WO2014093566A1

WO2014093566A1 - An improved process for the removal of palladium from 4-amino-3-halo-5-fluoro-6-(aryl) pyridine-2-carboxylates and 4-amino-3-halo-6-(aryl)pyridine-2-carboxylates

Info

Publication number: WO2014093566A1
Application number: PCT/US2013/074529
Authority: WO
Inventors: Jossian Oppenheimer; Mark V. M. EMONDS
Original assignee: Dow AgroSciences LLC
Current assignee: Corteva Agriscience LLC
Priority date: 2012-12-13
Filing date: 2013-12-12
Publication date: 2014-06-19
Anticipated expiration: 2015-06-13
Also published as: US20140170058A1; AR093947A1; BR102013031985A2

Abstract

Residual palladium is removed and recovered from 4-amino-3-halo-5-fluoro-6-(aryl)pyridine-2-carboxylates and 4-amino-3-halo-6-(aryl)pyridine-2-carboxylates by treatment with an aqueous solution containing from about 20 to about 50% of an alkali metal bisulfite at a temperature from about 60 to about 90 °C and a pH from about 2.0 to about 8.0.

Description

AN IMPROVED PROCESS FOR THE REMOVAL OF PALLADIUM FROM 4-AMINO-3- HALO-5-FLUORO-6-(ARYL) PYRIDINE-2-CARBOXYLATES AND 4-AMINO-3- H ALO- 6- ( ARYL)P YRIDINE-2- C ARB OX YLATES

Background Provided herein are improved processes for the removal of palladium from protected or unprotected 4-amino-3-halo-5-fluoro-6-(aryl)pyridine-2-carboxylates and 4-amino-3-halo- 6-(aryl)pyridine-2-carboxylates.

U.S. Patents 6,784,137 B2 and 7,314,849 B2 describe inter alia certain 4-amino-3- halo-5-fluoro-6-(aryl)pyridine-2-carboxylate and 4-amino-3-halo-6-(aryl)pyridine-2- carboxylate compounds and their use as herbicides. More often than not, these herbicides are prepared from coupling reactions involving a pyridine-2-carboxylate having either a facile leaving group or a metal derivative in the 6-position of the pyridine ring. Such coupling reactions usually employ a transition metal catalyst, in particular a palladium catalyst such as palladium(II) acetate or bis(triphenylphosphine)palladium(II) dichloride. For reasons of both product stewardship and economics, it is important to remove and recover the palladium used in the manufacturing process from the herbicide product.

Using a toluene extraction - sodium bisulfite (NaHS0₃) wash procedure, as described in Bullock, K. M. et al. Org. Process Res. Dev. 2008, 12, 896-899, for a pharmaceutical product synthesized via a Suzuki-Miyaura coupling, the palladium levels in the final product were reduced from 12,000 ppm to about 100 ppm. When this procedure, namely treatment with 20% NaHS0₃ at 60 °C for 1 hour (h), is applied to protected or unprotected 4-amino-3- halo-5-fluoro-6-(aryl)pyridine-2-carboxylate and 4-amino-3-halo-6-(aryl)pyridine-2- carboxylate herbicides, however, palladium levels are found to be reduced from about 1,500 ppm to only about 600 ppm. It would be desirable to have a process that reduces residual palladium levels in protected or unprotected 4-amino-3-halo-5-fluoro-6-(aryl)pyridine-2- carboxylate and 4-amino-3-halo-6-(aryl)pyridine-2-carboxylate herbicides to less than 100 ppm. It would also be desirable to be able to efficiently recover the palladium from the process. Summary

Provided herein are processes for the removal of residual palladium from the manufacture of protected or unprotected 4-amino-3-halo-5-fluoro-6-(aryl)pyridine-2- carboxylate and 4-amino-3-halo-6-(aryl)pyridine-2-carboxylate herbicides by a palladium- catalyzed coupling reaction. More particularly, provided herein are processes for the removal of residual palladium from the manufacture of a compound of Formula I

in which

X represents H or F, R¹ represents H or -C(0)CH₃, and

R² represents CrC₁₂ alkyl or an unsubstituted or substituted C₇-Cn arylalkyl by a palladium-catalyzed coupling reaction which comprises (a) contacting the compound of Formula I in a water-immiscible solvent with an aqueous solution containing from about 20 to about 50% of an alkali metal bisulfite at a temperature from about 60 to about 90 °C and a pH from about 2.0 to about 8.0; (b) separating the aqueous phase from the water-immiscible solvent phase; and (c) recovering the compound of Formula I from the water-immiscible solvent phase. Another aspect concerns recovering the residual palladium.

Detailed Description

The term "alkyl" and derivative terms such as "alkoxy," as used herein refer to straight chain or branched chain moieties. Typical CrC₁₂ alkyl groups are methyl, ethyl, propyl, 1-methylethyl, butyl, 1,1-dimethylethyl, 1-methylpropyl, 1-methylhexyl, 2- ethylhexyl, 1-methylheptyl and dodecyl. Methyl and ethyl are often preferred. The term "arylalkyl," as used herein, refers to a phenyl substituted alkyl group having a total of 7 to 11 carbon atoms, such as benzyl (-CH2C6H5), 2-methylnaphthyl (-CH2C1₀H7) and 1- or 2-phenethyl (-CH₂CH₂C6H₅ or -CH(CH₃)C₆H₅). The phenyl group may itself be unsubstituted or substituted with one or more substituents independently selected from halogen, nitro, cyano, Ci-C₆ alkyl, Ci-C₆ alkoxy, halogenated Ci-C₆ alkyl, halogenated Ci-C₆ alkoxy, Ci-C₆ alkylthio, C(0)OCi-C6 alkyl, or where two adjacent substituents are taken together as -0(CH₂)_nO- wherein n=l or 2, provided that the substituents are sterically compatible and the rules of chemical bonding and strain energy are satisfied.

Alkali metals refer to members of group 1 of the periodic table. Preferred alkali metal (group 1) salts are sodium and potassium salts.

Protected 4-amino-3-halo-5-fluoro-6-(aryl)pyridine-2-carboxylate and 4-amino-3- halo-6-(aryl)pyridine-2-carboxylate compounds refer to compounds in which the 4-amino group is protected by an acetyl group.

Protected or unprotected 4-amino-3-halo-5-fluoro-6-(aryl)pyridine-2-carboxylate and 4-amino-3-halo-6-(aryl)pyridine-2-carboxylate compounds are prepared from coupling reactions involving a pyridine-2-carboxylate having either a facile leaving group or a metal derivative in the 6-position of the pyridine ring. Such coupling reactions usually employ a transition metal catalyst, in particular a palladium catalyst such as palladium(II) acetate or bis(triphenylphosphine)palladium(II) dichloride (see U.S. Patents 6,784,137 B2 and

7,314,849 B2). After conventional work-up procedures, the isolated products typically contain between 900 and 1,500 ppm of residual palladium species.

For the palladium-removal process, the protected or unprotected 4-amino-3-halo-5- fluoro-6-(aryl)pyridine-2-carboxylate and 4-amino-3-halo-6-(aryl)pyridine-2-carboxylate compounds are dissolved in a water immiscible solvent or solvent mixture. Preferred water immiscible solvents or solvent mixtures are those which can also serve as solvents for the coupling reaction itself and include, for example, aromatic hydrocarbons such as toluene or xylene and solvent mixtures such as 4-methyl-2-pentanone, 1,2-dimethoxyethane and acetonitrile. The water immiscible solvent phase typically contains from about 10 to about 30% of the protected or unprotected 4-amino-3-halo-5-fluoro-6-(aryl)pyridine-2-carboxylate or 4-amino-3-halo-6-(aryl)pyridine-2-carboxylate compound. The protected or unprotected 4-amino-3-halo-5-fluoro-6-(aryl)pyridine-2-carboxylate or 4-amino-3-halo-6-(aryl)pyridine-2-carboxylate compound in the water-immiscible solvent is treated with from about 1 to about 6 molar equivalents of an aqueous solution containing from about 20 to about 50% of an alkali metal bisulfite at a temperature from about 60 to about 90 °C and a pH from about 2.0 to about 8.0 (pH ranges useful with the methods described herein can also be from about 3.8 to about 7.0, from about 5.5 to about 6.0, or be about 5.4). Preferably, from about 1 to about 2 molar equivalents of the aqueous solution containing about 20-30% of an alkali metal bisulfite at a temperature of about 80 °C and a pH of about 5.4 is employed. The pH is routinely controlled by the addition of sodium hydroxide (NaOH), most conveniently by the use of 20-50% aqueous NaOH.

After separating the aqueous phase from the water-immiscible solvent phase, the protected or unprotected 4-amino-3-halo-5-fluoro-6-(aryl)pyridine-2-carboxylate or 4-amino- 3-halo-6-(aryl)pyridine-2-carboxylate compound is recovered from the water-immiscible solvent phase by a crystallization process. The recovered protected or unprotected 4-amino- 3-halo-5-fluoro-6-(aryl)pyridine-2-carboxylate or 4-amino-3-halo-6-(aryl)pyridine-2- carboxylate contains less than 100 ppm of palladium, and in some embodiments, less than 50 ppm.

Sodium bisulfite forms an insoluble sodium palladium tetrasulfite dihydrate complex with the residual palladium in the protected or unprotected 4-amino-3-halo-5-fluoro-6- (aryl)pyridine-2-carboxylate or 4-amino-3-halo-6-(aryl)pyridine-2-carboxylate compound. This complex can be recovered by filtration and the palladium can be reclaimed by means well known to those of ordinary skill in the art.

The described embodiments and following examples are for illustrative purposes and are not intended to limit the scope of the claims. Other modifications, uses, or combinations with respect to the compositions described herein will be apparent to a person of ordinary skill in the art without departing from the spirit and scope of the claimed subject matter.

EXAMPLES

Example 1. Synthesis of methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3- methoxyphenyl)pyridine-2-carboxylate

To a 1 -liter (L) jacketed reactor equipped with a condenser, mechanical stirrer, thermocouple temperature probe, and nitrogen inlet was added methyl 4-(acetylamino)-3,6- dichloropyridine-2-carboxylate (40.0 grams (g), triphenylphosphine (0.4 g), and palladium(II) acetate (0.17 g) under a nitrogen atmosphere. A rinse with acetonitrile (previously degassed by sparging with nitrogen for 45 minutes (min); 25 milliliters (mL)) was employed to ensure all solids were transferred to the reactor. A 22 solution of 4-chloro-2-fluoro-3- methoxyphenylboronic acid (previously degassed by sparging with nitrogen for 45 min; total of 157.1 g) in 1,2-dimethoxyethane (DME) and methyl isobutyl ketone (MIBK) was added under nitrogen via a pump. The ratio of MIBK to DME (MIBK:DME) in the solution varies from 2:1 to 0.7:1 depending on the equivalents of the solvents used to prepare the 4-chloro-2- fluoro-3-methoxyphenylboronic acid solution; more commonly it varies from 1.6:1 to 1.2:1. Stirring at 300 RPM was initiated. Additional acetonitrile (previously degassed by sparging with nitrogen for 45 min; 100 mL) was added and complete dissolution was achieved. A 22.9% aqueous solution of potassium carbonate (previously degassed by sparging with nitrogen for 45 min; total of 275.3 g) was added via a pump. The solution was heated to about 50 °C for 3 hours. Toward the end of the reaction, the product tended to precipitate and a small product rind formed on the reactor wall. The organic phase of the mixture was sampled and analyzed by gas chromatography (GC) to determine reaction completion.

The mixture was heated to about 65 °C to ensure complete product dissolution. The mixture was filtered (polish filtration) at 65 °C to remove reduced palladium and inorganic salts. The organic and aqueous phases were separated at 65 °C.

Example 2. Removal of residual palladium from methyl 4-(acetylamino)-3-chloro-6- (4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate

Sixty-eight grams of the organic stream of the Suzuki coupling reaction (Example 1 ; containing 13 g of methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3- methoxyphenyl)pyridine-2-carboxylate, 1100 ppm palladium level in the solid) was warmed up to 60 °C using a water bath and transferred to a 250-mL reactor equipped with a water condenser, thermocouple temperature probe and a mechanical stirrer. A pH 5.4 (adjusted with sodium hydroxide) 30 weight percent (wt %) sodium bisulfite solution (NaHSC^; 93 mL) was added to the flask. The mixture was heated to 80 °C and held at that temperature for 6 h. After 6 h, the aqueous phase was drained and filtered through a Whatman #1 filter paper using a preheated filtration flask and a Buchner funnel. The hot organic phase was transferred to a heated bottle and 6 mL of organic solution was filtered using a 0.45 μιη syringe filter. The filtered organic phase was concentrated to dryness and further dried in a vacuum oven at 55 °C. The dried solid was submitted for palladium analysis using neutron activation analysis. The palladium content in the product was 82 ppm.

Claims

WHAT IS CLAIMED IS:

1. A process for the removal of residual palladium from the manufacture of a compound of Formula I

in which

X represents H or F,

R¹ represents H or -C(0)CH₃, and

R² represents CrC₁₂ alkyl or an unsubstituted or substituted C₇-Cn arylalkyl by a palladium-catalyzed coupling reaction which comprises

(a) contacting the compound of Formula I in a water-immiscible solvent with an aqueous solution containing from about 20 to about 50% of an alkali metal bisulfite at a temperature from about 60 to about 90 °C and a pH from about 2.0 to about 8.0;

(b) separating the aqueous phase from the water-immiscible solvent phase; and

(c) recovering the compound of Formula I from the water-immiscible solvent phase.

2. The process of claim 1, wherein the pH is between 5.5 and 6.0.

3. The process of claim 1 or claim 2, wherein the aqueous phase contains an insoluble sodium palladium tetrasulfite dihydrate complex that can be recovered by filtration.

4. A process for the recovery of residual palladium from the manufacture of a compound of Formula I

in which

X represents H or F, R¹ represents H or -C(0)CH₃, and R² represents CrC₁₂ alkyl or an unsubstituted or substituted C₇-Cn arylalkyl by a palladium-catalyzed coupling reaction which comprises

(a) contacting the compound of Formula I in a water-immiscible solvent with an aqueous solution containing from about 20 to about 50% of an alkali metal bisulfite at a temperature from about 60 to about 90 °C and a pH from about 2.0 to about 8.0; (b) separating the aqueous phase from the water-immiscible solvent phase; and

(c) recovering the residual palladium from the aqueous alkali metal bisulfite phase.

5. The process of claim 4, wherein the pH is between 5.5 and 6.0.

6. The process of claim 4 or claim 5, wherein the aqueous phase contains an insoluble sodium palladium tetrasulfite dihydrate complex that can be recovered by filtration.