description
Detailed description of the invention I Process
• t
An environment benign method of producing 5-substituted-l,3,4-oxadiazole-2-thiols has been developed. The process has higher atom utilization, higher yield, less reaction time and simple work up procedure. This objective has been accomplished by reacting carboxylic acid hydrazide, RCONHNH2, with carbon disulphide, CS2, in a suitable energy transfer medium under microwave irradiation (MW1).
The molar ratio of carboxylic acid hydrazide to carbon disulphide is generally from 0.1:1 to 2:1, preferably from 0.2:1 to 1.5:1, more preferably from 0.3:1 to l:land most preferably from 0.5:1 to 0.8:1.
Suitable energy transfer medium means a solvent, which absorbs microwave energy efficiently and is therefore heated rapidly under microwave irradiation. It also has a boiling point that is at least 20-30 °C higher than the desired reaction temperature.
Such suitable energy transfer medium may be any solvent having high dielectric constant and high boiling point. Suitable solvents arc generally alcohols, glycols, water, organic acids, sulphoxides, amides, azines, preferably pyridine, dimethyl sulphoxide, N,N-dimethyl amides, particularly dimethyl sulphoxide, N,N-dimethyl formamide, N,N-dimethy lacetamide.
The amount of solvent used is generally from 0.3 to 20 ml per gram of carboxylic acid hydrazide, preferably from 1 to 15 ml per gram of carboxylic acid hydrazide, more preferably from 1 to 10 ml per gram of carboxylic acid hydrazide and most preferably from 2 to 8 ml per gram of carboxylic acid hydrazide.

The power levels of microwave oven at which reaction was irradiated were generally from 90 to 900 watts, preferably rrom 270 to 900 watts, more preferably rrom 360 to 900 watts and most preferably from 540 to 900 watts.
The time of microwave irradiation varied generally from 10 seconds to 20 minutes, preferably from 20 seconds to 10 minutes, more preferably from 30 seconds to 8 minutes, and most preferably from 30 seconds to 5 minutes.
I'he work up procedure is simple. 'I'he reaction mixture is taken out from oven, cooled to room temperature; water added and the separated product filtered, dried and recrystallised. The amount of water added was generally from 1 to 200 ml per gram of carboxylic acid hydrazide taken initially, preferably from 5 to 100 ml per gram of carboxylic acid hydrazide taken initially, more preferably from 10 to 80 mi per gram of carboxylic acid hydrazide taken initially, and most preferably from 10 to 50 ml per gram of carboxylic acid hydrazide taken initially.
In case the product remains miscible after addition of water; it was extracted with ether. Organic layer was separated, passed through anhydrous sodium sulphate and the solvent removed to get the product. Examples 1. Preparation Example 1
In a 250 ml conical flask fitted with a gas outlet tube, 0.68 g (0.5 millimole) of benzoic acid hydrazide, 0.57 g (0.75 millimole) of carbon disulphide and 2 ml of dimethyl sulphoxide were taken and irradiated under microwaves tor 70 seconds at 900 watts.T'he reaction product was taken out from microwave oven, cooled and 20 ml water

added to it. The resulting suspension was filtered off, giving 0.77 g of 5-phenyl-1,3,4,-oxadiazole-2-thiol. The yield was 87 per cent. Example 2
In a 250 ml conical flask fitted with a gas outlet tube, 0.68 g (0.5 millimole) of benzoic acid hydrazide, 0.57 g (0.75 millimole) of carbon disulphide and 1 ml of dimethyl sulphoxide were taken and irradiated under microwaves for 120 seconds at 540 watts. The resultant reaction product was taken out from microwave oven, cooled and 15 ml water added to it. The resulting suspension was filtered off, giving 0.72 g of 5-phenyl-l,3,4,-oxadiazolc-2-thiol. The yield was 81 per cent. Example 3
In a 250 ml conical tlask fitted with a gas outlet tube, 0.68 g (0.5 millimole) of benzoic acid hydrazide, 0.57 g (0.75 millimole) of carbon disulphide and 2 ml of dimethyl formamide were taken and irradiated under microwaves for 120 seconds at 900 watts. The resultant reaction product was taken out from microwave oven, cooled and 25 ml water added to it. The resulting suspension was filtered off, giving 0.67 g of 5-phenyl-l,3,4,-oxadiazole-2-thiol. The yield was 75 per cent. Example 4
In a 250 ml conical tlask fitted with a gas outlet tube, 0.63 g (0.5 millimole) of furoic acid hydrazide, 0.57 g (0.75 millimole) of carbon disulphide and 2 ml of dimethyl sulphoxide were taken and irradiated under microwaves tor 75 seconds at 900 watts. The resultant reaction product was taken out from microwave oven, cooled and 20 ml water added to it. The resulting suspension was filtered off, giving 0.632 g of 5-furyl-1,3,4,-oxadiazole-2-thiol. The yield was 70 per cent.
Example 5
In a 250 ml conical flask fitted with a gas outlet tube, 0.44 g (0.5 millimole) of propanoic acid hydrazide, 0.57 g (0.75 millimole) of carbon disulphide and f 'ml of dimethyl sulphoxide were taken and irradiated under microwaves for 80 seconds at 900 watts. The resultant reaction product was taken out from microwave oven, cooled and 20 ml water added to it. The resulting suspension was filtered off, giving 0.468 g of 5-ethyl-l,3,4,-oxadiazole-2-thiol. The yield was 72.8 per cent. 11. Nitrification inhibition
Compounds suitable ibr use as nitrification inhibitors are 5-substituted-l,3,4-oxadiazole-2-thioIs of general formula 1
(Formula Removed)
in which R is generally C1 to C15, saturated or unsaturated alkyl, unsubstituted or substituted by halogen, nitro, OR' - R' = CH3, C2H5 and or hydroxy; C6 to C2o aralkyl or aryl, unsubstituted or substituted by C1 to C4 alkyl, halogen, nitro, OR' - R' = CH3, C2H5 and or hydroxy; heterocyclyl, heterocycloalkyl etc.
'1'he 5-substituted-l,3,4-oxadiazole-2-thiols of formula 1 preferably contain units which are derived from acetic acid hydrazide, propanoic acid hydrazide, butanoic acid hydrazide, pentanoic acid hydrazide, octanoic acid hydrazide, decanoic acid hydrazide, dodecanoic acid hydrazide, benzoic acid hydrazide, furoic acid hydrazide and the like.

The rate of application of 5-substituted-l,3,4-oxadiazole-2-thiols is generally from 0.01 to 30% of urea nitrogen, preierably 1 to 20% of urea nitrogen, and more preferably from 5 to 10% of urea nitrogen.
The 5-substituted-l,3,4-oxadiazole-2-thiols of formula 1 which can be prepared in a simple manner from cost effective starting materials are especially distinguished in their use as nitrification inhibitors in that they effectively inhibit the nitrification of ammonium nitrogen in the soil over a long period of time.
Example 6
Nitrification inhibitory activity: The test chemicals were evaluated in a sandy loam soil |lnceptisol| at 10% of applied urea-N, with urea alone as control. The experiments were laid following complete randomised design. One hundred gram of air dried, finely ground and sieved (10 mesh) soil was taken in 250 ml beakers and mixed with calculated amount of solutions of the test chemical followed by addition of 20 mg of urea-N in aqueous solution in each treatment. Nitrapyrin and DCL), Uicyandiamide, were employed as reference inhibitors at 5% of applied urea-N. The experiment was conducted in triplicate. The contents of beakers were mixed and incubated at 30 °C maintaining moisture at 50 per cent of water holding capacity of the soil throughout the study. The moisture level was maintained by adding the required amount of distilled water every alternate day. Samples were withdrawn at 14, 28, 42 and 56 days of incubation; extracted with 1M sodium sulphate solution and estimated for ammonium, nitrite and nitrate nitrogen
The percentage nitrification inhibition was calculated as follows {disclosed in Plant Soil 55, 487-490 (1980)}. Nitrification rate = {(NO3'-N + NO2"-N) x 100} / {(NH4'-N + NO3"-N + NO2"-N)}
Percentage nitrification inhibition =
{(Nitrification rate in control - Nitrification rate in sample) 100} / {Nitrification rate in control}
As an example 5-furyI-l,3,4-oxadiazole-2-thiol, 9, showed 60.6 and 45.4% nitrification inhibition on 28th and 42nd day of incubation as compared to 58.4 & 13% nitrification inhibition by dicyandiamide on respective days (Table 1). Table 1 Nitrification inhibitory activity of sonic l,3,4-oxadiazole-2-thiols (1-11)

(Table Removed)

US Patent references cited
James R King and James R Moran. Method and composition for inhibiting silver'sludge
in thiosulfate monobaths. 1965, 3,173,789. Jeffrey D Griffith. Soil treating method and composition for conserving nitrogen in soil
by addition ofapyrazole thereto. 1972, 3,635,690. Raymond C Erickson and Ronald E Bambury. 7-la-Amino-ε(3,4-methylenedioxy
phenyl)acylamidojcephalosporanic acid derivatives. 1977, 4,020,060. Kim E Arndt and Ronald W McCormick. Soil treating method and composition for
conserving nitrogen in naturally alkaline soil. 1972, 4,969,946. Stefan Rittinger, Norbert Rieber, Randall Evan Gold and Jurgen Dressel. Use of low-
volatlity pyrazole derivatives having hydrophilic groups as nitrification
inhibitors. 1999, 5,972,064. Thomas Barth, Norbert Rieber, Randall Evan Gold, Jurgen Uressel, Klaus Erhardt, Klaus
Horchler von Locquengh, Edgar Leibold and Stefan Rittinger. Nitrification
inhibitors, and the use of poly acids which contain a nitrification inhibitor Jor the
treatment of inorganic fertilizers. 2002, 6,488,734 Bl. I'homas Barth, Norbert Rieber, Randall Evan Gold, Jurgen Dressel, Klaus Erhardt, Klaus
Horchler von Locquengh, Edgar Leibold and Stetan Rittinger. Nitrification
inhibitors, and the use ofpolyacids which contain a nitrification inhibitor for the
treatment of inorganic fertilizers. 2004, 6,802,882 B2. Other references cited E 1 loggarth. 1952. Journal of Chemical Society. 4811 -4817.

R W young and K H Wood. 1955. Journal of American Chemical Society. 77: 400-403. C Ainsworth. 1956. Journal of American Chemical Society. 78: 4475-4478. S Joshi and A V Karnik. 2002. Synthetic Communications, 32( 1): 111 -114.
M Kidwai. Rajcsh Kumar and Y Goel. 1997. Main Groiip Metal Chemistry 20(6): 367-
372.
KL Sahrawat. 1980. Plant Soil 55: 487-490.

Claims
We claim:
1. 5-Substituted-l,3,4-oxadiazole-2-thiols of formula 1 as urease and
nitrification inhibitors and an environment benign process for the preparation of the same by reacting carboxylic acid hydrazide, RCONHNH2, with carbon disulphide, CS2, in an energy transier medium under microwave irradiation,
(Formula Removed)
1 MW1, wherein R in formula 1 is C1 to C15 saturated or unsaturated alkyl, unsubstituted or substituted by halogen, nitro, OR' - R' = CH3, C2H5 and or hydroxy; C6, to C2o aralkyl or aryl, unsubstituted or substituted by C1 to C'4 alkyl, halogen, nitro, OR' - R' = CH3, Calls and or hydroxy; heterocyclyl, heterocycloalkyl and the like.
2. A process as claimed in claim 1, wherein the molar ratio of carboxylic acid
hydrazide to carbon disulphide is generally Irom 0.1:1 to 2:1, preterably trom
0.2:1 to 1.5:1, more preferably trom 0.3:1 to l:land most preferably from
0.5:1 to 0.8:1.
3. A process as claimed in claim 1, wherein the energy transler medium may be
a solvent belonging to the group of alcohols, glycols, organic acids,
sulphoxidcs, amides, azines and the like, preterably pyridine, dimethyl

sulphoxide, N,N-dimethyl amides, more preferably dimethyl sulphoxide, N,N-dimethyl tbrrnamide and N,N-dimethylacetamide.
4. A process as claimed in claim 1, wherein the amount of solvent used is
generally from 0.3 to 20 ml per gram of carboxylic acid hydrazide, preferably
from 1 to 15 ml per gram of carboxylic acid hydrazide, more preferably from
1 to 10 ml per gram of carboxylic acid hydrazide and most preferably from 2
to 8 ml per gram of carboxylic acid hydrazide.
5. A process as claimed in claim 1, wherein the power levels of microwave oven
range generally from 90 to 900 watts, preferably from 270 to 900 watts, more
preferably from 360 to 900 watts and most preferably from 540 to 900 watts.
6. A process as claimed in claim 1, wherein the time of microwave irradiation is
generally from instantaneous to 20 minutes, preferably from 20 seconds to 10
minutes, more preferably from 30 seconds to 8 minutes, and most preferably
from 30 seconds to 5 minutes.
7. 5-Substitutcd-l,3,4-oxadiazole-2-thiols of claim 1-6 for use as urease and
nitrification inhibitors in compositions along with the nitrogenous materials
such as urea, ammonium sulphate, calcium ammonium nitrate and the like
made through their addition either separately or in combinations prepared at
the time of application or manufactured as ready to use materials.
8. 5-Substituted-l,3,4-oxadiazole-2-thiols and the compositions based on them
as claimed in claims 1-7 wherein the nitrification inhibitors of are used at
0.01-30% of nitrogen level of the fertilizer, preferably from 1 to 20% and
more preferably from 5-10% level.
9. 5-Substituted-l,3,4-oxadiazole-2-thiols and the various compositions as claimed in any of the above claims and as described in the body of the application, for use as effective use situations in the basic and "applied agriculture.

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Patent Number

279536

Indian Patent Application Number

3461/DEL/2005

PG Journal Number

04/2017

Publication Date

27-Jan-2017

Grant Date

25-Jan-2017

Date of Filing

23-Dec-2005

Name of Patentee

INDIAN COUNCIL OF AGRICULTURAL RESEARCH

Applicant Address

INDIAN COUNCIL OF AGRICULTURAL RESEARCH, KRISHI BHAWAN, DR.RAJENDRA PRASAD ROAD, NEW DELHI-110001

Inventors:

#	Inventor's Name	Inventor's Address
1	DR. RAJESH KUMAR	DIVISION OF AGRICULTURAL CHEMICALS,INDIAN AGRICULTURAL RESEARCH INSTITUTE, NEW DELHI-110 012,INDIA
2	DR. (MRS.) ANUPAMA	DIVISION OF AGRICULTURAL CHEMICALS,INDIAN AGRICULTURAL RESEARCH INSTITUTE, NEW DELHI-110 012,INDIA
3	DR. BALRAJ SINGH PARMAR	DIVISION OF AGRICULTURAL CHEMICALS,INDIAN AGRICULTURAL RESEARCH INSTITUTE, NEW DELHI-110 012,INDIA

PCT International Classification Number

A01N 43/76

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA