• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
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    • 专利摘要:
    process for providing a compound of the formula the present invention relates to a process for providing a compound of the formula (i), where r is hydrogen or r ?, in which r? is c1-c4 alkyl, and hal is a halogen, the process comprises the step of reacting a compound of formula (ii), in which hal is as defined above, with an alkali metal alkoxide of formula xor?, in which x is an alkali metal, er? is as defined above.
    公开号:BR112016006374B1
    申请号:R112016006374-0
    申请日:2014-10-02
    公开日:2021-03-23
    发明作者:Eric George Klauber；Michael Rack；Thomas Zierke；Nicole Holub；David Cortes；Gerald SCHMELEBECK；Junmin JI
    申请人:Basf Se；
    IPC主号:
    专利说明:

    [0001] [001] The present invention relates to a process for the hydrolysis of 1,2,4-trichlorobenzene with improved yield and / or regioselectivity. In a preferred embodiment, the present invention relates to the improved process for the hydrolysis of 1,2,4-trichlorobenzene to obtain 2,5-dichlorophenol, which is an important intermediate in the production of the herbicide dicamba (acid 3,6 -dichloro-2-methoxybenzoic). BACKGROUND OF THE INVENTION
    [0002] [002] Dicamba is a selective herbicide currently used to treat, for example, corn, wheat or pasture. It kills broadleaf weeds, before and after they sprout. The trivial name dicamba refers to the compound of 3,6-dichloro-2-methoxybenzoic acid. The estimated global demand for dicamba in 2012 was around 12,000 metric tons per year. However, it is expected that the global demand for dicamba will increase significantly.
    [0003] [003] Dicamba is normally produced on an industrial scale from 2,5-dichlorophenol using carboxylation under Kolbe-Schmitt conditions, methylation and later saponification / acidification. 2,5-dichlorophenol, in turn, can be obtained from 1,4-dichlorobenzene or 1,2,4-trichlorobenzene. A synthetic route by means of 1,4-dichlorobenzene involving nitration and later diazotization, however, may be undesirable for use on an industrial scale. A synthetic route by means of 1,2,4-trichlorobenzene can present limited availability of this starting material and the formation of several by-products that are formed in the synthesis of 2,5-dichlorophenol.
    [0004] [004] To satisfy the growing market demand for compounds such as dicamba, there is a need in the state of the art for processes that provide improved yield and / or regioselectivity in the hydrolysis of 1,2,4-trialobenzene, such as 1,2,4 trichlorobenzene, so that the limited resources of these compounds can be used more efficiently.
    [0005] [005] In view of the above, there is still a need in the state of the art for a process to obtain 2,5-dialogene substituted by phenols such as 2,5-dichlorophenol, with improved yield and / or regioselectivity. In addition, there is a special need in the state of the art for reaction processes and sequences to obtain the dialogene substituted by derivatives of salicylic acid, especially, including dicamba, in improved yields.
    [0006] [006] An additional object of the present invention is to provide the reaction conditions that enable an improved regioselectivity and / or yield in the hydrolysis of 1,2,4-trialobenzene to obtain dialogene substituted by phenols or, ultimately, dialogene replaced by derivatives of salicylic acid, including dicamba. Another object of the present invention is to provide an improved process for providing 2,5-dichlorophenol. It is an additional object of the present invention to implement the improved process for the synthesis of dicamba on an industrial scale. It is an additional object of the present invention to obtain 2,5-dialophenol with improved yield. In addition, since the 2,5-dialophenol alkyl ether can easily be transferred to the corresponding 2,5-dialophenol, it is an additional or alternative object of the present invention to obtain an increased 2,5-regioselectivity.
    [0007] [007] The object of the present invention is to satisfy the needs mentioned above. In this context, it should be noted that even small improvements in yield and / or 2,5-regioselectivity in reaction sequences to obtain dicamba would provide a great benefit. For example, an improvement in yield and / or 2.5-regioselectivity of 1% would provide an additional annual amount of 120 metric tons of dicamba. BRIEF DESCRIPTION OF THE INVENTION
    [0008] [008] The present invention relates to an improved process for the hydrolysis of 1,2,4-trialobenzene to obtain a compound of Formula (I):
    [0009] [009] In particular, the present invention relates to a process for providing the above compound of Formula (I), which comprises the step of: reacting a compound of Formula (II)
    [0010] [010] In a preferred embodiment, the above process is carried out in a solvent, where the solvent is an alcohol of Formula HOR ', where R' is as defined above.
    [0011] [011] Conventional processes for the hydrolysis of 1,2,4-trialobenzene are usually carried out using an alkali metal hydroxide, such as NaOH, and an alcoholic solvent such as methanol. The reaction results in a mixture of different regioisomers, that is, the 2,5-regioisomers, 2,4-regioisomers, and 3,4-regioisomers, and their derivatives as defined in more detail below.
    [0012] [012] For example, hydrolysis of 1,2,4-trichlorobenzene in methanol using NaOH results in a mixture of 2,5-dichlorophenol, 2,4-dichlorophenol, 3,4-dichlorophenol, methyl ether of 2, 5-dichlorophenol, 2,4-dichlorophenol methyl ether, and 3,4-dichlorophenol methyl ether. In view of the high commercial importance of 2,5-dichlorophenol, even small improvements in their yield in the reaction would provide an enormous benefit to the overall yield of the final product, that is, dicamba. In addition, since 2,5-dichlorophenol methyl ether, in principle, can still react to obtain 2,5-dichlorophenol, the processes that result in an enhancement of 2,5-regioselectivity (that is, the hydrolysis at position 2 of 1,2,4-trichlorobenzene) are also highly desired.
    [0013] [013] The present Depositors have found that through the use of alkali metal alkoxide for the hydrolysis reaction of 1,2,4-trialobenzene instead of alkali metal hydroxide, the yield of 2,5-dialophenol can be improved. The present Depositors have also discovered that 2,5-regioselectivity can be improved by employing an alkali metal alkoxide instead of the alkali metal hydroxide.
    [0014] [014] In a preferred embodiment, 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', where X and R 'are as defined above. In another preferred embodiment, the concentration of the alcoholic alkali metal alkoxide solution added to the reaction mixture is about 20% by weight, to about 67% by weight, based on the total weight of the HOR 'alcohol and the alkali metal alkoxide XOR '. In a most preferred embodiment, the concentration of the alcoholic alkali metal alkoxide solution added to the reaction mixture is from about 25% by weight to about 67% by weight.
    [0015] [015] In another preferred embodiment of the present invention, about one molar equivalent of the compound of Formula (II) is reacted in the presence of about 2 to about 3 molar equivalents of an alkali metal alkoxide of Formula XOR 'in about 2 to about 14 molar equivalents of a Formula HOR 'solvent. In another most preferred embodiment, about one molar equivalent of the compound of Formula (II) is reacted in the presence of about 2.2 to about 2.6 molar equivalents of an alkali metal alkoxide of Formula XOR 'in about from 11.5 to about 12.5 molar equivalents of a Formula HOR 'solvent. In addition, in even more preferred embodiments, about one molar equivalent of the compound of Formula (II) is reacted in the presence of about 2.4 molar equivalents of an alkali metal alkoxide of Formula XOR 'in about 12 molar equivalents of a solvent of Formula HOR '.
    [0016] [016] The step of reacting the compound of Formula (II) with an alkali metal alkoxide of Formula XOR 'is preferably carried out at a temperature of at least 150 ° C. Most preferably, the step of reacting the compound of Formula (II) with the alkali metal alkoxide is carried out at a temperature of 150 ° C to about 190 ° C. In a 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.
    [0017] [017] Regarding the reaction time, preferably, 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. In a most preferred embodiment, the reaction is carried out within 45 to 120 minutes, such as 90 minutes.
    [0018] [018] In a preferred embodiment, the present invention relates to a process as defined above providing the compound of Formula (I) at a 2.5-regioselectivity of at least 72%. Most preferably, the compound of Formula (I) is obtained with a 2,5-regioselectivity of at least 74%, most preferably of at least 75%, even more preferably of at least 76 % and even more preferably at least 77%.
    [0019] [019] The hydrolysis product of the compounds of Formula (I), according to the present invention, represents a valuable product or intermediate for chemical synthesis. Therefore, the hydrolysis product of Formula (I) can still react to obtain other valuable chemicals or intermediates. In a preferred embodiment of the present invention, the compound of Formula (I) is reacted to obtain a compound of Formula (III):
    [0020] [020] The above reaction from the compounds of Formula (I) to the compounds of Formula (III) is known in the art as the "Kolbe-Schmitt reaction". Reactions under Kolbe-Schmitt conditions can be carried out on an industrial scale, with good yields. For example, the above conversion is part of known reaction sequences for obtaining dicamba from 2,5-dichlorophenol. The reaction is usually carried out in the presence of an alkali metal hydroxide and carbon dioxide.
    [0021] [021] In another preferred embodiment, the compound of Formula (III) is used to obtain a compound of Formula (IV):
    [0022] [022] For example, in another preferred embodiment, according to the present invention, the resulting product of Formula (IV) is converted into the corresponding carboxylic acid by hydrolysis of an ester of Formula (IV) (i.e., in that R1 'is C1-C4 alkyl under basic conditions, and is subsequently acidified to obtain a compound of Formula (V):
    [0023] [023] The reaction step above can be carried out in a manner similar to the reaction sequences of the prior art for obtaining dicamba from 2,5-dichlorophenol with good yields on an industrial scale.
    [0024] [024] According to other embodiments especially preferably, R is selected from hydrogen and R '; and R 'is selected from methyl and ethyl. Most preferably, R 'is methyl. In the reaction step to obtain the compound of Formula (I), according to the present invention, usually a mixture of phenol derivatives, where R is hydrogen, and the corresponding alkyl phenol ether derivatives, in that R is R ', are obtained. In principle, alkyl phenol ether derivatives can still react with the corresponding phenol derivatives, as described in more detail below.
    [0025] [025] In especially preferred embodiments, according to the present invention, X is sodium or potassium. Most preferably, X is sodium. Therefore, the alkali metal alkoxide of Formula XOR 'used for the hydrolysis reaction to obtain the compound of Formula (I) is preferably a potassium alkoxide or sodium alkoxide, such as sodium methoxide.
    [0026] [026] In preferred embodiments, R1 is selected from sodium and potassium. R1 is derived from an alkali metal hydroxide, that is, the sodium hydroxide or potassium hydroxide used during the Kolbe-Schmitt reaction step. It may still be advantageous to replace an alkali metal with another alkali metal, in preferred embodiments of the invention, as described below. In a preferred embodiment, R1 is potassium in the Kolbe-Schmitt reaction step described above, that is, KOH is used in the step of providing the compound of Formula (III).
    [0027] [027] According to other preferred embodiments, according to the present invention, in the case of R1 not being an alkali metal, in the compound of Formula (IV) described above, R1 is ethyl or methyl. In these cases, R1 'is identical to R2. R2, according to the preferred embodiments, is also selected from ethyl and methyl. In a most preferred embodiment, R2 is methyl, therefore, also R1 ', more preferably, is methyl if it is not an alkali metal. In the case that R1 'is an alkali metal, it may be identical to R1, as defined above, or, preferably, it is an alkali metal other than R1, that is, it may be different at different stages of the reaction. For example, R1 'can be Na or it can be identical to R2.
    [0028] [028] In especially preferred embodiments, the processes, according to the present invention, are used to obtain dicamba. In these preferred embodiments, the compound of Formula (V) is:
    [0029] [029] Other preferred embodiments of the present invention are evident from the following Detailed Description of the Invention and the set of appended claims. DETAILED DESCRIPTION OF THE INVENTION
    [0030] [030] In the following, the illustrative embodiments of the present invention are described in more detail.
    [0031] [031] The term “Hal” or “halogen”, as used herein, refers to a halogen atom independently selected from F, Cl, Br and I. Most preferably, Hal is independently selected from of Cl and Br. In even more preferred embodiments, both hal substituents are identical and, most preferably, are Cl.
    [0032] [032] The term "alcoholic solution", as used, refers to a solution of a chemical compound in an alcohol, in particular, an alcohol of the Formula HOR ', where R' is as defined above. The term "alkali metal alkoxide alcoholic 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', where X and R 'are as defined above.
    [0033] [033] The present invention relates to an improved process for the hydrolysis of a Formula (II) compound to obtain a corresponding Formula (I) phenol or alkyl ether of improved yield and / or regioselectivity. According to industrial processes, in the prior art, the hydrolysis of 1,2,4-trialobenzenes, such as 1,2,4-trichlorobenzene, is carried out using NaOH in an alcoholic solvent. For example, hydrolysis of 1,2,4-trichlorobenzene with NaOH in methanol provides 2,5-dichlorophenol in 64.6% yield. In addition, in this reaction, several by-products are obtained, that is, 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 state of the art, is 71.9%.
    [0034] [034] The term “2,5-regioselectivity” refers to the ratio between the combined amount (s) of 2,5-dialophenol and 2,5-dialophenol alkyl ether to the total amount of 2,5-dialophenol, 2,5-dialophenol alkyl ether, 2,4-dialophenol, 2,4-dialophenol alkyl ether, 3,4-dialophenol, and 3,4-dialophenol alkyl ether obtained (s) in the reaction. For example, the term "2,5-regioselectivity" used above in connection with the prior art processes for obtaining 2,5-dichlorophenol from 1,2,4-trichlorobenzene using NaOH in methanol refers to the quantities combinations of 2,5-dichlorophenol and 2,5-dichlorophenol alkyl ether, for the total amount of 2,5-dichlorophenol, 2,5-dichlorophenol alkyl, 2,4-dichlorophenol, 2-alkyl ether , 4-dichlorophenol, 3,4-dichlorophenol, and 3,4-dichlorophenol alkyl ether obtained.
    [0035] [035] Similarly, the term “2,4-regioselectivity” refers to the ratio between the combined amount (s) of 2,4-dialophenol and 2,4-dialophenol alkyl ether for the total amount of 2,5-dialophenol, 2,5-dialophenol alkyl ether, 2,4-dialophenol, 2,4-dialophenol alkyl ether, 3,4-dialophenol, and 3,4 alkyl ether -dialophenol obtained.
    [0036] [036] In addition, the term “3,4-regioselectivity” refers to the ratio between the combined amount (s) of 3,4-dialophenol and 3,4-dialophenol alkyl ether for total amount of 2,5-dialophenol, 2,5-dialophenol alkyl ether, 2,4-dialophenol, 2,4-dialophenol alkyl ether, 3,4-dialophenol, and 3,4- alkyl ether dialophenol obtained.
    [0037] [037] 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 products of preference of Formula (V). A product preferably obtained in the processes, according to the present invention, is 2,5-dichlorophenol used in the production of dicamba.
    [0038] [038] The term "alkali metal", when used in the context of the present invention, refers to lithium, sodium or potassium. Sodium and potassium are preferred.
    [0039] [039] The present Depositors have found that the use of an alkali metal alkoxide, instead of an alkali metal hydroxide in the hydrolysis above provides better yields of 2,5-dialophenol, such as 2,5-dichlorophenol, and / or the enhanced 2.5-regioselectivity. The present Depositors have also discovered the specific reaction conditions of preference to further improve the yield of the desired compounds and / or the desired 2,5-regioselectivity.
    [0040] [040] Therefore, the present invention relates to an improved process for the hydrolysis of 1,2,4-trialobenzene of Formula (II) to obtain a compound of Formula (I):
    [0041] [041] The reaction is usually carried out in a pressure reactor. The solvent and reagents are added to the pressure reactor, the pressure of the reactor is sealed and then heated to the desired reaction temperature, with stirring. 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 separating device, such as a separating funnel, by acidifying the mixture using a suitable acid such as H2SO4 or HCl to a pH of, for example, less than 1 , 5, and extracting the mixture using a suitable organic solvent, such as an ether (for example, methyl tert-butyl ether) or methylene chloride (CH2Cl2). Continuous extraction in a suitable device or sequential extraction (for example, three times) can be employed.
    [0042] [042] Preferably, according to the present invention, 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', where X and R 'are as defined above. The present Depositors 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% by weight, up to about 67% by weight, based on the total weight of alcohol and alkali metal alkoxide. . In most preferred embodiments, the concentration of the alcoholic alkali metal alkoxide solution added to the reaction mixture is from about 25% by weight to about 67% by weight.
    [0043] [043] The reaction temperature is preferably at least 150 ° C, such as from 150 ° C to about 190 ° C. In a 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.
    [0044] [044] The reaction is preferably carried out within 30 to 180 minutes. In a most preferred embodiment, the reaction is carried out within 45 to 120 minutes, such as 90 minutes.
    [0045] [045] The present Depositors have found that, under specific reaction conditions, including the reaction temperature, concentration of the alkali metal alkoxide alcoholic solution, and the reaction time, the yield of the compound of Formula (I) can still be improved . Therefore, in this case, the yield of the compound of Formula (I) is optimized, the reaction is preferably carried out at relatively high reaction temperatures for a moderate reaction time using a relatively low concentration of the alkali metal alkoxide solution. alcoholic. In a preferred embodiment, the yield of the compound of Formula (I) is optimized to carry 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 a concentration of the alcoholic alkali metal alkoxide solution of about 20% by weight, by weight to about 30% by weight.
    [0046] [046] In alternative cases, when 2,5-regioselectivity is the main focus for optimization, the reaction is preferably carried out at moderate reaction temperatures for a moderate reaction time using a high concentration of the metal alkoxide solution alkaline alcohol. In a preferred embodiment, 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 the concentration of the alcoholic alkali metal alkoxide solution from about 50% by weight to about 67% by weight.
    [0047] [047] The compounds of Formula (I), where R is R ', can be hydrolyzed under basic conditions to the compounds of Formula (I) where R is hydrogen. Suitable bases include, for example, alkali metal hydroxides, such as NaOH or KOH. The conversion can be carried out in a suitable organic solvent, such as an alcohol. The alkali metal salts obtained later can be acidified with the acid such as H2SO4 or HCl to provide the compound of Formula (I), where R is hydrogen.
    [0048] [048] In another preferred embodiment, the compound of Formula (I), where R is hydrogen, is converted into valuable chemicals or intermediates. In an especially preferred embodiment, the compound of Formula (I), where R is hydrogen, is subjected to a carboxylation reaction, under Kolbe-Schmitt conditions to obtain a compound of Formula (III):
    [0049] [049] In the carboxylation step, the compound of Formula (I) is first converted to the corresponding phenolate by treatment with an alkali metal hydroxide R1OH. For example, sodium hydroxide or potassium hydroxide is used at present, of which, preferably, it is potassium hydroxide. Alkali metal hydroxide is used in about stoichiometric amounts in an aqueous solution that, for example, contains a concentration of 50% by weight. The conversion can be carried out in a suitable organic solvent, such as, for example, xylene. Water can be removed from the system using azeotropic distillation.
    [0050] [050] Subsequently, the phenolate is placed in contact with the CO2 gas under high pressure. The phenolate solution, for example, in xylene can be used without further processing. The reaction provides the carboxylic acid salt of Formula (III), which is not normally soluble in the reaction medium, such as toluene and, therefore, can be easily separated.
    [0051] [051] In another preferred embodiment, the compound of Formula (III) is alkylated to obtain a compound of Formula (IV).
    [0052] [052] The reaction is carried out by reacting the compound of Formula (III) with an alkyl halide of Formula YR2, where Y is the halogen, such as Cl, Br or I, preferably Cl or Br, of greater preferably, Cl. In a preferred embodiment, the alkyl halide is methyl chloride. The reaction can be carried out in an aqueous solution. During the reaction, the pH, pressure and temperature can be controlled in such a way 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 from about 500 to about 1,050 kPa. An excess of alkyl halide is usually used. Therefore, it is not excluded that the compound of Formula (IV) is partially esterified. In these cases, R1 'is identical to R2.
    [0053] [053] In addition, to increase the solubility of the compound of Formula (IV), the double salt can be converted before the reaction of a corresponding mixed salt by treatment with an alkali metal hydroxide other than 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) can be treated with sodium hydroxide before the alkylation step to obtain a mixed potassium / sodium salt. In these cases, R1 'may be an alkali metal other than R1. In other cases, R1 'is identical to R1.
    [0054] [054] In another preferred embodiment, the compound of Formula (IV) is converted to the compound of Formula (V):
    [0055] [055] In cases where the compounds of Formula (IV) include an ester in which R1 'is identical to R2, the ester is hydrolyzed under basic conditions using a suitable base to obtain the corresponding salts of carboxylic acid. For example, alkali metal hydroxides, such as NaOH, can be used at present. The compounds of Formula (IV) in which R1 'is an alkali metal can be present during hydrolysis, without damage. Therefore, a composition comprising a compound of Formula (IV) in which R1 'is an alkali metal, such as sodium, is obtained.
    [0056] [056] The alkali metal salt of Formula (IV) is then acidified in solution using a suitable acid, such as H2SO4 or HCl, preferably HCl, to obtain the compound of Formula (V). In cases where a compound of Formula (IV), in which R1 'is an alkali metal, is obtained in the previous reaction step, the composition can be directly subjected to acidification, without the hydrolysis above.
    [0057] [057] While the preferred processes and processes according to the present invention, as described above, can be employed to provide a variety of final and intermediate products, the present invention will be illustrated by describing a sequence of reaction to obtain dicamba from 1,2,4-trichlorobenzene. One skilled in the art will understand that certain reaction steps in this sequence are preferably in opposition to the essential, and will still be able to adapt the processes described herein for the production of other compounds and intermediates within the scope of the appended claims.
    [0058] [058] In an especially preferred embodiment, the present invention relates to the 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 hydrolysis reaction using sodium methoxide in methanol, as described above, to obtain 2,5-dichlorophenol with an improved yield and / or 2,5-regioselectivity.
    [0059] [059] 1,2,4-trichlorobenzene is a compound within the definition of Formula (II), as defined above, where Hal is Cl. In addition, 2,5-dichlorophenol is a compound within the definition of Formula (I) according to the present invention, where Hal is Cl, and R is H.
    [0060] [060] According to the preferred embodiments of the present invention, 2,5-dichlorophenol is subjected to carboxylation under Kolbe-Schmitt conditions using KOH and CO2, as described above, to obtain the dipotassium salt of acid 3 , 6-dichlorosalicyclic.
    [0061] [061] The dipotassium salt of 3,6-dichlorosalicylic acid is a compound according to Formula (III) of the present invention, where Hal is Cl, and R1 is K.
    [0062] [062] The dipotassium salt of 3,6-dichlorosalicylic acid is preferably methylated in a later reaction step, using methyl chloride. As described above, this conversion may include converting the dipotassium salt to a mixed salt to improve solubility in water. In a preferred embodiment, NaOH is used to supply the mixed salt. Because of this, dipotassium methylation of 3,6-dichlorosalicylic acid after conversion to a mixed salt usually provides a mixture of sodium and / or potassium form of 3,6-dichloro-2-methoxybenzoic acid and methyl ester of 3,6-dichloro-2-methoxybenzoic acid.
    [0063] [063] The product obtained in the reaction described above is a compound according to Formula (IV) of the present invention, in which Hal is Cl, R2 is methyl, and R1 'is K, Na or methyl.
    [0064] [064] The above mentioned mixture can be converted to dicamba by hydrolysis of the ester compounds in the mixture using NaOH, as described above and, later, by acidifying the resulting product using HCl, as described above.
    [0065] [065] Dicamba is a compound, according to Formula (V) of the present invention, in which Hal is Cl, and R2 is methyl.
    [0066] [066] The reaction sequence above can be carried out on an industrial scale. The overall yield of the final and intermediate products is improved in relation to the process as a whole since the required desired yield and / or regioselectivity is improved in the first step of the sequence process. Therefore, in a preferred embodiment, the present invention relates to the advantageous synthetic route for dicamba for production on an industrial scale with improved yields from 1,2,4-trichlorobenzene. EXAMPLES
    [0067] [067] The present invention will be further illustrated by means of a Comparative Example and Processing Examples. 1. COMPARATIVE EXAMPLE
    [0068] [068] The 1,2,4-trichlorobenzene (TCB), NaOH (in the form of a 50% by weight solution in water) and methanol were loaded into a pressure reactor. The molar ratio of TCB: NaOH: methanol was 1.0: 2.4: 10. Then, the pressure reactor was sealed, heated to 190 ° C with stirring and maintained at this temperature for 90 minutes. During the reaction, stirring was continued. The reactor was then cooled to room temperature using an ice-H2O bath.
    [0069] [069] The reaction mixture was then transferred to a separatory funnel and acidified with 10% H2SO4 at a pH below 1.5. The aqueous layer of the resulting two-layer mixture was then extracted three times with methylene chloride.
    [0070] [070] The yield obtained from 2,5-dichlorophenol was 64.6%. The regioselectivity obtained (2,5-dichlorophenol and 2,5-dichlorophenol / 2,4-dichlorophenol methyl ether and 2,4-dichlorophenol / 3,4-dichlorophenol methyl ether and 3,4- methyl ether dichlorophenol) was 71.9 / 15.5 / 12.6 (analysis using the GC). 2. PROCESSING EXAMPLE 1
    [0071] [071] The Comparative Example above was repeated except that a 25% solution of NaOMe in methanol as the base was used. The molar ratio of TCB: NaOMe: methanol was 1.0: 2.4: 12. The yield obtained for 2,5-dichlorophenol and 2,5-dichloroanisole combined was 73.9%. The 2,5-regioselectivity obtained was 74.2%. 3. PROCESSING EXAMPLE 2
    [0072] [072] Processing Example 1 was repeated with the exception of carrying out the reaction for 45 minutes. The yield obtained for 2,5-dichlorophenol and 2,5-dichloroanisole combined was 72.0%. The 2.5-regioselectivity obtained was 74.5%. 4. PROCESSING EXAMPLE 3
    [0073] [073] Processing Example 1 was repeated with the exception of carrying out the reaction at a temperature of 150 ° C. The 2,5-regioselectivity obtained was 75.4%. 5. PROCESSING EXAMPLE 4
    [0074] [074] Processing Example 1 was repeated except that a 35% NaOMe solution was used and carrying out the reaction at a temperature of 170 ° C. The yield obtained from 2,5-dichlorophenol and 2,5-dichloroanisole combined was 70.6%. The 2.5-regioselectivity obtained was 76.2%. 6. THE PROCESSING EXAMPLE 5
    [0075] [075] Processing Example 1 was repeated except that a 50% NaOMe solution was used and carrying out the reaction at a temperature of 160 ° C. The 2.5-regioselectivity obtained was 76.8%. 7. PROCESSING EXAMPLE 6
    [0076] [076] Processing Example 5 was repeated except that a 67% NaOMe solution was used. The 2,5-regioselectivity obtained was 78.0%.

    权利要求:
    Claims (11)
    [0001]
    PROCESS TO PROVIDE A COMPOUND OF FORMULA (I):
    [0002]
    PROCESS according to claim 1, characterized in that the process is carried out in a solvent, in which the solvent is an alcohol of Formula HOR ', in which R' is as defined in claim 1.
    [0003]
    PROCESS according to any one of claims 1 to 2, characterized in that a molar equivalent of the compound of Formula (II) reacts in the presence of 2 to 3 molar equivalents of an alkali metal alkoxide of Formula XOR 'in 2 to 14 molar equivalents of a solvent of Formula HOR '.
    [0004]
    PROCESS according to any one of claims 1 to 3, characterized in that the step of reacting the compound of Formula (II) with an alkali metal alkoxide of Formula XOR 'is carried out at a temperature of 150 ° C to 190 ° C.
    [0005]
    PROCESS according to any one of claims 1 to 4, characterized in that 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.
    [0006]
    PROCESS according to any one of claims 1 to 5, characterized in that it further comprises the step of reacting the compound of Formula (I) to obtain a compound of Formula (III)
    [0007]
    PROCESS according to claim 6, characterized by the step of reacting the compound of Formula (I) to obtain a compound of Formula (III) to be carried out in the presence of an alkali metal hydroxide and carbon dioxide.
    [0008]
    PROCESS according to any one of claims 6 to 7, characterized in that it further comprises the step of reacting the compound of Formula (III) to obtain a compound of Formula (IV):
    [0009]
    PROCESS, according to claim 8, characterized in that it further comprises the step of reacting the compound of Formula (IV) to obtain a compound of Formula (V):
    [0010]
    PROCESS according to any one of claims 1 to 9, characterized by: (a) R is selected from hydrogen and R '; and R 'be selected from methyl and ethyl; and / or (b) X is sodium or potassium; and / or (c) R1 is selected from sodium and potassium; and / or (d) R1 'is selected from sodium and potassium, or R1' is R2, and R2 is selected from ethyl and methyl.
    [0011]
    PROCESS according to any one of claims 9 to 10, characterized in that the compound of Formula (V) is:
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    法律状态:
    2019-12-17| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|
    2020-09-24| B07A| Technical examination (opinion): publication of technical examination (opinion)|
    2021-02-23| B09A| Decision: intention to grant|
    2021-03-23| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 02/10/2014, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US201361886679P| true| 2013-10-04|2013-10-04|
    US61/886,679|2013-10-04|
    EP13190194.4|2013-10-25|
    EP13190194|2013-10-25|
    PCT/EP2014/071210|WO2015049360A1|2013-10-04|2014-10-02|Selective hydrolysis and alcoholysis of chlorinated benzenes|
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