CLIAMS:1. A process for preparing a compound of formula (I):
formula (I)
wherein R represents straight-or branched-chain alkyl having from1 to 18 carbon atoms, or a salt thereof, which comprises a reacting a cyanoacetate of formula
(II):
wherein R is as defined above, with 2-haloacetonitrile under the presence of catalyst and base.

2. A process according to claim 1, wherein R represents straight-or branched-chain alkyl having from 1 to 6 carbon atoms.

3. A process according to claim 1, wherein the compound of formula (II) is ethyl cyanoacetate.

4. A process according to claim 1, wherein the reaction is performed in presence of a solvent which is inert to the reactants, like toluene, xylene, acetonitrile, acetone etc.

5. A process according to claim 1 wherein the reaction is carried out at a temperature from about -20° C. to about 100C.

6. A process according to claim 1 in which the reaction is performed using about 1 molar equivalent of the compound of formula (II); about 0.95 to 1.0 molar equivalent of 2-haloacetonitrile.

7. A process according to claim 1 in which the reaction is performed using catalyst like 1,4-diazabicyclo(2.2.2) octane , Triphenyl phoshine, adamantine, and hexamethylene tetraamine etc.

8. A process according to claim 1 in which the reaction is performed using base like potassium carbonate, sodium carbonate, sodium hydroxide, or potassium hydroxide and most preferably potassium carbonate. ,TagSPECI:TITLE

Process for The Preparation of Ethyl 2,3-dicyanopropionate

FIELD OF INVENTION
This invention relates to a process for preparing certain cyanomethylpropane derivatives and the use of these compounds in the synthesis of pesticides, and an important intermediate in the synthesis of FIPRONIL, an insecticide used widely over crops.


DESCRIPTION OF THE BACKGROUND
EthyI2,3-dicyanopropionate was first prepared and characterized by Higson and Thorpe (J.Chem.Soc. 89, 1460 (1906) who obtained the material by reaction of formaldehyde cyanohydrin with the sodium salt of ethyl cyanoacetate. Dickinson {J. A. Chern.Soc. 82, 6132 (1960)} repeated this work. This method of preparing the dicyano propionate has a drawback where it is first necessary to isolate the intermediate formaldehyde cyanohydrin. This highly water soluble cyanohydrin is obtained by continuous extraction and has a limited stability, often decomposing violently upon attempted distillation. Furthermore, this reaction has a risk of formation of dimeric side products.
The preparation of dicyano propionates has also been described by Whiteley and Marianelli (Synthesis (1978), 392) with the process leading to 2,3-disubstituted succino­dinitriles fromthe cyanoacetate, an aldehyde and potassium cyanide via 3-substituted-2,3-dicyanopropionates (which were not isolated). However, the yield decreases dramatically from isobutvraldehvde to acetaldehyde.
In the same manner Smith' and Horwitz (J. A. Chern.Soc. 1949, 71, 3418) described the same reaction with a ketone with a yield of 70%. This prior art therefore teaches that yields improve with increasing size of group adjacent to the carbonyl group.
US patent 6133432, of RHONE-POULENC Agro, describes a method of preparation of the said compound with the reaction of sodium or potassium cyanide, ethyl cyanoacetate and paraformaldehyde at room temperature. This process claims to be high purity and high yield but involves risk in usage of cyanide which is industrially difficult to handle on large scale operations.
Indian patent 552/MUM/2010, by GHARDA chemicals refers a process for making the same with the action of sodium methoxide on ethylcyanoacetate to form sodium salt of ethylcyanoacetate and reacting it with glycolonitrile (hydroxyacetonitrile) at room temperature. This process involves handling of sodium methoxide in methanol or ethanol solution and major impurity in this reaction is formation of disubstitution of hydroxyl acetonitrile which can be separated by distillation at higher temperature under vacuum, where polymeric formation can happen with subsequent loss in yield.
One aspect the present invention seeks to provide a process for preparing cyano methyl propane derivatives satisfying one or more of the following criteria:
1. avoiding the use of formaldehyde cyanohydrin;
2. avoiding the dimerisation side reaction;
3. avoiding use of sodium or potassium cyanide (which are toxic)
4. avoiding sodium methoxide in alcohol solutions
5. avoiding di-substitution and thereby avoiding distillation losses.
6. obtaining the required product directly in high yield and with high purity.
SUMMARY OF THE INVENTION
The present invention relates to synthesis of the said ethyl 2,3-dicaynopropionate with high purity and high yield in the presence of catalyst. Surprisingly we found that, 2-haloacetonitrile reacts with ethyl cyanoacetate to form the said compound in high yields in the presence of catalyst and base like potassium carbonate in solvent like toluene.

The present invention relates to synthesis of ethyl 2,3-dicyanopropionate in non-toxic environment, which is easy to handle, results in higher yield and industrially feasible. The present invention uses 2-haloacetonitrile as substrate to react with alkali salt of ethylcyano actate in the presence of catalyst.

The present invention involves formation of alkali salt of ethylcyano acetate on the alpha carbon with the base and subsequently reacting it with haloacetonitrile, where halogen is further neutralized with the base which is used in excess.
The substrate used in the above process is 2-chloroacetonitrile or 2-bromoacetonitrile, which can be synthesized as known to art of skill from 2-hydroxyacetonitrile and chlorinating or brominating agent.
The pH of the reaction medium is maintained on the basic side to increase the rate of reaction further and product will have more stability when compared to performing reaction in acidic condition. In order to maintain pH of the reaction medium on base i.e 8.0 to 13.5, and more preferably pH of the reaction at 10.5 to 11.5, excess base is used. The base used here can facilitate both the steps like forming alkali salt of ethylcyanoacetate and maintaining pH of the solution.
The base used in the above process is of choice like sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassiumbicarbonate, calcium carbonate and most preferably potassium carbonate.
The present process can be done at low temperatures like -20 to +100C, more preferably at 30 – 80C. The present process involves usage of catalysts which enhance rate of reaction both in homogenous phase and heterogenous phases like triethylbenzyl ammonium chloride, tetra methyl ammonium chloride and tribenzyl ammonium bromide and organic catalysts like 1,4-diazabicyclo(2.2.2) octane(DABCO) , hexamethylene tetraamine, adamantane, triphenyl phosphine.
The solvents used in the process are of choice of hydrocarbon solvents like toluene, xylene, chlorobenzene, dichlorobenzene, benzene, and halogenated solvents dichloroethane, dichloromethane, chloroform, polar solvents N,N-dimethylformamide, N-methyl-2-pyrollidone(NMP), acetonitrile, acetone and even nonpolar solvents hexane, heptanes, more preferably polar solvents acetonitrile, acetone, NMP, N,N-dimethylformamide, dimethyl carbonate, hydrocarbon solvents toluene, xylene, chlorobenzene, and most preferably in toluene, xylene, acetonitrile, acetone.
The mole ratios of ethylcyanoacetate to base to substrate to carry out the reaction is 1.0:1.0 to 1.5 : 0.8 to 1.2, and most preferably 1.0: 1.25: 1.0.
Below are some examples for best understanding the process.
Example-1: Into a four neck round bottomed flask, ethylcyanoacetate( ECA) (113 gm) is added into a mixture of toluene(500gm) and potassium carbonate(172.5gm) at room temperature. The reaction mass is heated to 60 C and 2-chloroacetonitrile is added over 30 min, and then DABCO 5 gm is added over 2 min. Then the reaction mass is heated to 80 C and maintained further for the next 4 hours. Reaction is terminated when ECA is less than 1.0%. The reaction mass is cooled and filtered. The filtrate is subjected to water washes to remove traces of alkali and then distilled under vacuum to remove solvent and to leave ethyl2,3-dicyano propionate as viscous red colored oil of 113 gm. Yield based on ECA is 75% and purity is 99.2%.
Example-2: Into a four neck round bottomed flask, ethylcyanoacetate( ECA) (113 gm) is added into a mixture of acetonitrile(500gm) and potassium carbonate(207gm) at room temperature. The reaction mass is heated to 60 C and 2-chloroacetonitrile is added over 30 min, and then DABCO 2 gm is added over 2 min. Then the reaction mass is heated to reflux and maintained further for the next 4 hours. Reaction is terminated when ECA is less than 1.0%. The reaction mass is cooled and filtered. The filtrate is subjected to distillation under vacuum to remove solvent and to leave ethyl2,3-dicyano propionate as viscous red colored oil of 128 gm. Yield based on ECA is 85% and purity is 99.0%.
Example-3: Into a four neck round bottomed flask, ethylcyanoacetate( ECA) (113 gm) is added into a mixture of acetonitrile(500gm) and potassium carbonate(207gm) at room temperature. The reaction mass is heated to 60 C and 2-chloroacetonitrile is added over 30 min, and then Triphenylphosphine 5 gm is added over 2 min. Then the reaction mass is heated to reflux and maintained further for the next 4 hours. Reaction is terminated when ECA is less than 1.0%. The reaction mass is cooled and filtered. The filtrate is subjected to distillation under vacuum to remove solvent and to leave ethyl2,3-dicyano propionate as viscous red colored oil of 124 gm. Yield based on ECA is 82% and purity is 98.7%.
Comparative example1 : Potassium cyanide (13.0 g, 0.2M) was stirred in absolute ethanol and ethyl cyanoacetate (22.6 g, O.2M) and paraformaldehyde (6.0 g, O.2m) were added at ambient temperature. After 5 minutes the white suspension was heated under 20 reflux conditions for 12 minutes, and the orange solution was evaporated to dryness in vacuo at below 25° C. to give a buffcolored solid. The solid (the potassium salt) was dissolved in water (400 ml), acidified to pH 5 with 2M hydrochloric acid solution, giving a red oil. This mixture was extracted with 25 dichloromethane and the extracts dried and evaporated to dryness in vacuo to give the title compound as a red oil (23.5 g)
Below table indicates the use of catalyst, substrate and solvent
Substrate A: 2-chloroacetonitrile Substrate B : 2-bromoacetonitrile
Srno Solvent Substrate Base Catalyst Temp Time Yield
1 Toluene A K2CO3 DABCO 80 4 82
2 Toluene A K2CO3 HEXAMINE 80 6 80
3 Xylene A Na2CO3 DABCO 80 4 79.8
4 Acetonitrile A K2CO3 DABCO reflux 4 85
5 Acetonitrile B K2CO3 DABCO reflux 4 88
6 Xylene B K2CO3 TPP 100 5 84.6
7 Dichloroethane B Na2CO3 TPP 75 6 82.3
8 Toluene A K2CO3 ADAMANTANE 80 8 77.2
9 Benzene B KOH ADAMANTANE reflux 5 79.45
10 Chlorobenzene A NaOH TPP 100 7 74
11 Toluene A K2CO3 HEXAMINE 80 6 78.6
12 Toluene A K2CO3 DABCO 90 5 87.8