WO2015075087A1

WO2015075087A1 - Process for selective chlorination of salicylic acid derivatives

Info

Publication number: WO2015075087A1
Application number: PCT/EP2014/075053
Authority: WO
Inventors: Eric George KLAUBER; Michael Rack; Thomas Zierke; Markus Kordes; Gerald SCHMELEBECK; Junmin JI; David Cortes
Original assignee: Basf Se
Priority date: 2013-11-21
Filing date: 2014-11-19
Publication date: 2015-05-28

Abstract

The present invention relates to a process for providing a compound of formula (IV), wherein R is - (C₁-C₄)alkyl, the process comprising the step of: reacting a compound of formula (III), wherein R is defined as above, in the presence of a Pd(ll) catalyst, a chlorine-containing reagent, a co-oxidant, and an acid.

Description

Process for selective chlorination of salicylic acid derivatives

Field of the invention The present invention relates to a process for selective chlorination of chlorine substituted salicylic acid derivatives. In particular, the present invention relates to a Pd(ll)-supported process for orf/70-chlorination of salicylic acid derivatives. The process according to the invention can in preferred embodiments be employed in improved reaction sequences in the production of the herbicide dicamba (3,6-dichloro-2- methoxybenzoic acid).

Background of the invention

Dicamba is a selective herbicide currently used for treating e.g. corn, wheat or grassland. It kills broadleaf weeds before and after they sprout. The trivial name dicamba refers to the compound 3,6-dichloro-2-methoxybenzoic acid, which is a dichlorinated salicylic acid derivative. The estimated global demand for dicamba in 2012 was about 12,000 million tons per year. However, it is expected that the global demand for dicamba will increase significantly.

Dicamba is typically produced on an industrial scale from 2,5-dichlorophenol using carboxylation under Kolbe-Schmitt conditions, methylation and subsequently

saponification/acidification. 2,5-Dichorophenol in turn can be obtained from 1 ,4- dichlorobenzene or 1 ,2,4-trichlorobenzene. A synthetic route via 1 ,4-dichlorobenzene involving nitration and subsequent diazotation may be undesired for use on an industrial scale. A synthetic route via 1 ,2,4-trichlorobenzenemay suffer from limited availability of this starting material and from the formation of several byproducts which are formed in the synthesis of 2,5-dichlorophenol.

In order to meet the increasing market demand for compounds such as dicamba, there is a need in the art for alternative processes providing acceptable yield and/or relying on alternative and readily available starting materials. Summary of the invention

In view of the above, it is the object of the present invention to provide a process suitable for providing 3,6-dichlorinated salicylic acid derivatives in alternative reaction sequences. It is a further object of the invention to provide a process for obtaining 3,6- dichlorinated salicylic acid derivatives with acceptable yield. According to a further object of the present invention, alternative reaction sequences for obtaining 3,6- dichlorinated salicylic acid derivatives are provided starting from alternative starting materials that are readily available. It is a further object of the present invention to implement the processes for the synthesis of 3,6-dichlorinated salicylic acid derivatives such as dicamba on an industrial scale.

The present invention relates to a process of providing 3,6-dichlorine substituted salicylic acid derivatives. In particular, the present invention relates to a process for providing a compound of formula (IV):

IV wherein R is -(Ci-C₄)alkyl.

The process comprises the step of: reacting a compound of formula (III)

III wherein R is defined as above,

in the presence of a Pd(ll) catalyst, a chlorine-containing reagent, a co-oxidant, acid. The above process can be employed in reaction sequences for obtaining commercially important 3,6-dichlorine substituted salicylic acid derivatives such as dicamba. The process can be employed on an industrial scale. Furthermore, reaction sequences for obtaining 3,6-dichlorine substituted salicylic acid derivatives employing the above process can make use of readily available starting materials that so far were not used for providing such products.

The present inventors have found that selective chlorination under Pd(ll) catalysis is suitable for providing 3,6-dichlorine substituted salicylic acid derivatives. A Pd(ll) catalyst suitable for use according to the invention is not specifically limited as long as it can support the above process. In a preferred embodiment, the Pd(ll) catalyst is selected from the group consisting of Pd(OAc)₂, PdCI₂, Pd(TFA)₂, Pd(OTf)₂,

PdCI₂(CH₃CN)₂, Pd(acac)₂ and PdCI₂(PPh₃)₂. More preferably, Pd(OAc)₂ is employed in the present invention as the Pd(ll) catalyst.

The term "OAc" refers in the context of the present invention to an acetate anion. The term "TFA" means according to the present invention an anion of trifluoroacetic acid. The term "OTf refers to an anion of trifluoromethanesulfonic acid. The term"acac" means an anion of acetylacetate. The term "PPh3" means phenylphosphine.

The chlorine-containing reagent used in the above process is not specifically limited as long as it can support the reaction. In a preferred embodiment, the chlorine-containing reagent is selected from the group consisting of N-chlorosuccinimide (NCS),

trichloroisocyanuric acid, trifluoromethanesulfonyl chloride, CuCI₂, CuCI₂/Cu(OAc)₂, and chlorine (Cl₂). The use of Cl₂ as a chlorine-containing reagent is e.g. described in

Fahey, J. Chem. Soc. Chem. Commun. 1970, 417 and D. Fahey, J. Organomet. Chem. 1971 , 27, 283. The use of a combination of CuCI₂ and Cu(OAc)₂ (CuCI₂/Cu(OAc)₂) as a chlorine-containing reagent is e.g. described in Wang et al., J. Am. Chem. Soc 2006, 128, 7416. More preferably, the chlorine-containing reagent is NCS or Cl₂. Most preferably, NCS is employed as the chlorine-containing reagent according to the present invention.

The co-oxidant employed according to the invention is not specifically limited as long as it can support the Pd(ll) catalyzed reaction. In a preferred embodiment, the co-oxidant is selected from the group consisting of K₂S₂Os, Na₂S₂Os, (NH₄)₂S₂O8, Cl₂, and oxygen (O₂). More preferably, the co-oxidant is Na₂S₂Os or Cl₂. In a specific embodiment, CI2 is employed as the chlorine-containing reagent and may also serve as the co-oxidant, so that it is not necessary to provide an additional agent as the co-oxidant. In another specific embodiment, CI2 is used as the co-oxidant and may also serve as the chlorine-containing reagent, so that it is not necessary to provide an additional agent as the chlorine-containing reagent. Rather, in these embodiments, CI2 may simultaneously serve as the chlorine-containing reagent and the co-oxidant.

The present inventors have further found that an additive selected from an acid is suitable to support the above process. In a preferred embodiment, the acid is selected from the group consisting of trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid (HOTf) and hydrogen chloride (HCI). More

preferably, the acid is HOTf.

In some embodiments, the above acid, e.g. trifluoroacetic acid, can also act as a solvent. In these embodiments, the use of an additional organic solvent is not required according to the invention. In other cases, the use of an additional solvent is preferred according to the invention. The organic solvent is not specifically limited and can be selected in accordance with the general knowledge of a person skilled in the art. In a preferred embodiment, the organic solvent is selected from the group consisting of dioxane, 1 ,2-dichloroethane (DCE), acetonitrile, dimethylsulfoxide (DMSO), N,N- dimethylformamide (DMF), N-methylpyrrolidone (NMP), Ν,Ν-dimethylacetamide (DMA), and Ν,Ν-dimethylpropionamide (DMP).More preferably, the organic solvent is DCE.

In the context of the present invention it is preferred to use only a small amount of Pd(ll) catalyst relative to the amount of the compound of formula (III), especially from the viewpoint of cost. Thus, in a preferred embodiment, about one molar equivalent of the compound of formula (III) is reacted in the presence of about 0.001 to about 0.1 molar equivalents of Pd(ll) catalyst, such as Pd(OAc)2. More preferably, about 0.02 to about 0.05 molar equivalents of Pd(ll) catalyst, e.g. Pd(OAc)2, are employed per one molar equivalent of the compound of formula (III).

The chlorine-containing reagent can be employed according to the invention in at least stoichiometric amounts. A large excess of chlorine-containing reagent is usually not necessary and, therefore, not preferred. Thus, in a preferred embodiment, about one molar equivalent of the compound of formula (III) is reacted in the presence of about 1 to about 1.5 molar equivalents of the chlorine-containing reagent, such as NCS. In case the chlorine-containing reagent can act as a donor of more than one chlorine atom, such as trichloroisocyanuric acid, the molar equivalents are calculated on the basis of the number of chlorine atoms capable to be donated. More preferably, about 1.1 molar equivalents of chlorine-containing reagent, e.g. NCS, are employed per one molar equivalent of the compound of formula (III).

In some embodiments, CI2 is used as the chlorine-containing reagent. In these embodiments, CI2 is preferably employed at a pressure of about 90 kPa to about 500 kPa.

The co-oxidant can be employed according to the invention in at least stoichiometric amounts. Too large an excess of co-oxidant is undesired in view of possible side reactions. Therefore, it is preferred according to the invention to employ the co-oxidant in an amount of about 1 to about 2 molar equivalents per one molar equivalent of the compound of formula (III). More preferably, the co-oxidant is employed in an amount of about 1.1 to about 1.3 molar equivalents per one molar equivalent of the compound of formula (III).

In embodiments where a gaseous co-oxidant such as O2 or CI2 is employed, it is preferably used at a pressure of about 90 kPa to about 500 kPa.

The acid can also be employed in at least stoichiometric amounts. An excess of acid is tolerated but usually not necessary. Therefore, it is preferred according to the invention to use about 1 to about 3 molar equivalents of the acid per one molar equivalent of the compound of formula (III). More preferably, about 1.1 to about 1.2 molar equivalents of the acid are used per one molar equivalent of the compound of formula (III).

The reaction temperature for carrying out the process is not specifically limited as long as the desired reaction can proceed at acceptable reaction rates. In a preferred embodiment, the step of reacting the compound of formula (III) is carried out at a temperature of about 40 °C to about 1 10 °C. More preferably, the reaction is carried out at a temperature of about 50 °C to about 100 °C, most preferably about 60 °C to about 90 °C, such as e.g. 60 °C. The above process can provide valuable chemical intermediates and can be implemented in reaction sequences for obtaining end products of high commercial importance. Thus, in one embodiment, the process according to the invention as defined above further comprises the step of reacting the compound of formula (IV) to obtain a compound of formula (V)

wherein R is as defined above.

The compounds of formula (III) used as starting material in the Pd(ll)-supported ortho- chlorination step can be obtained in various ways. In a preferred embodiment, the compound of formula (III) is obtained by reacting a compound of formula (II)

in the presence of an alkyl halide of the formula X-R, wherein X is CI, Br, or I, and is preferably CI, and R is as defined above.

The compound of formula (II) in turn also can be obtained in various ways. In a preferred embodiment, the compound of formula (II) is provided by reacting a compound of formula (I), i.e. 2-chlorophenol

in the presence of an alkali metal hydroxide and carbon dioxide to obtain the compound of formula (II). The compound of formula (I) is readily available on the market and can be provided on an industrial scale.

According to preferred embodiments of the present invention R is methyl.

In especially preferred embodiments, the processes according to the present invention are employed for obtaining dicamba. In these preferred embodiments, the compound of formula (V) is

Dicamba

Further embodiments of the present invention are apparent from the following detailed description and the attached claim set.

Detailed Description of the Invention

In the following, illustrative embodiments of the present invention are described in more detail.

The present invention relates to a process for ori/70-chlorination of salicylic acid derivatives under Pd(ll) catalysis as described in detail above. General principles for ori/70-chlorination reactions are e.g. described in X. Sun, et al., Angew. Chem. 2013, 125, 4536-4540. In preferred embodiments, the process according to the present invention can be implemented in reaction sequences for obtaining 3,6-dichlorine substituted salicylic acid derivatives starting from 2-chlorophenol. A person skilled in the art will comprehend that certain reaction steps in the following preferred sequences are preferred according to the invention as opposed to essential. In the preferred reaction sequence for obtaining 3,6-dichlorine substituted salicylic acid derivatives, 2-chlorophenol is employed as starting material. According to this preferred embodiment, the compound of formula (I), i.e. 2-chlorophenol, is subjected to a carboxylation reaction under Kolbe-Schmitt conditions to obtain a compound of formula (II).

In this carboxylation step, the compound of formula (I) may first be converted into the corresponding phenolate by treating with an alkali metal hydroxide. The term "alkali metal" when used in the context of the present invention refers to lithium, sodium or potassium. Sodium and potassium are preferred. Potassium hydroxide is a more preferred alkali metal hydroxide in this reaction step according to the invention. The alkali metal hydroxide can be used in about stoichiometric amounts in an aqueous solution having e.g. a concentration of 50 wt.-%. The conversion can be carried out in a suitable organic solvent such as e.g. xylene. Water can be removed from the system using azeotropic distillation.

Subsequently, the carboxylation step may involve contacting the phenolate with gaseous CO2 under high pressure. The phenolate solution in e.g. xylene can be used without further workup. The reaction affords the carboxylic acid salt of a compound formula (II), which typically is not soluble in the reaction medium such as xylene and, therefore, can easily be separated. The carboxylic acid salt of a compound of formula (II) may be used in the subsequent reaction step. Acidification using a suitable acid, such as HCI or H2SO₄, affords the corresponding acid of formula (II).

In a further preferred embodiment, the alkali metal salt of the compound of formula (II) is alkylated to obtain a compound of formula (III), wherein R is -(Ci-C₄)alkyl.

The alkylation reaction may be accomplished by reacting the compound of formula (II) in the form of a carboxylic acid salt of an alkali metal as described above with an alkyl halide of formula X-R, wherein X is halogen, such as CI, Br or I, preferably CI or Br, more preferably CI, and R is as defined above. In a preferred embodiment, the alkyl halide is methyl chloride. The reaction can be carried out in aqueous solution. During the reaction, the pH, temperature and pressure may be controlled such that the reaction is carried out at a pH of about 8 to about 10, a temperature of about 90 °C to about 100 °C and a pressure of about 500 to about 1050 kPa. An excess of alkyl halide is normally used.

Subsequently, the compound of formula (III) may be subjected to Pd(ll) catalyzed ortho- chlorination as described in detail above to obtain a compound of formula (IV).

Compounds of formula (IV) can be hydrolyzed under basic conditions using a suitable base to obtain the corresponding carboxylic acid salts of compounds of formula (V).

For example, alkali metal hydroxides such as NaOH may be employed here. The reaction is typically carried out in aqueous solution at a pH of about 1 1 to about 13 and a temperature of about 80°C to about 100°C. Thus, a composition comprising alkali metal salts, such as sodium salts, of a compound of formula (V) are obtained. The alkali metal salt of a compound of formula (V) is then acidified in solution using a suitable acid, such as H2SO₄ or HCI, preferably HCI, to afford the compound of formula (V). Although the processes and preferred processes according to the present invention as described above can be employed for providing a variety of final products and intermediates, the present invention will be illustrated by describing a reaction sequence for obtaining dicamba starting from 2-chlorophenol. A person skilled in the art will comprehend that certain reaction steps in this sequence are preferred as opposed to essential, and will further be able to adapt the processes described herein for the production of other compounds and intermediates within the scope of the appended claims.

In an especially preferred embodiment, the present invention provides a process for obtaining dicamba starting from 2-chlorophenol, which is the compound of formula (I) according to the present invention. In a first step of the reaction sequence, 2- chlorophenol is subjected to a carboxylation reaction under Kolbe-Schmitt conditions using KOH and CO2 as described above to obtain the dipotassium salt of 3-chloro-2- hydroxybenzoic acid.

2-Chloro-2-hydroxybenzoic acid is a compound according to formula (II) of the present invention.

It is further preferred that the di-potassium salt of 3-chloro-2-hydroxybenzoic acid is methylated in a subsequent reaction step using methyl chloride to obtain methyl 3- chloro-2-methoxybenzoate.

Methyl 3-chloro-2-methoxybenzoate is a compound within the definition of formula (III) as defined above, in which R is methyl. Methyl 3-chloro-2-methoxybenzoate is further subjected to orf/70-chlorination under Pd(ll) catalysis in accordance with the present invention to obtain methyl 3,6-dichloro-2- methoxybenzoate.

Methyl 3,6-dichloro-2-methoxybenzoate is a compound according to formula (IV) of the present invention, in which R is methyl.

In preferred embodiments, the compound is further subjected to hydrolysis as described above to afford dicamba.

The product obtained in the reaction is a compound according to formula (V) of the present invention in which R is methyl.

The above reaction sequence can be carried out on an industrial scale. Thus, the present invention provides in preferred embodiments a reaction sequence for obtaining dicamba in good yields starting from readily available starting materials.

Claims

C L A I M S

A process for providing a compound of formula (IV):

wherein R is -(Ci-C₄)alkyl,

the process comprising the step of:

reacting a compound of formula (III)

wherein R is defined as above,

in the presence of a Pd(ll) catalyst, a chlorine-containing reagent, a co-oxidant, and an acid.

The process according to claim 1 , wherein

(a) the Pd(ll) catalyst is selected from the group consisting of Pd(OAc)2, PdCI₂, Pd(TFA)₂, Pd(OTf)₂, PdCI₂(CH₃CN)₂, Pd(acac)₂ and PdCI₂(PPh₃)₂, and is optionally Pd(OAc)₂; and/or

(b) the chlorine-containing reagent is selected from the group consisting of N- chlorosuccinimide (NCS), and Cl₂, and is optionally NCS; and/or

(c) the co-oxidant is selected from the group consisting of K₂S₂Os, Na₂S₂Os, (NH₄)₂S₂O8, Cl₂, and O₂, and is optionally Na₂S₂Os or Cl₂; and/or

(d) the acid is selected from the group consisting of trifluoroacetic acid, p- toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid (HOTf), and HCI, and is optionally HOTf.

The process according to claim 1 or 2, wherein the step of reacting a compound of formula (III) is carried out in an organic solvent optionally selected from the group consisting of dioxane, 1 ,2-dichloroethane (DCE), acetonitrile, dimethylsulfoxide (DMSO), Ν,Ν-dimethylformamide (DMF), N-methylpyrrolidone (NMP), N,N- dimethylacetamide (DMA), and Ν,Ν-dimethylpropionamide (DMP), and wherein the organic solvent is preferably DCE.

4. The process according to any one of claims 1 to 3, wherein about one molar

equivalent of the compound of formula (III) is reacted in the presence of about 0.001 to about 0.1 molar equivalents of Pd(l I) catalyst, about 1 to about 1.5 molar equivalents of the chlorine-containing reagent, about 1 to about 2 molar

equivalents of the co-oxidant, and about 1 to about 3 molar equivalents of the acid, and wherein optionally about one molar equivalent of the compound of formula (III) is reacted in the presence of about 0.02 to about 0.05 molar equivalents of Pd(ll) catalyst, about 1.1 molar equivalents of the chlorine-containing reagent, about 1.1 to about 1.3 molar equivalents of the co-oxidant, and about 1.1 to about 1.2 molar equivalents of the acid.

5. The process according to any one of the preceding claims, wherein the step of reacting the compound of formula (III) is carried out at a temperature of about 40 °C to about 1 10 °C, optionally at about 60 °C to about 90 °C.

6. The process according to any one of claims 1 to 5, further comprising the step of reacting the compound of formula (IV) to obtain a compound of formula (V)

wherein R is as defined in claim 1.

7. The process according to any one of claims 1 to 6, further comprising the step of reacting a compound of formula (II)

II in the presence of an alkyl halide of the formula X-R, wherein X is CI, Br, or I, a is optionally CI, and R is as defined in claim 1 ,

to obtain the compound of formula (III).

The process according to claim 7, further comprising the step of reacting a compound of formula (I)

I in the presence of an alkali metal hydroxide and carbon dioxide to obtain the compound of formula (II).

The process according to any one of the preceding claims, wherein R is methyl.

10. The process according to claim 6, wherein the compound of formula (V) is