CH702298B1 - Making cyanoalkylpropane compound involves reacting sodium cyanide and paraformaldehyde in solvent to form slurry of glycolonitrile followed by neutralizing, mixing sodium ethoxide and cyanoacetate, neutralizing and concentrating filtrate - Google Patents

Abstract

Preparing cyanoalkylpropane compound (I) or its salts involves reacting sodium cyanide and paraformaldehyde in a solvent to obtain a slurry containing glycolonitrile followed by neutralization of the slurry using dry hydrochloric gas; mixing the neutralized slurry containing glycolonitrile with sodium ethoxide and cyanoacetate (II) to obtain an alkali salt of compound (I); neutralizing the alkali salt of compound (I) by using dry hydrochloric gas to obtain a clear filtrate; and concentrating the filtrate to remove alcohol followed by distillation to obtain a compound (I). Preparing cyanoalkylpropane compound of formula ROOC-CH(CN)-CH 2-CN (I) or its salts involves reacting sodium cyanide and paraformaldehyde in a solvent selected from anhydrous ethanol, dimethyl sulfoxide, N-methylpyrrolidone, dimethylacetamide and dimethylformamide to obtain a slurry containing glycolonitrile followed by neutralization of the slurry using dry hydrochloric gas; mixing the neutralized slurry containing glycolonitrile with sodium ethoxide and cyanoacetate of formula ROOC-CH 2CN (II) to obtain an alkali salt of compound (I); neutralizing the alkali salt of compound (I) by using dry hydrochloric gas followed by removal of sodium chloride by filtration to obtain a clear filtrate; and concentrating the filtrate at a temperature of 55-60[deg] C to remove alcohol followed by distillation under reduced pressure to obtain a compound (I). R : straight or branched chain 1-18C alkyl.

Description

Field of the invention:

The present invention relates to a process for the preparation of cyanoalkyl propionate derivatives which are used as intermediates in the synthesis of pesticides.

Background of the invention:

Ethyl 2,3-dicyanopropionate

CAS number: 40497-11-8 Molecular formula: C7H8N2O2 Molecular weight: 152.15 Structure: Uses: It is used as an intermediate in the synthesis of pesticides.

Ethyl 2,3-dicyanopropionate was first produced and characterized by Higson and Thorpe (J. Chem. Soc. 89, 1460 (1906)), who made the material by reacting formaldehyde cyanohydrin with the sodium salt of ethyl cyanoacetate in good yield ( 70.81%).

Dickinson (J. Am. Chem. Soc. 82, 6132 (1960)) has repeated this work. This process for the preparation of the dicyanopropionate suffers from the significant disadvantage that it is first necessary to isolate the intermediate product formaldehyde cyanohydrin. This highly water-soluble cyanohydrin is obtained by lengthy continuous extraction; it has limited stability and often decomposes violently on attempted distillation. Furthermore, this reaction requires some care in view of the risk of the formation of dimeric by-products.

The preparation of dicyanopropionates has also been described by Whiteley and Marianelli (Synthesis (1978), 392), the process using 3-substituted 2,3-dicyanopropionates to 2,3-disubstituted succinodinitriles from cyanoacetate, an aldehyde (a Alkylaldehyde or benzaldehyde with 1–3 carbon atoms), and potassium cyanide. However, the yield decreases dramatically from isobutyraldehyde to acetaldehyde.

In the same way, Smith and Horwitz (J. Am. Chem. Soc. 1949, 21, 3418) have described the same reaction with a ketone with a yield of 70%. This prior art therefore teaches that the yield improves as the size of the group adjacent to the carbonyl group increases.

The Australian patent AU 725 472 (B2) discloses the synthesis of 2,3-dicyanoethyl propionate by reacting potassium cyanide with ethyl cyanoacetate and paraformaldehyde in ethanol as a solvent. After dissolving in water, acidifying to pH 4 and extracting with dichloromethane, the potassium salt gave a yield of 77% 2,3-dicyanoethylpropionate. The method disclosed in Australian patent AU 725 472 avoids the use of formaldehyde cyanohydrin.

Chinese Patent CN 1 785 966 discloses a method for the synthesis of ethyl 2,3-dicyanopropionate. Said method comprises the following steps: reacting ethyl cyanoacetate, paraformaldehyde and sodium cyanide to synthesize ethyl 2,3-dicyanopropionate in dimethyl sulfoxide medium; Extracting the ethyl 2,3-dicyanopropionate with dichloromethane as solvent from the medium dimethyl sulfoxide; Removing the solvent from the extracted product under reduced pressure to obtain the crude product and rectifying the crude product to obtain the raffinate (ethyl 2,3-cynopropionate). The purity of the product obtained is greater than 98%.

The processes disclosed in the prior art for the synthesis of cyanoalkylpropane derivatives suffer from the significant disadvantage that it is first necessary to extract or isolate the intermediate product formaldehyde cyanohydrin (glycolonitrile), which is highly water-soluble. The isolation of cyanohydrin requires a laborious and lengthy continuous extraction process (countercurrent extraction with a polar solvent such as ether). Furthermore, cyanohydrin has limited stability and often decomposes violently when attempted distillation. Furthermore, the reaction requires some care in view of the risk of the formation of dimeric by-products.

There is thus a need for a method for the synthesis of cyanoalkylpropane derivatives that avoids the isolation of glycolonitrile.

Objects of the invention:

It is an object of the invention to provide a process for the preparation of cyanoalkylpropane derivatives.

It is a further object of the invention to provide a process for the preparation of cyanoalkylpropane derivatives using in situ generated glycolonitrile.

It is yet another object of the present invention to provide a process for the preparation of cyanoalkylpropane derivatives which avoids the isolation of glycolonitrile.

It is yet another object of the present invention to provide an energy saving and environmentally friendly process that avoids the addition of excess raw material such as ethyl cyanoacetate.

It is a further object of the present invention to provide a process for the preparation of cyanoalkylpropane derivatives which is simple, safe, convenient, easy to carry out on an industrial scale and inexpensive.

It is yet another object of the present invention to provide a method which involves the use / addition of raw material in optimal molar amounts.

It is a further object of the present invention to provide a method that involves quantifying the formation of glycolonitrile by raw GC analysis.

It is a further object of the present invention to provide a process for the preparation of cyanoalkylpropane derivatives which gives a highly pure product in a high yield.

Summary of the invention:

According to the present invention, there is provided a process for the preparation of a compound of the following formula (Formula I) and a salt thereof:

wherein R represents straight or branched chain alkyl of 1 to 18 carbon atoms; the method comprising the following steps: a. Reacting an alkali metal cyanide and paraformaldehyde in the presence of a solvent to obtain a glycolonitrile-containing slurry, and then neutralizing the slurry with dry HCl gas; b. Mixing the glycolonitrile-containing neutralized slurry with an alkali ethoxide and cyanoacetate of the following formula (Formula II): ROOC-CH2CN wherein R represents straight or branched chain alkyl of 1 to 18 carbon atoms; to obtain an alkali salt of the compound of formula I; c. Neutralizing the alkali metal salt of the compound of formula I with dry HCl gas and then removing sodium chloride by filtration in order to obtain a clear filtrate; and d. Concentrate the filtrate at a temperature of about 55 ° C to about 60 ° C to remove alcohol and then distill it under reduced pressure to obtain a compound of formula I.

Detailed description of the invention:

Glycolonitrile, also known as hydroxyacetonitrile or formaldehyde cyanohydrin (CAS No. 107-16-4), is an organic compound with the formula HOCH2CN. It is the simplest cyanohydrin made from formaldehyde. It is used in the synthesis of cyanoalkylpropane derivatives.

The processes disclosed in the prior art for the synthesis of cyanoalkylpropane derivatives suffer from the significant disadvantage that it is first necessary to extract or isolate the intermediate product formaldehyde cyanohydrin (glycolonitrile), which is highly water-soluble. The isolation of cyanohydrin requires a laborious and lengthy continuous extraction process (countercurrent extraction with a polar solvent such as ether). Furthermore, cyanohydrin has limited stability and often decomposes violently when attempted distillation. Furthermore, the reaction requires some care in view of the risk of the formation of dimeric by-products.

According to the present invention, a process for the synthesis of cyanoalkylpropane derivatives is provided in which glycolonitrile generated in situ is used instead of distilled glycolonitrile, which is obtained by a laborious and lengthy extraction process.

According to the present invention, there is provided a process for the preparation of a compound of the following formula (Formula I) and a salt thereof:

wherein R represents straight or branched chain alkyl having 1 to 18 carbon atoms.

The method comprises the following steps: In the first step, an alkali metal cyanide and paraformaldehyde are reacted in the presence of a solvent to obtain a glycolonitrile-containing slurry. This slurry is then neutralized with dry HCl gas.

According to the present embodiment, the alkali metal cyanide used in the above step is sodium cyanide.

According to the present invention, the solvent used in the reaction is at least one selected from the group consisting of polar protic solvents and polar aprotic solvents.

According to one of the embodiments of the present invention, the solvent used in the reaction is a polar protic solvent that includes C1-C4 alcohol.

According to the preferred embodiment of the present invention, the polar protic solvent used is anhydrous ethanol.

According to a further embodiment of the present invention, the solvent used in the reaction is a polar aprotic solvent which is at least one selected from the group consisting of dimethyl sulfoxide, N-methylpyrrolidone, dimethylacetamide and dimethylformamide.

The second step involves mixing the glycolonitrile-containing neutralized slurry with an alkali metal ethoxide and cyanoacetate of the following formula (Formula II): ROOC-CH2CN wherein R represents straight or branched chain alkyl of 1 to 18 carbon atoms; to obtain an alkali salt of the compound of formula I.

According to a preferred embodiment of the present invention, the alkali metal thoxide used in the second step is sodium ethoxide.

According to the present embodiment, the cyanoacetate used in the second step is alkyl cyanoacetate.

According to a preferred embodiment of the present invention, the cyanoacetate used in the second step is ethyl cyanoacetate.

According to a further embodiment of the present invention, the molar ratio of cyanide and paraformaldehyde is 1: 1.01.

According to the present embodiment, the process is carried out at a temperature in the range from about -10 to 10 ° C.

According to a preferred embodiment of the present invention, the process is carried out at a temperature in the range from about 0 to 10 ° C.

The resulting alkali salt of the compound of formula I is then neutralized with dry HCl gas, with sodium chloride being subsequently filtered off in order to obtain a clear filtrate.

The filtrate is further concentrated at a temperature of about 55 ° C to about 60 ° C in order to remove alcohol, followed by distillation under reduced pressure to obtain a compound of the formula I.

According to a preferred embodiment of the present invention, the compound of the formula I is 2,3-dicyanoethyl propionate.

The invention will now be described with reference to the following examples, which in no way limit the invention and are only intended to illustrate the invention.

example 1

98 g (2 mol) of sodium cyanide were added to 500 cm 3 of anhydrous ethanol to obtain a mixture, which was then cooled to 0 to 10 ° C. To this cooled mixture, 61.2 g (2.02 mol) of paraformaldehyde were slowly added over a period of about 1 hour while maintaining the reaction temperature. The obtained mixture was stirred for 2 hours to obtain a slurry. Dry HCl gas was then bubbled into the slurry to adjust the pH to 2. After equilibrating for about 1 hour, the pH was adjusted to 3 to obtain a glycolonitrile-containing slurry which was then filtered to remove NaCl.

The glycolonitrile-containing slurry was then mixed with 196 g (1.73 mol) of ethyl cyanoacetate at -5 to 0 ° C. 1.7 mol of sodium ethoxide solution (4 M) were then slowly added at 0-10 ° C. over a period of about 4 hours. After equilibrating at 0-10 ° C for 1 hour, the temperature was raised to 30 ° C for a period of about 2 hours to obtain an organic mixture containing the sodium salt of 2,3-dicyanoethylpropionate, which was then prepared by bubbling dry HCI- Gas has been acidified; the pH was adjusted to 4-5.

The obtained organic mixture was filtered to remove NaCl. The clear filtrate and wash were then concentrated under reduced pressure to remove ethanol at 55-60 ° C. The remaining mass was dissolved in MDC and the organic layer was washed with cold water and dried over magnesium sulfate. After distillation under reduced pressure, 2,3-dicyanoethyl propionate was obtained. Yield: 67% with a GC purity of 98%.

Example 2

98 g (2 mol) of sodium cyanide was added to 500 cc of anhydrous ethanol to obtain a mixture, which was then cooled to 5-10 ° C. To this cooled mixture was slowly added 60.6 grams (2.02 moles) of paraformaldehyde over a period of about 1 hour. The reaction mixture was kept at this temperature for a further 3 hours. The reaction mixture was then acidified by introducing dry HCl gas until the pH of the mixture reached 2 (330 mV). After equilibration, the pH was shifted to 3 by adding NaOEt to obtain a glycolonitrile slurry which was filtered to remove sodium chloride.

The filter cake obtained was washed with ethanol. The filtrate and glycolonitrile-containing wash were used for the next step.

The solution containing glycolonitrile was then charged to the reactor and cooled to 0-10 ° C. To this, the slurry of the sodium salt of ethyl cyanoacetate [prepared by adding 198 g (1.734 mol) of ethyl cyanoacetate to 1.70 mol of NaOEt solution (4 M) at 30-40 ° C.) was added over 3 hours. After equilibration, dry HCl was bubbled through to adjust the pH of the reaction mass to 4-5 (150 mV). The reaction mass was then filtered to obtain the filtrate, which was then concentrated to remove the solvent. After distillation under reduced pressure, 2,3-dicyanoethyl propionate (174 g) was obtained. Yield: 65%.

1 H-NMR in CDCl3 (200 MHz) (CH3 (from ester); triplet, at 1.33-1.4 ppm, -CH2 (from ester) quadruple at 4.3-4.4 ppm, -CH Triplet at 3.9 ppm, and CH2 doublet at 3.0 ppm. This confirms the formation of the product. GCMS shows a molecular ion peak at 152.

Example 3: Production and Distillation of Glycolonitrile

[0048] 99 g (2 mol, 99%) of sodium cyanide was added to 500 ml of anhydrous ethanol in a mechanically stirred reactor at 30 ° C and the contents were cooled to 5-10 ° C. To this mixture, 62.3 g (2.02 mol, 97.2%) of paraformaldehyde was added uniformly over 1 hour, and the resulting mixture was stirred at 5-10 ° C for 3 hours. After 3 hours, 475 ml of 4.62 N ethanolic HCl (anhydrous) was added at 5-10 ° C to shift the pH of the resulting mixture to strongly acidic, and the mixture was then left for an additional hour at the same temperature equilibrated. The obtained slurry was filtered at the same temperature, and the filter cake was washed with 75 ml of ethanol. Ethanol was vacuum distilled from the filtrate and wash at 50-55 ° C. Glycolonitrile was then vacuum distilled at 68-70 ° C vapor temperature to collect 109.8 g of distillate having a GC purity of 94.3%. The yield is 90.8%.

Example 4: Synthesis of 2,3-dicyanoethylpropionate with distilled glycolonitrile

In a further reactor, 38.6 g of sodium (1.68 mol) were dissolved in 500 ml of ethanol. The obtained sodium ethoxide solution was added to 201 g (1.76 mol, 99%) of ethyl cyanoacetate over half an hour to obtain a slurry of sodium salt of ethyl cyanoacetate. The above slurry was added to 107 g (1.77 mol) of distilled glycolonitrile (GC purity = 94.3%) in 330 ml of ethanol at 5-10 ° C. over 3 hours. The addition of a slurry of the sodium salt of ethyl cyanoacetate to glycolonitrile results in a clear solution with liberation of heat. The solution was stirred for an additional hour at 5-10 ° C and then the temperature of the liquid was raised to 30 ° C and equilibrated for 4 hours.

[0050] The mixture was then cooled to 5-10 ° C and neutralized to pH 4-4.5 (320-330 mV).

The slurry was further equilibrated for 1 hour. The mixture was filtered at 10 ° C and the filter cake was washed with ethanol. Then, ethanol was distilled off from the filtrate and washing liquid under reduced pressure at 50-55 ° C. The crude 2,3-dicyanoethyl propionate was dissolved in dichloromethane and the solution was washed with cold water and then with 10% sodium carbonate solution. The organic layer containing 2,3-dicyanoethyl propionate was further dried over MgSO4 and concentrated to obtain MDC. The oily layer was distilled through a column at 125-128 ° C (1-2 mm) under reduced pressure. Yield: 79.6%.

Example 5: Reaction of glycolonitrile solution in ethanol with the sodium salt of ethyl cyanoacetate

74.2 g (1.5 mol, 99%) of sodium cyanide was added to 400 ml of anhydrous ethanol in a mechanically stirred reactor at 30 ° C, and the contents were then cooled to 5-10 ° C. To this mixture, 46.9 g (1.52 mol, 97.2% o) of paraformaldehyde was added uniformly over 1 hour, and the resulting mixture was stirred at 5-10 ° C. for 3 hours. After 3 hours, dry HCl was slowly introduced at 5-10 ° C. over 3-4 hours to shift the pH of the slurry to strongly acidic. The slurry was filtered and the filter cake was washed with ethanol. A small portion was concentrated to constant weight under reduced pressure and the quality was determined by GC. The remaining organic layer is used for the next step.

In a further reactor, 29.5 g of sodium (1.28 mol) were dissolved in 450 ml of ethanol. The obtained sodium ethoxide solution was added to 154 g (1.35 mol, 99%) of ethyl cyanoacetate to obtain a slurry of sodium salt of ethyl cyanoacetate. The slurry of sodium salt of ethyl cyanoacetate was added to the glycolonitrile solution in ethanol obtained over a period of 4 hours at 5-10 ° C. The resulting clear solution was further equilibrated for an additional 2 hours at the same temperature. The temperature was then gradually raised to 30 ° C and the mixture was further stirred for 4 hours.

The mixture was then cooled to 5-10 ° C and neutralized to pH 4-4.5 (320-330 mV). The resulting slurry was equilibrated for 1 hour. The mixture was filtered at 10 ° C. and the filter cake was washed with ethanol. Ethanol was distilled off from the filtrate and washing liquid under reduced pressure at 50-55 ° C. The crude 2,3-dicyanoethyl propionate was dissolved by adding dichloromethane and the solution was washed with water and then with 10% sodium carbonate solution. The organic layer containing 2,3-dicyanoethyl propionate was dried over MgSO4 and concentrated to obtain MDC. The oily layer was distilled through a column at 125-128 ° C (1-2 mm) under reduced pressure. Yield: 75.2%.

Technical progress:

- The process disclosed in the present invention uses in situ generated glycolonitrile for the production of 2,3-dicyanoethyl propionate.

- The quantification of the glycolonitrile formed during the reaction takes place in the raw state by means of GC analysis.

- The process disclosed in the present invention is energy efficient and environmentally friendly, which avoids the addition of excess raw material such as ethyl cyanoacetate, i. the method disclosed in the present invention involves the use / addition of raw material in optimal molar amounts depending on the quantification of glycolonitrile in the reaction.

Further, the process disclosed in the present invention avoids the use of distilled glycolonitrile obtained through a troublesome and lengthy continuous extraction process. The isolation of glycolonitrile is still subject to practical difficulties; for example, the extraction of glycolonitrile from aqueous stream involves countercurrent extraction with polar solvents such as ethers over a long period of time. Second, the isolation of glycolonitrile by vacuum distillation may present an explosion hazard.

While particular emphasis has been placed herein on the specific steps of the preferred method, it should be understood that many steps can be performed and many changes made in the preferred steps without departing from the principles of the invention. These and other changes to the preferred steps of the invention will be apparent to those skilled in the art from the present disclosure, so it will be clearly understood that the foregoing description is to be understood as illustrative of the invention and not as a limitation.

Claims (9)

1. A process for the preparation of a compound of the following formula (Formula I) and salts thereof: wherein R represents straight or branched chain alkyl of 1 to 18 carbon atoms; the method comprising the following steps: a. Reacting an alkali metal cyanide and paraformaldehyde in the presence of an alcohol to obtain a glycolonitrile-containing slurry, and then neutralizing the slurry with dry HCl gas; b. Mixing the glycolonitrile-containing neutralized slurry with an alkali ethoxide and cyanoacetate of the following formula (Formula II): ROOC-CH2CN wherein R represents straight or branched chain alkyl of 1 to 18 carbon atoms; to obtain an alkali salt of the compound of formula I; c. Neutralizing the alkali metal salt of the compound of formula I with dry HCl gas and then removing sodium chloride by filtration in order to obtain a clear filtrate; and d. Concentrate the filtrate at a temperature of 55 ° C to 60 ° C to remove alcohol, followed by distillation under reduced pressure to obtain a compound of the formula I. 2. The method of claim 1, wherein the alkali metal cyanide is sodium cyanide. 3. The method of claim 1, wherein the alcohol is a C1-C4 alcohol. 4. The method of claim 1, wherein the alcohol is anhydrous ethanol. 5. The method of claim 1, wherein the molar ratio of cyanide and paraformaldehyde is 1: 1.01. 6. The method of claim 1, wherein the alkali ethoxide is sodium ethoxide. 7. The method of claim 1, wherein the cyanoacetate is an alkyl cyanoacetate, for example ethyl cyanoacetate. 8. The method of claim 1 which is carried out at a temperature in the range from -10 to 10 ° C or at a temperature in the range from 0 to 10 ° C. 9. The method according to claim 1, wherein the compound of formula I is 2,3-dicyanoethyl propionate.