process for the preparation of 3,6-dichlorosalicylic acid compounds

专利摘要:
3,6-DICHLOROSALICYLIC ACID COMPOUNDS AND RELATED SYNTHETIC PROCESSES The present description relates, in general, to 5-halo-3,6-dichlorosalicylic acid compounds, 5-halo-3,6-dichlorosalicialdehyde compounds, processes for the preparation of 5-halo-3,6-dichlorosalicylic acid compounds, processes for the preparation of 5-halo-3,6-dichlorosalicialdehyde compounds, processes for the preparation of 3,6-dichlorosalicylic acid compounds, and processes employing such compounds as intermediates in the preparation of the dicamba herbicide.
公开号:BR112016028370B1
申请号:R112016028370-8
申请日:2015-06-03
公开日:2021-03-09
发明作者:Terri L. Boehm；Mangesh Bore；Jeffery N. Carroll；G. Davis Harris Jr.；Matthew D. Mcreynolds；Justin R. Struble；Daniel P. Walker
申请人:Monsanto Technology Llc；
IPC主号:

专利说明:

CROSS REFERENCE TO RELATED REQUESTS
[0001] This application claims priority for US Provisional Application 62 / 007,578, filed on June 4, 2014, provisional application US 62 / 042,068, filed on August 26, 2014, Provisional Application US 62 / 111,303, filed on February 3 2015, the totality of each of which is incorporated by reference. FIELD OF THE INVENTION
[0002] The present description relates, in general, to 5-bromo-3,6-dichlorosalicylic acid compounds, 5-bromo-3,6-dichlorosalicialdehyde compounds, processes for preparing 5-bromo acid compounds - 3,6-dichlorosalicylic, processes for preparing 5-bromo-3,6-dichlorosalicialdehyde compounds, processes for preparing 3,6-dichlorosalicylic acid compounds and processes that employ such compounds as intermediates in the preparation of the dicamba herbicide. BACKGROUND OF THE INVENTION
[0003] 3,6-dichloro-2-methoxybenzoic acid (also known by its common name dicamba) is a highly effective and commercially important herbicide that is useful for controlling a wide variety of unwanted vegetation, including agricultural weeds. Consequently, the convenient and economical methods of preparing dicamba are of significant commercial importance.
[0004] Various synthetic routes for the preparation of dicamba have been reported in the literature. A reported pathway proceeds through a 2,5-dichlorophenol intermediate as illustrated in Scheme 1 below: Scheme 1
See, for example, US Patent 4,161,611.
[0005] Another reported route proceeds through an intermediate of 4-bromo-3,6-dichloro-2- (hydroxymethyl) phenol or an intermediate of (3-bromo-2,5-dichloro-6-methoxy-phenyl) methanol as illustrated in Scheme 2 below: Scheme 2
See, for example, US Patent 3,928,432.
[0006] Yet other reported pathways employ starting materials, or proceed through intermediates, such as 2,5-dichlorophenol (see, for example, US Patent 4,232,172); 2,5-dichloro-4-bromophenol (see, for example, US Patent 3,728,403); 1,2,4-trichlorobenzene (see, for example, US Patent 3,013,054), 2,3,6-trichlorobenzoic acid (see, for example, US Patent 3,444,192); or 2,6-dichlorobenzonitrile (see, for example, Romanowski et al., Prezem. Chem. 54 (1), pp. 26-31 (1975)).
[0007] Compared to currently known processes, however, the processes of the present description provide one or more advantages in the large-scale manufacture of dicamba with regard to the cost and / or availability of starting materials, processing and / or stages processing requirements (such as hazardous processing steps and / or separation / purification steps), equipment requirements (such as high pressure and temperature reactors), reaction conditions, reaction times, throughput, energy consumption, capital and the like. BRIEF DESCRIPTION OF THE INVENTION
[0008] The present description relates to 5-bromine-3,6-dichlorosalicylic acid compounds, 5-bromo-3,6-dichlorosalicialdehyde compounds, 3,6-dichlorosalicylic acid compounds, processes for the preparation of these compounds and processes for converting these compounds into dicamba.
[0009] In one aspect, the present description relates to a process for the preparation of a corresponding compound in the structure of Formula (III):
or a salt thereof, the process comprising: contacting a corresponding compound in the structure with Formula (II):
or a salt thereof, with a chlorinating agent in an acid reaction medium to provide the compound or salt of Formula (III); wherein R1 is hydrogen or C1-6-alkyl; and R2 is hydrogen or C1-6-alkyl.
[0010] In another embodiment, the present description refers to a process for the preparation of a corresponding compound in the structure of Formula (III):
or a salt thereof, the process comprising: contacting a corresponding compound in the structure with Formula (I):
or a salt thereof, with a brominating agent in an acid reaction medium comprising sulfuric acid to provide a corresponding compound in the structure of Formula (II):
or a salt thereof; Contact the Formula (II) compound or salt with a first chlorinating agent without first isolating the Formula (II) compound or salt from the reaction medium to provide a corresponding compound in the Formula (VI) structure:
or a salt thereof; and contacting the Formula (VI) compound or salt with a second chlorinating agent to provide the Formula (III) compound or salt; where: R1 is hydrogen or C1-6-alkyl; R2 is hydrogen or C1-6-alkyl; and the first chlorinating agent and the second chlorinating agent can be the same or different.
[0011] In another aspect, the present description refers to a process for the preparation of a corresponding compound in the structure of Formula (III):
or a salt thereof, the process comprising: contacting a corresponding compound in the structure with Formula (II):
O (II), or a salt thereof with a first chlorinating agent without first isolating the compound or salt of Formula (II) from the reaction medium to provide a corresponding compound in the structure of Formula (VI):
or a salt thereof, modify the acid reaction medium to provide an acid reaction medium comprising oil after the formation of the Formula (VI) compound or salt and contact the Formula (VI) compound or salt with a second agent chlorination without first isolating the Formula (VI) compound or salt from the reaction medium to provide the Formula (III) compound; where R 1 is hydrogen or C1-6-alkyl; and R2 is hydrogen or C1-6-alkyl; and the first chlorinating agent and the second chlorinating agent can be the same or different.
[0012] In another aspect, the present description refers to a process for the preparation of a corresponding compound in the structure of Formula (V):
or a salt thereof, the process comprising: contacting a corresponding compound in the structure with Formula (II):
or a salt thereof, with a chlorinating agent in an acid reaction medium to provide the compound or salt of Formula (III):
or a salt thereof; selectively debromination of the compound or salt of Formula (III) to provide a corresponding compound in the structure of Formula (IV):
or a salt thereof; when R1 is different from methyl and / or R2 is different from hydrogen, converting the compound or salt of Formula (IV) into the compound or salt of Formula (V), where R1 is hydrogen or C1-6-alkyl; and R2 is hydrogen or C1-6-alkyl.
[0013] In another aspect, the present description refers to a process for the preparation of a corresponding compound in the structure of Formula (V):
or a salt thereof, the process comprising: contacting a corresponding compound in the structure of Formula (III-1):
or a salt thereof, with a methylating agent to provide a corresponding compound in the structure of Formula (III-2):
or a salt thereof; selectively break down the compound or salt of Formula (III-2) to provide a corresponding compound in the structure of Formula (IV-2):
or a salt thereof; scaponify the Formula (IV-2) compound or salt to proportion the Formula (V) compound or salt.
[0014] In another aspect, the present description refers to a process for the preparation of a corresponding compound in the structure of Formula (IV-1):
or a salt thereof, the process comprising contacting a corresponding compound in the structure with Formula (X):
or a salt thereof, with an oxidizing agent to provide the compound or salt of Formula (VI-1); where R1 is hydrogen or C1-6-alkyl.
[0015] In another aspect, the present description refers to a process for the preparation of a compound corresponding to the structure of Formula (IV-1), or to a salt thereof, the process comprising counting a corresponding compound in the structure for Formula (VII-1):
or a salt thereof, with a first chlorinating agent to provide a corresponding compound in the structure of Formula (VIII-1):
or a salt thereof, contact the compound or salt of Formula (VIII-1) with a second chlorinating agent to provide a corresponding compound in the structure of Formula (IX-1):
or a salt thereof; contact the compound or salt of Formula (IX-1) with a de-bromination agent to provide a corresponding compound in the structure of Formula (X-1):
or a salt thereof; the same; and contacting the compound or salt of Formula (X-1) with an oxidizing agent to provide a corresponding compound in the structure of Formula (IV-1), or a salt thereof.
[0016] In another aspect, the present description refers to a corresponding compound in the structure of Formula (III):
or a salt thereof, where R1 is hydrogen or C1-6-alkyl; and R2 is hydrogen or C1-6-alkyl.
[0017] In another aspect, the present description refers to a corresponding compound in the structure of Formula (IX):
or a salt thereof, where R1 is hydrogen or C1-6-alkyl. DETAILED DESCRIPTION OF THE INVENTION
[0018] This written description uses examples to disclose the invention, including the best way, and also to allow anyone skilled in the art to practice the invention, including the manufacture and use of any of the salts, substances or compositions described, and making any of the disclosed methods or processes. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have elements that do not differ from the literal language of the claims, or if they include equivalent elements. I. Definitions
[0019] The section headings used in this section and the entire description are not intended to be limiting.
[0020] When a numerical range is recited, each intervention number within the range is explicitly considered with the same degree of precision. For example, for the range 6 to 9, the numbers 7 and 8 are included in addition to 6 and 9, and for the range 6.0 to 7.0, the numbers 6.0, 6.1, 6, 2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitly contemplated. Likewise, all the proportions mentioned also include all sub-proportions that are within the broadest proportion.
[0021] The singular forms "a", "one" and "o" include plural referents unless the context clearly dictates otherwise.
[0022] The term "fence" generally refers to a range of numbers that a person skilled in the art would consider equivalent to the recited value (ie, having the same function or result). In many cases, the term "about" can include numbers that are rounded to the nearest significant value.
[0023] Unless the context requires otherwise, the terms "understand", "understand" and "understanding" are used on the basis and in a clear understanding which should be interpreted inclusive, rather than exclusively, and that Applicant intends that each of these words be so interpreted in the interpretation of this patent, including the claims below.
[0024] The abbreviation "BCSA" refers to 5-bromo-3-chlorosalicylic acid (also known as 5-bromo-3-chloro-2-hydroxybenzoic acid).
[0025] The abbreviation "BDCSA" refers to 5-bromo-3,6-dichlorosalicylic acid (also known as 3-bromo-2,5-dichloro-6-hydroxybenzoic acid).
[0026] The abbreviation "3-Br-SA" refers to 3-bromosalicylic acid (also known as 3-bromo-2-hydroxybenzoic acid).
[0027] The abbreviation "5-Br-SA" refers to 5-bromosalicylic acid (also known as 5-bromo-2-hydroxybenzoic acid).
[0028] The abbreviation "3,5-Br2-SA" refers to 3,5-dibromosalicylic acid (also known as 3,5-dibromo-2-hydroxybenzoic acid).
[0029] The abbreviation "DBCSA" refers to 3,5-dibromo-6-chlorosalicylic acid (also known as 3,5-dibromo-2-chloro-6-hydroxybenzoic acid).
[0030] The abbreviation "HCl" refers to hydrochloric acid.
[0031] The abbreviation "SA" refers to salicylic acid.
[0032] The abbreviation "TCICA" refers to trichloroisocyanuric acid. II. Preparation of 5-Halo-3,6-Dichlorosalicylic Acid Compounds (Process BDCSA 1)
[0033] In one embodiment, the present description relates, in part, to processes for converting 5-bromoscicylic acid compounds to the corresponding 5-bromo-3,6-dichlorosalicylic acid compounds. The prepared 5-bromo-3,6-dichlorosalicylic acid compounds can be used as intermediates in the manufacture of dicamba. In particular, the present description relates to processes for converting 5-bromosalicylic acid to 5-bromo-3,6-dichlorosalicylic acid.
[0034] In an advantageous embodiment, salicylic acid, a relatively inexpensive and readily available material, is used as a starting material to prepare 5-bromo-salicylic acid which is then converted to 5-bromo-3,6-dichlorosalicylic acid. In other embodiments, 5-bromosalicylic acid can be prepared from a starting material which is an alkylated analogue of salicylic acid. Scheme 3 below illustrates a representative pathway for the preparation of dicamba that begins with a salicylic acid starting material and proceeds through a 5-bromo-3,6-dichloroscyllic acid intermediate.

[0035] Although illustrated mainly throughout this application with 5-bromo-3,6-dichlorosalicylic acid, the processes disclosed in this application can be used to synthesize other 5-bromo-3,6-dichlorosalicylic acid compounds from the corresponding compounds of 5-bromosalicylic acid. Therefore, in one embodiment, the present description refers to a process for the preparation of a corresponding compound in the structure of Formula (III):
or a salt thereof, the process comprising: contacting a corresponding compound in the structure with Formula (II):
or a salt thereof, with a chlorinating agent in an acid reaction medium to provide the compound or salt of Formula (III); wherein R1 is hydrogen or C1-6-alkyl; and R2 is hydrogen or C1-6-alkyl.
[0036] In certain embodiments of the compound or salt of Formula (II) and the compound or salt of Formula (III), R1 is hydrogen, methyl or ethyl; and R2 is hydrogen, methyl or ethyl. In another aspect, R1 is hydrogen or methyl; and R2 is hydrogen or methyl. In another aspect, R1 and R2 are each hydrogen (that is, the compound of Formula (II) is 5-bromosalicylic acid and (III) is 5-bromo-3,6-dichlorosalicylic acid) and the compounds of Formula ( II) and Formula (III) correspond in structure to Formula (II-1) and Formula (III-1), respectively:
in another respect, R1 and R2 are each methyl. In another aspect, one of R1 and R2 is hydrogen; and the other for R1 and R2 is methyl. A. Chlorination agent
[0037] The chlorinating agent in contact with the Formula (II) compound or salt is generally a compound that is suitable under the process conditions applicable to carry out the chlorination of a Formula (II) compound or salt according to with the disclosed processes. In one embodiment, the chlorinating agent is selected from the group consisting of chlorine gas, trichloroisocyanuric acid, 1,3-dichlorohydantoin, N-chlorosuccinimide and iodine monochloride. In one aspect, the chlorinating agent is selected from the group consisting of chlorine gas and trichloroisocyanuric acid. In another aspect, the chlorinating agent is trichloroisocyanuric acid. In another aspect, the chlorinating agent is chlorine gas. The use of chlorine gas as a chlorinating agent can be advantageous over another chlorinating agent. Among other advantages, chlorine gas is a relatively inexpensive reagent and generally reduces or eliminates residual by-products that are generated when other chlorinating agents are used (for example, cyanuric acid is produced when trichloroisocyanuric acid is used as the chlorinating agent ). B. Reaction Medium
[0038] The reaction medium is generally an acid reaction medium that is suitable for the chlorination of the Formula (II) compound or salt with the chlorinating agent under the applicable process conditions according to the disclosed processes. In one embodiment, the reaction medium comprises one or more acids selected from the group consisting of sulfuric acid, chlorosulfonic acid and oleum. In one aspect, the reaction medium comprises less than about 5% by weight of water. In another aspect, the reaction medium comprises less than about 2% by weight of water. In another aspect, the reaction medium is substantially anhydrous. The reaction medium can be prepared in any suitable way before the introduction of the chlorinating agent.
[0039] In one embodiment, the reaction medium comprises sulfuric acid. In one aspect, the reaction medium comprises at least about 95% sulfuric acid by weight. In another aspect, the reaction medium comprises at least about 96% sulfuric acid by weight. In another aspect, the reaction medium comprises at least about 97% sulfuric acid by weight. In another aspect, the reaction medium comprises at least about 98% sulfuric acid by weight. In another aspect, the reaction medium comprises at least about 99% sulfuric acid by weight.
[0040] In one embodiment, the reaction medium comprises oleum. The reaction medium will generally contain an amount of oleum that is sufficient to maintain the reaction medium in a liquid state under the applicable process conditions. See, for example, Sections 4.2.2 (page 37) and 12.3.1 (page 113) of Ashar, N.G., A Practical Guide to the Manufacture of Sulfuric Acid, Oleums, and Sulfonating Agents, Springer International Publishing AG (2013).
[0041] In one aspect, the reaction medium comprises at least about 5% oleum by weight. In another aspect, the reaction medium comprises at least about 10% oleum by weight. In another aspect, the reaction medium comprises at least about 15% oleum by weight. In another aspect, the reaction medium comprises at least about 20% oleum by weight. In another aspect, the reaction medium comprises at least about 25% oleum by weight. In another aspect, the reaction medium comprises at least about 50% oleum by weight. In another aspect, the reaction medium comprises at least about 60% oleum by weight. In another aspect, the reaction medium comprises from about 5% oleum by weight to about 70% oleum by weight. In another aspect, the reaction medium comprises from about 10% oleum by weight to about 50% oleum by weight. In another aspect, the reaction medium comprises between about 15% oleum by weight and about 40% oleum by weight. In another aspect, the reaction medium comprises from about 20% oleum by weight to about 40% oleum by weight. In another aspect, the reaction medium comprises from about 20% oleum by weight to about 30% oleum by weight. In another aspect, the reaction medium comprises between about 50% oleum by weight and about 80% oleum by weight. In another aspect, the reaction medium comprises from about 60% oleum by weight to about 70% oleum by weight. As illustrated later in this application, the desired concentration of oleum in the medium can be achieved, for example, by adding a sufficient amount of sulfur trioxide and / or oleum to a concentrated sulfuric acid medium (for example, by adding a sufficient amount of 65% oleum by weight to a medium containing 95% sulfuric acid by weight to provide a medium containing 25% oil by weight). C. Catalyst
[0042] In one embodiment, the reaction medium further comprises a catalyst. In one aspect, the catalyst is iodine (I2) or iodine monochloride ("ICI"). In another aspect, the catalyst is iodine. In another aspect, the catalyst is iodine monochloride. Iodine is a solid at room temperature while iodine monochloride is a liquid at room temperature. Since iodine and monochloride iodine provide substantially similar catalytic results in the chlorination reaction, the selection between the two catalysts may depend on whether a solid or liquid catalyst is desired. D. Reaction Stoichiometry
[0043] A stoichiometry of 2.0 equivalents of active chlorine in the chlorination agent is required for the chlorination reaction to convert the Formula (II) compound or salt to the Formula (III) compound or salt. Although smaller or larger amounts of the chlorinating agent can be used for the chlorination reaction, a stoichiometric amount or a stoichiometric excess of the active chlorine, for example, at least about 2.0 equivalents of active chlorine from the chlorinating agent, generally provides a better conversion of the Compound or salt of Formula (II) to the compound or salt of Formula (III). When a relatively expensive chlorinating agent, such as trichloroisocyanuric acid, is used, a stoichiometric excess of the active chlorine is generally more closely controlled than in the case of a relatively inexpensive chlorinating agent such as chlorine gas. Therefore, in one embodiment, the compound or salt of Formula (II) is brought into contact with about 2.0 to about 8.0 equivalents of active chlorine from the chlorinating agent. In one aspect, the compound or salt of Formula (II) is brought into contact with about 2.0 to about 6.0 equivalents of active chlorine from the chlorinating agent. In another aspect, the compound or salt of Formula (II) is brought into contact with about 2.0 to about 4.0 equivalents of active chlorine from the chlorinating agent. In another aspect, the compound or salt of Formula (II) is brought into contact with about 2.0 to about 3.0 equivalents of active chlorine from the chlorinating agent. In another aspect, the compound or salt of Formula (II) is brought into contact with about 2.0 to about 2.4 equivalents of active chlorine from the chlorinating agent. In another aspect, the compound or salt of Formula (II) is brought into contact with about 2.0 to about 2.2 equivalents of active chlorine from the chlorinating agent.
[0044] When the chlorinating agent is chlorine gas, chlorine gas can be introduced into the reaction medium, for example, by means of bubblers, or the like. In one aspect, chlorine gas is introduced into the reaction medium at a substantially constant feed rate. In another aspect, chlorine gas is introduced into the reaction medium at a feed rate and for a period of time sufficient to convert at least about 60% percent of the Formula (II) compound or salt to the Formula compound or salt. (III). In another aspect, the unreacted chlorine gas is recovered on top and recycled back to the reaction medium. The amount of chlorine gas used during the reaction can be measured by weighing the chlorine gas tank before and after the reaction. In another aspect, the compound or salt of Formula (II) is brought into contact with at least about 2.0 equivalents of the chlorine gas. Accordingly, in one embodiment, the compound or salt of Formula (II) is brought into contact with about 2.0 to about 10.0 equivalents of the chlorination gas. In another embodiment, the compound or salt of Formula (II) is brought into contact with about 2.0 to about 6.0 equivalents of chlorine gas. In another embodiment, the compound or salt of Formula (II) is brought into contact with about 2.0 to about 4.0 equivalents of chlorine gas.
[0045] In some embodiments, the compound or salt of Formula (II) is brought into contact with the chlorinating agent in the presence of a catalytic amount of a catalyst. In one aspect, the compound or salt of Formula (II) is brought into contact with the chlorinating agent in the presence of a catalytic amount of iodine or iodine monochloride. In another aspect, the catalytic amount of iodine or iodine monochloride is about 0.0001 equivalent to about 0.1 equivalent with respect to the compound or salt of Formula (II). In another aspect, the catalytic amount of iodine or iodine monochloride is about 0.0005 equivalent to about 0.1 equivalent with respect to the compound or salt of Formula (II). In another aspect, the catalytic amount of iodine or iodine monochloride is about 0.001 equivalent to about 0.1 equivalent with respect to the compound or salt of Formula (II). In another aspect, the catalytic amount of iodine or iodine monochloride is about 0.005 equivalent to about 0.1 equivalent with respect to the compound or salt of Formula (II).
[0046] The compound of Formula (II) can be introduced into the reaction medium as a single charge before the start of the chlorination reaction. Alternatively, part or all of the compound of Formula (II) can be introduced into the reaction medium, for example, as a continuous feed stream or in the form of one or more bolus additions throughout the chlorination reaction. In general, the total amount of the Formula (II) compound or salt introduced into the reaction medium is about 0.05 mol to about 4.0 moles per liter of reaction medium. In one aspect, the total amount of the compound or salt of Formula (II) introduced into the reaction medium is from about 0.1 mol to about 3.0 moles per liter of reaction medium. In another aspect, the total amount of the compound or salt of Formula (II) introduced into the reaction medium is about 1.0 mol to about 2.5 moles per liter of reaction medium. In another aspect, the total amount of the compound or salt of Formula (II) introduced into the reaction medium is about 0.1 mol to about 2.0 moles per liter of reaction medium. In another aspect, the total amount of the compound or salt of Formula (II) introduced into the reaction medium is about 0.4 mol to about 1.5 moles per liter of reaction medium.
[0047] In certain embodiments, for example, the concentration of the compound or salt of Formula (II) in a reaction medium comprising oleum (i.e. the payload) can be increased with acceptable results while maintaining an appropriate molar ratio of free sulfur to the compound or salt of Formula (II). Suitable molar ratios will generally be at least about 4.0 or greater. In one aspect, the reaction medium comprises at least 25% oleum and about 1.5 moles to about 3.0 moles per liter of the Formula (II) compound or salt. In another aspect, the reaction medium comprises at least 25% oleum and about 2.0 moles to about 3.0 moles per liter of the compound or salt of Formula (II). In another aspect, the reaction medium comprises at least 25% oleum and about 2.25 moles per liter of the compound or salt of Formula (II). When the concentration of the Formula (II) compound or salt is increased, the total volume of sulfuric acid and oil required for the reaction is correspondingly reduced, which can be a potential advantage in large-scale manufacturing and also results in savings of costs. In addition, the higher concentrations of the compound or salt of Formula (II) in these modalities also seem to allow a reduction in the amount of catalyst needed in relation to the modalities in which the reaction medium comprises about 20% oleum and about 1, 5 moles per Liter of the compound or salt of Formula (II). E. Reaction conditions
[0048] In general, the reaction medium is maintained at a temperature from about 0 ° C to about 100 ° C during the contact stage. In one aspect, the reaction medium is maintained at a temperature from about 0 ° C to about 60 ° C during the contact step. In another aspect, the reaction medium is maintained at a temperature from about 5 ° C to about 35 ° C during the contact step.
[0049] The improved processes of the present description provide for an adequate conversion of the Formula (II) compound or salt to the Formula (III) compound or salt. In one embodiment, the percentage conversion of the Formula (II) compound or salt to the Formula (III) compound or salt is at least about 60%. In one aspect, the percentage conversion of the Formula (II) compound or salt to the Formula (III) compound or salt is at least about 65%. In another aspect, the percentage conversion of the Formula (II) compound or salt to the Formula (III) compound or salt is at least about 70%. F. Illustrative mode: Chlorine gas
[0050] In a representative embodiment, the present description refers to a process for the preparation of a corresponding compound in the structure of Formula (III-1):
or a salt thereof, the process comprising: contacting a corresponding compound in the structure of Formula (II-1):
or a salt thereof, with chlorine gas in an acid reaction medium comprising oleum to provide the compound or salt of Formula (III-1) (i.e., R1 is hydrogen; and R2 is hydrogen in the compounds of Formula (II) and Formula (III)).
[0051] In another embodiment: the total amount of the compound or salt of Formula (II-1) introduced into the reaction medium is about 0.05 mol to about 4.0 moles per liter of reaction medium; the compound or salt of Formula (II-1) is brought into contact with at least about 2.0 equivalents of chlorine gas; and the reaction medium comprises from about 5% oleum by weight to about 70% oleum by weight.
[0052] In another embodiment: the total amount of the compound or salt of Formula (II-1) introduced in the reaction medium is about 0.1 mol to about 3.0 moles per liter of reaction medium; the compound or salt of Formula (II-1) is brought into contact with at least about 2.0 equivalents of chlorine gas; and the reaction medium comprises from about 10% oleum by weight to about 70% oleum by weight.
[0053] In another embodiment: the total amount of the compound or salt of formula (II-1) introduced into the reaction medium is about 1.0 mol to about 2.5 moles per liter of reaction medium; the compound or salt of Formula (II-1) is brought into contact with at least about 2.0 equivalents of chlorine gas; and the reaction medium comprises between about 15% oleum by weight and about 40% oleum by weight.
[0054] In another embodiment: the total amount of the compound or salt of formula (ii-1) introduced in the reaction medium is about 0.1 mol to about 2.0 moles per liter of reaction medium; the compound or salt of formula (ii-1) is brought into contact with at least about 2.0 equivalents of chlorine gas; and the reaction medium comprises from about 20% oleum by weight to about 40% oleum by weight.
[0055] In another embodiment: the total amount of the compound or salt of formula (ii-1) introduced into the reaction medium is about 0.4 mol to about 1.5 moles per liter of reaction medium; the compound or salt of formula (ii-1) is brought into contact with at least about 2.0 equivalents of chlorine gas; and the reaction medium comprises from about 20% oleum by weight to about 30% oleum by weight.
[0056] In another embodiment: the total amount of the compound or salt of formula (ii-1) introduced in the reaction medium is about 1.5 mol to about 3.0 moles per liter of reaction medium; the compound or salt of formula (ii-1) is brought into contact with at least about 2.0 equivalents of chlorine gas; and the reaction medium comprises from about 25% oleum by weight to about 80% oleum by weight.
[0057] In another embodiment: the total amount of the compound or salt of formula (ii-1) introduced into the reaction medium is about 2.0 moles to about 3.0 moles per liter of reaction medium; the compound or salt of formula (ii-1) is brought into contact with at least about 2.0 equivalents of chlorine gas; and the reaction medium comprises from about 25% oleum by weight to about 40% oleum by weight.
[0058] In each of the above modalities, the chlorine gas equivalent can be controlled by recovering the unreacted chlorine gas overhead and recycling back to the reaction medium. Therefore, in one embodiment, the compound or salt of Formula (II-1) is brought into contact with about 2.0 to about 10.0 equivalent of the chlorination gas. In another embodiment, the compound or salt of Formula (II-1) is brought into contact with about 2.0 to about 6.0 equivalents of chlorine gas. In another embodiment, the compound or salt of Formula (II-1) is brought into contact with about 2.0 to about 4.0 equivalents of chlorine gas.
[0059] In each of the above embodiments, the reaction medium may further comprise a catalyst such as iodine or iodine monochloride. In one aspect, the compound or salt of Formula (II-1) is contacted with chlorine gas in the presence of about 0.0001 equivalent to about 0.1 equivalent of iodine with respect to the compound or salt of Formula (II -1). In another aspect, the compound or salt of Formula (II1) is contacted with the chlorine gas in the presence of about 0.0005 equivalent to about 0.1 equivalent in relation to the compound or salt of Formula (II-1) . In another aspect, the compound or salt of Formula (II-1) is contacted with chlorine gas in the presence of about 0.001 equivalent to about 0.1 equivalent of iodine in relation to the compound or salt of Formula (II- 1). In another aspect, the compound or salt of Formula (II-1) is contacted with chlorine gas in the presence of about 0.005 equivalent to about 0.1 equivalent of iodine in relation to the compound or salt of Formula (II- 1). G. Illustrative mode: Trichloroisociuranic acid
[0060] In a representative embodiment, the present description refers to a process for the preparation of a corresponding compound in the structure of Formula (III-1):
or a salt thereof, the process comprising: contacting a corresponding compound in the structure of Formula (II-1):
or a salt thereof, with trichloroisocyanuric acid in an acid reaction medium comprising oleum to obtain the compound or salt of Formula (III-1) (i.e., R1 is hydrogen; and R2 is hydrogen in the compounds of Formula (II ) and Formula (III)).
[0061] A molecule of trichloroisocyanuric acid can supply up to three species of active chlorine (for example, Cl +) in the chlorination reaction. The equivalents disclosed herein are the active chlorine equivalents of trichloroisocyanuric acid (that is, 1.0 equivalent of trichloroisocyanuric acid is equal to about 3.0 equivalents of active chlorine).
[0062] Consequently, in another modality: the total amount of the amount of compound or salt of Formula (II-1) introduced in the reaction medium is from about 0.05 mol to about 4.0 moles per liter of reaction; the compound or salt of Formula (II-1) is brought into contact with about 2.0 to about 8.0 equivalents of active chlorine of trichloroisocyanuric acid; and the reaction medium comprises from about 5% oleum by weight to about 70% oleum by weight.
[0063] In another modality: the total amount of the amount of compound or salt of Formula (II-1) introduced in the reaction medium is about 0.1 mol and about 3.0 moles per liter of reaction medium; the compound or salt of Formula (II-1) is brought into contact with about 2.0 to about 6.0 equivalents of active chlorine of trichloroisocyanuric acid; and the reaction medium comprises from about 10% oleum by weight to about 70% oleum by weight.
[0064] In another embodiment: the total amount of compound or salt of Formula (II-1) introduced into the reaction medium is about 1.0 mol and about 2.5 moles per liter of reaction medium; the compound or salt of Formula (II-1) is brought into contact with about 2.0 to about 4.0 equivalents of active chlorine of trichloroisocyanuric acid; and the reaction medium comprises between about 15% oleum by weight and about 40% oleum by weight.
[0065] In another embodiment: the total amount of the compound or salt of formula (ii-1) introduced into the reaction medium is about 0.1 mol to about 2.0 moles per liter of reaction medium; the compound or salt of the formula (ii-1) is brought into contact with about 2.0 to about 3.0 equivalents of active chlorine of trichloroisocyanuric acid; and the reaction medium comprises from about 20% oleum by weight to about 40% oleum by weight.
[0066] In another embodiment: the total amount of the compound or salt of Formula (II-1) introduced into the reaction medium is about 0.4 mol to about 1.5 moles per liter of reaction medium; the compound or salt of Formula (II-1) is brought into contact with about 2.0 to about 2.4 equivalents of active chlorine of trichloroisocyanuric acid; and the reaction medium comprises from about 20% oleum by weight to about 30% oleum by weight.
[0067] In another embodiment: the total amount of the compound or salt of Formula (II-1) introduced in the reaction medium is about 1.5 mol to about 3.0 moles per liter of reaction medium; the compound or salt of Formula (II-1) is brought into contact with about 2.0 to about 4.0 equivalents of active chlorine of trichloroisocyanuric acid; and the reaction medium comprises from about 25% oleum by weight to about 80% oleum by weight.
[0068] In another embodiment: the total amount of the compound or salt of Formula (II-1) introduced in the reaction medium is about 2.0 moles to about 3.0 moles per liter of reaction medium; the compound or salt of Formula (II-1) is brought into contact with about 2.0 to about 4.0 equivalents of active chlorine of trichloroisocyanuric acid; and the reaction medium comprises from about 25% oleum by weight to about 40% oleum by weight.
[0069] In each of the above modalities, the reaction medium may further comprise a catalyst such as iodine or iodine monochloride. In one aspect, the compound or salt of Formula (II-1) is contacted with trichloroisocyanuric acid in the presence of about 0.0001 equivalent to about 0.1 equivalent of iodine with respect to the compound or salt of Formula (II-1 ). In another aspect, the compound or salt of Formula (II-1) is contacted with trichloroisocyanuric acid in the presence of about 0.0005 equivalent to about 0.1 equivalent in relation to the compound or salt of Formula (II-1) . In another aspect, the compound or salt of Formula (II-1) is contacted with trichloroisocyanuric acid in the presence of about 0.001 equivalent to about 0.1 equivalent of iodine in relation to the compound or salt of Formula (II- 1). In another aspect, the compound or salt of Formula (II-1) is contacted with trichloroisocyanuric acid in the presence of about 0.005 equivalent to about 0.1 equivalent of iodine in relation to the compound or salt of Formula (II-1) . III.Preparing Compounds 5-Bromosalicylic Acid
[0070] The compound or salt of Formula (II) used in the processes disclosed above, can be prepared by any suitable method. In one embodiment, the compound or salt of Formula (II) is prepared by bromination of a compound corresponding in structure to Formula (I):
or a salt thereof, to provide the compound of Formula (II):
or a salt thereof; wherein R1 is hydrogen or C1-6-alkyl; and R2 is hydrogen or C1-6 alkyl.
[0071] In certain embodiments of the compound or salt of Formula (I) and the compound or salt of Formula (II), R1 is hydrogen, methyl, or ethyl; and R2 is hydrogen, methyl, or ethyl. In another aspect, R1 and R2 are each hydrogen (that is, the compound of Formula (I) is salicylic acid and the compound of formula (II) is 5-bromosalicylic acid) and the compound of formula ( II) corresponds in structure to the formula (II-1):
in another aspect, R1 is R1 and R2 are each methyl. In another aspect, one of R1 and R2 is hydrogen; and the other for R1 and R2 is methyl.
[0072] The bromination step can be carried out in any suitable way, such as, for example, contacting the compound or salt of Formula (I) with bromine (Br2), hydrogen bromide (HBr), or an alkali metal halide (such as an alkali metal bromide) in a reaction medium comprising sulfuric acid to provide the compound or salt of Formula (II). In one embodiment, the compound or salt of Formula (I) is contacted with bromine (Br2). In another embodiment, the compound or salt of Formula (I) is contacted with hydrogen bromide (HBr). In another embodiment, the compound or salt of Formula (I) is contacted with an alkali metal halide. In another embodiment, the alkali metal halide is sodium bromide. The preparation of 5-bromosalicylic acid from salicylic acid has been reported, for example, in Hussey, Allen S. et al., "The Reaction of Magnesium with 2,4-Dibromoanisole," J. Am. Chem. Soc., 72 (2): 830-832 (1950); and Adibi, Hadi et al., "A convenient and regioselective oxidative bromination of electron-rich aromatic rings using potassium bromide and benzyltriphenylphosphonium peroxymonosulfate under nearly neutral reaction conditions," Tetrahedron Lett. 48: 1255-1259 (2007).
[0073] In one embodiment, the bromination step is conducted in a reaction medium comprising an acid selected from the group consisting of sulfuric acid, oleum, and acetic acid. In one aspect, the reaction medium comprises sulfuric acid. In another aspect, the reaction medium comprises at least about 95% sulfuric acid by weight. In another aspect, the reaction medium comprises at least about 98% sulfuric acid by weight. In another aspect, the reaction medium comprises oleum. In another aspect, the reaction medium comprises sulfuric acid and acetic acid. In another aspect, the reaction medium comprises oleum and acetic acid. IV. Alternative Process for the Preparation of 5-Bromo-3,6-Dichlorosalicylic Acid Compounds (Process BDCSA 2)
[0074] The present description also relates to an alternative process ("Process BDCSA 2") for the preparation of a compound of 5-bromo-3,6-dichlorosalicylic acid. This alternative process differs, in part, from the previously disclosed process (Process BDCSA 1) in which the starting material compound of salicylic acid is brominated and monochlorinated in the same reaction vessel to provide a 5-bromo-acid compound. 3-chlorosalicylic without first isolating the brominated intermediate. The resulting 5-bromo-3-chlorosalicylic acid compound is then again chlorinated to provide the 5-bromo-3,6-dichlorosalicylic acid compound. The 5-bromo-3-chlorosalicylic acid compound can be isolated and then further chlorinated to provide the 5-bromo-3,6-dichlorosalicylic acid compound or, alternatively, the reaction vessel medium can be modified to provide the appropriate conditions for the subsequent chlorination of the 5-bromo-3-chlorosalicylic acid compound as part of a "one container" process.
[0075] Although BDCSA Process 1 provides an acceptable overall yield of 5-bromo-3,6-dichlorosalicylic acid, Process BDCSA 2 likewise provides an acceptable overall yield and, in addition, can provide processing advantages in large manufacturing operations scale. BDCSA 1 process as conducted on a smaller scale, usually involves pouring the impure reaction mixture over ice water to stop the bromination reaction and then isolating the 5-bromosalicylic acid by organic extraction for use in the subsequent chlorination reaction. Such an aqueous treatment procedure, however, can present a number of processing challenges for larger scale production, including: (A) a large amount of ice water is required (typically at least a 10-fold excess) for extinction, (b) the extinction reaction is very exothermic, (c) sulfonylation of 5-bromosalicylic acid in the 3-position can occur if the temperature during extinction is not adequately controlled and becomes very hot, (d) a The resulting aqueous sulfuric acid solution is corrosive and may adversely affect the piping and equipment that comes in contact with the mixture, and (e) the 5-bromosalicylic acid must dry and be substantially anhydrous for use in the subsequent chlorination step (which can add cost and technical challenges). In addition, sulfonylation of the isolated 5-bromosalicylic acid in the 3-position can occur during the subsequent chlorination step. When the acidic reaction medium comprises oleum, for example, sulfonylation competes to some extent with chlorination in the electron-rich position 3 of the ring.
[0076] In contrast, Process BDCSA 2 generally comprises: (A) bromination of the salicylic acid starting material compound to provide a reaction mixture comprising a 5-bromosalicylic acid compound, (b) chlorination of the 5-bromos acid compound - salicylic to provide a 5-bromo-3-chlorosalicylic acid compound without first isolating the 5-bromosalicylic acid compound from the reaction mixture, and (c) further chlorination of the 5-bromo-3-chlorosalicylic acid compound to provide the 5-bromo-3,6-dichlorosalicylic acid compound. Proper control of reaction conditions effectively reduces the impact of the competing sulfonylation reaction and other processing challenges. For example, bromination and monochlorination of the salicylic acid starting compound material can be carried out in an acid reaction medium comprising sulfuric acid to provide the 5-bromo-3-chlorosalicylic acid compound. The resulting 5-bromo-3-chlorosalicylic acid compound can be isolated and then further chlorinated or chlorinated in situ to provide the 5-bromo-3,6-dichlorosalicylic acid compound. During the monochlorination of 5-bromosalicylic acid, the resulting 5-bromo-3-chlorosalicylic acid compound precipitates in the acid reaction medium, comprising sulfuric acid (for example, the concentrated sulfuric acid of about 96% sulfuric acid in Weight). Therefore, the 5-bromo-3-chlorosalicylic acid compound can be isolated as a solid by filtration from the acid reaction medium. If a "one container" process is desired, the reaction medium comprising the 5-bromo-3-chlorosalicylic acid compound can be modified to provide an acid reaction medium comprising oleum in which the 5-bromo-3 acid compound -chlorosalicylic acid is further chlorinated to provide the 5-bromo-3,6-dichlorosalicylic acid compound. Any suitable medium can be employed to convert the initial acid reaction medium to an acid reaction medium comprising oleum, for example, by adding a sufficient amount of sulfur trioxide and / or oleum to the reaction medium (for example, addition of a sufficient amount of 65% oleum in 95% sulfuric acid to obtain an acid reaction medium comprising 20%, 25%, or other suitable concentrations of oleum).
[0077] Therefore, in one embodiment, the present invention relates to a process for the preparation of a compound corresponding in structure to formula (VI):
or a salt thereof, the process comprising: contacting a corresponding compound in the structure with Formula (I):
or a salt thereof, with a brominating agent in an acid reaction medium to provide a corresponding compound in structure to formula (II):
or a salt thereof; and contacting the compound or salt of Formula (II) with a chlorinating agent to obtain the compound or salt of Formula (VI), wherein: R1 is hydrogen or C1-6-alkyl; eR2 is hydrogen or C1-6 alkyl.
[0078] In one aspect, the compound or salt of Formula (II) is contacted with the chlorinating agent without first isolating the compound or salt of Formula (II) from the reaction medium to provide the compound or salt of Formula ( SAW). In another aspect, the compound or salt of Formula (II) is isolated from the reaction mixture and then placed in contact with the chlorinating agent to obtain the compound or salt of Formula (VI).
[0079] In another embodiment, the present description refers to a process for the preparation of a corresponding compound in the structure of Formula (III):
or a salt thereof, the process comprising: contacting a corresponding compound in structure to formula (VI):
or a salt thereof, with a chlorinating agent in an acid reaction medium comprising oleum to obtain the compound or salt of Formula (III): wherein: R1 is hydrogen or C1-6-alkyl; and R2 is hydrogen or C1-6 alkyl.
[0080] In another embodiment, the present description refers to a process for the preparation of a corresponding compound in the structure of Formula (III):
or a salt thereof, the process comprising: contacting a corresponding compound in the structure with Formula (I):
or a salt thereof, with a brominating agent in an acid reaction medium comprising sulfuric acid to provide a corresponding compound in the structure of Formula (II):
or a salt thereof; contacting the Formula (II) compound or salt with a first chlorinating agent without first isolating the Formula (II) compound or salt from the reaction medium to provide a corresponding compound in the structure of the Formula (VI):
or a salt thereof; and contacting the Formula (VI) compound or salt with one second of the chlorinating agent to provide the Formula (III) compound or salt; wherein: R1 is hydrogen or C1-6-alkyl; R2 is hydrogen or C1-6-alkyl ; and the first chlorinating agent and the second chlorinating agent can be the same or different.
[0081] In one aspect, the compound or salt of Formula (VI) is contacted with the second chlorinating agent without first isolating the compound or salt of Formula (VI) from the reaction medium to provide the compound or salt of Formula (III). In another aspect, the compound or salt of Formula (VI) is isolated from the reaction medium and subsequently contacted with the second chlorinating agent to obtain the compound or salt of Formula (III).
[0082] In another embodiment, the present description refers to a process for the preparation of a corresponding compound in the structure of Formula (III):
or a salt thereof, the process comprising: contacting a corresponding compound in the structure with Formula (I):
or a salt thereof, with a brominating agent in an acid reaction medium comprising sulfuric acid to provide a corresponding compound in the structure of Formula (II):
or a salt thereof; contacting the Formula (II) compound or salt with a first chlorinating agent without first isolating the Formula (II) compound or salt from the reaction medium to provide a corresponding compound in the structure of the Formula (VI):
or a salt thereof, modify the acid reaction medium to provide an acid reaction medium comprising oleum after the formation of the Formula (VI) compound or salt, and the contact of the Formula (VI) compound or salt with a second agent chlorination without first isolating the compound or salt of formula (VI) from the reaction medium to provide the compound of formula (III); wherein: R1 is hydrogen or C1-6-alkyl; R2 is hydrogen or C1-6- alkyl; and the first chlorinating agent and the second chlorinating agent can be the same or different.
[0083] In certain embodiments of the processes disclosed above related to the compounds or salts of formula (I), Formula (II), Formula (III), and formula (VI), R1 is hydrogen, methyl, or ethyl; and R2 is hi-hydrogen, methyl, or ethyl. In one respect, R1 is hydrogen or methyl; and R2 is hydrogen or methyl. In another aspect, R1 and R2 are each methyl. In another aspect, one of R1 and R2 is hydrogen and the other of R1 and R2 is methyl. In another aspect, R1 and R2 are each hydrogen and the compounds of Formula (I), Formula (II), formula (VI), and Formula (III) correspond to the structures of formula (I-1), formula (II -1), formula (VI1), and Formula (III-1), respectively:

[0084] In some illustrative embodiments, 5-bromo-3,6-dichlorosalicylic acid is prepared from salicylic acid according to Process BDCSA 2, with or without isolation of 5-bromo-3-chlorosalicylic acid, as illustrated in the Scheme 4 to follow: Scheme 4
Salicylic acid is contacted with bromine in concentrated sulfuric acid (eg 98% sulfuric acid) as a reaction medium to obtain 5-bromosalicylic acid. The resulting 5-bromosalicylic acid, which is not isolated from the reaction medium, is then chlorinated to provide 5-bromo-3-chlorosalicylic acid (for example, by bubbling chlorine gas into the concentrated sulfuric acid medium) . In one embodiment, the 5-bromo-3-chlorosicylic acid compound is isolated by filtration of the concentrated sulfuric acid reaction medium. The 5-bromo-3-chlorosalicylic acid solid is then placed in the sulfuric acid reaction medium, comprising oleum (for example, a 20% oleum solution). In another embodiment, the concentrated sulfuric acid medium comprising 5-bromo-3-chlorosalicylic acid is then converted into a reaction medium that comprises oil (for example, by bubbling sulfur trioxide into the concentrated sulfuric acid medium). or by adding an oleum solution to the concentrated sulfuric acid medium to provide the desired oleum medium (for example, by adding a sufficient amount of a 65% oleum solution to the concentrated sulfuric acid medium to obtain a oleum medium to The 5-bromo-3-chlorosalicylic acid is then chlorinated to provide the 5-bromo-3,6-dichlorosalicylic acid (for example, by bubbling chlorine gas in the oleum medium in the presence of a suitable catalyst, such as As the 3- and 5- electron-rich positions of 5- bromo-3-chlorosalicylic acid are already substituted, exposure to sulfur trioxide should not result in significant sulfonylation of 5-bromo-3-chlorosalicylic acid. co.
[0085] In general, the bromination and chlorination conditions for Process BDCSA 2 are as previously disclosed for Process BDCSA 1, except as otherwise indicated. For example, chlorination stoichiometries are suitably adjusted for each chlorination reaction (ie reduced by about 50% for the chlorination reaction in position 3 and about 50% for the chlorination reaction in position 6).
The resulting 5-bromo-3,6-dichlorosalicylic acid can be isolated from the reaction mixture and, if desired, purified, using conventional techniques. Generally, a portion of 5-bromo-3,6-dichlorosalicylic acid will precipitate from the oleum medium during the chlorination reaction. It has been found, however, that dilution of the oleum medium to provide a sulfuric acid solution, once the chlorination reaction is complete (for example, diluting the reaction medium comprising oleum with, for example, a sufficient amount of a 50% to 95% sulfuric acid solution) may be advantageous, as it results in additional precipitation of 5-bromo-3,6-dichlorosalicylic acid. Alternatively, 5-bromo-3,6-dichlorosalicylic acid can be filtered directly from the oleum medium. The 5-bromo-3,6-dichlorosalicylic acid filtered solid can be further washed with a concentrated sulfuric acid followed by water, and subsequently dried. Direct filtration can be advantageous as it reduces the use of the sulfuric acid solution in the aforementioned dilution method. Other isolation techniques can be employed, however, such as distillation of the reaction medium to remove oleum and / or chlorosulfonic acid, thus promoting the precipitation of 5-bromo-3,6-dichlorosalicylic acid. V. Preparation of Compounds 3,6-Dichlorosalicylic Acid
[0087] The compounds and salts of formula (III) can be selectively broken down to provide the corresponding 3,6-dichlorosalicylic acid compounds (such as 3,6-dichlorosalicylic acid) which can be used as intermediate products in the manufacture of dicamba. Therefore, the processes previously disclosed may further comprise selectively de-bromine the compound or salt of Formula (III):
to provide a corresponding compound in structure to Formula (IV):
or a salt thereof; wherein R1 is hydrogen or C1-6-alkyl; and R2 is hydrogen or C1-6 alkyl.
[0088] In certain embodiments of the compound or salt of Formula (III) and the compound or salt of Formula (IV), R1 is hydrogen, methyl, or ethyl; and R2 is hydrogen, methyl, or ethyl. In another aspect, R1 and R2 are each hydrogen (ie the compound of Formula (III) is 5-bromo-3,6-dichlorosalicylic acid and the compound of formula (IV) is 3,6-dichlorosalicylic acid ) and the compound of Formula (III) and general formula (IV) corresponds in structure to Formula (III-1) and formula (IV-1):
in another aspect, R1 and R2 are each methyl (or here, the compound of Formula (III) is methyl 3-bromo-2,5-dichloro-6-methoxybenzoate and the compound of formula (IV) is methyl 2,5-dichloro-6-methoxybenzoate) and the compound of Formula (III) and general formula (IV) corresponds in structure to Formula (III-2) and Formula (IV-2):
in another aspect, one of R1 and R2 is hydrogen; and the other for R1 and R2 is methyl.
[0089] The de-bromine step can be carried out in any suitable manner, such as, for example, catalytically hydrogenolysing the compound or salt of Formula (III) to produce the compound or salt of Formula (IV). In one aspect, the compound or salt of Formula (III) is brought into contact with hydrogen in the presence of a suitable catalyst to produce the compound or salt of Formula (IV). In another aspect, the catalyst is selected from the group consisting of palladium catalysts and platinum catalysts. In another aspect, the catalyst is a palladium catalyst. In another aspect, the catalyst is a platinum catalyst.
[0090] The de-bromine step can be carried out in any suitable solvent or combination of solvents. In general, the de-bromine step will be conducted in a non-polar solvent or combination of solvents. In one aspect, the solvent or combination of solvents comprises one or more members of the group consisting of alkanoic acids, carboxylate esters, and aqueous sulfuric acid. In another embodiment, the solvent or combination of solvents comprises one or more members of the group consisting of acetic acid and ethyl acetate.
[0091] In one embodiment, the debromination step comprises contacting the compound or salt of Formula (III) with a catalyst in the presence of a base in a reaction medium comprising a non-polar solvent. In one aspect, the base is an alkali metal alkanoate. Additional non-limiting examples of suitable breaking conditions are illustrated in Table 10-A of Example 10.
[0092] Without being linked to a particular theory, in some embodiments, the impurities (for example, iodine-containing species) in the 5-bromo-3,6-dichlorosalicylic acid compound appear to be poisoning the catalyst; therefore, they can affect the efficiency of dehalogenation. Generally, such impurities can be removed by suspending the yellow-orange solid of 5-bromo-3,6-dichlorosalicylic acid in an organic solvent, for example, xylenes. The resulting filtered solid of 5-bromo-3,6-dichlorosalicylic acid can be substantially color-free and undergo de-bromination in the next step effectively. It was found, however, that the 5-bromo-3,6-dichlorosalicylic acid compound obtained from the direct filtration method disclosed above (ie direct filtration from the oleum medium) can be used directly for the dehalogenation without any other process. VII. Selective chlorination and disruption of 5-bromo-2-hydroxybenzaldehyde compounds
[0093] The present description further relates to an alternative process for the preparation of 3,6-dichlorosalicylic acid compounds from the 5-bromo-2-hydroxybenz-aldehyde compounds as shown in Scheme 5 below: Scheme 5
in particular, selective preparation of 3,6-dichlorosalicylic acid from 5-bromo-2-hydroxybenzaldehyde, that is, the compounds of Scheme 5, in which R1 is hydrogen.
[0094] Therefore, in one embodiment, the present invention relates to a process for the preparation of a compound corresponding in structure to Formula (VIII):
or a salt thereof, the process comprising: contacting a corresponding compound in structure to Formula (VII):
or a salt thereof, with a chlorinating agent to obtain the compound or salt of Formula (VIII), wherein R1 is hydrogen or C1-6 alkyl.
[0095] In another embodiment, the present description refers to a process for the preparation of a corresponding compound in structure to Formula (IX):
or a salt thereof, the process comprising: contacting a corresponding compound in structure to Formula (VIII):
or a salt thereof, with a chlorinating agent to obtain the compound or salt of Formula (IX), wherein R1 is hydrogen or C1-6 alkyl.
[0096] In another embodiment, the present invention relates to a process for the preparation of a corresponding compound in structure to formula (X):
or a salt thereof, the process comprising: contacting a corresponding compound in structure to Formula (X):
or a salt thereof, the process comprising: contacting a corresponding compound in structure to Formula (IX):
or a salt thereof, with a de-bromination agent to provide the compound or salt of Formula (X), wherein R1 is hydrogen or C1-6 alkyl.
[0097] In another embodiment, the present invention relates to a process for the preparation of a corresponding compound in structure to the formula (IV-1):
or a salt thereof, the process comprising: contacting a compound corresponding in structure to formula (X):
or a salt thereof, with an oxidizing agent to provide the compound or salt of formula (VI-1), wherein R1 is hydrogen or C1-6 alkyl.
[0098] In another embodiment, the present invention relates to a process for the preparation of a corresponding compound in structure to the formula (IV-1):
or a salt thereof, the process comprising: contacting a corresponding compound in structure to Formula (IX):
or a salt thereof, with a de-bromination agent to provide a compound corresponding in structure to formula (X):
or a salt thereof; and contacting the compound or salt of Formula (X) with an oxidizing agent to provide the compound or salt of formula (IV-1), wherein R1 is hydrogen or C1-6 alkyl.
[0099] In another embodiment, the present invention relates to a process for the preparation of a corresponding compound in structure to the formula (IV-1):
or a salt thereof, the process comprising: contacting a corresponding compound in structure to the Formula (VIII):
or a salt thereof, with a chlorinating agent to obtain a compound corresponding in structure to Formula (IX):
or a salt thereof, contact the compound or salt of Formula (IX) with a de-bromination agent to provide a corresponding compound in structure to formula (X):
or a salt thereof; and contacting the compound or salt of Formula (X) with an oxidizing agent to provide the compound or salt of formula (IV-1), wherein R1 is hydrogen or C1-6 alkyl.
[00100] In another embodiment, the present invention relates to a process for the preparation of a corresponding compound in structure to the formula (IV-1):
or a salt thereof, the process comprising: contacting a corresponding compound in structure to Formula (VII):
or a salt thereof, with a first chlorinating agent to obtain a compound corresponding in structure to Formula (VIII):
or a salt thereof, contact the compound or salt of Formula (VIII) with a second chlorinating agent to obtain a compound corresponding in structure to Formula (IX):
or a salt thereof; contact the compound or salt of Formula (IX) with a de-bromination agent to provide a compound corresponding in structure to formula (X):
or a salt thereof; and contacting the compound or salt of Formula (X) with an oxidizing agent to provide the compound or salt of formula (IV-1), wherein R1 is hydrogen or C1-6-alkyl; and the first chlorinating agent and the second chlorinating agent can be the same or different.
[00101] In certain modalities of the processes disclosed above related to the compounds or salts of formula (VII), formula (VIII), formula (IX), and formula (X), R1 is hydrogen, methyl, or ethyl. In one respect, R1 is hydrogen or methyl. In another aspect, R1 is methyl. In another aspect, R1 is hydrogen and the compounds of formula (VII), formula (VIII), formula (IX), and formula (X) of structure correspondence with Formula (VII-1), formula (VIII -1), formula (IX-1) and formula (X-1), respectively:

[0100] In general, appropriate process conditions for the selective chlorination and de-bromination of 5-bromo-2-hydroxybenzaldehyde compounds substantially correspond to the process conditions previously disclosed for the corresponding steps of Process BDCSA 1 Process BDCSA and 2, unless otherwise indicated. other way. A wide range of oxidizing agents and oxidation conditions can be employed to convert the compound of formula (X) to the compound of formula (IV-1). Examples of suitable oxidizing agents and oxidation conditions are disclosed, for example, in Richard C. Larock, Comprehensive Organic Transformations (Wiley-VCH Vertag GmbH 1999). VIII.Conversion of compounds 3,6-Dichlorosalicylic acid to dicamba A. Conversion of 3,6-Dichlorosalicylic acid to dicamba
[0101] As noted earlier, 3,6-dichlorosalicylic acid compounds prepared as disclosed above (for example, 3,6-dichlorosalicylic acid) can be further converted to dicamba.
[0102] Therefore, in one embodiment, the present invention relates to a process for the preparation of a compound corresponding in structure to formula (V):
or a salt thereof, the process comprising: contacting a corresponding compound in the structure with Formula (II):
or a salt thereof, with a chlorinating agent in an acid reaction medium to provide the compound or salt of Formula (III):
or a salt thereof; selectively de-bromination of the compound or salt of Formula (III) to provide a corresponding compound in the structure of Formula (IV):
or a salt thereof, wherein R1 is hydrogen or C1-6-alkyl; R2 is hydrogen or C1-6-alkyl; and in that the process further comprises converting the compound or salt of Formula (IV) to the compound or salt of Formula (V) when the compound of formula (IV) is different from dicamba.
[0103] In certain embodiments, R1 is hydrogen, methyl, or ethyl; and R2 is hydrogen, methyl, or ethyl. In one respect, R1 is hydrogen or methyl; and R2 is hydrogen or methyl. In another aspect, R1 and R2 are each hydrogen (that is, the compound of Formula (II) is 5-bromosalicylic acid and the compound of Formula (III) is 5-bromo-3,6-dichlorosalicylic acid) . In another aspect, R1 and R2 are each methyl. In another aspect, one of R1 and R2 is hydrogen and the other of R1 and R2 is methyl.
[0104] A number of synthetic pathways for converting 3,6-dichlorosalicylic acid to dicamba have been reported in the literature and any suitable pathway can be employed. For example, one approach involves methylation of 3,6-dichlorosalicylic acid to provide methyl 3,6-dichloro-2-methoxybenzoate (for example, methylation by treatment with dimethyl sulfate, dimethyl carbonate, or a halomethane such as methyl chloride, methyl bromide or methyl iodide), and then saponify the methyl ester group of 3,6-dichloro-2-methoxybenzoate (for example, saponification) to provide dicamba as shown in Scheme 6 below: Scheme 6

[0105] Another approach involves the selective methylation of 3,6-dichlorosalicylic acid to provide dicamba as shown in Scheme 7 below: Scheme 7

[0106] Among the various publications reporting synthetic methods employing 3,6-dichlorosalicylic acid as a starting material or an intermediate in the preparation of dicamba are, for example, the following: (a) US patent 3,345,157 reports a process for methylation of 3,6-dichlorosalicylic acid to provide dicamba. (b) US patent 4,161,611 reports a process for methylation of 3,6-dichlorosalicylic acid to provide dicamba. (c) Matyakh, et al., "2-Methoxy-3,6-dichloro-benzoic acid," Otkrytiya, Izobret. Prom. Obraztsy, Tovarnye, Znake 1973, 50 (18), 177-178, reports a process for the methylation of a sodium salt of 3,6-dichlorosalicylic acid to provide dicamba. (d) Zhang, et al., "Study on the O-Alkylation for 3,6-dichlorosalicylic Acid by Chloromethane," Huangong Shikan 2002, 16 (12) 45-48 (Ch.), reports O-alkylation 3,6-dichlorosalicylic acid to provide dicamba. (e) CN102942474A and CN 102838483A report a process for methylation of 3,6-dichlorosalicylic acid with chloromethane to provide dicamba. (f) CN102125035B reports a process for methylation of 3,6-dichlorosalicylic acid with dimethyl carbonate to provide dicamba. (g) Chinese patent application CN1830942A reports a process for methylation of 3,6-dichlorosalicylic acid with dimethyl sulfate to provide dicamba. (h) US patent 3,013,054 reports a process for preparing dicamba that proceeds through a 2,5-dichlorophenol intermediate. (i) Zhang, et al., "Synthesis of Herbicide Dicamba," Nongyao 2002, 41 (11), 13-14 (Ch.), reports a process for the preparation of dicamba that proceeds through a 2.5- dichlorophenol. (j) Zhang, et al., "Study on the Preparation of Dicamba," Nongyao 2002, 41 (7), 15-17 (Ch.), reports a process for preparing dicamba that proceeds through a 2,5-dichlorophenol intermediate. (k) Eckstein, et al., Przem. Chem. 1979, 58 (10), 533-536 (Pol.), Reports a process for the preparation of dicamba that proceeds through an intermediate 2,5-dichlorophenol.
[0107] In one embodiment, the present description relates to a process for the preparation of a corresponding compound in structure to formula (V):
or a salt thereof, the process comprising: contacting a corresponding compound in the structure of Formula (II-1):
or a salt thereof, with a chlorinating agent in an acid reaction medium to provide a corresponding compound in structure to Formula (III-1):
or a salt thereof; selectively de-bromine the compound or salt of Formula (III-1) to provide a compound corresponding in structure to formula (IV-1):
or a salt thereof, methylation of the compound or salt of formula (IV-1) to proportionate a compound corresponding in structure to the formula (IV-2):
or a salt thereof; scaponify the Formula (IV-2) compound or salt to proportion the Formula (V) compound or salt.
[0108] In another embodiment, the present invention relates to a process for the preparation of a corresponding compound in structure to formula (V):
or a salt thereof, the process comprising: contacting a corresponding compound in the structure of Formula (II-1):
or a salt thereof, with a chlorinating agent in an acid reaction medium to provide a corresponding compound in structure to Formula (III-1):
or a salt thereof; selectively de-bromine the compound or salt of Formula (III-1) to provide a compound corresponding in structure to formula (IV-1):
or a salt thereof; selectively emethylate the compound or salt of formula (IV-1) to provide the compound or salt of Formula (V).
[0109] In another embodiment, the present invention relates to a process for the preparation of a corresponding compound in structure to formula (V):
or a salt thereof, the process comprising: contacting a compound corresponding in structure to formula (I-1):
or a salt thereof, with a brominating agent in an acid reaction medium comprises sulfuric acid to obtain a compound corresponding in structure to the formula (II-1):
, or a salt thereof, contacting the compound or salt of Formula (II-1) with a first chlorinating agent without first isolating the compound or salt of Formula (II-1) from the reaction medium to provide a corresponding compound in structure to Formula (VI-1):
or a salt thereof; and contacting the compound or salt of formula (VI-1) with a second chlorinating agent to obtain the compound or salt of Formula (III-1):
or a salt thereof; wherein the first chlorinating agent and the second chlorinating agent can be the same or different; selectively de-bromine the compound or salt of Formula (III-1) to provide a compound corresponding in structure to formula (IV-1):
or a salt thereof, methylation of the compound or salt of formula (IV-1) to proportionate a compound corresponding in structure to the formula (IV-2):
or a salt thereof; and saponifying the compound or salt of Formula (IV-2) to provide the compound or salt of Formula (V).
[0110] In one embodiment, the present description refers to a process for the preparation of a corresponding compound in structure to formula (V):
or a salt thereof, the process comprising: contacting a corresponding compound in the structure with Formula (I):
or a salt thereof, with a brominating agent in an acid reaction medium comprises sulfuric acid to obtain a compound corresponding in structure to the formula (II-1):
or a salt thereof; contacting the compound or salt of Formula (II-1) with a first chlorinating agent without first isolating the compound or salt of Formula (II-1) from the reaction medium to provide a corresponding compound in structure to Formula (VI-1):
or a salt thereof; and contact the Formula (VI) compound or salt with a chlorinating second agent to obtain the Formula (III-1) compound or salt:
or a salt thereof; wherein the first chlorinating agent and the second chlorinating agent can be the same or different; selectively de-bromine the compound or salt of Formula (III-1) to provide a corresponding compound in structure to formula (IV-1):
or a salt thereof; selectively emethylate the compound or salt of formula (IV-1) to provide the compound or salt of Formula (V).
[0111] In another embodiment, the present invention relates to a process for the preparation of a corresponding compound in structure to formula (V):
or a salt thereof, the process comprising: contacting a corresponding compound in structure to the Formula (VII-1):
or a salt thereof, with a first chlorinating agent to provide a corresponding compound in the structure of Formula (VIII-1):
or a salt thereof; contacting the compound or salt of Formula (VIII-1) with a second chlorinating agent to provide a corresponding compound in the structure of Formula (IX-1):
or a salt thereof; wherein the first chlorinating agent and the second chlorinating agent can be the same or different; contacting the compound or salt of Formula (IX-1) with a de-bromination agent to provide a corresponding compound in the structure of Formula (X-1):
or a salt thereof; and contacting the compound or salt of Formula (X-1) with an oxidizing agent to provide a compound corresponding in structure to formula (IV-1):
or a salt thereof, methylation of the compound or salt of formula (IV-1) to provide a compound corresponding in structure to the formula (IV-2):
or a salt thereof; scaponify the Formula (IV-2) compound or salt to proportion the Formula (V) compound or salt.
[0112] In another embodiment, the present invention relates to a process for the preparation of a corresponding compound in structure to formula (V):
or a salt thereof, the process comprising: contacting a corresponding compound in structure to the Formula (VII-1):
or a salt thereof, with a first chlorinating agent to provide a corresponding compound in the structure of Formula (VIII-1):
or a salt thereof, contact the compound or salt of Formula (VIII-1) with a second chlorinating agent to provide a corresponding compound in the structure of Formula (IX-1):
or a salt thereof; wherein the first chlorinating agent and the second chlorinating agent can be the same or different; contacting the compound or salt of Formula (IX-1) with a de-bromination agent to provide a corresponding compound in the structure of Formula (X -1):
or a salt thereof; and contacting the compound or salt of Formula (X-1) with an oxidizing agent to provide a compound corresponding in structure to formula (IV-1):
or a salt thereof; selectively emethylate the compound or salt of formula (IV-1) to provide the compound or salt of Formula (V).
[0113] In alternative embodiments of the process described immediately above, the process employs the compounds of formula (VII), formula (VIII), formula (IX), and formula (X), instead of the compounds of formula (VII-1) , Formula (VIII-1), Formula (IX-1) and Formula (X-1) to provide a Formula (IV) compound in which R2 is hydrogen.When R1 is different from methyl, the conversion of the compound or salt of the Formula (IV) is still necessary to provide the compound or salt of Formula (V). B. Conversion of 5-bromo-3,6-dichlorosalicylic acid to dicamba
[0114] Alternatively, 5-bromo-3,6-dichlorosalicylic acid compounds prepared as disclosed above (for example, 5-bromo-3,6-dichlorosalicylic acid) can first be converted into the corresponding methyl ester compounds . Dicamba is converted by selective de-bromination of methyl ester compounds (for example, methyl 3-bromo-2,5-dichloro-6-methoxybenzoate) followed by saponification.
[0115] Therefore, in one embodiment, the present invention relates to a process for the preparation of a compound corresponding in structure to formula (V):
or a salt thereof, the process comprising: contacting a corresponding compound in the structure of Formula (III-1):
or a salt thereof, with a methylating agent to provide a corresponding compound in the structure of Formula (III-2):
or a salt thereof; selectively desbromine the compound or salt of Formula (III-2) to provide a corresponding compound in the structure of Formula (IV-2):
or a salt thereof; scaponify the Formula (IV-2) compound or salt to provide the Formula (V) compound or salt.
[0116] Therefore, the approach involves methylation of the 5-bromo-3,6-dichlorosalicylic acid compounds, selective de-bromination, and saponification to provide dicamba as shown in Scheme 8 below: Scheme 8

[0117] In one embodiment, the present description refers to a process for the preparation of a corresponding compound in structure to formula (V):
or a salt thereof, the process comprising: contacting a corresponding compound in the structure of Formula (II-1): or a salt thereof, with a chlorinating agent in an acid reaction medium to provide a corresponding compound in structure to Formula (III-1):
or a salt thereof; methylation of the compound or salt of Formula (III-1) to proportionate a compound corresponding in structure to Formula (III-2):
or a salt thereof; selectively desbromine the compound or salt of Formula (III-2) to provide a compound corresponding in structure to formula (IV-2):
or a salt thereof; scaponify the Formula (IV-2) compound or salt to proportion the Formula (V) compound or salt.
[0118] In another embodiment, the present invention relates to a process for the preparation of a corresponding compound in structure to formula (V):
or a salt thereof, the process comprising: contacting a compound corresponding in structure to formula (I-1):
or a salt thereof, with a brominating agent in an acid reaction medium comprises sulfuric acid to obtain a compound corresponding in structure to the formula (II-1):
or a salt thereof; contacting the compound or salt of Formula (II-1) with a first chlorinating agent without first isolating the compound or salt of Formula (II-1) from the reaction medium to provide a corresponding compound in structure to Formula (VI-1):
or a salt thereof; and contacting the compound or salt of formula (VI-1) with a second chlorinating agent to obtain the compound or salt of Formula (III-1):
or a salt thereof; wherein the first chlorinating agent and the second chlorinating agent can be the same or different; methylation of the compound or salt of Formula (III-1) to provide a compound corresponding in structure to Formula (III-2):
or a salt thereof; selectively de-bromine the compound or salt of Formula (III-2) to provide a compound corresponding in structure to formula (IV-2):
or a salt thereof; and saponifying the Formula (IV-2) compound or salt to proportion the Formula (V) compound or salt.
[0119] In each of the modalities disclosed in this application, whenever desirable and appropriate, the process may also comprise the isolation and / or purification of one or more of the intermediates used in the process before reacting the intermediates in a subsequent step of the process. For example, the disclosed processes may further comprise one or more of the following steps, where desirable and appropriate: (1) isolation and / or purification of the compound or salt of Formula (II), (2) isolation and / or purification of the compound or salt of Formula (III), (3) isolation and / or purification of the compound or salt of Formula (IV), and / or (4) isolating or purifying the compound or salt of Formula (V) (i.e., dicamba). IX. Compounds
[0120] In additional embodiments, the present invention relates to new process compounds as disclosed above.
[0121] In one embodiment, the present invention relates to a compound corresponding in structure to Formula (III):
or a salt thereof, where R1 is hydrogen or C1-6-alkyl; and R2 is hydrogen or C1-6-alkyl. In one respect, R1 is hydrogen, methyl, or ethyl; and R2 is hydrogen, methyl, or ethyl. In another aspect, R1 is hydrogen or methyl; and R2 is hydrogen or methyl. In another aspect, R1 and R2 are each hydrogen. In another aspect, R1 and R2 are each methyl.
[0122] In one embodiment, the present invention relates to a compound corresponding in structure to Formula (III-1):
or a salt of the same.
[0123] In one embodiment, the present invention relates to a compound corresponding in structure to Formula (III-2):
or a salt of the same.
[0124] As discussed earlier, these compounds or salts of formula (III); Formula (III-1); and Formula (III-2) are useful, for example, as intermediates in the processes for the preparation of dicamba.
[0125] In one embodiment, the present invention relates to a compound corresponding in structure to Formula (IX):
or a salt thereof, where R1 is hydrogen or C1-6-alkyl. In one respect, R1 is hydrogen, methyl, or ethyl. In another aspect, R1 is hydrogen or methyl. In another aspect, R1 is hydrogen.
[0126] In one embodiment, the present invention relates to a compound corresponding in structure to Formula (IX-1):
or a salt of the same.
[0127] As discussed earlier, these compounds or salts of formula (IX) and Formula (IX-1) are useful, for example, as intermediates in the processes for the preparation of dicamba. X. EXAMPLES
[0128] The following non-limiting examples are provided to further illustrate the present invention. Example 1: Analytical methods A. Reverse phase high performance liquid chromatography ("RP-HPLC") method
[0129] The RP-HPLC analysis used to monitor reactions was performed in an Agilent 1260 Infinity LC / MS Analytical Purification System equipped with a diopter UV detector and monitored at 315 nm. The column was an Agilent Poroshell 120 C-18CE, 4.6x50 mm, 2.7 micron, with a pre-column filter. The RP-HPLC was conducted at a flow rate of 2 ml / minute of water, mobile phase (0.05% trifluoroacetic acid) and acetonitrile, as disclosed in table 1-A below: Table 1-A: RP-HPLC method
B. Nuclear Magnetic Resonance Method
[0130] Nuclear magnetic resonance analysis was performed on a Bruker 600 MHz instrument. Deuterated solvents from Cambridge Isotope Laboratories, Ltd., including methanol-d 4, chloroform-d, and dimethylsulfoxide-6, were used as needed. Example 2: Preparation of 5-Bromosalicylic Acid
[0131] Salicylic acid (6.0 g, 43.47 mmol) and concentrated sulfuric acid (98%, 21.5 mL) were loaded into a 250-neck three-neck flask equipped with a temperature probe, heating blanket, overhead stirrer, and an inlet for a tungsten needle / syringe pump to release bromine. Stirring was initiated to dissolve the salicylic acid, which was slightly exothermic. Once the mixture reached room temperature, the syringe was charged with a slight excess of bromine to guarantee the release of 0.575 equivalent over 5 minutes. As bromine was added to the solution with rapid stirring, a slight exotherm was observed. Once the addition was complete, the reaction mixture was stirred for an additional five minutes before heating to 60 ° C, which required about 15 minutes. The reaction mixture was stirred at 60 ° C for a total of 60 minutes, then allowed to cool to room temperature. The ice water (about 100 g) was slowly added to the reaction mixture, which generated the formation of a white solid. During the addition of ice water, the temperature rose to about 50 ° C to 60 ° C. The reaction mixture was cooled in an ice bath at 10 ° C, then filtered through a sintered glass funnel. The precipitate was washed with 4 x 30 ml of cold water, resuspended from the cake each time before extracting the wash with water. The cake was air-dried for 30 minutes, then dried in vacuo (55 ° C) overnight to obtain the title compound as a white solid (8.7 g, 92%). RP-HPLC (315 nm) and 1H NMR (600 MHz, DMSO-d 6) indicated that the crude material had the following composition: 5-bromosalicylic acid (96%), 3-bromosalicylic acid (0.4%) and 3,5-dibromosalicylic acid (3.5%).
[0132] Analytical data for 5-bromosalicylic acid: 1H NMR (600 MHz, DMSO-d 6) δ 11.9-10.9, 7.85, 7.65, 6.95. LCMS (ESI) m / z 214.9 (M-H). Example 3: Preparation of 5-Bromosalicylic acid (alternative conditions)
[0133] Salicylic acid was brominated with molecular bromine as disclosed in Example 2, except that the reagent equivalents and heating time and temperature at the completion of the addition of bromine were varied as indicated in Table 3-A below. Table 3-A also reports salicylic acid ("SA"), 3-bromosalicylic acid ("3-Br-SA"), 5-bromosalicylic acid ("5-Br-SA), and 3,5-dibromosalicylic acid ("3,5-Br2-SA") present in the resulting crude material, as determined by peak areas RP-HPLC (which were adjusted using response factors from the respective analytes below). Table 3-A

[0134] Conditions A, B, and Referenced in Table 3-A are disclosed in more detail in Table 3-B below. Example 4: Preparation of 5-bromo-3,6-dichlorosalicylic acid Using sodium hypochlorite
[0135] 5-Bromosalicylic acid (1.0 g, 4.6 mmol) was dissolved in 2.5 M sodium hydroxide (3.7 mL). The resulting solution was cooled in an ice bath at 0 ° C in which time a solution of 12% by weight of sodium hypochlorite (4.6 ml) was added dropwise. Once the addition was completed, concentrated HCl was added dropwise until the mixture became cloudy. The reaction was heated to 40 ° C for 5 hours. An aliquot of the reaction mixture was removed and analyzed by RP-HPLC, which indicated that the main product was 5-bromo-3-chlorosalicylic acid when compared to a known standard. Heating overnight at 40 ° C, with an additional 4.6 mL of 12% by weight of sodium hypochlorite solution (4.6 mL) did not produce the desired 5-bromo-3,6-dichlorosalicylic acid. Example 5: Preparation of 5-bromo-3,6-dichlorosalicylic acid Using trichloroisocyanuric acid in concentrated sulfuric acid
[0136] 5-Bromosalicylic acid (1.0 g, 4.6 mmol) was dissolved in concentrated sulfuric acid (98%, 10 mL), which caused a mild exotherm. Iodine (25 mg, 0.1 mmol) was added, and the resulting reaction mixture was cooled to 0 ° C. Triclo roiso-cyanuric acid (0.440 g, 1.90 mmol) was added, and the reaction mixture was stirred at 0 ° C for one hour. An aliquot of the reaction mixture was removed and analyzed by RP-HPLC, which indicated that the main product was 5-bromo-3-chlorosalicylic acid when compared to a known standard. Additional trichloroisocyanuric acid (0.440 g, 1.90 mmol) was added, and the reaction mixture was warmed to room temperature for one hour, followed by heating at 40 ° C for one hour, and finally at 70 ° C for two hours . A liquefied reaction mixture was removed and analyzed by RP-HPLC. 5-bromo-3-chlorosalicylic acid was still present, along with two more polar components and a less polar component. The reaction mixture was poured over crushed ice and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo as a yellow solid. 1H NMR (600 MHz, DMSO-d 6) showed a mixture of four compounds: 5-bromo-3-chlorosalicylic acid, 5-bromo-3,6-dichloroslicicylic acid, 3,5,6-trichlorosalicylic acid, and a compound of unknown structure in a 20: 35: 20: 25 ratio. Example 6: Preparation of 5-bromo-3,6-dichlorosalicylic acid Using trichloroisocyanuric acid in Oleum (fuming sulfuric acid)
[0137] Iodine (29 mg, 0.115 mmol) was suspended in 20% oleum (50 mL) and the resulting mixture was stirred at room temperature for five minutes, at which time 5-bromosalicylic acid (5.00 g) was added , 23.04 mmol). The resulting suspension was cooled with an ice bath until an internal temperature of 5 ° C was reached. Trichloroisocyanuric acid (7.74 mmol) was added as a solid in one portion. The cooling bath was removed and the reaction mixture was allowed to self-heat for a period of 75 minutes at a temperature of 30 ° C. The reaction mixture was again placed in a cooling bath approximately two hours after the initial removal of the cooling bath and iodine (88 mg, 0.346 mmol) was added together with trichloroisocyanuric acid (7.74 mmol). The resulting mixture was allowed to stir overnight. The reaction mixture was cooled to 5 ° C with an ice bath and then slowly poured over crushed ice. The aqueous reaction mixture was extracted with ethyl acetate (2 x 100 ml). The combined organic layers were filtered through a Celite pad to remove insoluble material. The resulting filtrate was washed with brine, NaHSO3 solution (10 ml), dried (MgSO4), filtered, and concentrated. A portion of the resulting solid (2.0 g) was subjected to reverse phase chromatography (water with 0.1% TFA: Acetonitrile) to generate the desired product (0.730 g) as a tan-yellow crystalline solid. 1H-NMR (600 MHz, DMSO-d6) δ 12.8-10.0 (br s, 2H), 7.91 (s, 1H); ESI-MS m / z 284.9 (M + H). Example 7: Preparation of 5-bromo-3,6-dichlorosalicylic acid Using trichloroisocyanuric acid in Oleum (alternative conditions)
[0138] 5-Bromosalicylic acid was dichlorinated using trichloroisocyanuric acid (ACL® 90, Occidental Chemical Corporation) and catalytic iodine in fuming sulfuric acid as disclosed in Example 6, except that the reaction conditions were varied as indicated in Table 7-A below. Table 7-A also reports the yield of 5-bromo-3,6-dichlorosalicylic acid under the different conditions. Table 7-A
* BSA: 5-Bromosalicylic acid; BDCSA: 5-bromo-3,6-dichlorosalicylic acid; TCICA: Trichloroisocyanuric acid ** Yields based on peak RP-HPLC integrations at 315 nm. *** Yields based on integrations of aromatic signals in 1 H-NMR (600 MHz, DMSO d 6) spectrum of the crude product isolated. Example 8: Preparation of 5-bromo-3,6-dichlorosalicylic acid Using chlorine gas
[0139] Iodine (30 mg, 0.118 mmol) and 5-bromosalicylic acid (12.0 g, 55.3 mmol) were suspended in oleum (120 ml), and the resulting suspension was cooled with an ice bath to an internal temperature of 10 ° C to be reached. The bath was removed, and chlorine gas was bubbled into the reaction mixture for 10 hours. After two hours, an additional 30 mg (0.118 mmol) of iodine was added. After 3.5 hours at room temperature, the mixture became homogeneous. After 10 hours of bubbling chlorine in the mixture at room temperature, the mixture was a suspension. Stirring was stopped and the precipitate was allowed to settle. The oleum was decanted from the precipitate. The precipitate was washed with ice-water and dried in vacuo to provide 9.9 g of an off-white solid. The oleum was poured onto crushed ice (about 700 g), and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to provide 4.7 g of an almost white solid. This solid was combined with the solid precipitate from above, to obtain 14.6 g (92%) of the title compound as an off-white solid. RP-HPLC and 1H NMR in the solid indicated a purity of about 85%. 1H-NMR (600 MHz, DMSO-d6) δ 12.8-10.0 (br s, 2H), 7.91 (s, 1H); ESI-MS m / z 284.9 (M + H). Example 9: Preparation of 3,6-Dichlorosalicylic acid
[0140] A mixture containing 5-bromo-3,6-dichlorosalicylic acid (5.0 g, 18 mmol), sodium acetate (1.50 g, 18.5 mmol), and 10% Pd / C (content 50% water, 250 mg) in glacial acetic acid (80 ml) was hydrogenated (1 atm) at room temperature for 16 hours. The catalyst was filtered through Celite and washed with acetic acid. The solution was concentrated in vacuo. The remaining solid was partitioned between a 1.0 M HCl solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 3.5 g (97%) of a white solid. RP-HPLCe 1 H NMR (600 MHz, DMSO-d 6) of the crude material indicated a purity of about 90%, the remainder being the unreacted starting material (about 3%) and 3-chlorosalicylic acid (7%). The analytical data for 3,6-dichlorossylclic acid: 1H NMR (600 MHz, DMSO-d6) 14.5-13.5, 7.34, 6.77; LCMS (ESI) m / z 204.7 (M-H). Example 10: Preparation of 3,6-Dichlorosalicylic acid (alternative conditions)
[0141] 5-Bromo-3,6-di-dichlorosalicylic was hydro-debrominated to provide 3,6-dichlorosalicylic acid as disclosed in Example 9 except that the reaction conditions were varied as indicated in Table 10-A below. Table 10-A also reports the yield of 3,6-dichlorosalicylic acid under the different conditions. Table 10-A
Example 11: Preparation of 5-bromo-3-chlorosalicylic acid

[0142] The concentrated sulfuric acid (98%, 50 mL) was loaded into a three-necked round-bottom flask, equipped with a temperature probe and a mechanical stirrer. The solution was cooled in an ice bath, with stirring, until an internal temperature of 5 ° C was reached. Salicylic acid (15.0 g, 109 mmols) was then added in portions, keeping the internal temperature below 10 ° C. An inlet for a non-syringe teflo needle pump was then attached to the reaction flask through the remaining neck to release bromine. Bromine (3.2 ml, 62 mmols) was added slowly over 30 minutes, during which time the reaction mixture was kept below 10 ° C. After the addition was complete, the ice bath was removed and replaced with a heating mat. The reaction mixture was stirred at room temperature for 30 minutes and was then heated to 40 ° C for an additional 30 minutes. A UV trace of RP-HPLC from the reaction mixture indicated the formation of 5-bromosalicylic acid without remaining salicylic acid. The reaction mixture was diluted with concentrated sulfuric acid (98%, 151 ml). The chlorine gas was bubbled through a gas dispersion tube in the reaction mixture at 40 ° C. After 2.5 hours, a trace of UV RP-HPLC indicated that the remaining 5-bromosalicylic acid being less than 1% in the reaction mixture. The reaction mixture was cooled to 5 ° C, and then slowly poured over crushed ice to form solid precipitations. The resulting precipitate was filtered and the filtered solids were dissolved in ethyl acetate. The organic solution was washed twice with water, dried over anhydrous sodium sulfate, filtered, and concentrated to generate yellow solids. The crude solids were further dried in a vacuum oven at 55 ° C for 15 hours to generate the title compound as a yellow solid (26 g, 95%). A UV trace of RP-HPLC from the solid indicated that the crude material had the following composition: 5-bromo-3-chlorosalicylic acid (90%), 3,5-dibromosalicylic acid (9%) and 3-bromosalicylic acid ( 1%) Example 12: Preparation of 5-bromo-3,6-dichlorosalicylic acid

[0143] Oleum (20%, 125 mL) was placed in a 250 ml three-necked round-bottomed flask equipped with an overhead stirrer, a temperature probe, a gas dispersion tube and an inserted glass outlet tube in a base bath of sodium hydroxide solution to trap excess chlorine. The solution was cooled in an ice-water bath to reach an internal temperature of 5 ° C. 5-bromo-3-chlorosalicylic acid (25 g, 100 mmols) and iodine (190 mg, 0.75 mmol) were added, and the reaction mixture was stirred at 5 ° C with bubbling chlorine gas through the dispersal. After 15 minutes, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. After 1.5 hours, the reaction mixture was heated to 33 ° C with an oil bath. Another portion of iodine (190 mg, 0.75 mmol) was added to the reaction mixture after 3 hours at 33 ° C. During the course, chlorine was bubbled into the reaction mixture for a total of 5.5 hours. Heating and addition of chlorine were stopped after 5.5 hours and the reaction mixture was cooled to 5 ° C with an ice bath. The reaction mixture was poured onto crushed ice (about 1200 g) with vigorous stirring and extracted with ethyl acetate (1 x 300 ml, 3 x 200 ml). The combined organic layers were washed with water (3 x 100 ml), brine (1 x 100 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to generate yellow powders. The crude product was triturated in hexanes (100 ml) to generate the title compound as an off-white powder (26 g, 92%). 1H NMR (600 MHz, DMSO-d6) indicated that the material was about 81% pure. Example 13: Preparation of 5-bromo-3,6-dichlorosalicylic acid (Alternative conditions)

[0144] The concentrated sulfuric acid (96%, 145 ml) was loaded into a 1000 ml round bottom flask with three necks equipped with a temperature probe and a mechanical stirrer. The solution was cooled in an ice bath, with stirring, until an internal temperature of 5 ° C was reached. Salicylic acid (30.0 g, 217 mmols) was then added in portions, keeping the internal temperature below 10 ° C. An inlet for a teflon needle / syringe pump was then connected to the reaction flask through the remaining neck of the flask to release bromine. Bromine (6.12 ml, 119 mmols) was slowly added over 30 minutes, during which time the reaction mixture was kept below 10 ° C. After the addition and removal of the ice bath was complete, the reaction mixture was allowed to warm to room temperature and stirred for an additional 30 minutes. After consumption of salicylic acid, as monitored by RP-HPLC, the teflon needle / syringe pump was removed. The reaction vessel was applied with a vacuum (25 to 30 mm Hg) to remove excess bromine. A 5% aqueous sodium bisulfite in-line trap was used between the reaction vessel and the vacuum for the elimination of bromine. The reaction mixture was stirred under vacuum for about 1 hour, during which time the initial orange color of the mixture turned light yellow indicating that the excess bromine was removed.
[0145] The vacuum line has been replaced by a gas inlet / outlet system consisting of a dispersion tube for the introduction of chlorine gas and a separate needle / tube outlet connected to a base trap (5% NaOH solution) for excess chlorine. The chlorine gas was bubbled into the reaction mixture at room temperature for an initial period of 30 minutes, and then the resulting mixture was heated to 45 ° C. Chlorine was continuously bubbled into the reaction mixture for a total of 18 hours, while the temperature was maintained at 45 ° C. In 9 hours of chlorination, additional concentrated sulfuric acid (96%, 32 mL) was added to the reaction mixture in a single portion.
[0146] The above-mentioned gas inlet / outlet system was replaced with an addition funnel, and the reaction mixture was cooled to 5 ° C. Steaming sulfuric acid (65% oleum, 141 ml) was added through the addition funnel over 45 minutes, at such a rate that the internal temperature was kept below 20 ° C. At the end of the addition, the reaction solvent consisted of about 20% oleum. The addition funnel was connected to the gas inlet / outlet system. Iodine crystals (827 mg, 3.36 mmols) were added and chlorine gas was bubbled into the mixture continuously. The reaction mixture was stirred at room temperature for 30 minutes, followed by heating at 35 ° C for 6 hours.
[0147] The reaction was cooled to 5 ° C and the gas inlet / outlet system was replaced with an addition funnel. Aqueous sulfuric acid solution (75%, 174 mL) was added dropwise to the reaction mixture. After about 80 ml of aqueous sulfuric acid was added, the initial heterogeneous reaction mixture became almost homogeneous. At the point of about 85 ml of added aqueous sulfuric acid, gas was released and solids started to precipitate from the reaction mixture accompanied by some foams. Foaming was minimized, decreasing the rate of addition of sulfuric acid. Once the foaming ceased, the remaining aqueous sulfuric acid was added at such a rate that the internal temperature was kept below 10 ° C. The reaction solvent consisted of about 95% sulfuric acid.
[0148] The addition funnel was removed, and the heterogeneous reaction was filtered through a sintered glass filtration funnel (coarse porosity). The precipitate was washed with aqueous sulfuric acid (75%, 100 ml) and dried to a constant weight under vacuum. The precipitate was suspended in cold water at 5 ° C (100 ml) and extracted with ethyl ketate (300 ml). The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to provide the title compound as an off-white solid (49 g, 79%). RP-HPLCe 1H NMR (600 MHz, DMSO-d6) confirmed that the material obtained was 5-bromo-3,6-dichlorosalicylic acid with an 88% degree of purity. Example 14: Preparation of 3,6-Dichlorosalicylic acid

[0149] 5-Bromo-3,6-dichlorosalicylic acid with a purity of 88% by RP-HPLC (20.0 g, 70 mmols), sodium acetate (6.0 g, 74 mmols), and 5% Pd / C (50% water content, 8.9 g) in a 1: 1 mixture ratio of glacial acetic acid solvent (140 mL) and ethyl acetate (140 mL) were loaded into a 1000 vial. mL of round bottom. The mixture was placed under vacuum (25 to 30 mmHg), followed by purging with hydrogen. The mixture was hydrogenated (1 atm) with vigorous stirring at room temperature for 4 hours. The resulting mixture was placed under a vacuum / purge (N 2) in a circle for 3 times, filtered through celite and washed with methanol. The filtrate was concentrated in vacuo. The remaining material was partitioned between a 1.0 M solution of HCl (200 ml) and ethyl acetate (200 ml), and the aqueous layer was extracted with ethyl acetate (50 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude 3,6-dichlorosalicylic acid as a whitish solid (14 g, 95%) with a purity of 78% by RP-HPLC.
[0150] Crude 3,6-dichlorosalicylic acid (21.1 g, 107 mmols) was suspended in o-xylene (85 ml) in a 500 ml round bottom flask. The mixture was heated to 80 ° C for 5 hours with vigorous stirring. The suspension was cooled to room temperature, and the solid precipitate was filtered. The precipitate was washed with hexanes and dried in vacuo to provide the title compound as a white solid (16.0 g, 77%). RP-HPLC and 1H NMR (600 MHz, DMSO-d 6) confirmed that the desired material was 3,6-dichlorosalicylic acid with a purity of 98%. Example 15: Preparation of 3,6-Dichlorosalicylic acid
[0151] 5-Bromo-3,6-dichlorosalicylic acid with 85% purity by RP-HPLC (10.0 g, 35.0 mmol) and 5% Pd / C (50% water content, 2, 2 g) in a two-phase solvent mixture consisting of ethyl acetate (35 ml) and water (7 ml) were loaded into a 100 ml round bottom flask. The mixture was placed under vacuum (25 to 30 mmHg), followed by purging with hydrogen. The mixture was hydrogenated (1 atm) with vigorous stirring at room temperature. After 1 hour of stirring, the first portion of aqueous sodium hydroxide solution (2.5 M, 7.0 mL) was added via syringe. After 2 hours of stirring, another portion of aqueous sodium hydroxide solution was added (2.5 M, 5.0 mL). After 3 hours of total stirring, the resulting mixture was placed under a vacuum / purge (N2) in a circle for 3 times. The catalyst was filtered and washed with water (5 ml) and ethyl acetate (25 ml). The filtrate was transferred to a separatory funnel and the layers were separated. The organic layer was washed with brine (5 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to obtain the crude 3,6-dichlorosalicylic acid as an off-white solid (6.70 g, 93%) with 84% purity by RP-HPLC. Example 16: Preparation of 5-bromo-3,6-dichlorosalicylic acid (Use of iodine monochloride catalyst)

[0152] Oleum (20%, 30 ml) was placed in a 100 ml three-necked round-bottom flask equipped with an overhead stirrer, a temperature probe, a gas dispersion tube and a glass outlet tube inserted in a base bath of sodium hydroxide solution to trap excess chlorine. The solution was cooled in an ice-water bath to reach an internal temperature of 5 ° C. 5-bromo-3-chlorosalicylic acid (6 g, 24 mmol s) and iodine monochloride (18 mL, 0.36 mmol) were added, and the mixture was allowed to warm to room temperature with chlorine gas bubbling through the tube. dispersal. After one hour, the reaction mixture was heated to 35 ° C with an oil bath. Heating and addition of chlorine was stopped after 4 hours and the reaction mixture was cooled to 5 ° C with an ice bath. The mixture was poured over crushed ice with vigorous stirring and extracted with ethyl acetate (4 x 100 ml). The combined organic layers were washed with water (3 x 100 ml), brine (1 x 50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to generate the title compound as yellow-orange powder (6.44 g, 94%). Analysis by RP-HPLC indicated that the material obtained from 5-bromo-3,6-dichlorosalicylic acid was 82% pure. Example 17: Preparation of 5-bromo-3,6-dichlorosalicylic acid (2.25M Payload Salicylic acid)

[0153] The concentrated sulfuric acid (98%, 129 mL) was loaded into a 500 mL four-necked round-bottom flask equipped with a temperature probe and a mechanical stirrer. The solution was cooled in an ice bath, with stirring, until an internal temperature of 3 ° C was reached. Salicylic acid (40.0 g, 290 mmols) was then added in portions, keeping the internal temperature below 10 ° C. Bromine (8.02 mL, 157 mmols) was added slowly over 30 minutes, during which time the reaction mixture was kept below 10 ° C. After completing the addition of bromine and removing the ice bath, the reaction mixture was allowed to warm to room temperature and stirred for an additional 30 minutes. After the consumption of salicylic acid (monitored by RP-HPLC), the reaction vessel was placed under vacuum to remove excess bromine. The reaction mixture was stirred under vacuum for about 1.5 hours, during which time the color of the mixture changed from initial orange to light yellow.
[0154] After the reaction mixture was cooled to 3 ° C, steaming sulfuric acid (oleum 65%, 45 ml) was added dropwise through the addition funnel while the internal temperature was kept below 10 ° C. The resulting mixture became homogeneous with a final concentration of sulfuric acid of about 99.5%. The chlorine gas was bubbled into the reaction mixture through a gas inlet dispersion tube. A closed pseudo-closed reaction system was maintained by releasing excess chlorine gas in a flask connected to a gas outlet dispersion tube. The flask was emptied every hour, releasing excess chlorine gas in an aqueous sodium hydroxide trap. The resulting mixture was heated to 35 ° C for 8 hours, followed by heating to 40 ° C for an additional 3 hours. After stopping the chlorine gas bubbling and heating, the mixture was cooled to 3 ° C.
[0155] Steaming sulfuric acid (65% oleum, 82 mL) was added dropwise through the addition funnel while the internal temperature was maintained below 20 ° C. At the end of the addition, the reaction solvent consisted of about 25% oleum. Iodine crystals (550 mg, 2.2 mmols) were added and chlorine gas was bubbled into the mixture through inlet / outlet gas dispersion tubes. The reaction mixture was heated at 35 ° C for 4 hours, with constant stirring. The thick reaction mixture was cooled to 5 ° C, and an aqueous sulfuric acid solution (79%, 153 mL) was added dropwise through the addition funnel to the reaction mixture while the internal temperature was kept below 15 ° C. ° C. After about 40 ml of aqueous sulfuric acid was added, the release of HCl gas was observed and the initial heterogeneous reaction mixture turned into an almost homogeneous burnt orange solution. Vigorous bubbling and foaming was observed after the addition of 60 ml of aqueous sulfuric acid, and constant foaming occurred throughout the addition. At the end of the addition, the reaction solvent consisted of about 95.5% sulfuric acid.
[0156] The reaction mixture was filtered through a sintered glass filter funnel (coarse porosity). The precipitate was washed with an aqueous solution of sulfuric acid (79%, 1 x 200 ml, 1 x 100 ml) and dried under vacuum (about 30 mmHg) for one hour. The solid was suspended in cold water 5 ° C (400 ml) and was stirred for 45 minutes. The filtered solids were washed with 1% aqueous HCl solution (1 x 200 ml, 1 x 100 ml) and dried in vacuo (about 30 mmHg) for more than 12 hours. The solid was dissolved in ethyl acetate (400 ml) and the solution was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting solid was dried under high vacuum for about an hour to obtain the title compound as a pale yellow powder (66.6 g, 80.3%). Analysis by RP-HPLC indicated that the 5-bromo-3,6-dichlorosalicylic acid obtained was 83% pure. Example 18: Preparation of 5-bromo-3,6-dichlorosalicylic acid (Molar proportion SO3 / Salicylic acid)
[0157] Experiment 18.1: The procedure disclosed in Example 13 was repeated using a reaction medium with a concentration of 1.5 M, 20% oleum, and 0.1 eq. of I 2 as the catalyst for the second chlorination step. The molar ratio of SO3 to salicylic acid in the reaction medium in Experiment 6.3 was 18.1.
[0158] Experiment 18.2: The procedure disclosed in Example 13 was repeated using a reaction medium with a concentration of 2.25 M, 20% oleum, and 1.5 molar% I 2 as the catalyst for the second stage of chlorination. The molar ratio of SO 3 to salicylic acid in the reaction medium in Experiment 3.8 was 19.2. Experiment 18.2 failed to obtain 5-bromo-3,6-dichlorosalicylic acid during the second chlorination of 5-bromo-3-chlorosalicylic acid.
[0159] Experiment 18.3: The procedure described in Example 17 was repeated using a reaction medium with a concentration of 2.25 M, 25% oleum, and 0.75 molar I2 as the catalyst for the second chlorination step . The molar ratio of SO3 to salicylic acid in the reaction medium in Experiment 5.3 was 18.2.
[0160] The results of Experiments 18.1, 18.2, and 18.3 are shown below in Table 18-A and suggest that the molar SO 3 / salicylic acid ratio of at least about 4.0 or greater is generally required in the reaction medium for the proper conversion of 5-bromo-3-chlorosalicylic acid to 5-bromo-3,6-dichlorosalicylic acid by the second chlorination. Table 18-A: Effect of molar proportion of SO3 / salicylic acid (Second Chlorination Reaction)
Example 19: Preparation of 5-bromo-3,6-dichlorosalicylic acid (With isolation of 5-bromo-3-chlorosalicylic acid)

[0161] The concentrated sulfuric acid (98%, 145 ml) was loaded into a 1000 ml four-neck round bottom flask equipped with a temperature probe and a mechanical stirrer. The solution was cooled in an ice bath, with stirring, until an internal temperature of 3 ° C was reached. Salicylic acid (40.0 g, 290 mmols) was then added in portions, keeping the internal temperature below 10 ° C. Bromine (7.88 ml, 154 mmols) was slowly added over 30 minutes, during which time the reaction mixture was kept below 10 ° C. After completing the addition of bromine and removing the ice bath, the reaction mixture was allowed to warm to room temperature and stirred for an additional 30 minutes. After the consumption of salicylic acid (monitored by RP-HPLC), the reaction vessel was placed under vacuum to remove excess bromine. The reaction mixture was stirred under vacuum for about 1 hour, during which time the color of the mixture changed from initial orange to off-white.
[0162] After the reaction mixture was cooled to 4 ° C, the chlorine gas (78.1 g, 1101 mmols) was bubbled into the reaction mixture through a gas inlet dispersion tube. A closed pseudo-closed reaction system was maintained by releasing excess chlorine gas in a flask connected to a gas outlet dispersion tube. The flask was emptied every hour, releasing excess chlorine gas in an aqueous sodium hydroxide trap. The resulting mixture was heated to 40 ° C over 1 hour, followed by heating to 40 ° C for an additional 4.5 hours. During the reaction, the reaction mixture became substantially heterogeneous as the newly formed 5-bromo-3-chlorosalicylic acid precipitated from the reaction mixture. After stopping the bubbling of chlorine and heat gas, the mixture was cooled to room temperature. The solids were filtered from the reaction mixture. The filtered solids were washed with concentrated sulfuric acid (98%, 30 ml) and dried in vacuo (about 30 mmHg) to provide the crude product of 5-bromo-3-chlorosalicylic acid as a form of wet white solids cake (77.1 g).
[0163] A part of the crude product (30 g) was divided into a mixture of water (200 ml) and ethyl acetate (100 ml), and the aqueous layer was extracted with another portion of ethyl acetate (1 x 100 ml) ). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The resulting solid was dried under high vacuum to obtain the title compound as a white solid (23.0 g) with a mass recovery yield of 76.7%. A UV trace of RP-HPLC from the solid indicated that the crude material had the following composition: 5-bromo-3-chlorosalicylic acid (81.1%), 5-bromosalicylic acid (12.0%), acid 3, 5-dibromosalicylic acid (5.3%) and 3,5-dichlorosalicylic acid (1.7%).
[0164] A 20% oleum solution (129 mL) was placed in a 1000 mL four neck round bottom flask equipped with a temperature probe and a mechanical stirrer. The solution was cooled in an ice bath, with stirring, until an internal temperature of 3 ° C was reached. Sulfuric acid fumeg ante (oleum 65%, 22 mL) was added to swell the reaction medium to consist of about 25% oleum. The crude product of the 5-bromo-3-chlorosalicylic acid, isolated above, described as a wet cake form (47 g) (ie, containing the crude 5-bromo-3-chlorosalicylic acid of about 36 g, 144 mmols), was added, in portions, to the prepared 25% oleum solution while the internal temperature was kept below 15 ° C. Iodine crystals (273 mg, 1.1 mmols) were added and chlorine gas (19.8 g, 279 mmols) was bubbled into the mixture through gas inlet / outlet dispersion tubes. The reaction mixture was heated to 35 ° C for 3.5 hours with constant stirring. The thick reaction mixture was cooled to 3 ° C, and filtered. The filtered solids were washed with concentrated sulfuric acid (98%, 2 x 100 ml), sulfuric acid solution (75%, 1 x 100 ml), and water (1 x 100 ml). Additional solids formed in the filtrates resulting from washing with concentrated sulfuric acid and filtrates. The resulting filtered solids were washed with a solution of sulfuric acid (75%, 1 x 50 ml) and water (1 x 50 ml). The combined solids were dried under high vacuum overnight to obtain the title compound as a white powder (32.5 g, 70%). Analysis by RP-HPLC indicated that the 5-bromo-3,6-dichlorosalicylic acid obtained was 89% pure.
[0165] The 5-bromo-3,6-dichlorosalicylic acid material, prepared by the direct filtration described above, was subjected to the de-bromination reaction. The reaction was carried out with the procedure disclosed in Example 15 in a 4: 1 mixture of ethyl acetate and water. The desired product of 3,6-dichlorosalicylic acid was obtained without the need for an additional crude 5-bromo-3,6-dichlorosalicylic acid process. Example 20: Preparation of 5-bromo-3,6-dichlorosalicylic acid (With or without isolation of 5-bromo-3-chlorosalicylic acid)
[0166] Experiment 20.1: The procedure described in Example 17 was repeated, in which the acid reaction medium for the second chlorination was modified to provide an acid reaction medium comprising 25% oleum after the formation of 5- acid bromo-3-chlorosalicylic without isolation of the product 5-bromo-3-chlorosalicylic acid from the first chlorination.
[0167] Experiment 20.2: The same experiment in Example 19 was presented, in which the 5-bromo-3-chlorosalicylic acid product from the first chlorination was isolated and placed in the acid reaction medium comprising 25% oleum for the second chlorination.
[0168] The results of experiments 20.1 and 20.2 are shown below in Table 20-A and suggest that the isolation of 5-bromo-3-chlorosalicylic acid can improve the purity of 5-bromo-3,6-dichlorosalicylic acid from of the second chlorination. Table 20-A: Comparison of Purity 5-bromo-3,6-dichlorosalicylic acid with or without 5-bromo-3-chlorosalicylic acid isolation
Example 21: Preparation of 5-bromo-3,6-dichlorosalicylic acid (Chlorine gas equivalents)
[0169] Chlorine gas equivalents were controlled by recovering the unreacted chlorine gas overhead and recycling it back to the reaction medium. The amount of chlorine gas used during the reaction was measured by weighing the chlorine gas reservoir, before and after the reaction.
[0170] Experiment 21.1: The procedure described in Example 8 was repeated except that the reaction temperature was maintained at 33 ° C and 1.5 mol% of iodine catalyst was used for the conversion of 5-bromo-salicylic acid to 5-bromo-3,6-dichlorosalicylic acid.
[0171] Experiment 21.2: The procedure described in Example 12 was repeated for the conversion of 5-bromo-3-chlorosalicylic acid to 5-bromo-3,6-dichlorosalicylic acid.
[0172] Experiment 21.3: The procedure described in Example 17 was repeated for the conversion of 5-bromo-salicylic acid to 5-bromo-3,6-dichlorosalicylic acid.
[0173] Experiment 21.4: The procedure described in Example 17 was repeated for the conversion of 5-bromo-salicylic acid to 5-bromo-3,6-dichlorosalicylic acid.
[0174] Experiment 21.5: The same experiment in Example 19 was presented for the conversion of 5-bromo-salicylic acid to 5-bromo-3,6-dichlorosalicylic acid.
[0175] The results of experiments of 21.1, 21.2, 21.3, 21.4, 21.5 and are presented below in Table 21-A and suggest that the total chlorine equivalents were controlled from about 2.0 to about 6.0 equivalents related to 5-bromo-salicylic acid for the conversion of 5-bromo-salicylic to 5-bromo-3,6-dichlorosalicylic acid.Table 21-A: Equivalents of chlorine gas
Example 22: Preparation of methyl 3-Bromo-2,5-dichloro-6-methoxybenzoate

[0176] 5-Bromo-3,6-dichlorosalicylic acid with a purity of 81% by RP-HPLC (32 g, 112 mmols) was dissolved in acetone (340 ml), followed by the addition of anhydrous potassium carbonate (38, 6 g, 280 mmols) and dimethyl sulfate (24.6 ml, 258 mmols). The resulting reaction mixture was heated to reflux for 2 hours. The mixture was cooled to room temperature and filtered. The filtered solids were washed with acetone, and the combined organic filtrates were concentrated. The resulting brownish-colored oil was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain the title compound as a brown oil (38 g). Analysis by RP-HPLC indicated that the crude methyl obtained methyl 3-bromo-2,5-dichloro-6-methoxybenzoate was 85% pure and contained excess dimethyl sulfate.
[0177] This can be purified by vacuum distillation. The methyl 3-bromo-2,5-dichloro-6-methoxybenzoate crude (38 g) was placed in a flask and heated to 50 ° C. A short Vigreux column and a distillation head were connected to the system and a vacuum (~ 2-3 mm Hg) was applied. The mixture was heated to 100 ° C to remove the first excess methyl sulfate, and then heated to 180 ° C. The fractions were collected at the same time that the oil remaining in the flask was heated from 180 ° C to 270 ° C. The RP-HP LC and 1H NMR analysis indicated that the almost colorless distilled oil was the desired product of methyl 3-bromo-2,5-dichloro-6-methoxybenzoate (31 g, 88%) with 81% purity. 1H-NMR (600 MHz, CDCl3) δ 7.3 (s, 1H), 4.0 (s, 3H), 3.9 (s, 3H) .Example 23: Preparation of methyl 2,5-dichloro-6 -methoxybenzoate

[0178] 3-Bromo-2,5-dichloro-6-methoxybenzoate with a purity of 81% by RP-HPLC (5.0 g, 15.9 mmol) and 5% Pd / C (50% water content, 1.0 g) in a two-phase solvent mixture consisting of isopropyl acetate (17 ml) and water (4 ml) were loaded into a 100 ml round bottom flask. The mixture was placed under vacuum (25 to 30 mmHg), followed by purging with hydrogen. The mixture was hydrogenated (1 atm) with vigorous stirring at room temperature for 1.5 hours. After consuming 3-bromo-2,5-dichloro-6-methoxy-benzoate (monitored by RP-HPLC), the catalyst was filtered and washed with water (5 ml) and ethyl acetate (25 ml). The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, to generate crude methyl 2,5-dichloro-6-methoxybenzoate as a yellow solid (3 , 5 g, 91%) with a purity of 71%. ESI-MS m / z 235 (M + H).
[0179] Examples 24 to 27 describe the preparation of 3,6-dichloro-2-hydroxybenzoic acid (which can be further converted to dicamba) from 5-bromo-3-chloro-2-hydroxybenzaldehyde as illustrated in the diagram shown below:
Example 24: Preparation of 5-bromo-3-chloro-2-hydroxybenzaldehyde
[0180] 5-Bromo-2-hydroxybenzaldehyde (5.0 g, 24.9 mmol) was dissolved in acetic acid (100 ml). The chlorine gas was continuously bubbled into the solution with stirring for 4 hours at room temperature. The acetic acid was largely removed in vacuo and the solids were partitioned in water (100 ml) and ethyl acetate (100 ml). The organic layer was washed with water (1 x 50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the title compound (5.4 g, 93%). Analytical data for 5-bromo-3-chloro-2-hydroxybenzaldehyde: 1H (300 MHz, CDCl3) 11.20, 9.84, 7.7, 7.6. Example 25: Preparation of 3-Bromo-2,5-dichloro-6-hydroxybenzaldehyde
[0181] 5-Bromo-3-chloro-2-hydroxybenzaldehyde (2.0 g, 8.5 mmol) was dissolved in oleum (20%, 50 ml). Iodine (0.03 g, 0.12 mmol) was added and the resulting solution was stirred at 35 ° C for 24 hours, while the chlorine gas was bubbled into the solution. The reaction mixture was poured onto crushed ice (about 100 g), and the resulting suspension was extracted with ethyl acetate (3 x 100 ml). After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to generate the title product (1.7 g, 73%). Analytical data for 3-bromo-2,5-dichloro-6-hydroxy-benzaldehyde: 1H NMR (300 MHz, DMSO-d6) 12.2, 10.3, 8.2. Example 26: Preparation of 3,6-Dichloro-2-hydroxybenzaldehyde
[0182] 3-Bromo-2,5-dichloro-6-hydroxy-benzaldehyde (1.0 g, 3.7 mmol), potassium acetate (0.38 g, 3.9 mmol) and Pd / C (5 %, 0.1 g) were added to acetic acid (25 ml). After the system was purged under vacuum, the mixture was stirred under hydrogen (1 atm) for 18 hours. The reaction mixture was filtered over celite and the acetic acid was largely removed in vacuo. The solids were partitioned between ethyl acetate (25 ml) and water (25 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title product as a yellow solid (0.46 g, 65%). Analytical data for 3,6-dichloro-2-hydroxybenzaldehyde: 1H NMR (300 MHz, DMSO-d6) 12.1, 10.3, 7.8, 7.1. Example 27: Preparation of 3,6-Dichloro-2-hydroxybenzoic acid
[0183] 3,6-Dichloro-2-hydroxybenzaldehyde (0.050 g, 0.26 mmol), sulfamic acid (0.035 g, 0.37 mmol) and sodium dihydrogen phosphate (0.12 g, 1.0 mmol) were dissolved in a mixture of dioxane (2 ml) and water (1 ml). The mixture was cooled to 0 ° C and sodium chlorite trihydrate (0.04 g, 0.3 mmol) in water (0.2 ml) was added. The cooling bath was removed, and the mixture was stirred for one hour at room temperature. The solvents were largely removed in vacuo and the concentrate was diluted with water (10 ml). The pH of the solution was adjusted to pH = about 1 with concentrated hydrochloric acid and was extracted with ethyl acetate (2 x 10 mL). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated to generate the title product as an off-white solid (0.047 g, 88%). Analysis of RP-HPLC and 1 H NMR confirmed that the material obtained was 3,6-dichloro-2-hydroxybenzoic acid.
[0184] All references (patent and non-patent) mentioned above are incorporated by reference in this patent application. The discussion of these references is only intended to summarize the statements made by their authors. No admission is made that any reference (or a portion of any reference) is relevant prior art (or prior art as a whole). Applicants reserve the right to challenge the accuracy and relevance of the references cited.

权利要求:
Claims (15)
[0001]
1. Process for the preparation of a compound corresponding in structure to Formula (III):
[0002]
2. Process according to claim 1, characterized by the fact that the chlorinating agent is chlorine gas.
[0003]
3. Process according to claim 1 or 2, characterized by the fact that the reaction medium comprises a sulfuric acid, oleum or mixture thereof.
[0004]
Process according to any one of claims 1 to 3, characterized by the fact that the compound or salt of Formula (II) is brought into contact with the chlorinating agent in the presence of a catalytic amount of iodine.
[0005]
5. Process according to any one of claims 1 to 4, characterized by the fact that the process further comprises selectively de-combining the compound or salt of Formula (III) to provide a corresponding compound in structure to Formula (IV):
[0006]
6. Process according to any one of claims 1 to 5, characterized by the fact that it further comprises: contacting a corresponding compound in the structure with Formula (I):
[0007]
7. Process according to claim 6, characterized by the fact that it further comprises: contacting a compound or salt of formula (VI):
[0008]
8. Process according to any one of claims 1 to 5, characterized by the fact that it further comprises: contacting a corresponding compound in the structure with Formula (I):
[0009]
Process according to any one of claims 5 to 8, characterized by the fact that R1 is different from methyl and / or R2 is different from hydrogen; and the process further comprises converting the compound or salt of Formula (IV) to a compound corresponding in structure to Formula (V):
[0010]
Process according to any one of claims 5 to 8, characterized by the fact that R1 and R2 are both hydrogen and the process further comprises: methylation of a compound corresponding in structure to the formula (IV-1):
[0011]
11. Process according to any one of claims 1 to 10, characterized by the fact that R1 and R2 are both hydrogen and the process further comprises: selectively de-bromine a compound corresponding in structure to Formula (III-1):
[0012]
12. Process according to any one of claims 1 to 10, characterized by the fact that R1 and R2 are both hydrogen and the process further comprises: contacting a corresponding compound in the structure of Formula (III-1):
[0013]
13. Process for the preparation of a compound corresponding in structure to formula (V):
[0014]
14. Process according to claim 13, characterized by the fact that R1 is hydrogen and the process further comprises: methylation of the compound or salt of Formula (IV-1) to provide a corresponding compound in structure of Formula (IV-2) :
[0015]
15. Process according to claim 13, characterized by the fact that R1 is hydrogen and the process further comprises selectively methylating the Formula (IV-1) compound or salt to provide the Formula (V) compound or salt.

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Lewis et al.2009|Unexpected formation of 10-iodo-and 10-chlorocamphor under halosulfonylation conditions, and convenient routes to 10-chloro-and 10-bromocamphor

---

JP6912143B2|2021-07-28|4-Pentafluorothiophenol compounds and preparation method and preparation method of pentafluorosulfur-substituted benzopyran compound

---

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---

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---

JP2008031085A|2008-02-14|Method for production of 2-naphthol derivative

---

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---

Zhao et al.2021|Deoxyfluorination of Carboxylic, Sulfonic, Phosphinic Acids and Phosphine Oxides by Perfluoroalkyl Ether Carboxylic Acids Featuring CF2O Units

---

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---

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---

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---

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---

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---

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---

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---

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---

JPH0977719A|1997-03-25|Production of alkoxybiphenylcarboxylic acid derivative

---

JPH0952863A|1997-02-25|Production of alkoxynaphthalenecarboxylic acid derivative

---

CA1094107A|1981-01-20|Process for the preparation of substituted benzohydrols

同族专利:

---

公开号 | 公开日

---

BR112016028370A2|2017-08-22|

---

CN106659162A|2017-05-10|

---

WO2015187774A8|2016-02-04|

---

US20200181055A1|2020-06-11|

---

US20170190648A1|2017-07-06|

---

US10519092B2|2019-12-31|

---

CN112299983A|2021-02-02|

---

US9856201B2|2018-01-02|

---

ES2757074T3|2020-04-28|

---

EP3151670A4|2018-02-21|

---

CN106659162B|2020-10-27|

---

US20180155265A1|2018-06-07|

---

WO2015187774A1|2015-12-10|

---

EP3151670A1|2017-04-12|

---

EP3151670B1|2019-10-02|

---

US10807936B2|2020-10-20|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US3013054A|1958-08-04|1961-12-12|Velsicol Chemical Corp|2-methoxy-3, 6-dichlorobenzoates|

---

US3062877A|1959-11-02|1962-11-06|Velsicol Chemical Corp|Production of 3, 5, 6-trichlorosalicylic acid|

---

US3444192A|1961-04-17|1969-05-13|Hooker Chemical Corp|Process for preparing alkoxychlorinated benzoic acids|

---

US3345157A|1966-09-12|1967-10-03|Velsicol Chemical Corp|Herbicidal composition and method|

---

US3728403A|1968-09-09|1973-04-17|Velsicol Chemical Corp|Process for preparing 2,5-dichloro-4-bromophenol|

---

US3969403A|1973-06-22|1976-07-13|Celamerck Gmbh & Co. Kg|Process for preparation of 2-methoxy-3,6-dichloro-benzoic acid|

---

DE2331712A1|1973-06-22|1975-01-23|Celamerck Gmbh & Co Kg|PROCESS FOR THE PREPARATION OF 2METHOXY-3,6-DICHLOROBENZOIC ACID|

---

US4161611A|1976-02-23|1979-07-17|Veesicol Chemical Corporation|Process for the production of 2-methoxy-3,6-dichlorobenzoic acid|

---

US4232172A|1977-03-05|1980-11-04|Celamerck Gmbh & Co. Kg|Process for the preparation of 3,6-dichloro-salicyclic|

---

US4308395A|1980-07-11|1981-12-29|American Cyanamid Company|Processes for preparing 3,5,6-trichlorosalicylic acid and esters thereof|

---

US5194666A|1992-07-30|1993-03-16|American Cyanamid Company|Process for preparing esters of 3,5,6-trichlorosalicyclic acid|

---

US5442092A|1994-04-04|1995-08-15|Jame Fine Chemicals, Inc.|Preparation of esters of 3,5,6-trichlorosalicyclic acid|

---

AU2274795A|1994-04-08|1995-10-30|Degussa A.G.|Herbicidal bicyclic and tricyclic imides|

---

US5886210A|1996-08-22|1999-03-23|Rohm And Haas Company|Method for preparing aromatic compounds|

---

IL135632A|1997-10-16|2005-03-20|Fmc Corp|Process and intermediates for the preparation of a triazoline herbicide|

---

WO2003016286A1|2001-08-17|2003-02-27|Sankyo Agro Company, Limited|3-phenoxy-4-pyridazinol derivative and herbicide composition containing the same|

---

DE10335726A1|2003-08-05|2005-03-03|Bayer Cropscience Gmbh|Use of hydroxyaromatics as safener|

---

US7626021B2|2004-07-27|2009-12-01|Sgx Pharmaceuticals, Inc.|Fused ring heterocycle kinase modulators|

---

US7709645B2|2004-07-27|2010-05-04|Sgx Pharmaceuticals, Inc.|Pyrrolo-pyridine kinase modulators|

---

CN1830942A|2006-03-27|2006-09-13|江苏生花农药有限公司|Improved alkylation process for producing Mediben|

---

GB0819205D0|2008-10-20|2008-11-26|Syngenta Ltd|Novel herbicides|

---

WO2010054954A1|2008-11-13|2010-05-20|Basf Se|Process for manufacturing 5-chloromethyl-2,3-pyridine dicarboxylic acid anhydrides|

---

CN102125035B|2010-12-13|2013-07-31|上海力智生化科技有限公司|Preparation process of herbicide dicamba|

---

EP2852439A1|2012-05-23|2015-04-01|Stemergie Biotechnology SA|Inhibitors of the activity of complex of the mitochondrial electron transport chain and use thereof|

---

CN102838483A|2012-09-20|2012-12-26|山东潍坊润丰化工有限公司|Synthesis method of dicamba|

---

CN102942474B|2012-11-26|2015-07-08|江苏优嘉化学有限公司|Synthetic process of herbicide dicamba|

---

ES2757074T3|2014-06-04|2020-04-28|Monsanto Technology Llc|3,6-Dichlorosalicylic Acid Compounds and Related Synthetic Procedures|ES2757074T3|2014-06-04|2020-04-28|Monsanto Technology Llc|3,6-Dichlorosalicylic Acid Compounds and Related Synthetic Procedures|

---

CN109761786A|2017-11-09|2019-05-17|山东润博生物科技有限公司|A kind of preparation method of dicamba|

---

CN109761791A|2017-11-09|2019-05-17|山东润博生物科技有限公司|A kind of preparation method of dicamba methyl esters|

---

CN109761781A|2017-11-09|2019-05-17|山东润博生物科技有限公司|A kind of preparation method of dicamba|

---

CN109761758A|2017-11-09|2019-05-17|山东润博生物科技有限公司|A kind of synthetic method of 3,6- dichlorosalicylic acid|

---

CN109761802A|2017-11-09|2019-05-17|山东润博生物科技有限公司|A kind of preparation method of dicamba|

---

CN109763138A|2017-11-09|2019-05-17|山东润博生物科技有限公司|A kind of preparation method of 3,6- dichlorosalicylic acid|

---

CN109761788A|2017-11-09|2019-05-17|山东润博生物科技有限公司|The preparation method of the bromo- 3,6- dichlorobenzoic acid of 2- and the preparation method of dicamba|

---

CN109761787A|2017-11-09|2019-05-17|山东润博生物科技有限公司|The preparation method of the chloro- 2 bromo toluene of 3,6- bis- and the preparation method of dicamba|

---

CN109761805A|2017-11-09|2019-05-17|山东润博生物科技有限公司|A kind of preparation method of dicamba methyl esters|

---

CN109761806A|2017-11-09|2019-05-17|山东润博生物科技有限公司|A kind of continuous production technology of dicamba methyl esters and its missible oil|

---

CN109761745A|2017-11-09|2019-05-17|山东润博生物科技有限公司|A kind of selectively removing method of phenyl ring hydroxyl contraposition bromine and the preparation method of dicamba|

---

CN109761794A|2017-11-09|2019-05-17|山东润博生物科技有限公司|A kind of salicylic complete alternation method in 3,6- dichlorosalicylic acid preparation process|

---

CN109761789A|2017-11-09|2019-05-17|山东润博生物科技有限公司|A kind of preparation method of 3,6- dichlorosalicylic acid|

---

CN109761780A|2017-11-09|2019-05-17|山东润博生物科技有限公司|A kind of preparation method of dicamba|

---

CN108250060B|2018-01-26|2021-10-15|江苏尚莱特医药化工材料有限公司|Synthesis method of 5-bromo-2-chlorobenzoic acid|

法律状态:
2019-08-27| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|

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2020-12-29| B09A| Decision: intention to grant|

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2021-03-09| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 03/06/2015, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

---

申请号 | 申请日 | 专利标题

---

US201462007578P| true| 2014-06-04|2014-06-04|

---

US62/007,578|2014-06-04|

---

US201462042068P| true| 2014-08-26|2014-08-26|

---

US62/042,068|2014-08-26|

---

US201562111303P| true| 2015-02-03|2015-02-03|

---

US62/111,303|2015-02-03|

---

PCT/US2015/033894|WO2015187774A1|2014-06-04|2015-06-03|3,6-dichlorosalicylic acid compounds and related synthetic processes|

---