Method for recovering saflufenacil from process stream

Abstract

A process for increasing the yield of a process for preparing a compound (I) wherein compound (I) is obtained in the form of dissolution in an organic solvent phase, crystallized and separated from a mother liquor, comprising (I) step I) wherein the mother liquor is extracted with an alkaline buffer solution, the pH is adjusted to between 7 and 10, and compound (I) is extracted into an aqueous phase; and a step II) in which compound (I) is reextracted from the aqueous phase by reducing the pH to less than 6 in the presence of an organic solvent. # imgabs0 #

Description

[0001] The present invention relates to a new and efficient method for producing the herbicide saflufenacil.

[0002] Safensulfuron (Compound (I)) is the compound 2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1-(2H)pyrimidinyl]-4-fluoro-N-[[methyl(1-methylethyl)-

[0003] [Amino]sulfonyl]benzamide is a common name for herbicidal agents that inhibit the plant enzyme protoporphyrinogen oxidase (PPO).

[0004]

[0005] Bensulfuron has been described in WO 2001 / 083459. Other methods for its preparation are described in WO 2003 / 097589, WO 2005 / 054208, WO 2003 / 097589, WO 2006 / 125746 and WO 2008 / 043835. Bensulfuron is particularly useful for pre-planting application and selective pre-emergence weed control in various crops (including corn and soybean). Bensulfuron as described herein also includes different forms of the compound, such as crystalline or granular forms.

[0006] In the final reaction step of the process for preparing saflufenacil, the compound is obtained dissolved in an organic solvent phase. Subsequently, work-up is carried out according to known methods. WO 2008 / 043835 discusses the crystallization of dissolved saflufenacil.

[0007] However, during the post-processing procedures, a portion of the process yield may be lost. Up to 10% of the saflufenacil produced in the final step of the method may remain in the mother liquor after crystallization and be discarded as waste. This leads to increased raw material costs and procedurally laborious waste disposal. "Mother liquor" is a term that generally refers to the liquid or solution that remains after a component is removed by a method such as crystallization and filtration.

[0008] In general, there is a high demand to save raw materials, reduce costs and minimize the environmental impact of chemical processes.

[0009] Therefore, the object of the present invention is to provide an efficient method for increasing the total yield in the method for preparing saflufenacil. In addition, the object of the present invention is to provide an efficient method for recovering saflufenacil from an organic solvent with high yield and high purity. Specifically, the object of the present invention is to provide an efficient method for recovering a portion of compound (I) which remains dissolved in the mother liquor after the product is crystallized from the reaction mixture.

[0010] These and other objects are achieved by the method described below.

[0011] A variety of different synthetic routes are known to the skilled person to prepare compound (I), saflufenacil. Usually, compound (I) is obtained in the form of being dissolved in an organic solvent phase.

[0012] Therefore, the method according to the present invention can be used for post-treatment of any process for preparing saflufenacil (ie compound (I)), wherein compound (I) is obtained in the form of being dissolved in an organic solvent phase.

[0013] Furthermore, the process according to the present invention can be used to separate compound (I) present in a dissolved form in an organic solvent phase from impurities.

[0014] Suitable solvents for these reactions are, depending on the temperature range of the final reaction step, aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, cyclopentane, cyclohexane, toluene, xylene; chlorinated aliphatic and aromatic hydrocarbons, such as dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chlorobenzene, 1,2-, 1,3- or 1,4-dichlorobenzene, chlorotoluene, dichlorotoluene; open-chain dialkyl ethers, such as diethyl ether, di-n-propyl ether, diisopropyl ether, methyl tert-butyl ether; cyclic ethers, such as tetrahydrofuran, 1,4-dioxane, anisole; glycol ethers, such as dimethyl glycol ether, diethyl glycol ether, diethylene glycol dimethyl ether, diethyl diol diethyl ether; C1-C4-alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol; aliphatic C1-C6-alkylcarboxylates, such as methyl acetate, ethyl acetate or n-butyl acetate; ketones, such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, butanone; carbonates, such as diethyl carbonate and ethylene carbonate; N,N-dialkylamides, such as N,N-dimethylformamide or N,N-dimethylacetamide; N-alkyllactams, such as N-methylpyrrolidone; sulfoxides, such as dimethyl sulfoxide; tetraalkylureas, such as tetramethylurea, tetraethylurea, tetrabutylurea, dimethylethyleneurea, dimethylpropyleneurea; or mixtures of these solvents.

[0015] Preferred solvents are N,N-dimethylformamide, N-methylpyrrolidone, acetone, dichloromethane, tetrahydrofuran (THF), toluene, chlorobenzene, methyl acetate, ethyl acetate, butyl acetate or mixtures of these solvents.

[0016] In one embodiment, saflufenacil is obtained by alkylating compound (II), as described in WO 2006 / 125746:

[0017]

[0018] The post-treatment of the reaction mixture to obtain saflufenacil can be carried out by conventional methods for this purpose. Usually, the solvent used is removed by a suitable method (e.g., by distillation). Saflufenacil can then be absorbed in an organic solvent immiscible with water, and any impurities are then extracted using water (if appropriate, acidified water). After phase separation, the organic phase containing the product is dried, and the solvent is removed under reduced pressure. For further purification, common methods such as crystallization, precipitation, or chromatography can be used.

[0019] When compound (I) is crystallized from the organic solvent phase, a wet cake can be obtained by centrifugation. The mother liquor contains residual compound (I) and unreacted compound (II) as well as several organic impurities.

[0020] The mother liquor contains an organic solvent used in the final reaction step for preparing compound (I), such as N,N-dimethylformamide, N-methylpyrrolidone, acetone, dichloromethane, tetrahydrofuran (THF), toluene, chlorobenzene, methyl acetate, ethyl acetate, butyl acetate or a mixture of these solvents, preferably a mixture of tetrahydrofuran (THF) and toluene.

[0021] The concentration of the organic solvent in the mother liquor is >80% [w / w], preferably >90% [w / w].

[0022] The water content of the mother liquor is usually <1% [w / w], preferably <0.5% [w / w], more preferably <0.2% [w / w].

[0023] The concentration of residual compound (I) in the mother liquor is usually between 1% and 8% [w / w], often between 2% and 5% [w / w].

[0024] In addition to compound (I), the mother liquor also contains unreacted compound (II) and organic impurities, such as compounds (IV) and (V):

[0025]

[0026] Furthermore, compound (I) tends to degrade rapidly to compound (VI) over time and at elevated pH (>7):

[0027]

[0028] The rapid degradation of compound (I) to compound (VI) poses a significant challenge to the development of a process for recovering compound (I) from an organic mother liquor in high yield before a significant amount of compound (I) is lost due to degradation. In addition, the process should provide compound (I) with high purity, i.e., without the presence of significant amounts of organic impurities.

[0029] The problem of recovering compound (I) from an organic mother liquor without significant degradation and without significant amounts of unwanted impurities has been addressed by the following process (see Exemplary Scheme 1):

[0030] Step I: Extraction of compound (I) from the organic mother liquor (2) into the aqueous phase (aqueous process stream (3))

[0031] Step II: Stripping of compound (I) from the aqueous process stream (3) into the organic phase (9)

[0032] Step I: Extraction of compound (I) from the organic mother liquor (2) into the aqueous phase (aqueous process stream (3))

[0033] Ia) Preparation of an alkaline buffered aqueous solution (1) for converting a compound (I) into a salt

[0034] In order to extract compound (I) from the organic mother liquor into the aqueous phase, the compound is converted into a salt that is easily soluble in the aqueous phase. This can be achieved by changing the pH to alkaline values ​​by adding a suitable base. Therefore, the organic mother liquor stream (2) is mixed with a base, preferably an alkaline buffered aqueous solution (1).

[0035] Suitable bases for adjusting pH to convert compound (I) into salts are all conventional organic bases and inorganic bases.

[0036] Preferred bases are selected from the group consisting of alkali metal and alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkali metal and alkaline earth metal oxides, such as calcium oxide; alkali metal and alkaline earth metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, zinc carbonate; alkali metal bicarbonates, such as sodium bicarbonate; and also ammonia or tertiary amines, such as triethylamine.

[0037] Particularly preferred bases for adjusting the pH are selected from the group consisting of alkali metal and alkaline earth metal hydroxides, alkali metal and alkaline earth metal carbonates, ammonia and also tertiary amines.

[0038] The most preferred base for adjusting the pH to convert Compound (I) into a salt is an alkaline buffered aqueous solution of Na2CO3 or NH4OH (0.1% to 1% [w / w]).

[0039] In order to prevent the formation of emulsions in the organic phase, it is recommended to add a "density enhancer" to the alkaline buffered aqueous solution. Suitable density enhancers are water-soluble inorganic salts, such as sodium salts, such as Na2CO3, NaCl and Na2SO4; or ammonium salts, such as (NH4)2SO4. In a preferred embodiment, Na2SO4 is used as a density enhancer.

[0040] In one embodiment, the solid density enhancer salt is dissolved in water. In another embodiment, the solution containing the density enhancer salt is prepared by blending a mineral acid solution with a corresponding base solution, such as an aqueous solution of sulfuric acid and sodium hydroxide or ammonia.

[0041] The concentration of the density enhancer in the alkaline buffered aqueous solution (1) should be less than 5% [w / w], preferably between 1% and 3% [w / w].

[0042] The final alkaline buffered aqueous solution (1) for extraction comprises an alkaline buffered aqueous solution and optionally a density enhancer. In one embodiment, the alkaline buffered aqueous solution is charged into a solution of a density enhancer.

[0043] The pH of the alkaline buffered aqueous solution (1) should be above 8, preferably above 9, more preferably above 10, and most preferably 11.

[0044] Ib) Extraction of the salt of compound (I) into an aqueous process stream (3)

[0045] Extraction of the salt of compound (I) from the mother liquor into an aqueous process stream is achieved by mixing the mother liquor (2) with an alkaline buffered aqueous solution (1) and stirring well. The extraction relies on alkaline pH control in the range of 7-10, preferably 7.5 to 9, more preferably 7.8-8.5, to extract substantially all of compound (I) from the mother liquor into the aqueous phase in the form of a salt.

[0046] The weight ratio of the aqueous phase to the organic phase used for extraction (ratio Aq:Org) is between 0.15:1.0 and 1.0:1.0, preferably between 0.6:1 and 0.9:1.

[0047] Compound (I) begins to decompose on a time scale of minutes in the presence of a base. After one hour, up to 100% of compound (I) is degraded to compound (VI) at pH 11. For this reason, the extraction residence time should be as short as possible, and compound (I) extracted into the aqueous phase is back-extracted by lowering the pH in the presence of an organic solvent (see step II below).

[0048] The mixing and separation of the two phases is conveniently accomplished at ambient temperature and pressure. It is advantageous to pre-cool both the organic mother liquor (2) and the alkaline buffered aqueous solution (1) to allow extraction at a temperature between 10° C. and 60° C. Subsequently, the two phases (organic layer (4) and aqueous layer (3)) are separated.

[0049] In order to recover most of the salt of compound (I) in the aqueous process stream (3), the extraction should be carried out in at least two stages, preferably in three stages, more preferably in four stages.

[0050] The extraction is usually achieved by shaking the mother liquor (2) and the alkaline aqueous buffer solution (1) in a suitable container, such as a separatory funnel. The extraction can be performed batchwise, or alternatively in a continuous liquid-liquid extraction manner.

[0051] The extraction and separation should be achieved within a short period of time, so that the extracted aqueous phase comprising compound (I) can be back-extracted by lowering the pH within 30 min, preferably within 15 min, more preferably within 5 min.

[0052] Compound (I) can be extracted from the mother liquor into the aqueous phase in a multi-stage extractor / separator (e.g., Robatel Model LX-204), which allows very short residence times, i.e., less than 30 min, preferably less than 15 min, more preferably less than 5 min. The aqueous phase (alkaline buffered aqueous solution (1)) is fed to the top of the extractor, and the organic phase (mother liquor (2)) is fed to the bottom. Under centrifugal force, the streams mix and separate in each phase of the extractor. The organic phase (4) moves upward to the top discharge port, and the aqueous phase (aqueous process stream (3)) moves downward to the bottom discharge port.

[0053] The target recovery rate of compound (I) from the organic mother liquor (2) is greater than 70%, preferably greater than 80%, most preferably greater than 90%.

[0054] Step II: Re-extraction of compound (I) from the aqueous process stream (3) into the organic phase (9)

[0055] The aqueous process stream (3) obtained in step 1b) can be acidified with a suitable acid to convert the salt into compound (I). Since compound (I) is insoluble in water, it will crystallize from the aqueous stream. Once acidified, compound (I) is stable and can be stored for further use. Compound (I) can be recovered by filtering the aqueous phase, or can be redissolved by adding a suitable organic solvent (as described above), and the resulting solution can be further processed as described below.

[0056] Typically, the aqueous phase obtained in step Ib) is acidified without delay, i.e. the compound (I) extracted into the aqueous process stream (3) is stripped by lowering the pH to below 6, preferably to below 4, more preferably to 1.9 and 2.5, most preferably to 2 in the presence of an organic solvent (preferably corresponding to the original mother liquor (2)).

[0057] The pH of the aqueous process stream is maintained at the desired pH by adjusting the pH during stripping by adding a suitable acid.

[0058] The acidification of the stripping is achieved by adding a suitable acid. Suitable acids are conventional organic and inorganic acids. Examples of inorganic acids are hydrohalic acids and oxyacids, especially hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, phosphonic acid and phosphinic acid. Examples of organic acids are aliphatic and aromatic acids, such as alkylsulfonic acids, arylsulfonic acids, mono-C1-C6-alkyl phosphates, di-C1-C5-alkyl phosphates, monoaryl phosphates, diaryl phosphates, alkylcarboxylic acids, halogenated alkylcarboxylic acids and heterocyclic carboxylic acids, especially methanesulfonic acid, p-toluenesulfonic acid, citric acid, trifluoroacetic acid, acetic acid and proline.

[0059] Preferred acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and acetic acid, with sulfuric acid being particularly preferred.

[0060] The solvent system used for the back extraction is immiscible with water and in which compound (I) has an acceptable solubility. Suitable components of these solvent systems are aliphatic, alicyclic or aromatic hydrocarbons, such as pentane, hexane, cyclopentane, cyclohexane, toluene, xylene; chlorinated aliphatic and aromatic hydrocarbons, such as dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chlorobenzene, 1,2-, 1,3- or 1,4-dichlorobenzene, chlorotoluene, dichlorotoluene; open-chain dialkyl ethers, such as diethyl ether, di-n-propyl ether, diisopropyl ether, methyl tert-butyl ether; cyclic ethers, such as tetrahydrofuran, 1,4-dioxane, anisole; glycol ethers, such as dimethyl glycol ether, diethyl glycol ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether ; C1-C4-alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol; aliphatic C1-C6-alkylcarboxylates, such as methyl acetate, ethyl acetate or n-butyl acetate; ketones, such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, butanone; carbonates, such as diethyl carbonate and ethylene carbonate; N,N-dialkylamides, such as N,N-dimethylformamide or N,N-dimethylacetamide; N-alkyllactams, such as N-methylpyrrolidone; sulfoxides, such as dimethyl sulfoxide; tetraalkylureas, such as tetramethylurea, tetraethylurea, tetrabutylurea, dimethylethyleneurea, dimethylpropyleneurea; or mixtures of these solvents.

[0061] Preferred components of these solvent systems are N,N-dimethylformamide, N-methylpyrrolidone, acetone, dichloromethane, tetrahydrofuran (THF), toluene, chlorobenzene, methyl acetate, ethyl acetate, butyl acetate or mixtures of these components. Particularly preferred for stripping are mixtures of toluene and THF, for example in a ratio of 80:20 [v / v], preferably in a ratio of 90:10 [v / v] or in a ratio of 95:5 [v / v].

[0062] Stripping is usually achieved by mixing the aqueous process stream (3) from step 1b) with the solvent system (5) in a suitable container (e.g. in a separatory funnel) under appropriate stirring and at the desired pH. The desired pH is adjusted by continuous addition of a suitable acid (6). The weight ratio of the aqueous process stream (3) used for stripping to the organic phase (5) (ratio Aq:Org) is between 0.5:1 and 1:0.5, preferably about 1:1.

[0063] Stripping can be carried out in batches, or alternatively in a continuous liquid-liquid extraction. Preferably, stripping is carried out continuously. The residence time of stripping can vary over a wide range, because compound (I) is stable under these conditions. In fact, the approximate residence time in the stripping vessel varies between 20-40min. If stripping is carried out in two continuous containers, the residence time can total 40-80 minutes. The two-phase mixture is then sent to a decanter, where each phase is separated. The organic phase (9) comprises the recovered compounds (I) and (II) and significantly less organic impurities than the mother liquor.

[0064] The target recovery of compound (I) from the aqueous process stream of step Ib) is greater than 90%, preferably greater than 95%, most preferably greater than 99%.

[0065] The organic phase (9) obtained in step II) containing purified compound (I) and unreacted compound (II) can be combined with the reaction mixture in the final step of the process for preparing compound (I), or can be recycled for post-treatment after the final step of the process for preparing compound (I). By recycling the organic phase back to the process for preparing compound (I), the extraction allows for a higher overall yield of the process, lower commodity costs, better solvent recovery, and reduced waste generation.

[0066] The overall target recovery of compound (I) in the mother liquor stream is 75% to 100%, thereby increasing the yield of compound (I) by 7% to 10%.

[0067] An example of a suitable setup for performing steps I and II is described in Scheme 1.

[0068] Example 1:

[0069] Steps I) and II) are carried out at ambient temperature and pressure. The mother liquor comprises THF / toluene as solvent system; Na2SO4 is used as density enhancer.

[0070] In step I, extraction was performed in a centrifugal extractor (Robatel Model LX-204) at an Aq:Org ratio ([w / w]) of 0.75:1 and the pH was adjusted to 8.1.

[0071] In step II, the stripping was carried out as a continuous liquid-liquid extraction, wherein the ratio of Aq:Org ([w / w]) was 1:1, the pH was adjusted to 1.95,

[0072] Table 1: The data provided are the concentrations ([% w / w]) of the components in the process streams as shown in Scheme 1:

[0073] 2 3 4 7 8 9 Compound (I) 3.48 3.94 0.32 1.92 1.92 3.77 Compound (II) 0.10 0.13 Not detected 0.06 0.06 0.12 Compound (IV) 0.61 0.12 0.54 0.06 0.06 0.11 Compound (V) 0.66 0.00 0.69 0.00 0.00 0.00 Compound: (VI) - 0.05 Not detected 0.02 0.02 0.05

[0074] Compounds (I) and (II) are recovered in high yield from the mother liquor (2) in the organic stream (9) and can be recycled to the process for producing compound (I).

[0075] Impurities (IV) and (V) are removed from the process stream. In the process of the present invention, degradation of compound (I) to compound (VI) is prevented.

[0076] Example 2:

[0077] Analogously to Example 1, this method was implemented into the production process of compound (I). Datasets AJ show the results of the individual activities ([% w / w]) of each compound in the relevant process streams (2, 4 and 9):

[0078] Table 2:

[0079]

Claims

1. A method for increasing the yield of a process for preparing compound (I), wherein compound (I) is obtained in the form of being dissolved in an organic solvent phase, crystallized and separated from a mother liquor, the method comprising Step I) wherein the mother liquor is extracted with an alkaline buffer solution, the pH is adjusted to between 7 and 10, and compound (I) is extracted into the aqueous phase; and Step II) wherein compound (I) is stripped from the aqueous phase by lowering the pH to below 6 in the presence of an organic solvent.

2. The method of claim 1, wherein: The organic solvent containing the extracted compound (I) obtained in step (II) is recycled to the process for preparing compound (I).

3. The method according to claim 1 or 2, wherein: The pH of the alkaline buffer solution is between 7.5 and 9.

4. The method according to any one of claims 1 to 3, wherein: The alkaline buffer solution comprises a base selected from the group consisting of alkali metal and alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkali metal and alkaline earth metal oxides, such as calcium oxide; alkali metal and alkaline earth metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, zinc carbonate; alkali metal bicarbonates, such as sodium bicarbonate; and also ammonia or a tertiary amine, such as triethylamine.

5. The method according to any one of claims 1 to 4, wherein: The weight ratio of the alkaline buffer solution to the mother solution is between 0.15:1.0 and 1.0:1.

0.

6. The method according to any one of claims 1 to 5, wherein: The extraction time of step I) is less than 30 min.

7. A method for recovering compound (I) from a mother liquor comprising more than 80% of an organic solvent, compound (I) and optionally compound (II), (IV) or (V), in, Step I) extracting the mother liquor with an alkaline buffer solution, adjusting the pH to between 7 and 10, and extracting compound (I) into the aqueous phase; as well as Step II) Compound (I) is stripped from the aqueous phase by lowering the pH to below 6 in the presence of an organic solvent.

8. The method of claim 7, wherein: The pH of the alkaline buffer solution is between 7.5 and 9.

9. The method according to claim 7 or 8, wherein: The alkaline buffer solution comprises a base selected from the group consisting of alkali metal and alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkali metal and alkaline earth metal oxides, such as calcium oxide; alkali metal and alkaline earth metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, zinc carbonate; alkali metal bicarbonates, such as sodium bicarbonate; and also ammonia or a tertiary amine, such as triethylamine.

10. The method according to any one of claims 7 to 9, wherein: The weight ratio of the alkaline buffer solution to the mother solution is between 0.15:1.0 and 1.0:1.

0.

11. The method according to any one of claims 7 to 10, wherein: The extraction time of step I) is less than 30 min.

12. The method according to any one of claims 7 to 11, wherein: The organic phase obtained in step II contains more than 90% of the compound (I) contained in the organic mother liquor of step I.

13. The method according to any one of claims 7 to 12, wherein: The organic phase obtained in step II contains less than 50% of the compound (IV) contained in the organic mother liquor in step I.

14. The method according to any one of claims 7 to 13, wherein: The organic phase obtained in step II contains less than 80% of the compound (V) contained in the organic mother liquor in step I.

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