阅读说明：本技术 一种富马酸地洛昔醇的制备方法 (Preparation method of desloxinol fumarate ) 是由 魏万国 姜能桥 于 2019-09-18 设计创作，主要内容包括：本发明涉及原料药制备方法技术领域,具体涉及原料药富马酸地洛昔醇的制备方法。所述制备方法包括如下步骤：1)氨化反应：将丁二酸酐与氨化试剂进行反应,生成丁二酰亚胺；2)烷基化反应：将丁二酰亚胺与1,2卤代乙烷在催化剂、碱存在的条件下进行反应,生成式IV化合物；3)酯化反应：将式IV化合物与反式-富马酸单甲酯进行反应,生成富马酸地洛昔醇。本发明所需物料试剂方便易得、反应步骤较短总产率比较高、产品通过重结晶易于纯化、基毒杂质通过重结晶易于控制等优点。(The invention relates to the technical field of preparation methods of bulk drugs, in particular to a preparation method of a bulk drug of deloxitol fumarate. The preparation method comprises the following steps: 1) ammoniation reaction: reacting succinic anhydride with an ammoniation reagent to generate succinimide; 2) alkylation reaction: reacting succinimide with 1, 2-halogenated ethane in the presence of a catalyst and alkali to generate a compound shown in a formula IV; 3) esterification reaction: reacting the compound of formula IV with trans-monomethyl fumarate to produce desloxinol fumarate. The method has the advantages of convenient and easily obtained material reagents, short reaction steps, high total yield, easy purification of products through recrystallization, easy control of basic toxic impurities through recrystallization and the like.)

1. A preparation method of desloxydil fumarate comprises the following steps:

1) ammoniation reaction: reacting succinic anhydride with an ammoniating reagent to generate succinimide, wherein the reaction equation is as follows:

2) alkylation reaction: reacting succinimide with 1,2 halogenated ethane in the presence of a catalyst and alkali to generate a compound shown in a formula IV, wherein the reaction equation is as follows:

in the compound of the formula III, X is selected from Br, Cl or I, and X' is selected from Br, Cl or I;

3) esterification reaction: reacting a compound of formula IV with monomethyl trans-fumarate to form desloxinol fumarate, according to the following equation:

2. the method of claim 1, wherein in step 1), the molar ratio of succinic anhydride to ammoniating agent is 1: 1-1: 2.

3. the method according to claim 1, wherein in step 1), the ammoniating agent is selected from the group consisting of NH₃·H₂O、NH₂OH·HCl、NH₄Cl、NH₃、NH₄OAc and urea.

4. The method according to claim 1, wherein the step 1) further comprises one or more of the following technical features:

A1) adding a catalyst in the ammoniation reaction, wherein the catalyst is one or a combination of more of phosphorous acid, p-toluenesulfonic acid and methanesulfonic acid, and the mass of the catalyst is 1-10% of that of succinic anhydride;

A2) the reaction temperature of the amination reaction in the step 1) is 120-220 ℃;

A3) in the step 1), the post-reaction treatment method comprises the following steps: quenching and recrystallizing the reaction to obtain the compound shown in the formula II.

5. The method of claim 1, wherein the method comprisesIn the step 2), the catalyst is a phase transfer catalyst selected from Bu₄N⁺Br^-、Bu₄N⁺I^-Benzyl triethyl ammonium chloride, tetrabutyl ammonium hydrogen sulfate, trioctylmethyl ammonium chloride, dodecyl trimethyl ammonium chloride and 18 crown 6.

6. The method according to claim 1, wherein in step 2), the base is selected from inorganic bases, preferably from Na₂CO₃、K₂CO₃One or more of KOH and NaOH.

7. The method according to claim 1, wherein the step 2) further comprises one or more of the following technical features:

B1) in the step 2), the reaction is carried out under the protection of gas;

B2) in the step 2), the molar ratio of the succinimide to the 1,2 halogenated ethane is 1: 1-1: 3;

B3) in the step 2), the mass of the catalyst is 1-10% of that of the succinimide;

B4) in the step 2), the molar ratio of alkali to succinimide is 1-2;

B5) in the step 2), the reaction is carried out in the presence of a solvent, wherein the solvent is one or more of acetonitrile, DMF, acetone, tetrahydrofuran and 1, 4-dioxane;

B6) in the step 2), the reaction temperature is 20-90 ℃.

8. The method according to claim 1, wherein in the step 2), the post-reaction treatment is carried out by: quenching the reaction, extracting, removing the solvent of the organic phase, and purifying to obtain the compound shown in the formula IV.

9. The method according to claim 1, wherein step 3) further comprises one or more of the following technical features:

C1) in the step 3), the molar ratio of the compound shown in the formula IV to the trans-monomethyl fumarate is 1: 1-1: 1.5;

C2) in the step 3), the reaction is carried out under the condition of a solvent, wherein the solvent comprises one or more of tetrahydrofuran, dimethyl sulfoxide, 1,4-dioxane, water, toluene, chloroform, acetone and acetonitrile;

C3) in the step 3), a base is used in the reaction, and the base is an inorganic base, preferably selected from sodium carbonate and/or potassium carbonate;

C4) in the step 3), the molar ratio of the alkali to the compound of the formula IV is 1.0-2.0;

C5) in the step 3), the reaction temperature of the esterification reaction is 20-80 ℃.

10. The method according to claim 1, wherein the post-reaction treatment in step 3) is carried out by: quenching the reaction, extracting, desolventizing, dissolving in alcohol, and filtering to obtain the desloxy alcohol fumarate.

Technical Field

The invention relates to the technical field of preparation methods of bulk drugs, in particular to a preparation method of a bulk drug of deloxitol fumarate.

Background

Desloxydil fumarate (Diroximel Fumarete, ALKS-8700, BII098), tradename Vumerity, is a novel oral fumaric acid drug used for the treatment of Relapsing Multiple Sclerosis (RMS). Desloxinol fumarate, a monomethyl fumarate (MMF) prodrug that is an immunosuppressant, administered orally 2 times daily, in a controlled release dosage form, is developed by Alkermes, and is rapidly converted to MMF in vivo.

In 2019, Baijian in combination with the partner Alkermes announced that both parties have filed a New Drug Application (NDA) for diroximel fumarate (BIIB098) to the U.S. food and drug administration. On 25.02/2019, the FDA accepts the drug takermes/baijian multiple sclerosis, diloxitol fumarate (under the tradename Vumerity), for marketing application, and the indication is relapsing-remitting multiple sclerosis (RRMS).

The English name of the desloxydil fumarate is: 4-O- [2- (2, 5-dioxorolidin-1-yl) ethyl ] -1-O-methyl (E) -but-2-enedioate, Chinese name: 2- (2,5-dioxopyrrolidin-1-yl) ethylmethyl fumarate. CAS: 1577222-14-0, the molecular formula is C11H13NO6, the medicine molecule contains (E) -monomethyl fumarate and 2, 5-dioxopyrrolidine structural units, the structural formula is as follows:

in 2014, the Alkermes company firstly reported a synthesis method of the dloxitol fumarate (US 8669281B1, WO 2014152494a1), and patented the structure of the dloxitol fumarate as follows:

wherein R1 is unsubstituted C1-6 alkyl, L is unsubstituted C1-6 alkyl chain, unsubstituted C3-10 carbocycle, unsubstituted C6-10 aromatic ring, etc. R2 or R3 is H, C1-6 alkyl, C2-6 alkenyl, etc. Diloxinol fumarate was prepared in 35% yield from the condensation reaction of monomethyl fumarate and N- (2-hydroxyethyl) succinamide. The specific route is as follows:

disclosure of Invention

In view of the above-mentioned disadvantages of the prior art, the present invention aims to provide a novel synthesis route for preparing desloxinol fumarate, which has the advantages of easily available reagents, greatly improved reaction yield, easily purified product, easily controlled impurities, etc., and has obvious technical advantages.

To achieve the above and other related objects, an aspect of the present invention provides a method for preparing desloxinol fumarate, comprising the steps of:

1) ammoniation reaction: reacting succinic anhydride with an ammoniating reagent to generate succinimide, wherein the reaction equation is as follows:

2) alkylation reaction: reacting succinimide with 1,2 halogenated ethane in the presence of a catalyst and alkali to generate a compound shown in a formula IV, wherein the reaction equation is as follows:

in the compound of the formula III, X is selected from Br, Cl or I, and X' is selected from Br, Cl or I;

3) esterification reaction: reacting a compound of formula IV with monomethyl trans-fumarate to form desloxinol fumarate, according to the following equation:

in some embodiments of the invention, in step 1), the molar ratio of succinic anhydride to ammoniating agent is 1: 1-1: 2.

in some embodiments of the invention, it is characterized in that in step 1), the ammoniating agent is selected from NH₃·H₂O、NH₂OH·HCl、NH₄Cl、NH₃、NH₄OAc and urea.

In some embodiments of the invention, step 1) further comprises one or more of the following technical features:

A1) adding a catalyst in the ammoniation reaction, wherein the catalyst is one or a combination of more of phosphorous acid, p-toluenesulfonic acid and methanesulfonic acid, and the mass of the catalyst is 1-10% of that of succinic anhydride;

A2) the reaction temperature of the amination reaction in the step 1) is 120-220 ℃;

A3) in the step 1), the post-reaction treatment method comprises the following steps: quenching and recrystallizing the reaction to obtain the compound shown in the formula II.

In some embodiments of the invention, in step 2), the catalyst is a phase transfer catalyst selected from Bu₄N⁺Br^-、Bu₄N⁺I^-Benzyl triethyl ammonium chloride, tetrabutyl ammonium hydrogen sulfate, trioctylmethyl ammonium chloride, dodecyl trimethyl ammonium chloride and 18 crown 6.

In some embodiments of the invention, in step 2), the base is selected from inorganic bases, preferably from Na₂CO₃、K₂CO₃One or more of KOH and NaOH.

In some embodiments of the present invention, step 2) further includes one or more of the following technical features:

B1) in the step 2), the reaction is carried out under the protection of gas;

B2) in the step 2), the molar ratio of the succinimide to the 1,2 halogenated ethane is 1: 1-1: 3;

B3) in the step 2), the mass of the catalyst is 1-10% of that of the succinimide;

B4) in the step 2), the molar ratio of alkali to succinimide is 1-2;

B5) in the step 2), the reaction is carried out in the presence of a solvent, wherein the solvent is one or more of acetonitrile, DMF, acetone, tetrahydrofuran and 1, 4-dioxane;

B6) in the step 2), the reaction temperature is 20-90 ℃.

In some embodiments of the present invention, in the step 2), the method of post-reaction treatment is: quenching the reaction, extracting, removing the solvent of the organic phase, and purifying to obtain the compound shown in the formula IV.

In some embodiments of the invention, said step 3) further comprises one or more of the following technical features:

C1) in the step 3), the molar ratio of the compound shown in the formula IV to the trans-monomethyl fumarate is 1: 1-1: 1.5;

C2) in the step 3), the reaction is carried out under the condition of a solvent, wherein the solvent comprises one or more of tetrahydrofuran, dimethyl sulfoxide, 1,4-dioxane, water, toluene, chloroform, acetone and acetonitrile;

C3) in the step 3), a base is used in the reaction, and the base is an inorganic base, preferably selected from sodium carbonate and/or potassium carbonate;

C4) in the step 3), the molar ratio of the alkali to the compound of the formula IV is 1.0-2.0;

C5) in the step 3), the reaction temperature of the esterification reaction is 20-80 ℃.

In some embodiments of the present invention, in the step 3), the method of post-reaction treatment is: quenching the reaction, extracting, desolventizing, dissolving in alcohol, and filtering to obtain the desloxy alcohol fumarate.

Drawings

FIG. 1 shows a 1H-NMR spectrum of a compound of formula IV synthesized in example 1 of the present invention.

FIG. 2 shows the synthesis of desloxinol fumarate obtained in example 1 of the present invention₁H-NMR spectrum.

Detailed Description

The following details are the preparation method of the desloxinol fumarate and the application of the synthesized desloxinol fumarate in the preparation of the medicine for treating relapsing multiple sclerosis.

The invention provides a preparation method of desloxinol fumarate, which comprises the following steps:

1) ammoniation reaction: reacting succinic anhydride with an ammoniating reagent to generate succinimide, wherein the reaction equation is as follows:

2) alkylation reaction: reacting succinimide with 1,2 halogenated ethane in the presence of a catalyst and alkali to generate a compound shown in a formula IV, wherein the reaction equation is as follows:

in the compound of the formula III, X is selected from Br, Cl or I, and X' is selected from Br, Cl or I;

3) esterification reaction: reacting a compound of formula IV with monomethyl trans-fumarate to form desloxinol fumarate, according to the following equation:

in the preparation method provided by the invention, in the amination reaction in the step 1), succinic anhydride is reacted with an amination reagent to generate succinimide, wherein the molar ratio of the succinic anhydride to the amination reagent is 1: 1-1: 2. in some preferred embodiments, the molar ratio of succinic anhydride to ammoniating agent is 1: 1-1: 1.2,1: 1.2-1: 1.4,1: 1.4-1: 1.6,1: 1.6-1: 1.8, or 1: 1.8-1: 2. more preferably, the molar ratio of succinic anhydride to ammoniating agent is 1: 1. in the step 1), the ammoniation reagent is selected from NH₃·H₂O、NH₂OH·HCl、NH₄Cl、NH₃、NH₄OAc and urea. In a preferred embodiment, the ammoniating agent is preferably NH3 · H2O. In the step 1), the temperature of the ammoniation reaction is 120-220 ℃, and the reaction temperature refers to the temperature range of the compound of the formula II. The temperature of the ammoniation reaction can also be 120-150 ℃, 150-180 ℃, 180-220 ℃, 180-190 ℃, 190-200 ℃, 200-210 ℃ or 210-220 ℃. More specifically, in one embodiment, the succinic anhydride is added to the mixture at room temperatureAdding an ammoniation reagent, wherein the ammoniation reagent is added to release heat under the normal condition, the reaction temperature needs to be controlled within 60-80 ℃, then adding a catalyst, heating to 120-150 ℃, and heating to 180-220 ℃ for multiple times to obtain the compound shown in the formula II. The catalyst is selected from one or a combination of phosphorous acid, p-toluenesulfonic acid and methanesulfonic acid, the mass of the catalyst is 1-10% of the mass of succinic anhydride, and in some specific embodiments of the invention, the mass of the catalyst can be 1-2%, 2-3%, 3-4%, 4-5%, 5-6%, 6-7%, 7-8%, 8-9% and 9-10% of the mass of succinic anhydride. The reaction time can be adjusted by a person skilled in the art according to the actual reaction condition, for example, the reaction time is 3-12 h; in some embodiments, the reaction time of the ammonification reaction may be 3-4 hours, 4-5 hours, 5-6 hours, 6-7 hours, 7-8 hours, 8-9 hours, 9-10 hours, 10-11 hours, or 11-12 hours. The post-treatment method of the reaction comprises quenching and recrystallizing the reaction to obtain the compound of the formula II.

In the preparation method provided by the invention, the alkylation reaction in the step 2) is to react succinimide with 1,2 halogenated ethane in the presence of a catalyst and alkali to generate the compound shown in the formula IV. In the compound of the formula III, X is selected from one of Br, Cl and I, and X' is selected from one of Br, Cl and I. The choice of X and X' may be the same or different. In the step 2), the reaction is preferably performed under a gas protection condition, and the gas protection can be performed by using one or more of gases including, but not limited to, nitrogen, argon and the like.

Further, the molar ratio of the succinimide to the 1, 2-halogenated ethane in the alkylation reaction in the step 2) is 1: 1-1: 1.5, in some preferred embodiments, the molar ratio of succinimide to 1, 2-haloethane in the alkylation reaction may be 1: 1-1: 1.2,1: 1.2-1: 1.3,1: 1.3-1: 1.4, or 1: 1.4-1: 1.5.

further, the catalyst in the alkylation reaction in the step 2) is a phase transfer catalyst selected from, but not limited to, Bu₄N⁺Br^-、Bu₄N⁺I^-Benzyl triethyl ammonium chloride (TEBA), tetrabutyl ammonium chloride, tetrabutyl ammonium hydrogen sulfate (TBAB), trioctylmethyl ammonium chloride, dodecyl trimethyl ammonium chloride and 18 crown 6. The phase transfer catalyst is preferably Bu₄N⁺Br^-. The amount of the catalyst to be used is not particularly limited as long as it does not limit the object of the present invention, and the preferable amount of the catalyst to be used is: the mass of the catalyst is 1-10% of the mass of the succinimide, and in some specific embodiments of the invention, the mass of the catalyst can be 1-2%, 2-3%, 3-4%, 4-5%, 5-6%, 6-7%, 7-8%, 8-9%, 9-10% of the mass of the succinimide.

Further, the base in the alkylation reaction is selected from inorganic bases, but is not limited to Na₂CO₃、K₂CO₃One or more of KOH and NaOH. Preferably, the base is preferably K₂CO₃. The usage amount of the alkali in the step 2) is as follows: the molar ratio of the alkali to the succinimide is 1-2; in some preferred embodiments, the molar ratio of the base to the succinimide may be 1 to 1.2, 1.2 to 1.4, 1.4 to 1.6, 1.6 to 1.8, 1.8 to 2.

Further, the alkylation reaction may be carried out without the use of a reaction solvent, and may also be carried out in a reaction solvent, which is preferably an organic solvent including, but not limited to, acetonitrile, DMF, acetone, tetrahydrofuran, and combinations of one or more of 1, 4-dioxane. The amount of the reaction solvent can be adjusted by those skilled in the art according to the kind of the reaction solvent, the process conditions and the use environment, and the specific use ratio can be: the ratio of the volume of the solvent in the step 2) to the mass of the reactant in the step 2 is 5-10. The reactants in step 2 comprise N-succinimide, 1, 2-dihaloethane, a catalyst and a base.

Further, the reaction temperature of the alkylation reaction is 20-90 ℃. The temperature of the alkylation reaction can also be 20-30 ℃, 30-40 ℃, 40-50 ℃, 50-60 ℃, 60-70 ℃, 70-80 ℃ and 80-90 ℃. The reaction time can be adjusted by a person skilled in the art according to the actual reaction condition, for example, the reaction time is 3-12 h; in some embodiments, the reaction time of the alkylation reaction may be 3 to 4 hours, 4 to 5 hours, 5 to 6 hours, 6 to 7 hours, 7 to 8 hours, 8 to 9 hours, 9 to 10 hours, 10 to 11 hours, or 11 to 12 hours.

In the alkylation reaction of the invention, the specific method of post-treatment after the reaction is finished comprises the following steps: quenching the reaction, extracting, removing the solvent of the organic phase, and purifying to obtain the compound shown in the formula IV. More specifically, the reaction may be quenched by adding water to the reaction mixture in an amount such that the ratio of the amount of water added to the volume of the reaction mixture is 1: 1-1: 2. the extraction can be carried out for multiple times by using toluene, for example, the extraction is carried out for three times, organic phases are combined after the extraction, the solvent is removed under reduced pressure after the washing, and the extraction can be carried out by using saturated saline solution for washing. The purification step can adopt the intermediate compound shown in formula IV which is obtained by quickly purifying the residue after the organic phase is desolventized by silica gel column chromatography. The product was a colorless oil.

In the preparation method provided by the invention, in the esterification reaction in the step 3): reacting the compound of formula IV with trans-monomethyl fumarate to produce desloxinol fumarate. In the esterification reaction, the molar ratio of the compound of formula IV to the monomethyl trans-fumarate is 1: 1-1: 1.5; the molar ratio of the compound of formula IV to monomethyl trans-fumarate can be 1: 1-1: 1.2,1: 1.2-1: 1.3,1: 1.3-1: 1.4, or 1: 1.4-1: 1.5.

further, the esterification reaction is carried out under solvent conditions, including but not limited to, tetrahydrofuran, dimethylsulfoxide, 1,4-dioxane, water, toluene, chloroform, acetone, acetonitrile, or combinations of one or more thereof; the amount of the reaction solvent can be adjusted by those skilled in the art according to the kind of the reaction solvent, the process conditions and the use environment, and the specific use ratio can be: the ratio of the volume of the solvent in the step 3) to the mass of the reactant in the step 3) is 5-10. The reactants in step 3) comprise a compound of formula IV, trans-monomethyl fumarate and a base.

Further, a base is used in the esterification reaction, and the base is selected from inorganic bases, preferably sodium carbonate and/or potassium carbonate; the molar ratio of the alkali to the compound of the formula IV is 1.0-2.0; in some preferred embodiments, the molar ratio of the base to the compound of formula IV may be 1.0 to 1.2, 1.2 to 1.4, 1.4 to 1.6, 1.6 to 1.8, 1.8 to 2.0.

Further, the reaction temperature of the esterification reaction is 20-80 ℃; the temperature of the esterification reaction can also be 20-30 ℃, 30-40 ℃, 40-50 ℃, 50-60 ℃, 60-70 ℃ and 70-80 ℃. The reaction time can be adjusted by a person skilled in the art according to the actual reaction condition, for example, the reaction time is 3-12 h; in some embodiments, the reaction time of the esterification reaction can be 3 to 4 hours, 4 to 5 hours, 5 to 6 hours, 6 to 7 hours, 7 to 8 hours, 8 to 9 hours, 9 to 10 hours, 10 to 11 hours, or 11 to 12 hours.

In the esterification reaction of the invention, the specific method of post-treatment after the reaction is finished comprises the following steps: quenching the reaction, extracting, desolventizing, dissolving in alcohol, and filtering to obtain the desloxy alcohol fumarate. More specifically, the reaction may be quenched by adding water to the reaction mixture in an amount such that the ratio of the amount of water added to the volume of the reaction mixture is 1: 1-1: 2. the extraction can be carried out for multiple times by using toluene, for example, the extraction is carried out for three times, organic phases are combined after the extraction, the solvent is removed under reduced pressure after the washing, and the extraction can be carried out by using saturated saline solution for washing. The alcohol was dissolved by heating with methanol, cooled to room temperature, and stirred overnight. And carrying out suction filtration on the solid, leaching a filter cake with cold methanol, and drying the solid to obtain the desloxy fumarate.

In a second aspect, the invention provides the loxinol fumarate prepared by the preparation method described in the invention.

In a third aspect, the invention provides the use of the loxinol fumarate disclosed by the invention in a medicament for treating relapsing multiple sclerosis.

The invention has the beneficial effects that:

the preparation method has the advantages of convenient and easily obtained material reagents, short reaction steps, high total yield, easy purification of products through recrystallization, easy control of basic toxic impurities through recrystallization and the like, and has obvious technical advantages. The yield of the desloxinol fumarate prepared by the preparation method disclosed by the invention is as high as 81%.

The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.

In the following examples, reagents, materials and instruments used are commercially available unless otherwise specified.