Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
  • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
  • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
  • C07C303/42—Separation; Purification; Stabilisation; Use of additives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
  • C07C311/51—Y being a hydrogen or a carbon atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

• the invention relates to a process for the preparation of acylsulfamoylbenzamides, in particular the invention relates to an improved process for the preparation of A / - [4- (cyclopropylcarbamoyl) phenylsulfonyl] -2-methoxybenzamide.
• a / - [4- (cyclopropylcarbamoyl) phenylsulfonyl] -2-methoxybenzamide (or alternatively: A / - [4- (cyclopropylcarbamoyl) phenylsulfonyl] -o-anisamide) is also referred to by the common name cyprosulfamide. Cyprosulfamide is used in agriculture
• a safener serves to improve the selectivity of
• the term selectivity refers to the crop compatibility of a herbicide.
• WO 99/16744 discloses acylsulfamoylbenzamide derivatives and their preparation and use as safeners. However, the methods of preparation disclosed in WO 99/16744 relate to the laboratory scale and have not been found to be particularly suitable for the industrial preparation of the compounds.
• Document CN 101 838 227 A discloses constitutional isomers of cyprosulfamides and an alternative process for their preparation.
• Another two-stage process which includes the production of a for the
• the template contains the two starting materials, i. the amide chloride of the formula (II) and the secondary amine of the formula RRNH during the course of the reaction aqueous alkali metal hydroxide solution
• reaction is not possible. Without organic solvents, the reaction mixture forms a solid barely stirrable block, since massively little liquid amine meets much solid amide chloride. Out of ecological and out
• the undesired acid of amide chloride (II) is 4 - [[(2-methoxybenzoyl) amino] sulfonyl] benzoic acid, which forms the corresponding salt in the presence of alkliions (Na ions or K ions).
• This salt does not react sufficiently with the secondary amine of the formula RRNH to the end product. This leads to high yield losses.
• the object of the invention is to provide an improved alternative process for the preparation of Acylsulfamoylbenzamiden, the alternative method should be characterized by high robustness at the same time high yields.
• R 3a is selected from the group consisting of hydrogen and the
• radicals (C 1 -C 6 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) -alkynyl, (C 1 -C 6 ) -alkoxy, (C 2 -C 6 ) -alkenyloxy, - (CH 2) p-heterocyclyl, each of which is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, (Ci-C 4 ) alkoxy and (Ci-C 4 ) alkylthio, or
• R 3a and R 3b together with the connecting nitrogen atom form a 3- to 8-membered, saturated or unsaturated ring by reacting a compound of the formula (II)
• the process according to the present invention is based on the use of water as a solvent according to the above-mentioned option III, wherein the reaction template in the process according to the invention contains no alkali metal hydroxide solution.
• the method according to the invention is therefore characterized by the fact that water and no organic solvents are used as the solvent.
• the amount of amine remaining is preferred during the reaction
• Cyprosulfamides can be attenuated to an unexpected extent.
• the avoidance or weakening of the hydrolysis reaction is advantageous because it prevents the formation of 4 - [[(2-methoxybenzoyl) amino] sulfonyl] benzoic acid (present as reaction-inert salt due to the presence of alkali ions in the reaction solution) and so in the consequence the achievement of higher
• the invention thus relates to the optimization of the yield and the improvement of the robustness of the process. Due to the comparatively large quantities of industrial products in industrial production is already only one
• (C 1 -C 6) -alkyl where the alkyl radical is branched or unbranched and is unsubstituted or substituted by one or more substituents selected from the group consisting of (C 1 -C 4 ) -alkoxy or (C 3 -C 7) -cycloalkyl .
• (C 1 -C 6) -haloalkyl in which the alkyl radical is unsubstituted or substituted by one or more substituents selected from the group consisting of fluorine, chlorine, bromine and iodine,
• (C3-C7) -cycloalkyl where the cycloalkyl is unsubstituted or substituted by one or more substituents selected from the group consisting of (Ci-C 4) -alkyl or (C3-C7) - existing or cycloalkyl (Ci-C 4) -alkoxy Group, is substituted,
• (C 1 -C 6) -alkoxy where the alkoxy radical is branched or unbranched and is unsubstituted or substituted by one or more substituents selected from the group consisting of (C 1 -C 4 ) -alkoxy or (C 3 -C 7) -cycloalkyl .
• (C3-C7) cycloalkylthio said cycloalkylthio radical is unsubstituted or is substituted by one or more substituents selected from the group consisting of (Ci-C 4) -alkyl or (Ci-C 4) -alkoxy existing group.
• R 1a is selected from the group consisting of unsubstituted (C 1 -C 4 ) -alkoxy radicals and R 1 b to R 1e and R 2a to R 2d are each hydrogen.
• R 1a is methoxy (-O-CH 3)
• R 1 b to R 1 e and R 2a to R 2d are each hydrogen.
• Most preferred is a process for the preparation of compounds of formula (Ia) wherein
• R 1a is methoxy (-O-CH 3) and R 1 b to R 1 e and R 2a to R 2d are each hydrogen, and in which
• R 3a R 3b NH is the radical R 3a is cyclopropyl and R 3b is hydrogen.
• R 1 b to R 1e and R 2a to R 2d are each hydrogen.
• the pH of the template at the beginning of the reaction is at most 1 1, 5 (pH ⁇ 1 1, 5). This is achieved by the introduction of an appropriate amount of the amine of formula R 3a R 3b NH in water, only after this initial pH adjustment in the
• the addition of the solid amide chloride, ie the educt of the formula (II), to the aqueous amine solution which forms the reaction template can be quantitative.
• Particularly preferred is the one about Period of about 4 hours extending addition in 20 to 30 steps (portions).
• the first addition step concerns the amine addition at the beginning of the reaction, with the aim of adjusting the pH in the reaction mixture to pH ⁇ 1 1, 5.
• the addition of the remaining amount of the amine of the formula R 3a R 3b NH takes place either in one step (2-stage amine addition) or in several steps (at least 3-stage amine addition).
• the addition of the remaining amount of the amine of the formula R 3a R 3b NH in several steps also includes the metered addition of the amine in very small amounts, for example by adding the amine to
• Reaction mixture using one or more supply lines.
• Very particularly preferred in the industrial production is the continuous addition of the amine in very many steps, e.g. by the pH-controlled dropwise addition or the pumping of the amine to the reaction mixture.
• the pH-controlled addition of the amine of formula R 3a R 3b NH to the reaction mixture in the context of at least 3-stage amine addition is preferably to 1, 1 equivalents, based on the amount of amide chloride (acid chloride) submitted, are reached.
• the subsequent pH-controlled addition of amine takes place by dropwise addition or by pumping.
• the pH-controlled addition of the amine of formula R 3a R 3b NH to the reaction mixture is preferably carried out so that the pH during the addition in the further
• Carboxylic acid formation and at pH 13 are already about 5% of the amide chloride of the formula (II) as a carboxylic acid. This causes an undesirable reduction in the yield of the product of formula (Ia).
• a base selected from the group consisting of NaOH, KOH, Ca (OH) 2 and the group of tertiary amines, in particular triethylamine, provided for the regulation of the pH in the reaction mixture (pH regulation), wherein the pH of the reaction mixture should be stabilized by the addition of the base in the range of 8 to 10.
• pH regulation the regulation of the pH in the reaction mixture
• a drop in the pH below the pH 8 should be avoided, i. the pH desired by adding NaOH to complete the reaction is> 8.
• the additional base selected from the group consisting of NaOH, KOH, Ca (OH) 2 and the group of tertiary amines is therefore not added to the reaction template, but the additional base is added to the reaction mixture, which already contains the desired educt.
• a base selected from the group consisting of NaOH, KOH, Ca (OH) 2 and the group of tertiary amines is carried out during the reaction, preferably after complete addition of the amine and after addition of 20% of the amide chloride.
• the addition of the base also as a final addition, ie after complete addition of the amide chloride.
• radicals R 1a to R e 1 and the radicals R 2a to R 2d are each independently selected from the group consisting of
• (C 1 -C 6) -alkyl where the alkyl radical is branched or unbranched and is unsubstituted or by one or more substituents selected from among (C 1 -C 4 ) -
• (C 3 -C 7) -cycloalkyl where the cycloalkyl radical is unsubstituted or by one or more substituents selected from among (C 1 -C 4 ) -alkyl or (C 3 -C 7) -
• (C 1 -C 6) -alkoxy where the alkoxy radical is branched or unbranched and is unsubstituted or substituted by one or more substituents selected from the group consisting of (C 1 -C 4 ) -alkoxy or (C 3 -C 7) -cycloalkyl .
• Aprotic polar (dipolar) solvents are chemical compounds that are distinguished by the fact that they do not split protons and are also polar.
• carboxylic acid esters in the literature in spite of their polarity, are also assigned in part to the group of aprotic nonpolar solvents. In the context of the present invention, it is therefore stated for reasons of clarity that in the case of the present invention, carboxylic acid esters, in particular the esters of the
• Propionic acid and acetic acid e.g. Isopropyl acetate
• chlorobenzene despite its high dipole moment, is hydrophobic in water and thus hardly soluble, i. Chlorobenzene is nonpolar. Toluene also belongs to the group of nonpolar solvents.
• aprotic polar compounds which are suitable as solvents according to the invention must be chemically stable and distillable and should also have a molecular weight (molecular weight) of less than 200. Due to the upper limit of the molecular weight, these solvents are characterized by a comparatively low boiling point. Thus, an upper limit for the reaction temperature is determined at the same time by the selection of the solvents in question. This upper temperature limit also acts as a safety function and represents an additional advantage in the implementation of the manufacturing process on a technical and industrial scale in terms of reaction.
• the above table compares the solvent used according to the invention isopropyl acetate with the solvents toluene and chlorobenzene in a uniform Use of thionyl chloride as a chlorinating agent and in each case several hours reaction time and in a narrow range reaction temperatures.
• Reaction time significantly reduces the yield of the reaction. Only experiment B1 is an exception and does not confirm that a reduction of the yield must be expected even after just one hour of stirring.
• Example A1 is comparatively low when using isopropyl acetate as a solvent and the yield is nevertheless more than 90%, namely 91.4%.
• the yield using the solvents toluene and chlorobenzene in both cases is less than 90%, namely 88.7% (experiment B3) and 84.8% (experiment C3), with no stirring in the last two experiments , Is when using the solvents toluene and
• isopropyl acetate is advantageous in two respects and enables a robust process that is particularly suitable and advantageous for industrial use due to the potential savings of various resources for economic reasons.
• inventive method is preferred.
• Preferred aprotic polar solvent classes are open-chain ketones, cyclic ketones, esters, amides, nitriles or ethers, which are each unsubstituted or substituted, wherein the respective solvent molecules are unsubstituted or substituted by one or more substituents selected from
• reaction of the educts of the formula (III) and the formula (IV) is preferably carried out in a mixture of aprotic polar solvents having a molecular weight of less than 200 in each case, the mixture being at least two or more
• Solvents selected from the group consisting of cyclohexanone,
• reaction of the educts of the formula (III) and of the formula (IV) is particularly preferably carried out exclusively in a specific solvent, the
• Solvent is selected from the group consisting of cyclohexanone,
• the reaction of the educts of the formula (III) and the formula (IV) does not take place in only one specific aprotic polar solvent but in a mixture of different solvents.
• the solvent composition contains at least two solvents, each
• cyclohexanone methyl isobutyl ketone, di-isobutyl ketone, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate,
• the reaction of the starting materials of the formula (III) and the formula (IV) is carried out in a solvent which is selected from the group of Carboxylic acid ester or in a solvent composition having at least two selected from the group of carboxylic acid esters solvents.
• isopropyl acetate is used as the solvent, the compound of the formula (II) can be prepared by reacting the educts of the formula (III) and the formula (IV) with particularly good yield and good quality.
• chlorinating agent used in the reaction. This is in the interest of the environment and is also significant for cost reasons.
• any chlorinating agent known to the person skilled in the art as chlorinating agent can be used as the chlorinating agent in connection with the process according to the invention, it also being conceivable for a mixture consisting of a plurality of different chlorinating agents to be used.
• Preferred chlorinating agents are selected from the group of sulfur or phosphorus based chlorinating agents. These include thionyl chloride,
• Chlorinating agents such as oxalyl chlorides or phosgene.
• the latter are useful to convert a carboxylic acid to a corresponding acid chloride.
• chlorinating agents are CI 2, SO 2 Cl 2, SOCl 2 (thionyl chloride), N-chlorosuccinimide, with the chlorinating agent thionyl chloride being most preferred. Also conceivable is the use of a mixture consisting of at least two of the aforementioned chlorinating agents.
• usable chlorinating agents are silicon tetrachloride, trichloromethylsilane, dichloromethylsilane, trichlorophenylsilane, aluminum trichloride, boron trichloride, titanium tetrachloride, tin tetrachloride, zinc dichloride or bismuth trichloride, or a mixture thereof. It is also possible to use mixtures of halosilanes and aluminum trichloride or zinc dichloride, e.g.
• Chlorine atoms of a chlorinating agent, or chlorinating agent, a Chlorine atoms of a chlorinating agent, or chlorinating agent, a.
• the compounds of the formula (III) and (IV) are used in equimolar amounts.
• reaction temperatures can be varied in carrying out the method according to the invention in the areas specified below. Generally, temperatures are in the range of 20 ° C to 90 ° C. Preferred are Temperatures in the range of 40 ° C to 90 ° C. Particularly preferred are temperatures in the range of 80 ° C to 90 ° C.
• the process according to the invention is generally carried out under normal pressure
• the preferred pressure range for carrying out the reaction according to the invention is between 0.1 bar and 10 bar.
• Cyclopropylamine be submitted at about 20 ° C. (A maximum of 0.10 eq of cyclopropylamine (CPA), i.e., ⁇ 0.10 eq of cyclopropylamine is initially charged
• the suspension is stirred for 30 minutes at 80 ° C. and about pH 6 and then cooled to 20 ° C. to 30 ° C.
• the pH is adjusted to about pH 6 with 10% strength hydrochloric acid.
• the suspension is filtered through a suction filter. The filter cake is washed with water and pressed dry. The solid dried at 45 ° C and less than 50 mbar.
• the yield is 98.7% of theory (content 98.8% (HPLC vs. standard)).

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