Synthesis of diroximel fumarate.

Abstract

Disclosed is a one-pot process (without isolation of the three intermediates) for preparing diroximel fumarate, which is represented by the following structural formula: The method includes reacting ethylene carbonate with succinimide 5 to form 2-hydroxyethylsuccinimide; reacting the 2-hydroxyethylsuccinimide with maleic anhydride to form a (Z)-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid intermediate; isomerizing the (Z)-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid intermediate to an (E)-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid intermediate; and reacting the (E)-4-(2-10(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid intermediate with methanol to form the product compound.

Description

[Technical field]

[0001] Related Applications This application claims the benefit under 35 U.S.C. §119(e) of the filing date of U.S. Provisional Application No. 63 / 335,275, filed April 27, 2022, the entire contents of which are incorporated herein by reference.

[0002] An improved process for preparing diroximel fumarate is disclosed, which comprises reacting ethylene carbonate with succinimide to form a 2-hydroxyethylsuccinimide intermediate, reacting the 2-hydroxyethylsuccinimide intermediate with maleic anhydride in the presence of a catalytic amount of Lewis acid to form an (E)-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid intermediate, and reacting the (E)-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid intermediate with methanol in the presence of a carboxylic acid coupling agent and an acyl transfer catalyst to form diroximel fumarate. [Background technology]

[0003] Diroximel fumarate, sold under the trade name Vumerity, is a drug used to treat relapsing forms of multiple sclerosis. Diroximel fumarate was first disclosed in U.S. Patent No. 8,669,281 and was approved for medical use in the United States in October 2019.

[0004] Successful development of new drugs requires cost-effective, high-yielding syntheses suitable for large-scale production. U.S. Patent No. 8,669,281 discloses the preparation of diroximer fumarate by reacting monomethyl fumarate with 2-hydroxyethylsuccinimide in the presence of the coupling agent 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (hereinafter "TBTU") as follows: [ka] However, US Pat. No. 8,669,281 reports that this step only results in a 35% yield.

[0005] In commercial production, there are requirements in addition to high yields for the reactions used in the manufacturing process. The process must use reagents that are safe, inexpensive, and compatible with the equipment used in the factory. Furthermore, it is desirable to minimize the number of process steps to reduce waste and the need to clean equipment. Thus, there is a need for improved methodologies for preparing diroximel fumarate. Summary of the Invention

[0006] Disclosed herein is a highly efficient synthesis of diroximel fumarate, which involves four reaction steps. The process is shown diagrammatically below: [ka]

[0007] The process is highly efficient and can achieve an overall yield of 76% when carried out at pilot plant scale (see Example 3). Moreover, the disclosed process is environmentally friendly. Specifically, the reaction used in the disclosed process can be carried out in "one pot" without isolating the three intermediates, which allows efficient utilization of the manufacturing equipment and minimizes solvent usage and waste disposal. In addition, the production time is reduced to one-third of the production time required for currently used processes. This leads to efficient energy savings. Thus, the disclosed process is a highly efficient, cost-effective, and environmentally compatible process that is ideally suited for commercial production.

[0008] In one embodiment, the present invention relates to a method for producing compound (III): [ka] The present invention relates to an improved process for preparing

[0009] The process comprises the steps of: a) reacting ethylene carbonate with succinimide to produce a 2-hydroxyethylsuccinimide intermediate (I): [ka] forming a b) reacting 2-hydroxyethylsuccinimide intermediate (I) with maleic anhydride in the presence of a catalytic amount of Lewis acid to give (E)-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid intermediate (II): [ka] forming a c) reacting the (E)-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid intermediate of formula (II) with methanol in the presence of a carboxylic acid coupling agent and an acyl transfer catalyst to form the product compound (III).

[0010] Another embodiment of the present invention is a method for preparing a product compound (II) by reacting starting material (I) with maleic anhydride in the presence of a catalytic amount of magnesium bromide (MgBr2), magnesium chloride (MgCl2), or magnesium bromide ethyl etherate (MgBr2·OEt2). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The disclosed preparation of diroximer fumarate involves four reactions, including the in situ isomerization of (Z)-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid to (E)-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid. Advantageously, these reactions can all be carried out in "one pot", i.e., in one reactor, without isolation of intermediate reaction products.

[0012] The reaction of succinimide with ethylene carbonate in step a) is carried out in the presence of an amine base. Suitable amine bases are those that do not otherwise interfere with the reaction or cause side reactions. In one embodiment, a catalytic amount of base is used. In one embodiment, the amine base is diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazobicyclo(4.3.0)non-5-ene (DBN), dimethylaminopyridine (DMAP), or 1-methylimidazole. In another embodiment, the amine base is 1-methylimidazole 1,8-diazabicycloundec-7-ene (DBU).

[0013] The reaction of step a) is carried out at room temperature or at an elevated temperature. In one embodiment, the reaction of step a) is carried out at an elevated temperature, for example at a temperature at which the reaction solvent (if used) evaporates during the course of the reaction, for example at 50 ° C~120 ° In another embodiment, step a) is carried out between 80 o C~120 o Between C, 85 o C~115 o Between C and 90 o C~110 o The reaction is carried out at a temperature between 0.2 and 1.0 °C.

[0014] In one aspect, a first solvent is added to the reaction between succinimide and ethylene carbonate in step a). The amount of first solvent added is sufficient to disperse the reaction mixture to facilitate agitation or stirring of the reaction mixture. Suitable solvents include ether solvents, halogenated solvents, protic solvents, or polar aprotic solvents such as acetonitrile, or dipolar aprotic solvents such as dimethylformamide or dimethylsulfoxide. The solvent is selected to have a boiling point lower than the final reaction temperature (e.g., the boiling point of the solvent is about 10° lower than the final reaction temperature) so that the solvent is distilled as the reaction proceeds. o C~60 o C lower). This allows a minimal amount of solvent to be used. In some embodiments, the boiling point of the first solvent is 40o C~100 o Between C and 50 o C~90 o C. Examples of suitable solvents include acetonitrile, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, methyl acetate, ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, or mixtures thereof. In another embodiment, the first solvent is acetonitrile.

[0015] The reaction between 2-hydroxyethylsuccinimide and maleic anhydride in step b) is carried out in the presence of a catalytic amount of a Lewis acid. Suitable Lewis acids include magnesium bromide (MgBr2), magnesium bromide ethyl etherate (MgBr2·OEt2), magnesium chloride (MgCl2), magnesium iodide (MgI2), lithium chloride (LiCl), lithium bromide (LiBr), and nickel chloride (NiCl2). MgBr2 and MgBr2·OEt2 gave superior yields (>96%) compared to other Lewis acids tested. (See Table 1 in Example 4). Exemplary catalyst amounts include 0.01-0.20 or 0.05-0.15 molar equivalents based on the moles of ethylene carbonate. Similar results were obtained with magnesium chloride (MgCl2) when the reaction time was extended.

[0016] The reaction of step b) may be carried out in a second solvent. The second solvent is added in step b) prior to the addition of the Lewis acid. Suitable second solvents include acetone, 2-butanone, 2-pentanone, 3-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, ethyl acetate, isopropyl acetate, and mixtures thereof. In some examples, the second solvent is 2-butanone. In other examples, the second solvent is a mixture of acetonitrile and 2-butanone. In some examples, the second solvent is a 2:1 v / v mixture of 2-butanone and acetonitrile.

[0017] The Lewis acid may be added neat, i.e., as a solid, to the reactor. However, it is difficult to control the rate of addition of the solid during the scale-up process. Furthermore, it has been found that the addition of magnesium bromide anhydrous or magnesium bromide etherate at laboratory scale (e.g., 50 g) results in crusting in the reactor. "Crusting" refers to the formation of a precipitate on the reactor surface, typically on the reactor walls at or just above the fill level of the reaction mixture. Crusting can be reduced by adding the Lewis acid as a solution, i.e., dissolving the Lewis acid in the input solvent, e.g., a ketone, e.g., butanone or pentanone. To control the rate of addition, a solution containing the dissolved Lewis acid is added via a pump.

[0018] Adding a Lewis acid to a solution in which the Lewis acid is dissolved in butanone as the input solvent further reduces crust formation. It has been found that dosing magnesium bromide in one volume of butanone to a HES solution in a mixture of two volumes of butanone and one volume of acetonitrile minimizes or eliminates crust formation. In some examples, the Lewis acid of step b) is added to the reaction of step b) in a solution containing butanone. In some examples, the reaction solution of step b) is a 3:1 v / v mixture of butanone / acetonitrile butanone and acetonitrile after addition of the Lewis acid. However, other amounts of ketone may be used, which may result in a change in the volume ratio (v / v) of butanone and acetonitrile in the reaction mixture after the Lewis acid is added. That is, the reaction mixture may include a 5:1, 4:1, 3:2, 3:1, or 1:1 v / v mixture of butanone and acetonitrile, or may be butanone only.

[0019] In one embodiment, a second solvent is added to the reaction between hydroxyethylsuccinimide and maleic anhydride in step b). Exemplary solvents are selected from acetone, 2-butanone, 2-pentanone, 3-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, ethyl acetate, isopropyl acetate, and mixtures thereof. In another embodiment, the second solvent is 2-butanone or a mixture of butanone and acetonitrile.

[0020] In one embodiment, the reaction of step b) is o C~100 o Alternatively, the reaction in step b) is carried out at a temperature between 70 o C~90 o Between C, 75 o C~85 o Between C and 80 o The temperature is 0.2°C.

[0021] The reaction between (E)-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid and methanol in step c) is carried out in the presence of a carboxylic acid coupling agent and an acyl transfer catalyst.

[0022] A "carboxylic acid coupling reagent" activates the hydroxyl group of a carboxylic acid for nucleophilic substitution with an alcohol, such as the alcohol group of methanol. Carboxylic acid coupling reagents are known in the art and include, for example, carbodiimides, phosphonium reagents, aminium / uranium-immonium reagents, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, 2-propanephosphonic anhydride, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium salt, bis-trichloromethyl carbonate, 1,1'-carbonyldiimidazole, mesyl chloride, propylphosphonic anhydride, pivaloyl chloride, oxalyl chloride, and thionyl chloride. In one aspect, the carboxylic acid coupling agent in step c) is selected from carbodiimides, aminium / uranium-immonium reagents, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, 2-propanephosphonic anhydride, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium salts, bis-trichloromethyl carbonate, and 1,1'-carbonyldiimidazole. In another aspect, the carboxylic acid coupling agent is a carbodiimide. In yet another aspect, the carbodiimide is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or a salt thereof. In yet another aspect, the carbodiimide is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC·HCl).

[0023] The reaction between the carbodiimide and the carboxylic acid is believed to produce an O-acylisourea intermediate. The acyl transfer catalyst generally further promotes the formation of esters and suppresses acylurea impurities in addition to the carbodiimide coupling. The acyl transfer catalyst is a better nucleophile than alcohols and forms an activated intermediate. This activated intermediate reacts easily with alcohols to form ester products. The mediation of carbodiimide coupling with acyl transfer catalysts is described in Chan and Cox, J. Org. Chem., 72:8863 (2007). Examples of suitable acyl transfer catalysts for the carbodiimide coupling of step 3) are selected from dimethylaminopyridine, 1-methylimidazole, and 1H-benzo[d][1,2,3]triazol-1-ol (HOBt). In one embodiment, the acyl transfer catalyst for carbodiimide coupling is N-methylimidazole (NMI).

[0024] After the reaction of step c), the final product compound of formula (III) is isolated. In one embodiment, the compound of formula (III) is isolated by crystallization, for example by adding an anti-solvent such as isopropanol, followed by cooling to low temperature and then filtration.

[0025] The present invention is illustrated by the following examples which should not be construed as limiting in any way. EXAMPLES

[0026] Glossary: ACN Acetonitrile DBU 1-Methylimidazole 1,8-Diazabicycloundec-7-ene g grams h time HES Hydroxyethylsuccinimide HPLC High Performance Liquid Chromatography L Liter m mole min mL Milliliters mm millimeters mol. equivalent Molar equivalent based on moles of ethylene carbonate NMI 1-Methylimidazole μl microliter nm nanometer TFA Trifluoroacetic acid V. Volume equivalent %(v / v) Volume percentage

[0027] Example 1 - Preparation of Diroximel Fumarate with MgBr2·OEt2 The reactor was charged with ethylene carbonate (50.0 g, 0.568 m, 1.00 mol equiv.). Acetonitrile (50 mL, 1.0 V.) was added to facilitate stirring. Succinimide (59.6 g, 0.602 m, 1.06 mol equiv.) was added to the reactor, followed by DBU (1.74 g, 0.0114 m, 0.02 mol equiv.). The reactor was then cooled to 100° C. for 2 h. o The reactor was heated to 70° C. and the reaction was monitored for depletion of ethylene carbonate, which took approximately 6 hours. During the reaction, acetonitrile was removed from the reactor by distillation. The reactor was then cooled to 70° C. o The reactor was cooled to 80°C and 2-butanone (200 mL, 4.0 V) was added. Maleic anhydride (72.4 g, 0.738 m, 1.3 mol equiv.) was added to the reactor followed by acetic acid (4.09 g, 0.0682 m, 0.12 mol equiv.). Magnesium bromide ethyl etherate (MgBr2·OEt2) (11.0 g, 0.0426 m, 0.075 mol equiv.) was then added to the reactor over 1 h with stirring to minimize agglomeration of solids in the reactor. The reactor was then cooled to 80°C and 2-butanone (200 mL, 4.0 V) was added. Maleic anhydride (72.4 g, 0.738 m, 1.3 mol equiv.) was added to the reactor followed by acetic acid (4.09 g, 0.0682 m, 0.12 mol equiv.). Magnesium bromide ethyl etherate (MgBr2·OEt2) (11.0 g, 0.0426 m, 0.075 mol equiv.) was then added to the reactor over 1 h with stirring to minimize agglomeration of solids in the reactor. o The reactor was heated to 60° C. and the reaction was monitored by HPLC for depletion of 2-hydroxyethylsuccinimide (HES), which took approximately 24 hours. The reactor was heated to 60° C. for 2 hours. o The reactor was then cooled to 35° C. and methanol (36.4 g, 1.136 m, 2.0 mol equiv.) was added to the reactor. The reactor was then heated to 35° C. for an additional 2 hours. oThe reaction was cooled to 35°C. N-Methylimidazole (NMI) (0.699 g, 0.00852 m, 0.015 mol equiv.) was added to the reactor followed by N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC·HCl) (163.3 g, 0.852 m, 1.5 mol equiv.) over 1 h. The reaction was monitored by HPLC for depletion of the 4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid intermediate, which took approximately 3 h. The temperature of the reactor was increased to 35°C. o While maintaining the temperature at 55° C., water (25.0 ml, 0.5 V) was added to the reactor, followed by isopropanol (400 mL, 8.0 V). o C to create a homogeneous solution, and then the reactor was heated to 0 o Cool to 0°C and then o The contents of the reactor were collected by filtration, and the filter cake was then added to 250 mL (5.0 V) of pre-chilled (0 o C) Wash with an acetone / water mixture (1:4 v / v). The cake was then cooled under facility vacuum (with nitrogen bleed) for 50 min. o C for 24 hours to give 107.1 g (molar yield 73.9%) of the title compound as a white solid.

[0028] Example 2 - Preparation of Diroximel Fumarate Using MgBr2 and Butanone / Acetonitrile Mixture The reactor was charged with ethylene carbonate (9.20 g, 0.104 m, 1.00 mol equiv.). Acetonitrile (9.2 mL, 1.0 V.) was added to facilitate stirring. Succinimide (10.97 g, 0.111 m, 1.06 mol equiv.) was added to the reactor, followed by DBU (0.316 g, 0.00208 m, 0.02 mol equiv.). The reactor was then cooled to 100° C. o C and the reaction was monitored by GC for the depletion of ethylene carbonate, which took about 6 hours. During the reaction, acetonitrile was removed from the reactor by distillation. The reactor was then heated to 70 oThe reactor was cooled to 80° C. and 2-butanone (18.4 mL, 2.0 V) and acetonitrile (9.2 mL, 1.0 V) were added. Maleic anhydride (12.75 g, 0.130 m, 1.25 mol equiv.) was added to the reactor. Next, a solution of magnesium bromide (MgBr2) (1.44 g, 0.0078 m, 0.075 mol equiv.) in 2-butanone (9.2 mL, 1.0 V) was added to the reactor over 1 h. The reactor was then cooled to 80° C. and 2-butanone (18.4 mL, 2.0 V) and acetonitrile (9.2 mL, 1.0 V) were added. Maleic anhydride (12.75 g, 0.130 m, 1.25 mol equiv.) was added to the reactor. Next, a solution of magnesium bromide (MgBr2) (1.44 g, 0.0078 m, 0.075 mol equiv.) in 2-butanone (9.2 mL, 1.0 V) was added to the reactor over 1 h. o C and the reaction was monitored by HPLC for depletion of 2-hydroxyethylsuccinimide (HES), which took approximately 24 hours. The reactor was then heated to 60° C. for 2 hours. o Cool to 35° C., then add methanol (6.66 g, 0.208 m, 2.0 mol equiv.) to the reactor, then add 35° C. for 2 hours. o The reaction was further cooled to 35° C. N-Methylimidazole (NMI) (0.128 g, 0.00156 m, 0.015 mol equiv.) was added to the reactor followed by N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC·HCl) (31.90 g, 0.166 m, 1.60 mol equiv.) over 1 h. The reaction was monitored for depletion of the 4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid intermediate, which took approximately 3 h. The reactor temperature was increased to 35° C. o While maintaining the temperature at 55° C., water (1.84 mL, 0.2 V) was added to the reactor, followed by isopropanol (73.6 mL, 8.0 V). o C to produce a homogeneous solution; the reactor was then heated to 0 o Cool to 0°C; then o The contents of the reactor were collected by filtration, and the filter cake was then added to 46 mL (5.0 V) of pre-cooled (5 o C) Wash with an acetone / water mixture (1:4 v / v). The cake was then cooled under facility vacuum (with nitrogen bleed) for 50 min. o C for 24 hours to give 19.89 g (molar yield 74.9%) of the title compound as a white solid.

[0029] Example 3 - 50 Kilogram Scale Preparation of Diroximel Fumarate The reactor was charged with acetonitrile (3.4 kg, 0.17 V) and ethylene carbonate (25.0 kg, 1.00 mol equiv.) was added. Additional acetonitrile (2 kg, 0.1 V) was added to facilitate stirring. Succinimide (29.9 kg, 1.06 mol equiv.) was added to the reactor, followed by acetonitrile (3.2 kg, 0.16 V). The reactor temperature was increased to 75-85°C within 2.5 hours. o C, and then DBU (0.20 g, 0.005 mol equiv.) was added. The reactor was then heated to 90-100 °C within 1 h. o The reaction temperature was then heated to 90-110°C and then held at that temperature for an additional hour. o Additional DBU (0.65 kg, 0.015 mol equiv.) was added to the reactor within 3 h while maintaining the temperature at 100–110 °C. The reactor was then heated to 100–110 °C within 1 h. o The reactor was then heated to 45-55°C and then maintained at that temperature for 5 hours. During the reaction, acetonitrile was evaporated and collected by a condenser. The reactor was then heated to 45-55°C within 2.5 hours. o C and monitored the reaction by GC until less than 0.5% ethylene carbonate remained. 2-Butanone (41 kg, 2.0 V) was added to the reactor, followed by acetonitrile (19 kg, 0.97 V), then maleic anhydride (35 kg, 1.26 mol equiv).

[0030] Set the temperature of the input device to 55 o While maintaining the temperature below C, 2-butanone (24 kg, 1.2 V) was added to the dosing apparatus followed by the slow addition of magnesium bromide (MgBr2) (4 kg, 0.077 mol equiv.) with stirring. The resulting MgBr2 / 2-butanone solution was added to the reactor over 1.5 hours. The dosing apparatus was rinsed with 2-butanone (10 kg) and MEK was added to the reactor.

[0031] The reactor is then heated to 80-90°C for 2 hours. o The reactor was then heated to 55-65° C. and held at that temperature for 30 minutes and the reaction was monitored for depletion of 2-hydroxyethylsuccinimide (HES) until less than 0.4% remained and for depletion of maleic anhydride until less than 1.2% remained. The reactor was then heated to 55-65° C. for 1.5 hours.o C, then methanol (18.4 kg, 2.0 mol equiv.) is added to the reactor, and the reactor is then heated to 30-40 o C. N-methylimidazole (NMI) (0.35 kg, 0.015 mol equiv.) was added to the reactor followed by N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) within 4.4 h. . HCl) (90 kg, 1.66 mol equiv.) was added. The reaction was monitored for depletion of the cis-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid intermediate, which took approximately 4 hours.

[0032] The aqueous solution (5 kg, 0.2 V) was added to the reactor, followed by isopropanol (156 g, 7.9 V). The reactor was heated to 55–65 °C for 1 h. o C to produce a homogeneous solution; the reactor was then heated to -5 C for 3 hours. o Cool to -5 °C; then o The contents of the reactor were collected by filtration, and the filter cake was then poured into a 100 L pre-cooled (5 o C) Wash with acetone / water mixture (1:4 v / v). Then, the cake was washed with 45-55 ml of acetone / water. o C for 24 hours to give 55.3 kg of the white title compound (purity 99.2%, molar yield 75.7%).

[0033] Example 4 - Comparison of Lewis Acid Catalysts The reaction of 2-hydroxyethylsuccinimide with maleic anhydride is carried out in the presence of a catalytic amount of a Lewis acid. The results of a comparative study of various Lewis acids are shown in Table 1. [Table 1]

[0034] Magnesium bromide (MgBr2) and magnesium bromide etherate (MgBr2·OEt2) showed much higher yields (>96%) compared to the other Lewis acids tested at reaction times lasting 20-24 h, but magnesium chloride (MgCl2) gave similar yields when reaction times were extended.

Claims

1. The following structural formula (III): 【Chemistry 1】 A method for preparing a product compound represented by Steps below: a) Reacting ethylene carbonate with succinimide to give the 2-hydroxyethylsuccinimide intermediate (I): 【Chemistry 2】 forming a b) reacting said hydroxyethylsuccinimide intermediate of structural formula (I) with maleic anhydride in the presence of a catalytic amount of a Lewis acid to obtain a compound of the following structural formula (II): 【Chemistry 3】 forming an (E)-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid intermediate represented by c) reacting the (E)-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid intermediate of formula (II) with methanol in the presence of a carboxylic acid coupling agent and an acyl transfer catalyst to form the product compound (III).

2. 2. The method of claim 1, wherein steps a), b), and c) are carried out in one pot without said isolation of intermediates.

3. 3. The method of claim 1 or claim 2, wherein step a) is carried out in the presence of an amine base.

4. 4. The method of claim 3, wherein the amine base is diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazobicyclo(4.3.0)non-5-ene (DBN), dimethylaminopyridine (DMAP), or 1-methylimidazole.

5. The method of claim 3 or claim 4, wherein the amine base is diazabicyclo[5.4.0]undec-7-ene (DBU).

6. The reaction of step a) ｏ C to 120 ｏ The process according to any one of claims 1 to 5, wherein the process is carried out at a temperature between C.

7. The reaction of step a) ｏ C to 120 ｏ Between C, 85 ｏ C to 115 ｏ Between C and 90 ｏ ~110 ｏ 7. The method of claim 6, wherein the method is carried out at a temperature between 100° C.

8. The method according to any one of claims 1 to 7, wherein a first solvent is added in step a).

9. The first solvent is 50 ｏ C to 90 ｏ 9. The method of claim 8, wherein the mixture has a boiling point between C and C.

10. 10. The method of any one of claims 7 to 9, wherein the first solvent is selected from acetonitrile, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, methyl acetate, ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, and mixtures thereof.

11. The method of claim 10, wherein the first solvent is acetonitrile.

12. The method of any one of claims 1 to 11, wherein a second solvent is added in step b) prior to the addition of the Lewis acid.

13. 13. The method of claim 12, wherein the second solvent is selected from acetone, 2-butanone, 2-pentanone, 3-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, ethyl acetate, isopropyl acetate, and mixtures thereof.

14. The method of claim 12 or claim 13, wherein the second solvent is 2-butanone or a mixture of acetonitrile and 2-butanone.

15. The method of any one of claims 12 to 14, wherein the second solvent is a 2:1 v / v mixture of 2-butanone and acetonitrile.

16. The Lewis acid of step b) is magnesium chloride (MgCl ２ ), Magnesium bromide (MgBr ２ ), or magnesium bromide ethyl etherate (MgBr ２ ・OEt ２ The method according to any one of claims 1 to 15, wherein

17. 17. The method of any one of claims 1 to 16, wherein the Lewis acid of step b) is added to the reaction of step b) in a solution comprising the input solvent.

18. 18. The method of claim 17, wherein the input solvent is selected from acetone, 2-butanone, 2-pentanone, 3-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, ethyl acetate, isopropyl acetate, and mixtures thereof.

19. 19. The method of claim 17 or claim 18, wherein the input solvent is butanone.

20. 20. The method according to any one of claims 17 to 19, wherein step b) is carried out in a mixture of butanone and acetonitrile 3:1 (v / v) after addition of the Lewis acid.

21. The reaction of step b) ｏ C to 100 ｏ Temperature of C, e.g. 80 ｏ The method according to any one of claims 1 to 20, wherein the method is carried out at C.

22. 21. The method of any one of claims 1 to 20, wherein the carboxylic acid coupling agent of step c) is selected from carbodiimides, aminium / uranium-immonium reagents, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, 2-propanephosphonic anhydride, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium salts, bis-trichloromethyl carbonate, and 1,1'-carbonyldiimidazole.

23. 23. The method of claim 22, wherein the carboxylic acid coupling agent is a carbodiimide.

24. 24. The method of claim 23, wherein the carbodiimide is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or a salt thereof.

25. 25. The method of claim 24, wherein the carbodiimide is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride.

26. 26. The method of any one of claims 1 to 25, wherein the acyl transfer catalyst in step 3) is selected from dimethylaminopyridine, 1-methylimidazole, and 1H-benzo[d][1,2,3]triazol-1-ol (HOBt).

27. 27. The method of any one of claims 1 to 26, further comprising the step of: d) isolating the product compound represented by structural formula (III).

28. 28. The method of claim 27, wherein the product compound is isolated by crystallization.

29. The following structural formula (II): 【Chemistry 4】 A method for preparing a product compound represented by the formula: The following structural formula (I): 【Chemistry 5】 A starting material having Catalytic amount of MgCl ２ , MgBr ２ or MgBr ２ ・OEt ２ with maleic anhydride in the presence of to form the product represented by structural formula (II).

30. 30. The method of claim 29, wherein the reaction is carried out in acetonitrile, 2-butanone, 3-pentanone, 2-pentanone, or a mixture thereof.

31. The method of claim 29 or claim 30, wherein the reaction is carried out in a solution comprising 2-butanone and acetonitrile.

32. MgBr ２ A process according to any one of claims 29 to 31, wherein is added to the reaction as a solution comprising butanone.

33. 33. The method of claim 31 or 32, wherein the reaction is carried out in a 3:1 v / v mixture of butanone and acetonitrile.

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