Description:Technical filed:
The invention relates to a process for manufacture of 2-(2-methylphenoxymethyl) phenylglyoxylate. More particularly, the invention relates to a process for manufacture of 2-(2-methylphenoxymethyl) phenylglyoxylate by avoiding the formation of 2-(2-methylphenoxymethyl)-phenylglyoxylate dimethyl acetal and 2-(2-methylphenoxymethyl) benzoate.

Background and prior art:
2-(2-methylphenoxymethyl) phenylglyoxylate and its derivatives are used as an intermediate in the synthesis of a fungicides such as Kresoxim-methyl, Dimoxystrobin, Metominostrobin, Orysastrobin, Trifloxystrobin etc. Typically Kresoxim-methyl is a broad spectrum Strobilurin fungicide with a protective and curative mode of action. In addition to the spectrum of control it gives good residual activity and hence extended duration of control. Kresoxim Methyl is very effective against powdery mildew for most of the crops and has good greening effect and thus used for the control of scab on apples and pears and other fungal diseases on a wide range of crops.

DE 69722005 discloses agricultural and horticultural antibacterial composition using oxime with following structure of formula (I)-

(I)
Where R1= C1 to C4 alkyl, alkenyl, R2 = Phenyl radical or optionally substituted heterocycle
X1= C1 to C4 haloalkyl; and X2 to X4 =independently represents hydrogen, halogen, C1 to C4 haloalkyl, alkylthio etc.
US4999042 discloses Phenyl oximino-acetate fungicides with following structure-

(II)
Where X = Halogen, alkyl, cycloalkyl, arylalkyl, aryloxy alkyl, alkenyl, aryl, amino; and W, X, Y, Z = optionally joined to form fused ring either aromatic or aliphatic with one or more heteroatom.

These compounds contain at least one carbon nitrogen double bond and are sometimes obtained in the form of mixture of geometric isomers. These mixtures can be separated in to individual isomers thus consist of E and Z isomers.

US 5221762 (Example 6) describes synthesis of Methyl 2-(phenoxymethyl)phenylglyoxylate (without toluene), wherein, during the conversion of 2-(2-methylphenoxymethyl) benzoyl cyanide to 2-(2-methylphenoxymethyl) phenylglyoxylate, various by-products in substantial amounts were formed. The stoichiometry of HCl used for conversion is large excess (45m/m), also methanol used is 93m/m. For example, Methyl 2-(2-methylphenoxymethyl) phenylglyoxylamide formed in the range of 60%; due to the cleavage of 2-(2-methylphenoxymethyl) benzoyl cyanide, the corresponding ester formed to the extent of 19.3%; the formation of 2-(2-methylphenoxymethyl)-phenylglyoxylate dimethyl acetal to the extent of 11.8% and the formation of 2-(2-methylphenoxymethyl) phenylglyoxylate to the extent of 12.9 % was reported. Further, the synthesis of Methyl 2-(phenoxymethyl)phenylglyoxylate (with toluene) as a diluent provides methyl 2-(2-methylphenoxymethyl)benzoate (by-product) in an amount of 7.8 mol%; methyl 2-(2-methylphenoxymethyl)-phenylglyoxylate in an amount of 34.1 mol% and 2-(2-methylphenoxymethyl)phenylglyoxylamide in an amount of 54.1 mol%.
Example 7 of US’762 demonstrate the conversion of mixture of Methyl 2-(2-methylphenoxymethyl) phenylglyoxylamide (40%) and 2-(2-methylphenoxymethyl) phenylglyoxylate(60%) into2-(2-methylphenoxymethyl) phenylglyoxylate by refluxing in methanol and sulfuric acid. The HPLC analysis indicates Methyl 2-(2-methylphenoxymethyl) phenylglyoxylamide unreacted to the extent of 1.4% with product 2-(2-methylphenoxymethyl) phenylglyoxylate 81.6%. The Example no 8 of US’762 demonstrate the acidic cleavage of methyl 2-(2-methylphenoxymethyl) phenylglyoxylate dimethyl acetal to 2-(2-methylphenoxymethyl) phenylglyoxylate and this example also fails to provide 2-(2-methyl phenoxymethyl)phenylglyoxylate exclusively.

As is evident from the above, the exclusive formation of either Methyl 2-(2-methylphenoxymethyl) phenylglyoxylamide or 2-(2-methylphenoxymethyl) phenylglyoxylate is not formed during reaction. Therefore, the isolation of desired 2-(2-methylphenoxymethyl) phenylglyoxylate from a mixture of Methyl 2-(2-methylphenoxymethyl) phenylglyoxylamide & 2-(2-methylphenoxymethyl) phenylglyoxylate could not be possible for further conversion of amide moiety into desired ester. Moreover, 2-(2-methylphenoxymethyl)-phenylglyoxylate dimethyl acetal is another component which need reprocessing under acidic conditions to convert into 2-(2-methylphenoxymethyl) phenylglyoxylate.

As is evident from the above, the exclusive formation of 2-(2-methylphenoxymethyl) phenylglyoxylate to the extent of 85-90% by methodology described in US 5221762 is difficult to achieve and hence requires improved method to achieve the formation of 2-(2-methylphenoxymethyl) phenylglyoxylate upto the level of 85-90% by minimizing side products & thereby making the process suitable for large scale manufacture.

Therefore, the process disclosed in US5221762 is not economical to operate at commercial scale.
In the light of the above, there remains a need in the art to provide an improved process for the preparation of 2-(2-methylphenoxymethyl) phenylglyoxylate that minimises the formation of by-products thereby eliminates multistep operations involved in recycle and reuse of the by-products(intermediates) and further operational costs of the synthesis.

Objective of the invention:
It is an objective of the invention to provide an improved process for the preparation of 2-(2-methylphenoxymethyl) phenylglyoxylate that controls the formation of 2-(2-methylphenoxymethyl)-phenylglyoxylate dimethyl acetal and 2-(2-methylphenoxymethyl) benzoate and thereby facilitated effective isolation of Methyl 2-(2-methylphenoxymethyl) phenylglyoxylamide and further conversion of the same under biphasic conditions to isolate 2-(2-methylphenoxymethyl) phenylglyoxylate with 98-99% purity.

Summary of the invention:
In line with the above objective, the present invention provides a process for the preparation of 2-(2-methylphenoxymethyl) phenylglyoxylate, which process comprises;
a) Reacting 2-(2-methylphenoxymethyl) benzoyl cyanide in a organic solvent with dry HCl gas in presence of sulfuric acid at a temperature of -15 to 15ºC to obtain Methyl 2-(2-methylphenoxymethyl) phenylglyoxylamide; and

b) Reacting the Methyl 2-(2-methylphenoxymethyl) phenylglyoxylamide in a organic solvent under biphasic conditions using dry HCl gas in presence of organic solvent at a temperature of 5-15ºC, followed by heating the reaction mass to a temperature of 50 to 70ºC to obtain 2-(2-methylphenoxymethyl) phenylglyoxylate.

In an aspect, the organic solvent used in the process is selected from the group consisting of chlorinated aliphatic solvents such as dichloromethane, dichloroethane; ethers such as diethyl ether, THF; esters such as ethyl acetate; aromatic hydrocarbon solvents such as toluene, ortho xylene, para xylene etc.

In another aspect, the other organic solvent used under biphasic system is methanol.
In another aspect, the sulfuric acid used in the process is concentrated sulfuric acid with a concentration of about 70 to 98%.

In a further aspect, the molar ratio of dry HCl to 2-(2-methylphenoxymethyl) benzoyl cyanide is in the range of 1: 0.2 to 1:3.5.

In a further aspect, the molar ratio of dry HCl to Methyl 2-(2-methylphenoxymethyl) phenylglyoxylamide is in the range of 1: 0.2 to 1:5.

Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. To describe the invention, certain terms are defined herein specifically as follows.
Unless stated to the contrary, any of the words, “including”, “includes”, “comprising”, and comprises” mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items.

Accordingly, the present invention provides a process for the preparation of 2-(2-methylphenoxymethyl) phenylglyoxylate, which process comprises;
a) Reacting 2-(2-methylphenoxymethyl) benzoyl cyanide in an organic solvent with dry HCl gas in presence of sulfuric acid at a temperature of -15ºC to 15 ºC to obtain Methyl 2-(2-methylphenoxymethyl) phenylglyoxylamide; and

b) Reacting the Methyl 2-(2-methylphenoxymethyl) phenylglyoxylamide in an organic solvent under biphasic conditions using dry HCl gas in presence of organic solvent at a temperature of - 5 to 30ºC, followed by heating the reaction mass to a temperature of 50 to 140ºC to obtain 2-(2-methylphenoxymethyl) Phenylglyoxylate.


In an aspect, the organic solvent used in the process is selected from the group consisting of chlorinated aliphatic solvents such as dichloromethane, dichloroethane; ethers such as diethyl ether, THF; esters such as ethyl acetate; aromatic hydrocarbon solvents such as toluene, ortho xylene, para xylene etc. The use of organic solvent eliminates the formation of methyl 2-(2-methylphenoxymethyl) phenylglyoxylate dimethyl acetal in the process and thus recycle and reprocessing cost and materials for reprocessing are avoided. This improvement substantially reduces the burden of acidic and organic effluents.

In another aspect, the organic solvent used under biphasic system is methanol.

In another embodiment, the sulfuric acid used in the process is concentrated sulfuric acid with a concentration of about 70 to 98%.

In a further embodiment, the molar ratio of dry HCl to 2-(2-methylphenoxymethyl) benzoyl cyanide is in the range of 1: 0.2 to 1:3.5.

In a further aspect, the molar ratio of dry HCl to Methyl 2-(2-methylphenoxymethyl) phenylglyoxylamide is in the range of 1: 0.2 to 1:5.

Accordingly, in a reaction flask charged a non-polar solvent and 2-(2-methylphenoxymethyl) benzoyl cyanide and purged dry HCl at a temperature of 0-10 deg. Charged conc. sulfuric acid over a period of 6-12 hrs by maintaining temperature at 0-10 deg C. The reaction was maintained for another 10 hrs at 0-10 deg C and then slowly raised to 30 -50 deg C. Added water to the reaction mass and filtered the reaction mass to isolate Methyl 2-(2-methylphenoxymethyl) Phenylglyoxylamide with a purity of more than 98%.

Further, the isolated Methyl 2-(2-methylphenoxymethyl) Phenylglyoxylamide was taken in an organic solvent and cooled to 5 -25 deg C; purged dry hydrochloric acid gas and then charged methanol. Heated the reaction mass to 40-90 deg C and maintained for 12 hrs. Further, added water, stirred and separated the organic and aqueous layers. The organic solvent layer was neutralized using sodium bicarbonate and concentrated to isolate 2-(2-methylphenoxymethyl) phenylglyoxylate in more than 98% purity as solid.
The following examples are presented to further explain the invention with experimental conditions, which are purely illustrative and are not intended to limit the scope of the invention.

Examples

Example -1
Process for preparation of Methyl 2-(2-methylphenoxymethyl) phenylglyoxylamide

In 3.0 lit reaction flask charged 1500 ml ethylene dichloride and 251 g (1mole) of 2-(2-methylphenoxymethyl) benzoyl cyanide. Passed dry HCl (25.5g,0.69moles) at 0-9 deg. Charged 1.1mole of 85% sulfuric acid over a period of 8 hr maintaining temperature at 0-15 deg C. Further, maintained the temperature for 4 hrs at 0-15 deg C and then slowly raised to 40 deg C. Added 1400 ml water and filtered the reaction mass, to isolate Methyl 2-(2-methylphenoxymethyl) Phenylglyoxylamide.
Yield – 238.3g (0.87m) (Melting point – 138-140 deg C, Purity 98.57%)

Example -2
In 3.0 lit reaction flask charged 1200 ml Toluene and 251 g (1mole) of 2-(2-methylphenoxymethyl) benzoyl cyanide. Passed dry HCl (36.5g,1.0 mole) at 0-8 deg. Further, 1.1mole of 80% sulfuric acid was added slowly over a period of 12 hr maintaining the temperature 10-15 deg C. Further, the reaction mass was maintained at the same temperature for 10 hrs till the reaction is complete (by TLC). Drowned reaction mass in 1.2 lit water containing 300g ice. Stirred for 1 hr and filtered Methyl 2-(2-methylphenoxymethyl) Phenylglyoxylamide.
Yield – 234.g (0.85m) (Purity 98%)

Example -3
In 5.0 lit reaction flask charged 2200 ml Dichloromethane and 251 g (1mole) of 2-(2-methylphenoxymethyl) benzoyl cyanide. Passed dry HCl (36.5g,1.0 mole) at a temperature of 0-5 deg. 1.1mole of 80% sulfuric acid was added over a period of 9 hr maintaining temperature at 0-5 deg C and maintained the reaction mass for another 8 hrs till reaction is complete (by TLC). Added 1 lit water and separated layers. Organic layer was washed with 100 ml water and concentrated to obtain Methyl 2-(2-methylphenoxymethyl) phenylglyoxylamide.
Yield – 242.g (0.89m). Purity (98.6%)

Example -4
7.53 Kg (29.88m) of 2-phenoxymethyl benzoyl nitrile in 80 lit Dichloroethane in 200 lit MSGL reactor was cooled to 0-5 deg C by applying brine circulation. The dry HCl (766g) generated using 98% sulfuric acid and concentrated hydrochloric acid from another reactor was bubbled slowly into a solution of 2-phenoxymethyl benzoyl nitrile in dichloroethane maintaining the same temperature. 5.1 Kg 83% sulfuric acid was then metered via dip pipe in to reaction vessel over a period of 24 hrs. The reaction mass was stirred for additional 8 hrs. 50 lit water then added slowly over a period of 5 hrs. After completion of addition filtered reaction mass on Nutsche filter. The cake thus obtained was again taken in 40 lit water, stirred, filtered, dried under vacuum.
Crop 1- Dry wt: 5.7 Kg (20.93m) (Yield 69.8%, purity 98.8%). Organic layer was separated and washed with water and concentrated to isolate Methyl 2-(2-methylphenoxymethyl) Phenylglyoxylamide Crop 2- 1.5 Kg (5.47m) (Yield – 18.23%, Purity 98.2%)
Overall yield from crop 1 and crop 2 -89%.

Example 5:
Process for preparation of 2-(2-methylphenoxymethyl) phenylglyoxylate

To 20 lit glass assembly charged 9 lit toluene and added the isolated Crop 1 and Crop 2 isolated in Example 4. Cooled the reaction mass to 10-15 deg C and passed 1.45Kg dry HCl. During HCl passing, charged methanol (3 Kg) into the reactor. Heated the reaction mass to 55-90 deg C to complete the conversion of Methyl 2-(2-methylphenoxymethyl) Phenylglyoxylamide to the corresponding ester.
Added 8.5 lit water, stirred and separated layers. Toluene layer was neutralized using sodium bicarbonate and concentrated to isolate 7.2 Kg 2-(2-methylphenoxymethyl) phenylglyoxylate of 98.8% purity as solid.
Yield – 93.6%

Example 6
Isolated Methyl 2-(2-methylphenoxymethyl) Phenylglyoxylamide from Example 1 was mixed with 1600ml ortho xylene and cooled to 10 deg C. Passed 58g dry hydrochloric acid gas and then charged 100g methanol. Heated the reaction mass to 65-70 deg C and maintained for 8 hrs. The reaction mass worked up as in Example 5 to isolate 2-(2-methylphenoxymethyl) phenylglyoxylate 246g (99.1% purity) as white colour solids.
Yield: 98.6%

Example 7
Isolated Methyl 2-(2-methylphenoxymethyl) Phenylglyoxylamide from Example 2 was mixed with 1000ml Dichloroethane and cooled to 10 deg C. Passed 50g dry hydrochloric acid gas and then charged 120g methanol. Heated the reaction mass to 65-70 deg C and maintained at the same temperature for 8 hrs. The reaction mass worked up as in Example 1 to isolate 2-(2-methylphenoxymethyl) phenylglyoxylate 236g (98.8% purity).
Yield: 94.3%

Industrial advantages:
The present invention provides an improved process for economic commercial operation by minimizing side products thereby eliminates multistep operations involved in recycle and reuse of intermediates.
The present invention provides a process for manufacture of 2-(2-methylphenoxymethyl) phenylglyoxylate with the following benefits.
1) Isolation of Methyl 2-(2-methylphenoxymethyl) phenylglyoxylamide exclusively to the extent of 82-89% yield is possible.
2) The formation of 2-(2-methylphenoxymethyl)-phenylglyoxylate dimethyl acetal is avoided.
3) Quantitative Conversion of Methyl 2-(2-methylphenoxymethyl) phenylglyoxylamide under biphasic conditions to isolate 2-(2-methylphenoxymethyl) phenylglyoxylate with 98-99% purity.
, Claims:1. A process for the preparation of 2-(2-methylphenoxymethyl) phenylglyoxylate in high yield and purity, which process comprises;
a) Reacting 2-(2-methylphenoxymethyl) benzoyl cyanide in an organic solvent with dry HCl gas in presence of sulfuric acid at a temperature of -15 to 15ºC to obtain Methyl 2-(2-methylphenoxymethyl) phenylglyoxylamide;

b) Reacting the Methyl 2-(2-methylphenoxymethyl) phenylglyoxylamide in an organic solvent under biphasic conditions using dry HCl gas in presence of an organic solvent at a temperature of 5-15ºC, followed by heating the reaction mass to a temperature of 50 to 70ºC to obtain 2-(2-methylphenoxymethyl) phenylglyoxylate;
2. The process as claimed in claim 1, wherein, the organic solvent used in the process is selected from the group consisting of chlorinated aliphatic solvents such as dichloromethane, dichloroethane; ethers such as diethyl ether, THF; esters such as ethyl acetate; aromatic hydrocarbon solvents such as toluene, ortho xylene, para xylene etc.
3. The process as claimed in claim 1, wherein, the organic solvent used under biphasic system is methanol.
4. The process as claimed in claim 1, wherein, the sulfuric acid used in the process is concentrated sulfuric acid with a concentration of about 70 to 98%.
5. The process as claimed in claim 1, wherein, the molar ratio of dry HCl to 2-(2-methylphenoxymethyl) benzoyl cyanide is in the range of 1: 0.2 to 1:3.
6. The process as claimed in claim 1, wherein, the molar ratio of dry HCl to Methyl 2-(2-methylphenoxymethyl) phenylglyoxylamide is in the range of 1: 0.2 to 1:5.
7. The process claimed in claim 1 wherein the isolation of Methyl 2-(2-methylphenoxymethyl) phenylglyoxylamide in high purity and subsequent conversion to corresponding ester helps in non-formation of impurities such as diacetal and thereby substantially reducing the effluent load.