Description:FIELD OF THE INVENTION
The present invention relates to a novel and improved 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.
Conventional methods for synthesizing Metamitron, a triazinone-class herbicide, often suffer from significant limitations. These include the use of hazardous reagents such as methyl isocyanate, which pose severe health, safety, and environmental risks. Additionally, traditional synthetic routes involve multiple steps of purification, leading to longer processing times, increased solvent consumption, and higher operational costs.
The present invention overcomes these limitations by utilizing Mandelonitrile as a key intermediate—a compound that is safer, more stable, and readily available. This innovation enables a streamlined and industrially scalable synthetic route to Metamitron, providing high product yield, lower impurity profile, and reduced dependency on toxic or highly reactive intermediates. The process significantly enhances safety, cost-effectiveness, and environmental compatibility, making it well-suited for large-scale agrochemical production.
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, starting from Benzaldehyde as the primary raw material. The synthetic route comprises the following key steps:
1. Formation of Mandelonitrile via nucleophilic cyanide addition to Benzaldehyde.
2. Conversion of Mandelonitrile to an amidine intermediate through a sequence of hydrolysis and condensation reactions.
3. Cyclization of the amidine intermediate with methyl isocyanate or functional equivalents, facilitating the construction of the 1,2,4-triazinone core.
4. Final workup and purification, yielding high-purity Metamitron.
This process offers several significant advantages over conventional methods, including:
• Use of easily accessible and less hazardous raw materials.
• Improved process safety due to the avoidance of toxic and unstable intermediates.
• Simplified reaction steps and purification, facilitating better scalability.
• High yields and superior product purity, ideal for industrial manufacturing.

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 present invention relates to an efficient and improved method for the synthesis of Metamitron, an herbicidal compound belonging to the triazinone class. The process begins with Benzaldehyde as the starting material and comprises the following key steps:
1. Preparation of Mandelonitrile through nucleophilic addition of cyanide to Benzaldehyde, forming the cyanohydrin derivative.
2. Conversion of Mandelonitrile to an amidine intermediate via sequential hydrolysis and functional group transformation.
3. Cyclization of the amidine intermediate using methyl isocyanate or its functional equivalents, facilitating formation of the 1,2,4-triazinone ring system.
4. Subsequent workup and purification, resulting in high-purity Metamitron suitable for agrochemical applications.
Process for conversion of Mandelonitrile to Intermediate via Thionyl Chloride in Methanol:
Charge Methanol into the reactor at 30–35°C under continuous stirring (u/s).Add Mandelonitrile followed by Water, maintaining the temperature at 30–35°C.Gradually charge Thionyl Chloride (TC) — 394 g — over 2–3 hours at 30–40°C, with continuous stirring. Maintain the reaction mixture (RM) at 30–40°C for 2–2.5 hours.Gradually raise the temperature to reflux over 2–3 hours. Maintain reflux for 4–5 hours at boiling temperature. After 4.0 hours of reflux, take a sample for GC analysis: In a 100 ml beaker, mix 10 ml MDC + 1 ml sample. Adjust pH to ~7.0 using Sodium Bicarbonate. Filter through Sodium Sulphate, and inject 1 ml into GC. Confirm absence of Amide & HRT to proceed. Begin Methanol distillation at atmospheric pressure. Continue distillation until the bath temperature reaches 120–125°C. Recover 570 ml (approx. 450 g) of Methanol (density: 0.789 g/ml). Stop heating and cool the RM to 70–75°C under stirring. Charge Toluene, stir for 30 minutes, and cool to 30–35°C. Filter to separate the NH₄Cl cake. Wash the cake twice with Toluene (200 ml each). Add 341 ml water to the toluene layer. Adjust pH to 4–4.5 using 48% Caustic Soda Lye (CS Lye). Separate the aqueous and toluene layers. Take the toluene layer for further hypochlorite (Hypo) treatment (Step C28). Wash the toluene layer with hot water (60–65°C) — 200 ml. Repeat the hot water wash once more with 200 ml water. Take the final toluene layer for next oxidation step (e.g., Hypo treatment).

To oxidize Methyl Mandelate (MM) to Phenyl Glyoxylate Methyl Ester (PGME) under phase transfer conditions using sodium hypochlorite and TEBA.

Pre-Oxidation Setup:
• Cool the combined organic layer (MM + Toluene) to 18–22°C under stirring (u/s).
• Charge TEBA (Lot-1): 17 g at 18–22°C under stirring.
• Add 1st Lot of Sodium Hypochlorite (NaOCl):
Add over 2.0–2.5 hours while maintaining pH 6.5–7.0 using 30% HCl (44 ml, Lot-1).
• After complete addition, stir for 30 minutes at 18–22°C.
• Separate the organic and aqueous layers at the same temperature.
2. Second Hypo Addition
• Charge TEBA (Lot-2): 17 g to the separated organic layer at 18–22°C under stirring.
• Add 2nd Lot of NaOCl:
Add over 1.0–1.5 hours, maintaining pH = 6.5–7.0 using 30% HCl (44 ml, Lot-2).
• After addition, stir for 30 minutes at 18–22°C.
• Separate final aqueous and organic layers.
3. Quality Check
• Take a GC sample of the organic layer.
• Check for MM content, which should be < 0.2%.
4. Work-Up and Washing
1. Water Wash:
o Add 253 ml of water to the organic layer.
o Stir for 15–20 minutes, then separate aqueous (Aq.-1) and organic layers.
2. Bicarbonate Wash:
o Wash organic layer with 10% sodium bicarbonate solution.
o Stir for 15–20 minutes, separate Aq.-2 and organic layers.
3. Extract Aq.-1 & Aq.-2:
o Combine Aq.-1 & Aq.-2 and extract with fresh toluene.
o Stir for 15–20 minutes, then separate the organic extract.
5. Final Product Recovery
• Combine all organic layers.
• Distill off Toluene under vacuum using a water jet ejector system.
• Collect the residue as the crude Phenyl Glyoxylate Methyl Ester (PGME).

Process for condensation of Phenyl Glyoxylate Methyl Ester (PGME) with Acetyl Hydrazine (AH) in methanol medium using EDTA acid as chelating agent, to form the hydrazone derivative (intermediate for Metamitron synthesis).

At room temperature (RT), charge Methanol; add Acetyl Hydrazine (AH) solution in Methanol, add EDTA Acid, addition of Phenyl Glyoxylate Methyl Ester (PGME) over 20–25 minutes while maintaining reaction temperature at 30–35°C and stir for 30 minutes at 30–35°C. Gradually heat the reaction mass to 70–75°C and maintain temperature at 70–75°C for 4 hours.
After 4 hours, withdraw a sample and analyze by GC for PGME content → Should be < 0.5%, Hydrazone ("Zone") content → Should be > 92% and AH (Acetyl Hydrazine) content → Residuals as per process standard. cool reaction mass to ambient temperature for further processing or isolation.

Process for Preparation of hydrazone intermediate (Methyl-(2-acetylhydrazinylidene) phenyl acetate) into the corresponding hydrazide using Hydrazine Hydrate under controlled pH and temperature.

Cool the reaction mass to 40°C. Add Methanol (MeOH). Further cool the reaction mass to 10–15°C. Measure pH (4.5 to 5.4) of the reaction mass: Adjust pH to ~8.0 using 20–25% Ammonia Solution Approx. 3–4 ml per 250 g PGME batch. Charge TEBA (Tetra-n-butylammonium bromide) Stir well at 10–15°C. Add slow addition of 80% Hydrazine Hydrate (HH). Add over 2.5 hours, maintain 10–15°C. After HH addition, maintain at 10–15°C for another 2.5 hours. Check sample by HPLC for: Zone (hydrazone content) → < 1–1.5% and Zide (hydrazide product) → >90–93%. cool the mass to 0–5°C. Maintain for 1 hour at 0–5°C for complete crystallization. Filter (CF) the reaction mass. Wash the product cake with chilled Methanol (0–5°C):
 
Synthesis of Metamitron.
At room temperature (RT), charge the following into a clean and dry SS Autoclave. Methanol (MeOH) , Zide wet cake (Ensure known assay/purity before charging), EDTA Acid (Typically ~0.1% w/w of theoretical Metamitron yield), and Dry Sodium Acetate (NaOAc). Close the autoclave tightly. Start heating and raise the temperature to 100–105°C. Maintain temperature at 100–105°C for 16.0 hours and Pressure ~3.8 kg/cm² (monitor throughout). After completion of the hold time, cool the reaction mass to 40°C. Withdraw a sample and check on HPLC for Zide content: < 0.5% and Metamitron 95–98%. Transfer the mass to RBF. Distill off Methanol at atmospheric pressure, maintaining bath temperature at 75–80°C and MeOH Recovery: 711 ml. After distillation, cool the mass to 0–5°C. Filter (or Centrifuge) to isolate solid Metamitron. Wash the product cake with fresh, chilled Methanol (0°C). Dry the Metamitron under vacuum or in a tray dryer as per specifications. Record weight, appearance, and purity by HPLC.
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 aluminum 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, sodium nitrite, t-butyl nitrite, Sodium Hypochlorite (NaOCl), Ferric Chloride (III) and tert-butyl nitrite.
Solvent can be selected from the group consisting of dichloromethane, Methanol, 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, Ammonia , Caustic lye, Sodium acetate , Sodium bicarbonate, and Caustic Soda Solution .
Chelating agent can be selected from the group consisting of EDTA (Ethylenediaminetetraacetic Acid), DMSA (Dimercaptosuccinic Acid), NTA (nitrilotriacetic acid), Citric acid, Oxalic acid, and Diethylenetriaminepentaacetic acid (DTPA).
Phase-transfer catalysts can be selected from Tetra-n-butylammonium bromide and Triethylbenzylammonium chloride.
EXAMPLES:
Example 1: Synthesis of Mandelonitrile via Cyanohydrin Formation:
Benzaldehyde reacts with sodium cyanide (NaCN) or potassium cyanide (KCN) in a suitable proton source, such as acetic acid or ammonium chloride, in an aqueous or alcoholic medium. This reaction results in the formation of Mandelonitrile through a cyanohydrin formation pathway.
Reaction:

Example 2: Hydrolysis and Esterification of Mandelonitrile:
Mandelonitrile (α-hydroxybenzyl cyanide) undergoes hydrolysis in the presence of thionyl chloride (SOCl₂), water, and methanol. Under these conditions, the nitrile group is converted to a carboxylic acid derivative, followed by esterification with methanol to yield methyl mandelate. Depending on the precise reaction conditions—such as temperature, reagent ratio, and solvent system—the product may also include the acid chloride or amide derivative. During the reaction, ammonium chloride (NH₄Cl) forms as a by-product and is subsequently removed by filtration.
Reaction:

Example 3: Controlled Oxidation of Methyl Mandelate to Phenyl Glyoxylate Methyl Ester
The process involves the controlled oxidation of Methyl Mandelate using an aqueous Sodium Hypochlorite (NaOCl) solution as the oxidizing agent. The reaction is carried out at a slightly acidic to neutral pH range of 6.5 to 7.5, which is carefully maintained by gradual addition of 30% Hydrochloric Acid (HCl).
During oxidation, Methyl Mandelate is converted into Phenyl Glyoxylate Methyl Ester, the key intermediate. Upon completion of the reaction, the product is isolated by distillation under reduced pressure, allowing for efficient separation and purification.
 
Reaction:

Example 4: Synthesis of Acetyl Hydrazine from Ethyl Acetate and Hydrazine Hydrate.
Synthesis of Acetyl Hydrazine via the reaction of Ethyl Acetate with Hydrazine Hydrate. The process involves direct nucleophilic substitution of the ester group by hydrazine, forming Acetyl Hydrazine and Ethanol as the by-product.
This method avoids the use of acyl chlorides or acid anhydrides, and uses inexpensive, easily available starting materials. Acetyl hydrazine is a valuable intermediate in the synthesis of triazinone herbicides such as Metamitron.
Reaction:

Example 5: Condensation of Phenyl Glyoxylate Methyl Ester with Acetyl Hydrazine.
Condensation of Phenyl Glyoxylate Methyl Ester with Acetyl Hydrazine to form the hydrazone derivative, Methyl-(2-acetylhydrazinylidene)phenyl acetate, a pivotal intermediate in the synthesis of Metamitron.
The reaction proceeds via nucleophilic attack of the Hydrazine Nitrogen on the keto group of Phenyl Glyoxylate Methyl Ester, followed by elimination of water to form the Hydrazone (C=N) linkage. The reaction is typically carried out in Methanol, under mild reflux conditions.
Reaction:

Example 6: Preparation of Phenyl Glyoxylic Acid 2-Acetylhydrazide
Preparation of Phenyl Glyoxylic acid 2-acetylhydrazide by reacting Methyl-(2-acetylhydrazinylidene)phenyl acetate with hydrazine hydrate under mild heating conditions. The ester group undergoes hydrazinolysis, converting to the corresponding hydrazide, while retaining the existing hydrazone linkage from the previous step.
This hydrazide intermediate is critical for the subsequent cyclocondensation into the 1,2,4-triazinone ring of Metamitron.
Reaction:

Example 7: Cyclocondensation for the Synthesis of Metamitron.
Cyclocondensation reaction of Phenyl Glyoxylate acid 2-acetyl hydrazide in the presence of Sodium Acetate and a catalytic amount of EDTA, under thermal conditions, to yield Metamitron (4-amino-3-methyl-6-phenyl-1,2,4-triazin-5(4H)-one). The process proceeds via intramolecular condensation involving both hydrazine moieties and the carbonyl functionalities of the substrate.
The use of sodium acetate ensures a mildly basic to neutral pH favourable for cyclization, while EDTA functions as a chelating agent to suppress side reactions catalyzed by trace metal ions.
Reaction:

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

Formula (I)
Comprising the steps of:
(a) Reacting benzaldehyde 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) Hydrolysis mandelonitrile in the presence of thionyl chloride and water to yield ethyl mandelate;
(c) Oxidizing ethyl mandelate using sodium hypochlorite (NaOCl) solution at a pH of 6.5 to 7.5 to yield ethyl phenyl glyoxylate, followed by isolation via distillation under reduced pressure;
(d) Condensing ethyl phenyl glyoxylate with acetyl hydrazine to form the hydrazone derivative ethyl-(2-acetylhydrazinylidene)phenyl acetate, typically carried out in ethanol under mild reflux conditions;
(e) Alternatively, reacting methyl phenyl glyoxylate with acetyl hydrazine to form the hydrazone derivative methyl-(2-acetylhydrazinylidene)phenyl acetate, a pivotal intermediate in the synthesis of Metamitron;
(f) Reacting methyl-(2-acetylhydrazinylidene)phenyl acetate with hydrazine hydrate under mild heating to form phenyl glyoxylic acid 2-acetylhydrazide;
(g) Subjecting phenyl glyoxylic acid 2-acetylhydrazide to cyclocondensation in the presence of sodium acetate and a catalytic amount of EDTA, under thermal conditions, to yield Metamitron (4-amino-3-methyl-6-phenyl-1,2,4-triazin-5(4H)-one).
2) The process as claimed in claim 1, wherein the solvent used in step (a) is selected from the group consisting of toluene, acetonitrile, methylene chloride, chloroform, xylene, and mixtures thereof.
3) The process as claimed in claim 1, wherein the solvent used in step (b) is selected from the group consisting of ethanol, toluene, acetonitrile, methylene chloride, chloroform, xylene, and mixtures thereof.
4) The process as claimed in claim 1, wherein the base used in step (b) is selected from the group consisting of caustic soda lye, potassium carbonate, liquor ammonia, and sodium bicarbonate.
5) The process as claimed in claim 1, wherein the catalyst used in step (c) is a phase-transfer catalyst, specifically triethylbenzylammonium chloride (TEBA), Tetrabutylammonium bromide (TBAB) and Tetrabutylammonium hydrogen sulfate (TBAHS).
6) The process as claimed in claim 1, wherein the oxidizing agent used in step (c) is selected from the group consisting of hydrogen peroxide, m-chloroperbenzoic acid (m-CPBA), oxone, tert-butyl hydrogen peroxide (TBHP), copper sulfate, sodium hypochlorite (NaOCl), sodium nitrite, tert-butyl nitrite, ferric chloride (FeCl₃), and mixtures thereof.
7) The process as claimed in claim 1, wherein the base used in step (c) is selected from the group consisting of caustic soda, lye, potassium carbonate, liquor ammonia, and sodium bicarbonate.
8) The process as claimed in claim 1, wherein the solvent used in step (d) is selected from the group consisting of ethanol, toluene, acetonitrile, methylene chloride, chloroform, xylene, and mixtures thereof.
9) The process as claimed in claim 1, wherein the solvent used in step (e) is selected from the group consisting of ethanol , methanol, and Toluene.
9) The process as claimed in claim 1, wherein the buffering and chelating agents used in step (f) comprise sodium acetate and ethylenediaminetetraacetic acid (EDTA).
10) The process as claimed in claim 1, wherein the yield of the compound of Formula (I) is in the range of 55.50 % to 57.50 %. (Specify actual % range based on experimental data.)
11) 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).