• Field of the invention
The present invention relates to an improved process for the manufacture of dialkyl cyclopropyl carboxylic acid halide derivatives.

• Background
The present disclosure is by way of illustration only; it is in no way an acknowledgement of knowledge of prior art.

Dialkyl cyclopropyl carboxylic acid halide derivatives are important precursors for production of various synthetic pyrethroids, and are therefore of great commercial importance. The process for manufacturing dialkyl cyclopropyl carboxylic acid halides involves the use of batch processes for production of many intermediates before the production of the final product.

The most common process known in the art to manufacture dialkyl cyclopropyl carboxylic acid halide comprises reacting acrylonitrile and carbon tetrachloride in presence of catalyst to give a tetrachloro butyronitrile. The tetrachloro butyronitrile is hydrolyzed with sulphuric acid to form tetrachloro butyric acid. The tetrachloro butyric acid is reacted with thionyl chloride to make tetrachloro butyric acid chloride.

The tetrachloro butyric acid chloride is reacted with isobutylene in presence of triethyl amine to form 2-chlorocyclobutanone derivative. The 2-chlorocyclobutaone derivative is isomerized in presence of a catalyst to give the derivative 4-chlorocyclobutanone. 4-chlorocyclobutanone derivative thus obtained is reacted with caustic solution to form a sodium salt compound of formula XI.

The “TCA Sodium salt” is thereafter dehydrohalogenated to “DVA Sodium Salt”, which is hydrolyzed to compound DVA. The compound DVA is then chlorinated in the presence of a chlorinating agent to obtain DVA-Cl, which is the dialkyl cyclopropyl carboxylic acid halide target compound of the present invention.

Batch reactors have been conventionally used for the production of dialkyl cyclopropyl carboxylic acid halide derivatives. The yields obtained at each step are considerably low. Also, certain intermediates formed during the process react with other reactants resulting in the formation of impurities, which further decrease the yield at every step of the process. The intermediates are vital for the formation of the end product, and the yield of these affects the yield of the end product.

The process for manufacturing the intermediate, 2-chlorocyclobutanone derivatives is disclosed in US4242278 (Martin et. al. 1980). The patent describes a process for manufacturing halogenocycloalkanones. This patent discloses reaction of tetrachlorobutyric acid halide with organic bases to form an intermediate 2-(2', 2’, 2’- trihaolgenoalkyl)-4-halogenocyclobutan-1-one. The process mentions the formation of a ketene intermediate, but fails to appreciate as to how the impurities commonly found in the halocyclobutanone samples are formed. These impurities present with 2- and 4-chlorocyclobutanone derivatives are known to form polymers, which are extracted as muck, thereby decreasing the yield of the final product i.e. synthetic pyrethroid. It is thus important to avoid the formation of impurities at this stage of the process.

US 3646150 discloses a process for preparing halocyclobutanone by the thermal cycloaddition of monomeric ketene and ethylene.

There are various problems associated with the production of dihalo cyclopropyl carboxylic acids (DVA) or its derivatives using the known batch process. The process on reaching the stage of production of 2-halocyclobutanone encounters difficulties in handling the material as 2 halocyclobutanone is in slurry form. The slurry has to be dissolved in additional solvent to obtain the product for the next step in the reaction process. The formation of impurities at this stage is very high, thereby decreasing the yield of the product and increasing the impurities present in the product. Due to the frequent presence of these impurities in a sample of halocyclobutanone derivative, there is also a need in the art to provide compounds that are useful as reference markers for the analysis of a sample of halocyclobutanone derivative.

The efficacy or activity of an insecticide depends also on the level of impurities present in the technical compound at the time of its incorporation into the commercially marketed formulation. The absence of impurities also enhances the shelf-life of the technical compound and consequently that of the formulation incorporating the technical substance. Therefore, a manufacturer of a technical compound typically conducts analytical studies to ensure that the impurities are present in the technical substance only to a negligible level. These studies are usually conducted by testing a sample of the prepared technical compound against an external standard or a reference marker, which may be substantially pure sample of an impurity.

Residence time is another factor in the process that has a bearing on the quantity of the impurities formed. The batch processes known in the industry have a residence time of about 6 hours. This high residence time also increases the amount of impurities formed.

The present invention describes an improved process and apparatus for manufacture of dialkyl cyclopropyl carboxylic acid halide derivatives. The improved process involves the formation of the 2-chlorocyclobutanone intermediate 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 cyclopropyl carboxylic acid halide derivatives. Hitherto, there has been no known process that leads to the formation of a chlorocyclobutanone derivative in a continuous manner.

• Object of the invention:

An object of the present invention is to provide an improved process that affords a high yield of a dialkyl cyclopropyl carboxylic acid halide derivative.

Another object of the present invention is to obtain dialkyl cyclopropyl carboxylic acid halide of sufficient purity such that it could be used directly for the preparation of pyrethroid insecticides.

Another object of the present invention is to provide a reactor system for the preparation of 2-halocyclobutanone derivatives in a continuous manner.

Another object of the present invention is to provide haloketene dimer compounds that are suitable for the detection and determination of impurities in a sample of halohalocyclobutanone.

Yet another object of the present invention is to provide compounds that are capable of being used as reference markers in the analysis of the purity of a sample of halocyclobutanone.

These and other objects of the invention are realized in the manner described hereinafter.

• Summary
In an aspect, the present invention provides an improved process for the preparation of a compound having formula I:

wherein X1 is halogen;
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; and

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;

said process comprising allowing an in-situ generated haloketene derivative to react with an alkene to form a 2-halocyclobutanone derivative having formula VI

wherein X, Y, R1, R2 are as defined above and “Z” is halogen;

wherein, said improvement comprises reacting said in-situ generated haloketene derivative with said alkene without contacting said 2-halocyclobutanone derivative of formula VI.

In another aspect the present invention provides a compound having the formula A:

In yet another aspect the present invention provides a compound having the formula B:


A method for testing the purity of a sample of halocyclobutanone derivative, said method comprising:
(a) dissolving a sample of a halocyclobutanone derivative in a solvent to produce a sample solution;
(b) dissolving a sample of the compound of the formula A having the structure:


or a compound of the formula B having the structure:

in a solvent to product a reference marker standard solution; and
(c) assaying said sample of halocyclobutanone derivative for the presence of compound A or compound B to determine the purity of the sample.

In another aspect, the present invention provides a reactor system for the preparation of 2-halocyclobutanone derivative, said reactor system comprising a plurality of continuous-flow stirred-tank reactors placed in series or a plug-flow reactor, each said reactor comprising:
(a) at least a central reaction zone;
(b) at least an agitation means;
(c) at least one input nozzle and at least output nozzle, said input nozzle of first said reactor being capable of receiving the reaction mixture comprising an alkene, a tetrahalobutyric acid or a tetrahalobutyric acid halide, and an amine and conveying the received reaction mixture into said central reaction zone, the output nozzle of each preceding reactor being connected to the input nozzle of the subsequently placed reactor in series so as to allow the resultant reaction mixture from each said preceding reactor to flow into the input nozzle of the subsequently placed reactor in the series, the flow velocity through said reactors being selected so as to allow continuous removal of said 2-halocyclobutanone derivative immediately upon being formed in the reaction mixture;
(d) at least a static mixer connected to the outlet nozzle of the last reactor in the series; and
(e) at least a phase separator connected to the said static mixer.

In yet another aspect, the present invention provides an improved process for the preparation of dialkyl cyclopropyl carboxylic acid halide derivatives having formula I:

wherein X1 is halogen;
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; and

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;

said process comprising:
a.) reacting acrylonitrile with a halogen donating organic solvent XI to obtain halo-substituted butyronitrile X;

wherein X and Y are as defined above and Z is halogen;

b.) reacting said halo-substituted butyronitrile X with an inorganic acid to form halo butyric acid IX;

c.) reacting the said halo butyric acid IX with a chlorinating agent to form halo butyric acid halide VIII;

d.) reacting said halo butyric acid halide VIII with an alkene VII to form an in-situ generated haloketene derivative and allowing said in-situ generated haloketene derivative to react with said alkene to form 2-halocyclobutanone derivative VI;

e.) isomerizing said 2-halocyclobutanone derivative VI in presence of a catalyst to form a 4-halocyclobutanone derivative V;

f.) reacting said 4-halocyclobutanone derivative V with sodium hydroxide to form a cyclopropyl carboxylic acid sodium salt of formula IV

wherein M+ is an alkali metal cation;
g.) dehydrohalogenating said cyclopropyl carboxylic acid sodium salt of formula IV in a suitable reagent to obtain the compound III;

h.) hydrolyzing the said dihalo vinyl carboxylic acid salt compound of formula III with an acid to form a dihalo vinyl acid derivative II; and

i.) treating the said dihalo vinyl acid derivative with a halogenating agent to form the compound of formula I;

wherein said improvement comprises reacting said haloketene generated in-situ in step (d) with said alkene without contacting said 2-halocyclobutanone derivative compound of formula VI.

• Brief Description of the drawings
The presented drawings are by way of illustration only and in no way limit the scope of the invention.

Fig. 1 is a cross section of an embodiment of one of the reactor apparatus for carrying out the process of manufacturing 2 halocyclobutanone derivatives.

Fig. 2 is an embodiment of the reactor system to carrying out the process of manufacturing 2 halocyclobutanone derivatives.

Fig. 3 represents the 1H-NMR spectrum of the compound of formula A.

Fig. 4 represents the 13C-NMR spectrum of the compound of formula A.

Fig. 5 represents the mass spectrum of the compound of formula A.

• Detailed Description of the invention

It has now been found that the compounds having the structures A and B are useful reference markers for the analysis of halocyclobutanone derivatives. Incidentally, these compounds A and B are potential contaminants arising as by-products during the synthesis of halocyclobutanone derivatives.

Accordingly, in one aspect, the present invention provides a compound having the formula A:


wherein Z is halogen. In an embodiment, Z is chloro-.

In another aspect, the present invention provides a compound having the formula B.


wherein Z is halogen. In an embodiment, Z is chloro-.

In an embodiment, the compounds A and B are in a substantially pure form in order to be useful reference markers. Therefore, these compounds of formulae A and B may be purified in order to achieve the necessary purity level.

In an embodiment, the process of the present invention for the preparation of dialkyl cyclopropyl carboxylic acid derivative may include the additional step of purifying the compounds of formulae A and B formed therein. This purification may be carried out by conventional methods which are routine in organic syntheses and do not form a critical part of the present invention.

These compounds of formulae A and B are preferably finally recovered in substantially pure form. The purity level of a final sample of either compound is typically at least 90%. Purity levels above 90% may be desirable but are not essential. The purity level may be, for instance, at least 92%, at least 95% or at least 98%. Even more desirably the purity level is 99% or 99.5%.

The halocyclobutanone derivatives prepared according to an embodiment of the present invention may be analyzed for purity using the compounds of formula A or formula B as reference markers. These halocyclobutanone derivatives are assayed for the presence of compounds A and B to check the purity of the sample of the halocyclobutanone derivative. The halocyclobutanone derivative to be tested may be assayed by one or more conventional analytical techniques. The analytical technique used for assaying the halocyclobutanone derivative against the reference solution comprising compounds of formula A or formula B may be the conventional assaying method that is known to a skilled technician and does not form a critical feature of the present invention.

The results obtained are then compared with the results obtained from testing substantially pure forms of compounds of formulae A and B. The percentage purity of each sample of the halocyclobutanone derivative can thereafter be determined in a conventional manner that is known in the art for such analyses.

Therefore, in another aspect, the present invention provides a method of determining the purity of the compound of formula V or formula VI comprising assaying a sample of a compound of formula V or formula VI obtained from the phase separator of the reactor system for the presence of a compound selected from compounds having formula A and formula B.

Therefore, in this embodiment, the present invention provides a method for testing the purity of a sample of halocyclobutanone derivative of formula V or formula VI, said method including the steps of dissolving a sample of the halocyclobutanone derivative in a solvent and preparing a standard marker sample solution by dissolving a sample of compound A or compound B. The standard marker sample and the sample containing the halocyclobutanone derivative is then subjected to analysis by various analytical means such as Thin Layer Chromatography (TLC), gas chromatography (GC) to determine the Rf value of the reference marker as well as the sample solution in a conventional manner. The percentage purity of the compound of formula V or formula VI may thereafter be calculated from the Rf values in a conventional manner.

In a further embodiment, the prepared sample containing a halocyclobutanone derivative is analyzed for presence of compound A or B by injecting the sample solution along with a reference sample containing the compounds A or B into an High Performance Liquid Chromatography (HPLC) column and determining the main peak areas of each solution and calculating the content of the reference marker in a conventional manner.

In another embodiment, the analytical method used for detection of the compound A or B in a halocyclobutanone derivative sample includes Gas Chromatography (GC), Mass Spectrometry or any other method that is conventionally known in the art for quantitative assaying.

It has been seen that the analytical testing of the halocyclobutanone derivative serves principally to confirm that compounds A and/or B are absent or are present only at levels below the limit of detection for the analytical technique in question. The present invention therefore ensures that only a substantially pure halocyclobutanone derivative i.e. which is substantially free of the compound of formula A or formula B is utilized for the preparation of the target compound of formula I, and consequently also for the preparation of the end pyrethroid compound. Therefore, an advantage of the present invention is in providing high purity halocyclobutanone derivative (i.e. being substantially free of the compounds of formulae A and B), which lead to the preparation of a synthetic pyrethroid compound in high purity.

Thus, in an aspect, the present invention also provides a method for testing the purity of a sample of halocyclobutanone derivative, said method comprising:
(a) dissolving a sample of a halocyclobutanone derivative in a solvent to produce a sample solution;
(b) dissolving a sample of the compound of the formula A having the structure:


or a compound of the formula B having the structure:

in a solvent to product a reference marker standard solution; and
(c) assaying said sample of halocyclobutanone derivative for the presence of compound A or compound B to determine the purity of the sample.

The halobutyric acid halide usually reacts with an amine e.g. triethylamine, to form an in-situ generated haloketene, which reacts with the alkene to form a halocyclobutanone derivative. It is a surprising finding made by the present inventors that said intermediate in-situ generated haloketene also reacts with 2-halocyclobutanone already formed in the reactor in a 2-2 cycloaddition reaction to form impurities. The impurities so formed are the compounds of formulae A and B described hereinabove. Still more surprisingly, the present inventors have found that a process which avoided contact between the haloketene intermediate and the halocyclobutanone compound would inevitably result into negligible formation of impurities, which constitutes an embodiment of the present invention.

Therefore, in an aspect, the present invention provides an improved process for the preparation of a compound having formula I:


wherein X1 is halogen;
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; and

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;

said process comprising allowing an in-situ generated haloketene derivative to react with an alkene to form a 2-halocyclobutanone derivative having formula VI

wherein X, Y, R1, R2 are as defined above and “Z” is halogen;

wherein, said improvement comprises reacting said in-situ generated haloketene derivative with said alkene without contacting said 2-halocyclobutanone derivative of formula VI.

In an embodiment, X1 is a halogen selected from fluorine, chlorine, bromine and iodine. In another embodiment, X1 is a halogen selected from chlorine, bromine and iodine.

In an embodiment, Z is a halogen selected from fluorine, chlorine, bromine and iodine. In another embodiment, X1 is a halogen selected from chlorine, bromine and iodine.

In an embodiment, the precise manner of reacting said in-situ generated haloketene derivative with an alkene without contacting 2-halocyclobutanone derivative is not particularly limiting and may be carried out according to the instant invention in a plurality of ways, all of which form alternate embodiments of the present invention. Moreover, the selection of one of said plurality of manners does not preclude preventing the contact between haloketene and 2-halocyclobutanone concurrently through other manners contemplated according to the present invention.

In an embodiment, reacting said in-situ generated haloketene derivative with an alkene without contacting 2-halocyclobutanone comprises continuously removing said 2-halocyclobutanone immediately upon being formed in the reaction mixture. It has been surprisingly found that continuously removing 2-halocyclobutanone from the reaction system is achieved in a series of continuous flow stirred tank reactors or in a plug-flow reactor, wherein the forward flow of the fluid inside the reactor prevents 2-halocyclobutanone from contacting in-situ generated haloketene. Therefore, in this embodiment, reacting said in-situ generated haloketene derivative with an alkene without contacting 2-halocyclobutanone comprises reacting in-situ generated haloketene derivative with an alkene in a plurality of continuous-flow stirred-tank reactors placed in series or in a plug-flow reactor.

In another embodiment, reacting said in-situ generated haloketene derivative with an alkene without contacting 2-halocyclobutanone comprises reacting in-situ generated haloketene immediately upon being generated in the reaction mixture. In an embodiment, immediate consumption of in-situ generated haloketene in its said reaction with an alkene is achieved by using an excess of alkene in the reaction mixture in a continuous reactor such as a plurality of continuous flow stirred tank reactors placed in series or a plug-flow reactor. In this embodiment, use of an excess of alkene in the reaction mixture ensures that the in-situ generated haloketene concentration remains negligible throughout the reaction time and reacts with alkene instantly upon being generated. Therefore, in this embodiment, said step of reacting said in-situ generated haloketene derivative with an alkene without contacting 2-halocyclobutanone comprises reacting said in-situ generated haloketene with an excess of alkene, said reaction being carried out in a plurality of continuous flow stirred tank reactors placed in series or in a plug-flow reactor. In another preferred embodiment, said excess alkene may be an alkenic solvent such that it surprisingly also acts as a self-solvent for the reaction.

In one embodiment, the alkenic solvent may be isobutylene.

In another embodiment, reacting said in-situ generated haloketene derivative with an alkene without contacting 2-halocyclobutanone comprises allowing said in-situ generated haloketene and the reactant alkene a minimum possible residence time within said reactor. In this embodiment, said minimum residence time of the in-situ generated haloketene using selective flow velocities of the reaction mixture through a plurality of continuous flow stirred tank reactors placed in series or through a plug-flow reactor prevents reaction of the haloketene with the generated 2-halocyclobutanone surprisingly reducing the level of impurities formed along with the desired end product. Therefore, in this embodiment, reacting said in-situ generated haloketene derivative with an alkene without contacting 2-halocyclobutanone comprises reacting said in-situ generated haloketene derivative with an alkene in a plurality of continuous flow stirred tank reactors placed in series or in a plug-flow reactor, wherein said haloketene derivative or the starting materials thereof and alkene are fed into said plurality of continuous flow stirred tank reactors placed in series or into said plug-flow reactor at a predetermined minimum charging rate. In an embodiment, said predetermined minimum charging rate varies for each component such that the contact between the haloketene and 2-halocyclobutanone derivative is kept to a minimum.

In an embodiment, the trialklyl amine is fed to the plurality of continuous flow stirred tank reactors placed in series or in a plug-flow reactor at a charging rate varying from about 1 kg per hour to about 50 kg per hour, more preferably from about 5 kg per hour to about 25 kg per hour. In another embodiment, the trialkyl amine is fed to the plurality of continuous flow stirred tank reactors placed in series or in a plug flow reactor at a charging rate between about 15 kg per hour to about 25 kg per hour.

In an embodiment, the tetrahalo butyric acid halide derivative is fed to the plurality of continuous flow stirred tank reactors placed in series or in a plug-flow reactor at a charging rate varying from about 2.5 kg per hour to about 125 kg per hour, more preferably from about 12.5 kg per hour to about 75 kg per hour. In another embodiment, the tetrahalo butyric acid halide derivative is fed to the plurality of continuous flow stirred tank reactors placed in series or in a plug flow reactor at a charging rate between about 20 kg per hour to about 65 kg per hour.

In an embodiment, the excess alkenic solvent is fed to the plurality of continuous flow stirred tank reactors placed in series or in a plug-flow reactor at a charging rate varying from about 10 kg per hour to about 700 kg per hour, more preferably from about 70 kg per hour to about 350 kg per hour. In another embodiment, the excess alkenic solvent is fed to the plurality of continuous flow stirred tank reactors placed in series or in a plug flow reactor at a charging rate between about 200 kg per hour to about 350 kg per hour.

In another embodiment, reacting said in-situ generated haloketene derivative with an alkene without contacting 2-halocyclobutanone comprises allowing said in-situ generated haloketene and the reactant alkene a residence time within said reactor that is preferably less than 5 minutes to less than 180 minutes. In another embodiment, the residence time of the reacting materials within the plurality of continuous flow stirred tank reactors placed in series or within the plug-flow reactor is less than about 120 minutes, preferably less than about 60 minutes. In another embodiment, the in-situ haloketene is formed by reacting a tetra-substituted butyric acid halide (preferably a tetrahalobutyric acid chloride) with an amine. The olefin used in this embodiment of the invention also acts as a self-solvent for the reaction, which eliminates the need to externally add an organic solvent. The in-situ generated haloketene reacts with the olefin/alkene solvent in a 2-2 cycloaddition reaction to form a 2- halohalocyclobutanone of the formula II. The olefin may be an alkene and preferably an isobutylene. The amine may be an alkyl amine, preferably a 2-5 carbon compound, and in particular may be triethyl amine.

In another embodiment, reacting said in-situ generated haloketene derivative with an alkene without contacting 2-halocyclobutanone comprises reacting said substituted butyric acid halide with an alkene at an elevated pressure. It has been found that carrying out the reaction at an elevated pressure ensures a continuous excess of the alkene in the reaction system as well as maintains a negligible concentration of the in situ generated haloketene thereby avoiding the contact between the haloketene and the halocyclobutanone, which leads to surprising reduction in the quantity of the reaction impurities.

In an embodiment, the term elevated pressure is defined as carrying out the reaction between the alkene and halocyclobutanone at a pressure between about 2 atm to 15 atm. In another embodiment, the term elevated pressure is defined herein to denote a pressure between about 5 atm to about 10 atm.

In an embodiment, the reaction is carried out at an elevated temperature between 30-800C, more preferably between 40-700C.

In another embodiment, reacting said in-situ generated haloketene derivative with an alkene without contacting 2-halocyclobutanone comprises carrying out the reaction between haloketene and alkene in the absence of an externally added organic solvent. Conventionally, the reaction between the halobutyric acid halide and the alkene is carried out in a non-polar organic solvent such as hexane.

According to the present embodiment of the invention, it has been found that in the absence of an externally added non-polar organic solvent, the reactant alkene acts as a self-solvent for the reaction, which ensures a large excess of the alkene in the reaction system. It has further been found that the presence of the reactant alkene in a large excess in the reaction system maintains a negligible concentration of the halocyclobutanone in the reaction system and avoids the contact of the in-situ generated haloketene with halocyclobutanone, thereby leading to the generation of a surprisingly negligible quantity of the impurities.

In an embodiment, the process of the present invention leads to a surprisingly reduced generation of the impurity of formula A that is less than about 1% of the total weight of the 2-halocyclobutanone derivative. The quantity of the same impurity formed in an experimental batch process was at least about 6% of the total weight of the 2-halocyclobutanone derivative.

In an embodiment, the tetrahalobutyric acid halide may be formed by reacting a tetrahalobutyric acid with a halogenating agent. In an embodiment, the halogenating agent is thionyl halide, more preferably thionyl chloride although other halogenating agents are not excluded.

In an embodiment, the tetrahalo butyric acid is formed by reacting a tetrahalo butyronitrile with an inorganic acid such as sulphuric acid.

In an embodiment, the tetrahalo butyronitrile may be obtained by reacting an alkylnitrile having 1- 5 carbon atoms, such as acrylonitrile and an organic solvent which may act as halogen donor, such as carbon tetrahalides.

Therefore, in this aspect, the present invention provides an improved process for the preparation of dialkyl cyclopropyl carboxylic acid halide derivatives having formula I:

wherein X1 is halogen;
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; and

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;

said process comprising:
i) reacting acrylonitrile with a halogen donating organic solvent XI to obtain halo-substituted butyronitrile X;

wherein X and Y are as defined above and Z is halogen;

ii) reacting said halo-substituted butyronitrile X with an inorganic acid to form halo butyric acid IX;

iii) reacting said halo butyric acid IX with a halogenating agent to form halo butyric acid halide VIII; and

iv) reacting said halo butyric acid halide VIII with an alkene VII to form an in-situ generated haloketene derivative and allowing said in-situ generated haloketene derivative to react with an alkene to form 2-halocyclobutanone derivative VI;

wherein said improvement comprises reacting said haloketene generated in-situ in step (d) with said alkene without contacting said 2-halocyclobutanone derivative compound of formula VI.

In this aspect, the substituents X1, X, Y, Z, R1 and R2 are as defined hereinabove.

In another aspect of the invention, the conversion of tetrahalobutyric acid halide into 2-halocyclobutanone may in one embodiment be carried out in a plurality of continuous-flow stirred-tank reactors placed in series or in a plug-flow reactor.

In an embodiment of this aspect of the invention, said system of a plurality of continuous-flow stirred-tank reactors placed in series or a plug flow reactor may have, at least a central reaction zone, wherein the reaction zone may have at least an agitation means located centrally, additionally the reaction zone may have a plurality of baffles located around the sides of the reaction zone. The reactor may have at least one input nozzle and at least one output nozzle. The input nozzle of the first reactor conveys the reactants comprising an alkene, a tetrahalobutyric acid, and an amine to the central reaction zone.

On entering the reaction zone, the intermediate haloketene formed in-situ, in presence of the alkene, forms 2-halocyclobutanone. The reaction mixture moves to the subsequent reactor in the series through the output nozzle and the forward flow is received through the input nozzle of the subsequent reactor.

The flow rate of the reactants through the reactors is selected so as to allow 2-halocyclobutanone to be removed immediately upon formation. Preferably, the flow rates of the reactants are selected such that the reacting materials have a predetermined residence time within the reactor. The residence time of the reacting materials within the plurality of continuous flow stirred tank reactors placed in series or within the plug-flow reactor is less than about 180 minutes, preferably less than about 60-120 minutes.

However, in another embodiment, the reaction mixture may remain in a particular reactor of the plurality of continuous-flow stirred-tank reactors placed in series or in the plug-flow reactor for up to 180, preferably for less than about 60 minutes before being transferred to the next reactor in series or, in case of a plug-flow reactor, before being taken out of the reactor, as long as the in-situ generated haloketene does not come into contact with the halocyclobutanone, using any of the approaches described above for avoiding the contact between the haloketene and halocyclobutanone.

The 2-halocyclobutanone obtained from the outlet nozzle of the plug-flow reactor or from the last reactor in the continuous-flow stirred-tank reactor system may then be subjected to an aqueous wash in a static mixer, and then transferred to a phase separator so as to separate the 2-halocyclobutanone from the product mixture.

In an embodiment the 2-halocyclobutanone obtained from the phase separator may then be subjected to an isomerization reaction in presence of an amine and a suitable catalyst to form 4-halocyclobutanone.

In an embodiment, the 4-halocyclobutanone is subjected to a treatment with caustic soda to form a dihalo vinyl carboxylic acid salt, which upon treatment with acids such as sulphuric acid forms dihalo vinyl acid derivative. The dihalo vinyl acid derivative is then treated with thionyl halide to form the compound of the formula I.

Therefore, in another aspect, the present invention provides an improved process for the preparation of dialkyl cyclopropyl carboxylic acid halide derivatives having formula I:

wherein X1 is halogen;
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; and

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;

said process comprising:
(i) reacting acrylonitrile with a halogen donating organic solvent XI to obtain halo-substituted butyronitrile X;

wherein X and Y are as defined above and Z is halogen;
(ii) reacting said halo-substituted butyronitrile X with an inorganic acid to form halo butyric acid IX;

(iii) reacting the halo butyric acid IX with a halogenating agent to form halo butyric acid halide VIII;

(iv) reacting said halo butyric acid halide VIII with an alkylamine to form an in-situ generated haloketene derivative and allowing said in-situ generated haloketene derivative to react with an alkene to form 2-halocyclobutanone derivative VI;

(v) isomerizing said 2-halocyclobutanone derivative VI in presence of a catalyst to form a 4-halocyclobutanone derivative V;

(vi) reacting said 4-halocyclobutanone derivative V with an aqueous alkali to form a cyclopropyl carboxylic acid sodium salt of formula IV;

(vii) dehydrohalogenating said cyclopropyl carboxylic acid sodium salt of formula IV in a suitable reagent to obtain the compound III;

(viii) hydrolyzing the dihalo vinyl carboxylic acid salt compound of formula III with an acid to form a dihalo vinyl acid derivative II; and

(ix) treating the said dihalo vinyl acid derivative with a halogenating agent to form the compound of formula I;

wherein said improvement comprises reacting said haloketene generated in-situ in step (d) with said alkene without contacting said 2-halocyclobutanone derivative compound of formula VI.

In this aspect, the substituents X1, X, Y, Z, R1 and R2 are as defined hereinabove.

Description of the preferred embodiments

Turning now to Figure 1, illustrated is one of the reactors in a system of reactor system as described in Fig.1. In addition the present invention includes allowing an in-situ generated haloketene derivative to react with an alkene to form a 2-halocyclobutanone derivative having formula II.

With reference to Fig. 1 the vertical cylindrical reactor has reaction zone A which starts from the proximal end of the reactor to the distal end of the reactor and has a uniform circumference. The distal and proximal ends of the reactor are curved.

Reaction zone A may have baffles 11A and 11B that may be placed diametrically opposite each other around the walls of the reactor. The baffles may extend vertically along the entire length of the reaction zone.

Reaction Zone A has an agitator means, wherein the agitator means may be an impeller system B, wherein in one embodiment of the invention, the impeller B1 and B2 may be a pitch blade type impeller. Impeller system B is attached to motor C and gear box D by means of rod E, which runs along the entire length of the cylindrical part of the reactor to meet impeller system B which may be positioned at the distal and central ends of Zone A. The reactor vessel has inlet nozzles 1 and 2 placed on opposite shoulders of the proximal curved surface of the reactor. Inlet nozzles 1 and 2 introduce the reactants into the reactor. Inlet nozzles 1 and 2 have extended dip pipes that enable the reactants to be introduced just above impeller B1, thus allowing for maximum turbulence and mixing. An overflow nozzle 3 maybe placed on the side wall of the reactor, at the proximal end of the reaction zone, to siphon off any excess reactants. Outlet nozzle 4 may be placed in the center of the distal curved bottom of the reactor. Outlet nozzle 4 is used to evacuate the reactant mixture from the reactor and transfer the reactant mixture to the subsequent reactor in the system. Once the reaction mixture has passed through all the reactors of the system, the product mixture obtained may be transferred to a static mixer, G. The product mixture may be removed continuously or periodically at intervals. The flow velocity through reactors being selected so as to allow continuous removal of the product immediately upon being formed in the reaction mixture.

Nozzles 5 and 6 are utility inlet and outlet respectively used for absorption of excess heat from the reactor. Nozzles 8, 9 and 10 are thermowells provided to sense the temperature.

A heating means such as limpet coil E is placed around the outer surface of the reactor which corresponds to reaction zone A.

The reactor system in one of the embodiments may be used to manufacture 2-halocyclobutanone or dihalo vinyl acid derivative that is substantially free of impurities, particularly the impurities of formulae A and B.

Therefore, in another embodiment, the present invention provides a dihalo vinyl halide derivative compound of formula I, wherein said compound of formula I is substantially free of impurities.

In an embodiment, the impurities of the aforesaid aspect of the invention are the compounds of formula A and B.

Unless otherwise indicated, the compound of formula I being substantially free of impurities denotes the compound of formula I having less than 1% by weight of impurities.

In this particular embodiment, the 2-halocyclobutanone derivative of the formula II may be a 2-(2', 2’, 2’- trihalogenoethyl)-2-halocyclobutan-1-one. The process comprises providing using at least a plurality of continuous-flow stirred-tank reactors placed in series or a plug-flow reactor, wherein the reactor comprises at least a central reaction zone, at least an agitation means, a plurality of nozzles, a system of heating means and a plurality of baffles.

In the same embodiment, reactants comprising a tetrahalo butyric acid halide, an olefin, and a trialkyl amine, preferably triethylamine, are introduced into at least one reactor at a time through inlet nozzles 1 and 2. The olefin is preferably an alkene, most preferably isobutylene. The addition of the reactants is carried out in a predetermined ratio as mentioned above and therefore, in an embodiment, the reactor system has an automated system for addition of exactly pre determined moles of the reactants tetrahalo butyric acid halide, the trialkyl amine, the alkenic solventand the organic base. Also, the organic solvent may be added in excess, before the acid and the base are introduced into the reactor.

In one embodiment, the tetrahalo butyric acid halide is 2, 4, 4, 4-tetrochloro butyric halide. The aspects and embodiments described above are exemplified in the non-limiting examples following herein.

• Examples

Example 1:
As shown in Fig. 2 the introduced reactants were agitated in the reaction zone, by means of impeller system B, wherein, the reactants were introduced just above impeller blade B2.

In one embodiment, the tetrahalobutyric acid halide was reacted with an amine to form in-situ generated haloketene derivative. In the same embodiment, the immediate consumption of the in-situ generated haloketene derivative through its reaction with the alkene present in the reaction mixture was achieved by using an excess of alkene in the reaction mixture. The use of an excess of alkene in the reaction mixture ensured that the concentration of the in-situ generated haloketene derivative remained negligible throughout the reaction time within each reactor and reacted with alkene instantly upon being generated.

In the same reaction, the haloketene derivative formed in situ immediately reacted with the alkene to form the said 2-halocyclobutanone derivative. Immediately upon formation of the 2-halocyclobutanone derivative, the reactant mixture from the first reactor R1 in the series was transferred by means of connecting pipes (not shown) to R2 and so on, till the reactant mixture reached the last reactor in the series at a predetermined flow rate and after a predetermined residence time in each reactor in the series, so that the 2-halocyclobutanone derivative was immediately removed before it reacted with the in situ haloketene to form an impurity.

The product mixture was then moved to a static mixer G through the outlet nozzle 4 provided at the distal end of the last reactor in the series. Once introduced into the static mixer G, the product mixture was subjected to a water wash, and then sent to a phase separator H where, the product mixture separated into two layers, H1 and H2, wherein, the upper layer H1 being the 2-halocyclobutanone derivative. The upper layer so obtained comprised the 2-halocyclobutanone derivative dissolved in the excess alkenic solvent. The excess alkenic solvent was thereafter evaporated.

The 2-halocyclobutanone obtained from the separator may have traces of the solvents such as isobutylene, which was collected through evaporation. The collected isobutylene was reused in the production process. The organic salt obtained in lower layer H2 was triethyl amine hydrohalide in the form of slurry. The slurry was treated with water and the recovered triethyl amine was reused in the process.

Example 2 – Isolation of compound of formula A
The compound of formula A was isolated by column chromatography of the reaction mixture formed with the 2-halocyclobutanone derivative. The halocyclobutanone derivative was formed by reacting the halobutyric acid VIII with isobutylene in the presence of triethylamine. The in-situ generated haloketene was reacted with the alkene to form the 2-halocyclobutanone derivative VI mixture. This mixture of 2-halocyclobutanone derivative was subjected to crystallization by cooling such that the impurities of formulae A and B, more of formula A, were enriched in the filtrate. The filtrate mother liquor was concentrated further to prepare a concentrate mixture of the impurities. A column of 3.5 foot length and 3.0 cm diameter was taken. The column was filled with a slurry of 200 gm silica gel of 60-120 mesh size in hexane solvent. The slurry was then carefully poured into the column avoiding air bubbles. A mobile phase was prepared with a mixture of hexane and methylene dichloride in a ratio of 9:1. The mobile phase was rinsed completely through the column. About 15 gm of the concentrated mixture of the impurities was placed on top of the stationary phase. The mobile phase was slowly passed through the column to advance the two impurities through the column.

The individual impurities were retained by the stationary phase differently and separated from each other. They were also seen running at different speeds through the column with the eluent. The impurities were also seen to elute one at a time and were collected as different fractions. The composition of the eluent flow was monitored and each fraction analyzed for the impurities by GC. The individual impurities fractions were each 20-25 mL in volume. The impurities were non-polar and were collected at fractions numbers 7-12. The retention time of the impurity A was 22.5-22.6 minutes .

The two fractions were found to have greater than 98% purity for the impurities A and B. The solvent was removed from the eluted fractions by heating up to 550C and pressure of 2 torr. The impurities were in a liquid state. The individual impurities were analyzed and recorded.

Example 3
2-Halocyclobutanone derivative was used an intermediate for the preparation of dichlorovinyl acid chloride, which was used for preparing cypermethrin.

Batch 3A (batch mode):
Hexane was charged as a solvent in an pressure reactor. A known quantity of isobutylene was added. The mixture was heated to 620C and tetrachloro butyric acid chloride was added parallely to triethyl amine at a constant predetermined flow rate for about 6 hours. After completion of the reaction, isbutylene was vented out and absorbed in hexane and used as a feed for the subsequent batches. Subsequent to the venting out of isobutylene, the mixture was washed with water to remove triethyl amine hydrochloride salt in aqueous phase. Subsequently, a bicarbonate wash was done to remove acidity. The 2-halocyclobutanone derivative product was soluble in hexane. The batches were repeated successfully for batch sizes of 1000 L and 30,000 L.

Batch 3B (Continuous-flow stirred-tank reactor):
A pilot plant with 3 continuous-flow stirred-tank reactors placed in series was commissioned. Isobutylene, tetrachloro butyric acid chloride and triethyl amine were added in the first reactor in series. The residence time through each of the three reactors was monitored to be less than about 60 minutes to ensure complete conversion of tetrachloro butyric acid chloride. There was no hexane used in the process as isobutylene acted as a self-solvent for the reaction.

A water wash was done in the static mixer. The organic phase comprising 2-halocyclobutanone dissolved in isobutylene was separated from aqueous phase comprising triethyl amine hydrochloride in a provided phase separator. Isobutylene was recovered from the organic phase in a continuous manner to release the target product 2-halocyclobutanone in a molten form. A bicarbonate wash was done to remove acidity from the end product. The rate of production of 2-halocyclobutanone using this set up was about 80 kg/h.

Batch 3C (plug-flow reactor):
A pilot plant with a plug-flow reactor was commissioned. Isobutylene, tetrachloro butyric acid chloride and triethyl amine were charged in the reactor at a predetermined rate. The residence time through the reactor was monitored (to remain within about 60 minutes) to ensure complete conversion of tetrachloro butyric acid chloride. There was no hexane used in the process as isobutylene acted as a self-solvent for the reaction. The rate of production of 2-halocyclobutanone using this set up was again about 80 kg/h.

The molar quantities of the starting material and the end product TCBA-Cl in the batch mode and continuous mode were noted as hereunder:

Molar Quantity Batch 3A (Batch Process) Batch 3B (CSTR) Batch 3C (PFR)
TCBA-Cl 20 20 20
TEA 21 21 21
Isobutylene 140 200 200
Hexane 61 0 0
Formula A ≥ 6% ≤ 1% ≤ 1%

The process of the present invention therefore enabled complete elimination of the use of an organic solvent without compromising the yield, purity etc. of the target compounds.

Example 5 (Comparative example using the batch process):

TCBA-Cl-- 2-CB:
284 g of tetrachloro butyric acid chloride was reacted with 122 g of triethylamine in 580 g hexane. The reaction mixture was agitated at about 910 RPM while 240 g isobutylene was charged at 210C. The reaction mixture was maintained for one hour. At the end of the reaction, the reaction mixture was analyzed as follows: trichloro butyric acid chloride 0.66%; 4-halocyclobutanone 2.62%; 2-halocyclobutanone 73.06; formula A 7.29% and formula B 4.16%. It was thus concluded on comparison with Batches 3B and 3C that the process of the present invention led to a surprising reduction in the formation of impurities. The remaining process according to the instant invention was carried out as described hereinafter.

2-CB---4-CB:
232 g of 2-halocyclobutanone was taken in a charging vessel, to which about 600 g of hexane was added. The heating was continued for 2 hours, after which an azeotropic recovery of hexane was initiated. Hexane was completely recovered in an hour. The resulting product was analyzed, to give a product mixture as follows: 2-CB 1.30% and 4-CB 76.8% gm.

4-CB --- trichloro cyclopropyl carboxylic acid – sodium (Na-TCA):

254 g of Na-TCA was taken and about 70 g of caustic soda was added to it. Heating was continued for about 3-4 hours between 100-1100C at a pH between 7.5 to 10.5. At the end of the reaction, about 11 g of 4-CB remained in the reaction vessel as residue. The total quantity of Na-TCA was weighed around 744 g.

Na-TCA --- Na-DVA ---- DVA --- DVA-Cl:

The isolated quantity of Na-TCA was taken and alcoholic potassium hydroxide was added to it. Heating was continued for 3-5 hours at a temperature range of 100-1100C at a pH of 8.0 – 10.0. The resultant Na-DVA compound was separated and directly used for the preparation of DVA – Na.

About 1148 g of Na-DVA was taken, to which a desired quantity (about 190 mL level) of hydrochloric acid was added in 380 g of hexane. At the end of the reaction, about 974 g of DVA was separated. Importantly, about 90 g of muck (mainly comprising the impurities) was also separated for the sample using the batch process 3A described above.

The invention has been described above by way of illustration, and the specific embodiment disclosed is not intended to limit the invention to the particular forms disclosed. For example, the embodiments described in the foregoing were directed to providing a clear idea about the preferred modes, including the best mode, of making and using the present invention. However, in alternate embodiments, those skilled in the art may implement the invention without deviating from the central idea of the invention. The invention therefore covers all modifications, equivalents, and alternatives falling within the spirit and scope of the following claims:

We claim:

1. A 2-halocyclobutanone derivative of formula VI

;
or a 4-halocyclobutanone derivative of formula V

;

wherein 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;

Z is halogen; and

wherein said compounds of formula V or VI are substantially free of impurities, said impurities including compounds of formula A or formula B:

2. The 2-halocyclobutanone derivative or a 4-halocyclobutanone derivative as claimed in claim 1 comprising less than about 1% of said impurities.

3. Use of the 2-halocyclobutanone derivative or 4-halocyclobutanone derivative as claimed in claim 1 or claim 2 for the preparation of a dihalo vinyl carboxylic acid halide derivative that is substantially free of impurities.

4. A dihalo vinyl carboxylic acid halide derivative of formula I being substantially free of impurities:


wherein X1 is a halogen; 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; and

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

wherein said impurities include compounds of formula A and/or formula B:

5. The dihalo vinyl carboxylic acid halide derivative as claimed in claim 4 comprising less than 1% of said impurities of formula A and/or formula B.

6. Use of the dihalo vinyl carboxylic acid halide derivative of formula I as claimed in claim 4 or claim 5 for the preparation of a synthetic pyrethroid.

7. A synthetic pyrethroid compound prepared using the dihalo vinyl carboxylic acid halide derivative of formula I as claimed in claim 4 to claim 7.

8. A process for the preparation of a compound having formula I:


wherein X1 is halogen;
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; and

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;

said process comprising allowing an in-situ generated haloketene derivative to react with an alkene to form a 2-halocyclobutanone derivative having formula VI

wherein X, Y, R1, R2 are as defined above and “Z” is halogen;

wherein, said improvement comprises reacting said in-situ generated haloketene derivative with said alkene without contacting said 2- halocyclobutanone derivative of formula VI.

9. The process as claimed in claim 8, wherein said haloketene is generated by reaction of a halobutyric acid halide VIII

with trialkylamine.

10. The process as claimed in claim 9, wherein said haloketene is generated in-situ during the reaction between halo butyric acid halide VIII with an alkene VII, said reaction being carried out in the presence of triethylamine, wherein said halobutyric acid halide reacts with triethylamine to generate haloketene, said haloketene further reacting with the alkene to form 2-halocyclobutanone derivative VI:

11. The process as claimed in claim 10, wherein the halobutyric acid halide VIII is formed by reacting a halobutyric acid IX with a chlorinating agent:

12. The process as claimed in claim 11, wherein said halobutyric acid IX is formed by reacting a halo-substituted butyronitrile X with an inorganic acid:

13. The process as claimed in claim 12, wherein said halo-substituted butyronitrile X is formed by reacting acrylonitrile with a halogen donating organic solvent XI:


14. The process as claimed in claim 8, comprising isomerizing said 2-halocyclobutanone derivative VI to form a 4-halocyclobutanone derivative V:
.
15. The process as claimed in claim 14 comprising reacting said 4-halocyclobutanone derivative V with an alkali to form a cyclopropyl carboxylic acid sodium salt of formula IV:

16. The process as claimed in claim 15 comprising dehydrohalogenating said cyclopropyl carboxylic acid sodium salt of formula IV in a suitable reagent to obtain the compound III;

17. The process as claimed in claim 16, wherein said suitable reagent is alcoholic alkali metal hydroxide.

18. The process as claimed in claim 16 comprising hydrolyzing said dihalo vinyl carboxylic acid salt compound of formula III with an acid to form a dihalo vinyl acid derivative II:

19. The process as claimed in claim 18 comprising treating said dihalo vinyl acid derivative II with a halogenating agent to form the compound of formula I;

20. The process as claimed in claim 8, wherein X1 and Z are both halogen atoms, each being individually selected from F, Cl, Br and I.

21. The process as claimed in claim 8 wherein reacting said in-situ generated haloketene derivative with an alkene without contacting 2-halocyclobutanone comprises continuously removing said 2-halocyclobutanone immediately upon being formed in the reaction mixture.

22. The process as claimed in claim 21 wherein said continuously removing said 2-halocyclobutanone immediately upon being formed in the reaction mixture comprises reacting the in-situ generated haloketene derivative with an alkene in a plurality of continuous-flow stirred-tank reactors placed in series or in a plug-flow reactor.

23. The process as claimed in claim 22, wherein the forward flow of the reaction mixture inside the plurality of continuous-flow stirred-tank reactors or inside the plug-flow reactor prevents 2-halocyclobutanone from contacting the in-situ generated haloketene.

24. The process as claimed in claim 8, wherein reacting said in-situ generated haloketene derivative with an alkene without contacting 2-halocyclobutanone comprises reacting in-situ generated haloketene immediately upon being generated in the reaction mixture.

25. The process as claimed in claim 8 or claim 24 comprising reacting said in-situ generated haloketene with an excess of alkene.

26. The process as claimed in claim 8 or claim 24 or claim 25 wherein said reaction is carried out in a continuous reactor.

27. The process as claimed in claim 26, wherein said continuous reactor is a plurality of continuous-flow stirred-tank reactors placed in seriesor a plug-flow reactor.

28. The process as claimed in claim 8, wherein reacting said in-situ generated haloketene derivative with an alkene without contacting 2-halocyclobutanone comprises maintaining a negligible concentration of haloketene during the reaction.

29. The process as claimed in claim 8 or claims 24-28, wherein said alkene is an alkenic solvent.

30. The process as claimed in claim 29, wherein said alkene is isobutylene.

31. The process as claimed in claim 8, wherein reacting said in-situ generated haloketene derivative with an alkene without contacting 2-halocyclobutanone comprises allowing said in-situ generated haloketene and the reactant alkene a predetermined minimum residence time within said reactor.

32. The process as claimed in claim 31, wherein said predetermined minimum residence time is less than 180 minutes.

33. The process as claimed in claim 31, wherein said step of allowing said in-situ generated haloketene and the reactant alkene a predetermined minimum residence time within said reactor comprises reacting the haloketene with an alkene in a continuous reactor, wherein said haloketene derivative and alkene are fed into said continuous reactor at a predetermined minimum charging rate.

34. The process as claimed in claim 33, wherein said predetermined minimum charging rate is:

(a) trialkylamine charged at a rate of about 1 kg per hour to about 50 kg per hour;
(b) tetrahalobutyric acid halide derivative charged at a rate of about 2.5 kg per hour to about 125 kg per hour; and
(c) alkenic solvent charged at a rate of about 10 kg per hour to about 700 kg per hour.
35. The process as claimed in claim 8, wherein said reacting the in-situ generated haloketene derivative with an alkene without contacting 2-halocyclobutanone comprises reacting said substituted butyric acid halide with an alkene at an elevated pressure.

36. The process as claimed in claim 35, wherein the elevated pressure is a pressure between 2 atm to 15 atm.

37. The process as claimed in claim 8, wherein reacting said in-situ generated haloketene derivative with an alkene without contacting 2-halocyclobutanone comprises carrying out the reaction between haloketene and alkene in the absence of an externally added organic solvent.

38. An improved process for the preparation of dialkyl cyclopropyl carboxylic acid halide derivatives having formula I:

wherein X1 is halogen;
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; and

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;

said process comprising:
(a) reacting acrylonitrile with a halogen donating organic solvent XI to obtain halo-substituted butyronitrile X;

wherein X and Y are as defined above and Z is halogen;

(b) reacting said halo-substituted butyronitrile X with an inorganic acid to form halo butyric acid IX;

(c) reacting the said halo butyric acid IX with a chlorinating agent to form halo butyric acid halide VIII;

(d) reacting said halo butyric acid halide VIII with an alkene VII to form an in-situ generated haloketene derivative and allowing said in-situ generated haloketene derivative to react with an alkene to form 2-halocyclobutanone derivative VI;

(e) isomerizing said 2-halocyclobutanone derivative VI in presence of a catalyst to form a 4-halocyclobutanone derivative V;

(f) reacting said 4-halocyclobutanone derivative V with sodium hydroxide to form a cyclopropyl carboxylic acid sodium salt of formula IV;

(g) dehydrohalogenating said cyclopropyl carboxylic acid sodium salt of formula IV in a suitable reagent to obtain the compound III;

(h) hydrolyzing the said dihalo vinyl carboxylic acid salt compound of formula III with an acid to form a dihalo vinyl acid derivative II; and

(i) treating the said dihalo vinyl acid derivative with a halogenating agent to form the compound of formula I;

wherein said improvement comprises reacting said haloketene generated in-situ in step (d) with said alkene without contacting said 2-halocyclobutanone derivative compound of formula VI.

39. The process as claimed in claim 38, wherein said improvement in reacting haloketene with the alkene without contacting the halocyclobutanone derivative comprises carrying out the reaction such that the reaction parameters satisfy at least one of the following conditions:
(a) continuously removing said 2-halocyclobutanone immediately upon being formed in the reaction mixture;
(b) reacting the in-situ generated haloketene derivative with an alkene in a continuous-flow stirred-tank reactor or in a plug-flow reactor;
(c) reacting the in-situ generated haloketene immediately upon being generated in the reaction mixture;
(d) reacting the in-situ generated haloketene with an excess of alkene;
(e) maintaining a negligible concentration of haloketene during the reaction;
(f) allowing the in-situ generated haloketene and the reactant alkene a predetermined minimum residence time within said reactor;
(g) reacting the haloketene with an alkene in a continuous reactor, wherein said haloketene derivative and alkene are fed into said continuous reactor at a predetermined minimum charging rate;
(h) reacting said substituted butyric acid halide with an alkene at a high pressure; and
(i) reacting the haloketene and alkene in the absence of an externally added organic solvent.

40. The process as claimed in claim 14 or claim 38 wherein said process comprises:
(a) isolating the 2-halocyclobutanone derivative prior to isomerizing it to produce 4-halocyclobutanone derivative;
(b) dissolving a sample of the isolated 2-halocyclobutanone derivative in a solvent to produce a sample solution;
(c) dissolving a sample of the compound of the formula A having the structure:


or a compound of the formula B having the structure:

in a solvent to product a reference marker standard solution; and
(a) assaying said sample of the isolated 2-halocyclobutanone derivative for the presence of compound A or compound B to determine the purity of the isolated 2-halocyclobutanone; and
(b) utilizing isolated 2-halocyclobutanone samples having a minimum chemical purity of 80% for isomerization to 4-halocyclobutanone derivative.

41. A compound of formula A:

wherein Z is a halogen selected from F, Cl, Br and I.

42. The compound of formula A as claimed in claim 41 in a substantially pure form.

43. A compound of formula B:

wherein Z is a halogen selected from F, Cl, Br and I.

44. The compound of formula B as claimed in claim 43 in a substantially pure form.

45. A method for testing the purity of a sample of a halocyclobutanone derivative, said method comprising:
(c) dissolving a sample of a halocyclobutanone derivative in a solvent to produce a sample solution;
(d) dissolving a sample of the compound of the formula A having the structure:


or a compound of the formula B having the structure:

in a solvent to product a reference marker standard solution; and
(e) assaying said sample of halocyclobutanone derivative for the presence of compound A or compound B to determine the purity of the halocyclobutanone sample.

46. A reactor system for the preparation of 2-halocyclobutanone derivative, said reactor system comprising a plurality of continuous-flow stirred-tank reactors placed in series or a plug-flow reactor , each said reactor comprising:
(a) at least a central reaction zone;
(b) at least an agitation means; at least one input nozzle and at least output nozzle, said input nozzle of first said reactor being capable of receiving the reaction mixture comprising an alkene, a tetrahalobutyric acid or a tetrahalobutyric acid halide, and an amine and conveying the received reaction mixture into said central reaction zone, the output nozzle of each preceding reactor being connected to the input nozzle of the subsequently placed reactor in series so as to allow the resultant reaction mixture from each said preceding reactor to flow into the input nozzle of the subsequently placed reactor in the series, the flow velocity through said reactors being selected so as to allow continuous removal of said 2-halocyclobutanone derivative immediately upon being formed in the reaction mixture;
(c) at least a static mixer connected to the outlet nozzle of the last reactor in the series; and
(d) at least a phase separator connected to the said static mixer.

47. The reactor system as claimed in claim 46, wherein said central reaction zone comprises at least an agitation means located centrally.

48. The reactor system as claimed in claim 46 or claim 47 wherein the central reaction zone comprises a plurality of baffles located around the sides of the reaction zone.

ABSTRACT

An improved process for the manufacture of dialkyl cyclopropyl carboxylic acid halide derivatives and a reactor system for the same.