WO2014203270A2

WO2014203270A2 - Process for the preparation of acrylate derivatives

Info

Publication number: WO2014203270A2
Application number: PCT/IN2014/000303
Authority: WO
Inventors: Vinay DURGAM; Sai Lakshmi BIKKINI; Komali BOTLA; Sivarami Reddy BONTHU
Original assignee: Bhagiradha Chemicals & Industries Limited
Priority date: 2013-06-19
Filing date: 2014-05-06
Publication date: 2014-12-24
Also published as: WO2014203270A3

Abstract

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

Title:

Process for the preparation of Acrylate derivatives.

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 (structure-1] and (E) Methyl 2-[2-(6-chloropyrimidine-4-yloxy) phenyl]-3-methoxypropenoate (structure -2) can be made in high yielding process and more economical for industrial production.

This is in continuation to our earlier patent Indian patent application number 5360/CHE/2012, for the preparation of Azoxystrobin intermediates which are acrylate class derivatives using the catalysts mentioned in the above patent application, like HEXAMINE, TRIPHENYLPHOSPHINE, ADAMANTANE. The catalysts used in the above patent are for the condensation reaction to from azoxystrobin using (E) Methyl 2-[2-(6-chloropyrimidine-4-yloxy) phenyl]-3-methoxypropenoate and o-cyanophenol in the presence of inorganic base and catalyst. However the same catalysts can be used in to prepare the above mentioned intermediate [(E) Methyl 2-[2-(6-chloropyrimidine-4- yloxy] phenyl]-3-methoxypropenoate] in nonpolar solvents.

It is known that Structure-1 and Structure-2 can be made using 4,6-dichloropyrimidine (structure - 4) and 3-(alpha-methoxy)methylene benzofuran-2(3H)-one (Structure-3) in a solvent and in the presence of sodium methoxide.

US patent 5760250 refers to the preparation of Structure -1 and structure-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.

UK Patent application no GB2291874 refers to the preparation of methyl 3,3-dimethoxy-2-[2- hydroxyphenyl]propionate using structure-3 and sodium methoxide in methanol under low temperature and subsequent neutralization with acetic acid. Major impurity formed in the above process is structure-5 when neutralized with acetic acid and the formed compound doesn't react with 4,6-dichloropyrimidine to yield structure-1 or structure-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 structure-1 and structure-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 structure -1 and structure-2 in 51% yielding process. The above process results in the formation of structure-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 structure-2 from structure -1 with acetic anhydride and methane sulfonic acid. The above patent also mentions formation of structure- 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 (structure-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 Structure-1 and structure-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 structure-3 with structure-4 in the presence of nonpolar solvent with sodium methoxide in methanol under the action of catalyst which is bicyclic, tricyclic organic catalysts and are very cheap in terms of commercial usuage. The catalyst used in this patent are mostly Tirphenyl phosphine, Adamantane, and Hexamine, and are used for the condensation reaction in nonpolar solvent or polar aprotic solvents in reduced time.

Adamantane, tricyclo-[3.3.1.1] decane ring, is a colorless crystalline solid with a characteristic camphor smell. It opputunates the condensation reaction of (E) Methyl 2-[2-[6-chloropyrimidine-4- yloxy) phenyl]-3-methoxypropenoate with o-cyanopehnol at a greater rate.

Hexamine, which is a tetrahedron and similar to Adamatane cage like structure, with only having Nitrogens molecules on its corner, facilitates the reaction for greater purity and higher conversion to form structure-1 and structure-2. It is a highly water soluble catalyst, which helps in removal of the catalyst by water wash, without carrying forward till the end of product. Triphenyl phosphine is of choice which helps in improving the reaction rate at a higher rate.

The present invention mentioned here provides a process for the preparation of structure- 1 and structure-2 comprising the following steps:

a. Preparation of structure-7 compound from structure-3 compound under the presence of sodium methoxide in methanol and in nonpolar solvent with or without presence of base. b. Preparing the structure- 1 and structure-2 compound in nonpolar solvent using structure-4 compound and catalyst

The said process involves nonpolar 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 be of 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 structure-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 structure-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 structure-5 compound just by acidification or by removing methanol. This reaction for the formation of structure-7 cannot be made easily in other solvents.

Surprisingly, this invention provides an easy way to form structure-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 structure-7 in the presence of sodium methoxide in methanol and in nonpolar solvent.

The condensation reaction for the structure-7 compound and structure-4 compound is done in the presence of catalyst 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 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 10, preferably in the range of 1.0:0.005 to 10. The catalyst used in the process is Hexamine or Triphenylphosphine or Adamantane 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 Structure-3 to structure-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 structure-3 and structure-4 compounds.

Example-1:

Into the four neck round bottomed 500ml flask, was added dichloroethane 1000ml and 3-(alpha- methoxy) methylene benzofuran-2(3H)-one 176 gm. To this slurry, potassium carbonate 160gm and sodium methoxide solution (in methanol) 224 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 161gm and Hexamine 17.6gm were added and stirred for again 10 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 71.2% yield.

Example-2:

Into the four neck round bottomed 500ml flask, was added toluene 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 Triphenylphosphine 8.8 gm were added and stirred for again 10 hours. Reaction mass was analysed to found Methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyI]-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 examplel.

Example-3:

Into the four neck round bottomed 500ml flask, was added toluene 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 Adamantane 15gm were added and stirred for again 12 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

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Claims

What we claim here is:

1. The structure-1 and structure-2 compounds can be made easily in non polar and polar aprotic solvents involving the following steps:

A. Raw materials of structure-3 and structure-4 are reacted in a solvent in the presence of sodium methoxide in Methanol along with auxiliary base and in the presence of catalysts Triphenylphosphine, Adamantane, Hexamine 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 claim 1 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 claim 1 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 G and most preferably in the range of 80- 100C.

6. A process as claimed in claim 1 wherein the catalysts used are Hexamine, Triphenyl phosphine, Adamantane, which are organic bicyclic or tricyclic compounds.

7. A process as claimed in claim 1 wherein the reaction can be conducted as a single step or in multiple steps as claimed.

8. A process as claimed in claim 1 wherein the filtration in step2 of the reaction steps, can be conducted to remove inorganics by filtration or by directly dissolving the inorganics in water there by reducing the time can be done.