Process for the preparation of cis-alkoxyl substituted spirocyclic 1-h-pyrrolidine-2,4-dione derivatives

Abstract

The present invention relates to a novel process for the preparation of cis-alkoxy substituted spirocyclic 1-H-pyrrolidine-2,4-dione derivatives, as well as to novel intermediates or starting compounds for the processes of the present invention.

Description

[0001] The present invention relates to a new process for the preparation of cis-alkoxy-substituted spiro 1-H-pyrrolidine-2,4-dione derivatives, as well as new intermediates and starting compounds, which undergo or are used in the process of the invention.

[0002] Multi-stage reactions of alkoxyl-substituted spiro 1-H-pyrrolidine-2,4-dione derivatives are known (WO 98 / 05638, WO 04 / 007448).

[0003] Hitherto, the disadvantage of this process was that intermediates had to be isolated. The isolation of intermediates makes the process technically very cumbersome and leads to a loss of yield. The work-up produces waste water, which is difficult to dispose of.

[0004] The object of the present invention includes the provision of a new process for the preparation of compounds of formula (I) which is more economically and ecologically viable.

[0005] Surprisingly, by the process of the present invention, cis-alkoxy-substituted spiro 1-H-pyrrolidine-2,4-dione derivatives (compounds of formula (I)) can be prepared in a simpler manner in a one-pot process from compounds of formula (II) in relatively high purity and with a better yield without isolation of intermediates. By using a one-pot process, the amount of base (acid binding agent) and the amount of waste water can also be reduced.

[0006] It has now been found that compounds of formula (I)

[0007]

[0008] wherein

[0009] X is Ci-C6-alkyl, halogen, Ci-C6-alkoxy, Ci-C6-haloalkyl or Ci-C6-haloalkoxy,

[0010] Y is hydrogen, Ci-C6-alkyl, Ci-C6-alkoxy, halogen, Ci-C6-haloalkyl or Ci-C6-haloalkoxy, wherein only one of the groups X or Y can be Ci-C6-haloalkyl or Ci-C6-haloalkoxy,

[0011] A is Ci-C6-alkyl,

[0012] G is the following group

[0013]

[0014] wherein

[0015] R, is in each case optionally halogen-substituted Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-Ci-C4-alkyl, phenyl, phenyl-Ci-C4-alkyl, heteroaryl, heteroaryl-Ci-C4-alkyl, heterocycloalkyl or heterocycloalkyl-Ci-C4-alkyl, 20 -alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-Ci-C4-alkyl, phenyl, phenyl-Ci-C4-alkyl, heteroaryl, heteroaryl-Ci-C4-alkyl, heterocycloalkyl or heterocycloalkyl-Ci-C4-alkyl, 20-Alkenyl, C1-C8-alkoxy-C2-C8-alkyl or poly-C1-C8-alkoxy-C2-C8-alkyl,

[0016] C3-C8-cycloalkyl or C1-C6-alkyl or C1-C6-alkoxy substituted with halogen, C1-C6-alkyl or C1-C6-alkoxy

[0017] In each case, the phenyl or benzyl group may be optionally substituted with halogen, cyano, nitro, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkyl, or C1-C6-haloalkoxy.

[0018] Obtained through the following steps:

[0019] First, the compound of formula (II) is cyclized in the presence of a base and a solvent.

[0020]

[0021] Where X, Y, and A are as defined above, and

[0022] R`` is a C1-C6-alkyl group.

[0023] Compound of formula (III) was obtained

[0024]

[0025] Where X, Y, and A are as defined above, and

[0026] M is an ionic equivalent of an alkali metal ion, an ionic equivalent of an alkaline earth metal ion, an ionic equivalent of an aluminum ion, or an ionic equivalent of a transition metal ion, or further...

[0027] The ammonium ion is wherein, optionally, one, two, three, or all four hydrogen atoms may be substituted by the same or different groups from the following: C1-C5-alkyl, C1-C5-isoalkyl, or C3-C7-cycloalkyl, which in each case may be substituted once or multiple times by fluorine, chlorine, bromine, cyano, or hydroxyl, or interrupted by one or more oxygen or sulfur atoms, or further

[0028] It is a cyclic aliphatic or heteroaliphatic secondary or tertiary ammonium ion, such as morpholinium, thiomorpholinium, piperidinium, pyrrolidineium, or in each case protonated 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,5-diazabicyclo[4.3.0]undec-7-ene (DBU), or further

[0029] It is a heterocyclic ammonium cation, such as, in each case, protonated pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2,4-dimethylpyridine, 2,5-dimethylpyridine, 2,6-dimethylpyridine, 5-ethyl-2-methylpyridine, pyrrole, imidazole, quinoline, quinoxaline, 1,2-dimethylimidazolium, methyl 1,3-dimethylimidazolium sulfate, or further...

[0030] For sulfonium ions, or further

[0031] It is a magnesium halogen cation.

[0032] m is the number 1, 2, or 3.

[0033] n is a number 1, 2, or 3.

[0034] and optionally, in the presence of a solvent and optionally in the presence of an acid-binding agent and optionally in the presence of a phase-transfer catalyst, reacting with compounds of formula (IV).

[0035]

[0036] in

[0037] R' is a C1-C6-alkyl group.

[0038] q is the number 0 or 1.

[0039] And Hal represents halogen.

[0040] In the above method, the redissociation of compounds of formula (I) to (III) may occur, and the compounds of formula (III) are recycled to produce compounds of formula (I) by reacting with the compounds of formula (IV) (recycling).

[0041] Furthermore, the one-pot reaction can also be carried out in a solvent free of DMAC (dimethylacetamide), representing a further improvement in the method, as the treatment of DMAC-containing wastewater is associated with high costs. Specifically, this method aims to utilize common solvents. Toluene, xylene, alkanes such as n-hexane, n-heptane, n-octane, hydrocarbons such as pentane, hexane, heptane, cyclohexane, methylcyclohexane, benzene, and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, o-dichlorobenzene, and dichloroethane can be used. Toluene or xylene is preferred. Xylene is particularly preferred.

[0042] In equations (I), (II), (III) and (IV)

[0043] X is preferably chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy.

[0044] Y is preferably hydrogen, chlorine, bromine, methoxy, methyl, ethyl, propyl, trifluoromethyl, or trifluoromethoxy, wherein only one of the groups X or Y can be trifluoromethyl or trifluoromethoxy.

[0045] A is preferably a C1-C6-alkyl group.

[0046] Hal is preferably composed of chlorine, bromine, fluorine, or iodine.

[0047] R′ is preferably a C1-C6-alkyl group.

[0048] R″ is preferably a C1-C6-alkyl group.

[0049] q is preferably the number 0 or 1.

[0050] X is particularly preferably chlorine, bromine, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, or difluoromethoxy.

[0051] Y is particularly preferably chlorine, bromine, methyl, ethyl, propyl, methoxy, trifluoromethyl, or trifluoromethoxy, wherein only one of the groups X or Y may be trifluoromethyl or trifluoromethoxy.

[0052] A is particularly preferred to be a C1-C4-alkyl group.

[0053] Hal is particularly preferably chlorine, bromine, or fluorine.

[0054] R′ is particularly preferred to be a C1-C4-alkyl group.

[0055] R″ is particularly preferred to be a C1-C4-alkyl group.

[0056] q is preferably the number 0 or 1.

[0057] X is particularly preferred to be chloro, bromine, methyl, or trifluoromethyl (especially chloro, bromine, or methyl).

[0058] Y is particularly preferably chlorine, bromine, or methyl (especially methyl).

[0059] A is particularly preferred to be methyl, ethyl, propyl, butyl, or isobutyl (especially methyl or ethyl).

[0060] Hal is particularly preferred to be chlorine or bromine.

[0061] R′ is particularly preferably methyl, ethyl, propyl, butyl, or isobutyl.

[0062] R″ is particularly preferably methyl, ethyl, propyl, butyl, or isobutyl.

[0063] q is especially preferred to be the number 0 or 1.

[0064] X is specifically methyl.

[0065] Y is specifically methyl.

[0066] A is specifically methyl.

[0067] Hal is specifically chlorine.

[0068] R′ is specifically ethyl.

[0069] R″ is specifically methyl.

[0070] q is specifically the number 0 or 1.

[0071] In equation (III)

[0072] M is preferably a lithium ion, sodium ion, potassium ion, cesium ion, magnesium ion, calcium ion, or ammonium ion, wherein optionally one, two, three, or all four hydrogen atoms may be replaced by the same or different groups from the following: C1-C5-alkyl, C1-C5-isoalkyl, or C3-C7-cycloalkyl, which in each case may be substituted once or more by fluorine, chlorine, bromine, cyano, or hydroxyl, m is a number 1 or 2, and n is a number 1 or 2.

[0073] M is preferably lithium, sodium, potassium, cesium, magnesium, or calcium, where m is a number 1 or 2 and n is a number 1 or 2.

[0074] M is particularly preferably lithium, sodium, potassium, or cesium, where m is a number 1 and n is a number 1.

[0075] M is specifically sodium, m is the number 1, and n is the number 1.

[0076] Compounds of particularly preferred formula (I-1)

[0077]

[0078] Compounds of particularly preferred formula (II-1)

[0079]

[0080] Compounds of particularly preferred formula (III-1)

[0081]

[0082] The general definitions and descriptions of the groups listed above, or those listed in the preferred ranges, can be combined arbitrarily with each other; in other words, combinations between the various ranges and preferred ranges are possible. They apply to both the final product and, consequently, to the precursors and intermediates.

[0083] The symbols given in the above equation are defined using set terms that typically represent the following substituents:

[0084] Halogens: fluorine, chlorine, bromine, and iodine

[0085] Alkyl: A saturated straight-chain or branched hydrocarbon group having 1-8 carbon atoms, such as C1-C6-alkyl, e.g., methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl 2-Methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl; heptyl, octyl.

[0086] Haloalkyl: Straight-chain or branched alkyl groups having 1-8 carbon atoms, wherein some or all of the hydrogen atoms in these groups may be substituted with halogen atoms, as described above, for example, C1-C3-haloalkyl, such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and 1,1,1-trifluoropropyl-2-yl.

[0087] The compounds of formula (I) are known (WO 98 / 05638, WO 04 / 007448) or can be prepared by the methods described therein.

[0088] The compounds of formula (II) are known (WO 98 / 05638, WO 04 / 007448, WO 13 / 144101) or can be prepared by the methods described therein.

[0089] The compound of formula (III) is new and is the subject of this invention.

[0090] The compound of formula (IV) is commercially available.

[0091] Scheme 1 : One-pot reaction including recycling

[0092] The route of the method of the present invention is represented by the following reaction scheme:

[0093]

[0094] Due to the cis / trans isomer ratio of the compound of formula (II) used in the preparation method, the compounds of formulas (I) and (III) are obtained as a mixture of cis / trans isomers, wherein the cis isomer is mainly formed in the method of the present invention.

[0095] The method is characterized by cyclizing the compound of formula (II), which has a high proportion of cis isomers, into the corresponding compound of formula (III) in the presence of a base and in the presence of a solvent. Subsequently, the compound of formula (III) is reacted with the compound of formula (IV) in the presence of a solvent, an acid-binding agent, and a phase-transfer catalyst, to give the compound of formula (I).

[0096] The reaction temperature for preparing compound (III) can be varied when carrying out the method of the present invention. Typically, a temperature of 20°C to 110°C is used, preferably 60°C to 90°C.

[0097] Alkoxides can be used as bases in both solid and solution forms. Examples include solid NaOMe or as a methanol solution, solid NaOEt or NaOEt solution, sodium bicarbonate, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, alkali metal carbonates or alkoxides such as sodium carbonate or potassium carbonate, sodium tert-butoxide or potassium tert-butoxide. In these bases, sodium may be replaced by potassium. Solid sodium methoxide or a 30% sodium methoxide methanol solution is preferred. A 30% sodium methoxide methanol solution is particularly preferred.

[0098] The solvents used may be DMAC, DMF, toluene, xylene, acetonitrile, alkanes such as n-hexane, n-heptane, n-octane, ethers such as diethyl ether, isopropyl ether, butyl ether, anisole, methyl tert-butyl ether, methyl tert-amyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, or dioxane, ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone, or methyl isobutyl ketone (MIBK), hydrocarbons such as pentane, hexane, heptane, cyclohexane, methylcyclohexane, benzene, and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, o-dichlorobenzene, and dichloroethane. Polar solvents or mixtures of polar and non-polar solvents may be used as solvents. Preferably, DMAC, DMF, acetonitrile, ethers such as methyl tert-butyl ether, methyl tert-amyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, or dioxane, and ketones such as acetone are used. DMAC is a preferred choice.

[0099] The reaction temperature for preparing compound (I) can be varied when carrying out the method of the present invention. Typically, a temperature of 20°C to 100°C is used, preferably 50°C to 70°C.

[0100] The solvents used may be DMAC, DMF, toluene, xylene, acetonitrile, alkanes such as n-hexane, n-heptane, n-octane, ethers such as diethyl ether, isopropyl ether, butyl ether, anisole, methyl tert-butyl ether, methyl tert-amyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, or dioxane, ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone, or methyl isobutyl ketone (MIBK), hydrocarbons such as pentane, hexane, heptane, cyclohexane, methylcyclohexane, benzene, and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, o-dichlorobenzene, and dichloroethane. Polar solvents or mixtures of polar and non-polar solvents may be used as solvents. Preferably, DMAC, DMF, acetonitrile, ethers such as methyl tert-butyl ether, methyl tert-amyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, or dioxane, and ketones such as acetone are used. DMAC is a preferred choice.

[0101] All conventional acid acceptors can be used as acid-binding agents. Preferred substances include: tertiary amines such as triethylamine, dimethylbenzylamine, pyridine, diazabicyclooctane (DABCO), diazabicycloundecene (DBU), diazabicyclononene (DBN), Hünig bases, and N,N-dimethylaniline; alkaline earth metal oxides such as magnesium oxide and calcium oxide; alkali metal carbonates and alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, and calcium carbonate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; and sodium bicarbonate. Triethylamine is preferred. Dimethylbenzylamine is also preferred.

[0102] The phase transfer catalyst used can be Aliquat 336, quaternary ammonium salts such as triethylbenzylammonium chloride, tetrabutylammonium bromide, or Adogen 464 (methyltrialkyl(C8-C)). 10 Ammonium chloride or TDA 1 (tris(methoxyethoxyethyl)amine) and quaternary phosphonium salts such as tetrabutylphosphonium bromide. Aliquat 336 is preferred.

[0103] When carrying out the method of the present invention, the reaction component of formula (II) is typically used in an equimolar amount to about twice the equimolar amount.

[0104] In a preferred method, the compound of formula (II) reacts with NaOCH3 (solid or methanol solution) in a DMAC to give the sodium salt of the compound of formula (III). The resulting methanol must be distilled off to avoid secondary components in subsequent stages. A subsequent reaction with the acyl chloride of formula (IV) is then carried out in the presence of a catalytic acid-binding agent (e.g., triethylamine). The solvent can then be distilled off substantially completely under reduced pressure. Depending on the distillation conditions, the compound of formula (I) can be further decomposed into the compound of formula (III).

[0105] In a particularly preferred method, after solvent distillation, a small amount of acid-binding agent (e.g., triethylamine) is added to the residue, and the acyl chloride of formula (IV) is recycled to produce the compound of formula (I). Using a variant of this method, starting with the compound of formula (II), a near-quantitative yield (>95%) of the compound of formula (I) is achieved.

[0106] Surprisingly, if the reaction of compound (III) with compound (IV) is carried out in the presence of water, the reaction of compound (II) in the presence of a base and in the presence of a solvent to produce compound (III), and the subsequent reaction of compound (IV) with compound (I) in the presence of a solvent, an acid-binding agent, and a phase-transfer catalyst, can also be carried out in nonpolar solvents (e.g., toluene, xylene, alkanes such as n-hexane, n-heptane, n-octane, hydrocarbons such as pentane, hexane, heptane, cyclohexane, methylcyclohexane, benzene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, o-dichlorobenzene, dichloroethane; toluene or xylene is preferred, and xylene is particularly preferred). In this case, during the acylation stage (reaction with compound (IV)), a suitable pH (preferably pH 3 to 12, particularly preferably pH 8 to 10) should be observed, in which the reactivity of compound (III) remains sufficiently high, while the stability of the product of formula (I) and the acyl chloride of compound (IV) is protected against alkaline saponification. The pH can be adjusted, for example, by continuously adding a base (e.g., MOH or M(OH)₂ or M(OH)₃, where M is as defined above). An aqueous solution of sodium hydroxide is preferred. The reaction can be assisted by adding a catalytic amount of phase transfer catalyst. In preferred variations of the method, the acid-binding agent can be completely or partially replaced by a phase transfer catalyst. The reaction of compound (II) to compound (III) can be assisted by adding a cosolvent. Alcohols such as methanol or ethanol are used as cosolvents, with methanol being preferred.

[0107] Preparative Examples:

[0108] Example 1 : One-pot process for the preparation of compounds of formula (I-1 ) in DMAC (no recycling after distillation of DMAC)

[0109] First, a solution of 807.69 g (0.81 mol) of the compound of formula (II-1) was added to DMAC. At an internal temperature of 60-65°C, 159.04 g (0.88 mol) of a 30% sodium methoxide methanol solution was added metered over approximately 2.5 h. The methanol was then distilled off under reduced pressure. The reaction solution was cooled to 50°C and 9.62 g of triethylamine was added metered. Subsequently, at 52-56°C, 101.54 g (0.94 mol) of ethyl chloroformate was added metered over approximately 2.5 h. The mixture was then stirred for another half hour, and a portion of the DMAC was distilled off.

[0110] Subsequently, the remaining DMAC was completely distilled off.

[0111] After adding 403.85g of xylene, the contents of the reactor were cooled to 56°C.

[0112] The xylene solution was then heated to approximately 80°C and 173.08 g of 1.6% sodium bicarbonate solution was added to separate the aqueous phase. The mixture was then washed twice with 107.69 g of water each time.

[0113] The washed xylene phase was distilled and concentrated under reduced pressure (307.69 g xylene). Subsequently, 148.08 g methylcyclohexane was added, and the mixture was cooled from about 78 °C to 23 °C.

[0114] Filter the suspension at 23-25°C. Wash the wet filter cake with methylcyclohexane and dry it.

[0115] The yield is 90% of the theoretical value.

[0116] Example 2: One-pot process for the preparation of compounds of formula (I-1 ) in DMAC (recycling after distillation of DMAC)

[0117] First, a solution of 807.69 g (0.81 mol) of the compound of formula (II-1) was added to DMAC. At an internal temperature of 60-65°C, 159.04 g (0.88 mol) of a 30% sodium methoxide methanol solution was added metered over approximately 2.5 h. The methanol was then distilled off under reduced pressure. The reaction solution was cooled to 50°C and 9.62 g of triethylamine was added metered. Subsequently, at 52-56°C, 101.54 g (0.94 mol) of ethyl chloroformate was added metered over approximately 2.5 h. The mixture was then stirred for another half hour, and a portion of the DMAC was distilled off.

[0118] Subsequently, the remaining DMAC was completely distilled off.

[0119] After adding 403.85g of xylene, the contents of the reactor were cooled to 56°C.

[0120] Recirculation: Add 3.85 g of triethylamine and 9.62 g of ethyl chloroformate (0.09 mol) by metering.

[0121] The xylene solution was then heated to approximately 80°C and 173.08 g of 1.6% sodium bicarbonate solution was added to separate the aqueous phase. The mixture was then washed twice with 107.69 g of water each time.

[0122] The washed xylene phase was distilled and concentrated under reduced pressure (307.69 g xylene). Subsequently, 148.08 g methylcyclohexane was added, and the mixture was cooled from about 78 °C to 23 °C.

[0123] Filter the suspension at 23-25°C. Wash the wet filter cake with methylcyclohexane and dry it.

[0124] The yield is 95% of the theoretical value.

[0125] Example 3: Preparation of compounds of formula (I-1 )

[0126] First, 537.8 g of the compound of formula (II-1) was added to xylene / methanol (0.500 mol, approximately 31%). Methanol was distilled off at atmospheric pressure. Then, 105 g of a methanol solution of sodium methoxide (0.583 mol, 30%) was added metered over 1 hour at 85°C. Methanol was distilled off at 85°C during the metered addition of sodium methoxide. At the end of the metered addition, the mixture was stirred at 85°C for 4 hours. Methanol was distilled off intermittently to maintain the temperature at 85°C. After 4 hours, the reaction was complete. The reaction mixture was cooled to 80°C for further reaction.

[0127] First, add 118.1 g of 2% HCl (0.06 mol) at room temperature. Add 437.8 g of a xylene / methanol solution (34%, 0.495 mol) of the compound of formula (III-1) to this feed. Then distill the mixture under reduced pressure until methanol is no longer present. Cool the mixture to 50°C and add 150 g of xylene and 15.3 g of triethylamine (0.150 mol). Subsequently, add 76.74 g of ethyl chloroacetate (0.700 mol, 99%) metered over 2 h at 50°C. Maintain the pH between 9.5 and 10 by adding 32% sodium hydroxide aqueous solution in parallel metered amounts. Then stir the mixture at 50°C for 1 / 2 h. Adjust the pH to 2 using 18% hydrochloric acid solution and add water. Heat the mixture to 75°C for phase separation, readjust the pH with sodium hydroxide aqueous solution, and then separate the phases. Add 150 g of 2% sodium bicarbonate solution at 75°C and separate the phases. The pH value is approximately 8. The organic phase was dehydrated and concentrated at approximately 75 mbar and 60–70 °C. 90.6 g of methylcyclohexane was added at 75 °C, resulting in a precipitate of a solid (compound of formula (I-1)). The reaction mixture was heated to 109 °C (reflux), cooled to 20 °C, and separated. The solid (compound of formula (I-1)) was washed with MCH by displacement washing, followed by drying. Based on the compound of formula (II-1), the separation yield was 92–93% of the theoretical value.

[0128] Example 4: Preparation of compounds of formula (I-1 )

[0129] First, 537.8 g of the compound of formula (II-1) was added to xylene / methanol (0.500 mol, approximately 31%). Methanol was distilled off at atmospheric pressure. Then, 105 g of a methanol solution of sodium methoxide (0.583 mol, 30%) was added metered over 1 hour at 85°C. Methanol was distilled off at 85°C during the metered addition of sodium methoxide. At the end of the metered addition, the mixture was stirred at 85°C for 4 hours. Methanol was distilled off intermittently to maintain the temperature at 85°C. After 4 hours, the reaction was complete. The reaction mixture was cooled to 70°C for further reaction.

[0130] 118.1 g of 2% HCl (0.06 mol) was added to the mixture (a xylene / methanol solution of compound (III-1) 34%, 0.495 mol). The mixture was stirred at 70 °C for 15 min, followed by distillation under reduced pressure of 350–250 mbar and at 50–70 °C until methanol was removed. The residue was biphasic. The mixture was cooled to 50 °C and 150 g of xylene and 15.3 g of triethylamine (0.150 mol) were added. Subsequently, 76.74 g of ethyl chloroacetate (0.700 mol, 99%) was added metered over 2 h at 50 °C. The pH was maintained between 9.5 and 10 by metered addition of 32% sodium hydroxide solution. The mixture was then stirred at 50 °C for 1 / 2 h. The pH was adjusted to 2 using 18% hydrochloric acid solution and water was added. The mixture was heated to 75 °C for phase separation, the pH was readjusted with sodium hydroxide solution, and the phases were then separated. 150 g of a 2% sodium bicarbonate solution was added at 75 °C, and the phases were separated. The pH was approximately 8. The organic phase was dehydrated and concentrated at approximately 75 mbar and 60–70 °C. 90.6 g of methylcyclohexane was added at 75 °C, thereby precipitating a solid (the compound of formula (I-1)). The reaction mixture was heated to 109 °C (reflux), cooled to 20 °C, and separated. The solid (the compound of formula (I-1)) was washed by displacement washing with MCH, and then dried.

[0131] Based on compounds of formula (II-1), the separation yield is 96-98% of the theoretical value.

[0132] Example 5: Preparation of compounds of formula (I-1 )

[0133] First, 537.8 g of the compound of formula (II-1) was added to xylene / methanol (0.500 mol, approximately 31%). Methanol was distilled off at atmospheric pressure. Then, 105 g of a methanol solution of sodium methoxide (0.583 mol, 30%) was added metered over 1 hour at 85°C. Methanol was distilled off at 85°C during the metered addition of sodium methoxide. At the end of the metered addition, the mixture was stirred at 85°C for 4 hours. To maintain the temperature at 85°C, methanol was distilled off intermittently. After 4 hours, the reaction was complete. The reaction mixture was cooled to 80°C for further reaction.

[0134] First, add 80 g of water at room temperature. Add 437.8 g of a xylene / methanol solution (34%, 0.495 mol) of compound (III-1) to this feed. Stir the mixture at 70 °C for 15 minutes, then distill under reduced pressure (350-250 mbar) and at 50-70 °C until methanol is removed. Cool the mixture to 50 °C and add 150 g of xylene and 15.3 g of triethylamine (0.150 mol). Subsequently, add 76.74 g of ethyl chloroacetate (0.700 mol, 99%) metered over 2 hours at 50 °C. Maintain the pH between 9.5 and 10 by metered addition of 32% sodium hydroxide solution in parallel. Then stir the mixture at 50 °C for 1 / 2 hour. Adjust the pH to 2 using 18% hydrochloric acid solution and add water. Heat the mixture to 75 °C for phase separation, readjust the pH with sodium hydroxide solution, and then separate the phases. Add 150g of 2% sodium bicarbonate solution at 75℃ and separate the phases. The pH value is approximately 8.

[0135] The organic phase was dehydrated and concentrated at about 75 mbar and 60–70 °C. 90.6 g of methylcyclohexane was added at 75 °C, causing a solid (compound of formula (I-1)) to precipitate. The reaction mixture was heated to 109 °C (reflux), cooled to 20 °C, and separated. The solid (compound of formula (I-1)) was washed by displacement washing with MCH, followed by drying.

[0136] Based on compounds of formula (II-1), the separation yield is 96-98% of the theoretical value.

[0137] Example 6: Preparation of compounds of formula (I-1 )

[0138] First, 537.8 g of the compound of formula (II-1) was added to xylene / methanol (0.500 mol, approximately 31%). Methanol was distilled off at atmospheric pressure. Then, 105 g of a methanol solution of sodium methoxide (0.583 mol, 30%) was added metered over 1 hour at 85°C. Methanol was distilled off at 85°C during the metered addition of sodium methoxide. At the end of the metered addition, the mixture was stirred at 85°C for 4 hours. To maintain the temperature at 85°C, methanol was distilled off intermittently. After 4 hours, the reaction was complete. The reaction mixture was cooled to 80°C for further reaction.

[0139] Add 80 g of water (forming MeOH and NaCl) to the reaction mixture (437.8 g of a xylene / methanol solution of formula (III-1) 34%, 0.495 mol). Stir the mixture at 70 °C for 15 min, then distill under reduced pressure of 350–250 mbar and at 50–70 °C until methanol is removed. The residue is biphasic. Cool the mixture to 50 °C and add 150 g of xylene and 15.3 g of triethylamine (0.150 mol). Then, add 76.74 g of ethyl chloroacetate (0.700 mol, 99%) metered over 2 h at 50 °C. Maintain the pH between 9.5 and 10 by metered addition of 32% sodium hydroxide solution in parallel. Then stir the mixture at 50 °C for 1 / 2 h. Adjust the pH to 2 using 18% hydrochloric acid solution and add water. Heat the mixture to 75 °C for phase separation, readjust the pH with sodium hydroxide solution, and then separate the phases.

[0140] Add 150g of 2% sodium bicarbonate solution at 75℃ and separate the phases. The pH value is approximately 8.

[0141] The organic phase was dehydrated and concentrated at about 75 mbar and 60–70 °C. 90.6 g of methylcyclohexane was added at 75 °C, causing a solid (compound of formula (I-1)) to precipitate. The reaction mixture was heated to 109 °C (reflux), cooled to 20 °C, and separated. The solid (compound of formula (I-1)) was washed by displacement washing with MCH, followed by drying.

[0142] Yield: 94% of theoretical value, based on compound (II-1).

[0143] Example 7: Preparation of compounds of formula (I-1 )

[0144] First, 537.8 g of the compound of formula (II-1) was added to xylene / methanol (0.500 mol, approximately 31%). Methanol was distilled off at atmospheric pressure. A methanol solution of 20.69 g of sodium methoxide (0.15 mol, 98%) was added metered over 1 h at 85 °C. Methanol was distilled off at 85 °C during the metered addition. At the end of the metered addition, the mixture was stirred at 85 °C for 4 h. To maintain the temperature at 85 °C, methanol was distilled off intermittently. After 4 h, the reaction was complete. The reaction mixture was cooled to 80 °C for further reaction.

[0145] First, add 118.1 g of 2% HCl (0.06 mol) at room temperature. Add 437.8 g of a xylene / methanol solution (34%, 0.495 mol) of compound (III-1) to this feed (forming MeOH and NaCl). Stir the mixture at 70 °C for 15 minutes, then distill under reduced pressure (350-250 mbar) and at 50-70 °C until methanol is removed. Cool the mixture to 50 °C and add 150 g of xylene and 20.69 g of dimethylbenzylamine (0.150 mol). Subsequently, add 76.74 g of ethyl chloroacetate (0.700 mol, 99%) metered over 2 hours at 50 °C. Maintain the pH between 9.5 and 10 by metered addition of 32% sodium hydroxide aqueous solution in parallel. Then stir the mixture at 50 °C for 1 / 2 hour. Adjust the pH to 2 using 18% hydrochloric acid solution and add water. The mixture was heated to 75°C to allow phase separation, the pH was readjusted with an aqueous sodium hydroxide solution, and then the phases were separated.

[0146] 150 g of a 2% sodium bicarbonate solution was added at 75 °C, and the phases were separated. The pH was approximately 8. The organic phase was dehydrated and concentrated at approximately 75 mbar and 60–70 °C. 90.6 g of methylcyclohexane was added at 75 °C, thereby precipitating a solid (the compound of formula (I)). The reaction mixture was heated to 109 °C (reflux), cooled to 20 °C, and separated. The solid (the compound of formula (I-1)) was washed by displacement washing with MCH, and then dried.

[0147] Yield: 83% of theoretical value, based on compounds of formula (II-1).

[0148] Example 8: Preparation of compounds of formula (I)

[0149] First, 537.8 g of the compound of formula (II-1) was added to xylene / methanol (0.500 mol, approximately 31%). Methanol was distilled off at atmospheric pressure. Then, 105 g of a methanol solution of sodium methoxide (0.583 mol, 30%) was added metered over 1 hour at 85°C. Methanol was distilled off at 85°C during the metered addition of sodium methoxide. At the end of the metered addition, the mixture was stirred at 85°C for 4 hours. Methanol was distilled off intermittently to maintain the temperature at 85°C. After 4 hours, the reaction was complete. The reaction mixture was cooled to 80°C for use in the reaction to generate the active ingredient.

[0150] First, add 118.1 g of 2% HCl (0.06 mol) at room temperature. Add 437.8 g of a xylene / methanol solution (34%, 0.495 mol) of compound (III-1) to this feed. Stir the mixture at 70 °C for 15 minutes, then distill under reduced pressure (350-250 mbar) and at 50-70 °C until methanol is removed. Cool the mixture to 50 °C and add 150 g of xylene and 15.3 g of triethylamine (0.150 mol). Subsequently, add 76.74 g of ethyl chloroacetate (0.700 mol, 99%) metered over 2 hours at 50 °C. Maintain the pH between 9.5 and 10 by metered addition of 32% sodium hydroxide aqueous solution in parallel. Then stir the mixture at 50 °C for 1 / 2 hour. Adjust the pH to 2 using 18% hydrochloric acid solution and add water. Heat the mixture to 75 °C for phase separation, readjust the pH with sodium hydroxide aqueous solution, and then separate the phases.

[0151] Add 150g of 2% sodium bicarbonate solution at 75℃ and separate the phases. The pH value is approximately 8.

[0152] The organic phase was dehydrated at about 75 mbar and 60–70 °C. The reaction mixture was heated to 109 °C (reflux), cooled to 0 °C, and separated. The solid (the compound of formula (I-1)) was washed by displacement washing with xylene, and then dried.

[0153] Yield: 95% of theoretical value, based on compounds of formula (II-1).

[0154] Example 9: Preparation of compounds of formula (I-1 )

[0155] First, 537.8 g of the compound of formula (II-1) was added to xylene / methanol (0.500 mol, approximately 31%). Methanol was distilled off at atmospheric pressure. Then, 105 g of a methanol solution of sodium methoxide (0.583 mol, 30%) was added metered over 1 hour at 85°C. Methanol was distilled off at 85°C during the metered addition of sodium methoxide. At the end of the metered addition, the mixture was stirred at 85°C for 4 hours. To maintain the temperature at 85°C, methanol was distilled off intermittently. After 4 hours, the reaction was complete. The reaction mixture was cooled to 80°C for further reaction.

[0156] First, add 118.1 g of 2% HCl (0.06 mol) at room temperature. Add 437.8 g of a xylene / methanol solution (34%, 0.495 mol) of compound (III-1) to this feed. Stir the mixture at 70 °C for 15 min, then distill under reduced pressure (350-250 mbar) and at 50-70 °C until methanol is removed. Cool the mixture to 50 °C and add 150 g of xylene and 4.06 g of Aliquat 336 (0.01 mol). Subsequently, add 76.74 g of ethyl chloroacetate (0.700 mol, 99%) metered over 2 h at 50 °C. Maintain the pH between 9.5 and 10 by adding 32% sodium hydroxide aqueous solution in parallel metered amounts. Then stir the mixture at 50 °C for 1 / 2 h. Adjust the pH to 2 using 18% hydrochloric acid solution and add water. Heat the mixture to 75 °C for phase separation, readjust the pH with sodium hydroxide aqueous solution, and then separate the phases.

[0157] Add 150g of 2% sodium bicarbonate solution at 75℃ and separate the phases. The pH value is approximately 8.

[0158] The organic phase was dehydrated and concentrated at about 75 mbar and 60–70 °C. 90.6 g of methylcyclohexane was added at 75 °C, causing a solid (compound of formula (I-1)) to precipitate. The reaction mixture was heated to 109 °C (reflux), cooled to 20 °C, and separated. The solid (compound of formula (I-1)) was washed by displacement washing with MCH, followed by drying.

[0159] Yield: 85% of theoretical value, based on compounds of formula (II-1).

[0160] Example 10: Preparation of compounds of formula (I-1 )

[0161] First, 537.8 g of the compound of formula (II-1) was added to xylene / methanol (0.500 mol, approximately 31%). Methanol was distilled off at atmospheric pressure. Then, 105 g of a methanol solution of sodium methoxide (0.583 mol, 30%) was added metered over 1 hour at 85°C. Methanol was distilled off at 85°C during the metered addition of sodium methoxide. At the end of the metered addition, the mixture was stirred at 85°C for 4 hours. To maintain the temperature at 85°C, methanol was distilled off intermittently. After 4 hours, the reaction was complete. The reaction mixture was cooled to 80°C for further reaction.

[0162] First, add 118.1 g of 2% HCl (0.06 mol) at room temperature. Add 437.8 g of a xylene / methanol solution (34%, 0.495 mol) of compound (III-1) to this feed. Stir the mixture at 70 °C for 15 minutes, then distill under reduced pressure (350-250 mbar) and at 50-70 °C until methanol is removed. Cool the mixture to 50 °C and add 150 g of xylene, 6.12 g of triethylamine (0.150 mol), and 4.06 g of Aliquat 336 (0.01 mol). Subsequently, meteredly add 76.74 g of ethyl chloroacetate (0.700 mol, 99%) over 2 hours at 50 °C. Maintain the pH between 9.5 and 10 by metered addition of 32% sodium hydroxide aqueous solution in parallel. Then stir the mixture at 50 °C for 1 / 2 hour. Adjust the pH to 2 using 18% hydrochloric acid solution and add water. The mixture was heated to 75°C to allow phase separation, the pH was readjusted with an aqueous sodium hydroxide solution, and then the phases were separated.

[0163] Add 150g of 2% sodium bicarbonate solution at 75℃ and separate the phases. The pH value is approximately 8.

[0164] The organic phase was dehydrated and concentrated at about 75 mbar and 60–70 °C. 90.6 g of methylcyclohexane was added at 75 °C, causing a solid (compound of formula (I-1)) to precipitate. The reaction mixture was heated to 109 °C (reflux), cooled to 20 °C, and separated. The solid (compound of formula (I-1)) was washed by displacement washing with MCH, followed by drying.

[0165] Yield: 86% of theoretical value, based on compounds of formula (II-1).

[0166] Example 11 : Preparation of compounds of formula (I-1 )

[0167] First, 537.8 g of the compound of formula (II-1) was added to xylene / methanol (0.500 mol, approximately 31%). Methanol was distilled off at atmospheric pressure. A methanol solution of sodium methoxide (0.583 mol, 30%) was added metered over 1 hour at 85°C. Methanol was distilled off at 85°C during the metered addition of sodium methoxide. At the end of the metered addition, the mixture was stirred at 85°C for 4 hours. To maintain the temperature at 85°C, methanol was distilled off intermittently. After 4 hours, the reaction was complete. The reaction mixture was cooled to 60°C and water was added. The phases were separated, and the organic phase was discarded.

[0168] The enol aqueous phase was distilled under reduced pressure (350-250 mbar) and at 50-70 °C until methanol-free. The mixture was cooled to 65 °C, and hydrochloric acid was added, followed by solid sodium bicarbonate. 67.11 g of ethyl chloroacetate (0.600 mol, 97%) was metered into the mixture over 2 h at 65 °C. The mixture was stirred at 75 °C for another 3 h. The conversion (of the compound of formula (I-1)) was determined to be 85% (HPLC).

[0169] Example 12: Preparation of compounds of formula (I-1 )

[0170] First, 537.8 g of the compound of formula (II-1) was added to xylene / methanol (0.500 mol, approximately 31%). Methanol was distilled off at atmospheric pressure. A methanol solution of sodium methoxide (0.583 mol, 30%) was added metered over 1 hour at 85°C. Methanol was distilled off at 85°C during the metered addition of sodium methoxide. At the end of the metered addition, the mixture was stirred at 85°C for 4 hours. To maintain the temperature at 85°C, methanol was distilled off intermittently. After 4 hours, the reaction was complete. The reaction mixture was cooled to 60°C and water was added. The phases were separated, and the organic phase was discarded.

[0171] The enol aqueous phase was distilled under reduced pressure (350-250 mbar) and at 50-70 °C until methanol-free. The mixture was cooled to 65 °C, and hydrochloric acid was added, followed by solid sodium bicarbonate. At 65 °C, 10 g (0.098 mol) of triethylamine and 89.48 g of ethyl chloroacetate (0.800 mol, 97%) were added to the mixture over 2 h. The mixture was stirred at 75 °C for another 3 h. The conversion (of the compound of formula (I-1)) was determined to be 75% (HPLC).

[0172] Example 13: Preparation of compounds of formula (I-1 )

[0173] First, 537.8 g of the compound of formula (II-1) was added to xylene / methanol (0.500 mol, approximately 31%). Methanol was distilled off at atmospheric pressure. A methanol solution of sodium methoxide (0.583 mol, 30%) was added metered over 1 hour at 85°C. Methanol was distilled off at 85°C during the metered addition of sodium methoxide. At the end of the metered addition, the mixture was stirred at 85°C for 4 hours. Methanol was distilled off intermittently to maintain the temperature at 85°C. After 4 hours, the reaction was complete. The reaction mixture was cooled to 60°C and water was added. The phases were separated, and the organic phase was discarded.

[0174] The enol aqueous phase was distilled under reduced pressure (350-250 mbar) and at 50-70 °C until methanol-free. The mixture was cooled to 55 °C and solid sodium bicarbonate was added. 72.70 g of ethyl chloroacetate (0.650 mol, 97%) was added to the mixture over 2 hours at 65 °C. The mixture was stirred at 55 °C for another 3 hours and distilled until alcohol-free. 150 mL of xylene was added, and the mixture was heated to 80 °C. To allow crystallization, the mixture was cooled to 20 °C and filtered. The conversion (of the compound of formula (I-1)) was determined by HPLC to be approximately 79%.

[0175] Comparative Example: Preparation of compounds of formula (I-1 ) including isolation of intermediates of formula (III-1 )

[0176] First, a solution of 807.69 g (0.81 mol) of compound (II-1) was added to DMAC. Then, over approximately 2.5 h, 159.04 g (0.88 mol) of a 30% sodium methoxide methanol solution was added. Subsequently, the methanol was distilled off under reduced pressure.

[0177] Subsequently, 440 g of water was added, and the mixture was acidified to pH 5.5 with 60.3 g of concentrated hydrochloric acid (37%) at 60 °C. The precipitated solid was filtered off at 20 °C, washed twice with 130 g of water each time, and dried under reduced pressure. 159.9 g of solid containing 98.0 g of compound (III-1) was given, corresponding to a yield of 94.5%.

[0178] Under boiling conditions, 30.4 g of ethyl chloroformate (98%) was metered and added over 15 minutes to a mixture of 500 g methylcyclohexane, 28.4 g triethylamine (98%), and 76.9 g of the compound of formula (III-1) (98.0%). After stirring under reflux for 4 h, the mixture was cooled to 80 °C and 180 g of water was added. The aqueous phase was removed with dissolved triethylamine hydrochloride. Residual water was removed from the organic phase by azeotropic distillation, and the mixture was cooled to 10 °C to allow complete crystallization of the active ingredient.

[0179] The precipitated solid was filtered off, washed with 100g of methylcyclohexane, and dried under reduced pressure.

[0180] Yield: 88.6 g, spirotetramat content of 98.8% (compound of formula (I-1)), equivalent to a yield of 93.4%.

[0181] Based on the compound of formula (II-1), the yield of the two stages is 88.3% of the theoretical value.

Claims

1. A method for preparing compounds of formula (I) in X is a methyl group. Y is a methyl group. A is a methyl group. G is one of the following groups in R' is ethyl. Its features are, In a one-pot reaction, the compound of formula (II) is first reacted. Where X, Y, and A are as defined above, and R" stands for methyl. Cyclization with sodium methoxide as a base and with dimethylacetamide (DMAC) yields a compound of formula (III). Where X, Y, and A are as defined above, and M is sodium. m is the number 1 and n is the number 1. And optionally react with the compound of formula (IV) in the presence of dimethylacetamide (DMAC), optionally in the presence of triethylamine as an acid-binding agent, and optionally in the presence of Aliquat 336 as a phase transfer catalyst. in R' is ethyl. q is the number 0 or 1. And Hal is chlorine; The compound of formula (III) formed in the further decomposition of the compound of formula (I) is recycled to produce the compound of formula (I) by reacting with the compound of formula (IV) in the presence of xylene and, optionally, triethylamine as an acid-binding agent.

2. A method for preparing compounds of formula (I) Where X, Y, A, and G are as defined in claim 1, Its features are, First, the compound of formula (II) is used. Where X, Y, A, and R are as defined in claim 1, Cyclization in the presence of sodium methoxide and xylene yields a compound of formula (III). Where X, Y, A, M, m, and n are as defined in claim 1, And optionally react with the compound of formula (IV) in the presence of xylene, and optionally in the presence of triethylamine as an acid-binding agent, and optionally in the presence of Aliquat 336 as a phase transfer catalyst. Where R', q, and Hal are as defined in claim 1, The reaction of the compound of formula (III) with the compound of formula (IV) is carried out at a pH of 8 to 10 and in the presence of water.

3. The method according to claim 2, wherein methanol is used as a co-solvent in the reaction of compound (II) to generate compound (III).

4. The method according to claim 2, wherein the aqueous sodium hydroxide solution is used as a base to adjust the pH.

5. A method for preparing compounds of formula (I) in X is a methyl group. Y is a methyl group. A is a methyl group. G is one of the following groups in R' is ethyl. Its features are, In a one-pot reaction, the compound of formula (II) is first reacted. Where X, Y, and A are as defined above, and R" stands for methyl. Cyclization with sodium methoxide as a base and with dimethylacetamide (DMAC) yields a compound of formula (III). Where X, Y, and A are as defined above, and M is sodium. m is the number 1 and n is the number 1. And optionally react with the compound of formula (IV) in the presence of dimethylacetamide (DMAC), optionally in the presence of triethylamine as an acid-binding agent, and optionally in the presence of Aliquat 336 as a phase transfer catalyst. in R' is ethyl. q is the number 0 or 1. And Hal is chlorine.

Images