Method for preparing [1,4,5]-oxadiazepine derivatives

Abstract

In the presence of alcoholic solvents, 1 -C(O)-NH-NH-C(O)-R 2 R 3 -CH2-CH2-O-CH2-CH2-R 4 a compound of formula (I) comprising reacting with: A method for preparing JPEG2025515318000016.jpg48160, comprising the steps of: 1 and R 2 are independently selected from linear or branched alkyl groups or are joined to form a 4-, 5-, or 6-membered heterocycle; R 3 and R 4 is independently selected from a halide or a sulfate.

Description

[Technical field]

[0001] The present invention relates to a novel process for the preparation of [1,4,5]-oxadiazepine derivatives and their use as intermediates in the preparation of herbicides of the tetrahydropyrazolodione type. [Background technology]

[0002] Pinoxaden ([8-(2,6-diethyl-4-methylphenyl)-7-oxo-1,2,4,5-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepin-9-yl]2,2-dimethylpropanoate) is a well-known grass herbicide. Current commercial methods for preparing pinoxaden include preparing diacetyloxadiazepine (DAODA) as a key intermediate.

[0003] DAODA is typically prepared from the reaction of diacetylhydrazine (DAH) with dichloroethyl ether (DCEE) in the presence of dimethylsulfoxide (DMSO), as described in WO 03 / 051853.

[0004] However, the use of DMSO has quite a few technical problems associated with it. The thermal decomposition of DMSO, low isolated yields, poor volumetric yields, and a large number of waste streams pose major process safety issues. The process requires at least three distillation steps and different solvents for reaction and crystallization, making it overall very complicated and costly.

[0005] Therefore, a method to solve the above technical problems is required. Summary of the Invention [Means for solving the problem]

[0006] Thus, the present invention relates to a process for the preparation of a cyclohexanediamine in the presence of an alcohol-based solvent. 1 -C(O)-NH-NH-C(O)-R 2 R 3 -CH2 -CH 2 -O-CH 2 -CH 2 -R 4 a compound of formula (I) comprising reacting with: [ka] A process for preparing a compound of the formula In the formula, R 1 and R 2 are independently selected from straight or branched chain alkyl groups or are joined to form a 4-, 5-, or 6-membered heterocycle; R 3 and R 4 is independently selected from a halide or a sulfate; A method is provided.

[0007] The claimed method offers a significant advantage over the use of DMSO since DMSO does not have the thermal instability issue that poses a potential serious accident risk and can therefore be safely operated at higher process concentrations. This also avoids the highly toxic DCEE / DMSO combination. Furthermore, this method eliminates solvent exchange from the process since the process solvent can be used for both the reaction and product crystallization. Combined with the reduction in inorganic and solvent waste, this method is more economical than methods known in the art. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Preferably, R 1 and R 2 are independently selected from straight chain alkyl groups, preferably from straight chain alkyl groups having a chain length of 1 to 4 carbons, and more preferably from methyl or ethyl. 1 and R 2 may both be methyl.

[0009] In another preferred embodiment, R 1 and R 2are linked to form a five-membered heterocycle derived from pyrazolidine (i.e., R 1 and R 2 is the same CH 2 (represents the part).

[0010] Optionally, the ring may have one or more carbonyl groups. Preferably, the ring contains two carbonyl groups to form a pyrazolidinedione derivative, more preferably the carbonyl groups are at the 3- and 5-positions. The ring may be substituted in any manner, for example the ring may have a phenyl substituent (e.g. at the 4-position) or may itself be substituted.

[0011] Preferably, R 3 and R 4 is independently selected from methylsulfonyl (e.g., 2-(2-methylsulfonyloxyethoxy)ethyl methanesulfonate), chlorine, and / or bromine, most preferably R 3 and R 4 is chlorine (DCEE).

[0012] Solvent System The alcoholic solvent may be a polyhydric or monohydric alcohol, preferably a monohydric alcohol. Advantageously, the alcohol is a C 1-7 Alcohols (e.g., methanol), e.g., C 2-6 An alcohol (e.g., ethanol). The alcohol may be a straight-chain or branched-chain alcohol.

[0013] Most advantageously, the solvent is selected from butanol, pentanol (such as n-pentanol and / or iso-pentanol), or 2-methoxyethanol, preferably butanol (such as n-butanol).

[0014] The solvents of choice for the methods described herein are 1) It must be chemically compatible with the process (i.e., thermally stable); 2) It must have high polarity for speed improvement; 3) It must provide good solubility of the base and the DAH salt; 4) It must be immersible in water (which is advantageous as the sole solvent for reactions and crystallization); and 5) It must have an appropriate boiling point taking into account the reaction temperature of 115 to 125°C.

[0015] Surprisingly, it has been found that n-butanol meets all of the above criteria (1) to (5).

[0016] phase transfer catalyst Advantageously, the process is carried out in the presence of a phase transfer catalyst (PTC) to increase the rate of the reaction.

[0017] Preferably, the PTC is 1) Nucleophilic catalyst; 2) an ammonium catalyst; or 3) phosphonium catalysts; It is.

[0018] When the PTC is the 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).

[0019] When the PTC is an ammonium catalyst, it is preferably of the formula R a R b R c NX, where R a , R b , and R c is independently selected from an alkyl group, a substituted alkyl group, and a phenyl group, and X is selected from a halide, hydroxide, or sulfate.

[0020] More preferably, it is selected from tetramethylammonium chloride (TMAC), tetrabutylammonium bromide (TBAB), N-methyl-N,N,N-trioctylammonium chloride (ALIQUAT336), trimethylamine hydrochloride (TMA HCl), and / or 1,4,7,10,13,16-hexaoxacyclooctadecane (18-CROWN-6).

[0021] When the PTC is a phosphonium catalyst, it preferably has the structure R a R b R c PX, in which R a , R b , and R c is independently selected from an alkyl group, a substituted alkyl group, and a phenyl group, and X is selected from a halide, hydroxide, or sulfate.

[0022] 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).

[0023] The PTC is preferably 1,4-diazabicyclo[2.2.2]octane (DABCO) or a phosphonium catalyst, 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).

[0024] These catalysts not only improve both the rate and yield, but have also been found to be stable at the relevant reaction temperatures.

[0025] Advantageously, the PTC comprises R 1 -C(O)-NH-NH-C(O)-R 2 It is present in an amount of 0.005 to 0.05 molar equivalents, preferably 0.01 to 0.02 molar equivalents, relative to the amount of the aryl group.

[0026] Bases It has been found that the presence and identity of the base plays an important role in the optimization of the process. Advantageously, therefore, the process is carried out in the presence of a base. The base can be selected from potassium carbonate, sodium carbonate and cesium carbonate, but is preferably potassium carbonate.

[0027] Preferably, the base is R 1 -C(O)-NH-NH-C(O)-R 2 It is present in an amount of 1.5 to 3.0 molar equivalents, preferably 1.8 to 2.5 molar equivalents, relative to the amount of the aryl group.

[0028] However, the process typically requires a large amount of base, which inhibits the yield and generates a significant amount of solid waste. Therefore, the process is preferably carried out in the presence of a base and a co-base to address these issues. The co-base can be selected from potassium hydroxide, potassium n-butoxide, sodium hydroxide, and cesium hydroxide, and is preferably potassium hydroxide.

[0029] Advantageously, the ratio of base to cobase is between 10:1 and 1:2, preferably between 5:1 and 1:1.

[0030] Method steps The process comprises reaction step (1) as defined herein. The reaction rate and yield are highly dependent on the pot temperature. Advantageously, the reaction temperature can be controlled by carrying out the reaction at reflux under atmospheric pressure or reduced pressure. The reaction is preferably carried out at the reflux temperature of the solvent, preferably between 110 and 125°C.

[0031] Advantageously, the process comprises a salt filtration step (2) following the reaction step, which preferably comprises the addition of additional alcoholic solvent as defined herein. This step may also comprise the removal of solid waste.

[0032] Preferably, there is a solvent distillation stage (3) in which the solvent can be recycled back to reaction stage (1). Advantageously, but not necessarily, this is the only solvent distillation stage.

[0033] Alternatively, after product filtration, residual solvent and excess R 3 -CH 2 -CH 2 -O-CH 2 -CH 2 -R 4 There is a second distillation stage to recover the mother liquor. The mother liquor contains the PTC and a significant amount of the reagents. Therefore, the mother liquor can replace part of the solvent of the next reaction batch, which results in an increase in yield and a reduction in the use of reagents.

[0034] The process advantageously comprises a step (4) of crystallization of the product. Steps (3) and (4) are preferably combined in a single step.

[0035] Preferably, there is a filtration and drying (5) step to isolate the compound of formula (I), advantageously comprising the addition of an alcoholic solvent as defined herein to wash the product.

[0036] Since the reaction is sensitive to water content, the process preferably includes removal of water by 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.

[0037] In a second aspect of the present invention, there is provided a method for preparing pinoxaden comprising the process defined herein. Such a method may comprise hydrolyzing a compound of formula (I) to form oxadiazepine (ODA). ODA may react with 2-(2,6-diethyl-4-methylphenyl)malonamide to form a pinoxaden intermediate.

[0038] In a third aspect of the present invention there is provided a compound of formula (I) prepared by a process as defined herein.Such a compound is preferably used in a process for preparing pinoxaden.

[0039] Unless otherwise specified, all percentages are expressed as percentages by total weight, and all embodiments and preferred features can be combined in any combination.

[0040] The invention is illustrated by the following non-limiting examples. EXAMPLES

[0041] Example 1

[0042] [Table 1]

[0043] procedure An Easymax 402 reactor (500 mL) equipped with an overhead stirrer, thermocouple, and a reflux condenser connected to a Dean-Stark trap was charged with DAH (40 g, 1 equiv.), n-butanol (150.1 g), powdered K 2 CO 3(28.3 g, 0.6 equiv.), and 1,4-diazabicyclo[2.2.2]octane (0.74 g). A 14.5 wt. % solution of KOH in n-butanol (26 g) was fed subsurface over 15 min at room temperature. The suspension was heated to gentle reflux (over 60 min) and the distillate was collected. DCEE (73.2 g, 1.5 equiv.) and a 14.5 wt. % solution of KOH in n-butanol (130.6 g) were fed subsurface separately by syringe pump. Both DCEE and KOH solutions were fed over 4 h. The rate of water / solvent removal was adjusted to match the base feed rate. The reaction was sampled periodically over 12 h.

[0044] After the reaction was complete, the inorganic solids (58.5 g) were removed by filtration at room temperature, followed by an n-butanol wash (110 g). The filtrate and wash combined (366.2 g) gave a solution yield of 55.3%. Concentration under reduced pressure at 55-60°C gave a concentrate (98.3 g) containing approximately 37% DAODA.

[0045] To crystallize DAODA, the concentrate was cooled slowly (over 60 min) with mixing to −10° C. The product was isolated by filtration, washed with cold n-butanol (12 g) at −5° C., and dried in vacuum at 60° C. to give DAODA (29.0 g) in 46% yield and 99.1% purity.

[0046] Example 2

[0047] [Table 2]

[0048] procedure An Easymax 402 reactor (500 mL) equipped with an overhead stirrer, thermocouple, and a reflux condenser connected to a Dean-Stark trap was charged with DAH (40 g, 1 equiv.), n-butanol (112.9 g), powdered K 2 CO 3(28.3 g, 0.6 equiv.), and 1,4-diazabicyclo[2.2.2]octane (0.74 g). A 14.5 wt. % solution of KOH in n-butanol (26 g) was fed subsurface over 15 min at room temperature. The suspension was heated to gentle reflux (over 60 min) and the distillate was collected. DCEE (73.2 g, 1.5 equiv.) and a 14.5 wt. % solution of KOH in n-butanol (130.6 g) were fed subsurface separately by syringe pump. Both DCEE and KOH solutions were fed over 4 h. The rate of water / solvent removal was adjusted to match the base feed rate. The reaction was sampled periodically over 12 h.

[0049] After the reaction was completed, the inorganic solids (59.2 g) were removed by filtration at room temperature, followed by an n-butanol wash (112 g). The filtrate and wash combined (342 g) gave a solution yield of 54.7%. Concentration under reduced pressure at 55-60°C gave a concentrate (88.5 g) containing approximately 37% DAODA.

[0050] To crystallize DAODA, the concentrate was cooled slowly (over 60 min) with mixing to −10° C. The product was isolated by filtration, washed with cold n-butanol (12 g) at −5° C., and dried in vacuum at 60° C. to give DAODA (28.5 g) in 45% yield and 98.6% purity.

[0051] Example 3

[0052] [Table 3]

[0053] procedure An Easymax 402 reactor (500 mL) equipped with an overhead stirrer, thermocouple, and a reflux condenser connected to a Dean-Stark trap was charged with DAH (30 g, 1 equiv.), n-butanol (140.7 g), and powdered K. 2 CO 3(28.3 g, 0.8 equiv.) was charged. 14.5 wt. % KOH in n-butanol (19.6 g) was fed subsurface over 15 min at room temperature. The suspension was heated to gentle reflux (over 60 min) and the distillate was collected. Trimethylamine hydrochloride (1.19 g) in 1.0 mL water was charged. DCEE (54.9 g, 1.5 equiv.) and 14.5 wt. % KOH in n-butanol (78.6 g) were fed subsurface separately by syringe pump. Both DCEE and KOH solutions were fed over 4 h. The water / solvent removal rate was adjusted to match the base feed rate. The reaction was sampled periodically over 12 h.

[0054] After the reaction was completed, the inorganic solids (48.0 g) were removed by filtration at room temperature, followed by an n-butanol wash (110 g). The filtrate and wash combined (312.2 g) gave a solution yield of 51.0%.

[0055] Example 4

[0056] [Table 4]

[0057] procedure An Easymax 402 reactor (500 mL) equipped with an overhead stirrer, thermocouple, and a reflux condenser connected to a Dean-Stark trap was charged with DAH (30 g, 1 equiv.), n-butanol (140.7 g), powdered K 2 CO 3 (28.3 g, 0.8 equiv.), and quinuclidine (0.55 g). A 14.5 wt. % solution of KOH in n-butanol (19.6 g) was fed subsurface over 15 min at room temperature. The suspension was heated to gentle reflux (over 60 min) and the distillate was collected. DCEE (54.9 g, 1.5 equiv.) and a 14.5 wt. % solution of KOH in n-butanol (78.4 g) were fed subsurface separately by syringe pump. Both DCEE and KOH solutions were fed over 4 h. The rate of water / solvent removal was adjusted to match the base feed rate. The reaction was sampled periodically over 12 h.

[0058] After the reaction was completed, the inorganic solids (50.0 g) were removed by filtration at room temperature, followed by an n-butanol wash (100 g). The filtrate and wash combined (314.4 g) gave a solution yield of 53.7%.

[0059] Example 5

[0060] [Table 5]

[0061] procedure An Easymax 402 reactor (500 mL) equipped with an overhead stirrer, thermocouple, and a reflux condenser connected to a Dean-Stark trap was charged with DAH (30 g, 1 equiv.), n-butanol (140.7 g), powdered K 2 CO 3 (28.3 g, 0.8 equiv.), and tetrabutylphosphonium chloride (1.22 g). A 14.5 wt. % solution of KOH in n-butanol (19.6 g) was fed subsurface over 15 min at room temperature. The suspension was heated to gentle reflux (over 60 min) and the distillate was collected. DCEE (54.9 g, 1.5 equiv.) and a 14.5 wt. % solution of KOH in n-butanol (78.4 g) were fed subsurface separately by syringe pump. Both DCEE and KOH solutions were fed over 4 h. The water / solvent removal rate was adjusted to match the base feed rate. The reaction was sampled periodically over 12 h.

[0062] After the reaction was completed, the inorganic solids (50.0 g) were removed by filtration at room temperature, followed by an n-butanol wash (100 g). The filtrate and wash combined (292.8 g) gave a solution yield of 55.5%. Concentration under reduced pressure at 55-60°C gave a concentrate (55.8 g) containing approximately 43.5% DAODA.

[0063] To crystallize DAODA, the concentrate was cooled slowly (over 60 min) with mixing to −10 °C. The product was isolated by filtration, washed with cold n-butanol (12 g) at −5 °C, and dried in vacuum at 60 °C to give DAODA (20.6 g) in 45% yield and 99% purity.

[0064] Example 6

[0065] [Table 6]

[0066] procedure An Easymax 102 reactor (150 mL) equipped with an overhead stirrer, thermocouple, and a reflux condenser connected to a Dean-Stark trap was charged with DAH (12 g, 1 equiv.), n-butanol (56.3 g), powdered K 2 CO 3 (11.4 g, 0.8 equiv.), and tetrabutylphosphonium chloride (0.6 g). A 14.5 wt. % solution of KOH in n-butanol (7.9 g) was fed subsurface over 15 min at room temperature. The suspension was heated to gentle reflux over 30 min. DCEE (24.9 g, 1.7 equiv.) and a 14.5 wt. % solution of KOH in n-butanol (31.4 g) were fed subsurface separately by syringe pump. DCEE was fed over 4 h and the KOH solution over 6 h. The water / solvent removal rate was adjusted to match the base feed rate. The reaction was sampled periodically over 16 h.

[0067] After the reaction was completed, the inorganic solids (25.4 g) were removed by filtration at room temperature, followed by a n-butanol wash (30 g) at room temperature. The filtrate and wash combined (163.5 g) gave a solution yield of 60.4%.

[0068] Example 7

[0069] [Table 7]

[0070] procedure An Easymax 402 reactor (500 mL) equipped with an overhead stirrer, thermocouple, and a reflux condenser connected to a Dean-Stark trap was charged with DAH (39.6 g, 1 equiv.), n-butanol (186.7 g), powdered K 2 CO 3 (37.1 g, 0.8 equiv.), and tetrabutylphosphonium chloride (1.98 g). A 14.5 wt. % solution of KOH in n-butanol (26 g) was fed subsurface over 30 min at room temperature. The suspension was heated to gentle reflux (over 30 min). DCEE (82.5 g, 1.7 equiv.) and a 14.5 wt. % solution of KOH in n-butanol (103.9 g) were fed subsurface separately by syringe pump. DCEE was fed over 4 h and the KOH solution over 6 h. The water / solvent removal rate was adjusted to match the base feed rate. The reaction was sampled periodically over 12 h. The GC chemical yield of DAODA was 55.3%.

[0071] After the reaction was completed, the inorganic solids (57.4 g) were removed by filtration at room temperature, followed by an n-butanol wash (112 g). The filtrate (311.9 g) and the wash (112 g) were combined and concentrated under reduced pressure at 55-60°C to give a concentrate (101.5 g) containing approximately 35% DAODA.

[0072] To crystallize DAODA, the concentrate was cooled slowly (over 60 min) to -10 °C with mixing. The product was isolated by filtration, washed with cold n-butanol (20 g) at -5 °C, and dried in vacuum at 60 °C to give DAODA (30.0 g) in 48.7% yield and 99% purity. The mother liquor (64 g) containing DAODA (5.1 g, 8.2% yield) and the n-butanol wash (18.5 g) containing DAODA (0.7 g, 0.9% yield) were the major sources of product loss.

[0073] Example 8

[0074] [Table 8]

[0075] procedure In an Easymax 102 reactor, add DAH (12 g, 1 equiv.), n-butanol (64 g), powdered KOH (6.4 g, 1 equiv.), powdered KOH (1.0 g, 1 equiv.), and 2 CO 3 (21.4 g, 1.5 equiv.), and tetrabutylphosphonium hydroxide (1.5 g at 40%) were charged in sequence. The suspension was heated to gentle reflux (over 15 min) and DCEE (22.4 g, 1.5 equiv.) was fed subsurface via syringe pump over 4 h while azeotropically removing water from the system. Azeotropic distillation was continued after feeding until the reaction was complete. The reaction was sampled periodically over a 12-h period.

[0076] After the reaction was completed, the inorganic solids were removed by filtration at room temperature, followed by a n-butanol wash (30 g) at room temperature. The combined solution yield of the filtrate (87 g) and wash (32 g) was 55%.

[0077] Example 9

[0078] [Table 9]

[0079] procedure In an Easymax 402 reactor, add DAH (52.9 g, 1 equiv.), n-butanol (192 g), tetrabutylphosphonium hydroxide (6.75 g at 40%), powdered K 2 CO 3 (154.4 g, 2.5 equiv.) was charged. The suspension was heated to a gentle reflux over 15 min, after which DCEE (100.8 g, 1.5 equiv.) was fed subsurface via syringe pump over 4 h and the reaction was held at reflux for an additional 8 h.

[0080] After completion of the reaction, the inorganic solids were removed by filtration at 80° C., followed by a hot n-butanol wash (150 g) at 80° C. The filtrate (250 g) and wash (155.8 g) were combined and concentrated under reduced pressure at 60-65° C. to give a concentrate (92.6 g) containing approximately 55% DAODA.

[0081] To crystallize DAODA, the concentrate was cooled slowly to -5°C over 30 min with mixing. The product was isolated by filtration, washed with cold n-butanol (34 g) at -5°C, and dried in vacuum at 60°C to give DAODA (37.5 g) in 45% yield and 99% purity. The mother liquor (41.5 g) containing DAODA (6.1 g, 7.3% yield) and the n-butanol wash (36.6 g) containing DAODA (3.4 g, 4% yield) were the major sources of product loss.

[0082] Example 10

[0083] [Table 10]

[0084] procedure In an Easymax 102 reactor, DAH (18 g, 1 equiv.), n-butanol (55 g), crystallization mother liquor (15 g, from Example 9), powdered K 2 CO 3 (53.6 g, 2.5 equiv.) was charged. The suspension was heated to gentle reflux over 15 min, after which DCEE (33.6 g, 1.5 equiv.) was fed subsurface via syringe pump over 4 h while maintaining the reaction temperature at gentle reflux. The reaction was held at reflux for an additional 8 h. The GC chemical yield of DAODA was 56%.

[0085] To better judge the reaction performance, the DAODA and DCEE in the crystallization mother liquor were subtracted from the direct determination of the reaction mass.

[0086] Example 11

[0087] [Table 11]

[0088] procedure An Easymax 102 reactor was charged with DAH (12 g, 1 equiv.), 2-methoxyethanol (58 g), and powdered K 2 CO 3 (37.5 g, 2.55 equiv.) was charged in turn. The suspension was heated to gentle reflux over 15 min and DCEE (22.4 g, 1.5 equiv.) was fed subsurface via syringe pump over 4 h. The reaction was held at reflux for an additional 8 h. The reaction was sampled periodically over 12 h.

[0089] After the reaction was complete, the inorganic solids were removed by filtration at room temperature, followed by a 2-methoxyethanol wash (25 g) at room temperature. The combined filtrate (95.4 g) gave a solution yield of 58%.

[0090] Example 12

[0091] [Table 12]

[0092] procedure An Easymax 102 reactor was charged with DAH (18 g, 1 equiv.), 2-methoxyethanol (64 g), and powdered K 2 CO 3 (42.0 g, 2.0 equiv.) was charged in turn. The suspension was heated to gentle reflux over 15 min and DCEE (33.6 g, 1.53 equiv.) was fed subsurface via syringe pump over 4 h. The reaction was held at reflux for an additional 8 h. The reaction was sampled periodically over 12 h.

[0093] After the reaction was complete, the inorganic solids were removed by filtration at room temperature, followed by a 2-methoxyethanol wash (40 g) at room temperature. The combined filtrate (149.9 g) gave a solution yield of 54.8%.

[0094] From the above, it can be seen that the present invention as claimed provides an efficient, low cost and safer reaction than those known in the prior art.

[0095] The invention is defined by the claims.

Claims

1. In the presence of an alcoholic solvent, R 1 -C(O)-NH-NH-C(O)-R 2 to R 3 -CH 2 -CH 2 -O-CH 2 -CH 2 -R 4 Compounds of formula (I), including those that react with: [Chemical 1] A method for preparing, In the formula, R 1 and R 2 are independently selected from linear or branched alkyl groups or are bonded to form a 4-, 5- or 6-membered heterocyclic ring, R 3 and R 4 is selected independently from halides or sulfates. method.

2. R 1 and R 2 The method according to claim 1, wherein i) it is methyl, or ii) it is bonded to form a five-membered heterocycle.

3. R 3 and R 4 The method according to claim 1, wherein the substance is independently selected from methylsulfonyl, chlorine, and / or bromine, and is preferably chlorine.

4. The method according to claim 1, wherein the alcoholic solvent is selected from monohydric alcohols.

5. The method according to claim 4, wherein the solvent is selected from butanol, pentanol, or 2-methoxyethanol, and preferably butanol.

6. The method according to claim 1, 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, 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), and preferably 1,4-diazabicyclo[2.2.2]octane (DABCO).

9. The method according to claim 1, carried out in the presence of a base.

10. The method according to claim 9, carried out in the presence of a base and a cobase.

11. The method according to claim 10, wherein the base-to-cobase ratio is 10:1 to 1:2, preferably 5:1 to 1:

1.

12. The method according to claim 9, wherein the base is selected from potassium carbonate, sodium carbonate, and cesium carbonate, and is preferably potassium carbonate.

13. The method according to claim 10, wherein the cobase is selected from potassium hydroxide, potassium n-butoxide, sodium hydroxide, and cesium hydroxide, and preferably potassium hydroxide.

14. The method according to claim 1, wherein the reaction is carried out at a solvent reflux temperature, preferably 110 to 125°C.

15. The method according to claim 1, comprising the removal of water by azeotropic distillation.

16. The method according to claim 1, comprising a salt filtration step.

17. The method according to claim 1, comprising a solvent distillation step, preferably only one solvent distillation step.

18. The method according to claim 1, comprising a product crystallization step.

19. A method for preparing pinoxadene, comprising the method according to any one of claims 1 to 18.

20. A compound of formula (I) produced by the method described in any one of claims 1 to 18.

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