INTERMEDIATE OF TRIFLOXYSTROBIN IN SINGLE ISOLATION STAGE”

RELATED APPLICATION

This application claims the benefit to Indian Provisional Application No. IN202121022967 filed on May 24, 2021, the contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of intermediate of Trifloxystrobin in single isolation stage. The present invention provides an improved process for the preparation of (T)-2-(2-halomcthylphcnyl)-2-mcthoxy iminoacetic acid methyl ester of formula (I) in an environment friendly commercially viable manner with greater yield and high chemical purity. where X is Cl, Br, F

BACKGROUND OF THE INVENTION

Trifloxystrobin is a member of Strobilurin class of fungicides. It is known to possess wide range of fungicidal action with good preventive and curative properties. On that account various synthetic routes leading to Trifloxystrobin, and its intermediates were reported in the literature. The one of the most important intermediates of Trifloxystrobinis (E)- 2-(2- halomethylphenyl)-2-methoxy iminoacetic acid methyl ester.

The numerous prior art discloses various processes for preparation (E)- 2-(2- halomethylphenyl)-2-methoxy iminoacetic acid methyl ester which involved one or the other disadvantages, for example: i) more number of isolation steps; ii) excessive use of expensive and hazardous reagents such as thionyl chloride, sodium bromate; iii) generation of environmentally harmful gases such as methylene chloride, sulfur dioxide; iv) generation of more effluent; v) tedious reaction processes for removal of salts, emulsion or slug; vi) more percentage of undesired isomer; vii) troublesome operations such as extraction, distillation for removal of the multiple solvents; viii) low process yield and low purity of desired isomer.

To overcome the drawbacks of prior known processes, the inventors of the instant invention have developed a simple, cost efficient, environment friendly single isolation stage process for production of (£)-2-(2-halomcthylphcnyl)-2-mcthoxy iminoacetic acid methyl ester (I).

The process involved readily available C oluidinc and methoxy amine hydrochloride as a key starting material.

SUMMARY OF THE INVENTION

One aspect of the present invention is to provide a process for preparation of Trifloxystrobin intermediate of formula (I) in single isolation stage in an economic, environmental, and industrial viable manner. where X is Cl, Br, F

Another aspect of the present invention is to provide a process for the preparation of a compound of formula (I) with greater chemical purity, yield, and minimum unwanted Z- isomer of formula (Vila).

In another aspect of the present invention provides an improved process for the preparation of compound of formula (I) in single isolation stage, which comprises: a) reacting a compound of formula (II) with alkali metal nitrite in presence of an acid to obtain diazonium salt of formula (III); b) reacting a compound of formula (III) with a compound of formula (V) in presence of base, metal sulphate, in solvent to obtain compound of formula (VI) in acidic medium; wherein the compound of formula (V) is prepared by reacting compound (IV) with methoxyamine hydrochloride; c) reacting compound of formula (VI) with thionyl chloride, methanol in presence of solvent to obtain compound of formula (VII); d) obtaining a compound of formula (I) by reacting compound of formula (VII) with metal halogenate in presence of sodium bisulphate, with or without catalyst in solvent; e) purifying compound (I).

In yet another aspect of the present invention is to provides an improved process for the preparation of intermediate of formula (I) in single isolation stage, which comprises: a) reacting a compound of formula (II) with alkali metal nitrite in presence of an acidto obtain diazonium salt of formula (III); b) reacting a compound of formula (III) with a compound of formula (V) in presence of base and metal sulphate in solvent, isolating compound of formula (VI) in acidic medium; wherein the compound of formula (V) is prepared by reacting compound (IV) with methoxyamine hydrochloride; c) reacting compound of formula (VI) with sulfuric acid, methanol in presence of solvent to obtain compound of formula (VII); d) obtaining a compound of formula (I) by reacting compound of formula (VII) with metal halogenate in presence of sulfuric acid, sodium bromide, with or without catalyst in solvent; e) purifying compound (I).

The above process is illustrated in the following general synthetic scheme:

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described more fully hereinafter. As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains" or "containing," or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, a mixture, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus. Further, unless expressly stated to the contrary, "or" refers to an inclusive or and not to an exclusive. As used in the specification, and in the appended claims, indefinite articles "a" and "an" preceding an element or component of the invention are intended to be non-restrictive regarding the number of instances (i.e., occurrences) of the element or component. Therefore "a" or "an" should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular indicates otherwise.

The term “solvent”, as used herein, refers to single solvent or mixture of solvents.

In another embodiment, the instant invention provides the preparation of compound of formula (I) in a single isolation stage, which avoids isolation of compounds of formula (III), (V), (VI) and (VII), tedious isolation, distillation and purification steps; thus, reduces overall time cycle and cost, hence industrially viable. In another embodiment, the instant invention provides the preparation of intermediate compound of formula (I) a single isolation stage, which involved the use of commercially available reagents, solvents and avoid generation of hazardous effluents, thus the process is efficient, economical, and environmentally acceptable.

In another embodiment, the instant invention relates to an improved process for the preparation of compound of formula (I) with single (E) isomeric form of formula (VII) and minimize the formation of undesired (Z) isomeric form of formula (Vila) up to 1 to 2%.

In another embodiment of the instant invention, wherein the said alkali metal nitrite used in step (a) is selected from sodium nitrite (NaNCE), potassium nitrite (KNO ₂ ) and the like, preferably sodium nitrite.

In another embodiment of the present invention, wherein the said metal in metal sulfate is selected from copper, magnesium, zinc, sodium and potassium.

In another embodiment of the present invention, wherein the acid of step (a) is selected from hydrochloric acid (HC1), sulfuric acid (H ₂ SO ₄ ) _, acetic acid and the like, preferably hydrochloric acid.

In another embodiment of the instant invention, wherein the compound of step (a) having a formula (III) is prepared in in-situ manner.

In another embodiment of the instant invention, wherein the said base of step (b) is selected from sodium hydroxide (NaOH), potassium hydroxide (KOH), potassium carbonate (K2CO3), potassium bicarbonate (KHCO3), sodium carbonate (Na ₂ C0 ₃ ), sodium bicarbonate (NaHCCE) and the like, preferably sodium carbonate.

In another embodiment of the instant invention, wherein the said solvent used in step (b) is selected from water, methyl alcohol, ethyl alcohol, isopropyl alcohol, butanol, isobutanol, ethylene glycol and the like or mixture of solvents thereof; most preferably water.

In another embodiment of the instant invention, wherein the step (b) is performed in presence of an antifoaming agents, where the antifoaming agent is selected from alcohol alkoxylates such as DOBANOL, alcohol ethoxylates such as GENAPOL and/or propoxylates, octanol, heptane, monochlorobenzene (MCB), isoparaffinic hydrocarbon (ISOPAR-G); preferably ISOPAR-G.

In another embodiment of the instant invention, wherein the acidic mediumin step (b) is prepared by adding acid in reaction mixture and maintaining pH between 0 to 5; where the acid is selected from hydrochloric acid, acetic acid, sulfuric acid, trifluoro acetic acid; preferably hydrochloric acid.

In another embodiment of the instant invention, wherein the resulting compound (VI) of step (b) is store in organic solvent selected from monochlorobenzene, ethylene dichloride, dichlorobenzene, methylene dichloride and the like, preferably ethylene dichloride.

In another embodiment of the instant invention, wherein the step (c) is performed using an acid selected from thionyl chloride, sulfuric acid, hydrochloric acid, acetic acid, and the like; preferably thionyl chloride, sulfuric acid.

In another embodiment of the present invention, wherein the acid used for preparation of compound of formula (VII) is thionyl chloride or sulfuric acid.

In another embodiment of the instant invention, wherein reagents used in step (c) is 1.0 to 5.0 equivalent.

In another embodiment of the instant invention, wherein the compound of formula (VII) is obtained by treating organic layer with 5 to 20% carbonate solution.

In another embodiment of the instant invention, wherein purity of desired isomer (E) of formula (VII) is greater than 98% and undesired isomer (Z) of formula (Vila) less than 2%.

In another embodiment of the instant invention, wherein the said metal halogenate (NaXCh/ KXO3) of step (d) is selected from sodium bromate (NaBrOr), sodium chlorate (NaClO ), sodiumiodate (Na b), potassium bromate (KBrOs), potassium chlorate (KCIO3), potassium iodate (KIO3), N-bromosuccinimide (NBS) and the like; preferably sodium bromate.

In another embodiment of the present invention, wherein the said substituent X is selected from the group consisting of chlorine, bromine, iodine. In another embodiment of the present invention, wherein the said catalyst of step (d) is selected from the group consisting of sodium bromide (NaBr), potassium bromide (KBr), sodium iodide (Nal), potassium iodide (KI), azobisisobutyronitrile (AIBN) and the like; preferably azobisisobutyronitrile.

In another embodiment of the present invention, wherein the compound of formula (I) is prepared by reacting (VII) using metal halogenate in presence of sodium bisulfate or using sulfuric acid and sodium bromide with or without use of catalyst in a solvent.

In another embodiment of the present invention, wherein the said solvent of step (d) in combination with water is selected from ethylene dichloride, dichloromethane, chloroform, monochlorobenzene, acetonitrile, diisopropyl ether, ethyl acetate and the like or mixture of solvents thereof, preferably ethylene dichloride.

In another embodiment of the present invention, wherein compound of formula (I) isolated by quenching reaction mixture in basic solution, where base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, and sodium metabisulfite.

In another embodiment of the present invention, wherein the purification step (e) is performed by crystallization in alcoholic solvent, which is selected from methyl alcohol, ethyl alcohol, isopropyl alcohol and the like, preferably isopropyl alcohol.

In another embodiment of the present invention, wherein any one of the steps or all the said steps from (a) to (e) is performed in in-situ manner.

In another embodiment of the present invention, wherein compound (VI) and compound (VII) inorganic solvent and further used as such for the next stage without distillation, isolation, or purification.

The preparation of the starting material used in the present invention are well known in prior art.

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway. EXPERIMENTAL

Example 1: Preparation of (£')-2-methoxyimino-2-(o-tolyl)acetic acid (compound (VI).

Pot-A

The four neck R. B. flask equipped with mechanical stirrer, thermo pocket and water condenser was arranged. The water (3-5V) followed by concentrate hydrochloric acid (3.0 V) was charged under stirring and cooled the reaction mass to -5°C to 0°C. OToluidine (1.0 eq.) was added drop wise over 30 min to reaction mass under stirring at -5°C to 0°C and stirred for 30 min. The solution of NaNC (1 to 1.5 eq.) in water (1.0 vol) was added to reaction mixture lot wise over 30 min. at -5°C to 0°C. After complete addition, the solution was used for the next operation.

Pot-B

To the four necks R. B. flask equipped with mechanical stirrer, thermo pocket, condenser and addition funnel, water (3- 5V), a solution of glyoxylic acid (1.5-1.8 eq.) and methoxy amine hydrochloride (1.2- 1.5 eq.) was charged under stirring and reaction mixture further stirred at 20°C to 30°C for 1.0 h. To the reaction mixture water (IV), sodium carbonate (1.5-1.8 eq.), a liquid ISOPAR-G (2.0V) was added and cooled to 15°C to 25°C under stirring. The solid copper sulphate pentahydrate (0.5 eq) was added to reaction mixture under stirring and maintained temperature at 15°C to 25°C. The reaction mixture from Pot-A was slowly added to Pot-B over period of 1-2 h and maintaining reaction temperature 15°C to 25 °C. The pH of reaction mixture was maintained between 6.0 to 7.0 by addition of aqueous Na ₂ C0 ₃ solution. The reaction mixture was stirred at 25°C to 30°C for 1-2 h and concentrated hydrochloric acid (1.0V) was added. The reaction mixture was filtered, and the wet solid is washed with ISOPAR-G (1.0V). To this wet solid ethylene dichloride (6-8V) was charged and stirred for 15 min. The organic layer containing compound of formula (VI) was send to HPLC purity. (Yield-78% on assay basis, Purity 98%, MC: less than 2.0%).

Example 2: Preparation of (£')-2-methoxyimino-2-(o-tolyl) acetic acid methyl ester (Compound VII).

To the four neck R.B. Flask with mechanical stirrer, condenser, thermo pocket, a solution of compound (VI, Purity 97%, 1.0 eq.), methanol (3-5eq.) was charged. The thionyl chloride (1- 1.2 eq.) was added slowly to reaction mixture at 20°C to 30°C over 15 min and heated at 40°C to 50°C for 1-2 h. The reaction completion was monitored by HPLC, after completion the reaction mixture was cooled to 20°C to 30°C and water was added. The reaction mixture was allowded to settle and organic layer was separated. The organic layer was further treated with aq. sodium carbonate and separated. The separated organic layer containing compound of formula (VII) (Yield 90% on assay basis, Purity: (E) isomer 95%, (Z) isomer 2-3%).

Example 3: Preparation of (£')-2-methoxyimino-2-(o-tolyl) acetic acid methyl ester (Compound VII).

To the four neck R.B. Flask with mechanical stirrer, condenser, thermo pocket, a solution of compound (VI, Purity 97%, 1.0 eq.), methanol (3-5 eq.) was charged. The concentrated sulfuric acid (1-1.2 eq.) was added slowly to reaction mixture at 20°C to 30°C over 15 min and heated at 40°C to 50°C for 2-4 h. The reaction completion was monitored by HPLC, after completion the reaction mixture was cooled to 20°C to 30°C and water was added. The reaction mixture was allowded to settle and organic layer was separed. The organic layer was further treated with aq. sodium carbonate and organic layer was separated. The obtained organic layer containing compound of formula (VII) (Yield-91% on assay basis, Purity 97%).

Example 4: Preparation of (/?)-2-(2-bromomethylphenyl)-2-methoxyiminoacetic acid methyl ester (compound I).

To the four neck R.B. Flask with mechanical stirrer, condenser, thermo pocket and oil bath a solution of compound (VII, Purity 96%, 1.0 eq) and water (3-5 eq) was charged to under stirring at 25°C to 30°C and stirred for 30 min. The catalyst (0.07 eq), sodium bromate (1-1.2 eq.) was added to the reaction mixture and further heated to 60°C to 70°C under stirring for 30 min. The solution of sodium bisulphite (1.5 eq.) in water (2.0 vol) was added to reaction mixture slowly and maintaining reaction temperature at 65 °C to 75°C for over 2 h and further heated for 1 h. The completion of reaction is monitored by HPLC. After completion, the reaction is quenched in basic solution and organic layer separated. The solvent was removed from organic layer by distillation under vacuum to obtain crude compound (VII). The crude- compound was purified by simple recrystallization process using IPA to obtain pure compound of formula (I) (Yield- 62% on assay basis, Purity 98%).