Title:
Process for the preparation of Azoxystrobin key intermediates
Field of invention
The present invention relates to the process for preparation of Methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3 3-dimethoxypropionate and (E) Methyl 2-[2-(6-chloropyrimidine-4-yloxy) phenyl]-3-methoxypropenoate  which are important intermediates in the preparation of Azoxystrobin  a fungicide widely used world over in the protection of food and fruit crops.
DESCRIPTION OF THE BACKGROUND
Methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3 3-dimethoxypropionate (Formula-1) and (E) Methyl 2-[2-(6-chloropyrimidine-4-yloxy) phenyl]-3-methoxypropenoate (Formula-2) can be made in high yielding process and more economical for industrial production.
It is known that Formula-1 and Formula-2 can be made using 4 6-dichloropyrimidine (Formula-4) and 3-(alpha-methoxy)methylene benzofuran-2(3H)-one (Formula-3) in a solvent and in the presence of sodium methoxide.
US patent 5760250 refers to the preparation of Formula -1 and formula-2 in various solvents like acetonitrile  Tetrahydrofuran and methylacetate. The yield mentioned in the above patent is very low and time consuming. Handling of Tetrahydrofuran is uneconomical as distillation losses are more  whereas in Methylacetate and Acetonitrile  reaction time is more than 24 hours  which is industrially infeasible as it may effect on production.
UK Patent application no GB2291874 refers to the preparation of methyl 3 3dimethoxy-2-[2-hydroxyphenyl]propionate using formula-3 and sodium methoxide in methanol under low temperature and subsequent neutralization with acetic acid. Major impurity formed in the above process is formula-5 when neutralized with acetic acid and the formed compound doesn’t react with 4 6-dichloropyrimidine to yield formula-1 or formula-2. One of the major drawbacks in the process is that Methanol is used in excess and under base presence  methanol has to be removed under vacuum at less than or equal to 10C to proceed for the next reaction with 4 6-dichloropyrimidine  if formula-1 and formula-2 are to be prepared  but removal of Methanol under 10C temperature industrially is not economical and time consuming. Methanol cannot be removed completely as sodium methoxide is present in excess.
The above patent also refers to the formation of formula -1 and formula-2 in 51% yielding process. The above process results in the formation of formula-5 compound at significant levels which effects the yield as condensation with 4 6-dichloropyrimidine is done after neutralization with acetic acid. The condensation reaction takes place in Dimethylformamide and under presence of potassium carbonate  which involves different solvents and again for purification another solvent has to be used  which is industrially not feasible.
World patent WO9807707 refers mainly for the formation of formula-2 from formula -1 with acetic anhydride and methane sulfonic acid. The above patent also mentions formation of formula-1 in the presence of sodium methoxide employing Methyl formate as solvent. Methyl formate is very low boiling solvent and industrially distillation losses are unavoidable. The reaction process involves formation of major impurity 4-chloro-6-methoxy pyrimidine (formula-6) which affects the yield. According to the patent after completion of reaction methyl formate was distilled under atmospheric conditions  which cannot be made industrially as sodium methoxide is used in excess and its presence in the reaction mass will not allow to distill the solvent without neutralizing it.
Chinese patent CN101157657 refers for the formation of Formula-1 and formula-2 using lewis acid such as titanium tetrachloride with trimethylorthoformate or methyl formate for formylating 2-(2-[6-chloropyrimidloxy]phenyl)methylacetate. The above process involves usage of titanium tetrachloride in excess  which is unfavorable for the industry and major drawback of this reaction lies in the hydrolysis of the said formylated product. Without completion of hydrolysis the yields of the reaction are quite low. One of the other drawback is that this process number of raw materials like titanium tetrachloride  triethylamine  hydrochloric acid  methyl formate or trimethylortho formate  then dimethylsulfate for esterification and caustic soda lye. Other drawback is that dimethylsulfate is used in molar quantities and it requires lot of care as Dimethylsulfate is poisonous.
Summary of the invention
The present invention in this process involves resolving the said above problems. The process is very easy to handle and mostly happens in single solvent without implementing different solvents.
The process involves reacting formula-3 with formula-4 in the presence of nonpolar solvent with sodium methoxide in methanol under the action of catalyst 1 4-diazabicyclo[2.2.2]octane (DABCO). Catalyst DABCO is used for the condensation reaction in nonpolar solvent in reduced time.
The present invention mentioned here provides a process for the preparation of formula-1 and formula-2 comprising the following steps:
a. Preparing a formula-7 compound from formula-3 compound under the presence of Sodium methoxide in methanol and in nonpolar solvent with or without presence of base.
b. Preparing the formula-1 and formula-2 compound in nonpolar solvent using formula-4 compound and DABCO as catalyst
The said process involves non-polar or polar aprotic solvents  and inorganics can be removed easily and washed with water. The solvents are more like toluene  dichloroethane  dichloromethane  xylene  dichlorobenzene  chlorobenzene. Preferably dichloroethane  toluene  xylene and most preferably toluene and dichloroethane.
The base used in the process can of be alkali carbonate or metal hydroxide  metal carbonate  organic carbonates  and organic bases. Base used can be of potassium hydroxide  sodium hydroxide  sodium carbonate  potassium carbonate  triethylamine  trimethylamine  ethylene carbonate  bicarbonates such as sodium bicarbonate  potassium bicarbonate. Preferably potassium carbonate  sodium carbonate  potassium hydroxide  sodium hydroxide and most preferably potassium carbonate  and sodium carbonate. The ratio of base to be used with respective of formula-3 compound is in the range of 1.0:0.1 to 2.0  preferably in the range of 1.0:0.1 to 1.2 most preferably in the range of 1.0:0.8 to 1.2.
The compound of formula-7 can be made easily in the presence of sodium methoxide in methanol  however retaining in the same form  is much more difficult as it may soon convert into formula-5 compound just by acidification or by removing methanol. This reaction for the formation of formual-7 cannot be made easily in other solvents.
Surprisingly  this invention provides an easy way to form formula-7 compound without forming any impurities  and avoiding methanol removal  as methanol is used in very little quantity. The process describes a simple way of obtaining formula-7 in the presence of sodium methoxide in methanol and in nonpolar solvent.
The condensation reaction for the formula-7 compound and formula-4 compound is done in the presence of Catalyst DABCO in nonpolar solvent and in single pot only. Usually methanol absence can facilitate the condensation reaction fast in polar solvents and in nonpolar solvents reactions happen at a prolonged time. Surprisingly the catalyst DABCO facilitate the reaction at a faster rate in nonpolar solvents.
The catalyst used in the process is in the range of 1:0.005 to 0.5. preferably in the range of 1.0:0.005 to 0.2. The catalyst used in the process is DABCO in anhydrous form or in hydrous form with Moisture content in the range of 0.1 to 0.5%. Most preferably moisture content to be less than or equal to 0.3%.
The Formula-3 to formula-4 ratios are in the range of 1.0:1.0-1.5  preferably in the range of 1.0:1.2.
The following examples describes the simple way of making formula-3 and formula-4 compounds.
Example-1:
Into the four neck round bottomed 500ml flask  was added Dichloroethane 100ml and 3-(alpha-methoxy) methylene benzofuran-2(3H)-one 17.6 gm. To this slurry  potassium carbonate 16gm and sodium methoxide solution (in methanol) 22 gm was added over a period of 10 min at a temperature of -5-0C. After 1 hour stirring at this temperature  4  6-dichloropyrimidine 16gm and DABCO 2gm were added and stirred for again 3 hours. Upon completion of reaction  inorganics were filtered and washed organic layer with water. To this organic layer dimethylsulfate was added and stirred at 90 C for 8 hours and methanol was removed azeotropically. After completion of reaction  organic layer was analyzed to found ((E) Methyl 2-[2-(6-chloropyrimidine-4-yloxy) phenyl]-3-methoxypropenoate at 74.2% yield.

Example-2:
Into the four neck round bottomed 500ml flask  was added Xylene 1000ml and 3-(alpha-methoxy) methylene benzofuran-2(3H)-one 176 gm. To this slurry  potassium carbonate 160gm and sodium methoxide solution (in methanol) 220 gm was added over a period of 10 min at a temperature of -5-0C. After 1 hour stirring at this temperature  4 6-dichloropyrimidine 160gm and DABCO 20gm were added and stirred for again 3 hours. Reaction mass was analysed to found Methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3 3-dimethoxypropionate forming at 72% and (E) Methyl 2-[2-(6-chloropyrimidine-4-yloxy) phenyl]-3-methoxypropenoate at 10%. Workup of this reaction is done in the same way as in example1.
Example-3:
Into the four neck round bottomed 500ml flask  was added 1 2-dichlorobenzene 1000ml and 3-(alpha-methoxy) methylene benzofuran-2(3H)-one 88 gm. To this slurry  potassium carbonate 80gm and sodium methoxide solution (in methanol) 110 gm was added over a period of 10 min at a temperature of -10 C. After 60minutes stirring at this temperature  4 6-dichloropyrimidine 81gm and DABCO 8gm were added and stirred for again 6 hours. Reaction mass was analysed to found Methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3 3-dimethoxypropionate forming at 70% and (E) Methyl 2-[2-(6-chloropyrimidine-4-yloxy) phenyl]-3-methoxypropenoate at 10%.
Product A: Methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3 3-dimethoxypropionate
Product B: (E) Methyl 2-[2-(6-chloropyrimidine-4-yloxy) phenyl]-3-methoxypropenoate
Table-1 shows different solvents and formation of the product at different temperatures
Solvent Temperature Product A:B Raw material left
EDC -5 72% : 8% 3.5%
Dichlorobenzene -10 70% : 10% 2%
Xylene -8 72% : 10% 3.2%
MDC -5 74% : 6% 0%
Chlorobenzene 5 68% : 11% 1.4%

Table -2 shows the percentage of DABCO against percentage of raw material
Solvent Temperature Product A:B DABCO %
EDC -8 65% : 8% 5%
EDC -8 56% : 5% 1.5%
EDC -8 72% : 10% 10%
EDC -5 58% : 8% 2.0%

What we claim here is:
1. The process of preparation of compounds of formula-1 and formula-2 in non-polar and polar aprotic solvents involving the following steps:
A. Raw materials of formula-3 and formula-4 are reacted in a solvent in the presence of sodium methoxide in Methanol along with auxiliary base and in the presence of catalyst 1 4-diazabicyclo[2.2.2]octane (DABCO) at a temperature of -20 to 20C.
B. After completion of reaction  reaction medium is subjected to filtration and washed with water to remove inorganics.
C. The subsequent reaction to demethanolysis is done in the same solvent at elevated temperatures in the range of 80-90C and crystallized.

2. A process as claimed in claim1  wherein the solvent used for all steps is Dichloroethane  Toluene  Dichloromethane  Chlorobenzene  dichlorobenzene  preferably Dichloroethane and toluene.

3. A process as claimed in claim1  wherein the auxiliary base used is potassium hydroxide  sodium hydroxide  potassium carbonate  sodium carbonate  most preferably potassium carbonate and sodium carbonate.

4. A process as claimed in claim1  wherein the temperatures used in the reaction for the step A is in the range of -20 to 100C  preferably in the range of -20 to +30  most preferably between -10 to 10C.

5. A process as claimed in claim 1  wherein the temperatures used for the STEP C reaction is in the range of 50 to 150C  preferably 80-120 C and most preferably in the range of 80-100C.