WO2009114589A1

WO2009114589A1 - Improved process for the manufacture of 2,3-dichloropyridine

Info

Publication number: WO2009114589A1
Application number: PCT/US2009/036747
Authority: WO
Inventors: Rafael Shapiro
Original assignee: E. I. Du Pont De Nemours And Company
Priority date: 2008-03-13
Filing date: 2009-03-11
Publication date: 2009-09-17
Also published as: CN101959862B; TW200946504A; CN101959862A; AR070895A1

Abstract

A method for preparing 2,3-dichloropyridine is disclosed in which 3-amino-2- chloropyridine is contacted with a nitrite salt in the presence of aqueous hydrochloric acid to form a diazonium salt; and the diazonium salt is subsequently decomposed in the presence of sulfamic acid and a copper catalyst wherein at least about 50% of the copper is the copper (II) oxidation state.

Description

TITLE IMPROVED PROCESS FOR THE MANUFACTURE OF 2,3-DICHLOROPYRIDINE

BACKGROUND OF THE INVENTION

A need exists for efficient and practical processes for the manufacture of 2,3- dichloropyridine. 2,3-Dichloropyridine is an important raw material for the preparation of crop protection agents, pharmaceuticals and other fine chemicals.

PCT Patent Publication WO 2005/070888 discloses the preparation of 2,3- dichloropyridine in which 3-amino-2-chloropyridine is contacted with a nitrite salt in the presence of aqueous hydrochloric acid to form a diazonium salt, which is subsequently decomposed in the presence of a copper catalyst. For diazotization reactions commercially practiced on large scale, the amount of nitrite cannot always be precisely controlled, and therefore excess (i.e. greater than stoichiometric relative to the aromatic amine) nitrite is typically used to ensure the amine is completely converted to the diazonium salt. Although the method disclosed in WO 2005/070888 gives high product yields when a stoichiometric (i.e. equimolar) amount of nitrite is used, using excess nitrite can result in deactivation of the copper catalyst in the diazonium salt decomposition step. Deactivation of the copper catalyst can decrease yield of 2, 3 -dichloropyridine product due to the diazonium salt instead thermally hydrolyzing to a hydroxypyridine by-product. Even more significantly in commercial-scale manufacture, deactivation of the catalyst can result in a delayed and sudden increase in pressure from nitrogen gas generated in the decomposition reactor. Although residual nitrous acid formed from excess nitrite can be removed by adding a nitrous acid scavenger, such as urea or sulfamic acid, to the diazonium solution prior to the decomposition step, this can cause unacceptable gas evolution and foaming of the liquid, producing excessive pressure or overflow from the reactor. Although intentionally using a less than stoichiometric amount of nitrite avoids copper catalyst deactivation, this results in a lower yield of 2,3-dichloropyridine and leaves residual 3-amino-2-chloropyridine, which must be separated and recycled. A better solution to this problem has now been discovered.

SUMMARY OF THE INVENTION

This invention relates to a method of preparing 2,3-dichloropyridine (1),

l comprising the steps of:

(1) contacting 3-amino-2-chloropyridine (2) or a solution comprising 3-amino-2- chloropyridine (2)

with hydrochloric acid to form a 3-amino-2-chloropyridine hydrochloric acid salt;

(2) contacting the 3-amino-2-chloropyridine hydrochloric acid salt with a nitrite salt to form a corresponding diazonium chloride salt; and (3) contacting the corresponding diazonium chloride salt with hydrochloric acid in the presence of sulfamic acid and a copper catalyst wherein at least about 50% of the copper is the copper(II) oxidation state, optionally in the presence of an organic solvent, to form 2,3- dichloropyridine (1).

DETAILED DESCRIPTION OF THE INVENTION As used herein, the terms "comprises," "comprising," "includes," "including," "has,"

"having," "contains" or "containing," or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, a mixture, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus. Further, unless expressly stated to the contrary, "or" refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).

Also, the indefinite articles "a" and "an" preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore "a" or "an" should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.

In some instances herein ratios are recited as single numbers, which are relative to the number 1; for example, a ratio of 4 means 4 : 1.

As referred to herein, the term "molar equivalent" relates to the chemically active component of a chemical compound. For example, in the context of the present method, molar equivalents of hydrochloric acid refers to the number of moles of hydrogen chloride (e.g., relative to the number of moles of 3-amino-2-chloropyridine (2). Molar equivalents of a nitrite salt refers to the number of moles of nitrite ion (e.g., relative to the number of moles of 3-amino-2-chloropyridine (2)). Molar equivalents of copper catalyst refers to the number of moles of copper, particularly copper(II), in the catalyst (e.g., relative to the number of moles of 3-amino-2-chloropyridine (2) converted to the diazonium salt). As referred to herein, the term "nominal" as used in expression such as "nominal mole ratio" means approximate.

Embodiments of the present invention include:

Embodiment 1. The method of preparing 2,3-dichloropyridine (1) as set forth in the Summary of the Invention wherein the nominal mole ratio of hydrochloric acid (i.e. hydrogen chloride in aqueous solution) to the 3-amino-2-chloropyridine (2) in step (1) is at least about 1.

Embodiment IA. The method of Embodiment 1 wherein the nominal mole ratio of hydrochloric acid to the 3-amino-2-chloropyridine (2) in step (1) is at least about 2. Embodiment IB. The method of Embodiment IA wherein the nominal mole ratio of hydrochloric acid to the 3-amino-2-chloropyridine (2) in step (1) is at least about 3.

Embodiment 1C. The method of preparing 2,3-dichloropyridine (1) as set forth in the Summary of the Invention or any one of Embodiments 1 through IB wherein the nominal mole ratio of hydrochloric acid (i.e. hydrogen chloride in aqueous solution) to the 3- amino-2-chloropyridine (2) in step (1) is not more than about 10.

Embodiment ID. The method of Embodiment 1C wherein the nominal mole ratio of hydrochloric acid to the 3 -amino-2-chloropyridine (2) in step (1) is not more than about 6.

Embodiment 2. The method of preparing 2,3-dichloropyridine (1) as set forth in the Summary of the Invention or any one of Embodiments 1 through ID wherein the nominal mole ratio of hydrochloric acid (i.e. hydrogen chloride in aqueous solution) in step (3) to the 3 -amino-2-chloropyridine (2) is at least about 1.

Embodiment 2A. The method of preparing 2,3-dichloropyridine (1) as set forth in the Summary of the Invention or any one of Embodiments 1 through ID or 2 wherein the nominal mole ratio of hydrochloric acid (i.e. hydrogen chloride in aqueous solution) in step (3) to the 3 -amino-2-chloropyridine (2) is not more than about 10.

Embodiment 2B. The method of preparing 2,3-dichloropyridine (1) as set forth in the Summary of the Invention of Embodiment 2A wherein the nominal mole ratio of hydrochloric acid in step (3) to the 3 -amino-2-chloropyridine (2) is not more than about 5.

Embodiment 3. The method of preparing 2,3-dichloropyridine (1) as set forth in the Summary of the Invention wherein the nominal mole ratio of the nitrite salt (based on moles of nitrite ion) in step (2) to the 3 -amino-2-chloropyridine (2) is at least about 0.95.

Embodiment 3A. The method of Embodiment 3 wherein the nominal mole ratio of the nitrite salt in step (2) to the 3 -amino-2-chloropyridine (2) is at least about 1.

Embodiment 3B. The method of Embodiment 3 wherein the nominal mole ratio of the nitrite salt in step (2) to the 3 -amino-2-chloropyridine (2) is at least about 1.05.

Embodiment 3C. The method of preparing 2,3-dichloropyridine (1) as set forth in the Summary of the Invention or any one of Embodiments 3 through 3B wherein the nominal mole ratio of the nitrite salt in step (2) to the 3 -amino-2-chloropyridine (2) (i.e. ratio of molar equivalents of the nitrite salt to moles of 3-amino-2-chloropyridine) is not more than about 2.

Embodiment 3D. The method of Embodiment 3C wherein the nominal mole ratio of the nitrite salt in step (2) to the 3-amino-2-chloropyridine (2) is not more than about 1.1. Embodiment 3E. The method of preparing 2,3-dichloropyridine (1) as set forth in the

Summary of the Invention or any one of Embodiments 3 through 3D wherein the nitrite salt is sodium nitrite.

Embodiment 4. The method of preparing 2,3-dichloropyridine (1) as set forth in the Summary of the Invention wherein the nominal mole ratio of copper in the copper catalyst to the 3-amino-2-chloropyridine (2) (i.e. ratio of molar equivalents of copper to moles of 3- amino-2-chloropyridine) is at least about 0.05.

Embodiment 4A. The method of Embodiment 4 wherein the nominal mole ratio of copper in the copper catalyst to the 3-amino-2-chloropyridine (2) is at least about 0.2.

Embodiment 4B. The method of preparing 2,3-dichloropyridine (1) as set forth in the Summary of the Invention or any one of Embodiments 4 through 4A wherein the nominal mole ratio of copper in the copper catalyst to the 3-amino-2-chloropyridine (2) is not more than about 2.

Embodiment 4C. The method of Embodiment 4B wherein the nominal mole ratio of copper in the copper catalyst to the 3-amino-2-chloropyridine (2) is not more than about 0.6. Embodiment 5. The method of preparing 2,3-dichloropyridine (1) as set forth in the

Summary of the Invention or any one of Embodiments 4 through 4A wherein at least about 75% of the copper is in the copper(II) oxidation state.

Embodiment 5 A. The method of Embodiment 5 wherein at least about 90% of the copper is in the copper(II) oxidation state. Embodiment 5B. The method of Embodiment 5A wherein at least about 95% of the copper is in the copper(II) oxidation state.

Embodiment 5C. The method of Embodiment 5B wherein at least about 99% of the copper is in the copper(II) oxidation state.

Embodiment 5D. The method of Embodiment 5C wherein about 100% of the copper is in the copper(II) oxidation state.

Embodiment 6. The method of preparing 2,3-dichloropyridine (1) as set forth in the Summary of the Invention wherein the nominal mole ratio of copper(II) in the copper catalyst to the 3-amino-2-chloropyridine (2) (i.e. ratio of molar equivalents of copper(II) to moles of 3-amino-2-chloropyridine) is at least about 0.05. Embodiment 6A. The method of Embodiment 6 wherein the nominal mole ratio of the copper(II) in the copper catalyst to the 3-amino-2-chloropyridine (2) is at least about 0.2.

Embodiment 6B. The method of preparing 2,3-dichloropyridine (1) as set forth in the Summary of the Invention or any one of Embodiments 6 through 6A wherein the nominal mole ratio of copper(II) in the copper catalyst to the 3-amino-2-chloropyridine (2) is not more than about 2.

Embodiment 6C. The method of Embodiment 6B wherein the nominal mole ratio of the copper(II) in the copper catalyst to the 3-amino-2-chloropyridine (2) is not more than about 0.6.

Embodiment 7. The method of preparing 2,3-dichloropyridine (1) as set forth in the Summary of the Invention or any one of Embodiments 4 through 4A, 5 through 5D, or 6 through 6C wherein the copper catalyst comprises copper(II) chloride or copper(II) oxide.

Embodiment 7A. The method of Embodiment 7 wherein the copper catalyst comprises copper(II) chloride.

Embodiment 8. The method of preparing 2,3-dichloropyridine (1) as set forth in the Summary of the Invention wherein the nominal mole ratio of sulfamic acid to the nitrite salt (i.e. moles of nitrite ion) in excess relative to 3-amino-2-chloropyridine (2) is at least about 1. Embodiment 8 A. The method of Embodiment 8 wherein the nominal mole ratio of sulfamic acid to the nitrite salt in excess relative to 3-amino-2-chloropyridine (2) is at least about 2.

Embodiment 8B. The method of preparing 2,3-dichloropyridine (1) as set forth in the Summary of the Invention or any one of Embodiments 8 through 8A wherein the nominal mole ratio of sulfamic acid to the nitrite salt in excess relative to 3-amino-2- chloropyridine (2) is not more than about 4.5.

Embodiment 8C. The method of Embodiment 8B wherein the nominal mole ratio of sulfamic acid to the nitrite salt in excess relative to 3-amino-2-chloropyridine (2) is not more than about 2.5. Embodiment 9. The method of preparing 2,3-dichloropyridine (1) as set forth in the

Summary of the Invention wherein step (1) is conducted at a temperature of at least about -15 ⁰C.

Embodiment 9 A. The method of Embodiment 9 wherein step (1) is conducted at a temperature of at least about -10 ⁰C. Embodiment 9B. The method of preparing 2,3-dichloropyridine (1) as set forth in the Summary of the Invention or any one of Embodiments 9 through 9 A wherein step (1) is conducted at a temperature of not more than about 45 ⁰C.

Embodiment 9C. The method of Embodiment 9B wherein step (1) is conducted at a temperature of not more than about 20 ⁰C. Embodiment 10. The method of preparing 2,3-dichloropyridine (1) as set forth in the

Summary of the Invention wherein step (2) is conducted at a temperature of at least about Embodiment 1OA. The method of Embodiment 10 wherein step (2) is conducted at a temperature of at least about -10 ⁰C.

Embodiment 1OB. The method of preparing 2,3-dichloropyridine (1) as set forth in the Summary of the Invention or any one of Embodiments 10 through 1OA wherein step (2) is conducted at a temperature of not more than about 20 ⁰C.

Embodiment 1OC. The method of Embodiment 1OB wherein step (2) is conducted at a temperature of not more than about 10 ⁰C.

Embodiment 11. The method of preparing 2,3-dichloropyridine (1) as set forth in the Summary of the Invention wherein step (3) is conducted at a temperature of at least about 30 ⁰C.

Embodiment 1 IA. The method of Embodiment 11 wherein step (3) is conducted at a temperature of at least about 50 ⁰C.

Embodiment HB. The method of preparing 2,3-dichloropyridine (1) as set forth in the Summary of the Invention or any one of Embodiments 11 through HA wherein step (3) is conducted at a temperature of not more than about 90 ⁰C.

Embodiment 11C. The method of Embodiment 1 IB wherein step (3) is conducted at a temperature of not more than about 80 ⁰C.

Embodiments of this invention, including Embodiments 1 through HC above as well as any other embodiments described herein, can be combined in any manner. Combinations of Embodiments 1 through 11C are illustrated by:

Embodiment A. The method of preparing 2,3-dichloropyridine (1) as set forth in the Summary of the Invention wherein the copper catalyst comprises copper(II) chloride or copper(II) oxide; the nominal mole ratio of the nitrite salt to the 3-amino-2-chloropyridine (2) is from about 0.95 to about 2; the nominal mole ratio of copper(II) in the copper catalyst to the 3-amino-2-chloropyridine (2) is from about 0.05 to about 2; the nominal mole ratio of sulfamic acid to the nitrite salt in excess relative to 3-amino-2-chloropyridine (2) is from about 1 to about 4.5; the nominal mole ratio of hydrochloric acid to the 3-amino-2- chloropyridine (2) in step (1) is from about 3 to about 10; and the nominal mole ratio of hydrochloric acid in step (3) to the 3-amino-2-chloropyridine (2) is from 0 to about 10. Embodiment B. The method of Embodiment A wherein the nominal mole ratio of the nitrite salt to the 3-amino-2-chloropyridine (2) is from about 0.95 to about 1.1; the nominal mole ratio of the copper(II) in the copper catalyst to the 3-amino-2-chloropyridine (2) is from about 0.2 to about 0.6; the nominal mole ratio of sulfamic acid to the nitrite salt in excess relative to 3-amino-2-chloropyridine (2) is from about 2 to about 2.5; the nominal mole ratio of the hydrochloric acid to 3-amino-2-chloropyridine (2) in step (1) is from about 3 to about 6; and the nominal mole ratio of the hydrochloric acid in step (3) to 3-amino-2- chloropyridine (2) is from about 1 to about 5. Embodiment C. The method of preparing 2,3-dichloropyridine (1) as set forth in the Summary of the Invention wherein step (1) is conducted at a temperature ranging from about -15 to about 45 ⁰C; Step (2) is conducted at a temperature ranging from about -15 to about 20 ⁰C; and step (3) is conducted at a temperature ranging from about 30 to about 90 ⁰C. Embodiment D The method of Embodiment C wherein step (1) is conducted at a temperature ranging from about -10 to about 25 ⁰C; Step (2) is conducted conducted at a temperature ranging from about -10 to about 10 ⁰C; and step (3) is conducted at a temperature ranging from about 50 to about 80 ⁰C.

According to the method of the present invention as shown in Scheme 1, 2,3-dichloropyridine (1) is prepared by forming the hydrochloric acid salt of 2-chloro-3- aminopyridine (2), and then followed by decomposition of the diazonium chloride salt in the presence of sulfamic acid and a copper(II) catalyst wherein at least about 50% of the copper is the copper(II) oxidation state.

Scheme 1

2¹

In the present method, the diazonium salt is prepared from the hydrochloride salt (alternatively described as the hydrochloric acid salt) of 3-amino-2-chloropyridine (2). The hydrochloride salt is prepared by contacting 3-amino-2-chloropyridine or a solution comprising 3-amino-2-chloropyridine with hydrochloric acid (i.e. hydrogen chloride dissolved in water. A wide variety of procedures are useful for preparing the hydrochloride salt of 3-amino-2-chloropyridine. For example, solid 3-amino-2-chloropyridine can be added to aqueous hydrochloric acid, or aqueous hydrochloric acid can be added to solid 3- amino-2-chloropyridine. Alternatively, a solution of 3-amino-2-chloropyridine in a water- immiscible or miscible solvent can be mixed with aqueous hydrochloric acid, in either order of addition. Most conveniently, aqueous hydrochloric acid is added to solid 3-amino-2- chloropyridine to form an aqueous solution of the hydrochloride salt of 3-amino-2- chloropyridine. Stoichiometry requires at least one mole (i.e. molar equivalent) of hydrochloric acid (i.e. hydrogen chloride dissolved in water) per mole of 3-amino-2- chloropyridine to completely form the hydrochloride salt. Typically at least about 3 molar equivalents of hydrochloric acid is used, and typically the amount does not exceed about 10 molar equivalents and more typically does not exceed about 6 molar equivalents. Although lower concentrations of aqueous hydrogen chloride (HCl) can be used in this step, typically the concentration of hydrogen chloride in water before contact with 3-amino-2- chloropyridine is at least about 10% and can be as high as about 37% by weight, which is limited by the solubility of hydrogen chloride in water. The 3-amino-2-chloropyridine can be contacted with hydrochloric acid over a wide range of temperatures. Typically for sake of convenience, 3-amino-2-chloropyridine is contacted with hydrochloric acid near ambient temperature. Because the formation of the hydrochloride salt is exothermic, cooling the hydrochloric acid can be advantageous, such that contact occurs at a temperature between about -15 and 45 ⁰C, and more particularly between about -10 and 20 ⁰C. Although the hydrochloride salt of 3-amino-2-chloropyridine can be isolated (e.g., by evaporation of the hydrochloric acid and any other solvents) before forming the solution for diazotization, most conveniently the aqueous solution of the hydrochloride salt of 3-amino-2-chloropyridine is used directly in the diazotization step.

The diazonium chloride salt can be prepared by reaction of the hydrochloride salt of 3-amino-2-chloropyridine (2) with nitrous acid in an aqueous solution at a suitable temperature. The nitrous acid can be generated in situ from a nitrite salt and hydrochloric acid. As the nitrite ion is all that is required to form nitrous acid in the presence of hydrochloric acid, a wide range of nitrite salts can be used. Common examples of nitrite salts include alkali and alkaline earth metal nitrites, such as sodium nitrite, potassium nitrite or calcium nitrite. A preferred nitrite salt is sodium nitrite, because it is commercially available at low cost. Although any amount of nitrite will result in some yield of product, typically at least about 0.95 and more typically at least about one molar equivalent of nitrite salt (i.e. providing one mole of nitrite ion) per mole of compound of Formula 2 is used so that the compound of Formula 2 is completely diazotized. As the amount of nitrite salt cannot always be precisely measured particularly in commercial-scale manufacture, preferably an excess of nitrite is used to ensure complete diazotization of the compound of Formula 2. Furthermore the benefits of including sulfamic acid in the copper catalyst mixture according to the present invention are primarily realized when more than one molar equivalent of nitrite salt per mole of compound of Formula 2 is employed. Although larger amounts of nitrite salts can be used, typically no more than about 2 molar equivalents and more typically no more than about 1.1 molar equivalents of nitrite salt is added to diazotize the compound of Formula 2. For references on how to prepare diazonium salts, see H. Zollinger, Azo and Diazo Chemistry, Wiley-Interscience, New York, 1961; S. Patai, The Chemistry of Diazonium and Diazo Groups, Wiley, New York, 1978, Chapters 8, 11 and 14; and H. Saunders and R. L. M. Allen, Aromatic Diazo Compounds, Third Edition, Edward Arnold, London, 1985. In one embodiment of the process of the present invention, a solution comprising 3-amino-2-chloropyridine (2) is contacted with an aqueous solution comprising hydrochloric acid to form a solution of 3-amino-2-chloropyridine hydrochloric acid salt. The 3-amino-2-chloropyridine hydrochloric acid salt solution is then contacted with an aqueous solution comprising a nitrite salt to form a diazonium chloride salt. Diazotization of the 3-amino-2-chloropyridine hydrochloric acid salt is accomplished by adding aqueous nitrite (e.g., sodium nitrite) solution to a mixture of the 3-amino-2- chloropyridine (2) in aqueous HCl (i.e. hydrochloric acid). Although lower concentrations of aqueous HCl can be used in this step, typically the concentration of HCl before addition of other components into the aqueous reaction mixture is at least about 10% and can be as high as about 37%, which is limited by the solubility of hydrogen chloride in water. Additional embodiments for these steps of the present method are described above.

To form 2,3-dichloropyridine (1), the diazonium chloride salt is decomposed in the presence of hydrochloric acid, sulfamic acid and a copper catalyst wherein at least about 50% of the copper is the copper(II) oxidation state. In additional embodiments, at least about 75%, at least about 90%, at least about 95%, at least about 99%, or 100% of the copper is the copper(II) oxidation state. As a Cu⁺² ion (i.e., copper(II)) complexed with chloride ligands is believed to be the catalytic species in the aqueous decomposition solution containing hydrochloric acid, a wide range of copper salts and other compounds can be added as the copper catalyst. As the copper catalyst is dissolved in aqueous decomposition solution, typically the copper catalyst is soluble in water and particularly hydrochloric acid. However, copper compounds such as copper(II) oxide that are insoluble in water, can nevertheless be used as the catalyst, because on contact with hydrochloric acid they are converted to soluble copper(II) chloride. The copper catalyst can comprise, for example but not limited to, copper(II) acetate, copper(II) nitrate, copper(II) sulfate, copper(II) oxide or copper(II) chloride. In one embodiment the copper catalyst comprises copper(II) oxide, copper(II) chloride or copper(II) chloride generated in situ from CuO and hydrochloric acid. In other embodiments at least 75% of the copper is copper(II) chloride; at least 90% of the copper is copper(II) chloride; at least 99% of the copper is copper(II) chloride; at least 99% of the copper is copper(II) chloride; 100% of the copper is copper(II) chloride; at least 75% of the copper is copper(II) oxide; at least 90% of the copper is copper(II) oxide; at least 95% of the copper is copper(II) oxide; at least 99% of the copper is copper(II) oxide; and 100% of the copper is copper(II) oxide.

The decomposition is conducted in an aqueous solution, which can be in a single liquid phase or, alternatively, one liquid phase of a two-phase system. The aqueous decomposition solution typically starts with up to about 10 molar equivalents, more typically from about 1 to about 5 molar equivalents, of HCl (relative to starting 3-amino-2-chloropyridine (2)) in the form of typically from about 10% to about 37% aqueous hydrochloric acid.

Although a wide range of amounts of copper catalyst can be included in the aqueous decomposition solution, typically at least about 0.05 molar equivalent of copper catalyst (particularly Cu(II)) relative to starting 3-amino-2-chloropyridine (2) is used to obtain a significant reaction rate. More typically at least about 0.2 molar equivalent of copper catalyst (particularly Cu(II)) is used to obtain a rapid reaction rate. Although large amounts of copper catalyst can be used, this adds to cost and waste processing. Typically no advantage is found from using more than about 2 molar equivalents of copper catalyst (particularly Cu(II)), and as a catalyst, the amount used is typically less than 1 molar equivalent. Typically the amount of copper catalyst (particularly Cu(II)) does not exceed about 0.6 molar equivalents.

According to the present improved method, sulfamic acid (in the form of H₂NSO₃H) is included in the aqueous decomposition solution. Remarkably, the sulfamic acid has been discovered not to interfere with the decomposition reaction forming the compound of Formula 1. Although sulfamic acid can be added concurrently or in portions during addition of the diazonium salt solution, most conveniently all of the sulfamic acid is added to the decomposition solution before beginning addition of diazonium salt solution. If the sulfamic acid is added concurrently during addition of the diazonium salt solution, best results are obtained if a sufficient amount of sulfamic acid is maintained in the aqueous decomposition solution to scavenge the excess nitrous acid in the diazonium salt solution being added. The stoichiometry of the scavenging reaction of sulfamic acid with nitrous acid is believed to be equimolar. Although any amount of sulfamic acid helps prevent catalyst deactivation caused by excess nitrous acid, scavenging all the excess nitrous acid requires at least about 1 mole of sulfamic acid per molar equivalent of nitrite salt in excess of the compound of Formula 2. As excess sulfamic acid has little disadvantage other than added cost, typically at least about 2 moles of sulfamic acid is used per molar equivalent of nitrite salt in excess of the compound of Formula 2. Typically no more than about 4.5 moles, more typically no more than about 2.5 moles, of sulfamic acid is used per molar equivalent of nitrite salt in excess of the compound of Formula 2.

The temperature of the aqueous decomposition solution during addition of the diazonium salt solution is typically maintained in a range from about 40 to about 90 ⁰C. More typically the decomposition temperature is maintained in a range from about 50 to about 80 ⁰C, which provides convenient rates of reaction and gives high product yields. Achieving these temperatures can require externally heating the aqueous decomposition solution, but as the decomposition is exothermic, cooling may be required, particularly for large-scale preparations.

If the decomposition is conducted using a single liquid phase, the 2,3- dichloropyridine (1) product can be isolated by allowing the reaction mixture to cool to ambient (e.g., 15-30 ⁰C) temperature, optionally adding a base to neutralize the reaction mixture, and then collecting the solid product by filtration. Steam-distillation is particularly convenient for isolating 2,3-dichloropyridine (1) from the reaction mixture in large-scale preparations. For this isolation method, steam (typically at about atmospheric pressure) is injected into the neutralized reaction mixture. The resulting distillate is condensed at about 80 ⁰C into a liquid mixture consisting essentially of a mixture of 2,3-dichloropyridine and water. The liquid condensate mixture is added into water maintained at about 15-25 ⁰C, causing the 2,3-dichloropyridine to crystallize. The 2,3-dichloropyridine product is then isolated by filtration of the resulting slurry. As already mentioned, the decomposition can also be conducted using a two-phase system comprising a suitable organic solvent along with the aqueous solution of the one- phase system. To be suitable, the organic solvent needs only to be immiscible with water (to form a two-phase system) and be inert to the reaction conditions. Therefore a very wide variety of organic solvents are suitable. Examples of common suitable organic solvents include ethers such as tetrahydrofuran, hydrocarbons such as cyclohexane, benzene and toluene, halogenated hydrocarbons such as 1-chlorobutane, and esters such as ethyl acetate. The volume ratio of the organic phase to the aqueous phase in the two-phase system typically ranges from about 1 :10 to about 10:1. The product, 2,3-dichloropyridine (1), in the two-phase system can be isolated by dilution of the reaction mass with water or aqueous base, phase-separation, and concentration of the organic phase to dryness. The 2,3- dichloropyridine (1) product can also be isolated from the organic phase by crystallization. The crystallization can be achieved by partial concentration of the organic solution, optionally with addition of an "antisolvent" such as heptane or water. The term "antisolvent" means a liquid diluent which when added to a solution of the desired product reduces the solubility of the product in the resulting mixture. Thus, if the solvent is a polar solvent such as an amide (e.g., Λ/,Λ/-dimethylformamide) or a lower alcohol (e.g., ethanol), water can be used as an antisolvent. On the other hand, if the solvent is a moderately nonpolar solvent, such as ethyl acetate or dichloromethane, a nonpolar solvent such as a hydrocarbon (e.g., cyclohexane or heptane) can be used as an antisolvent. With the present method, the isolated yield of 2,3-dichloropyridine (1) (ca. 98% purity) can be as high as 90- 95% starting from pure 3-amino-2-chloropyridine (2). The aqueous phase from the phase- separation can be recycled directly into a subsequent decomposition batch, optionally with partial concentration, to reuse the Cu(II) salt catalyst and excess hydrochloric acid.

According to the multi-step method shown in Scheme 2, 2,3-dichloropyridine (1) can be prepared by chlorination of 3-aminopyridine (3) followed by diazotization of the resulting 2-chloro-3-aminopyridine (2) intermediate and decomposition of the diazonium chloride salt in the presence of sulfamic acid. Scheme 2

3 2 1

Preparing 3-amino-2-chloropyridine (2) by reacting 3-aminopyridine (3) with hydrochloric acid and hydrogen peroxide at a temperature of 70-80 ⁰C has been reported (O. von Schickh, A. Binz, and A. Schultz, Chem. Ber., 1936, 69, 2593). This method was optimized by Yuan et al. (Zhongguo Yiyao Gongye Zazhi, 2000, 31, 420), to reduce the amount of over-chlorinated product to 8% by weight by lowering the reaction temperature to 20-30 ⁰C and using 1 molar equivalent of 15% by weight hydrogen peroxide and concentrated aqueous HCl (ca. 37 % by weight) as chlorinating agent. Preparation of 3-amino-2-chloropyridine (2) by transition metal-catalyzed chlorination of 3-aminopyridine (3) has also been reported (Blank et al., US 3,838,136). This method, while providing better yields on production scale than von Schickh's method described above, has the disadvantages that a hazardous material (chlorine) is required, the product is isolated as a solid in relatively impure form (ca. 87 % by weight), and the metal catalysts are not easily recyclable, thus potentially causing waste-disposal issues. Purification of 3-amino-2-chloropyridine (2), prepared by the method of Blank et al., from the by-product, 3-amino-2,6-dichloropyridine, was described by K. Ieno in JP 09227522.

A more selective chlorination method to produce higher quality 3-amino-2- chloropyridine (2) from 3-aminopyridine (3) was described by R. Shapiro in WO 2005/070888. High strength hydrogen peroxide (from about 20 to about 50 % by weight), concentrated HCl, and a low temperature (from about 10 to about 35 ⁰C) were employed to minimize over-chlorinated products (primarily 3-amino-2,6-dichloropyridine). Furthermore, a modification of the Ieno method by using sodium hydroxide instead of NH₃ to adjust the pH of the reaction mixture to about 0.4 followed by extraction with dichloroethane instead of toluene allows easy purification of 3-amino-2-chloropyridine (2) and the formation of a hydrochloric acid salt of 3-amino-2-chloropyridine (2) suitable for the diazotization step without recourse to recrystallization and filtration. A reaction yield of about 70 to about 80% with greater than 90% conversion of 3-aminopyridine (3) can be obtained by this improved method. A method to prepare 2,3-dichloropyridine (1) without having to isolate intermediate solids was also described by R. Shapiro in WO 2005/070888. Scheme 3 depicts this method improved according to the present invention by including sulfamic acid with the Cu(II)- containing catalyst in the conversion of 3-aminopyridine (3) to 2,3-dichloropyridine (1). The improved method thus involves Hofmann rearrangement of nicotinamide (4) to form 3- aminopyridine (3), selective chlorination of 3-aminopyridine (3) with a suitable chlorinating agent, diazotization of the 2-chloro-3-aminopyridine (2), and decomposition of the diazonium chloride salt with copper catalyst wherein at least about 50% of the copper is the copper(II) oxidation state in the presence of sulfamic acid.

Scheme 3

It is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Percentages are by weight except for where otherwise indicated. Quantitative HPLC of the product was performed using a Zorbax Eclipse XDB-C8® pre-packed chromatography column (reversed phase column manufactured by Agilent Technologies, Palo Alto, CA 94303) (3 μm particle size, 4.6 mm x 15 cm, eluent 15-95% acetonitrile / water containing 0.05% trifluoroacetic acid).

COMPARISON EXAMPLE 1

Preparation of 2,3-dichloropyridine (1)

In this example, a 7% molar excess of sodium nitrite was used to diazotize 3-amino-2- chloropyridine (2), resulting in residual nitrous acid in the diazonium salt solution to be contacted with the copper catalyst. Portions of this diazonium salt solution were contacted with the copper catalyst in the presence or absence of sulfamic acid in order to evaluate the effect of including sulfamic acid according to the present method.

A l-L reactor equipped with a thermometer, addition funnel and nitrogen inlet was charged with 52.2 g (0.40 mol) of commercial grade 3-amino-2-chloropyridine (2) and 320 g (1.75 mol, 4.35 eq) of 20% aqueous HCl while maintaining the temperature at around 15 ⁰C.

After the mixture was cooled to 5 ⁰C, a solution of 30.4 g (0.428 mmol, 1.07 eq) of sodium nitrite in 60 g of water was added over 30 minutes at 5 to 10 ⁰C. The mixture was allowed to stir for 15 minutes at 5 ⁰C. The diazonium salt solution was then divided into 2 equal portions (232 g each). The two portions of diazonium salt solution were maintained at 5 ⁰C before proceeding to Procedures A and B below.

Procedure A (without sulfamic acid):

One half of the diazonium salt solution prepared above was pumped into a solution of 10.23 g (60 mmol, 0.30 eq) of copper(II) chloride dihydrate in 60.0 g (0.325 mol) of 20% aqueous HCl over 30 minutes while maintaining the reaction temperature at 55-62 ⁰C and qualitatively monitoring nitrogen evolution with an oil bubbler. Off-gassing started about 5 minutes into the addition (beginning with vigorous off-gassing and foaming) and stopped almost immediately when the addition was completed. Noteworthy was the fact that the reaction temperature started to drop during the addition and the heat input had to be increased to maintain the reaction temperature between 55 and 62 ⁰C, thus indicating that the catalyst had been deactivated.

Procedure B (with sulfamic acid): The other half of the diazonium salt solution was pumped into a solution of 10.23 g (60 mmol, 0.30 eq) of copper(II) chloride dihydrate and 2.72 g (28 mmol, 2 moles per mole of excess nitrite) of sulfamic acid in 60.0 g (0.325 mol) of 20% aqueous HCl over 30 minutes while maintaining the reaction temperature at 55-62 ⁰C and qualitatively monitoring nitrogen evolution with an oil bubbler. Noteworthy was the fact that no delay in off-gassing was observed, and that the reaction temperature started increasing during the addition and the heat input had to be turned off to keep the reaction temperature between 55 and 62 ⁰C, thus indicating that the catalyst had not been deactivated.

Both reaction mixtures were allowed to cool to room temperature, and 37% aqueous HCl was then added until all of the solids were dissolved (more acid was required for procedure B due to the higher content of product). Upon completion of hydrochloric acid addition, the solution from Procedure A weighed 377 g whereas the solution from Procedure B weighed 436 g due to the additional acid required to dissolve the solids. The solutions were assayed for 3-amino-2-chloropyridine (2) and 2,3-dichloropyridine (1) by HPLC weight % analysis relative to an external standard, and results are shown in Table A below.

Table A

The results in Table A show that the presence of sulfamic acid during the decomposition of the diazonium salt significantly improved the yield of the 2,3- dichloropyridine (1) according to the present invention.

Claims

CLAIMSWhat is claimed is:

1. A method for preparing 2,3-dichloropyridine (1),

comprising the steps of:

with hydrochloric acid to form a 3-amino-2-chloropyridine hydrochloric acid salt; (2) contacting the 3-amino-2-chloropyridine hydrochloric acid salt with a nitrite salt to form a corresponding diazonium chloride salt; and

(3) contacting the corresponding diazonium chloride salt with hydrochloric acid in the presence of sulfamic acid and a copper catalyst wherein at least about 50% of the copper is the copper(II) oxidation state, optionally in the presence of an organic solvent, to form 2,3- dichloropyridine (1).

2. The method of Claim 1 wherein the nitrite salt is sodium nitrite.

3. The method of Claim 1 wherein at least about 75% of the copper is the copper(II) oxidation state.

4. The method of Claim 3 wherein at least about 95% of the copper is the copper(II) oxidation state.

5. The method of Claim 4 wherein 100% of the copper is the copper(II) oxidation state.

6. The method of Claim 1 wherein the copper catalyst comprises copper(II) chloride or copper(II) oxide.

7. The method of Claim 6 wherein the nominal mole ratio of the nitrite salt to the 3- amino-2-chloropyridine (2) is from about 0.95 to about 2; the nominal mole ratio of copper(II) in the copper catalyst to the 3-amino-2-chloropyridine (2) is from about 0.05 to about 2; the nominal mole ratio of sulfamic acid to the nitrite salt in excess relative to 3- amino-2-chloropyridine (2) is from about 1 to about 4.5; the nominal mole ratio of hydrochloric acid to the 3-amino-2-chloropyridine (2) in step (1) is from about 3 to about 10; and the nominal mole ratio of hydrochloric acid in step (3) to the 3-amino-2-chloropyridine (2) is from O to about 10.

8. The method of Claim 7 wherein the nominal mole ratio of the nitrite salt to the 3-amino-2-chloropyridine (2) is from about 0.95 to about 1.1; the nominal mole ratio of the copper(II) in the copper catalyst to the 3-amino-2-chloropyridine (2) is from about 0.2 to about 0.6; the nominal mole ratio of sulfamic acid to the nitrite salt in excess relative to 3- amino-2-chloropyridine (2) is from about 2 to about 2.5; the nominal mole ratio of the hydrochloric acid to 3 -amino-2-chloropyridine (2) in step (1) is from about 3 to about 6; and the nominal mole ratio of the hydrochloric acid in step (3) to the 3 -amino-2-chloropyridine (2) is from about 1 to about 5.

9. The method of Claim 1 wherein step (1) is conducted at a temperature ranging from about -15 to about 45 ⁰C; Step (2) is conducted at a temperature ranging from about

-15 to about 20 ⁰C; and step (3) is conducted at a temperature ranging from about 30 to about 90 ⁰C.

10. The method of Claim 9 wherein step (1) is conducted at a temperature ranging from about -15 to about 20 ⁰C; Step (2) is conducted at a temperature ranging from about -10 to about 10 ⁰C; and step (3) is conducted at a temperature ranging from about 50 to about 80 ⁰C.