WO2015102016A1

WO2015102016A1 - Process for the preparation of methyl 2-[2-(6-chloropyrimidin-4-yloxy) phenyl]-3,3- dimethoxypropionate

Info

Publication number: WO2015102016A1
Application number: PCT/IN2014/000304
Authority: WO
Inventors: Vinay DURGAM; Sai Lakshmi BIKKINI; Komali BOTLA; Sivarami Reddy BONTHU
Original assignee: Bhagiradha Chemicals & Industries Limited
Priority date: 2013-12-31
Filing date: 2014-05-06
Publication date: 2015-07-09

Abstract

The present invention relates to the process for preparation of Methyl 2-[2-(6-chloropyrimidin-4- yIoxy)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 Methyl 2-[2-(6-chloropyrimidin-4-yloxy) phenyl]-3,3- dimethoxypropionate

Field of invention

The present invention relates to the process for preparation of Methyl 2-[2-(6-chloropyrimidin- 4-yloxy)phenyi]-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 (Figure-1] and (E] Methyl 2-[2-(6-chloropyrimidine-4-yloxy) phenyl]-3-methoxypropenoate (Figure -2) can be made in high yielding process and more economical for industrial production.

This is in continuation to our earlier patent Indian patents application numbers 4800/CHE/2013 and 2658/CHE/2013, for the preparation of Azoxystrobin intermediates which are acrylate class derivatives, using quinuclidine, quinuclidine hydrochloride and quinuclidinol as catalysts.

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, methanol and an auxiliary base.

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. 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 IOC to proceed for the next reaction with 4,6-dichloropyrimidine, if . structure- 1 and structure-2 are to be prepared, but removal of methanol below IOC temperature is industrially 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 N,N-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.

Indian patent application nos2658/CHE/2013, 4800/CHE/2013, reports to produce structure 1 and structure2 compounds in high yielding process. The above applications refers to use the Hexamine, triphenyl phosphine and etc for the condensation reaction of structure 3 and structure 4, and silica sulfuric acid , boric anhydride, and phosphorus pentaoxide for the demethanolysis of the structurel compound to form structure 2 compound in high yielding.

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 amine and is very cheap in terms of commercial usuage. The catalyst used in the present invention are quinuclidine hydrochloride, quinuclidine and quinuclidinol and used for the condensation reaction in nonpolar solvent or polar aprotic solvents in reduced time.

Quinuclidine is an organic compound and a bicyclic amine and used as a catalyst and a chemical building block. It is a strong base with pKa of the conjugate acid of 11.0. This is due to greater availability of the nitrogen lone pair. This enchances the condensation reaction of 4,6- dichloropyrimidine with the sodium salt of 2-(l,l,3-trimethoxy-3-oxopropan-2-yf)phenolate.

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 polar or non polar solvent with or without the presence of base.

b. Preparing the structure- 1 and structure-2 compound in nonpolar solvent using structure-4 compound and catalyst.

c. Preparing the structure-2 compound by demthanolysis of the structure 1 in the same solvent used in process b, under the action of catalyst.

The said process involves polar aprotic solvents like acetonitrile, Ν,Ν-dimethylformamide for the formation of structurel and structure 2 compounds. With the use of the solvents reaction rates are better when compared to nonpolar solvents, however these polar aprotic solvents are less favored as they are not suitable for water washings. Hence the choice of non polar solvent is better suited as 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 quinuclidine hydrochloride or quinuclidine 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 said catalyst can be used directly or converted into any other form which facilitates the reaction at faster rate.

The temperature zones for better condensation of the reaction is between -20 to 50C. The reaction can happen at defined time at lower temperatures inorder to avoid formation of impurities. The more preferred temperature range is between -10 to 15, and most preferably between 5- IOC.

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. Usually lower amounts of raw materials will avoid the risk of recycling the unused material, and impurities formation is also lowered when compared to usuage of higher amounts.

The following examples describes the simple way of making structure-3 and structure-4 compounds.

Example-1:

Into the four neck round bottomed 2000ml flask, was added 1,2-dichloroethane 1000ml and 3- (alpha-methoxy) methylene benzofuran-2(3H)-one 176 gm. To this slurry, potassium carbonate 138gm and sodium methoxide solution (in methanol) 224 gm was added over a period of 10 min at a temperature of 5-lOC. After 1 hour stirring at this temperature, 4, 6-dichloropyrimidine 178gm and 5gm of quinuclidine hydrochloride are added and stirred for again 5 hours. Upon completion of reaction, inorganics were filtered and washed organic layer with water. The organic layer was analysed to found Methyl 2-[2-(6-chloropyrimidine-4-yloxy) phenyl] -3,3-dimethoxypropenoate at a yield of 75.2% and ((E) Methyl 2-[2-(6-chIoropyrimidine-4-yloxyJ phenyl]-3-methoxypropenoate at 2.8% yield.

Example-2:

Into the four neck round bottomed 2000ml flask, was added toluene 1000ml and 3-(alpha- methoxy) methylene benzofuran-2(3H)-one 176 gm. To this slurry, potassium carbonate 138gm and sodium methoxide 54 gm was added along with methanol at a temperature of 15-20C. After 1 hour stirring at this temperature, 4,6-dichloropyrimidine 178gm and quinuclidine hydrochloride 8.0 gm were added and stirred for again 3 hours. Reaction mass was analysed to found Methyl 2-[2- (6-chIoropyrimidin-4-yloxy) phenyl] -3,3-dimethoxypropionate forming at 69.2% and (E) Methyl 2- [2-(6-chloropyrimidine-4-yloxy) phenyl] -3-methoxypropenoate at 6.7%. The organic layer after inorganics were filtered is subjected to water washes and then taken directly to step c, for the formation of (E) Methyl 2-[2-(6-chloropyrimidine-4-yloxy) phenyl] -3-methoxypropenoate using catalyst at 95C. After the completion of the reaction, catalyst is filtered and solvent is removed under vacuum. To the crude Methanol is added and crystallized to found 220gm of dry (E) Methyl 2-[2-(6-chloropyrimidine-4-yloxy) phenyl] -3-methoxypropenoate product and leaving 15 gm equivalent in the mother liquor.

ExampIe-3: Into the four neck round bottomed 1000ml flask, was added chlorobenzene 1000ml and 3-(alpha- methoxy) methylene benzofuran-2(3H]-one 88 gm. To this slurry, potassium carbonate 70gm and sodium methoxide solution (in methanol) 110 gm was added over a period of 10 min at a temperature of 20 C. After 60 minutes stirring at this temperature, 4,6-dichloropyrimidine 81gm and quinuclidine 2 gm were added and stirred for again 8 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%. Workup is done in the similar manner as described in example 2.

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

Rawmaterial

Solvent Temperature Product A:B left

1,2-dichloroethane -5 72.00 % : 8.23 % 3.50 %

1,2-dichloroethane 15 68.51 % : 6.90 % 2.00 %

Toluene 10 72.12 % : 10.14% 3.20 %

Toluene 0 74.34 % : 6.23 % 0.67 %

Acetonitrile 5 68.97 % : 2.61 % 5.40 %

N,N-dimethylformamide 10 72.66 % : 5.66 % 1.24 %

methylenechloride -5 68.03 % : 11.00 % 1.40 %

Structures:

methyl 2-(2-(6-chloropyrimidin-4-yloxy)phenyl)-3,3- (ii)-methyl 2-(2-(6-chloropyrimidin-4-yloxy)phenyl)-3- dimethoxypropionate methoxypropenoate Structure- 1 Structure-2

(£^')-3-(methoxymethylene)ben2ofuran-2(3 )-one

Structure-3

meth

sodium 2-(l,l,3-trimethoxy-3-oxopropan-2-yI)phenolate

Structure-7

Claims

We claim:

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 catalyst quinuclidine or quinuclidine hydrochloride 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, acetonitrile, acetone, N,N- dimethylformamide preferably dichloroethane, dichloromethane, toluene and moste preferably toluene and dichloroethane.

3. A process as claimed in claiml 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 claiml wherein the temperatures used in the reaction for the step A is in the range of -20 to l OOC, preferably in the range of -20 to +30, most preferably between -10 to I OC.

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.

6. A process as claimed in claim 1 wherein the catalysts used are quinuclidine and quinuclidine hydrochloride which are organic bicyclic amines. A process as claimed in claim 1 wherein the reaction can be conducted as a single step or in multiple steps as claimed.

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.