WO2015059712A1 - Process for the preparation of methyl 2-[2-(6-chloropyrimidin-4-yioxy)phenyl}- 3-methoxypropanoate - Google Patents
Process for the preparation of methyl 2-[2-(6-chloropyrimidin-4-yioxy)phenyl}- 3-methoxypropanoate Download PDFInfo
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- WO2015059712A1 WO2015059712A1 PCT/IN2014/000305 IN2014000305W WO2015059712A1 WO 2015059712 A1 WO2015059712 A1 WO 2015059712A1 IN 2014000305 W IN2014000305 W IN 2014000305W WO 2015059712 A1 WO2015059712 A1 WO 2015059712A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Definitions
- This invention relates to the preparation of Methyl 2-[2-(6-chloropyrimidin-4- yloxy)phenyl ⁇ -3-methoxypropanoate, more economically with non-recyclable or recyclable catalyst, which can be reused without losing its activity, where the said compound in turn reacts with 2-hydroxybenzonitrile to produce Azoxystrobin, a fungicide of strobilurium class.
- WO9807707 discloses the route to prepare Compound A by reacting Compound B with Methane sulphonic acid or p-toluenesulphonic acid, direct handling of sulphonic acids are corrosive in nature and not of interest industrially. It also indicates the use of o-cyanophenol for preparing the Compound A, o-cyanophenol is one of the key intermediate in the preparation of Azoxystrobin, which is not cost effective. Above patent also explains use of Acetic anhydride for the removal of methanol, but use of acetic anhydride increases the cost of production and by products obtained are methylacetate and acetic acid which are not desirable.
- Chinese patent CN indicates the process for manufacturing the said Compound A by reacting it in the presence of potassium bisulfate at a temperature of 125-130C in the absence of solvent. The said process is not feasible as the compound A degrades at higher temperatures forming polymeric material.
- the present invention relates to the preparation Methyl 2-[2-(6-chloropyrimidin-4- yloxy)phenyl ⁇ -3-methoxypropanoate economically as the catalyst used here may or may not recyclable and removal of methanol is done physically as an azeotrope with solvent of choice as a part of reaction more easily.
- the introduction of solvent and operating the process at lower temperature is always encouraged as the compound physical status will not be hindered and thus by avoiding the charring of the compound.
- the present invention sophisticates the process by removing the methanol as an azeotrope with the solvent, where usage of acid anhydrides may or may not be done and thus by reducing the cost of production.
- the catalysts used in the present invention is of heterogeneous with the reaction medium, which can be recyclable, can be separated by just filtering of the reaction mass and reusing it.
- the catalyst used here is proton activator catalyst and is very useful in the preparation of compound A as the step requires proton activator for the compound B to get demethylate and form Compound A.
- the choice of catalyst is in utmost interest, being heterogeneous with the reaction medium, its interference with the deterioration of the compound A is negligible.
- the said catalyst is a sulphuric acid adsorbed on silica, phosphorus pentoxide and boron trioxide. So here the catalyst of desired nature is in utmost interest where it is heterogeneous and yet it will have the action of demethylating the Compound B, but which will not damage the products formed.
- Silica sulfuric acid catalyst is in such an interest where it is heterogeneous and it can demethylate the Compound B very easily.
- the Solvent used in the present invention is of one's choice to remove methanol easily as an azeotrope.
- the solvents which are preferred are methylacetate, ethylacetate, ethylformate, methyl formate, acetone, acetonitrile, tetrahydrofuran, methylethyl ketone or hydrocarbon solvents such as benzene, toluene, xylene, cyclohexane, chlorobenzene, pentane, heptane, and chlorinated solvents such as dichloromethane, dichloroethane, carbon tetrachloride, tetrachloroethylene and most preferably toluene and chlorobenzene.
- the catalyst amount used varies normally from 0.01 % to 20% of the weight of compound B and preferably in the range of 0.5% to 5% and most preferably in the range of 1% to 5%.
- the temperature of the process in the present invention in depedent on the interest where the azeotrope with methanol is formed between - I OC to 150C and preferably between 95C to 135C and most preferably in the range of 105C to 130C.
- Methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl ⁇ -3,3-dimethoxypropanoate 352.5 gm was taken in toluene ( 1000 ml) and 5.0 gm of SSA catalyst was added and heated to 1 IOC. The reaction mass was stirred there for 4 hrs and completion of raw material was observed on GC, to form Methyl 2-[2-(6-chloropyrimidin-4- yloxy)phenyl ⁇ -3-methoxypropanoate.
- the dry product 225gm obtained is methyl 2-[2-(6-chloropyrimidin-4- yloxy)phenyl ⁇ -3-methoxypropanoate, and leaving 15gm equivalent in the mother liquor.
- Table 1 shows the catalyst ratios and time taken for recycle and fresh.
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Abstract
This invention relates to the preparation of Methyl 2-[2-(6-chloropyrimidin-4- yloxy)phenyl}-3-methoxypropanoate, more economically with non-recyclable or recyclable catalyst, which can be reused without losing its activity, where the said compound in turn reacts with 2-hydroxybenzonitrile to produce Azoxystrobin, a fungicide of strobilurium class.
Description
Process for the preparation of methyl 2-[2-(6-chloropyrimidin-4-yIoxy)phenyl}- 3-methoxypropanoate
This invention relates to the preparation of Methyl 2-[2-(6-chloropyrimidin-4- yloxy)phenyl}-3-methoxypropanoate, more economically with non-recyclable or recyclable catalyst, which can be reused without losing its activity, where the said compound in turn reacts with 2-hydroxybenzonitrile to produce Azoxystrobin, a fungicide of strobilurium class.
Background of Invention
The earlier patents and literature available for the preparation of Methyl 2-[2-(6- chloropyrimidin-4-yloxy)phenyl}-3-methoxypropanoate (compound A) from Methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl}-3,3-dimethoxypropanoate (Compound B) have used different acidic catalysts and basic catalysts which involves high cost, low yields and which are not reusable.
WO9807707 discloses the route to prepare Compound A by reacting Compound B with Methane sulphonic acid or p-toluenesulphonic acid, direct handling of sulphonic acids are corrosive in nature and not of interest industrially. It also indicates the use of o-cyanophenol for preparing the Compound A, o-cyanophenol is one of the key intermediate in the preparation of Azoxystrobin, which is not cost effective. Above patent also explains use of Acetic anhydride for the removal of methanol, but use of acetic anhydride increases the cost of production and by products obtained are methylacetate and acetic acid which are not desirable.
US Patent 5760250 and 5847138 explains the use of potassium bisulfate in the crude of Compound B at higher temperatures like 160C and 250C, but the conducting a process at that temperature leads to discoloration and may sometimes leads to charring of the compound, which is not suitable industrially, which in turn affects the cost of production.
Chinese patent CN indicates the process for manufacturing the said Compound A by reacting it in the presence of potassium bisulfate at a temperature of 125-130C in the absence of solvent. The said process is not feasible as the compound A degrades at higher temperatures forming polymeric material.
The present invention relates to the preparation Methyl 2-[2-(6-chloropyrimidin-4- yloxy)phenyl}-3-methoxypropanoate economically as the catalyst used here may or may not recyclable and removal of methanol is done physically as an azeotrope with solvent of choice as a part of reaction more easily. The introduction of solvent and operating the process at lower temperature is always encouraged as the compound physical status will not be hindered and thus by avoiding the charring of the compound.
The present invention sophisticates the process by removing the methanol as an azeotrope with the solvent, where usage of acid anhydrides may or may not be done and thus by reducing the cost of production.
Indian patent application 276/CHE/201 1 , explains the use of Sulfonated nitro coal catalyst for demethanolysis the compound B to form Compound A. This catalyst is a proton activator and being heterogeneous with the reaction medium facilitates the reaction in high yield and low cost.
Field of Invention
The catalysts used in the present invention is of heterogeneous with the reaction medium, which can be recyclable, can be separated by just filtering of the reaction mass and reusing it. The catalyst used here is proton activator catalyst and is very useful in the preparation of compound A as the step requires proton activator for the compound B to get demethylate and form Compound A.
As earlier literature suggested the use of sulphonic acids as proton activators in the reaction medium with or without solvent, but under some circumstances in which solvent is used or not, these sulphonic acids are dangerous over the compounds formed after certain period of time because of their homogeneity with the solvent or with the crude at higher temperature and act on the compounds, and slowly deteriorate the yield.
Here the choice of catalyst is in utmost interest, being heterogeneous with the reaction medium, its interference with the deterioration of the compound A is negligible. The said catalyst is a sulphuric acid adsorbed on silica, phosphorus pentoxide and boron trioxide. So here the catalyst of desired nature is in utmost interest where it is heterogeneous and yet it will have the action of demethylating the Compound B, but which will not damage the products formed. Silica sulfuric acid catalyst is in such an interest where it is heterogeneous and it can demethylate the Compound B very easily.
The Solvent used in the present invention is of one's choice to remove methanol easily as an azeotrope. The solvents which are preferred are methylacetate, ethylacetate, ethylformate, methyl formate, acetone, acetonitrile, tetrahydrofuran, methylethyl ketone or hydrocarbon solvents such as benzene, toluene, xylene, cyclohexane, chlorobenzene, pentane, heptane, and chlorinated solvents such as dichloromethane, dichloroethane, carbon tetrachloride, tetrachloroethylene and most preferably toluene and chlorobenzene.
The catalyst amount used varies normally from 0.01 % to 20% of the weight of compound B and preferably in the range of 0.5% to 5% and most preferably in the range of 1% to 5%.
The temperature of the process in the present invention in depedent on the interest where the azeotrope with methanol is formed, between - I OC to 150C and preferably between 95C to 135C and most preferably in the range of 105C to 130C.
Examples:
Preparation of silica sulfuric acid
// can be prepared by known process as indicated in International Journal of Organic Chemistry, 2012, 2, 93-99
To a slurry of silica gel ( 10 g, 200 - 400 mesh) in dry diethyl ether (50 ml) was added concentrated H2S04 (3 ml) with shaking for 5 min. The solvent was evaporated under reduced pressure to obtain dry H2S04 Si02 catalyst which was then heated at 120°C for 3 hrs.
Example 1:
Methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl}-3,3-dimethoxypropanoate (352.5 gm) was taken in toluene ( 1000 ml) and 5.0 gm of SSA catalyst was added and heated to 1 IOC. The reaction mass was stirred there for 4 hrs and completion of raw material was observed on GC, to form Methyl 2-[2-(6-chloropyrimidin-4- yloxy)phenyl}-3-methoxypropanoate.
Example 2:
A Mixture of Methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl }-3,3- dimethoxypropanoate ( 197 gm, 0.56moles) and Methyl 2-[2-(6-chloropyrimidin-4- yloxy)phenyl}-3-methoxypropanoate (50gm, 0.156moles ) was taken in toluene (500 gm) and 6 gm of SSA was added and heated to 1 I OC. The reaction mass was stirred there for 3 hrs and during proceeding of the reaction low volatiles are distilled out, and completion of raw material was observed on GC, to form. After the end of reaction the reaction mass is filtered and the catalyst is reused. The filtrate thus obtained contained Methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl}-3- methoxypropanoate(220gm, 0.688moles) in an yield of 95% in Toluene layer.
Example 3:
A reaction mixture of 285gms containing Methyl 2-[2-(6-chloropyrimidin-4- yloxy)phenyl}-3,3-dimethoxypropanoate (220 gm, 0.624moles) and Methyl 2-[2-(6- chloropyrimidin-4-yloxy)phenyl}-3-methoxypropanoate (50gm, 0.156moles ) was taken in toluene (1000 ml) and 10 gm of phosphorus pentaoxide was added and heated to 1 I OC. The reaction mass was stirred there for 8 hrs and during proceeding
of the reaction low volatiles are distilled out, and completion of raw material was observed on GC, to form. After the end of the reaction, water was added to the reaction mass and layers were separated. The organic layer was then subjected to distillation and to the left over crude of 255gm was added methanol and crystallized.
The dry product 225gm obtained is methyl 2-[2-(6-chloropyrimidin-4- yloxy)phenyl}-3-methoxypropanoate, and leaving 15gm equivalent in the mother liquor.
Example 4:
A Mixture of Methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl}-3,3- dimethoxypropanoate (197 gm, 0.56moles) and Methyl 2-[2-(6-chloropyrimidin-4- yloxy)phenyl}-3-methoxypropanoate (50gm, 0.156moles ) was taken in toluene (500 gm) and 10 gm of borontrioxide was added and heated to 1 IOC. The reaction mass was stirred there for 8 hrs and during proceeding of the reaction low volatiles are distilled out, and completion of raw material was Observed on GC, to form. After the end of reaction, workup was done as in example 3 and toluene layer contained Methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl}-3-methoxypropanoate(220gm, 0.688moles) in an yield of 95%.
Table 1 shows the catalyst ratios and time taken for recycle and fresh.
Conversion Time
Solvent Temperature % Catalvst Catalvst
Toluene 1 10 95% 4 5 gm SSA
Toluene 1 10 96% 3 10 gm SSA
3.5 5gm + 2 Reused S!
Toluene 1 10 94.5% gm freshSSA
Toluene 1 10 94.8% 3.5 5 gm Reused SSA- cycle-
Toluene 1 10 93.7% 6.0 5 gm Reused SSA-cycle-i
Toluene 1 10 94.1% 6 10 gm Boron trioxide
Toluene 1 10 94.9% 5 10 gm Phosphorus pentaox
Toluene 1 10 93.5% 8 5 gm Phosphorus pentaox
Toluene 1 10 92% 9 5 gm Boron trioxide chlorobenzene 120 94.0% 7 5 gm Phosphorus pentaox chlorobenzene 130 93.9% 5 5 gm Boron, trioxide chlorobenzene 130 95.1% 4 10 gm Phosphorus pentaox
Chlorobenzene 125 96.7% 2 l Ogm SSA
Dichloroethane 88 85.0% 16 10 SSA
chlorbbenzene 125 92% 3 5+2 gm Reused SSA- cycle-
All the above data is done on same scale, with the reaction mixture containing compound B-0.624 moles and Compound A-0.156moles.
Claims
1. We claim here the preparation of Compound A using a heterogeneous catalyst which may or may not be recycle.
2. We claim here the claim 1 as formation of compound A in the solvent, thereby avoiding the higher temperatures.
3. We claim here the claim 1 as formation of Compound A by demethylating Compound B.
4. We claim here the claim 1 as demethylating the compound B using any catalyst and removing the formed methanol as an azeotrope with the solvent.
5. As per Claim 1 , the usage of catalyst which demethylates the compound B and it may or may not be reused without losing its activity for many times.
6. As per Claim 1 , the catalyst here mentioned is silica sulfuric acid, which is heterogeneous catalyst at a temperature for the occurrence of demethanolysis between -10 to 150C, most preferably at 105 to 130C.
7. As per Claim 1 , the catalyst here mentioned are phosphorus penta oxide, boron trioxide, to demethylate compound B to form compound A.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN4800/CHE/2013 | 2013-10-24 | ||
| IN4800CH2013 | 2013-10-24 |
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| Publication Number | Publication Date |
|---|---|
| WO2015059712A1 true WO2015059712A1 (en) | 2015-04-30 |
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| PCT/IN2014/000305 Ceased WO2015059712A1 (en) | 2013-10-24 | 2014-05-06 | Process for the preparation of methyl 2-[2-(6-chloropyrimidin-4-yioxy)phenyl}- 3-methoxypropanoate |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2430803A (en) * | 1942-07-09 | 1947-11-11 | Atlantic Refining Co | Preparation of a sulfuric acid-silica gel catalyst |
| WO1998007707A1 (en) * | 1996-08-19 | 1998-02-26 | Zeneca Limited | Process for the preparation of pyrimidine compounds |
| US20120203047A1 (en) * | 2008-01-14 | 2012-08-09 | Catalytic Distillation Technologies | Process and catalyst for cracking of ethers and alcohols |
-
2014
- 2014-05-06 WO PCT/IN2014/000305 patent/WO2015059712A1/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2430803A (en) * | 1942-07-09 | 1947-11-11 | Atlantic Refining Co | Preparation of a sulfuric acid-silica gel catalyst |
| WO1998007707A1 (en) * | 1996-08-19 | 1998-02-26 | Zeneca Limited | Process for the preparation of pyrimidine compounds |
| US20120203047A1 (en) * | 2008-01-14 | 2012-08-09 | Catalytic Distillation Technologies | Process and catalyst for cracking of ethers and alcohols |
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