Synthesis of diloxamel fumarate
Through the four reaction steps, the problem of low production rate and complicated process in the existing technology in the existing technologies has achieved efficient and environmentally friendly preparation technology, which is suitable for commercial production.
Patent Information
- Application Number
- CN202380047063.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2022-04-27
- Filing Date
- 2023-04-26
- Publication Date
- 2025-01-24
AI Technical Summary
The prior art is used to prepare diloxemes fumarate with low yields and complex processes, making it difficult to meet the requirements of commercial manufacturing.
The process of four reaction steps, including the reaction of carbonate ethyl and altericide, the reaction between 2-hydroxyethyl alter and macar anhydride, and (E) -4- (2- (2, (2, (2, (2, (2, (2, 5-ethylene-1-yl) Acerumoxyl) -4-oxygenenocyl-2-hydrite and methanol response, all reactions are performed in the "one pot" to avoid the separation of the intermediate body.
The total output rate of 76%has been achieved, reducing one -third of the production time to the original process, and the process is friendly and suitable for commercial production.
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Abstract
Description
[0001] Related Applications
[0002] This application claims the benefit of the filing date of U.S. Provisional Application No. 63 / 335,275, filed on April 27, 2022, under 35 U.S.C. 119(e), the entire contents of which are incorporated herein by reference. Technical Field
[0003] An improved method for preparing diroximel fumarate is disclosed. The method 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 a Lewis acid to form a (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 Art
[0004] Deloxime fumarate is sold under the trade name Vumerity and is a drug used to treat relapsing forms of multiple sclerosis. Deloxime 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.
[0005] The successful development of new drugs requires cost-effective, high-yield synthesis suitable for large-scale manufacturing. U.S. Patent No. 8,669,281 discloses the preparation of deloxime fumarate by reacting monomethyl fumarate with 2-hydroxyethylsuccinimide in the presence of a coupling agent, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (hereinafter "TBTU"):
[0006]
[0007] However, U.S. Patent No. 8,669,281 reports that the yield of this step is only 35%.
[0008] In addition to high yields of the reactions used in the manufacturing process, commercial manufacturing has other requirements. The process should use reagents that are safe, inexpensive, and compatible with the equipment used in the factory. In addition, the number of process steps is preferably minimized to reduce waste and the need to clean equipment. Therefore, there is a need for an improved method for preparing deloxime fumarate. Summary of the invention
[0009] The present invention discloses an efficient synthesis of desiroximel fumarate, which comprises four reaction steps. The process is schematically shown below:
[0010]
[0011] The process is efficient and can achieve an overall yield of 76% when carried out on a pilot plant scale (see Example 3). In addition, the disclosed process is environmentally friendly. Specifically, the reaction used in the disclosed process can be carried out in "one pot" without separating three intermediates, which effectively utilizes manufacturing equipment and minimizes solvent use and waste disposal. In addition, the production time is reduced to one-third of the production time required for the current process. This translates into effective energy saving. Therefore, the disclosed process is an efficient, cost-effective and environmentally compatible process that is ideally suitable for commercial production.
[0012] In one embodiment, the present invention relates to an improved process for preparing the product compound (III):
[0013] (III).
[0014] The process comprises the following steps: a) reacting ethylene carbonate with succinimide to form a 2-hydroxyethylsuccinimide intermediate (I):
[0015] (I);
[0016] b) reacting the 2-hydroxyethylsuccinimide intermediate (I) with maleic anhydride in the presence of a catalytic amount of a Lewis acid to form a (E)-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid intermediate (II):
[0017] (II); and
[0018] 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).
[0019] Another embodiment of the present invention is a method for preparing the product compound (II) by reacting the starting material (I) with maleic anhydride in the presence of a catalytic amount of magnesium bromide (MgBr2), magnesium chloride (MgCl2) or magnesium bromide etherate (MgBr2·OEt2) to form the product (II). DETAILED DESCRIPTION
[0020] The disclosed preparation of deloxime 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, all reactions can be carried out in one pot, i.e., in one reactor, without the need to isolate intermediate reaction products.
[0021] The reaction between succinimide and ethylene carbonate in step a) is carried out in the presence of an amine base in one aspect. Suitable amine bases are those that do not otherwise interfere with the reaction or cause side reactions. In one aspect, a catalytic amount of base is used. In one aspect, the amine base is diazabicyclo [5.4.0] 11 carbon-7-ene (DBU), 1,5-diazabicyclo (4.3.0) non-5-ene (DBN), dimethylaminopyridine (DMAP) or 1-methylimidazole. On the other hand, the amine base is 1-methylimidazole 1,8-diazabicyclo 11 carbon-7-ene (DBU).
[0022] The reaction of step a) is carried out at room temperature or at an elevated temperature. In one aspect, the reaction of step a) is carried out at an elevated temperature, such as a temperature at which the reaction solvent (if used) evaporates during the reaction (e.g., between 50°C and 120°C). In another aspect, step a) is carried out at a temperature between 80°C and 120°C, 85°C and 115°C, or 90°C and 110°C.
[0023] In one aspect, the first solvent is added to the reaction between succinimide and ethylene carbonate in step a). The amount of the first solvent added is enough to disperse the reaction mixture to promote the 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 dimethyl sulfoxide. Select solvent so that the solvent has a boiling point lower than the final reaction temperature, so that the solvent is distilled as the reaction proceeds (for example, when the boiling point of the solvent is about 10°C to 60°C lower than the final reaction temperature). This allows the use of a minimum amount of solvent. In one aspect, the first solvent has a boiling point between 40°C and 100°C or between 50°C and 90°C. Examples of suitable solvents include acetonitrile, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, methyl acetate, ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol or a mixture thereof. On the other hand, the first solvent is acetonitrile.
[0024] The reaction between 2-hydroxyethyl succinimide 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 etherate (MgBr2·OEt2), magnesium chloride (MgCl2), magnesium iodide (MgI2), lithium chloride (LiCl), lithium bromide (LiBr) and nickel chloride (NiCl2). Compared with other Lewis acids tested, MgBr2 and MgBr2·OEt2 obtained excellent yields (>96%). (See Table 1 in Example 4). Exemplary catalytic amounts include 0.01 to 0.20 or 0.05 to 0.15 molar equivalents based on the moles of ethylene carbonate. When the reaction time is extended, magnesium chloride (MgCl2) obtains similar results.
[0025] The reaction in step b) can be carried out in the second solvent. In step b), the second solvent is added before adding 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 instances, the second solvent is 2-butanone. In other instances, the second solvent is a mixture of acetonitrile and 2-butanone. In some instances, the second solvent is a 2:1 v / v mixture of 2-butanone and acetonitrile.
[0026] Lewis acid can be added to the reactor in pure form (i.e., in solid form). However, it is difficult to control the addition rate of solids during the scale-up process. In addition, it is found that even at laboratory scale (e.g., 50 grams), crusting in the reactor also occurs when anhydrous magnesium bromide or magnesium bromide etherate is added. "Crusting" refers to the formation of a precipitate on the reactor surface, usually on the reactor wall at the filling level of the reaction mixture or slightly above the filling level of the reaction mixture. Crusting can be reduced by adding a Lewis acid in the form of a solution, i.e., wherein the Lewis acid is dissolved in a feed solvent, such as a ketone (e.g., butanone or pentanone). In order to control the addition rate, a solution containing the dissolved Lewis acid is added by a pump.
[0027] When Lewis acid is added as a solution, crusting is further reduced, wherein Lewis acid is dissolved in the butanone as a feed solvent. It is found that relative to the solution of HES in a mixture of 2 volumes of butanone and 1 volume of acetonitrile, crusting is minimized or eliminated by adding magnesium bromide in 1 volume of butanone. In some instances, the Lewis acid of step b) is added to the reaction of step b) in a solution comprising butanone. In some instances, the reaction solution of step b) is a 3:1 v / v mixture of butanone and acetonitrile after adding Lewis acid. However, the ketone of other amounts can be used so that the volume ratio (v / v) of butanone and acetonitrile in the reaction mixture after adding Lewis acid can be changed, that is, the reaction mixture can include 5:1,4:1,3:2,3:1 or 1:1 v / v mixtures of butanone and acetonitrile, or can be only butanone.
[0028] In one aspect, 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 aspect, the second solvent is 2-butanone or a mixture of butanone and acetonitrile.
[0029] In one aspect, the reaction of step b) is carried out at a temperature between 60°C and 100°C. Alternatively, the reaction of step b) is carried out at a temperature between 70°C and 90°C, between 75°C and 85°C, or at 80°C.
[0030] In step c), the reaction between (E)-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid and methanol is carried out in the presence of a carboxylic acid coupling acid agent and an acyl transfer catalyst.
[0031] "Carboxylic acid coupling reagents" activate the hydroxyl group of a carboxylic acid so that it is nucleophilically substituted by, for example, an alcohol (such as an alcohol group of methanol). Carboxylic acid coupling reagents are known in the art and include, for example, carbodiimides, phosphonium reagents, ammonium / uranium-immonium reagents, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, 2-propanephosphonic anhydride, 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium salt, bis-trichloromethyl carbonate, 1,1'-carbonyldiimidazole, methanesulfonyl chloride, propylphosphonic anhydride, pivaloyl chloride, oxalyl chloride, and thionyl chloride. In one aspect, the carboxylic acid coupling agent of step c) is selected from carbodiimide, ammonium / uranium-immonium reagent, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, 2-propanephosphonic anhydride, 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium salt, bis-trichloromethyl carbonate and 1,1'-carbonyldiimidazole. On the other hand, the carboxylic acid coupling agent is carbodiimide. On the other hand, the carbodiimide is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or its salt. On the other hand, the carbodiimide is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC . HCl).
[0032] It is believed that the reaction between carbodiimide and carboxylic acid produces O-acylisourea intermediate.Acyl transfer catalyst is usually added to carbodiimide coupling to further accelerate the formation of ester and suppress acylurea impurities.Acyl transfer catalyst is a better nucleophile than alcohol and forms an activated intermediate. This activated intermediate easily reacts with alcohol to form product ester. Using acyl transfer catalyst to mediate carbodiimide coupling is described in Chan and Cox, J. Org. Chem., 72: 8863 (2007). The example of suitable acyl transfer catalyst for carbodiimide coupling of step 3) is selected from dimethylaminopyridine, 1-methylimidazole and 1H-benzo [d] [1,2,3] triazole-1-ol (HOBt). In one aspect, the acyl transfer catalyst for carbodiimide coupling is N-methylimidazole (NMI).
[0033] After the reaction in step c), the final product compound represented by formula (III) is isolated. In one aspect, 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 filtering.
[0034] The present invention is illustrated by the following examples, which are not intended to be limiting in any way.
[0035] Example
[0036] Glossary of terms:
[0037]
[0038] Example 1 - Preparation of Deloxime Fumarate Using MgBr2·OEt2
[0039] Ethylene carbonate (50.0 g, 0.568 m, 1.00 mol. eq.) is loaded into the reactor. Acetonitrile (50 mL, 1.0 V.) is added to promote stirring. Succinimide (59.6 g, 0.602 m, 1.06 mol. eq.) is added into the reactor, and then DBU (1.74 g, 0.0114 m, 0.02 mol. eq.) is added. The reactor is then heated to 100 ° C, and the consumption of ethylene carbonate in the monitoring reaction is required for about six hours. In the reaction process, acetonitrile is removed from the reactor by distillation. Next, the reactor is cooled to 70 ° C and 2-butanone (200 mL, 4.0 V) is added. Maleic anhydride (72.4 g, 0.738 m, 1.3 mol. eq.) was added to the reactor, followed by acetic acid (4.09 g, 0.0682 m, 0.12 mol. Eq.). Next, magnesium bromide etherate (MgBr2·OEt2) (11.0 g, 0.0426 m, 0.075 mol. eq.) was added to the reactor under stirring over 1 hour to minimize the aggregation of solids in the reactor. The reactor was then heated to 80°C and the depletion of 2-hydroxyethylsuccinimide (HES) in the reaction was monitored by HPLC, which took about 24 hours. The reactor was cooled to 60°C over a two-hour period, and methanol (36.4 g, 1.136 m, 2.0 mol. eq.) was then added to the reactor. Next, the reactor was further cooled to 35°C over a two-hour period. N-methylimidazole (NMI) (0.699 g, 0.00852 m, 0.015 mol.eq.) was added to the reactor, followed by the addition of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) over a period of 1 hour. .HCl) (163.3 g, 0.852 m, 1.5 mol. eq.). The depletion of the 4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid intermediate in the reaction was monitored by HPLC, which took about 3 hours. The reactor temperature was maintained at 35°C, and water (25.0 ml, 0.5 V) was added to the reactor, followed by isopropanol (400 mL, 8.0 V). The reactor was heated to 55°C to make a homogeneous solution, then the reactor was cooled to 0°C over 3 hours, and then stirred at 0°C for 1 hour. The reactor contents were collected by filtration, and the filter cake was then washed with 250 mL (5.0 V) of pre-cooled (0°C) acetone / water mixture (1:4 v / v). The filter cake was then dried at 50°C for 24 hours under house vacuum (using nitrogen venting) to give 107.1 g (73.9% molar yield) of the white title compound.
[0040] Example 2 - Preparation of Deloxime Fumarate Using MgBr2 and Butanone / Acetonitrile Mixture
[0041] Ethylene carbonate (9.20 g, 0.104 m, 1.00 mol. eq.) is loaded into the reactor. Acetonitrile (9.2 mL, 1.0 V.) is added to promote stirring. Succinimide (10.97 g, 0.111 m, 1.06 mol. eq.) is added into the reactor, and then DBU (0.316 g, 0.00208 m, 0.02 mol. eq.) is added. The reactor is then heated to 100 ° C, and the consumption of ethylene carbonate in the GC monitoring reaction is required for about six hours. In the reaction process, acetonitrile is removed from the reactor by distillation. Next, the reactor is cooled to 70 ° C, and 2-butanone (18.4 mL, 2.0 V) and acetonitrile (9.2 mL, 1.0 V) are added. Maleic anhydride (12.75 g, 0.130 m, 1.25 mol. eq.) is added into the reactor. Next, a solution of magnesium bromide (MgBr2) (1.44 g, 0.0078 m, 0.075 mol. eq.) in 2-butanone (9.2 mL, 1.0 V) was added to the reactor over a 1 hour period. The reactor was then heated to 80°C and the depletion of 2-hydroxyethylsuccinimide (HES) in the reaction was monitored by HPLC, which took about 24 hours. The reactor was then cooled to 60°C over a 2 hour period, and methanol (6.66 g, 0.208 m, 2.0 mol. eq.) was then added to the reactor, which was then further cooled to 35°C over a 2 hour period. N-methylimidazole (NMI) (0.128 g, 0.00156 m, 0.015 mol. eq.) was added to the reactor, and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) was then added over a 1 hour period. . HCl) (31.90 g, 0.166 m, 1.60 mol. eq.). The reaction was monitored for consumption of the 4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid intermediate, which took about 3 hours. The reactor temperature was maintained at 35°C, and water (1.84 mL, 0.2 V) was added to the reactor, followed by isopropanol (73.6 mL, 8.0 V). The reactor was heated to 55°C to make a homogeneous solution; the reactor was then cooled to 0°C over 3 hours; and then stirred at 0°C for 1 hour. The reactor contents were collected by filtration, and the filter cake was then washed with 46 mL (5.0 V) of pre-cooled (5°C) acetone / water mixture (1:4 v / v). The filter cake was then dried at 50°C under house vacuum (with nitrogen bleed) for 24 hours to give 19.89 g (74.9% molar yield) of the title compound as a white color.
[0042] Example 3 - Preparation of Deloxime Fumarate on a 50 kg scale
[0043] Acetonitrile (3.4 kg, 0.17 V) was loaded into the reactor and ethylene carbonate (25.0 kg, 1.00 mol.eq.) was added. Additional acetonitrile (2 kg, 0.1 V) was added to facilitate stirring. Succinimide (29.9 kg, 1.06 mol.eq.) was added to the reactor, followed by acetonitrile (3.2 kg, 0.16 V). The reactor was brought to a temperature of 75°C-85°C over a 2.5 hour period, followed by the addition of DBU (0.20 g, 0.005 mol.eq.). The reactor was then heated to 90°C-100°C within 1 hour, followed by another 1 hour at this temperature. Additional DBU (0.65 kg, 0.015 mol.eq.) was added to the reactor over a 3 hour period while the reaction temperature was maintained at 90°C-110°C. The reactor was then heated to 100°C-110°C within 1 hour, followed by a 5 hour period at this temperature. During the reaction, acetonitrile evaporates and is collected by a condenser. Next, the reactor is cooled to 45°C-55°C over a 2.5 hour period, and the reaction is monitored by GC until less than 0.5% ethylene carbonate remains. 2-Butanone (41 kg, 2.0 V) is added to the reactor, followed by acetonitrile (19 kg, 0.97 V), and then maleic anhydride (35 kg, 1.26 mol. eq.).
[0044] 2-Butanone (24 kg, 1.2 V) was added to the charging apparatus, followed by the slow addition of magnesium bromide (MgBr2) (4 kg, 0.077 mol. eq.) with stirring while maintaining the charging apparatus temperature below 55°C. The resulting MgBr2 / 2-butanone solution was added to the reactor over a period of 1.5 hours. The charging apparatus was rinsed with 2-butanone (10 kg), and MEK was added to the reactor.
[0045] The reactor was then heated to 80-90°C over a 2 hour period and then held at that temperature for 30 minutes and the reaction was monitored for 2-hydroxyethylsuccinimide (HES) depletion until less than 0.4% remained and maleic anhydride depletion was monitored until less than 1.2% remained. The reactor was then cooled to 55-65°C over a 1.5 hour period and methanol (18.4 kg, 2.0 mol. eq.) was then added to the reactor and then the reactor was further cooled to 30-40°C over a 1 hour period. N-methylimidazole (NMI) (0.35 kg, 0.015 mol. eq.) was added to the reactor and then N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) was added over a 4.4 hour period. . HCl) (90 kg, 1.66 mol.eq.). The reaction was monitored for consumption of the cis-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid intermediate, which took about 4 hours.
[0046] Water (5 kg, 0.2 V) was added to the reactor, followed by isopropanol (156 g, 7.9 V). The reactor was heated to 55°C-65°C over a 1 hour period to make a homogeneous solution; the reactor was then cooled to -5°C over a 3 hour period; and then stirred at -5°C for 3 hours. The reactor contents were collected by filtration, and the filter cake was then washed with 100 L of pre-cooled (5°C) acetone / water mixture (1:4 v / v). The filter cake was then dried at 45°C-55°C for 24 hours to give 55.3 kg (99.2% purity, 75.7% molar yield) of the white title compound.
[0047] Example 4 - Comparison of Lewis Acid Catalysts
[0048] The reaction between 2-hydroxyethylsuccinimide and maleic anhydride was 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:
[0049] Table 1: Comparison of Lewis acid catalysts
[0050]
[0051] Compared to other Lewis acids tested for reaction times lasting 20-24 hours, magnesium bromide (MgBr2) and magnesium bromide etherate (MgBr2.OEt2) provided much higher yields (> 96%). However, magnesium chloride (MgCl2) gave similar yields when the reaction time was extended.
Claims
1. A method for preparing a product compound represented by the following structural formula (III): (III); The method comprises the following steps: a) reacting ethylene carbonate with succinimide to form a 2-hydroxyethylsuccinimide intermediate represented by the following structural formula (I): (I)； b) reacting the hydroxyethylsuccinimide intermediate of formula (I) with maleic anhydride in the presence of a catalytic amount of Lewis acid to form a (E)-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid intermediate represented by the following formula (II): (II); and 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. The process of claim 1, wherein steps a), b) and c) are carried out in one pot without isolating intermediates.
3. The process of claim 1 or claim 2, wherein step a) is carried out in the presence of an amine base.
4. The method of claim 3, wherein the amine base is diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), dimethylaminopyridine (DMAP) or 1-methylimidazole.
5. A process as claimed in claim 3 or claim 4, wherein the amine base is diazabicyclo[5.4.0]undec-7-ene (DBU).
6. The process of any one of claims 1 to 5, wherein the reaction in step a) is carried out at a temperature between 50°C and 120°C.
7. The process of claim 6, wherein the reaction in step a) is carried out at a temperature between 80°C and 120°C, 85°C and 115°C, or 90°C and 110°C.
8. The method of any one of claims 1 to 7, wherein a first solvent is added in step a).
9. The method of claim 8, wherein the first solvent has a boiling point between 50°C and 90°C.
10. The method of any one of claims 7-9, 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 process of any one of claims 1 to 11, wherein in step b) a second solvent is added before the Lewis acid is added.
13. The method of claim 12, wherein the second solvent is selected from the group consisting of acetone, 2-butanone, 2-pentanone, 3-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, ethyl acetate, isopropyl acetate, and mixtures thereof.
14. A method as claimed in 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 12-14, wherein the second solvent is a 2:1 v / v mixture of 2-butanone and acetonitrile.
16. The process of any one of claims 1 to 15, wherein the Lewis acid of step b) is magnesium chloride (MgCl2), magnesium bromide (MgBr2) or magnesium bromide etherate (MgBr2.OEt2).
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 a feed solvent.
18. The method of claim 17, wherein the feed solvent is selected from the group consisting of acetone, 2-butanone, 2-pentanone, 3-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, ethyl acetate, isopropyl acetate, and mixtures thereof.
19. The method of claim 17 or claim 18, wherein the feed solvent is butanone.
20. The process of any one of claims 17-19, wherein step b) is performed in a 3:1 v / v mixture of butanone and acetonitrile after adding the Lewis acid.
21. The process of any one of claims 1-20, wherein the reaction of step b) is carried out at a temperature between 60°C and 100°C, such as at 80°C.
22. The method of any one of claims 1 to 20, wherein the carboxylic acid coupling agent of step c) is selected from carbodiimide, ammonium / uranium-immonium reagent, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, 2-propanephosphonic anhydride, 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium salt, bis-trichloromethyl carbonate and 1,1'-carbonyldiimidazole.
23. The method of claim 22, wherein the carboxylic acid coupling agent is a carbodiimide.
24. The method of claim 23, wherein the carbodiimide is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or a salt thereof.
25. The method of claim 24, wherein the carbodiimide is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride.
26. The process of any one of claims 1 to 25, wherein the acyl transfer catalyst of step 3) is selected from dimethylaminopyridine, 1-methylimidazole and 1H-benzo[d][1,2,3]triazol-1-ol (HOBt).
27. The method of any one of claims 1 to 26, wherein the method further comprises the following steps: d) isolating the product compound represented by structural formula (III).
28. The process of claim 27, wherein the product compound is isolated by crystallization.
29. A method for preparing a product compound represented by the following structural formula (II): (II) The method comprises the following steps of preparing a starting material having the following structural formula (I): (I) React with maleic anhydride in the presence of a catalytic amount of MgCl2, MgBr2 or MgBr2.OEt2 to form the product represented by structural formula (II).
30. The process of claim 29, wherein the reaction is carried out in acetonitrile, 2-butanone, 3-pentanone, 2-pentanone or a mixture thereof.
31. A method as claimed in claim 29 or claim 30, wherein the reaction is carried out in a solution comprising 2-butanone and acetonitrile.
32. The process of any one of claims 29-31, wherein MgBr2 is added to the reaction as a solution comprising butanone.
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.
Citation Information
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