CLIAMS:1. A process comprising continuously hydrolyzing sodium dialkyl cyclopropane carboxylate derivative of the formula 1

in the presence of a mineral acid to obtain dialkyl cyclopropane carboxylic acid derivative of the formula 2

wherein R1 and R2 are each independently selected from C1-C4 alkyl or together with the carbon to which they are attached form a 5-membered ring selected from methylidenecyclopentane, 3-methylidenetetrahydrofuran, 3-methylidenepyrrolidine, 3-methylidenetetrahydrothiophene, 2-methylidenecyclopentanone, 3-methylidenedihydrothiophen-2(3H)-one, 3-methylidenepyrrolidin-2-one and 3-methylidenedihydrofuran-2(3H)-one;

X and Y are each independently selected from hydrogen; halogen; C1-C4 alkyl; halogenated C1-C4 alkyl; unsubstituted or halogen-substituted aryl or phenyl; - C(O) – A – R3 wherein A is an – O -, - N – or – S – spacer group and R3 is C1-C4 alkyl or halogenated C1-C4 alkyl; and

M is alkali or alkaline earth metal cationic moiety, r is ½ or 1;

characterized in that said hydrolysis is carried out in the absence of a solvent.

2. The process as claimed in claim 1 additionally comprising treating the dialkyl cyclopropane carboxylic acid derivative of formula 2 with a halogenating agent to form the compound of formula 3:

3. The process as claimed in claim 1, wherein r is 1 when M is an alkali metal or r is ½ when M is an alkaline earth metal.

4. The process as claimed in claim 1, wherein R1 and R2 are both independently C1 – C4 alkyl and X and Y are indepedently a halogen selected from chlorine and bromine.

5. The process as claimed in claim 4 wherein R1 and R2 are both independently methyl, and X and Y are indepedently chloro-substituents.

6. The process as claimed in any one of the preceding claims, wherein the continuous reaction is carried out in a continuous reactor selected from a continuous flow stirred tank reactor or a plurality of continuous flow stirred tank reactors placed in a sequence.

7. The process as claimed in any one of the preceding claims comprising charging said alkali or alkaline earth metal-dialkyl cyclopropyl carboxylate to the continuous reactor along with a mineral acid.

8. The process as claimed in any one of the preceding claims wherein the mineral acid is hydrochloric acid.

9. The process as claimed in any one of the preceding claims wherein the hydrolysis is carried out at a temperature of about 600C to about 1000C.

10. A process comprising:
(a) continuously hydrolyzing sodium dialkyl cyclopropane carboxylate derivative of the formula 1

in the presence of a mineral acid to obtain dialkyl cyclopropane carboxylic acid derivative of the formula 2

wherein R1 and R2 are each independently selected from C1-C4 alkyl or together with the carbon to which they are attached form a 5-membered ring selected from methylidenecyclopentane, 3-methylidenetetrahydrofuran, 3-methylidenepyrrolidine, 3-methylidenetetrahydrothiophene, 2-methylidenecyclopentanone, 3-methylidenedihydrothiophen-2(3H)-one, 3-methylidenepyrrolidin-2-one and 3-methylidenedihydrofuran-2(3H)-one;

X and Y are each independently selected from hydrogen; halogen; C1-C4 alkyl; halogenated C1-C4 alkyl; unsubstituted or halogen-substituted aryl or phenyl; - C(O) – A – R3 wherein A is an – O -, - N – or – S – spacer group and R3 is C1-C4 alkyl or halogenated C1-C4 alkyl; and

M is alkali or alkaline earth metal cationic moiety, r is ½ or 1;

characterized in that said hydrolysis is carried out in the absence of a solvent;

(b) maintaining the reaction product in the reactor for a residence time of 5-60 min;
(c) separating the reaction product mixture of step (b) into an organic phase and an inorganic phase in a provided gravity separator, the settling time in the provided gravity separator being from about 10 to about 55 minutes;
(d) drying the separated organic phase comprising the dialkyl cyclopropane carboxylic acid derivative in an evaporator; and
(e) treating the dialkyl cyclopropane carboxylic acid derivative of formula 2 with a halogenating agent to form the compound of formula 3:

,TagSPECI:TECHNICAL FIELD:
The present invention relates to a process for preparing cyclopropane carboxylic acid derivatives.

BACKGROUND OF THE INVENTION:
Synthetic pyrethroids are commercially important insecticides that demonstrate good insecticidal activity, low mammalian toxicity, and rapid biodegradation. These are known from M. Elliott in Synthetic Pyrethroids--ACS--Symposium Series no. 42 Washington (1977).

Cylcopropane carboxylic acid esters are known to be the precursors for preparing various synthetic pyrethroid esters. The process for the preparation of such pyrethroids involves the formation of many intermediates; therefore commercial viability of such intermediates is very high.

Dialkyl cyclopropane carboxylic acid chloride derivatives are important precursors for production of various synthetic pyrethroids. These compounds are known to be derived from many starting materials including by reacting cyclobutanones with an alkali metal hydroxide to form alkali metal salts of dialkyl cyclopropane carboxylic acids as disclosed in US4242278 (Martin et.al). The salt is then subjected to hydrolysis followed by halogenation. The process for hydrolysis of the alkali metal salt of dialkyl cyclopropane carboxylic acids results in the formation of dialkyl cyclopropane carboxylic acids.

Conventional methods used for hydrolysis of the cyclopropane carboxylic acid alkali metal salts involve the use of solvents for extraction of dialkyl cyclopropane carboxylic acid. The amount of solvent used in a day in a conventional industrial setup can range from about 5000 to 2000 liters, which is then evaporated. The total amount of solvent used per month amounts to 65000 KL. There are several disadvantages related to the existing process, the large amount of solvent usage increases the cost of the production. Another disadvantage of using such a large amount of solvent is the threat of fire as the volatile solvent may accumulate and ignite. Another problem associated with such a process is the release of the evaporated solvent into the surrounding environs, making the process highly damaging to the environment.

Batch reactors have been conventionally used for the production of dialkyl cyclopropane carboxylic acid derivatives. In the batch extraction, multiple extractions are required to improve the recovery. Multiple extractions in batch mode requires large amount of solvent and in turn increases the absolute solvent losses. Solvent recovery is another energy extensive process for recycling solvent. As muck (impurities) separates in the form of a solid, continuous reactive extraction of valuable product becomes difficult.

As the scale of production increases the volume of the reactor required for the batch process increases and the number of reactors required also increases. This results in a strain on other resources like space (land), manpower, power, reactor size etc. Batch cycle time for this operation known in the prior art is ~20-22 hrs. This high residence time also increases the amount of impurities formed. There is therefore a need in the art to overcome the problems associated with such conventionally known processes.
.
Objective of the invention:
An object of the present invention is to provide a novel process for the production of dialkyl cyclopropane carboxylic acid derivatives.

It is another object of the present invention to provide a novel process that has improved yield of production of dialkyl cyclopropane carboxylic acid derivatives.

It is another object of the present invention to provide a continuous process for the production of dialkyl cyclopropane carboxylic acid derivatives.

It is yet another object of the present invention to provide a process for the production of dialkyl cyclopropane carboxylic acid derivatives that is environmentally friendly.

It is yet another object of the present invention to provide a process for the production of dialkyl cyclopropane carboxylic acid derivatives that is non-hazardous.

Summary of the invention:
In an aspect the present invention provides a process comprising continuously hydrolyzing sodium dialkyl cyclopropane carboxylate derivative of the formula 1

in the presence of a mineral acid to obtain dialkyl cyclopropane carboxylic acid derivative of the formula 2

wherein R1 and R2 are each independently selected from C1-C4 alkyl or together with the carbon to which they are attached form a 5-membered ring selected from methylidenecyclopentane, 3-methylidenetetrahydrofuran, 3-methylidenepyrrolidine, 3-methylidenetetrahydrothiophene, 2-methylidenecyclopentanone, 3-methylidenedihydrothiophen-2(3H)-one, 3-methylidenepyrrolidin-2-one and 3-methylidenedihydrofuran-2(3H)-one;

X and Y are each independently selected from hydrogen; halogen; C1-C4 alkyl; halogenated C1-C4 alkyl; unsubstituted or halogen-substituted aryl or phenyl; - C(O) – A – R3 wherein A is an – O -, - N – or – S – spacer group and R3 is C1-C4 alkyl or halogenated C1-C4 alkyl; and

M is alkali or alkaline earth metal cationic moiety, r is ½ or 1;

characterized in that said hydrolysis is carried out in the absence of a solvent.

Detailed Description:

The present invention thus describes an improved process and apparatus for manufacture of dialkyl cyclopropane carboxylic acid derivatives. The improved process involves the formation of the dialkyl cyclopropane carboxylic acid derivatives in a continuous manner, thereby decreasing costs and increasing yield and purity of the product, as well as decreasing the amount of time taken for the overall process to obtain diakyl cyclopropane carboxylic acid derivatives. Hitherto, there has been no known process that leads to the formation of dialkyl cyclopropane carboxylic acid derivatives in a continuous manner.

The present invention thus relates to a continuous process for the production of dialkyl cyclopropane carboxylic acid derivatives from their alkali or alkaline earth metal salt forms. Dialkyl cyclopropane carboxylic acid derivatives of the formula 2 are commercially important intermediates in the production of synthetic pyrethroids.

It is known in the art that the hydrolysis of dialkyl cyclopropane carboxylic acid metal salts to their acid forms require a large amount of solvent for extraction and azeotropic separation of the organic dialkyl cyclopropane carboxylic acid and aqueous phase. The solvent used is then evaporated, increasing the cost of production and causing harm to the environment.

It has surprisingly been found that hydrolytic conversion of alkali metal salts of dialkyl cyclopropane carboxylic acid to their acid forms can be carried out in a continuous manner without using any solvent. Hitherto, such hydrolysis has never been carried out in the absence of a solvent and in a continuous manner.

Thus, in an aspect the present invention provides a process comprising continuously hydrolyzing sodium dialkyl cyclopropane carboxylate derivative of the formula 1

in the presence of a mineral acid to obtain dialkyl cyclopropane carboxylic acid derivative of the formula 2

wherein R1 and R2 are each independently selected from C1-C4 alkyl or together with the carbon to which they are attached form a 5-membered ring selected from methylidenecyclopentane, 3-methylidenetetrahydrofuran, 3-methylidenepyrrolidine, 3-methylidenetetrahydrothiophene, 2-methylidenecyclopentanone, 3-methylidenedihydrothiophen-2(3H)-one, 3-methylidenepyrrolidin-2-one and 3-methylidenedihydrofuran-2(3H)-one;

X and Y are each independently selected from hydrogen; halogen; C1-C4 alkyl; halogenated C1-C4 alkyl; unsubstituted or halogen-substituted aryl or phenyl; - C(O) – A – R3 wherein A is an – O -, - N – or – S – spacer group and R3 is C1-C4 alkyl or halogenated C1-C4 alkyl; and

M is alkali or alkaline earth metal cationic moiety, r is ½ or 1;

characterized in that said hydrolysis is carried out in the absence of a solvent.

In an embodiment, r is 1 when M is an alkali metal moiety.

In another embodiment, r is ½ when M is an alkaline earth metal moiety.

In a preferred embodiment, R1 and R2 are both independently C1 – C4 alkyl.

In another embodiment, X and Y are indepedently a halogen selected from chlorine and bromine.

In a preferred embodiment, R1 and R2 are both independently methyl, and X and Y are indepedently chloro-substituents.

In an embodiment, the hydrolysis of the alkali metal-dialkyl cyclopropane carboxylate is carried out in a continuous reactor or in a plurality of continuous reactor placed sequentially. In the embodiment wherein a plurality of continuous reactors are employed, the reacted mixture from a prior placed continuous reactor is fed to a subsequently placed continuous reactor, and so on till the intended reaction is complete.

In an embodiment, the continuous reactor employed is a continuous flow stirred tank reactor or a plurality of such continuous flow stirred tank reactor placed in sequence.

In the embodiment wherein the alkali or alkaline earth metal-dialkyl cyclopropyl carboxylate is hydrolyzed continuously, said alkali or alkaline earth metal-dialkyl cyclopropyl carboxylate is charged continuously to the continuous reactor along with a mineral acid. Care must be taken to charge the reactants in the absence of a solvent to fully realize the benefits of the present invention.

In an embodiment, the mineral acid is hydrochloric acid although other mineral acids conventionally known in the art such as nitric acid, sulfuric acid and phosphoric acid may also be used.

In an embodiment, the hydrolysis of said alkali or alkaline earth metal-dialkyl cyclopropyl carboxylate is carried out at a temperature of about 600C to about 1000C. Preferably, the hydrolysis is carried out at a temperature of about 800C.

In an embodiment, the hydrolysis of said alkali or alkaline earth metal-dialkyl cyclopropyl carboxylate is carried out using a solution of the carboxylate. In a preferred embodiment, a 10 – 20% solution of the alkali or alkaline earth metal-dialkyl cyclopropyl carboxylate is charged along with the mineral acid, in the absence of a solvent, to a continuous reactor at the predetermined temperature.

In an embodiment, the reaction product of the hydrolysis step is conveyed into a provided gravity separator, wherein the received reaction product mixture is separated into an organic phase and an inorganic phase. The inorganic phase comprises the alkali or alkaline earth metal salt of the corresponding mineral acid. The organic phase substantially comprises the dialkyl cyclopropane carboxylic acid derivative, which is subsequently dried and halogenated to afford the corresponding halide derivative.

In an embodiment, the dialkyl cyclopropane carboxylic acid derivative is preferably dried by removal of water in an evaporator. Such evaporators for the removal of water are conventionally known in the art and may be used as available for drying the dialkyl cyclopropane carboxylic acid derivative containing organic phase.

In an embodiment, the phase separation in the gravity separator is carried out at a temperature of about 700C to about 1000C, preferably at about 800C.

In an embodiment, the removal of water in the evaporator is carried out at a temperature of 700C to about 1000C, preferably at about 800C. In this embodiment, the pressure may be maintained at 20 to 40 torr.

In an aspect, the dialkyl cyclopropane carboxylic acid derivative of formula 2 is halogenated, preferably chlorinated, to afford the corresponding halide derivative, which is a useful derivative for the preparation of synthetic pyrethroids.

Thus, in this aspect, the process of the present invention additionally comprises treating the dialkyl cyclopropane carboxylic acid derivative of formula 2 with a halogenating agent to form the compound of formula 3:

In an embodiment, the halogenation is preferably carried out at a temperature of 600C to about 1000C, preferably at about 800C.

Conventionally, the organic layer of dialkyl cyclopropane carboxylic acid had to be treated with caustic alkali so as to neutralize the excess acid before the next step in the production of pyrethroids could be initiated. The process of the present invention eliminates the use of alkali in high quantities and ensures that high purity organic layer of dialkyl cyclopropane carboxylic acid is separated from the aqueous layer under vacuum and a constant temperature of 60 to 100 degrees, preferably 70-80 degrees Celsius, most preferably 80 degrees Celsius.

Accordingly, in one preferred embodiment, the present invention provides a process comprising:
(a) continuously hydrolyzing sodium dialkyl cyclopropane carboxylate derivative of the formula 1

in the presence of a mineral acid to obtain dialkyl cyclopropane carboxylic acid derivative of the formula 2

wherein R1 and R2 are each independently selected from C1-C4 alkyl or together with the carbon to which they are attached form a 5-membered ring selected from methylidenecyclopentane, 3-methylidenetetrahydrofuran, 3-methylidenepyrrolidine, 3-methylidenetetrahydrothiophene, 2-methylidenecyclopentanone, 3-methylidenedihydrothiophen-2(3H)-one, 3-methylidenepyrrolidin-2-one and 3-methylidenedihydrofuran-2(3H)-one;

X and Y are each independently selected from hydrogen; halogen; C1-C4 alkyl; halogenated C1-C4 alkyl; unsubstituted or halogen-substituted aryl or phenyl; - C(O) – A – R3 wherein A is an – O -, - N – or – S – spacer group and R3 is C1-C4 alkyl or halogenated C1-C4 alkyl; and

M is alkali or alkaline earth metal cationic moiety, r is ½ or 1;

characterized in that said hydrolysis is carried out in the absence of a solvent;

(b) maintaining the reaction product in the reactor for a residence time of 5-60 min;
(c) separating the reaction product mixture of step (b) into an organic phase and an inorganic phase in a provided gravity separator, the settling time in the provided gravity separator being from about 10 to about 55 minutes;
(d) drying the separated organic phase comprising the dialkyl cyclopropane carboxylic acid derivative in an evaporator; and
(e) treating the dialkyl cyclopropane carboxylic acid derivative of formula 2 with a halogenating agent to form the compound of formula 3:
.

It has been further surprisingly been found that the hydrolysis reaction for the conversion of the alkali or alkaline earth metal salt of dialkyl cyclopropane carboxylic acid derivatives, when charged with a mineral acid does not occur if the temperature is lower than 60 degrees or higher than 100 degrees. Without wishing to be bound by theory, the present inventors believe that if the temperature of the reaction falls below 60 degrees the organic layer did not easily separate. The conversion was found to be optimum at the temperature range of 60 to 800C. The yield obtained at the range of 60 to 100 degrees was higher than the yield obtained in conventional methods, making the process of the present invention highly economical and environmentally friendly.

The inventors of the present process have also surprisingly found that the pH of the reaction is critical for the hydrolysis reaction which results in the conversion of salt to acid. The pH of the reaction if increased above 2 will result into the hydrolysis reaction being suspended. Both the pH and the temperature are therefore important parameters for the hydrolysis of the alkali metal salts of dialkyl cyclopropane carboxylic acids to their acid forms, according to an embodiment of the present invention.

The residence time has a bearing on the quantity of the impurities formed. The conventional batch processes known in the prior art have a residence time of about 6 hours. This high residence time also increases the amount of impurities formed.

The process of the present invention also has a surprisingly low residence time in the reactor, which could range from 5-60 minutes, preferably 15-50 minutes, most preferably 25-30min, without compromising the yield or purity of the target product. It has been found that the continuous process of the present invention enables the residence time of the reactant mixture to be considerably reduced, without compromising the yield of the target product. Additionally, the lower residence time enabled by the present invention enabled a substantially pure product to be obtained, which has hitherto not been made possible in the art.

The reaction mixture is then fed into a gravity separator, where the residence time may be 11-55 minutes, preferably 20-40 minutes.

The process of the present invention demonstrates several advantages over the conventional process used in the prior art. The process of the present invention eliminates the use of very large quantities of solvents, making the process environmentally friendly. The process of the present invention eliminates the use of large batch reactors, which may be replaced with lower volume continuous system reactors. In a typical plant setting, large volumes of the batch reactor of about 85 KL could be reduced to continuous reactor volumes of about 7 KL. The process of the present invention delivers higher yields as compared to conventional process known in the art. Importantly, the use of a solvent such as hexane, which had been conventionally known in the art, was completely eliminated, offering both enhanced industrial safety and lesser environmental footprint.

These and other advantages of the invention may become more apparent from the examples set forth herein below. These examples are provided merely as illustrations of the invention and are not intended to be construed as a limitation thereof.

EXAMPLES:

Example 1: Preparation of 3-(2, 2-dichloroethenyl)-2, 2-dimethyl- cyclopropane carboxylic acid at 70 degrees centigrade:

3-(2,2-dichloroethenyl)-2,2-dimethyl- cyclopropane carboxylic acid sodium salt (0.87 mole) was neutralized with 30% hydrochloric acid till pH 1-2, at 70 degrees in a glass stirred tank reactor. The organic and inorganic layers were separated in a gravity separator and the organic layer comprising (3-(2, 2-dichloroethenyl)-2, 2-dimethyl- cyclopropane carboxylic acid 0.832 mole) was obtained.

Example 2: Preparation of 3-(2, 2-dichloroethenyl)-2, 2-dimethyl- cyclopropane carboxylic acid at 80 degrees centigrade:

1000 gm of (2,2-dichloroethenyl)-2,2-dimethyl- cyclopropane carboxylic acid sodium salt was taken in a glass agitated reactor and 125 gm of 35% hydrochloric acid was slowly added to the reactor while keeping the reaction temperature at 80 deg C. After the complete addition of hydrochloric acid, the reaction mass was maintained at 80 deg for 10-20 min and then allowed the layers to separate for 20-30 min at 80 deg C. Separated the aqueous and organic layers. The organic layer was taken for water removal at 80 deg C under vacuum 720-740 mm Hg.

Example 3: Preparation of 3-(2, 2-dichloroethenyl)-2, 2-dimethyl- cyclopropane carboxylic acid at 90 degrees centigrade:

1500 gm of (2,2-dichloroethenyl)-2,2-dimethyl- cyclopropane carboxylic acid sodium salt was taken in a glass agitated reactor and 220 gm of 30% hydrochloric acid was slowly added to the reactor while keeping the reaction temperature at 90 deg C. After the addition of hydrochloric acid pH of the reaction mass was checked (~2.1), and the reaction mass was maintained at 90 deg for 10-20 min. The product was then transferred to a separating funnel maintained at 90 deg C for gravity separation of aqueous and organic layers. A separation time of 20-30 min was provided and the aqueous and organic layers were separated. The organic layer was taken for water removal at 80-90 deg C under vacuum 720-740 mm Hg. The concentration of DVA in the organic mass was in the range of 80-85%.
Comparative Example:

About 1148 g of Na-DVA was taken, to which a desired quantity (about 190 mL level) of hydrochloric acid was added in 403 g of hexane. At the end of the reaction, about 571 g of DVA+hexane was separated. Importantly, about 23 g of muck (mainly comprising the impurities) was also separated for the sample using the batch process. The muck was dissolved in aqueous by adding sodium hydroxide and sent for evaporation.