JPS6221774B2 - - Google Patents

Description

[Detailed description of the invention]

Methods for producing a corresponding alkoxyalkylidene compound by reacting an orthoacid ester with an active methylene compound have been described in numerous literatures. For example, the production of alkoxymethylene malonic acid ester, which is one of the above compounds, is described in JP-A-51-4123. This method involves reacting orthoformic acid ester and malonic acid ester in the presence of a mixed catalyst of (1) a carboxylic acid or carboxylic acid anhydride and (2) a Lewis acid such as zinc chloride or iron chloride. Although this method is advantageous in that a high-quality product can be easily obtained, studies by the present inventors have revealed that the method has the following problems. Since the chloride used as a catalyst is extremely corrosive, even stainless steel, which is the most typical corrosion-resistant material, is corroded during the reaction and some of it is eluted into the reaction solution and cannot be used in the reaction. Since this has an undesirable effect and also has an adverse effect on the strength of the reactor itself, it is necessary to produce the above-mentioned compound by a method that does not cause corrosion of the reactor. Furthermore, in this method, it is necessary to recover unreacted orthoformic acid ester after completion of the reaction, carry out over-operation of the reaction, separate the catalyst, and then carry out fractional distillation of the product. If such catalyst separation is not performed, the product will decompose and the yield will decrease. When viewed as an industrial production method, such an operation is not necessarily an advantageous production condition, as it increases the complexity and time required, such as thermal aging and temporary suspension of vacuum distillation. However, as a result of extensive research in order to solve this problem, the inventors of the present invention found that in the presence or absence of a solvent, the formula R ₂ C (OR ₁ ) ₃ [where R ₁ is an alkyl group,
R ₂ represents hydrogen, an alkyl group, an allyl group, or an aralkyl group. ] and the orthoacid ester represented by the formula

[Formula] [Here, R ₃ and R ₄ represent -COOR ₁ , -CO・R ₁ , -CN, -CO・COOR ₁ . ] by reacting with an active methylene compound represented by the general formula

[Formula] In the method for producing an alkoxyalkylidene compound represented by [R ₁ R ₂ R ₃ R ₄ is the same as above], (1) a nickel salt of a carboxylic acid or a nickel salt of an inorganic oxyacid and (2) a nickel salt of a carboxylic acid or an inorganic oxyacid as a catalyst. When using a carboxylic acid or a carboxylic acid anhydride, corrosion of the equipment can be completely prevented and the reaction can proceed smoothly without being inhibited by elution of the material of the equipment; The present invention was completed by discovering new facts such as the fact that the reaction solution can be distilled without separating the catalyst from the reaction solution and the target compound can be easily obtained. Catalysts used in the present invention that belong to (1) include nickel acetate, nickel sulfate, nickel phosphate, and the like. Furthermore, those belonging to (2) include lower saturated carboxylic acids having 1 to 5 carbon atoms, such as acetic acid, acetic anhydride, propionic acid, propionic anhydride, succinic acid, and succinic anhydride, or their anhydrides. Among such catalysts, acetic anhydride-
Particularly effective are the combinations of nickel acetate and acetic anhydride-nickel sulfate. The amount of the catalyst used is 0.00001 to 0.001 mole of component (1) and 0.05 to 0.05 mole of component (2) based on the orthoacid ester.
About 0.5 mol is preferable. Further, in the present invention, a solvent can be used as appropriate. Examples of the solvent used include hydrocarbon solvents such as n-octane, benzene, toluene, and o-xylene, with toluene and o-xylene being particularly effective.
The amount of such solvent used is preferably 80 to 1000 ml per mole of orthoacid ester. Examples of orthoacid esters used in the present invention include methyl orthoformate, ethyl orthoacetate, ethyl orthoformate, orthopropionate, and active methylene compounds include malonitrile, ethyl cyanoacetate, dimethyl malonate, and malonic acid. Examples include diethyl, methyl acetoacetate, acetylacetone, and ethyl oxalacetate. Specifically, the alkoxyalkylidene compounds targeted in the present invention include ethoxymethylenemalonitrile, α-ethoxyethylidenemalonnitrile, α-ethoxypropylidenemalonitrile, ethyl ethoxymethylenecyanoacetate, ethyl α-ethoxyethylidenecyanoacetate, ethyl α-ethoxypropylidene cyanoacetate, ethyl ethoxymethyleneacetoacetate, ethyl α-ethoxyethylideneacetoacetate, ethyl ethoxymethyleneoxalacetate, ethyl ethoxymethyleneacetylacetone,
Examples include methoxymethylene dimethyl malonate, ethoxymethylene diethyl malonate, etc., and the method of the present invention produces ethoxymethylene diethyl malonate from ethyl orthoformate and diethyl malonate, and methoxymethylene diethyl malonate from methyl orthoformate and dimethyl malonate. It is particularly useful in producing dimethyl acid. In carrying out the method of the present invention, the orthoacid ester, the active methylene compound, and preferably a hydrocarbon solvent are mixed and heated under stirring. The charging ratio of raw materials is preferably orthoacid ester:active methylene compound=1:1 to 3:1 (mole ratio)
A ratio of about 1.1:1 to 2.0:1 is appropriate. The reaction temperature is
Preferably, the temperature is 100-180°C and the reaction time is 1-14 hours.
In the above reaction, the yield can be improved by distilling the alcohol by-product out of the system, and when using a solvent, the solvent is always present in the reaction system. For this purpose, it is usually sufficient to select a hydrocarbon solvent that has a boiling point higher than the reaction temperature and the boiling point of the alcohol produced, but this is not necessarily the case. is also available. When using such a solvent with a relatively low boiling point, a rectifier may be attached to the reaction tank to distill out only the alcohol produced, and the reaction may be carried out while the solvent is refluxed. In addition, when using a solvent with a boiling point much lower than the reaction temperature, if there is a risk that it will be difficult to raise the temperature to the desired reaction temperature, reduce the amount of solvent used or charge it in parts. It can be solved. Further, even if the produced alcohol forms an azeotropic composition with the solvent used and the solvent is distilled off together with the produced alcohol, the solvent may be added as appropriate during the reaction. The reaction can be carried out under normal pressure, increased pressure, or reduced pressure. After the reaction is completed, the reaction solution is distilled under reduced pressure to obtain the desired product. In the method of the present invention, in addition to the catalysts (1) and (2), it is also possible to use a small amount of zinc salts, such as zinc acetate, zinc sulfate, zinc chloride, etc. In particular, the presence of a zinc salt catalyst at the time of carrying out the reaction can improve the yield of the target compound. The appropriate amount of zinc salt to be added is about 0.00001 to 0.001 mole per mole of orthoacid ester.
The zinc salt may be added at any time, such as from the beginning or in the middle of the reaction, but it is usually added during the final stage of the reaction, that is, when the consumption of the active methylene compound as a raw material in the reaction system reaches 90 mol% or more. Advantageously, it is added at the same time. The alkoxyalkylidene compounds obtained in the present invention are useful as intermediates for pharmaceuticals or other organic synthetic products. Next, the method of the present invention will be explained in more detail by giving examples. Example 1 1.5 ethyl orthoformate in a 500 ml flask equipped with a stirrer, a dropper and a rectifying tube (25 cm x 40 cm)
mole, diethyl malonate 1.0 mole, acetic anhydride 0.10
mole, nickel acetate (tetrahydrate) 0.0012 mole, o
-I charged 100ml of xylene. The reaction was carried out at 150-160°C for 7 hours and then continued at 160°C for 0.5 hour. The obtained reaction-completed liquid was distilled under reduced pressure to give a concentration of 130 to 135
The C/5 mmHg fraction was collected. The yield of ethoxymethylene diethyl malonate based on the consumed ethyl orthoformate was 76%, and the yield based on diethyl malonate was 81%. In addition, the following experiment was conducted to test the corrosivity of the reaction solution. A polished mild steel plate (30 mm x 50 mm x 1.0 mm) that had been degreased and dried with acetone was immersed in 200 ml of the crude reaction solution.
The amount of corrosion after 7 days at ℃ was measured by weight loss before and after immersion, and the corrosion rate was determined in g/m ² /hr. As a result, in the case of the present invention, the corrosion rate was 0, and there was no change in the surface of the test piece. On the other hand, as Control Example 1, the same experiment as Example 1 was conducted except that zinc chloride was used instead of nickel acetate. (However, before distilling the reaction solution, unreacted ethyl orthoformate was expelled and zinc chloride was separated.) The yield of ethoxymethylene diethyl malonate relative to ethyl orthoformate was 75%, and the yield relative to diethyl malonate was 75%. It was 81%. Also, corrosion
0.01 g/m ² /hr, and the surface of the test piece turned black, indicating progress of corrosion. In Control Example 1, if zinc chloride was not used separately, the yield decreased to 70%. Example 2 The same experiment as in Example 1 was conducted except that nickel sulfate was used in place of nickel acetate.
The yield of diethyl ethoxymethylene malonate based on ethyl orthoformate was 78%, and the corrosion rate was 0. Example 3 In Example 1, the conversion rate of diethyl malonate is 95
0.00023 mol of zinc acetate (2
The same experiment as in the same example was conducted except that hydrate) was added. The yield of ethoxymethylene diethyl malonate based on ethyl orthoformate was 70%, and the yield based on diethyl malonate was 90%. The corrosion rate was 0. As a control example 2, zinc chloride was used in place of nickel acetate in the above example, and the yield of diethyl ethoxymethylene malonate was 70% and the corrosion rate was 0.01 g/m ² /hr. (However, the zinc chloride was separated before distillation after the reaction.) When the reaction solution was distilled in the presence of zinc chloride, the yield of the target product decreased to 65%. Example 4 The same experiment as in Example 3 was conducted except that nickel sulfate was used instead of nickel acetate, and almost the same results as in Example 3 were obtained. Example 5 In the same apparatus as Example 1, 1.3 mol of methyl orthoformate, 1.0 mol of dimethyl malonate, 0.12 mol of acetic anhydride, 0.0002 mol of nickel acetate, and 120 mol of o-xylene.
I prepared ml. The reaction was carried out at 145-155°C for 5 hours, and further continued at 155°C for 0.5 hour. The resulting reaction-completed liquid was distilled under reduced pressure, and a dimethyl methoxymethylene malonate fraction was collected. The yield of dimethyl methoxymethylene malonate based on the consumed ethyl orthoformate was 65%, and the yield based on dimethyl malonate was 80%. In addition, the following experiment was conducted to test the corrosivity of the reaction solution. A polished mild steel plate (30 mm x 50 mm x 1.0 mm) that had been degreased and dried with acetone was immersed in 200 ml of the crude reaction solution.
The amount of corrosion after 7 days at ℃ was measured by weight loss before and after immersion, and the corrosion rate was determined in g/m ² /hr. As a result, in the case of the present invention, the corrosion rate was 0, and there was no change in the surface of the test piece. On the other hand, as Control Example 3, the same experiment as Example 5 was conducted except that zinc chloride was used in place of nickel acetate. (However, before distilling the reaction solution, unreacted ethyl orthoformate was expelled and zinc chloride was separated.) The yield of methoxymethylene dimethyl malonate relative to methyl orthoformate was 65%, and the yield relative to dimethyl malonate was 65%. It was 78%. Further, the corrosion rate was 0.01 g/m ² /hr, and the surface of the test piece turned black, suggesting that corrosion had progressed. In Control Example 3, when zinc chloride was not used, the yield decreased to 70%. Example 6 The same experiment as in Example 5 was conducted except that nickel sulfate was used instead of nickel acetate.
The yield of dimethyl methoxymethylene malonate based on methyl orthoformate was 63%, and the corrosion rate was 0. Example 7 In Example 5, the rate of change of dimethyl malonate is 96
0.00025 mol of zinc acetate (2
The same experiment as in the same example was conducted except that hydrate) was added. The yield of dimethyl methoxymethylene malonate based on methyl orthoformate was 70%, and the corrosion rate was 0. As Control Example 4, when zinc chloride was used in place of nickel acetate in the above example, the yield of dimethyl methoxymethylene malonate based on methyl orthoformate was 70%, and the corrosion rate was 0.01 g/m ² /hr. (However, the zinc chloride was separated before distillation after the reaction.) When the reaction solution was distilled in the presence of zinc chloride, the yield of the target product decreased to 65%. Example 8 The same experiment as in Example 5 was conducted except that nickel sulfate was used instead of nickel acetate, and almost the same results as in Example 5 were obtained. Example 9 In the same apparatus as in Example 1, 1.3 mol of methyl orthoformate, 1.0 mol of methyl acetoacetate, 0.12 mol of acetic anhydride, 0.0002 mol of nickel acetate, and o-xylene were added.
I planted 120m. The reaction was carried out at 145-160°C for 7 hours, and further continued at 160°C for 0.5 hour. The resulting reaction-completed liquid was distilled under reduced pressure, and a methyl methoxymethylene acetoacetate fraction was collected. The yield of methyl methoxymethylene acetoacetate based on the consumed methyl orthoformate was 73%, and the yield based on methyl acetoacetate was 80%. Example 10 The same 1.3 mol of ethyl orthoformate, 1.0 mol of ethyl cyanacetate, 0.12 mol of acetic anhydride, 0.0002 mol of nickel acetate, and 120 m of o-xylene as in Example 1 were charged. The reaction was carried out at 150-165℃ for 4 hours and further
The reaction was continued for 0.5 hour at 165°C. The resulting reaction-completed liquid was distilled under reduced pressure, and an ethoxymethylenecyanoethyl acetate fraction was collected. The yield of ethoxymethylene ethyl cyanacetate is 72% based on the consumed ethyl orthoformate, and the yield is 82% based on the consumed ethyl cyanacetate.
It was %.

Claims (1)

[Claims] 1. In the presence or absence of a solvent, the formula R ₂ C
(OR ₁ ) ₃ [Here, R ₁ is an alkyl group, and R ₂ is hydrogen or an alkyl group. ] and the formula [Formula] [where R ₃ and R ₄ are −COOR ₁ , −CO・R ₁ , −CN
shows. In a method for producing an alkoxyalkylidene compound represented by the general formula [R ₁ , R ₂ , R ₃ , R ₄ are the same as above] by reacting an active methylene compound represented by 1. A method for producing an alkoxyalkylidene compound, which comprises using a nickel salt of a carboxylic acid or a nickel salt of an inorganic oxyacid, and (2) a carboxylic acid or a carboxylic acid anhydride. 2. The manufacturing method according to claim 1, wherein the alkoxyalkylidene compound is dimethyl methoxymethylenemalonate. 3. The manufacturing method according to claim 1, wherein the alkoxyalkylidene compound is diethyl ethoxymethylenemalonate.