Process for preparing diroximel fumarate

Abstract

Described is a process for preparing high purity diroximelfumarate in a non- halogenated solvent.

Description

[0001] PROCESS FOR PREPARING DIROXIMEL FUMARATE

[0002] FIELD OF THE INVENTION

[0003] Disclosed is an improved method for preparing diroximel fumarate. The method comprises reacting ethylene carbonate with succinimide to form a hydroxy ethyl succinimide intermediate; and reacting the intermediate with monomethyl fumarate to form diroximel fumarate.

[0004] BACKGROUND OF THE INVENTION

[0005] Diroximel fumarate is an oral medication for the treatment of relapsing forms of multiple sclerosis. It is marketed under the brand name Vumerity. It was first described in WO2014152494 Al as:

[0006] In WO2014152494, Diroximel fumarate is prepared following the below procedure:

[0007] As a typical research phase procedure, it uses expensive reagents, results in low yields and is purified using column chromatography. An alternative procedure is described in W02017108960, which couples maleic anhydride with hydroxyethylsuccinimide followed by isomerisation of the maleic acid part to a fumarate: WO2021053476 folows the basic patent process. It starts with isomerising mono- methylmaleate to monomethylfumarate followed by coupling with hydroxyethylsuccinimide:

[0008] The same order of steps, but different solvents are used in WO2022266082: WO2021053476 couples monomethylfumarate with hydroxyethylsuccinimide using

[0009] EDC.HC1 (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride) / DMAP (dimethyl aminopyridine) in dichloromethane. Diroximelfumarate is isolated in 70% yield after 1st crystallisation from ethylacetate, which is reduced to 59% yield after microfiltration. The material is reported to have 100% purity according to HPLC. An atempt to run the coupling toluenesulphonic acid in toluene using toluenesulphonic acid and azeotropic distillation to remove water, results in only 30% yield.

[0010] In one example WO2022266082 uses the same reagents EDC.HC1 / DMAP but a more environment friendly solvent, acetone. It does not report a yield or purity.

[0011] In another example the reaction is performed in a mixture of acetone and acetonitrile resulting in 83% crude yield. This example does not describe any purification atempt, and thus, no purified yield, nor purity.

[0012] WO2021053476 reports that the material can be obtained in high purity, but with a none-exciting yield using a halogenated solvent. WO2022266082 uses an environmentally friendlier solvent and shows an interesting crude yield, but does not report how much material remains after purification.

[0013] There still remains a need to identify how to achieve a good quality diroximelfumarate in an acceptable yield using solvents that are more acceptable from an environmental perspective, e.g. non-halogenated solvents.

[0014] SUMMARY OF THE INVENTION

[0015] It is an object of this invention to provide a process for preparing diroximelfumarate

[0016] (7). The process uses halogen free solvents and produces diroximelfumarate with high purity In a first aspect the invention deals with a process for coupling 2-hydroxy ethylsuccinimide (3) with monomethylfumarate (6) at low reaction temperature, preferably the reaction temperature is between 0°C and -10°C, more preferably the reaction temperature is between -3°C and -7°C, most preferably the reaction temperature is -5°C.

[0017] In a second aspect the invention deals with a process for coupling 2-hydroxy ethylsuccinimide (3) with monomethylfumarate (6) in a non-halogenated solvent that does not induce transesterification of the methylesterfunction, preferably the solvent is a nonhalogenated solvent that can dissolve the reagents and reactants and is not an ester with an alcohol other than methanol and is not an alcohol other than methanol, more preferably the solvent is a non-halogenated solvent that can dissolve the reagents and reactants and is not an ester or an alcohol, most preferably the solvent is acetonitrile.

[0018] In a third aspect the invention deals with a process for coupling 2-hydroxy ethylsuccinimide (3) with monomethylfumarate (6) with low water-content. The low water content conditions can be achieved by carefully drying the reagents, reactants and solvents, more preferably the low water content conditions are achieved by addition of magnesium sulfate to the reaction mixture.

[0019] In a fourth aspect the invention deals with a process for coupling 2-hydroxy ethylsuccinimide (3) with monomethylfumarate (6) comprising the step of adding activated charcoal to the reaction mixture.

[0020] In a fifth aspect the invention deals with a process for coupling 2-hydroxy ethylsuccinimide (3) with monomethylfumarate (6) comprising two recrystallisations of the crude product, preferable these two recrystallisations are from acetonitrile and from methanol / water.

[0021] The process of the invention uses EDC.HC1 (l-ethyl-3-(3-dimethylaminopropyl) carbodiimide) as coupling agent and DMAP (4-dimethylaminopyridine) as base. As well known in the art, many alternative coupling agents and bases are known. Not all will give the same results, but finding an alternative pair of coupling agent / base among the many options that achieves the same result is considered routine experimentation.

[0022] DETAILED DESCRIPTION OF THE INVENTION

[0023] In the search for non-halogenated solvents to use in the reaction, several solvents were tested for suitability. Of these solvents (MeTHF, EtOAc, iPrOAc, THF, toluene, acetonitrile), THF was not able to dissolve the starting materials and toluene drove the reaction to poor conversion only, EtOAc and iPrOAc reached full conversion, but caused significant levels (14% resp. 8%) of transesterification.

[0024] The reaction was run under several reaction conditions to search for optimal conditions, the results are summarised in the table below. These variations were all run using EDC.HC1 (l-ethyl-3-(3-dimethylaminopropyl)carbodiimide) as coupling agent and DMAP (4-dimethyl- aminopyridine) as base. The reaction mixture was concentrated after work-up and the material recrystallised once from the same solvent:

[0025]

[0026] #1 starting materials dried

[0027] #2 MgSC added to reaction mixture

[0028] Initial experiments a and b tested the two preferred solvents. Due to limited solubility of the starting materials, the reaction in MeTHF had to be heated to 50°C. The yields are reasonable, but purity < 99% is not good enough for pharmaceutical purposes.

[0029] Experiments c and d show the results in acetonitrile at low temperatures (-5 and -10 °C), yields are still reasonable and purity at -5 is good with 99.4%. However, the content of impurity (8) did not decrease. Impurity (8) is an impurity that was known to be present in high amounts in the product if the monomethylfumarate contained a high amount of fumaric acid. The reaction is quite exothermic. It is therefore important to control the addition of the coupling agent to stay in control of the temperature.

[0030] Experiment e shows the effect of thoroughly drying the starting materials before the reaction by using methods common in the art. For instance, solvents can be dried by distilling over common drying agents such as alkali hydroxides, calcium chloride, calcium hydride, lithium aliminium hydride, mol sieves, sodium, magnesium, etc. A person skilled in the art commonly knows which of the drying agents to apply for which level of dryness for which solvent. Reactants and reagents can be dried by applying vacuum eventually in combination with elevated temperatures. The total purity of the product goes down slightly, but impurity (8) amount is reduced to an acceptable level. The remaining impurity(ies) are mostly coupling agent related urea impurities, that can be removed from the reaction mixture by treatment with charcoal during work-up. Addition of an extra crystallisation step from MeOH / FhO and scale-up generated the final conditions that result in isolation of diroximelfumarate in 78% yield with 99.97% purity.

[0031] EXAMPLES

[0032] N-(2-hydroxyethyl)succinimide (3)

[0033] N-(2-hydroxyethyl)succinimide (3) is prepared by the solvent-free reaction of succinimide (1) with molten ethylene carbonate (2) catalyzed by potassium hydroxide at 110-120°C. After reaction completion, the mixture is diluted with toluene and n-butanol treated with activated charcoal and filtered. The mixture is cooled down and solid (3) is filtered. The crude product is stirred with MTBE (methyl ter-butyl ether), filtered and dried.

[0034] Yield: 74.5% relative to succinimide (1)

[0035] Purity: 97.3%

[0036]

[0037] Monomethylfumarate (6)

[0038] Maleic anhydride (4) (120 kg, 1 molar eq.) was weighed to a reactor and molten at 70

[0039] °C. After melting, stirring is initiated and methanol (54.8 kg, 1.4 molar eq.) is dosed over 30- 45 minutes. Reaction mixture is stirred at 60 - 65 °C for next 2h.

[0040] Ethyl acetate (420 kg) is added to the reaction mixture and temperature is set to 50- 55°C. Thiourea (1.39 kg, 0.006 molar eq.) and Methanesulfonic acid (1.76 kg, 0.006 molar eq.) were added and the mixture was stirred at 52-56 °C for 40 minutes. The reaction mixture diluted with ethyl acetate (340 kg) and washed with brine (prepared from 20 kg NaCl and 100 kg purified water) at 30 - 40 °C. Layers are separated and lower aqueous layer is discarded.

[0041] The organic layer is washed with aqueous sodium hydrogen carbonate (prepared from 7.2 kg NaHCCL, 1 kg NaCl and 120 kg purified water). Layers are separated and lower aqueous layer is discarded.

[0042] The organic solvent is removed by vacuum distillation (65 °C). 180 kg of distillate is re-heated to 65-70 °C and returned to reactor making all solids dissolved. Resulting solution is cooled to -17 to -13 °C over 90 minutes and the formed suspension is isolated using a centrifuge. Crystals in the centrifuge are washed with n-heptane. monomethylfumarate (6) (122 kg (dry-basis), 77 % yield) is obtained as a white crystalline material with 99.3 % purity.

[0043] Diroximelfumarate (7)

[0044] Acetonitrile (250 kg), Monomethyl fumarate (6) (47 kg, 1 molar equiv.), N-(2- hydroxyethyl)succinimide (3) (49 kg, 1 molar equiv.), DMAP (2.1 kg, 0.05 molar equiv.) and anhydrous magnesium sulfate (8.2 kg, 0.2 molar equiv.) were mixed in a reactor and another 90 kg of acetonitrile were added.

[0045] The mixture was stirred for 20 min at 25°C and then cooled to -20°C. Subsequently EDC.HC1 (72.2 kg, 1.1 molar equiv.) was added portion wise at -10 to -20 °C. The reactor walls were rinsed with acetonitrile (20 kg). The mixture was stirred at -7 to -3°C for 2h, after which it was quenched with an aqueous solution of brine (340 kg purified water+34 kg NaCl). The mixture was allowed to reach 25°C with stirring and phases were separated, the aqueous phase was extracted with 180 kg of acetonitrile and phases were separated.

[0046] To the combined organic extracts activated charcoal (2.5 kg) and acetonitrile (20 kg) were added. The mixture was stirred for 15 minutes at 25 °C and filtered, the filter was washed with acetonitrile (30 kg). The filtrate was re-charged to the reactor and heated to 100 °C. Vacuum was applied (65 mbar) and acetonitrile was distilled off (boiling temperature 50 °C).

[0047] Crystallization:

[0048] The distillation residue was mixed with a mixture of 75 kg of acetonitrile and 750 kg of purified water, the mixture was heated to dissolve the residue (70 °C), the formed solution was gradually cooled to -2 °C and stirred at this temperature for 1 h. the resulting suspension is isolated using a centrifuge. Crystals in the centrifuge are washed with purified water. The wet product is then recrystallized.

[0049] Recrystallization: The crude product was charged to a reactor containing a mixture of 122 kg of methanol and 610 kg of purified water. The mixture was heated to dissolve the material (70-95°C). The formed solution was gradually cooled to -2 °C and stirred at this temperature for 1 h. The resulting suspension is isolated using a centrifuge. Crystals in the centrifuge are washed with chilled purified water. The wet crystals were dried at 45 °C for 15 h (100 mbar, nitrogen stripping) giving dry diroximelfumarate (7) (72 kg, yield 78 %, purity 99.97 %).

Claims

CLAIMS1. A process for preparing diroximelfumarate (7) which comprises reacting 2-hydroxy- ethylsuccinimide (3) with monomethylfumarate (6) in a non-halogenated solvent in the presence of a coupling agent and a base wherein the reaction is performed at a temperature between 0°C and -10°C.

2. The process of claim 1 wherein the reaction is performed at a temperature between - 3°C and -7°C.

3. The process of any of claims 1-2 wherein the non-halogenated solvent is not an ester or an alcohol and capable of dissolving the reagents at the reaction temperature.

4. The process of any of claims 1-2 wherein the non-halogenated solvent is acetonitrile.

5. The process of any of the previous claims wherein the reaction mixture is essentially free from water.

6. The process of claim 5 wherein the reaction mixture is made essentially free from water by thoroughly drying starting materials, reagents and solvents before the reaction.

7. The process of claim 5 wherein the reaction mixture is made essentially free from water by adding magnesium sulfate to the reaction mixture before addition of the last reactant / reagent.

8. The process according to any of the preceding claims wherein the reaction mixture is treated with activated charcoal during work-up.

9. The process of any of the preceding claims wherein the crude material is recrystallised from acetonitril and from methanol / water.

10. The process of any of the preceding claims wherein the coupling agent is l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC).

11. The process of any of the preceding claims wherein the base is 4-dimethylamino- pyridine (DMAP).

12. A process for preparing diroximelfumarate (7) comprising the steps of:Mixing N-(2-Hydroxyethyl)succinimide (3), Monomethyl fumarate (6), 4- dimethylpyridine (DMAP) and magnesium sulphate in acetonitrile at 25°C until N-(2-Hydroxyethyl)succinimide (3), Monomethyl fumarate (6) and 4- dimethylpyridine (DMAP) are dissolved, followed by cooling the mixture to -20°C;Adding the hydrochloride salt of l-ethyl-3-(3-dimethylaminopropyl)- carbodiimide (EDC.HC1) to the reaction mixture while maintaining the temperature of the reaction mixture between -10°C and -20°C; - Stirring the reaction mixture at a temperature between -3°C and -7°C until completion;Treatment of the organic phase with activated charcoal after quenching and separation of the layers;Recrystallisation from acetonitrile; - Recrystallisation from methanol / water.

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