WO2015082422A2

WO2015082422A2 - Process for reacting chemical compounds

Info

Publication number: WO2015082422A2
Application number: PCT/EP2014/076149
Authority: WO
Inventors: Eric George KLAUBER; Michael Rack; Thomas Zierke; Nicole HOLUB; Gerald SCHMELEBECK; Junmin JI; David Cortes
Original assignee: Basf Se
Priority date: 2013-12-04
Filing date: 2014-12-01
Publication date: 2015-06-11
Also published as: WO2015082422A3

Abstract

A process for reacting chemical compounds comprising the step of oxidizing a compound of formula (II) wherein R¹ and R² are halogen, and R³ is -(C₁-C₄) alkyl, in the presence of a peroxy reagent to obtain a compound of formula (III).

Description

Process for reacting chemical compounds

The present invention relates to a process for reacting 2,5-dihalogen substituted phenyl acyls under the conditions of Baeyer-Villiger oxidation. In a preferred embodiment, the present inven- tion provides a new process for obtaining 2,5-dichlorophenol, which is an important intermediate 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. 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 carboxyla- tion 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. The synthetic route via 1 ,4-dichlorobenzene involves nitration and subsequent diazotation, and, therefore is undesired for use on an industrial scale. The synthetic route via 1 ,2,4- trichlorobenzene suffers from limited availability of this compound and from the formation of several byproducts which are formed in the synthesis of 2,5-dichlorophenol. In view of the above, there is a need in the art for alternative reaction sequences for obtaining 2,5-dihalogen substituted phenols, such as 2,5-dichlorophenol, preferably involving readily available starting materials. Moreover, there is a special need in the art for processes and reaction sequences for obtaining dihalogen substituted salicylic acid derivatives, especially including dicamba, in good yields. The object of the present invention is to meet the above needs. In particular, one object of the present invention is to provide crucial synthesis steps in alternative routes to dihalogen substituted phenols or dihalogen substituted salicylic acid derivatives, including dicamba. The processes according to the present invention can be carried out on an industrial scale. Furthermore, the processes according to the present invention should involve starting materials readily available in the market or intermediates obtainable from available starting materials in processes that can be carried out on an industrial scale. In an especially preferred embodiment, the object of the present invention is the provision of a process for providing 2,5-dichlorophenol and finally dicamba on an industrial scale in good yields.

Summary of the invention

The present invention provides a process for reacting chemical compounds comprising the step of oxidizing a compound of formula (II)

II wherein R¹ and R² are halogen, and R³ is -(C1-C4) alkyl, in the presence of a peroxy reagent to obtain a compound of formula (III)

III wherein R¹, R², and R³ are as defined above.

The above compound of formula (II) is a 2,5-dihalogen substituted phenyl acyl derivate. The inventors of the present invention have found that the compound of formula (II) can be subjected to conditions known in the art as Baeyer-Villiger oxidation to obtain the corresponding phenol derivatives of formula (III). The reaction can be carried out in good yields on an industrial scale. The compound of formula (III) easily can be converted to the corresponding 2,5-dihalogen substituted phenol as outlined in further detail below. Thus, the compound of formula (III) repre- sents a valuable intermediate for chemical synthesis. Furthermore, the compound of formula (II) used as a starting material can be obtained from readily available starting material on an industrial scale in good yields as described in further detail below.

In a preferred embodiment, the process according to the present invention further comprises the step of hydrolyzing the compound of formula (III) to produce the corresponding phenol of formu- la (IV)

IV wherein R¹ and R² are as defined above.

Hydrolyzing an ester as described above is a reliable reaction that can be and is carried out on an industrial scale in good yields. In addition, the obtained reaction product easily can be separated from the reaction mixture in high purity. Thus, by employing Baeyer-Villiger oxidation on 2,5-dihalogen substituted phenyl acyl derivatives and subsequent hydrolysis, the present invention provides an advantageous reactions sequence for obtaining valuable intermediates, such as 2,5-dichlorophenol, avoiding the problems associated with prior art processes.

In a further preferred embodiment, the above compound of formula (II) is obtained by acylation of a compound of formula (I)

wherein R¹ and R² are as defined above, using an acyl halide of the formula XC(0)R³, wherein R³ is as defined above, and X is halogen, preferably CI or Br, more preferably CI.

The above acylation reaction is known in the art under the term "Friedel-Crafts acylation". Acylation deactivates the benzene ring for further acylation. Furthermore, the acylation reaction can be carried out in good yields on an industrial scale. Thus, by subjecting 1 ,4-dihalogen substitut- ed benzene, such as 1 ,4-dichlorobenzene, to Friedel-Crafts acylation, subjecting the obtained reaction product to Baeyer-Villiger oxidation, and subjecting the resulting product to ester hydrolysis, the present invention provides an advantageous reaction sequence to highly valuable intermediates starting from readily available starting materials. For example, according to the present invention, 1 ,4-dichlorobenzene, which is readily available at low costs, can eventually be converted to 2,5-dichlorophenol, which is a highly desired intermediate e.g. in the synthesis of dicamba, on an industrial scale in good yields.

In preferred embodiments according to the present invention, the above compound of formula (IV) is further converted to other useful intermediates and/or end products. In one preferred embodiment, the compound of formula (IV) is reacted to obtain a compound of formula (V)

V wherein R¹ and R² are as defined above, and R⁴ is an alkali metal.

The above reaction from compounds of formula (IV) to compounds of formula (V) is known in the art as the "Kolbe-Schmitt reaction". Reactions under Kolbe-Schmitt conditions can be carried out on an industrial scale in good yields. For example, the above conversion is part of known reaction sequences for obtaining dicamba from 2,5-dichlorophenol.

In an additional preferred embodiment, the present invention further comprises the step of reacting the compound of formula (V) to obtain an ether of formula (VI)

VI wherein R⁵ is -(C1-C4) alkyl, R^4' is an alkali metal or is the same as R⁵, and R¹ and R² are as defined above. This reaction step is also carried out in prior art reaction sequences for obtaining dicamba. Since dicamba is the preferred reaction product according to the present invention, and dicamba contains a free carboxylic acid group, it is not relevant in these preferred embodiments that in the reaction the carboxylic acid group is partly converted to the corresponding ester and partly remains in neutralized from.

Rather, in preferred embodiments according to the invention, the resulting product of formula (VI) is converted to the corresponding neutralized carboxylic acid by hydrolyzing an ester of formula (VI) (i.e. wherein R^4' is -(C-C4) alkyl) under basic conditions, and is subsequently acidified to obtain a compound of formula (VII)

VI I wherein R¹, R² and R⁵ are as defined above. The above reaction step can be carried out analogously to prior art reactions sequences for obtaining dicamba from 2,5-dichlorophenol in good yields on an industrial scale.

In especially preferred embodiments according to the present invention, R¹ and R² are selected from CI and Br. More preferably, R¹ and R² are identical, and most preferably are both CI. In further preferred embodiments according to the present invention, R³ is selected from ethyl and methyl. R³ is not present in the most preferred product of the processes according to the invention and, therefore, can be selected freely with regard e.g. to availability and costs of the corresponding carboxylic acid halide from which it is derived or in view of usability in parallel processes in integrated plants of the resulting carboxylic acid obtained as a byproduct from hy- drolyzing the ester of formula (III). In a preferred embodiment, R³ is methyl, derived from the corresponding acetic acid halide, such as acetic acid chloride, which subsequently after hydrolysis provides acetic acid.

R⁴ is preferably selected from Na and K. R⁴ is derived from an alkali metal hydroxide, i.e. sodium hydroxide or potassium hydroxide used during the Kolbe-Schmitt reaction step. It may fur- ther be advantageous to replace one alkali metal with another alkali metal in preferred embodiments of the invention as described below. In a preferred embodiment, R⁴ is K in the above- described Kolbe-Schmitt reaction step, i.e. KOH is used in the step of providing the compound of formula (V).

In further preferred embodiments according to the present invention, in case R^4' is not an alkali metal in the compound of formula (VI) described above, R^4' is ethyl or methyl. In these cases, R^4' is identical to R⁵. R⁵ is, according to preferred embodiments, also selected from ethyl and methyl. In a more preferred embodiment, R⁵ is methyl, thus also R^4' is more preferably methyl in case it is not an alkali metal. In case R^4' is an alkali metal, it may be identical to R⁴ as defined above, or preferably is an alkali metal different from R⁴, i.e. can be different in different reaction steps. For example, R^4' may be Na or may be identical to R⁵.

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

Dicamba Further preferred 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.

In a preferred embodiment of the present invention, the compound of formula (II) is obtained by subjecting the compound of formula (I) to Friedel-Crafts acylation.

Friedel-Crafts acylation is carried out with the compound of formula (I) and at least stoichiometric amounts of a Lewis acid catalyst. Suitable Lewis acid catalysts include but are not limited to AlC , FeC or BF3. AICI3 is preferably used. The reaction can be carried out in the presence or absence of a solvent. Furthermore, a carboxylic acid halide, such as acetic acid chloride or acetic acid bromide, is added in at least stoichiometric amounts to the mixture, e.g. dropwise, and the mixture is heated until the reaction is complete.

According to the present invention, the compound of formula (II) is subjected to Baeyer-Villiger oxidation to obtain a compound of formula

Baeyer-Villiger oxidation is carried out in the presence of a peroxy reagent. Key features of the reaction are its stereospecificity. Suitable peroxy reagents include but are not limited to peroxyethers, peroxides, peroxyanhydrides and peroxy acids, such as percarboxylic acids, alkylhydroperoxides, inorganic peracids or complex peroxygen carriers. The reaction may be carried out in the presence of a suitable solvent such as organic carboxylic acids, aliphatic hydrocarbons, chlorinated hydrocarbons or alcohols. Furthermore, catalysts such as inorganic acids, sulphonic acids, or metal ions may be employed. The molar ratio of the compound of formula (II) to peroxy reagent may be about 1 :0.2 to about 1 :5. The oxidation reaction may be carried out in about 1 to about 10 volumes of solvent at a temperature of between about 0 °C and about 80 °C and a reaction time of between about 5 and about 50 hours. In a preferred embodiment, Baeyer-Villiger oxidation of the compound of formula (II) is performed with one or more of permaleic acid, peracetic acid, perphthalic acid or pertrifluoroacetic acid preferably at a molar ratio of about 1 :2 to about 1 :3 in a chlorinated aliphatic solvent such as dichloromethane, dichloroethane or chloroform at a temperature of between about 35 °C and about 45 °C and a reaction time of between about 5 and about 12 hours. In addition, the reaction mixture may contain carboxylic acids or carboxylic acid anhydrides which may have been employed in the in situ generation of the essentially anhydrous peracid. For example, the compound of formula (II) may be oxidized with anhydrous permaleic acid in a molar ratio of about 1 :3 in dichloromethane at about 42 °C for about 5 hours.

Under the latter conditions the oxidative transformation is virtually quantitative. The product of formula (III) is obtained in high purity by simple work-up procedure. At this stage the levels of undesired contaminants are at acceptably low levels. In a further preferred embodiment, the compound of formula (III) is hydrolyzed to obtain a compound of formula (IV).

The conversion of the ester of formula (III) to the corresponding phenol of formula (IV) may be accomplished by acid catalyzed hydrolysis, or more preferably by transesterification with an excess of aliphatic primary alcohol using an acid catalyst such as a mineral acid (i.e. an inorganic proton donor), a sulfonic acid, a Lewis acid (i.e. an electron pair acceptor), a solid acid, such as an acidic resin, or a titanium tetra-alkoxide. Alternatively, the hydrolysis may be carried out using a base selected from the group consisting of alkali metal hydroxides, alkali metal amides, alkali metal alkoxides, alkali earth metal hydroxides, alkali earth metal amides, alkali earth metal alkoxides, alkali metal carbonates, ammonia and primary amines.

The transesterification is preferably effected by treatment of one molar equivalent of the ester in about 2 to about 50 molar equivalents of an aliphatic primary alcohol containing about 0.02 to about 1 molar equivalents of acid catalyst at a temperature of between about 20 °C and the boiling point of the alcohol for about 4 to about 12 hours. Preferably the transesterification is performed in about 6 to about 8 molar equivalents of methanol, ethanol or propanol containing about 0.02 to about 0.05 molar equivalents of mineral acid or sulphonic acid at a temperature of between about 50 °C to the boiling point of the alcohol for between about 5 to about 9 hours. Most preferably the reaction is performed by refluxing about 1 molar equivalent of the ester in about 7 molar equivalents of methanol containing about 0.03 equivalents of hydrochloric acid for about 6 hours.

Removal of the solvent and acid catalyst normally affords the compound of formula (IV) in pure form. A further step of distillation and/or one recrystallization is typically not required according to the invention. In a further preferred embodiment, the compound of formula (IV) is subjected to a carboxylation reaction under Kolbe-Schmitt conditions to obtain a compound of formula (V).

IV V

In the carboxylation step, the phenol of formula (IV) is first converted into the corresponding phenolate by treating with an alkali metal hydroxide R⁴OH. For example, sodium hydroxide or potassium hydroxide is employed here, wherein potassium hydroxide is preferred. The alkali metal hydroxide is used in about stoichiometric amounts in an aqueous solution having e.g. a concentration of about 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 phenolate is contacted 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 formula (V), which normally is not soluble in the reaction medium such as xylene and, therefore, can easily be separated.

The compound of formula (V) is in a preferred embodiment alkylated to obtain a compound of formula (VI).

The reaction is accomplished by reacting the compound of formula (V) with an alkyl halide of formula HaIR⁵, wherein Hal is halogen, such as CI, Br or I, preferably CI or Br, more preferably CI. 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 con- trolled such that the reaction is carried out at a pH of about 9 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. Thus, it is not excluded that the compound of formula (V) is partly esterified. In these cases, R^4' is identical to R⁵.

Furthermore, in order to increase solubility of the compound of formula (V), the double salt may be converted in advance of the reaction to a corresponding mixed salt by treating with an alkali metal hydroxide different from the alkali metal hydroxide used in the previous reaction step. For example, when potassium hydroxide is used in the Kolbe-Schmitt reaction, the compound of formula (V) may be treated with sodium hydroxide in advance of the alkylation step to obtain a mixed potassium/sodium salt. In these cases, R^4' may be an alkali metal different from R⁴. In other cases, R^4' is identical to R⁴.

In a further preferred embodiment, the compound of formula (VI) is converted to the compound of formula (VII).

VI VII

In cases where the compounds of formula (VI) include an ester in which R^4' is identical to R⁵, the ester is hydrolyzed under basic conditions using a suitable base to obtain the corresponding carboxylic acid salts. For example, alkali metal hydroxides such as NaOH may be employed here. Compounds of formula (VI) in which R^4' is an alkali metal salt may be present during hydrolysis without harm. Thus, a composition comprising a compound of formula (VI) in which R^4' is an alkali metal, such as sodium, is obtained.

The alkali metal salt of formula (VI) is then acidified in solution using a suitable acid, such as H2SO4 or HCI, preferably HCI, to afford the compound of formula (VII). In cases where a compound of formula (VI) in which R^4' is an alkali metal is obtained in the previous reaction step, the composition can be directly subjected to acidification without the above hydrolyzation. Although the processes and preferred processes according to the present invention as described above can be employed for providing a variety of final end products and intermediates, the present invention will be illustrated by describing a reaction sequence for obtaining dicamba starting from 1 ,4-dichlorobenzene. A person skilled in the art will comprehend that certain reac- tion 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 from 1 ,4-dichlorobenzene. In a first step of the reaction sequence, 1 ,4- dichlorobenzene is subjected to Friedel-Crafts acylation as described above to obtain 2,5- dichlorophenyl ethanone.

1 ,4-dichlorobenzene is a compound within the definition of formula (I) as defined above, in which R¹ and R² are both CI. Furthermore, 2,5-dichlorophenyl ethanone is a corresponding acylated derivative thereof, obtained using an acetic acid halide, such as acetic acid chloride or acetic acid bromide, within the definition of the above formula (II), wherein R³ is methyl. In the context of the present invention, it is preferred to employ acetic acid chloride for the acylation step, especially from the viewpoint of costs and availability of starting materials.

In a further reaction step of the most preferred reaction sequence according to the present invention, 2,5-dichorophenyl ethanone is subjected to Baeyer-Villiger oxidation using a peroxy reagent as described above to obtain 2,5-dichlorophenyl acetate.

2,5-dichlorophenyl acetate is a compound within the definition of formula (III) according to the present invention, in which R¹ and R² are both CI and R³ is methyl. Preferred peroxy reagents to be employed in this reaction step include permaleic acid, peracetic acid, perphthalic acid or pertrifluoroacetic acid. The preferred reaction sequence according to the present invention includes a further step of hydrolyzing 2,5-dichlorophenyl acetate to obtain 2,5-dichlorophenol.

2,5-dichlorophenol is a compound within the definition of formula (IV) according to the present invention, in which R¹ and R² are both CI. The reaction can be carried out as generally described above.

According to preferred embodiments of the invention, 2,5-dichlorophenol is further subjected to carboxylation under Kolbe-Schmitt conditions using KOH and CO2 as described above to obtain the dipotassium salt of 3,6-dichlorosalicylic acid.

The dipotassium salt of 3,6-dichlorosalicylic acid is a compound according to formula (V) of the present invention, in which R¹ and R² are CI, and R⁴ is K.

It is further preferred that the dipotassium salt of 3,6-dichlorosalicylic acid is methylated in a subsequent reaction step using methyl chloride. As described above, this conversion may in- elude converting the dipotassium salt into a mixed salt in order to improve solubility in water. In a preferred embodiment, NaOH is used for the provision of the mixed salt. In view of this, meth- ylation of dipotassium 3,6-dichlorosalicylic acid after conversion into a mixed salt affords typically a mixture of the sodium and/or potassium form of 3,6-dichloro-2-methoxybenzoic acid and 3,6-dichloro-2-methoxybenzoic acid methyl ester.

The product obtained in the reaction is a compound according to formula (VI) of the present invention in which R¹ and R² are both CI, R⁵ is methyl, and R^4' is either K, Na or methyl. The above mixture is subsequently preferably converted to dicamba by hydrolyzing the ester compounds in the mixture using NaOH as described above and subsequently acidifying the resulting product using HCI as outlined above.

Dicamba is a compound according to formula (VII) of the present invention, in which R¹ and R² are CI, and R⁵ is methyl.

The above reaction sequence can be carried out on an industrial scale with good yields. The starting materials required for the reactions sequence including 1 ,4-dichlorobenzene are readily available at low costs. Thus, in a preferred embodiment, the present invention provides an ad- vantageous synthetic route to dicamba for production on industrial scale with good yields starting from readily available 1 ,4-dichlorobenzene.

Claims

Claims:

1 . A process for reacting chemical compounds comprising the step of oxidizing a compound of formula (II)

wherein R¹ and R² are halogen, and R³ is -(C1-C4) alkyl,

in the presence of a peroxy reagent to obtain a compound of formula (III)

III wherein R¹, R², and R³ are as defined above.

The process of claim 1 , wherein the peroxy reagent selected from the group consisting of peroxyether, peroxide, peroxyanhydride and peroxy acid.

The process of claims 1 or 2, further comprising the step of hydrolyzing the compound of formula (III) to produce the corresponding phenol of formula (IV)

IV wherein R¹ and R² are as defined in claim 1.

4. The process of claim 3, wherein the step of hydrolyzing the compound of formula (III) comprises (a) transesterification using an alcohol as the recipient of the acyl group and using an acid catalyst selected from the group consisting of a mineral acid, a sulphonic acid, a Lewis acid, and a solid acid, or

(b) hydrolysis using a base selected from the group consisting of alkali metal hydroxides, alkali metal amides, alkali metal alkoxides, alkali earth metal hydroxides, alkali earth metal amides, alkali earth metal alkoxides, ammonia and primary amines.

5. The process of any one of claims 1 to 4, wherein the compound of formula (II) is obtained by acylation of a compound of formula (I)

wherein R¹ and R² are as defined above,

using an acyl halide of the formula XC(0)R³, wherein R³ is as defined in claim 1 , and X is halogen, preferably CI or Br, more preferably CI.

6. The process of any one of claims 3 to 5, further comprising the step ofreacting the compound of formula (IV) to obtain a compound of formula (V)

wherein R¹ and R² are as defined in claim 1 , and R⁴ is an alkali metal. 7. The process of claim 6, wherein the step of reacting the compound of formula (V) to obtain a compound of formula (VI) is carried out in the presence of an alkali metal hydroxide and carbon dioxide.

The process according to claims 6 or 7, further comprising the step of reacting the compound of formula (V) to obtain an ether of formula (VI)

VI wherein R⁵ is -(C1-C4) alkyl, R^4' is an alkali metal or is the same as R⁵, and R¹ and R² are as defined in claim 1.

The process of claim 8, further comprising the step of reacting the compound of formula (VI) to obtain a compound of formula (VII)

VII wherein R¹ and R² are as defined in claim 1 , and R⁵ is as defined in claim 8.

10. The process of any one of the preceding claims, wherein

(a) R¹ and R² are selected from CI and Br, and preferably are both CI.; and/or

(b) R³ is selected from ethyl and methyl, and preferably is methyl; and/or

(c) R⁴ is selected from Na and K, and preferably is K; and/or

(d) R^4' is selected from Na and K, or R^4' is R⁵; and/or

(e) R⁵ are selected from ethyl and methyl, and preferably are methyl.

The process of claims 9 or 10, wherein the compound of formula (VII) is