MXPA06010987A - Processes for the preparation of iodinated amino-aryl compounds - Google Patents

Abstract

The present invention provides processes for the preparation of amino-aryl iodides wherein a micronized amino-aryl compounds is reacted with an iodinating reagent.

Description

PROCEDURES FOR THE PREPARATION OF COMPOUNDS OF AMINOARILO YODADOS FIELD OF THE INVENTION The present invention relates to processes for the high yield production of iodinated arylamines wherein an arylamine of reduced particle size is reacted with an iodinating agent.

BACKGROUND OF THE INVENTION Iodinated aminoaryl compounds have considerable value as synthetic intermediates for a wide range of useful substances in various industrial establishments including the pharmaceutical industry. For example, 2-iodoanilines are known precursors useful in the synthesis of a large number of Índles, including 2,3-disubstituted Índols, some with reported utility as potential drugs against migraine headache. Larock, R.C., Yum, E.K., Refvik, M.D., J. Org. Chem., 1998, 63, 7652, and references cited therein. A number of methods for the iodination of aminoaryl compounds have been reported in the literature, but result in either low to moderate yields or require the use of expensive reagents that require separate preparation. For example, the mono-iodination of 4-chloroaniline shown in Scheme I has been described in the literature, but the most common reported methods of adding molecular iodine to an aqueous solution of sodium bicarbonate, Xiao, W .; Alper, H. J. Org. Chem. 1999, 64, 9646-9652; Caliaghan, P.D .; Gibson, M.S .; J. Chem. Soc. (C), 1970, 2106-2111, or calcium carbonate, Dains, F.B .; Vaughn, T.H .; Janney, W.M., J. Am. Chem. Soc, 1918, 40, 932; Breukink, K.W .; Krol, L.H .; Verkade, P.E .; Wepster, B.M., Rec. Trav Chim. Pay-Bas, 1957, 76, 401; Rosowsky, A .; Marini, J. L .; Nadel, M. E .; Modesi, EJ. J. Med. Chem., 1970, 13, 882, result in only moderate reported returns from 53% to 69%. Higher yields have been achieved with specially developed reagents such as benzyltrimethylammonium dichloroiodate (BnNMe3ICI2, 86%), Kajigaeshi, S., Kakínami, T .; Yamasaki, H .; Fujisaki, S .; Okamoto, T. Bull. Chem. Soc. Japan 1988, 61, 600-602 and bis (pyridino) iodonium (l) tetrafluoroborate (lpy2BF4, 99%). Ezquerra, J .; Concepción, L .; Barluenga, J .; Pérez, M. J. Org. Chem. 1996, 61, 5804-5812.

SCHEME I Iodination of 4-chloroaniline to make 4-chloro-2-iodoaniline Accordingly, improved synthetic routes are needed for iodinated amines such as 4-chloro-2-iodoaniline.

BRIEF DESCRIPTION OF THE INVENTION In some embodiments, the present invention provides processes for the preparation of a compound of formula I: wherein: Ar is a mono-, bi- or tricyclic aryl or heteroaryl ring system optionally containing up to four substituents independently selected from the group consisting of halogen, C1-6 alkyl, CN, NO2, CHO, CO- C1-6alkyl, CO2H, CO2-d-6alkyl, C1-6alkoxy, phenyl, and C? -6 thioalkyl, wherein the phenyl may be optionally substituted with 1 to 3 substituents independently selected from the group it consists of C? _3 alkyl, halogen, C? -3 alkoxy, CN, NO2, CHO, and phenyl; R6 and R7 are each independently selected from the group consisting of H, C1-6 alkyl and a nitrogen protecting group; comprising: reacting an aminoaryl compound of formula II: Ar NR6R ^ with an iodinating agent, wherein the aminoaryl compound of formula II has an average particle size of about 100 μm or less. In some preferred embodiments, the compound of formula II is an aniline of formula III: II) wherein R5 is selected from the group consisting of halogen, C1-6alkyl, CN, NO2, -CHO, CO-C1-6alkyl, CO2H, CO2-C1-6alkyl, C1-6alkoxy , phenyl and thioalkyl of C -? - 6, wherein the phenyl may be optionally substituted with 1 to 3 substituents selected from the group consisting of C? _3 alkyl, halogen, C? -3 alkoxy, CN, NO2, CHO and phenyl; and R?, R2, 3 and 4 are each independently selected from the group consisting of hydrogen, halogen, C? -6 alkyl, CN, N02, CHO, C? -C6 alkyl, C02H, CO2-akyl of C1-6, C6-6 alkoxy, C1-6 thioalkyl and phenyl, wherein the phenyl may be optionally substituted with from 1 to 3 substituents selected from the group consisting of C? -3 alkyl, halogen, alkoxy of C1-3, CN, NO2, CHO and phenyl; provided that at least one of R i and R 3 is H. In some embodiments, R 5 is halogen or C 6 alkyl, preferably halogen, and R i, R 2, R 3, R, R b and R 7 are each hydrogen. In some preferred embodiments, the compound of formula II is 4-chloroaniline, and the reaction of 4-chloroaniline with an iodinating agent is carried out under conditions effective to form 2-iodo-4-chloroaniline. In some embodiments of the foregoing, the compound of formula II has an average particle size of less than about 80 μm, or an average particle size of less than about 60 μm, or an average particle size of less than or equal to at about 50 μm, or an average particle size of less than or equal to about 40 μm. A typical lower limit is about 30 μm or less, e.g., 10 μm. In some preferred embodiments, the compound of formula II has an average particle size of between about 30 μm and about 60 μm, or between about 40 μm and about 50 μm. In some embodiments, the iodinating agent is molecular iodine. In further embodiments, the reaction of the aminoaryl compound of the formula II and the iodinating agent is carried out in the presence of a metal iodide of the group I or group II group, preferably potassium iodide. In some embodiments, the reaction of the aminoaryl compound of the formula II and the iodinating agent is carried out in an aqueous solution, preferably regulated at its pH with a weak base, preferably regulated in its pH with NaHCO3. In some embodiments, the reaction of the aminoaryl compound of the formula II and the iodinating agent is carried out in an aqueous solution comprising molecular iodine, or a metal iodide of group I or group II, or both molecular iodine and a iodide of metal of group I or group II. Preferably, the metal iodide is potassium iodide. Preferably, the aqueous solution is regulated at its pH with a weak base, preferably NaHC03. In some embodiments, potassium iodide, molecular iodine, or both are added to a mixture of the aminoaryl compound of formula II, NaHCO3 and water. In further embodiments, the potassium iodide and molecular iodine are added as an aqueous solution to a mixture of the aminoaryl compound of the formula II, NaHCO3 and water. In some embodiments, the molecular iodine is used in an amount of about 1 to about 1.5 equivalents relative to the aminoaryl compound of formula 11. In further embodiments, the methods further comprise the step of adding an inorganic reducing agent to the mixture. after the addition of iodine and before the isolation of the product. Preferably, the inorganic reducing agent is a metal thiosulfate of group I or II, a metal sulphite of group I or II or a metal bisulfite of group I or II, preferably sodium thiosulfate. In some embodiments, the compound of formula I is isolated by filtration. In further embodiments, the filtered compound of the formula I is washed with a solvent, preferably water.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides methods for the highly efficient production of iodinated aminoaryl compounds. The methods described herein utilize micronized aminoaryl compounds as efficient iodination substrates for the preparation of iodinated aminoaryl compounds. The term "micronized" as used herein refers to the use of aminoaryl compounds having an average particle size of less than 1 mm, preferably less than about 100 μm, most preferably less than about 80 μm, most preferably less than about 60 μm , most preferably less than or equal to about 50 μm, or less than or equal to about 40 μm. In some preferred embodiments, the aminoaryl compounds have an average particle size of between about 30 μm and about 60 μm, or between about 40 μm and about 50 μm. It has been found, in accordance with the present invention, that the use of said micronized aminoaryl compounds confers significant advantages in the iodation reaction in providing a product of high purity and yield, without the use of more expensive reagents.

The micronization of the aminoaryl derivatives can be achieved by a variety of physical techniques well known to those skilled in the art, including but not limited to grinding (ball milling, friction grinding, and variants of these procedures), microfluidization , spray drying or extrusion followed by exposure to a supercritical fluid. As used herein, the term "average particle size" means the average particle size of the aminoaryl starting materials as determined by any of the standard techniques known in the art. In some preferred embodts, the particle size is determined by microscopic, sieving, or light scattering, using standard instrumentation, for example and without limitation, a Mastersizer S particle size analyzer, available from Malvern Instruments (Southborough, MA). The iodination reactions described herein are preferably carried out on aryl substrates having an amine functionality directly connected to an aryl group. As will be recognized by those skilled in the art, the regiochemistry and stoichiometry of iodination is determined by several factors, including the positions available for substitution, the particular aryl ring being iodinated, the presence of other activation / deactivation groups, the solvent, reaction tand temperature, the number of iodization equivalents used, etc. The overall reaction is shown later in Scheme II.

SCHEME II Reaction of amino-aryl compound with iodination reagent As used herein, the term "aryl", used alone or in combination with other terms, is defined herein, unless otherwise indicated, as an aromatic hydrocarbon of up to 14 carbon atoms, e.g. -14 carbon atoms, which may be a single ring (monocyclic) or multiple rings (bicyclic, up to three rings) fused together or covalently linked. Examples of aryl moieties include, but are not limited to, chemical groups such as phenyl, 1-naphthyl, 2-naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenyl, anthryl, phenanthryl, fluorenyl, indanyl, biphenylenyl, acenaphthenyl, acenaphthylenyl, and the like. In some embodts, the aryl moiety may be optionally substituted with from 1 to 4 substituents selected from the group consisting of halogen, d-β alkyl, CN, NO 2, CHO, CO-C 1-6 alkyl, CO 2 H, CO 2 -alkyl of C1-6, Ci-β alkoxy, C-α-6-thioalkyl and phenyl optionally substituted with 1 to 3 substituents selected from C?-3 alkyl, halogen, C 1-3 alkoxy, CN, NO 2, CHO and unsubstituted phenyl. As used herein, the term "heteroaryl" denotes an aryl group as defined above, ie, of up to 14 ring atoms, e.g., 5-14 ring atoms, containing at least one ring atom that is not carbon ("hetero"). Preferably, the heteroaryl groups contain from one to four of those heteroatoms, preferably selected from one or more of O, N and S. The micronized aminoaryl compounds can be reacted with a number of different iodination reagents in accordance with the present methods to achieve the desired results. In general, iodization reagents are reactants that are capable of donating an iodine atom to a target substrate. Useful reagents or iodization procedures include molecular iodine with or without the addition of an oxidant, a metal salt or alumina; metal iodide salts together with oxidants; yodomercuración; electrochemical iodization; Iodoamides; iodonium salts or transiodination procedure. In some preferred embodts, the micronized aminoaryl compounds are reacted with molecular iodine to form iodinated aminoaryl compounds. In some embodts, the micronized aminoaryl compounds react with molecular iodine in the presence of a metal iodide salt of group I or group II such as Lil, Nal, Kl, Cal2, and the like. In some preferred embodiments, the metal iodide salt is Kl. The reaction between the aminoaryl compound and the iodination reagent can be carried out by any of a variety of protocols known in the art, for example, by introducing the iodination reagent into a mixture of the aminoaryl compound in an appropriate solvent, or by adding the aminoaryl compound to the iodination reagent in said solvent. It is not necessary that the aminoaryl compound or the iodination reagent be completely soluble in the solvent. Therefore, in some embodiments, the aminoaryl compound will possess limited solubility in the solvent, and in other embodiments the iodination reagent will possess limited solubility in the reaction solvent. The solvent used to react the aminoaryl compound and the iodination reagent may consist of a single solvent, or may be a mixture of two or more solvents. Where the reaction mixture includes two or more solvents, the mixture may be homogeneous or heterogeneous. The reactions of the processes described herein can be carried out in suitable solvents, which can be easily selected by one skilled in the art of organic synthesis. Suitable solvents include organic solvents, aqueous solvents, and combinations thereof. Suitable solvents are preferably substantially non-reactive with the starting materials (reagents), intermediates, and / or products of the reaction at the temperatures at which the reactions are carried out, which can be any suitable temperature from the temperature of freezing the solvent at the boiling temperature of the solvent. Suitable organic solvents include, but are not limited to, hydrocarbons and halohydrocarbons, including pentanes, hexanes, heptanes, benzene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, toluene, mesitylene, chlorobenzene, polychlorobenzenes, bromobenzene, and the like; alcohols, including methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, and the like; amides, including dimethylformamide, diethylformamide, acetamide, dimethylacetamide, and the like; ketones, including acetone, methyl ethyl ketone, 3-pentanone, and the like; esters, including methyl acetate, ethyl acetate, isopropyl acetate, methyl formate, ethyl formate, and the like; carboxylic acids, including formic acid, acetic acid, propionic acid, and the like; and ethers, including diethyl ether, dipropyl ether, dibutyl ether, diphenyl ether, diisopropyl ether, anisole and the like. Aqueous solvents include water, or water with inorganic salts dissolved therein. As used herein, the term "react" or "reaction" refers to bringing together chemical reagents designated in such a way that a chemical transformation takes place by generating a compound different from any initially introduced into the system. In some embodiments, prior to product isolation, a reducing agent can be added to the reaction mixture to quench any remaining molecular iodine or any other source capable of undergoing transfer of iodine atoms. Those skilled in the art will recognize that the particular reducing reagent used will depend on the particular iodination reagent used, the solvents used for the reaction and production isolation, and the product of the reaction to be isolated. Preferred reducing agents include reagents containing inorganic sulfur such as metal sulphites, bisulfites and thiosulfates of group I or group II. In some preferred embodiments, the reducing agent is sodium thiosulfate and / or SO 2 (gas). Those skilled in the art will appreciate that the reaction between the micronized aminoaryl compound and the iodination reagent, depending on the identity of the iodination reagent, can generate highly acidic byproducts such as hydrogen iodide. In some cases, it is possible that said by-products may be reactive with the starting material of the reaction, reaction product or both, and may result in a reduced yield of the desired product. Therefore, it is sometimes preferable to include a weak base to regulate the pH of any strongly acidic reaction byproducts, such as hydrogen iodide. Preferred bases include weak inorganic bases such as carbonates, bicarbonates, phosphates, acid phosphates and the like of metals of group I or II. Some preferred weak bases include NaHCO3 and CaCO3. As used herein, the term "alkyl" or "alkylene" refers to a saturated hydrocarbon group that is straight or branched chain. Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl) , pentyl (e.g., n-pentyl, isopentyl, neopentyl) and the like. In some preferred embodiments, the alkyl groups may contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms. As used herein, "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine. As used herein, "alkoxy" refers to an -O-alkyl group.

Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the compounds of the formula I may contain a nitrogen protecting group in the Re or R7 position. Representative protective groups can be found, for example, in Greene, T.W., and Wuts, P.M., Protective Groups In Organic Synthesis, 3rd ed., John Wíley & Sons, NY, 1999, incorporated herein by reference. In various places in the present specification, substituents of compounds of the invention are described in groups or in ranges. It is specifically intended that the invention include each and every individual sub-combination of the members of said groups and ranges. For example, it is specifically intended that the term "d-β alkyl" individually include methyl, ethyl, C3-alkyl, C4-alkyl, C5-alkyl, and C-alkyl. The reagents or products of the present invention may contain an asymmetric atom, and some of the compounds may contain one or more asymmetric atoms or centers, which can therefore give rise to optical isomers (enantiomers) and diastereomers. The present invention includes said optical isomers (enantiomers) and diastereomers (geometric isomers); as well as the racemic and resolved, enantiomerically pure stereoisomers R and S; as well as other mixtures of R and S stereoisomers and salts, including pharmaceutically acceptable salts thereof. The optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, including but not limited to diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. It is also understood that this invention encompasses all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation methods known to those skilled in the art, including but not limited to column chromatography, layer chromatography. thin, and high performance liquid chromatography. The methods described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or spectrometry by mass, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography. The reactions of the processes described herein can be carried out at appropriate temperatures, which can be easily determined by the person skilled in the art. The reaction temperatures will depend, for example, on the melting and boiling points of the reagents and solvent, if present; the thermodynamics of the reaction (e.g., vigorously exothermic reactions are typically carried out at reduced temperatures); and the kinetics of the reaction (e.g., a high activation energy barrier typically needs high temperatures). The "elevated temperature" refers to temperatures above room temperature (approximately 20 ° C) and "reduced temperature" refers to temperatures below room temperature. The reactions of the processes described herein can be carried out in air or under an inert atmosphere. Typically, reactions containing reagents or products that are substantially reactive with air can be carried out using air sensitive synthesis techniques that are well known to those skilled in the art. It is appreciated that certain features of the invention which, for purposes of clarity, are described in the context of separate embodiments may also be provided in combination in a single embodiment. On the contrary, several characteristics of the invention which, for brevity, are described in the context of a single modality, they can also be provided separately or in any suitable sub-combination. The methods of this invention are suitable for the preparation of compounds of formula I at any convenient scale, for example, greater than about 0.01 mg, 0.10 mg, 1 mg, 10 mg, 100 mg, 1 g, 10 g, 100 g, 1 kg, 10 kg or more. The processes are particularly advantageous for the large-scale preparation (e.g., greater than about ten grams) of iodinated amino-aromatics. The invention will be described in more detail by means of a specific example. The following example is offered for illustrative purposes, and is not intended to limit the invention in any way. Those skilled in the art will readily recognize a variety of non-critical parameters that can be changed or modified to give essentially the same results.

EXAMPLE 1 Preparation of 2-chloro-iodoaniline An aqueous solution of potassium iodide (50 g, 0.301 mole), iodine (76 g, 0.299 mole) and water (100 ml) is added over 45 minutes to a stirred suspension of 4-chloroaniline (35 g, 0.276 mole, size average particle size of 50 um), sodium bicarbonate (37 g, 0.440 mol) and water (210 ml). The mixture is stirred for 3-5 hours. The solid is collected by filtration and washed with water, then dried to give 4-chloro-2-iodoaniline (69.6 g, 100% yield, 98.5% purity). 1 H NMR (CDCl 3): d 7.56 (d, 1 H, J = 2.4 Hz), 7.12 (dd, 1 H, J = 2.4 Hz, 8.6 Hz), 6.75 (d, 1 H, J = 8.6 Hz), 5.37 (br s, 2 H). As will be appreciated by those skilled in the art, numerous changes and modifications can be made to the preferred embodiments of the invention without departing from the spirit of the invention. It is intended that all such variations fall within the scope of the invention. This application claims the priority benefit of the provisional application of E.U.A. with serial number 60 / 557,014 filed from 03/26/04, which is incorporated herein by reference in its entirety. It is intended that each of the patents, applications and printed publications, including books, mentioned in this patent document be incorporated herein by reference in its entirety.

Claims (38)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for the preparation of a compound of the formula I: . I wherein: Ar is a mono-, bi- or tricyclic aryl or heteroaryl ring system optionally containing up to four substituents independently selected from the group consisting of halogen, C? -6 alkyl, CN, NO2, CHO, CO- C 1-6 alkyl, CO 2 H, C 2 -C 6 alkyl, C 6 alkoxy, phenyl and thioalkyl of d 6, wherein the phenyl may be optionally substituted with from 1 to 3 substituents independently selected from the a group consisting of d-3 alkyl) halogen, C? -3 alkoxy, CN, NO2, CHO, and phenyl; R6 and R are each independently selected from the group consisting of H, C? -6 alkyl and a nitrogen protecting group; comprising: reacting an aminoaryl compound of formula II: Ar NR6R7 li wherein Ar NR6R7 is as defined above, wherein the aminoaryl compound of formula II has an average particle size of about 100 μm or less.

2. The process according to claim 1, further characterized in that the aminoaryl compound of the formula II is an aniline of the formula III: wherein R5 is selected from the group consisting of halogen, d-6 alkyl, CN, NO2, -CHO, CO-alkyl of d-6, C02H, CO2-C1-6alkyl, alkoxy of d. 6, phenyl and thioalkyl of d-6, wherein the phenyl may be optionally substituted with from 1 to 3 substituents selected from the group consisting of C? -3 alkyl, halogen, C? -3 alkoxy, CN, NO2, CHO and phenyl; and R-i, R 2, R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl. CN, NO2, CHO, CO-alkyl of d-6, C02H, C02-alkyl of d-6, alkoxy of C? -6, thioalkyl of d-6 and phenyl, wherein the phenyl can be optionally substituted with 1 to 3 substituents selected from the group consisting of C? -3 alkyl, halogen, C? -3 alkoxy, CN, N02, CHO and phenyl; provided that at least one of RT and R3 is H.

3. - The process according to claim 2, further characterized in that R 5 is halogen or C 1-6 alkyl; and R-i, R2, R3, R, R6 and R7 are each hydrogen.

4. The process according to claim 3, further characterized in that R5 is halogen.

5. The process according to any of claims 1 to 4, further characterized in that the compound of formula II or III has an average particle size of less than about 80 μm.

6. The process according to any of claims 1 to 4, further characterized in that the compound of formula II or III has an average particle size of less than about 60 μm.

7. The process according to any of claims 1 to 4, further characterized in that the compound of formula II or III has an average particle size of less than or equal to about 50 μm.

8. The process according to any of claims 1 to 4, further characterized in that the compound of formula II or III has an average particle size of less than or equal to about 40 μm.

9. The process according to any of claims 1 to 4, further characterized in that the compound of the formula II or III has an average particle size of between about 30 μm and about 60 μm.

10. The process according to any of claims 1 to 4, further characterized in that the compound of formula II or III has an average particle size of between about 40 μm and about 50 μm.

11. The process according to claims 1 to 10, further characterized in that the reaction of the aminoaryl compound of the formula II or III and the iodation agent is carried out in an aqueous solution.

12. The method according to any of claims 1 to 11, further characterized in that the reaction of the aminoaryl compound of the formula II or III and the iodinating agent is carried out in the presence of a metal iodide of group I or group II.

13. The process according to any of claims 1 to 12, further characterized in that the reaction of the aminoaryl compound of the formula II or III and the iodinating agent is carried out in an aqueous solution comprising molecular iodine, or an iodide metal of group I or group II, or both molecular iodine and a metal iodide of group I or group II.

14. The process according to claim 12 or claim 13, further characterized in that the metal iodide is potassium iodide.

15. - The process according to any of claims 11 to 14, further characterized in that the aqueous solution is regulated at its pH with a weak base.

16. The process according to claim 15, further characterized in that the aqueous solution is regulated in its pH with NaHCO3.

17. The process according to any of claims 1 to 16, further characterized in that the iodation agent is molecular iodine.

18. The process according to claim 17, further characterized in that the molecular iodine is used in an amount of about 1 to about 1.5 equivalents relative to the aminoaryl compound of the formula II.

19. The process according to claim 16, further characterized in that potassium iodide, molecular iodine or both are added to a mixture of the aminoaryl compound of the formula II, NaHCO 3 and water.

20. The process according to claim 16, further characterized in that potassium iodide and molecular iodine are added as an aqueous solution to a mixture of the aminoaryl compound of the formula II, NaHCO 3 and water.

21. The process according to any of claims 17 to 20, further characterized in that it comprises the step of adding an inorganic reducing agent to the mixture after the addition of iodine and before the isolation of the product.

22. The process according to claim 21, further characterized in that the inorganic reducing agent is a metal thiosulfate of group I or II, a metal sulfite of group I or II or a metal bisulfite of group I or II.

23. The process according to claim 22, further characterized in that the inorganic reducing agent is sodium thiosulfate.

24. The method according to any of claims 1 to 23, further characterized in that the compound of the formula I is isolated by filtration.

25. The process according to claim 24, further characterized in that the filtered compound of the formula I is washed with a solvent.

26. The process according to claim 24, further characterized in that the filtered compound of the formula I is washed with water.

27. A process comprising the steps of: (a) providing 4-chloroaniline in the form of particles having an average size of about 100 or less; and (b) reacting the 4-chloroaniline with an iodination agent under effective conditions to form 2-iodo-4-chloroaniline.

28. The process according to claim 27, further characterized in that the 4-chloroaniline particles have an average size of about 60 or less.

29. The process according to claim 27, further characterized in that the 4-chloroaniline particles have an average size of about 50 μm or less.

30. The process according to any of claims 27 to 29, further characterized in that the iodinating agent is molecular iodine.

31. The process according to claim 30, further characterized in that the reaction of 4-chloroaniline and molecular iodine is carried out in an aqueous solution further comprising a metal iodide of group I or group II and a pH regulator weak base

32. The process according to claim 31, further characterized in that the metal iodide is potassium iodide, and the weak base pH regulator is NaHCO3.

33. The process according to claim 32, further characterized in that the potassium iodide and molecular iodine are added to a mixture of 4-chloroaniline and NaHCO3 in water.

34. The process according to claim 32, further characterized in that the potassium iodide and molecular iodine are added as an aqueous solution to a mixture of 4-chloroaniline and NaHCO3 in water.

35. - The method according to any of claims 30 to 34, further characterized in that the molecular iodine is used in an amount of about 1 to about 1.5 equivalents relative to the amount of 4-chloroaniline.

36. The process according to any of claims 30 to 35, further characterized in that it further comprises the step of adding an inorganic reducing agent to the mixture after the addition of iodine and before product isolation. 37.- The process according to claim 36, further characterized in that the inorganic reducing agent is sodium thiosulfate. 38.- The method according to any of claims 30 to 37, further characterized in that it further comprises isolating the 2-iodo-4-chloroaniline by filtration.