Preparation method of [1, 4, 5]-oxadiazepine derivative
By using a phase transfer catalyst and a base in an alcohol solvent, the safety and efficiency problems of DMSO in the preparation of zolinoles are solved, and a more efficient and economical preparation process of zolinoles is achieved.
Patent Information
- Application Number
- CN202380036846.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2022-04-29
- Filing Date
- 2023-04-20
- Publication Date
- 2024-12-17
AI Technical Summary
The method of preparing zolinol esters using dimethyl sulfoxide (DMSO) in the prior art has problems of thermal decomposition, low separation yield, low volume yield and large waste streams, resulting in complex and unsafe methods.
Reactions in alcohol solvents, using phase transfer catalysts and bases, avoiding the use of DMSO, reducing solvent exchange and inorganic waste, and using a more economical method for reactions and product crystallization.
It achieves higher safety, yield and economy, avoids the use of thermal instability and toxic substances, and simplifies the process flow.
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Figure CN119156378A_ABST
Abstract
Description
[0001] The present invention relates to a novel method for preparing [1,4,5]-oxadiazepine derivatives and use of the derivatives as intermediates in preparing tetrahydropyrazoledione-type herbicides.
[0002] Pinoxaden ([8-(2,6-diethyl-4-methylphenyl)-7-oxo-1,2,4,5-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-9-yl]2,2-dimethylpropionate) is a well-known grass herbicide. The current commercial process for preparing pinoxaden involves the preparation of diacetyloxadiazepine as a key intermediate. (DAODA).
[0003] DAODA is usually prepared by reacting diacetylhydrazine (DAH) and dichloroethyl ether (DCEE) in the presence of dimethyl sulfoxide (DMSO). This is described in WO 03 / 051853A1.
[0004] However, the use of DMSO has a large number of technical problems associated therewith. Due to the thermal decomposition of DMSO, low separation yield, low volumetric yield and a large amount of waste streams, there are significant process safety issues. Due to the need for at least three distillation steps and different solvents for reaction and crystallization, the method has a high level of complexity and cost as a whole.
[0005] Therefore, a method for solving the above technical problems is needed.
[0006] Therefore, the present invention provides a method for preparing a compound of formula (I):
[0007]
[0008] The method includes making
[0009] R 1 -C(O)-NH-NH-C(O)-R 2 With R 3 -CH2-CH2-O-CH2-CH2-R 4
[0010] reacting in the presence of an alcohol solvent;
[0011] Where R 1 and R 2 are independently selected from straight or branched alkyl groups, or are bonded to form a 4-, 5- or 6-membered heterocyclic ring, and
[0012] Where R 3 and R 4 Independently selected from halides or sulfates.
[0013] The claimed method provides significant advantages for the use of DMSO, as it does not suffer from thermal instability leading to potential major accident hazards, and can therefore be safely operated at higher process concentrations. It also avoids the highly toxic combination of DCEE / DMSO. In addition, the method is able to remove solvent exchange from the method, as the process solvent can be used for both the reaction and the crystallization of the product. Coupled with the reduction of inorganic waste and solvent waste, the method is more economical than methods known in the art.
[0014] Preferably, R 1 and R 2 R is independently selected from straight chain alkyl groups, preferably having a chain length of 1 to 4 carbons, even more preferably selected from methyl or ethyl. 1 and R 2 They may all be methyl.
[0015] In an alternative preferred embodiment, R 1 and R 2 bonded to form a 5-membered heterocyclic ring derived from pyrazolidine (ie, R 1 and R 2 represents the same CH2 moiety).
[0016] Optionally, the ring may have one or more carbonyl groups. Preferably, the ring comprises two carbonyl groups to form a pyrazolidinedione derivative, even more preferably the carbonyl groups are at positions 3 and 5. The ring may be substituted in any manner, for example the ring may have a phenyl substituent (e.g. at position 4), which itself may be substituted.
[0017] Preferably, R 3 and R 4 are independently selected from methylsulfonyl (e.g., 2-(2-methylsulfonyloxyethoxy)ethyl methanesulfonate), chloro and / or bromo; most preferably, R 3 and R 4 It is chlorine (DCEE).
[0018] Solvent system
[0019] The alcohol solvent may be a polyol or a monool, preferably a monool. Advantageously, the alcohol is C 1-7 Alcohols (e.g. methanol), such as C 2-6 Alcohol (eg ethanol). The alcohol may be a straight chain alcohol or a branched chain alcohol.
[0020] Most advantageously, the solvent is selected from butanol, pentanol (such as n-pentanol and / or isopentanol) or 2-methoxyethanol, preferably butanol (such as n-butanol).
[0021] The optimal solvent for the methods described in this article must:
[0022] 1) chemically compatible with the process (i.e. thermally stable);
[0023] 2) High polarity for rate enhancement;
[0024] 3) Provide good solubility of base and DAH salt;
[0025] 4) can be soaked in water (which is advantageous as a single solvent for reaction and crystallization); and
[0026] 5) Considering the reaction temperature of 115°C to 125°C, it has an appropriate boiling point.
[0027] Surprisingly, it was found that n-butanol exhibits all of the above criteria (1) to (5).
[0028] Phase transfer catalyst
[0029] Advantageously, the process is carried out in the presence of a phase transfer catalyst (PTC) in order to increase the speed of the reaction.
[0030] Preferably, the PTC is
[0031] 1) Nucleophilic catalyst;
[0032] 2) ammonium catalyst; or
[0033] 3) Phosphonium catalyst.
[0034] When the PTC is a nucleophilic catalyst, it is preferably selected from 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and / or 4-dimethylaminopyridine (DMAP).
[0035] When the PTC is an ammonium catalyst, it preferably has the formula R a R b R c NX, where R a , R b and R c are independently selected from alkyl, substituted alkyl and phenyl groups, and X is selected from halide, hydroxide or sulfate.
[0036] More preferably, it is selected from tetramethylammonium chloride (TMAC), tetrabutylammonium bromide (TBAB), N-methyl-N,N,N-trioctylammonium chloride (ALIQUAT 336), trimethylamine hydrochloride (TMA HCl) and / or 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6).
[0037] When the PTC is a phosphonium catalyst, it preferably has the structure R a R bR c PX, where R a , R b and R c are independently selected from alkyl, substituted alkyl and phenyl groups, and X is selected from halide, hydroxide or sulfate.
[0038] More preferably, it is selected from (methoxymethyl)triphenylphosphonium chloride (MMTPPCl), formylmethyltriphenylphosphonium chloride (FMTPPCl), n-butyltriphenylphosphonium chloride (BuTPPCl), benzyltriphenylphosphonium chloride (benzylTPPCl), tetraphenylphosphonium bromide (TPPBr), n-propyltriphenylphosphonium bromide (PrTPPBr), tetrabutylphosphonium hydroxide (TBPOH), tri(n-hexyl)tetradecylphosphonium chloride (THTDPCl), tetra(hydroxymethyl)phosphonium chloride (THMPCl), tetrabutylphosphonium bromide (TBPBr), triphenylphosphine (TPP), tributyltetradecylphosphonium chloride (TBTDPCl) and tetrabutylphosphonium chloride (TBPCl).
[0039] The PTC is preferably 1,4-diazabicyclo[2.2.2]octane (DABCO) or a phosphonium catalyst, even more preferably 1,4-diazabicyclo[2.2.2]octane (DABCO) or a phosphonium catalyst selected from tributyltetradecylphosphonium chloride (TBTDPCl), tetrabutylphosphonium chloride (TBPCl) and / or tetrabutylphosphonium hydroxide (TBPOH).
[0040] These catalysts have been found to increase both rate and productivity, as well as being stable at relevant reaction temperatures.
[0041] Advantageously, the PTC is 1 -C(O)-NH-NH-C(O)-R 2 The amount of 0.005 to 0.05 molar equivalent, preferably 0.01 to 0.02 molar equivalent is present.
[0042] Alkali system
[0043] It has been found that the presence and nature of a base plays an important role in the optimization of the process. Therefore, advantageously, the process is carried out in the presence of a base. The base may be selected from potassium carbonate, sodium carbonate and cesium carbonate, but is preferably potassium carbonate.
[0044] Preferably, the base is in an amount relative to R 1 -C(O)-NH-NH-C(O)-R 2 The amount of 1.5 to 3.0 molar equivalents, preferably 1.8 to 2.5 molar equivalents, is present.
[0045] However, the process typically requires a high loading of base, which limits the yield and produces a large amount of solid waste. Therefore, the process is preferably carried out in the presence of a base and a co-base to address these problems. The co-base can be selected from potassium hydroxide, potassium n-butoxide, sodium hydroxide and cesium hydroxide, preferably potassium hydroxide.
[0046] Advantageously, the ratio of base to co-base is from 10:1 to 1:2, preferably from 5:1 to 1:1.
[0047] Methods Phase
[0048] The process comprises a reaction stage (1) as defined herein. The reaction rate and yield are highly dependent on the pot temperature. Advantageously, the reaction temperature can be controlled by running the reaction at reflux at one atmosphere or under reduced pressure. The reaction is preferably carried out at the reflux temperature of the solvent (preferably 110° C. to 125° C.).
[0049] Advantageously, the process comprises a salt filtration stage (2) after the reaction stage, preferably comprising the addition of a further alcohol solvent as defined herein. This stage may also comprise the removal of solid waste.
[0050] Preferably, there is a solvent distillation stage (3) in which the solvent can be recycled back to the reaction stage (1). Advantageously, but not necessarily, this can be the only solvent distillation stage.
[0051] Alternatively, there is a second distillation stage after product filtration to recover residual solvent and excess R 3 -CH2-CH2-O-CH2-CH2-R 4 The mother liquor contains PTC and a large amount of reagents. Therefore, the mother liquor can replace part of the solvent in the next reaction batch, resulting in an increase in yield and a reduction in the use of reagents.
[0052] The process advantageously comprises a product crystallization stage (4). Stages (3) and (4) are preferably combined into a single stage.
[0053] Preferably, there is a filtering and drying (5) stage to isolate the compound of formula (I), advantageously comprising the addition of an alcoholic solvent as defined herein to wash the product.
[0054] The reaction is sensitive to water content and therefore the process preferably includes removing water via azeotropic distillation.Water content can be controlled by azeotropic distillation, which has been found to be particularly effective when a co-base (such as potassium hydroxide) is used.
[0055] In a second aspect of the present invention there is provided a process for preparing pinoxaden, the process comprising a process as defined herein. Such a process may comprise hydrolyzing a compound of formula (I) to form an oxadiazepine (ODA). ODA can be reacted with 2-(2,6-diethyl-4-methylphenyl)malonamide to form a pinoxaden intermediate.
[0056] In a third aspect of the present invention there is provided a compound of formula (I) produced by a process as defined herein. Such a compound is preferably used in a process for the preparation of pinoxaden.
[0057] Unless otherwise stated, all percentages are given as percentages by weight of the total and all embodiments and preferred features may be combined in any combination.
[0058] The invention is described by the following non-limiting examples.
[0059] Examples
[0060] Example 1
[0061] Table 1
[0062]
[0063]
[0064] program
[0065] DAH (40 g, 1 eq.), n-butanol (150.1 g), powdered K2CO3 (28.3 g, 0.6 eq.) and 1,4-diazabicyclo[2.2.2]octane (0.74 g) were loaded into an Easymax402 reactor (500 mL) equipped with an overhead stirrer, a thermocouple and a reflux condenser attached to a Dean-Stark water trap. A solution of 14.5 w / w% KOH in n-butanol (26 g) was fed below the liquid surface at room temperature over 15 minutes. The suspension was heated to gentle reflux (over 60 minutes), and distillate was collected. A solution of DCEE (73.2 g, 1.5 eq.) and 14.5 w / w% KOH in n-butanol (130.6 g) was fed below the liquid surface, respectively, via a syringe pump. Both DCEE and KOH solutions were fed over 4 hours. The water / solvent removal rate was adjusted to match the base feed rate.The reaction was sampled periodically over a 12 hour period.
[0066] After the reaction was completed, inorganic solids (58.5 g) were removed by filtration at room temperature, which were subsequently washed with n-butanol (110 g). The filtrate and washings (366.2 g) were combined to give a solution yield of 55.3%. Concentration under reduced pressure at 55° C.-60° C. gave a concentrate (98.3 g) containing about 37% DAODA.
[0067] To crystallize DAODA, the concentrate was slowly cooled (over 60 min) to -10° C. with mixing. Product isolation by filtration, washing with cold n-butanol at -5° C. (12 g) and drying under vacuum at 60° C. gave DAODA (29.0 g) in 46% yield and 99.1% purity.
[0068] Example 2
[0069] Table 2
[0070]
[0071] program
[0072] DAH (40 g, 1 eq.), n-butanol (112.9 g), powdered K2CO3 (28.3 g, 0.6 eq.) and 1,4-diazabicyclo[2.2.2]octane (0.74 g) were loaded into an Easymax402 reactor (500 mL) equipped with an overhead stirrer, a thermocouple and a reflux condenser attached to a Dean-Stark trap. A solution of 14.5 w / w% KOH in n-butanol (26 g) was fed below the liquid surface at room temperature over 15 minutes. The suspension was heated to gentle reflux (over 60 minutes), and distillate was collected. A solution of DCEE (73.2 g, 1.5 eq.) and 14.5 w / w% KOH in n-butanol (130.6 g) was fed below the liquid surface, respectively, via a syringe pump. Both DCEE and KOH solutions were fed over 4 hours. The water / solvent removal rate was adjusted to match the base feed rate.The reaction was sampled periodically over a 12 hour period.
[0073] After the reaction is complete, inorganic solids (59.2 g) are removed by filtration at room temperature, which are then washed with n-butanol (112 g). The filtrate and washings (342 g) are combined to give a solution yield of 54.7%. Concentration under reduced pressure at 55° C.-60° C. gives a concentrate (88.5 g) containing about 37% DAODA.
[0074] To crystallize DAODA, the concentrate was slowly cooled (over 60 min) to -10° C. with mixing. Product isolation by filtration, washing with cold n-butanol at -5° C. (12 g) and drying under vacuum at 60° C. gave DAODA (28.5 g) in 45% yield and 98.6% purity.
[0075] Example 3
[0076] Table 3
[0077]
[0078] program
[0079] DAH (30 g, 1 eq.), n-butanol (140.7 g) and powdered K2CO3 (28.3 g, 0.8 eq.) were loaded into an Easymax 402 reactor (500 mL) equipped with an overhead stirrer, a thermocouple and a reflux condenser attached to a Dean-Stark water trap. A solution of 14.5 w / w% KOH in n-butanol (19.6 g) was fed below the liquid level at room temperature over 15 minutes. The suspension was heated to gentle reflux (over 60 minutes), and distillate was collected. Trimethylamine hydrochloride (1.19 g) was loaded into 1.0 mL of water. A solution of DCEE (54.9 g, 1.5 eq.) and 14.5 w / w% KOH in n-butanol (78.6 g) was fed below the liquid level, respectively, via a syringe pump. Both DCEE and KOH solutions were fed over 4 hours. The water / solvent removal rate was adjusted to match the base feed rate.The reaction was sampled periodically over a 12 hour period.
[0080] After the reaction was complete, the inorganic solid (48.0 g) was removed by filtration at room temperature, which was then washed with n-butanol (110 g). The filtrate and washings (312.2 g) were combined to give a solution yield of 51.0%.
[0081] Example 4
[0082] Table 4
[0083]
[0084] program
[0085] DAH (30 g, 1 eq.), n-butanol (140.7 g), powdered K2CO3 (28.3 g, 0.8 eq.) and quinuclidine (0.55 g) were loaded into an Easymax 402 reactor (500 mL) equipped with an overhead stirrer, a thermocouple and a reflux condenser attached to a Dean-Stark trap. A solution of 14.5 w / w% KOH in n-butanol (19.6 g) was fed below the liquid surface at room temperature over 15 minutes. The suspension was heated to gentle reflux (over 60 minutes) and the distillate was collected. A solution of DCEE (54.9 g, 1.5 eq.) and 14.5 w / w% KOH in n-butanol (78.4 g) was fed below the liquid surface via a syringe pump, respectively. Both DCEE and KOH solutions were fed over 4 hours. The removal rate of water / solvent was adjusted to match the feed rate of alkali. The reaction was sampled periodically over a 12 hour period.
[0086] After the reaction was complete, the inorganic solid (50.0 g) was removed by filtration at room temperature, which was then washed with n-butanol (100 g). The filtrate and washings (314.4 g) were combined to give a solution yield of 53.7%.
[0087] Example 5
[0088] Table 5
[0089]
[0090] program
[0091] DAH (30 g, 1 eq.), n-butanol (140.7 g), powdered K2CO3 (28.3 g, 0.8 eq.) and tetrabutylphosphonium chloride (1.22 g) were loaded into an Easymax 402 reactor (500 mL) equipped with an overhead stirrer, a thermocouple and a reflux condenser attached to a Dean-Stark water trap. A solution of 14.5 w / w% KOH in n-butanol (19.6 g) was fed below the liquid level at room temperature over 15 minutes. The suspension was heated to gentle reflux (over 60 minutes), and distillate was collected. A solution of DCEE (54.9 g, 1.5 eq.) and 14.5 w / w% KOH in n-butanol (78.4 g) was fed below the liquid level via a syringe pump, respectively. Both DCEE and KOH solutions were fed over 4 hours. The removal rate of water / solvent was adjusted to match the feed rate of alkali. The reaction was sampled periodically over a 12 hour period.
[0092] After the reaction is complete, inorganic solids (50.0 g) are removed by filtration at room temperature, which are then washed with n-butanol (100 g). The filtrate and washings (292.8 g) are combined to give a solution yield of 55.5%. Concentration under reduced pressure at 55° C.-60° C. gives a concentrate (55.8 g) containing about 43.5% DAODA.
[0093] To crystallize DAODA, the concentrate was slowly cooled (over 60 min) to -10° C. with mixing. Product isolation by filtration, washing with cold n-butanol at -5° C. (12 g) and drying under vacuum at 60° C. gave DAODA (20.6 g) in 45% yield and 99% purity.
[0094] Example 6
[0095] Table 6
[0096]
[0097] program
[0098] DAH (12 g, 1 eq.), n-butanol (56.3 g), powdered K2CO3 (11.4 g, 0.8 eq.) and tetrabutylphosphonium chloride (0.6 g) were loaded into an Easymax 102 reactor (150 mL) equipped with an overhead stirrer, a thermocouple and a reflux condenser attached to a Dean-Stark water trap. A solution of 14.5 w / w% KOH in n-butanol (7.9 g) was fed below the liquid level at room temperature over 15 minutes. The suspension was heated to a gentle reflux over 30 minutes. A solution of DCEE (24.9 g, 1.7 eq.) and 14.5 w / w% KOH in n-butanol (31.4 g) were fed below the liquid level via a syringe pump, respectively. DCEE was fed over 4 hours, and KOH solution was fed over 6 hours. The removal rate of water / solvent was adjusted to match the feed rate of alkali. The reaction was sampled periodically over a 16 hour period.
[0099] After the reaction was complete, the inorganic solids (25.4 g) were removed by filtration at room temperature, followed by washing with n-butanol (30 g) at room temperature. The filtrate and n-butanol washings (163.5 g) were combined to give a solution yield of 60.4%.
[0100] Example 7
[0101] Table 7
[0102]
[0103] program
[0104] DAH (39.6 g, 1 eq.), n-butanol (186.7 g), powdered K2CO3 (37.1 g, 0.8 eq.) and tetrabutylphosphonium chloride (1.98 g) were loaded into an Easymax 402 reactor (500 mL) equipped with an overhead stirrer, a thermocouple and a reflux condenser attached to a Dean-Stark water trap. A solution of 14.5 w / w% KOH in n-butanol (26 g) was fed below the liquid level at room temperature over 30 minutes. The suspension was heated to gentle reflux (over 30 minutes). A solution of DCEE (82.5 g, 1.7 eq.) and 14.5 w / w% KOH in n-butanol (103.9 g) was fed below the liquid level via a syringe pump. DCEE was fed over 4 hours, and KOH solution was fed over 6 hours. The removal rate of water / solvent was adjusted to match the feed rate of alkali. The reaction was sampled periodically over a 12 hour period.The GC chemical yield of DAODA was 55.3%.
[0105] After the reaction is complete, the inorganic solid (57.4 g) is removed by filtration at room temperature, which is then washed with n-butanol (112 g). The combined filtrate (311.9 g) and washings (112 g) are concentrated at 55° C.-60° C. under reduced pressure to obtain a concentrate (101.5 g) containing about 35% DAODA.
[0106] To crystallize DAODA, the concentrate was slowly cooled (over 60 min) to -10°C with mixing. Product separation by filtration, washing with cold n-butanol (20 g) at -5°C and drying under vacuum at 60°C gave DAODA (30.0 g) with a yield of 48.7% and a purity of 99%. The mother liquor (64 g) containing DAODA (5.1 g, 8.2% yield) and the n-butanol washing (18.5 g) containing DAODA (0.7 g, 0.9% yield) were the main sources of product loss.
[0107] Example 8
[0108] Table 8
[0109]
[0110] program
[0111] DAH (12 g, 1 eq.), n-butanol (64 g), powdered KOH (6.4 g, 1 eq.), powdered K2CO3 (21.4 g, 1.5 eq.) and tetrabutylphosphonium hydroxide (1.5 g, 40%) were sequentially charged into an Easymax 102 reactor. The suspension was heated to gentle reflux (over 15 min.) and DCEE (22.4 g, 1.5 eq.) was fed subsurface via a syringe pump over 4 h while water was azeotropically removed from the system. Azeotropic distillation was continued after the feeds until the reaction was complete. The reaction was sampled periodically over a 12 h period.
[0112] After the reaction was complete, the inorganic solids were removed by filtration at room temperature, followed by washing with n-butanol (30 g) at room temperature. The filtrate (87 g) and the washings (32 g) were combined to give a solution yield of 55%.
[0113] Example 9
[0114] Table 9
[0115]
[0116] program
[0117] DAH (52.9 g, 1 eq.), n-butanol (192 g), tetrabutylphosphonium hydroxide (6.75 g, 40%), powdered K2CO3 (154.4 g, 2.5 eq.) were charged into an Easymax 402 reactor. After the suspension was heated to gentle reflux over 15 min, DCEE (100.8 g, 1.5 eq.) was fed subsurface via a syringe pump over 4 h, and the reaction was kept under reflux for an additional 8 h.
[0118] After the reaction was completed, the inorganic solids were removed by filtration at 80° C., which were then washed with hot n-butanol (150 g) at 80° C. The combined filtrate (250 g) and washings (155.8 g) were concentrated at 60° C.-65° C. under reduced pressure to obtain a concentrate (92.6 g) containing about 55% of DAODA.
[0119] To crystallize DAODA, the concentrate was slowly cooled to -5°C under mixing over 30 min. Product separation by filtration, washing with cold n-butanol at -5°C (34 g) and drying under vacuum at 60°C gave DAODA (37.5 g) with a yield of 45% and a purity of 99%. The mother liquor (41.5 g) containing DAODA (6.1 g, 7.3% yield) and the n-butanol washing (36.6 g) containing DAODA (3.4 g, 4% yield) were the main sources of product loss.
[0120] Example 10
[0121] Table 10
[0122]
[0123] program
[0124] DAH (18 g, 1 eq.), n-butanol (55 g), crystallization mother liquor (15 g, from Example 9), powdered K2CO3 (53.6 g, 2.5 eq.) were charged into an Easymax 102 reactor. After the suspension was heated to gentle reflux over 15 minutes, DCEE (33.6 g, 1.5 eq.) was fed subsurface via a syringe pump over 4 hours while maintaining the reaction temperature under gentle reflux. The reaction was kept under reflux for an additional 8 hours. The GC chemical yield of DAODA was 56%.
[0125] In order to be able to better determine the reaction performance, DAODA and DCEE in the crystallization mother liquor were subtracted from the direct quantification of the reaction mass.
[0126] Example 11
[0127] Table 11
[0128]
[0129] program
[0130] DAH (12 g, 1 eq.), 2-methoxyethanol (58 g) and powdered KCO (37.5 g, 2.55 eq.) were sequentially charged into an Easymax 102 reactor. The suspension was heated to gentle reflux over 15 minutes and DCEE (22.4 g, 1.5 eq.) was fed below the liquid level via a syringe pump over 4 hours. The reaction was maintained at reflux for an additional 8 hours. The reaction was sampled periodically over a 12 hour period.
[0131] After the reaction was complete, the inorganic solids were removed by filtration at room temperature, followed by washing with 2-methoxyethanol (25 g) at room temperature. The filtrates (95.4 g) were combined to give a solution yield of 58%.
[0132] Example 12
[0133] Table 12
[0134]
[0135] program
[0136] DAH (18 g, 1 eq.), 2-methoxyethanol (64 g) and powdered KCO (42.0 g, 2.0 eq.) were sequentially charged into an Easymax 102 reactor. The suspension was heated to gentle reflux over 15 minutes and DCEE (33.6 g, 1.53 eq.) was fed below the liquid level via a syringe pump over 4 hours. The reaction was maintained at reflux for an additional 8 hours. The reaction was sampled periodically over a 12 hour period.
[0137] After the reaction was complete, the inorganic solids were removed by filtration at room temperature, followed by washing with 2-methoxyethanol (40 g) at room temperature. The filtrates (149.9 g) were combined to give a solution yield of 54.8%.
[0138] It can thus be seen that the claimed invention provides a more efficient, less expensive and safer reaction than those known in the prior art.
[0139] The invention is defined by the claims.
Claims
1. A method for preparing a compound of formula (I): The method comprises making R 1 -C(O)-NH-NH-C(O)-R 2 With R 3 -CH2-CH2-O-CH2-CH2-R 4 reacting in the presence of an alcohol solvent; Where R 1 and R 2 are independently selected from straight or branched alkyl groups, or are bonded to form a 4-, 5- or 6-membered heterocyclic ring, and Where R 3 and R 4 Independently selected from halides or sulfates.
2. The method according to claim 1, wherein: R 1 and R 2 is i) a methyl group; or ii) is bonded to form a 5-membered heterocyclic ring.
3. The method according to claim 1 or 2, wherein: R 3 and R 4 Independently selected from methylsulfonyl, chlorine and / or bromine, preferably chlorine.
4. A method according to any one of the preceding claims, wherein: The alcohol solvent is selected from monohydric alcohols.
5. The method according to claim 4, wherein: The solvent is selected from butanol, pentanol or 2-methoxyethanol, preferably butanol.
6. A method according to any one of the preceding claims, wherein: The process is carried out in the presence of a phase transfer catalyst (PTC).
7. The method according to claim 6, wherein: The PTC is a nucleophilic catalyst, an ammonium catalyst or a phosphonium catalyst, preferably a phosphonium catalyst.
8. The method according to claim 6 or 7, wherein: The PTC is selected from 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine, trimethylamine hydrochloride (TMA HCl), tetrabutylphosphonium chloride (TBPCl), tetrabutylphosphonium hydroxide (TBPOH) and tributyltetradecylphosphonium chloride (TBTDPCl), preferably 1,4-diazabicyclo[2.2.2]octane (DABCO).
9. A method according to any one of the preceding claims, wherein: The method is carried out in the presence of a base.
10. The method according to claim 9, wherein: The process is carried out in the presence of a base and a co-base.
11. The method according to claim 10, wherein: The ratio of base to co-base is from 10:1 to 1:2, preferably from 5:1 to 1:
1.
12. The method according to claims 9 to 11, wherein: The base is selected from potassium carbonate, sodium carbonate and cesium carbonate, preferably potassium carbonate.
13. The method according to any one of claims 10 to 12, wherein: The co-base is selected from potassium hydroxide, potassium n-butoxide, sodium hydroxide and cesium hydroxide, preferably potassium hydroxide.
14. A method according to any one of the preceding claims, wherein: The reaction is carried out at the reflux temperature of the solvent, preferably 110°C to 125°C.
15. A process according to any one of the preceding claims comprising removing water via azeotropic distillation.
16. A method according to any one of the preceding claims comprising a salt filtration step.
17. A method according to any one of the preceding claims, comprising a solvent distillation step, preferably only one solvent distillation step.
18. A process according to any one of the preceding claims comprising a product crystallization step.
19. A method for preparing pinoxaden, the method comprising the method according to any one of claims 1 to 18.
20. A compound of formula (I) produced by the process according to any one of claims 1 to 18.