FIELD OF THE INVENTION

The present invention relates to process for preparing SGLT2 inhibitor intermediate, 2-chloro-5-iodobenzoic acid, by iodination of 2-cholorobenzoic acid. The present invention further relates to a process for preparing a pharmaceutically acceptable form of 2-chloro-5-iodobenzoic acid with purity not less than 99.8% and not greater than 99.95%.

BACKGROUND OF THE INVENTION

Type 2 diabetes is a progressive disease typically requiring multiple medications in order to control blood glucose levels. In 1969, it was established that the mechanism for the intestinal glucose absorption is dependent on Sodium Glucose cotransport. This discovery led to active research in Sodium-glucose cotransporter-2 (SGLT2) inhibitors. SGLT2 inhibitors, also called as Glifozins, are a class of drugs used in the treatment of type 2 diabetes (T2D). SGLT2 inhibitors are the latest class of anti-hyperglycemic agents to receive U.S. Food and Drug Administration (FDA) approval. SGLT2 inhibitors function through a novel mechanism of reducing renal tubular glucose reabsorption, producing a reduction in blood glucose without stimulating insulin release. Other benefits may include favorable effects on blood pressure and weight concerns that have led to multiple FDA advisories for SGLT2 inhibitors.

Three drugs have been accepted by the Food and Drug Administration (FDA) in the United States; dapagliflozin, canagliflozin and empagliflozin. Canagliflozin was the first SGLT-2 inhibitor that was approved by the FDA, being accepted in March 2013. Dapagliflozin and empagliflozin were accepted in 2014. Other drugs in this category is Ertuglifozin and Sotaglifozin in the pipeline.

As the requirement for GLIFOZINS has risen around the world, the demand for the common intermediate 2-chloro-5-iodobenzoic acid has tremendously increased. Hence, it is very important for industry to arrive at a cost-effective process for the manufacture of 2-chloro-5-iodobenzoic acid.

There are several methods available in the literature for the synthesis of 5-iodo- 2R-benzoic acid (Where R= alkyl, F, Cl, Br) substituents. 2-R-5-iodobenzoic acid (where R=methyl, ethyl etc.) is known to be obtained when 2-alkyl benzoic acid is treated with iodine in presence of sodium nitrite and fuming sulfuric acid (Journal of Indian Chemical Society, 503-504, 1930). The same compound can also be obtained when the substrate is treated with potassium iodide in the presence of thallium trifluoroacetate. However, the yield in the above methods has been in the range of 18-20%, therefore, the methods are not suitable for industrial scale production of product. Furthermore, the large amounts of residual sulfuric acid and sodium nitrite makes the product inappropriate for pharmaceutical purposes.

Other possible approaches for iodination of aromatic compounds include: i. Sandmeyer Reaction in which the aromatic amine is subjected to diazo removal and iodination (Organic Synthesis, Collective vol. II, 351, 1943), ii. Trans halogenation or Haloform reaction where chlorination or bromination is performed, followed by substitution of Cl or Br by Iodine (Organic Synthesis Collective Vol V, 1973, p 478), iii. The method employing iodine monochloride (Russian Journal of Organic Chemistry, 34, 7, 1998, 997-999), and iv. Methods in which iodine and sodium per iodate are employed in the presence of acid catalyst (Bulletin of the Chemical Society of Japan, Vol 73, 951-956, 2000).

In method for synthesis of 2-chloro-5-iodobenzoic acid through the aforementioned Sandmeyer process, involves use ofanthranilic acid (a narcotic) as the key starting material which is a classified chemical and difficult to obtain. Further, a multi-step reaction including nitration, reduction, diazotization, and diazo removal chlorination must be performed. Steps such as nitration and diazotization are problematic as they raise safety issues, making the overall process very cumbersome. In addition the method employsuse of sodium iodide, potassium iodide, or similar iodine compound in excessive amounts for introduction of iodine, subsequent removal of excessive unutilized iodine compound must be separated and collected after completion of reaction through burdensome steps, thereby increasing the production cost. Moreover, these iodides must be preprepared as opposed to elemental iodide which is readily available. Further, there are chances of increased amounts of impurities if the separation process is not carried out carefully which again makes the final product not suitable for pharmaceutical purposes.

Although the method employing iodine monochloride is a simple and can be carried out through single reaction step, when iodine monochloride is reacted with an aromatic compound having an electron attractive group such as benzoic acid compound, high electron efficiency cannot be attained, due to low reactivity. The aforementioned method employing iodine monochloride describes the iodination of benzoic acid with an overall yield of 43% of 3-iodobenzoic acid. The low yield and the presence of impurities in the form of multiple iodinated products and starting material is unsatisfactory. When this method was applied to 2- chloro benzoic acid good yield was difficult to obtain and purification was cumbersome. Iodination methods employing elemental iodine and an oxidizing agent such as iodic acid or periodic acid are conventionally known. For example, in the method wherein iodine and sodium periodate are employed in the presence of an acid catalyst (Bulletin of Chemical Society of Japan (Vol. 73, 951-956, 2000), a comparatively high electron reaction efficiency can be attained even when the aromatic compound having an electron attractive group is reacted. Nonetheless, the method employs large amount of sulfuric acid which is toxic and poses environmental issues when disposing chemicals after synthesis in industrial production. Further, the method employs periodate which is an expensive material which makes the overall process awfully expensive.

JP2003270652A discloses a similar method for iodination of 2-methyl benzoic acid byreacting it with iodine and periodic acid in the presence of an acid catalyst, thereby producing mono iodinated benzoic acid compound. However, the product yield obtained is only 50-60% which is unsatisfactory. Inaddition the maximum purity obtained under controlled conditions is only 95% and in commercial level it is lower than 80%. Thus, in order to obtain high purity product, additional purification stepsare required. A considerable amount of the product still remains in the mother liquor after recovery of the pure product which adds to the cost. Since mother liquor also contains sulfuric acid serving as catalyst and other high boiling point compounds, separation and recovery of the product is difficult. The above citation discloses a technique of recycling the mother liquor in the reaction system, but the purity of the product decreases below 90%. Thus, recycling is not considered as an appropriate option. Said method includes an improved step, but still is not suitable for industrial scale production and the process cost remains to be improved.

When a similar process described above is employed for the synthesis of 2-chloro- 5-iodobenzoic acid from 2-chloro benzoic acid, one obtains substantial amount of 2-chloro-3-iodobenzoic acid as impurity which is an isomer of the iodo-chloro benzoic acid along with 2-chloro-3,5-diiodobenzoic acid impurities and certain unknown impurities with longer retention time. Since these isomers are difficult to separate from 2-chloro-5-iodobenzoic acid by normal conventional crystallization method, it is difficult to obtain compound of high purity useful in pharmaceutical application especially in the synthesis of Dapaglifozin, Canaglifoxin and Ertuglifozin and Sotaglifozin. The product purity and isolation yield are problematic and unsatisfactory. The above mentioned conventional techniques used in the synthesis of 2-methyl-5-iodo benzoic acid does not suggest reduction in amounts of undesired isomers when applied to the synthesis of 2- chloro-5-iodobenzoic acid.

CN106748721A discloses a method for preparing 2-chloro-5-iodobenzoic acid using cheap O-chloro-benzoic acid as the starting material through nitrification, reduction, diazotizing iodo. However, the method employs a lengthy procedureinvolving several reactions steps, and operational inconvenience. The solvent used in the method is concentrated sulfuric acid which is toxic. Further, several steps of the method such as nitrification reaction and diazotizing iodide reactionrequires to be carried out and controlled at very low temperatures such as -10°C~50 °C, preferably-5°C~5°C which is inefficient and uneconomical. This makes the industrial scale production very expensive with purity of only 99.6% of final 2-chloro-5-iodobenzoic acid and no defined impurities.

CN 110078613A discloses a method for synthesis of 2-halo-5-iodobenzoic acid by iodinating 2-halogenbenzoic acid in a single step. The method employs sulfuric acid as organic solvent and the mass ratio of the o-halobenzoic acid to the amount of sulfuric acid is in the range of 1:0.5-50, which is again excess use of toxic sulfuric acid as a solvent which makes the process less environmental friendly. Further, the method employs an oxidant and iodine for iodination of 2- halogenbenzoic acid. The oxidant is potassium periodate, sodium periodate, potassium iodate, sodium iodate, and iodic acid. The method further provides a product of 2-chloro-5-iodobenzoic acid with only 99.1-99.3% purity with impurities of 3-iodo-2-halo-benzoic acid, 5-diiodo-2-halo-benzoic acid etc. The final product is therefore not suitable for pharmaceutical purposes where the purity levels need to be higher and the process further needs to be feasible for industrial production.

There have already been known some techniques for site specific iodination of aromatic compound e.g., methods including reacting iodine monochloride with an aromatic compound in the presence of Zeolite (Catalysis Tetters, 40, 257, 1996) and methods including oxy-iodination of aromatic compounds in the presence of zeolite (Japanese Patent Application Taid-Open (kokai) No. 59- 219241 and No. 1-502819). However, in employment of these methods or any of these methods for the synthesis of 2-chloro-5-iodobenzoic acid, selectivity of the reaction is not always satisfactorily altered. In addition, there are very few reports about such reaction of compounds each having plurality of substituents and an electron attractive group.

Thus none of the conventional techniques or prior art cited provide an effective and simple method for producing 2-chloro-5-iodobenzoic acid which attains high selectivity, high yield at industrial scale production with high purity for pharmaceutical purposes.

OBJECT(S) OF THE INVENTION

Accordingly, the present invention takes into account the drawbacks of the prior art and provides an invention with the main object of providing a novel process for preparing and purifying SGTT2 inhibitor intermediate 2-chloro-5-iodobenzoic acid of formula II, wherein, thecrude crystalline precipitate of formula II obtained has yield 65.0 - 68.5% and purity in the range of 95.5% - 98.6%%; the purified product of formula II obtained has yield60 to 65%yield and purity of 95.5-99.7%; and pharmaceutically accepted product of formula II is obtained with 56.25-59.5% yield and purity not less than 99.8% and not greater than 99.95%.

Another object of the present invention is to provide a novel process for preparing and purifying formula II using 2-chlorobenzoic acid of formula I as the starting material, wherein, the process involves a single step reaction for conversion of formula I to formula II in the presence of iodine, a solvent, an oxidizing agent, and a dehydrating agent as depicted below in the reaction:

Yet another object of the invention is provide a novel process for preparing and purifying formula II with high yield and purity at industrial scale, wherein, the process involves iodination of formula I, iodine sublimation, precipitation of crude formula II to form crystalline precipitate, purification of crude crystalline precipitate of formula II by recrystallization in mixture of acetic acid and water, and producing a pharmaceutically acceptable form of formula II by recrystallization using hydrocarbon solvents or aliphatic hydrocarbons solvent, preferably toluene.

Yet another object of the invention is provide a novel process for preparing a pharmaceutically acceptable form of formula II with purity not less than 99.8% and not greater than 99.95%, and 2-chloro-3-iodobenzoic acid impurity not less than 0.005% and not greater than 0.1%, formula I impurity not less than 0.005% and not greater than 0.1%;2,5-dichlorobenzoic acid impurity not less than 0.005% and not greater than 0.3%;2-chloro3,5-diiodobenzoic acid impurity not less than 0.005% and not greater than 0.5%;Impurities such as iodine, inorganic salts, transition metal compounds, metal oxidesin the range of 500ppm or less, and any other unidentified impurity below 0.005%.

Yet another object of the invention is provide a novel process for preparing and purifying formula II with high yield and purity at industrial scale with simple and economical procedure without use of expensive solvents such as concentrated sulfuric acid which is also toxic to environment if used in excess amounts.

Yet another object of the invention is provide a novel process for preparing and purifying formula II with high yield and purity using iodine alone for iodination of formula I which is cheap and easy to procure for industrial production, further the process eliminates the requirement of expensive forms of iodine salts such as sodium iodide, potassium iodide which increase the production cost.

SUMMARY OF THE INVENTION

In the main embodiment of the invention, provides a novel process for preparing and purifying SGLT2 inhibitor intermediate 2-chloro-5-iodobenzoic acid of formula II using 2-chlorobenzoic acid of formula I as the starting material. The process for preparing formula II from formula I is a single step reactionas depicted in the reaction below:

The process comprises steps of: a) Iodinating formula I by forming a reaction mixture comprising formula I, iodine, a solvent, and an oxidizing agent to form formula II, wherein, the solvent is acetic acid, formic acid, propionic acid, butyric acid, iso-butyric acid, or any other straight chain aliphatic organic acid, preferably acetic acid; the oxidizing agent is hydrogen peroxide, sodium persulfate, ammonium persulfate, sodium borate, sodium chlorate, sodium perborate, nitric acid iodic acid and/or periodic acid, preferably ammonium persulfate; b) Heating the reaction mixture during iodination at high temperatures of about 50-60°C and simultaneously slowly adding a dehydrating agent to the reaction mixture to remove water content, wherein, the dehydrating agent is sulfuric acid; c) Carrying out iodine sublimation by heating the reaction mixture to form an off white to yellow colored crude product of formula II in the solvent suspension; d) Obtaining crude crystalline precipitate of formula Ilby slowly cooling the solvent suspension containing the crude product by adding demineralized water; e) Filtering, washing and drying the crude crystalline precipitate of formula II; f) Drying the crude crystalline precipitate of formula II to obtain crude formula II crystals; g) Carrying out first round of purification of crude formula II crystals using a mixture of acetic acid and water and obtaining purified product of formula II by recrystallization at low temperature; and h) Carrying out second round of purification for obtaining a pharmaceutically acceptable product of formula II of high purity by recrystallization of purified product of formula II using hydrocarbon solvents or aliphatic hydrocarbons solvent, preferably toluene.

In the present invention, the dried crude crystalline precipitate of formula Ilis obtained with 65-68.5% yield, and 92-95% conversion. The purity of the crystals in terms of 2-chloro-5-iodobenzoic acid is around 95.5-98.6%.

In another embodiment, the invention provides a process for obtaining purified product of formula II with yield 60-65% and purity in the range of 95.5-99.7% using formula I as the starting material in a single step reaction.

In another embodiment, the invention provides a process for obtaining a pharmaceutically accepted product of formula II withyield 56.25-59.5% and purity not less than 99.8% and not greater than 99.95% using formula I as the starting material in a step reaction. The invention further provides pharmaceutically accepted product of formula II with impurity profile of 2- chloro-3-iodobenzoic acid impurity not less than 0.005% and not greater than 0.1%, formula I impurity not less than 0.005% and not greater than 0.1%, 2, 5- dichlorobenzoic acid impurity not less than 0.005% and not greater than 0.3%, 2- chloro3,5-diiodobenzoic acid impurity not less than 0.005% and not greater than 0.5%, iodine, inorganic salts, transition metal compounds, metal oxidesin the range of 500ppm or less, and any other unidentified impurity below 0.005%.

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described hereinafter with reference to the detailed description, in which some, but not all embodiments of the invention are indicated. Indeed, the invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. The present invention is described fully herein with nonlimiting embodiments and exemplary experimentation.

The industrial process of the present invention for producing 2-chloro-5- iodobenzoic acid of formula Ilusing 2-chlorobenzoic acid of formula I as the starting materialincludes, as essential steps, an iodination reaction step of formula I, and a purification step including sublimation, distillation, crystallization or a combination of two or more of thesewhereby high purity product of 2-chloro-5-iodo benzoic acid is obtained.

In the main embodiment, the present invention provides a process for preparing and purifying SGTT2 inhibitor intermediate 2-chloro-5-iodobenzoic acid of formula II using 2-chlorobenzoic acid of formula I as the starting material. The process for preparing formula II from formula I is a single reaction step as depicted below

The process for preparation and purification of formula II comprises the steps of: a) Iodination of formula I byforming a reaction mixture by combining formula I with iodine in a solvent in the presence of an oxidizing agent to obtain formula II; b) Heating the reaction mixture during iodination at high temperatures of about 50-60°C and simultaneously slowly adding a dehydrating agent to the reaction mixture to remove water content; c) Carrying out iodine sublimation by heating the reaction mixture containing the dehydrating agent in step ii to form an off white to yellow colored crude product of formula II in the solvent suspension; d) Obtaining crystalline precipitate of crude product of formula II by slowly cooling the solvent suspension containing the crude product by adding demineralized water; e) Filtering, washing and drying the crude crystalline precipitate of formula II; f) Carrying out first round of purification of crude formula II crystals using a mixture of acetic acid and water and obtaining purified product of formula II by recrystallization at low temperature; and g) Carrying out second round of purification for obtaining a pharmaceutically acceptable product of formula II of high purity by recrystallization of purified product of formula II using hydrocarbon solvents or aliphatic hydrocarbons solvent, preferably toluene.

In the present invention, no limitation is imposed on the purity or grade of 2- chlorobenzoic acid of formula I which serves as the starting. However, the purity of formula I is preferably 98% or higher by HPLC analysis to enhance the purity of the final product. Furthermore, the purity of formula I is limited to the presence to 2,5-dichlorobenzoic acid at 0.2 to 0.5% by HPLC analysis having an UV-Vis detector operating at 240nm.

In the present invention, for iodination of formula I, a reaction mixture is formed by combining formula I with iodine in a solvent in the presence of an oxidizing agent to obtain formula II, wherein, iodine is taken in an amount of 0.5-1.5 parts by weight with respect to 1 part by weight of formula I for forming the reaction mixture, preferably 1.0 to 1.5 parts with respect to 1 part by weight of formula I. In the present invention, the solvent used in forming the reaction mixture for iodination of formula Ineeds to be inert with respect to iodination, and examples of organic solvent include acetic acid, formic acid, propionic acid, butyric acid, iso-butyric acid, or any other straight chain aliphatic organic acids, trifluoroacetic acid, dichloromethane, tetrachloroethane, dichlorobenzene, and chlorobenzene. However, in the present invention acetic acid is particularly employed as the solvent to carry out the iodination reaction of formula I. Further, the solvent is taken in an amount of 1-100 parts by weight with respect to 1 part by weight of formula I for forming the reaction mixture, more preferably 1-50 parts by weight with respect to 1 part by weight of formula I. Another solvent that may be preferably employed is propionic acid.

The iodination reaction proceeds through the exclusive use of iodine. However, since a formula I has an electron attractive group it has poor reactivity. Therefore, the reactivity is enhanced through the addition of an oxidizing agent and a dehydrating agent in combination.

In the present invention, iodination of formula lis carried out in the presence of an oxidizing agent to obtain formula II, wherein, the oxidizing agent in the reaction mixture is hydrogen peroxide, sodium persulfate, ammonium persulfate, sodium borate, sodium chlorate, sodium perborate, nitric acid iodic acid and/ or periodic acid, preferably ammonium persulfate. Further, the oxidizing agent is taken in an amount of 0.01-1 part by weight with respect to 1 part by weight of iodine for forming the reaction mixture, preferably 0.05-0.5 parts by weight with respect to 1 part by weight of iodine, for iodination of formula I. Further, the oxidizing agent may be in the form of solid or in the form of a solution or suspension with an appropriate solvent. During the course of iodinationreaction step, water is generated. Hence, addition of a dehydrating agent aids in removal of the water generated and this promotes high conversion of formula I to formula II in terms of yield. The dehydrating agent preferably should interact exclusively with water and should not react with other components in the reaction mixture. Examples of dehydrating agent include inorganic compounds such as sodium sulfate anhydrous, magnesium sulfate anhydrous, calcium chloride anhydrous, acid anhydrides such as acetic anhydride, propionic anhydride, pyruvic anhydride, phthalic anhydride or inorganic acids like sulfuric acid. Among them, acetic anhydride enjoys the privilege from the viewpoint of ease of separation and purification after reaction. However, the compound falls under the narcotic category and hence it is not available easily for industry application in large quantities. Moreover, the consumption must be documented and presented to the regulatory authorities making it less attractive for industrial application. Hence the preferred dehydrating agent is sulfuric acid because it is cheap and easily available and can be removed from reaction mixture by the addition of a base.

In the present invention, during the iodination of formula I the reaction mixture is heated to 50-60°C and simultaneously a dehydrating agent is added to the reaction mixture slowly. The dehydrating agent is sulfuric acid. Further, the dehydrating agent is added to the reaction mixture in an amount of 0.01-2 parts by weight with respect to 1 part by weight of formula I, preferably 0.1 to 1.5 parts by weight with respect to 1 part by weight of formula I.

Through controlling the amount of sulfuric acid so as to fall within the above range, a sufficient reaction promoting effect can be attained, whereby conversion of formula I to formula II is enhanced. Thus, formula II can be produced at low cost without increasing load of separation/ recovery during the purification step. Notably, in the case in which iodine and ammonium persulfate or similar species is dissolved or suspended in water and the solution or suspension placed in a reactor the dehydrating agent must be added in an amount in excess of the above amount in order to remove water forming the solution or suspension.

In the present invention, the reaction temperature is 50°C to 150°C, preferably 70-120°C. Through controlling the reaction temperature so as to fall within the ranges, sufficient rate of reaction can be attained while side reaction such as the formation of high boiling point substances is prevented. The reaction pressure (absolute pressure) is 0.005 to 2 MPa, preferably 0.01 to 1 MPa.

In the present invention, no particular limitation is imposed on the mode of iodination reaction and iodination of formula I may be carried out in a batch manner, semi batch manner, a complete mixed flow manner, a flow on immobilized bed manner etc. The mode of reaction may be selected in accordance with the production scale. In the case of small scale production a batch manner is appropriate, whereas in the case of mass production continuous modes such as a complete mixed flow manner and a flow on immobilized bed manner are more effective production methods. In most cases production is carried out in a batch manner considering the equipment available on that site.

In the present invention, the time for reaction in a batch or semi batch kind of production is generally 1-20 hours, preferably 1-10 hours and most preferably 1-5 hours.

In the present invention, iodine sublimation is carried out after iodinationby heating the reaction mixture containing the dehydrating agentto 90°C and maintaining the temperature at 90°C till the reaction mixture completely loses the color of iodine to form an off white to yellow colored crude product of formula II in the solvent suspension.

In the present invention, crude product of formula II is purified by crystallization after sublimation. Wet crystals of crude product of formula II are preferably precipitated through cooling. Specifically, in the course of cooling of the reaction mixture, crystals start to precipitate at 60°C or lower and 80% or more of the formed 2-chloro-5-iodobenzoic acid of formula II is crystallized when cooled to 50°C or lower.

Alternatively, the wet crystals may be obtained by slowly cooling the solvent suspension containing the crude product of formula II to room temperature by adding demineralized water forming solvent-water suspension and allowing the crude product of formula II to settle as a wet crystalline precipitate of crude formula II in the solvent- water suspension. Specifically, when water is added in an amount of 1 to 5 parts by weight with respect to 1 part by weight of the reaction mixture, about 90% or more of the crude product of formula II is precipitated.

In the present invention, the precipitated wet crystals of crude product of formula II are collected through filtration.

In the present invention, wet crystalline precipitate of crude formula II is washed to remove residual solvent and iodine. The wet crystalline precipitate of crude formula II is washed with 10% aqueous solution of sodium sulfite in an amount of 0.05 parts by weight or less with respect to 1 parts by weight of iodine employed in the reaction mixture for iodination to remove residual iodine, and with demineralized water to remove residual solvent. Alternately, to prevent precipitation of iodine in the crystals of crude product of formula II, sodium sulfite, sodium hydrogen sulfite, or sodium thiosulfate may be directly added to the reaction mixture in advance before crystallization. Sodium sulfite, sodium hydrogen sulfite and sodium thiosulfate may be added 0.05parts by weight or less with respect to 1 part by weight of iodine employed in the reaction and such an amount is sufficient in the present invention.In other words, through subjecting the reaction mixture to crystallization at 10°C - 80°C, crystals of formula II can be precipitated. To enhance recovery of the product, crystallization is more preferably performed at 10°C - 50°C. Further, water is added to the mixture in an amount of 0.1 to 5 parts by weight with respect to 1 part by weight of the reaction mixture, preferably 0.5 to 3 part by weight. The thus precipitated crystals can be readily collected through filtration, and further washed with demineralized water.

In the present invention, the acetic acid solvent which has been employed in the reaction step can be recovered through distillation of the mother liquor after collection of the precipitated crystals and the recovered solvent may be reused in another cycle of the reaction step. The distillation bottom product also contains, in addition to formula I high boiling point substances at high concentration and sulfuric acid, the dehydrating agent. Hence, it is essential that a portion of the bottom product is not recycled in the crystallization system but removed from the distillation vessel by adding an appropriate amount of water to dilute sulfuric acid and precipitate other iodinated products. The products can be isolated by filtration and sent for recovery of valuable iodine, thereby reducing the cost of manufacture of the product of formula II. In order to enhance percent recovery of 2-chloro-5-iodobenzoic acid and prevent impairment in product purity, 50-90 percent of the component which has been formed through removal of solvent from mother liquor is recycled which is appropriate.

In the present invention, the wet crystalline precipitate of crude formula II after being washed is dried under vacuum at 45°C-55°C to obtain dried crude formula II crystals with 65-68.5% yield, and 92-95% conversion. The purity of the crystals in terms of 2-chloro-5-iodobenzoic acid is around 95.5-98.6%.

In the present invention, the crude formula II crystals are subjected to first round of purification to obtain purified product of formula II, the first round of purification comprises steps of: a) Taking the crude formula II crystals in a mixture of acetic acid and waterand heating until the solution becomes clear; b) Treating the solution from step a) with activated carbon 5%w/w and heating followed by filtering the solution to remove activated carbon; and c) Slowly cooling the above obtained solution to 15-20°C and maintaining the temperature for at least 1 hour for recrystallizing the product to obtain purified product of formula II.

The crude formula II crystals are dissolved in a mixture of acetic acid and water, wherein, the composition of mixture is in the range of 50-70% of acetic acid and 50-30% water, preferably the composition of mixture is in the range of 60-70% of acetic acid and 60-30% water. Further, the volume of the mixture should be kept not below 4.0v/w or above 7v/w with respect to the weight of crude crystalline precipitate of formula II.

In the present invention, the first round of purification provides purified formulall crystals with 60-65% yield and 97% conversion.The purity of the crystals in terms of 2-chloro-5-iodobenzoic acid is around95.5-99.7% In the present invention, the purified crystals of formula II are subjected to a second round of purification to obtain highly purified crystals of formula II which is in a pharmaceutically accepted form, the purification comprises steps of: a) Addingpurified product of formula II after acetic acid-water mixture purification to a hydrocarbon solvent and heating under reflux to dissolve formula II in the hydrocarbon solvent; b) Separating aqueous and organic layers in the solvent, with the formula II dissolved in the organic layer; c) Washing the organic layer with water and a 1% solution of sodium bi carbonate to remove any inorganic acidic material and finally washing with water; d) Treating the washed organic layer with activated charcoal 5%w/ w, followed by heating; e) Filtering the heated organic layer to remove charcoal; f) Slowly cooling the organic layer to 10°C-20°C and maintaining the temperature for 1-2 hours to precipitate formula II as highly purified crystals of formula II; and g) Filtering the highly purified crystals of formula II.

The wet product obtained after the purification process is dried to constant weight by a normal drying process to obtain the final iodinated product of formula II.

In the present invention, the hydrocarbon solvent used to purify formula II in the second round of purification is either an aromatic hydrocarbon solvent such as toluene, benzene, xylenes etc.; or it is an aliphatic hydrocarbon solvent such as hexane, heptane, pentane etc. The hydrocarbon solvent is preferably toluene. In the present invention, the highly purified crystals of formula II of pharmaceutically accepted form have the following purity and impurity profile: purityof formula Ilnot less than 99.8% and not greater than 99.95%;

2-chloro-3-iodobenzoic acid impurity not less than 0.005% and not greater than 0.1% formula limpurity not less than 0.005% and not greater than 0.1%;

2,5-dichlorobenzoic acid impurity not less than 0.005% and not greater than 0.3%;

2-chloro3,5-diiodobenzoic acid impurity not less than 0.005% and not greater than 0.5%;

Impurities such as iodine, an iodine compound, an inorganic salt, transition metal compound, metal oxide in the pharmaceutically accepted product of formula Ilare in the range of 500ppm or less; and any other unidentified impurity in the pharmaceutically accepted product of formula II is below 0.005%.

EXAMPLES

The present invention will be described in more detail below by way ofthe following examples. It should however be understood that the followingexamples are not intended to limit the present invention thereto. Those skilled in the art will appreciate that various adaptations and modifications of the just described embodiments can be configured without departing from the scope and spirit of the invention. Therefore, it is to be understood that, within the scope of the appended claims, the invention may be practiced other than as specifically described herein Example- 1

In a 200 ml three necked round bottomed flask equipped with a reflux condense, acetic acid (90.0g), 2-chlorobenzoic acid of formula I (20.0g 0.127 mol), iodine (16.2g, 0.06 mol) and ammonium persulfate(26.0g, 0.11 mol) were taken and stirred vigorously. The reaction mixture was slowly warmed to 50°C and during this process sulfuric acid (20g, 0.20) was added. The temperature was slowly raised and was kept below 60°C during the addition of sulfuric acid. Once the addition of sulfuric acid was over the reaction mixture was warmed up to 90°C and maintained at that temperature for nearly 4 hours. During this period, iodine sublimation was observed and the reaction slowly started to lose iodine colour. When the reaction mass completely lost its iodine colour to an off white product copious amount of pale yellow solid formation was observed. The reaction mass was cooled to 60°C by adding demineralized water to the reaction mixture (approximately 80ml) and further cooled to room temperature. Further, more water was added and the mass was allowed to settle. The water acetic acid mixture was removed by filtration and the solid material isolated by filtration and washed free of acid with copious amount of water. The product was removed from the filter and dried at 50°C under vacuum to obtain 2-chloro-5-iodobenzoic acid of formula II (crude 21.06 g, 58% yield and 97% conversion)

The thus obtained crude product crystals (1g) of formula II were dissolved in methanol(25ml) and a 4% aqueous KI solution (25ml) and 17% sulfuric acid (5ml) were added to the solution. The resulting solution was titrated with 0.02M aqueous sodium thiosulfate solution. The free iodine content was found to be 5 ppm. Through ICP basis total elemental analysis , Ti, Na, K, Mg, Ca, Sr, BA, Sc, Y, Ti, Zr, V, Nb, Mo, W, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu,Ag, Au, Zn, Cd, Al, Si, Sn, Pb, P, Sb, or S were not detected, and the group 1 element content and group 2 element content were both 1.00 ppm or less. Example -2

The procedure in Example- 1 was repeated with 2-chlorobenzoic acid of formula I, (20.0g 0.127 mol), acetic acid (90g) and sulfuric acid (20g) and iodine (14.4g), but instead of ammonium persulfate, potassium persulfate was employed as the oxidizing agent (30.7g). The following reaction analysis was obtained for the crude product of formula II as provided in Table 1.

TABLE 1

Example -3 The reaction of Example 1 was repeated under the same conditions except that the catalyst used is sodium persulfate (26g). Normal work up conditions yielded 20g of crude product of formula II. The following reaction analysis were obtained as provided in Table 2.

TABLE 2

The crude product of formula Ilwas purified with two rounds of purification, first using mixture of acetic acid and water, and second using toluene to obtain highly purifiedformula II which had a purity of 99.8% as analyzed by HPLC.

Example-4

The wet crystals from the above Examples 1-3 were collected after filtrationthereby obtained lOO.OOg(wet) of crystalswith TOD of 30%, andwere recycled in the crystallization system. The crystals to be recycled were dissolved in acetic acid: water mixture (50:50v/v) and heated to dissolve. The solution was treated with activated carbon 5%w/w and filtered. The solution was allowed to cool to room temperature and then to 10°C. The precipitated crystals were collected by filtration, washed with copious amount of water and dried in vacuum at 50°C. The yield obtained is 30g, 85.7% yield. The purity of the crystals in terms of 2-chloro-5-iodobenzoic acid of formula Ilwas found to be 99.6%

Example-5 (comparative process)

To a 100ml three necked flak equipped with a reflux condenser, sulfuric acid (25ml, 30%) and 2-chlorobenzoic acid of formula I (1.56g, 10 mmol) were fed to form a suspension. Iodine monochloride(92.4g, 15mmol) was added dropwise to the suspension. The mixture was allowed to react at 90°C for five hours and the reaction mass was poured into water (90ml). The precipitated product was collected through filtration, followed by washing with aqueous sodium sulfite solution to thereby yield a crystalline solid as the reaction product (1.00g).

Example -6

In the apparatus as employed in Example -1, acetic acid (50ml), 2-chlorobenzoic acid (20g), iodine (16.2g) and ammonium persulfate (26.0g) was taken and stirred to form a suspension. Sulfuric acid (20g) was added slowly maintaining the temperature around 70°C and once the addition was completed the complex mixture was heated to 120°C for seven hours. After completion of the reaction, the reaction mixture was cooled to room temperature. The precipitated crystals were collected by filtration to there by yield 40g(wet) of product. The following reaction analysis results were obtained as provided in Table 3.

TABLE 3

Thus when concentrated sulfuric acid was employed as the acid catalyst at high temperature the yield of 2-chloro-5-iodobenzoic acid was unsatisfactory.

Comparative Example- 1 The procedure in Example -1 was repeated except that the ammonium persulfate was not employed to there by yield 5g of a product. The following reaction analysis results were obtained as provided in Table 4.

TABLE 4

Thus the conversion was less in absence of ammonium persulfate and purity was also less.

Comparative Example-2 The procedure of Example- 1 was repeated except that sulfuric acid was not employed, to thereby yield of 18.5g of a product. The following reaction analysis were obtained as provided in Table 5.

TABLE 5

Thus the conversion was less in absence of sulfuric acid and purity was also less.

Example -7

2-chlorobenzoic acid of formula I (56.22g, 0.36mol), acetic acid (200g), water (20g) and concentrated sulfuric acid (20g) and ammonium persulfate (42.2g, 0.15mol) and iodine (16.2g 0.063mol) were added to a clean three necked flask of 500ml capacity equipped with stirrer, thermometer, condenser and addition funnel charge. The temperature was slowly raised to 50°C and maintained for 1 hour. Then the temperature was slowly raised to 70°C and maintained for 2 hours. Further the temperature was slowly raisedto 90°C and maintained for 3-4 hours or until the reaction was complete as indicated by thin layer chromatography (TEC). The colour of iodine in the solution slowly disappeared at this stage, mass produced was pale yellow in colourand the pale yellow solid started to precipitate.

A sample of the precipitated wet product was sent for HPLC analysis. The crude wet product contained only 10% 2-chlorobenzoic acid of formula I, 75%2-chloro- 5-iodobenzoic acid of formula II. Whereas impurities such as 2-chloro-3- iodobenzoic acid was 20%, and 2-chloro-3,5-diiodobenzoic acid less than 1.0%.

The stirring was slowed down and the mass is cooled to 15-20°C. The precipitated solid was filtered off washed with copious amount of water to remove the acetic acid and with a 10% aqueous solution of sodium sulfite and water to remove the residual iodine. The product was removed from the filter and dried in vacuum at 55°C for 6 hours. The yield of the product is 71.7g (70% theoretical based on the 2-chlorobenzoic acid).

The following reaction analysis is obtained as provided in Table 6.

TABLE 6

The mother liquor of the mixture on analysis contained 2-chlorobenzoic acid, 2- chloro-5-iodobenzoic acid, 2-chloro-3-iodobenzoic acid, 2-chloro-3,5- diiodobenzoic acid as its components.

The crude product obtained above (55.00g) was taken in a mixture of acetic acid water (l:lv/v, 200.0ml) and heated until the solution become clear. Any undissolved material was removed by filtration under the hot condition so as to obtain a clear solution. The mass was slowly cooled to 15-20°C and maintained it at that temperature for 1 hour. The product was isolated by filtration and washed with 50% acetic acid- water mixture and finally with water to obtain a pure product. The product after drying weighed 45.0g (95% based on the input).

Analysis of the product gave the following results as provided in Table 7.

TABLE 7

Example -8

In a clean reactor of 3000 liter capacity equipped with stirrer, thermometer, condenser and addition funnel charge, 2-chlorobenzoic acid (120.0kg), acetic acid (230 lit), and iodine (100kg) and ammonium persulfate (133 kg) were added. The reaction mass was stirred at room temperature for 30minutes so as to make a uniform slurry. Concentrated sulfuric acid (230 Kg)was charged in an addition tank and dripped into the reactor at a constant rate so as to maintain the temperature of the reaction mass below 60°C. The temperature was slowly raised to 70°C and maintained for 1 hour. Then the temperature was slowly raised to 80°C and maintained for 2 hours. Further, the temperature was slowly raised to 90°C and maintained for 3-4 hours or until the reaction was complete as indicated by thin layer chromatography (TEC). The colour of iodine in the solution slowly disappeared at this stage, mass become pale yellow and a pale yellow solid started to precipitate.

A sample of the precipitated wet product was sent for HPLC analysis. The crude wet product contained only 0.44% 2-chlorobenzoic acid of formula I, 82.86%2- chloro-5-iodobenzoic acid of formula II. Whereas impurities such as 2-chloro-3- iodobenzoic acid was 15.12%, and 2-chloro-3,5-diiodobenzoic acid less than 1.0%. The stirring was slowed down and the mass was cooled to 15-20°C. The precipitated solid was filtered off, washed with copious amount of water to remove the acetic acid, and with a 10% aqueous solution of sodium sulfite to remove the residual iodine. The product was removed from the filter and dried in vacuum at 55°C for 6 hours. The yield of the product is 120.7kg (56.1% theoretical based on the 2-chlorobenzoic acid).

The following reaction analysis is obtained as provided in Table 8.

TABLE 8

Example -9

In a clean reactor of 3000 lit capacity equipped with stirrer, thermometer, condenser and addition funnel charge, 2-chlorobenzoic acid (123.2 kg), acetic acid (460 lit), and iodine (100kg) and ammonium persulfate (140kg) were added. The reaction mass was stirred at room temperature for 30minutes so as to make a uniform slurry. Concentrated sulfuric acid (150 Kg)was charged in an addition tank and dripped into the reactor at a constant rate so as to maintain the temperature of the reaction mass below 60°C. The temperature was slowly raised to 80°C to 85°C and maintained for three hours. Samples were withdrawn every hour and analyzed and recorded. At the end of third hour the starting material was found to be less than 1%. The colour of iodine in the solution slowly disappeared at this stage, mass becomes pale yellow and a pale yellow solid started to precipitate.

Now the reaction mass is cooled to 60°C and water (1200 lit) was added to it slowly so as to maintain the temperature around 60°C. Once the water was added, 5% sodium thiosulfate solution (lOOlit) was added to completely remove the iodine. If required more thiosulfate solution may be added. The stirring was slowed down and the mass was cooled to 15-20°C. The precipitated solid was filtered off, washed with copious amount of water to remove the acetic acid. The product was removed from the filter and dried in vacuum at 55°C for 6 hours. The HPTC analysis of the crude product sample had the following composition: 2-chlorobenzoic acid (0.82%), 2-chloro-5-iodobenzoic acid(96.25%), 2-chloro-3-iodobenzoic acid (2.3%) and 2-chloro-3,5-diiodobenzoic acid (0.11%)%.

The product was purified from toluene. The yield of the product was 124.4 kg (1.24w/w based on iodine input). The following reaction analysis is obtained after purification as provided in Table 9.

TABLE 9

Example- 10 In a clean reactor of 3000 litre capacity equipped with stirrer, thermometer, condenser and addition funnel charge, 2-chlorobenzoic acid (378 kg), acetic acid (1260 lit), and iodine (300kg) and ammonium persulfate (420kg) were added. The reaction mass was stirred at room temperature for 30minutes so as to make a uniform slurry. Concentrated sulfuric acid (690Kg)was charged in an addition tank and dripped into the reactor at a constant rate so as to maintain the temperature of the reaction mass below 60°C. The temperature was slowly raised to 80°C to 85°C and maintained for 3-4 hours. At the end of third hour the starting material was found to be less than 1%. The colour of iodine in the solution slowly disappeared at this stage, mass become pale yellow and a pale yellow solid started to precipitate.

Now the reaction mass was cooled to 60°C and water (1800 lit) was added to it slowly so as to maintain the temperature around 60°C. Once the water was added, 5% sodium thiosulfate solution (3001it) was added to completely remove the iodine. The product is filtered to obtain the crude material. The yield of the product obtained is 840.0kg(wet).

The HPTC analysis of the crude product sample had the following composition: 2-chlorobenzoic acid -0.34%, 2-chloro-5-iodobenzoic acid -84.21%, 2-chloro-3- iodobenzoic acid -13.51% and 2-chloro-3,5-diiodobenzoic acid -<0.50%.

To the crude product thus obtained was subjected to first round of purification, thus acetic acid (690.01it) and water (3001it) was added to the crude product and heated to 80°C for dissolution into a clear solution. The clear solution was cooled to 10°C to obtain 2-chloro5-iodobenzoic acid of purity greater than 98% by HPTC.

The purified product was further subjected to a second round of purification using toluene. The product was taken in toluene (8001it) and heated to reflux so as to dissolve most of the iodinated product formed. The aqueous and organic layers were separated at this stage and the organic layer was washed with water and a 1% solution of sodium bi carbonate to remove any acidic material and finally with water. The toluene layer was treated with charcoal and filtered hot. The toluene layer was slowly cooled to room temperature and then to 10°C and kept at that temperature for 1 hour. The precipitated mass was filtered off to obtain 2-chloro-5-iodobenzoic acid of formal II with high purity levels.

The highly purified product of formula II after second round of purification with toluene hadan yield of 394.00 kg, having a melting point of 158-161°C. Analysis of the highly purified product of formula II had the following composition as provided in Table 10.

TABLE 10