Description:FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of Metamitron of Formula I

Formula (I)
BACKGROUND OF THE INVENTION
Metamitron (oxaziclomefone) is chemically known as 4-amino-3-methyl-6-phenyl-1,2,4-triazin-5(4H)-one of Formula (I).
The Metamitron is a low-toxicity and low-residue herbicide developed in 1975 by Bayer company, belongs to a triazinone selective pre-emergent herbicide, is mainly absorbed by plant roots and then is conveyed into leaves, and plays a role in killing weeds by inhibiting the Hill reaction of photosynthesis. It is widely used in agriculture for selective weed control.
CN106187929 A discloses a process for the production of metamitron, comprising the following steps; benzoyl cyanide is hydrolyzed under the condition of H 2SO4, and then alcoholized into ester; reacting hydrazine hydrate with methyl acetate to generate acetyl hydrazine hydrate; methyl benzoate reacts with acetyl hydrazine hydrate to generate hydrazine hydrate ester under the condition of H 2SO4; the hydrazine hydrate ester suspension reacts with hydrazine hydrate, acyl is hydrazinized again to generate benzoyl hydrazine, and by-product methanol and water are produced; the benzoyl hydrazine is distilled, refluxed, dehydrated, cyclized and crystallized in butanol solvent and under the condition of catalyst to generate the oxaziclomefone.
CN102952089 A discloses a preparation method of oxaziridone, which is obtained by carrying out dehydration cyclization reaction on 2-hydrazone-2-phenyl-acethydrazide in the presence of a polar organic solvent and a water absorbent, wherein the dehydration cyclization reaction is carried out under the pressure of 0.3-1 MPa for 10-20 hours, the mol ratio of the 2-hydrazone-2-phenyl-acethydrazide to the water absorbent is 1:0.05-0.3, the water absorbent is anhydrous sodium acetate, and the dehydration cyclization reaction temperature is 100-150 ℃. The technical method does not need a phase transfer catalyst, and the dehydration cyclization reaction is carried out under the high-pressure sealing condition.
CN111377877A discloses a method for preparing oxaziclomefone by a one-pot method, which comprises the following steps: ① A first step of reaction of ethyl benzoate and acethydrazide in the presence of an alcohol solvent and ethylenediamine tetraacetic acid; ② A second step of reacting the reaction solution of step ① with hydrazine hydrate; ③ A third reaction step in which the reaction liquid of step ② is reacted in the presence of a water absorbing agent and a phase transfer catalyst; ④ And (3) carrying out post-treatment on the reaction liquid in the step ③ to obtain the oxaziclomefone. The alcohol solvent used in the technology of the patent is methanol or ethanol, and the water absorbing agent is still required.
CN118221600A disclose the synthesizing the oxazinone by the one-pot method comprises the steps of heating and refluxing methyl benzoate and/or ethyl benzoate and acethydrazide in n-butyl alcohol to react to obtain an intermediate I (2-acethydrazide methyl benzoate and/or ethyl 2-acethydrazide benzoate), cooling after the reaction is finished, adding hydrazine hydrate to react to obtain an intermediate II (2-acethydrazide hydrazone-2-phenyl-acethydrazide), adding acetic acid and/or acetic anhydride after the reaction is finished to consume excessive hydrazine hydrate, and heating, refluxing and dehydrating to ring to obtain the oxazinone.
These synthetic routes involve multistep procedures with varying yields and the use of expensive or less readily available intermediates.Metamitron synthesis often employ hazardous reagents (e.g., methyl isocynate) or involve multiple purification steps.
The present invention addresses the aforementioned drawbacks by utilizing Mandelonitrile as a safer and industrially preferred intermediate, thereby enabling a simplified synthetic route for the production of Metamitron. This improved process offers high yields, significantly reduced levels of impurities, and enhanced ease of scalability, making it particularly suitable for commercial manufacturing.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a simple and cost-effective process for the preparation of Metamitron of Formula (I) with high purity and good yield on a commercial scale.
SUMMARY OF THE INVENTION
The present invention provides an efficient and improved method for the synthesis of Metamitron, a triazinone-class herbicide, using Benzaldehyde as the starting material. The process comprises the following key steps:
1. Formation of Mandelonitrile via nucleophilic addition of cyanide to Benzaldehyde;
2. Conversion of Mandelonitrile to the corresponding amidine intermediate through a controlled reaction sequence;
3. Cyclization of the amidine intermediate with methyl isocyanate or its equivalents, resulting in the formation of the triazinone ring structure;
4. Final work-up and purification, yielding Metamitron of high chemical purity and yield.
This novel synthetic approach offers advantages in terms of reaction efficiency, step economy, and product purity, making it suitable for both laboratory-scale and industrial-scale production of Metamitron.
DETAILED DESCRIPTION OF THE INVENTION
Prior to setting forth the present subject matter in detail, it may be helpful to provide definitions of certain terms to be used herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this subject matter pertains.
The term “a” or “an” as used herein includes the singular and the plural, unless specifically stated otherwise. Therefore, the terms “a,” “an,” or “at least one” can be used interchangeably in this application.
Throughout the application, descriptions of various embodiments use the term “comprising”; however, it will be understood by one skilled in the art, that in some specific instances, an embodiment can alternatively be described using the language “consisting essentially of” or “consisting of”.
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 in light of the number of reported significant digits and by applying ordinary rounding techniques. In this regard, use of the term “about” herein specifically includes ±10% from the indicated values in the range. 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.
 
The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention.
"The process comprises the synthesis of Mandelonitrile via cyanohydrin formation through cyanide addition to benzaldehyde, followed by conversion to an amidine intermediate. This intermediate is subsequently subjected to cyclization with methyl isocyanate or its functional equivalents, and the resulting reaction mixture is worked up to afford high-purity Metamitron."
Process for Reaction of Mandelonitrile with Thionyl Chloride comprises the following steps.
The required quantity of ethanol into the reactor and begin stirring. Maintain the temperature at 30–35°C. Under stirring, charge the specified amount of Mandelonitrile, followed by water. Maintain the temperature at 30–35°C. Subsequently, cool the reaction mass (RM) to 12–15°C under continuous stirring. Slowly charge the required quantity of Thionyl Chloride (TC) over a period of 2–3 hours, maintaining the temperature between 12–15°C with continuous stirring. Allow the RM to gradually warm up to 20–25°C and maintain this temperature range for 2–2.5 hours under stirring. Heat the RM to 40°C and maintain this temperature for 4 hours under continuous stirring. Gradually increase the temperature of the RM to reach reflux temperature (83–85°C) over a span of 2–3 hours. Maintain the RM at reflux (83–85°C) for 4–4.5 hours under stirring.
GC Monitoring (After 4 hrs Reflux). Add Methylene Dichloride (MDC) and 1.0 mL of reaction sample ,adjust pH to 7.0 using sodium bicarbonate. Filter through anhydrous sodium sulfate (Na₂SO₄). Inject 1.0 mL of the clear filtrate into GC. Ensure absence of Amide and High Retention Time (HRT) peaks.Start distillation of ethanol at atmospheric pressure. Continue until bath temperature reaches 120–125°C. Record the recovered ethanol quantity (Expected ~205 gm). Cool the reaction mass to 70–75°C under stirring (u/s). Add Toluene (exact quantity as per BMR), stir for 30 minutes. Further cool the mass to 30–35°C. Filter the mass to isolate the Ammonium Chloride (NH₄Cl) cake. Wash the cake twice with 50 mL toluene each time. Collect the filtrate . To the EM + Toluene layer, add 170 mL water. Adjust the pH to 4.0–4.5 using 48% Caustic Soda Lye (CS Lye). Mix well and allow for phase separation. Separate and discard the aqueous layer. Record the weight and volume of the organic layer (EM + Toluene).
Process for Preparation of Ethyl Phenyl Glyoxylate by Oxidation of Ethyl Mandelate:
Cool the combined organic layer (Ethyl Mandelate + Toluene) to 15–16°C under continuous stirring (u/s). Add Tetra-n-butylammonium bromide (TEBA) – Lot-1 – to the reaction mass at 15°C under stirring. Slowly add Sodium Hypochlorite (Hypo – Lot-1) over a period of 7–8 hours while maintaining the reaction temperature at 18–22°C. Maintain the pH between 6.5–7.0 during addition by controlled dosing of Hydrochloric Acid (HCl – Lot-1). Stir the reaction mass for 30 minutes at 18–22°C after completing the addition. Perform layer separation at 18–22°C. Separate and discard the aqueous layer. Retain the organic layer for the second treatment cycle.
Second Oxidation Cycle
Add TEBA – Lot-2 to the retained organic layer at 18–22°C under stirring. Add Sodium Hypochlorite (Hypo – Lot-2) over 6–7 hours, maintaining the temperature at 18–22°C. Ensure the pH remains between 6.5–7.0 using 22 mL of HCl (Lot-2) as required. Continue stirring the reaction mass for 30 minutes at 18–22°C after addition is complete. Separate the aqueous and organic layers. Retain the organic phase for final analysis. Analyze the final organic layer for residual content of Ethyl Mandelate (EM) and Ethyl Phenyl Glyoxylate (EPG) through GC (GAS Chromatography). Ethyl Mandelate (EM) content must be less than 0.2%.
 
Process for Acetyl Hydrazine and Zone Preparation (Stage I):
Charge Acetyl Hydrazine (A.H.) 308 into reactor and fresh IS (Internal Standard). Cool to 25°C. Add 30% HCl to bring pH to 6.0. Add more HCl if required. Add Ethyl Phenyl Glyoxylate (EPG) slowly over 4 hours, maintaining temperature at 25–30°C. Maintain for 4 hours at 25–30°C.
Isomerization
Cool reaction mass to 18°C. Add 30% HCl gradually to adjust pH to 2.8–3.2. Keep the temperature at 20°C for 4 hours. Send sample for HPLC analysis: check pH, Hzone %, Bis, and Antizone content.
Crystallization
Add Cold Water Cool to 5°C.and maintain at 5°C for 1 hour. Filter the mass and suck dry under vacuum for 30 minutes.
Mother Liquor (ML): Retain for second crop recovery.
Product Analysis
Check Hzone powder for LOD (8-10%), Hzone % via GLC and HPLC.
Process for Zide preparation (Stage II)
Charge the Zone cake and Fresh Internal Standard (IS) into the reactor. Cool the reaction mass and bring the temperature to 18–20°C. Attach an online pH meter for continuous monitoring. Add Ammonia Solution (NH₃) gradually while maintaining 18–20°C. Adjust pH to 9.0–10.0. Maintain at this pH and temperature for 10–15 minutes. Check pH to ensure it stabilizes between 9.0 and 10.0. Slowly add 80% H.H. (likely Hydrazine Hydrate or another reagent depending on context) over 3–4 hours while keeping temperature at 18–20°C. After the addition is complete, add Acetic Acid gradually to adjust pH down to 6.8. Maintain temperature at 18–20°C during this step.
 
Process for preparation of Hydrazide Reflux and Metamitron Formation
Receive the hydrazide batch from Stage II. And measure pH and adjust to 7.0 using caustic soda lye (CS lye). Verify pH with a calibrated pH meter and ensure it remains at ~7.0 before heating.Add the specified amount of potassium carbonate into the reactor.Transfer the reaction mass to a round-bottom flask (RBF). Heat gradually to 80–85 °C over 3–4 hours to establish reflux. Maintain reflux at 80–85 °C for 16 hours. Every 2 hours, measure pH and, if it has dropped below 7.0, adjust with CS lye. After 16 hours, withdraw a sample and send to the lab to confirm Hydrazide content < 2 %,Metamitron (Meta) content (measured %) pH > 7.0 Upon meeting the quality criteria, begin cooling the RBF. Lower the temperature to 65–67 °C in preparation for the next stage.
Process of meta-Crystallisation, Filtration, and Drying
Filter the reaction mass (RM). Apply vacuum for 30 minutes to remove maximum mother liquor (ML). If cracks are observed during filtration, press the cake gently to close gaps and ensure uniform drying. Add sufficient quantity of hot water to the filter cake. Do not apply vacuum for the first 10 minutes — allow the cake to slurry thoroughly. After 10 minutes, suck the ML completely under vacuum. Add tap water for the final wash. Vacuum filter for 30 minutes to remove remaining wash water and impurities.Transfer the filtered cake to a drying oven. Dry for 12 hours under controlled conditions. After drying, check Moisture Content (M/C) and purity via QC methods (e.g., Karl Fischer for M/C, HPLC/GC for purity).
According to an embodiment, the chlorination step is carried out in the presence of a chlorination agent selected from the group consisting of but not limited to Thionyl Chloride, N-chlorosuccinimide and sulfuryl chloride.
Acids can be selected from the group consisting of hydrochloric acid, hydrobromic acid, acetic acid, benzoic acid, substituted benzoic acid, trifluoroacetic acid, and formic acid. Acids can also be Lewis acids such as, aluminium chloride, stannous chloride, stannic chloride, titanium tetrachloride, boron trifluoride diethyl etherate, boron THF complex, or zinc chloride.
According to an embodiment, the chlorination step is carried out in the presence of a chlorination agent selected from the group consisting of but not limited to Thionyl Chloride, N-chlorosuccinimide and sulfuryl chloride.
Oxidizing agents can be selected from the group consisting of hydrogen peroxide, m-chloro perbenzoic acid (ra-CPBA), oxone, tert-butyl hydrogen peroxide (TBHP), copper sulphate,using Sodium Hypochlorite (NaOCl) sodium nitrite, t-butyl nitrite, Ferric Chloride (III) and tert-butyl nitrite.
Solvent can be selected from the group consisting of dichloromethane, Ethanol – IS (10% loss),Toluene,chloroform, carbon tetrachloride, Ethyl Acetate, bromoethane, or dichloroethane.
Base can be selected from the group consisting of Potassium Carbonate, Liquor Ammonia,Sodium Bicarbonate, and Caustic Soda Solution .
Phase-transfer catalyst is Tetra-n-butylammonium bromide.
EXAMPLES:
Example 1: Preparation of Mandelonitrile (α-Hydroxybenzyl Cyanide)
Benzaldehyde is reacted with sodium cyanide or potassium cyanide in the presence of a proton source such as acetic acid or ammonium chloride, in an aqueous or alcoholic medium, to afford Mandelonitrile via cyanohydrin formation.

Example 2: Preparation of Ethyl Mandelate using Mandelonitrile
Mandelonitrile (α-hydroxybenzyl cyanide) is hydrolyzed in the presence of thionyl chloride and water, resulting in the formation of ethyl mandelate, its acid chloride, or an amidated derivative, depending on the specific reaction conditions employed. During the reaction, ammonium chloride is generated as a by-product and is subsequently removed by filtration.

Example 3: Preparation of Ethyl Phenyl Glyoxylate by oxidation of Ethyl Mandelate.
The process involves the controlled oxidation of Ethyl Mandelate using Sodium Hypochlorite (NaOCl) as the oxidizing agent under slightly acidic to neutral pH conditions (pH 6.5–7.5). The reaction pH is carefully maintained by the controlled addition of 30% Hydrochloric Acid (HCl). Upon completion, the resulting Ethyl Phenylglyoxylate is isolated by distillation under reduced pressure, affording the product in high purity.

 
Example 4: Preparation of Acetyl Hydrazine using Ethyl Acetate and Hydrazine Hydrate
The process involves a method for synthesizing Acetyl Hydrazine via the reaction of Ethyl Acetate with Hydrazine Hydrate. The process proceeds through a direct nucleophilic substitution mechanism, wherein the ester group of Ethyl Acetate is displaced by Hydrazine to yield Acetyl Hydrazine, with Ethanol as the by-product.
This method offers several advantages, including:
• Elimination of the need for acyl chlorides or acid anhydrides;
• Use of inexpensive and readily available starting materials;
• A mild and operationally simple reaction setup.
Acetyl Hydrazine produced by this method serves as a key synthetic intermediate in the preparation of triazinone herbicides, including Metamitron

Example 5: Preparation of Ethyl-(2-acetylhydrazinylidene)phenyl acetate using Ethyl Phenyl Glyoxylate and Acetyl Hydrazine.
Condensation of Ethyl Phenylglyoxylate with Acetyl Hydrazine
The process involves the condensation of Ethyl Phenylglyoxylate with Acetyl Hydrazine to form the hydrazone derivative, Ethyl-(2-acetylhydrazinylidene)phenyl acetate—a key intermediate in the synthesis of Metamitron.
The reaction proceeds via nucleophilic attack of the terminal nitrogen atom of Acetyl Hydrazine on the carbonyl group of Ethyl Phenylglyoxylate, followed by elimination of water to yield the hydrazone product featuring a C=N (imine) linkage.
The condensation is typically conducted in ethanol as the solvent, under mild reflux conditions, providing good yield and purity of the intermediate.

Example 6: Preparation of Phenyl Glyoxylate acid hydrazide 2-acetyl hydrazine using Ethyl-(2-acetylhydrazinylidene)phenyl acetate and hydrazine hydrate.
Preparation of Phenylglyoxylic Acid 2-Acetylhydrazide
The compound Phenylglyoxylic acid 2-acetylhydrazide is prepared by reacting ethyl-(2-acetylhydrazinylidene)phenyl acetate with hydrazine hydrate under mild heating conditions. The reaction proceeds via hydrazinolysis of the ester group, which is converted into the corresponding hydrazide, while retaining the existing hydrazone (C=N) linkage formed in the previous condensation step.
This hydrazide intermediate plays a crucial role in the subsequent cyclocondensation reaction leading to the formation of the 1,2,4-triazinone ring system characteristic of Metamitron.

Example 7: Preparation of Metamitron using Sodium Acetate, Phenyl Glyoxylate acid hydrazide 2-acetyl hydrazine, and EDTA catalyst.
Cyclocondensation to Synthesize Metamitron
The final step in the synthesis of Metamitron (4-amino-3-methyl-6-phenyl-1,2,4-triazin-5(4H)-one) involves the cyclocondensation of Phenylglyoxylic acid 2-acetylhydrazide under controlled thermal conditions in the presence of Sodium Acetate and a catalytic amount of EDTA.
The reaction proceeds via an intramolecular condensation, wherein the two hydrazine-derived nitrogen atoms and carbonyl functionalities within the substrate undergo ring closure to form the 1,2,4-triazinone core. Sodium acetate acts as a buffering agent, maintaining a mildly basic to neutral pH that is favorable for cyclization, while EDTA serves as a chelating agent, effectively sequestering trace metal ions that could otherwise catalyze undesired side reactions or cause decomposition.
This step efficiently furnishes high-purity Metamitron, suitable for formulation as a triazinone herbicide.

, Claims:
1) An improved process for the preparation of Metamitron of Formula (I)

Formula (I)
Comprising the steps of:
(a) Benzaldehyde is reacted with sodium cyanide and a proton source (such as acetic acid or ammonium chloride) in an aqueous or alcoholic medium to form Mandelonitrile via cyanohydrin formation.
(b) Mandelonitrile (α-hydroxybenzyl cyanide) is hydrolyzed in the presence of thionyl chloride and water to yield Ethyl Mandelate.
(c) Ethyl Mandelate is oxidized using sodium hypochlorite (NaOCl) solution at a pH of 6.5–7.5, to yield Ethyl Phenyl Glyoxylate, which is isolated by distillation under reduced pressure.
(d) Ethyl Phenyl Glyoxylate is condensed with acetyl hydrazine to form the hydrazone derivative, Ethyl-(2-acetylhydrazinylidene)phenyl acetate, typically carried out in ethanol under mild reflux conditions.
(e) Ethyl-(2-acetylhydrazinylidene)phenyl acetate reacts with hydrazine hydrate under mild heating conditions to form the Phenyl Glyoxylic acid 2-acetylhydrazide (a key intermediate)
(f) Phenyl Glyoxylic Acid 2-acetylhydrazide undergoes intramolecular cyclocondensation in the presence of sodium acetate and a catalytic amount of EDTA under thermal conditions to afford Metamitron (4-amino-3-methyl-6-phenyl-1,2,4-triazin-5(4H)-one).
2. The process as claimed in claim 1, wherein a suitable solvent used in step (a) is selected from ethanol, methanol, toluene, acetonitrile, methylene chloride, chloroform, and xylene, or a mixture thereof.
3. The process as claimed in claim 1, wherein a suitable solvent used in step (b) is selected from ethanol, toluene, acetonitrile, methylene chloride, chloroform, and xylene, or a mixture thereof.
4. The process as claimed in claim 1, wherein a suitable base used in step (b) is selected from caustic soda lye, potassium carbonate, liquor ammonia, or sodium bicarbonate.
5. The process as claimed in claim 1, wherein a suitable catalyst used in step (c) is a phase-transfer catalyst selected from Tetrabutylammonium bromide (TBAB) ,triethylbenzylammonium chloride (TEBA) and Tetrabutylammonium hydrogen sulfate (TBAHS)
6. The process as claimed in claim 1, wherein an oxidizing agent used in step (c) is selected from hydrogen peroxide, m-chloroperbenzoic acid (m-CPBA), oxone, tert-butyl hydrogen peroxide (TBHP), copper sulphate, sodium hypochlorite (NaOCl), sodium nitrite, t-butyl nitrite, ferric chloride (FeCl₃), and tert-butyl nitrite.
7. The process as claimed in claim 1, wherein a suitable base used in step (c) is selected from caustic soda lye, potassium carbonate, liquor ammonia, and sodium bicarbonate.
8. The process as claimed in claim 1, wherein a suitable solvent used in step (d) is selected from ethanol, toluene, acetonitrile, methylene chloride, chloroform, and xylene, or a mixture thereof.
9. The process as claimed in claim 1, wherein a suitable solvent used in step (e) is selected from ethanol and Methanol.
10. The process as claimed in claim 1, wherein buffering and chelating agents used in step (f) are selected from sodium hydroxide and potassium carbonate.
11. The process as claimed in claim 1, wherein the process provides a product yield in the range of 48.5 % to 50.5 %.
12. The process as claimed in claim 1, wherein the compound of formula (I) has a purity in the range of 98.5 % to 99.5 %, as determined by High Performance Liquid Chromatography (HPLC).