Selective hydrolysis and alcoholysis of chlorinated benzenes

Abstract

The present invention relates to a process for providing a compound of formula (I): ##STR00001##
wherein R is hydrogen or R, wherein R is (C.sub.1-C.sub.4)alkyl, and Hal is a halogen, the process comprising the step of:
reacting a compound of formula (II) ##STR00002##
wherein Hal is defined as above,
with an alkali metal alkoxide of the formula XOR, wherein X is an alkali metal, and R is defined as above.

Claims

1. A process for providing a compound of formula (I): ##STR00018## wherein R is hydrogen or R, wherein R is (C.sub.1-C.sub.4)alkyl, and Hal is chloro, the process comprising the step of: reacting a compound of formula (II) ##STR00019## wherein Hal is defined as above, with an alkali metal alkoxide of the formula XOR, wherein X is an alkali metal, and R is defined as above, wherein the alkali metal alkoxide of formula XOR is added to the reaction mixture in the form of an alcoholic solution in an alcohol of formula HOR having a concentration of 25 wt.-% to 67 wt.-%, based on the weight of the total weight of the alcohol HOR and the alkali metal alkoxide of the formula XOR; and wherein the step of reacting the compound of formula (II) with an alkali metal alkoxide of formula XOR is carried out at a temperature of at least 150 C.

2. The process according to claim 1, wherein the process is carried out in a solvent, wherein the solvent is an alcohol of formula HOR, wherein R is as defined in claim 1.

3. The process according to claim 1, wherein about one molar equivalent of the compound of formula (II) is reacted in the presence of 2 to 3 molar equivalents of the alkali metal alkoxide of formula XOR in 2 to 14 molar equivalents of a solvent of formula HOR.

4. The process according to claim 3, wherein about one molar equivalent of the compound of formula (II) is reacted in the presence of 2.2 to 2.6 molar equivalents of the alkali metal alkoxide of formula XOR in 11.5 to 12.5 molar equivalents of a solvent of formula HOR.

5. The process according to claim 4, wherein about one molar equivalent of the compound of formula (II) is reacted in the presence of about 2.4 molar equivalents of the alkali metal alkoxide of formula XOR in about 12 molar equivalents of a solvent of formula HOR.

6. The process according to claim 1, wherein the step of reacting the compound of formula (II) with an alkali metal alkoxide of formula XOR is carried out at 150 C. to 190 C.

7. The process according to claim 1, wherein the step of reacting the compound of formula (II) with an alkali metal alkoxide of formula XOR is carried out within 30 to 180 minutes.

8. The process according to claim 7, wherein the step of reacting the compound of formula (II) with an alkali metal alkoxide of formula XOR is carried out within 45 to 120 minutes.

9. The process according to claim 1, wherein the compound of formula (I) is obtained in a 2,5-regioselectivity of at least 72.

10. The process according to claim 9, wherein the compound of formula (I) is obtained in a 2,5-regioselectivity of at least 77%.

11. The process according to claim 1, wherein the compound of formula (I), in which R is hydrogen or (C.sub.1-C.sub.4)alkyl, is obtained in a yield of at least 70%.

12. The process according to claim 11, wherein the compound of formula (I), in which R is hydrogen or (C.sub.1-C.sub.4)alkyl, is obtained in a yield of at least 74%.

13. The process according to claim 1, further comprising the step of reacting the compound of formula (I) to obtain a compound of formula (III) ##STR00020## wherein R.sup.1 is an alkali metal.

14. The process according to claim 13, wherein the step of reacting the compound of formula (I) to obtain a compound of formula (III) is carried out in the presence of an alkali metal hydroxide and carbon dioxide.

15. The process according to claim 13, further comprising the step of reacting the compound of formula (III) to obtain a compound of formula (IV) ##STR00021## wherein R.sup.2 is (C.sub.1-C.sub.4)alkyl, R.sup.1 is an alkali metal or is the same as R.sup.2.

16. The process according to claim 15, further comprising the step of reacting the compound of formula (IV) to obtain a compound of formula (V) ##STR00022## wherein R.sup.2 and Hal are as defined in claim 15.

17. The process according to claim 1, wherein (b) R is selected from hydrogen and R; and R is selected from methyl and ethyl; and/or (c) X is sodium or potassium.

18. The process according to claim 17, wherein (f) R is methyl.

19. The process according to claim 17, wherein (g) X is sodium.

20. The process according to claim 15, wherein (a) R is selected from hydrogen and R; and R is selected from methyl and ethyl; and/or (b) X is sodium or potassium; and/or (c) R.sup.1 is selected from sodium and potassium; and/or (d) R.sup.1 is selected from sodium and potassium, or R.sup.1 is R.sup.2, and R.sup.2 is selected from ethyl and methyl.

21. The process according to claim 16, wherein the compound of formula (V) is ##STR00023##

22. The process according to claim 20, wherein (h) R.sup.1 is R.sup.2, and R.sup.2 is methyl.

Description

DETAILED DESCRIPTION OF THE INVENTION

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

(2) The term Hal or halogen as used herein refers to a halogen atom independently selected from F, Cl, Br and I. More preferably, Hal is independently selected from Cl and Br. In still further preferred embodiments both substituents Hal are identical and most preferably are Cl.

(3) The term alcoholic solution as used refers to a solution of a chemical compound in an alcohol, in particular, an alcohol of formula HOR, wherein R is as defined above. The term alcoholic alkali metal alkoxide solution refers to the solution of an alkali metal alkoxide in an alcohol, especially a solution of an alkali metal alkoxide of formula XOR in an alcohol of formula HOR, wherein X and R are as defined above.

(4) The present invention relates to an improved process for hydrolyzing a compound of formula (II) to obtain a corresponding phenol or phenol alkyl ether of formula (I) with improved yield and/or regioselectivity. According to industrial processes in the prior art, hydrolyzation of 1,2,4-trihalobenzenes, such as 1,2,4-trichlorobenzene, is carried out using NaOH in an alcoholic solvent. For example, hydrolyzation of 1,2,4-trichlorobenzene with NaOH in methanol affords 2,5-dichlorophenol in a yield of 64.6%. Furthermore, in this reaction several byproducts are obtained, namely 2,5-dichlorophenol methyl ether, 2,4-dichlorophenol methyl ether, 3,4-dichlorophenol methyl ether, 2,4-dichlorophenol, and 3,4-dichlorophenol. The 2,5-regioselectivity obtained in the above reaction according to the prior art is 71.9%.

(5) The term 2,5-regioselectivity refers to the ratio of the combined amount(s) of 2,5-dihalophenol and 2,5-dihalophenol alkyl ether to the total amount of 2,5-dihalophenol, 2,5-dihalophenol alkyl ether, 2,4-dihalophenol, 2,4-dihalophenol alkyl ether, 3,4-dihalophenol, and 3,4-dihalophenol alkyl ether obtained in the reaction. For example, the term 2,5-regioselectivity employed above in connection with prior art processes for obtaining 2,5-dichlorophenol from 1,2,4-trichlorobenzene using NaOH in methanol refers to the combined amounts of 2,5-dichlorophenol and 2,5-dichlorophenol methyl ether to the total amount of 2,5-dichlorophenol, 2,5-dichlorophenol methyl ether, 2,4-dichlorophenol, 2,4-dichlorophenol methyl ether, 3,4-dichlorophenol, and 3,4-dichlorophenol methyl ether obtained.

(6) Analogously, the term 2,4-regioselcetivity refers to the ratio of the combined amount(s) of 2,4-dihalophenol and 2,4-dihalophenol alkyl ether to the total amount of 2,5-dihalophenol, 2,5-dihalophenol alkyl ether, 2,4-dihalophenol, 2,4-dihalophenol alkyl ether, 3,4-dihalophenol, and 3,4-dihalophenol alkyl ether obtained.

(7) In addition, the term 3,4-regioselectivity refers to ratio of the combined amount(s) of 3,4-dihalophenol and 3,4-dihalophenol alkyl ether to the total amount of 2,5-dihalophenol, 2,5-dihalophenol alkyl ether, 2,4-dihalophenol, 2,4-dihalophenol alkyl ether, 3,4-dihalophenol, and 3,4-dihalophenol alkyl ether obtained.

(8) In the context of the present invention it is desired to reduce the degree of 2,4-regioselectivity and 3,4-regioselectivity, since the corresponding compounds cannot be converted to the preferred products of formula (V). A preferred product obtained in the processes according to the invention is 2,5-dichlorophenol used in the production of dicamba.

(9) The term alkali metal when used in the context of the present invention refers to lithium, sodium or potassium. Sodium and potassium are preferred.

(10) The present inventors have found that the use an alkali metal alkoxide instead of an alkali metal hydroxide in the above hydrolysis provides better yields of 2,5-dihalophenol, such as 2,5-dichlorophenol, and/or improved 2,5-regioselectivity. The present inventors have further found specific preferred reaction conditions for further improving the yield of the desired compounds and/or the desired 2,5-regioselectivity.

(11) Thus, the present invention relates to an improved process for hydrolyzing 1,2,4-trihalobenzene of formula (II) to obtain a compound of formula (I):

(12) ##STR00010##
wherein R is hydrogen or R, wherein R is (C.sub.1-C.sub.4)alkyl, and Hal is a halogen, in the presence of an alkali metal alkoxide of the formula XOR, wherein X is an alkali metal, and R is defined as above. The process may be carried out in a solvent, wherein the solvent is an alcohol of formula HOR, wherein R is as defined above. As shown in the below working examples, the use of an alkali metal alkoxide instead of an alkali metal hydroxide results in improved yields and/or improved 2,5-regioselectivity.

(13) The reaction is typically carried out in a pressure reactor. The solvent and the reactants are added to the pressure reactor, the pressure reactor is sealed and subsequently heated to the desired reaction temperature under agitation. After the desired reaction time, the pressure reactor is cooled to room temperature. The product can be isolated by transferring the reaction mixture into a separation device, such as a separation funnel, acidifying the mixture using a suitable acid such a H.sub.2SO.sub.4 or HCl to a pH of e.g. less than 1.5, and extracting the mixture using a suitable organic solvent, such as an ether (e.g. methyl tert.-butyl ether) or methylene chloride (CH.sub.2Cl.sub.2). Continuous extraction in a suitable device or sequential extraction (e.g. three times) can be employed.

(14) It is preferred according to the present invention that the alkali metal alkoxide of formula XOR is added to the reaction mixture in the form of an alcoholic solution in an alcohol of formula HOR, wherein X and R are as defined above. The present inventors have found that the concentration of the alcoholic alkali metal alkoxide solution added to the reaction mixture has an influence on the yields obtained and/or 2,5-regioselectivity. Therefore, the concentration of the alcoholic alkali metal alkoxide solution added to the reaction mixture is preferably about 20 wt.-% to about 67 wt.-%, based on the total weight of alcohol and alkali metal alkoxide. In more preferred embodiments, the concentration of the alcoholic alkali metal alkoxide solution added to the reaction mixture is about 25 wt.-% to about 67 wt.-%.

(15) The reaction temperature is preferably at least 150 C., such as 150 C. to about 190 C. In one preferred embodiment, the reaction is carried out at a temperature of about 150 C. to about 170 C. In another preferred embodiment, the reaction is carried out at a temperature of about 170 C. to about 190 C.

(16) The reaction is preferably carried out within 30 to 180 minutes. In a more preferred embodiment, the reaction is carried out within 45 to 120 minutes, such as 90 minutes.

(17) The present inventors have found that under specific reaction conditions including reaction temperature, concentration of the alcoholic alkali metal alkoxide solution, and reaction time, the yield of the compound of formula (I) can be further improved. Thus, in case the yield of the compound of formula (I) should be optimized, the reaction is preferably carried out at relatively high reaction temperatures for a moderate reaction time using a relatively low concentration of the alcoholic alkali metal alkoxide solution. In a preferred embodiment, the yield of the compound of formula (I) is optimized by carrying out the reaction at a temperature of about 180 C. to about 190 C. for a reaction time of about 80 to about 100 minutes using concentration of the alcoholic alkali metal alkoxide solution of about 20 wt.-% to about 30 wt.-%.

(18) In alternative cases, when the 2,5-regioselectivity is the main focus for optimization, it is preferred to carry out the reaction at moderate reaction temperatures for a moderate reaction time using a high concentration of the alcoholic alkali metal alkoxide solution. In a preferred embodiment, the 2,5-regioselectivity is optimized by carrying out the reaction at a temperature of about 150 C. to about 170 C. for a reaction time of about 80 to about 100 minutes using concentration of the alcoholic alkali metal alkoxide solution of about 50 wt.-% to about 67 wt.-%.

(19) Compounds of formula (I) in which R is R can be hydrolyzed under basic conditions to compounds of formula (I) in which R is hydrogen. Suitable bases include e.g. alkali metal hydroxides such as NaOH or KOH. The conversion can be carried out in a suitable organic solvent such as an alcohol. The obtained alkali metal salts can be subsequently acidified with acid such as H.sub.2SO.sub.4 or HCl to give compound of formula (I) in which R is hydrogen.

(20) In a further preferred embodiment, the compound of formula (I), in which R is hydrogen, is converted into valuable chemical products or intermediates. In an especially preferred embodiment, the compound of formula (I), in which R is hydrogen, is subjected to a carboxylation reaction under Kolbe-Schmitt conditions to obtain a compound of formula (III).

(21) ##STR00011##

(22) In the carboxylation step, the compound of formula (I) is first converted into the corresponding phenolate by treating with an alkali metal hydroxide R.sup.1OH. For example, sodium hydroxide or potassium hydroxide is employed here, whereof potassium hydroxide is preferred. The alkali metal hydroxide is 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.

(23) Subsequently, the phenolate is contacted with gaseous CO.sub.2 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 (III), which normally is not soluble in the reaction medium such as toluene and, therefore, can easily be separated.

(24) In a further preferred embodiment, the compound of formula (III) is alkylated to obtain a compound of formula (IV).

(25) ##STR00012##

(26) The reaction is accomplished by reacting the compound of formula (III) with an alkyl halide of formula YR.sup.2, wherein Y is halogen, such as Cl, Br or I, preferably Cl or Br, more preferably Cl. 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 12, 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 (IV) is partly esterified. In these cases, R.sup.1 is identical to R.sup.2.

(27) Furthermore, in order to increase solubility of the compound of formula (IV), 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 step, the compound of formula (IV) may be treated with sodium hydroxide in advance of the alkylation step to obtain a mixed potassium/sodium salt. In these cases, R.sup.1 may be an alkali metal different from R.sup.1. In other cases, R.sup.1 is identical to R.sup.1.

(28) In a further preferred embodiment, the compound of formula (IV) is converted to the compound of formula (V).

(29) ##STR00013##

(30) In cases where the compounds of formula (IV) include an ester in which R.sup.1 is identical to R.sup.2, 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 (IV) in which R.sup.1 is an alkali metal salt may be present during hydrolysis without harm. Thus, a composition comprising a compound of formula (IV) in which R.sup.1 is an alkali metal, such as sodium, is obtained.

(31) The alkali metal salt of formula (IV) is then acidified in solution using a suitable acid, such as H.sub.2SO.sub.4 or HCl, preferably HCl, to afford the compound of formula (V). In cases where a compound of formula (IV) in which R.sup.1 is an alkali metal is obtained in the previous reaction step, the composition can be directly subjected to acidification without the above hydrolyzation.

(32) 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 1,2,4-trichlorobenzene. 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.

(33) In an especially preferred embodiment, the present invention provides a process for obtaining dicamba starting from 1,2,4-trichlorobenzene. In a first step of the reaction sequence, 1,2,4-trichlorobenzene is subjected to a hydrolyzation reaction using sodium methoxide in methanol as described above to obtain 2,5-dichlorophenol with an improved yield and/or 2,5-regioselectivity.

(34) ##STR00014##

(35) 1,2,4-trichlorobenzene is a compound within the definition of formula (II) as defined above, in which Hal is Cl. Furthermore, 2,5-dichlorophenol is a compound within the definition of formula (I) according to the present invention, in which Hal is Cl, and R is H.

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

(37) ##STR00015##

(38) The dipotassium salt of 3,6-dichlorosalicylic acid is a compound according to formula (III) of the present invention, in which Hal is Cl, and R.sup.1 is K.

(39) 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 include 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, methylation 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.

(40) ##STR00016##

(41) The product obtained in the reaction is a compound according to formula (IV) of the present invention in which Hal is Cl, R.sup.2 is methyl, and R.sup.1 is either K, Na or methyl.

(42) 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 HCl as outlined above.

(43) ##STR00017##

(44) Dicamba is a compound according to formula (V) of the present invention, in which Hal is Cl, and R.sup.2 is methyl.

(45) The above reaction sequence can be carried out on an industrial scale. The overall yield of the final products and intermediates is improved over the overall process since the yield and/or desired regioselectivity required is improved in the first process step of the sequence. Thus, in a preferred embodiment, the present invention provides an advantageous synthetic route to dicamba for production on industrial scale with improved yields starting from 1,2,4-trichlorobenzene.

EXAMPLES

(46) The present invention will be further illustrated by means of a comparative example and working examples.

1. Comparative Example

(47) 1,2,4-trichlorobenzene (TCB), NaOH (in the form of a 50 wt-% solution in water) and methanol were charged into a pressure reactor. The molar ratio of TCB:NaOH:methanol was 1.0:2.4:10. Afterwards, the pressure reactor was sealed, heated to 190 C. under agitation and held at this temperature for 90 minutes. During the reaction, agitation was continued. The reactor was then cooled to room temperature using an ice-H.sub.2O bath.

(48) The reaction mixture was then transferred into a separation funnel and acidified with 10% H.sub.2SO.sub.4 to a pH of below 1.5. The aqueous layer of the resulting two-layer mixture was then extracted three times with methylene chloride.

(49) The obtained yield of 2,5-dichlorophenol and 2,5-dichloroanisole combined was 64.6%. The obtained regioselectivity (2,5-dichlorophenol and 2,5-dichlorophenol methyl ether/2,4-dichlorophenol and 2,4-dichlorophenol methyl ether/3,4-dichlorophenol and 3,4-dichlorophenol methyl ether) was 71.9/15.5/12.6 (analysis using GC).

2. Working Example 1

(50) The above comparative example was repeated except for using a 25% solution of NaOMe in methanol as the base. The molar ratio of TCB:NaOMe:methanol was 1.0:2.4:12. The obtained yield of 2,5-dichlorophenol and 2,5-dichloroanisole combined was 73.9%. The obtained 2,5-regioselectivity was 74.2%.

3. Working Example 2

(51) Working example 1 was repeated except for carrying out the reaction for 45 minutes. The obtained yield of 2,5-dichlorophenol and 2,5-dichloroanisole combined was 72.0%. The obtained 2,5-regioselectivity was 74.5%.

4. Working Example 3

(52) Working example 1 was repeated except for carrying out the reaction at a temperature of 150 C. The obtained 2,5-regioselectivity was 75.4%.

5. Working Example 4

(53) Working example 1 was repeated except for using a 35% solution of NaOMe and carrying out the reaction at a temperature of 170 C. The obtained yield of 2,5-dichlorophenol and 2,5-dichloroanisole combined was 70.6%. The obtained 2,5-regioselectivity was 76.2%.

6. Working Example 5

(54) Working example 1 was repeated except for using a 50% solution of NaOMe and carrying out the reaction at a temperature of 160 C. The obtained 2,5-regioselectivity was 76.8%.

7. Working Example 6

(55) Working example 5 was repeated except for using a 67% solution of NaOMe. The obtained 2,5-regioselectivity was 78.0%.

(56) TABLE-US-00001 TABLE 1 Improvement in yield of 2,5-dichlorophenol and 2,5-dichloroanisole combined Combined Yield [%] Comparative Example 64.6 Working Example 1 73.9 Working example 2 72.0

(57) TABLE-US-00002 TABLE 2 Improvement in 2,5-regioselectivity 2,5-regioselectivity [%] Comparative Example 71.9 Working Example 3 75.4 Working Example 4 76.2 Working Example 5 76.8 Working Example 6 78.0