A synthetic method for a brivaracetam intermediate

Abstract

The present invention relates to the field of pharmaceutical synthesis technology, and more particularly to a method for synthesizing a brivaracetam intermediate. The method for synthesizing a brivaracetam intermediate provided by the present invention comprises the following four steps: Step 1: reacting glyoxylic acid with n-valeraldehyde under alkaline conditions to produce compound I; Step 2: reacting compound I with L-menthol in the presence of a catalyst, followed by crystallization and purification to produce chiral compound II; Step 3: hydrogenating and reducing the double bond of chiral compound II under alkaline conditions to produce compound III; and Step 4: subjecting compound III to a reduction reaction to produce compound IV. The present invention significantly reduces the cost of preparing a brivaracetam intermediate, simplifies the operation, and is very suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing a brivaracetam intermediate. Background Art

[0002] Brivaracetam (trade name Brivaracetam), also known as (S)-2-((R)-2-oxo-4-propylpyrrolidin-1-yl)butanamide, is a third-generation antiepileptic drug developed by UCB (Belgium). It was approved for marketing by the European Medicines Agency (EMA) on January 14, 2016, and by the U.S. Food and Drug Administration (FDA) on February 18, 2016. It is indicated for the treatment of partial-onset epilepsy in patients aged 16 years and older, as an adjunctive treatment for seizures with or without secondary generalized seizures. (R)-4-Propyl-dihydrofuran-2-one is a key intermediate in the synthesis of Brivaracetam, and its synthesis is of great significance for the industrial synthesis of Brivaracetam.

[0003] To date, various synthetic routes for (R)-4-propyl-dihydrofuran-2-one have been reported in the prior art. For example, Chinese patent application CN 113336726A discloses the following synthetic route:

[0004]

[0005] Chinese patent application CN 113717132A discloses the following synthetic route:

[0006]

[0007] Chinese patent application CN 112521352A discloses the following synthetic route:

[0008]

[0009] Chinese patent application CN 111349007A discloses the following synthetic route:

[0010]

[0011] Chinese patent applications CN 107827845A and CN 107652254A disclose the following synthetic routes:

[0012]

[0013] Chinese patent applications CN 110790731A and CN 110790730A disclose the following synthetic routes:

[0014]

[0015] A review of the previously disclosed methods for synthesizing the brivaracetam intermediate (R)-4-propyl-dihydrofuran-2-one reveals common drawbacks such as harsh reaction conditions and a large amount of impurities during the reaction process. This makes it difficult to obtain the brivaracetam intermediate (R)-4-propyl-dihydrofuran-2-one in high yield and purity. Therefore, the development of new synthetic routes is urgently needed. Summary of the Invention

[0016] In order to solve the problems existing in the prior art, the object of the present invention is to provide a method for synthesizing a brivaracetam intermediate. The synthesis method provided by the present invention is simple to operate and uses inexpensive raw materials. The relatively high-cost palladium carbon and L-menthol can be recycled and reused, which significantly reduces costs. Secondly, the chiral resolution in the synthesis method of the present invention only requires low-temperature crystallization to obtain a chiral compound of good purity, which is simple to operate. In addition, the isomers can be racemized and continuously resolved, which greatly improves the yield of the chiral resolution. Furthermore, the present invention has relatively few three wastes, is environmentally friendly, and is easy to industrialize.

[0017] The technical solution of the present invention is:

[0018] A method for synthesizing a brivaracetam intermediate comprises the following steps:

[0019] Step 1: Glyoxylic acid reacts with n-valeraldehyde to obtain compound I;

[0020] Step 2: reacting the compound I with L-menthol to obtain a chiral compound II;

[0021] Step 3: Reduction of the double bond of the chiral compound II to obtain compound III;

[0022] Step 4: Compound III is subjected to reduction reaction to obtain compound IV;

[0023]

[0024] Furthermore, in step 1, glyoxylic acid reacts with n-valeraldehyde under alkaline conditions to obtain compound I; the molar ratio of the base to glyoxylic acid is 1:(1-1.1).

[0025] Furthermore, in step 1, the molar ratio of glyoxylic acid to n-valeraldehyde is 1:(1-1.1); and / or, in step 1, n-hexane is used as the reaction solvent, and the volume ratio of n-valeraldehyde to the reaction solvent is 1:3-5.

[0026] Furthermore, in step 2, compound I reacts with L-menthol in the presence of a catalyst to obtain chiral compound II; the weight ratio of compound I to catalyst is 1:0.01-0.05; and / or, the molar ratio of compound I to L-menthol in step 2 is 1:(1-1.2).

[0027] Furthermore, the catalyst in step 2 is p-toluenesulfonic acid; and / or, toluene or xylene is used as the reaction solvent in step 2, and the volume ratio of compound I to the reaction solvent is 1:8-10.

[0028] Furthermore, in step 3, the chiral compound II is reduced to a double bond under alkaline conditions to generate compound III, wherein the molar ratio of compound II to the base is 1:1 to 1.1; palladium carbon is used as a catalyst in step 3; and / or, ethyl acetate is used as a reaction solvent in step 3, and the volume ratio of compound II to the reaction solvent is 1:5 to 10.

[0029] Furthermore, in step 4, sodium borohydride or lithium aluminum hydride is used as a reducing agent, and the molar ratio of compound III to the reducing agent is 1:1 to 1.1; in step 4, compound III undergoes a reduction reaction under alkaline conditions, and the molar ratio of compound III to the base is 1:1 to 1.2; and / or, in step 4, methanol is used as a reaction solvent, and the weight ratio of compound III to the reaction solvent is 1:5 to 6.

[0030] Furthermore, the reaction temperature of step 1 is 0-45°C; the reaction temperature of step 2 is 120-150°C; the reaction temperature of step 3 is 0-30°C; and / or, step 3 reduces double bonds by hydrogenation, wherein the hydrogen pressure is 0.2-0.4 MPa.

[0031] Further, the following steps are included:

[0032] Step 1: Add a base to the reaction solvent, add glyoxylic acid dropwise at a temperature of 0-45°C, stir for 1.8-2.2 hours, add n-valeraldehyde dropwise at a temperature of 0-45°C, react at a temperature of 0-45°C for 18-24 hours, separate the system into three layers, separate the middle layer, dissolve it in hydrochloric acid, extract it three times with isopropyl ether, combine the isopropyl ether layers, dry them, and desolventize to obtain Compound I;

[0033] Step 2: Add compound I, catalyst and L-menthol to the reaction solvent, heat it, reflux it with water at a temperature of 120-150°C for 12-16 hours, stop the reaction when the content of compound I is less than 1%, cool it to room temperature, wash the reaction solution with alkaline water, desolventize and recover the reaction solvent, and distill the residue under reduced pressure by oil pump to obtain a crude product of compound II. Add the crude product of compound II to the crystallization solvent, cool it to -15--20°C for crystallization for 20-24 hours, filter out a white needle-shaped solid to obtain chiral compound II; recover the filtrate and crystallize it again for racemization to obtain chiral compound II, and combine chiral compound II;

[0034] Step 3: Add chiral compound II, palladium carbon, base and reaction solvent to the reaction kettle, replace the hydrogen atmosphere three times, introduce pressurized hydrogen, and react at 0-30°C for 6-8 hours. When the content of chiral compound II is less than 1%, stop the reaction, filter out the palladium carbon, and recover it for reuse. The filtrate is desolvated to obtain compound III;

[0035] Step 4: Add alkali to the reaction solvent and stir, then add compound III to the alkali solution, add the reducing agent in batches, stop the reaction after the addition is complete, adjust the pH to neutral with hydrochloric acid, remove the reaction solvent, dissolve the residue in water, adjust the pH to 14 with alkali, extract with organic solvent dichloromethane, and recover L-menthol; adjust the pH of the aqueous phase to 2-3 with concentrated hydrochloric acid, stir for 6-8 hours, extract with organic solvent dichloromethane, combine the organic solvent dichloromethane layers, dry and desolventize, and purify to obtain compound IV.

[0036] Furthermore, the base in step 1 is morpholine;

[0037] The alkaline water in step 2 is an aqueous solution of sodium carbonate, potassium carbonate or sodium bicarbonate;

[0038] The crystallization solvent in step 2 is n-hexane or n-heptane; the volume ratio of the crude product of compound II to the crystallization solvent is 1:5;

[0039] The base in step 3 is triethylamine;

[0040] and / or,

[0041] The base in step 4 is sodium hydroxide or potassium hydroxide.

[0042] Compared with the prior art, the synthesis method of a brivaracetam intermediate provided by the present invention has the following advantages:

[0043] 1. The synthesis reaction provided by the present invention is simple to operate and has cheap raw materials. The relatively high-cost palladium carbon and L-menthol can be recycled and reused, which greatly reduces the production cost and is conducive to industrial production.

[0044] 2. The chiral resolution in the synthesis method of the present invention only requires low-temperature crystallization to obtain a chiral compound of good purity. The operation is simple, and the isomers can also be racemized and continuously resolved, which greatly improves the chiral resolution yield.

[0045] 3. The present invention produces relatively less three kinds of waste, is environmentally friendly, and is easy to industrialize. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 The synthetic route of the brivaracetam intermediate (R)-4-propyl-dihydrofuran-2-one of the present invention is shown in FIG.

[0047] Figure 2This is the H NMR spectrum of compound II obtained in Example 1.

[0048] Figure 3 This is the mass spectrum of compound II obtained in Example 1.

[0049] Figure 4 This is the H NMR spectrum of compound III obtained in Example 1.

[0050] Figure 5 This is the mass spectrum of compound III obtained in Example 1.

[0051] Figure 6 This is the mass spectrum of compound IV obtained in Example 1. DETAILED DESCRIPTION

[0052] The present invention is further illustrated below through the description of specific implementation methods, but this is not a limitation of the present invention. Those skilled in the art can make various modifications or improvements based on the basic idea of the present invention, but as long as they do not deviate from the basic idea of the present invention, they are all within the scope of protection of the present invention.

[0053] In the following examples and comparative examples, reagents not otherwise specified are conventional reagents and can be purchased from conventional reagent production and sales companies.

[0054] Example 1

[0055] The synthesis of (R)-4-propyl-dihydrofuran-2-one includes the following four steps:

[0056] Synthesis of Compound I

[0057] To a 500ml four-necked flask, add n-hexane (190ml) and morpholine (60.1g, 0.69mol) with stirring. The system was cooled to 0-10°C, and 50% glyoxylic acid (93.5g, 0.63mol) was added dropwise, maintaining the internal temperature below 40°C. The reaction was stirred at 25-30°C for 2h. Then, n-valeraldehyde (57.7g, 0.67mol) was added dropwise at 25°C, maintaining the reaction at 40-42°C for 18h. The system was cooled to 25°C, and the mixture separated into three layers. The middle layer was separated and dissolved in 116ml of hydrochloric acid. Impurities were extracted once with 100ml of n-hexane. The aqueous phase was then extracted with 100g of isopropyl ether (3 times). The combined isopropyl ethers were dried over anhydrous sodium sulfate, and filtered to remove the solvent, yielding 83.2g of Compound I (brown oily liquid) with a yield of 92.85%. GC analysis revealed 96.5%.

[0058] Synthesis of Compound II

[0059] Toluene (1000 ml), compound I (142 g, 1.0 mol), p-toluenesulfonic acid (1.42 g, 1% W / W) and L-menthol (187.5 g, 1.2 mol) were added to a 2000 ml four-necked flask with a water separator. The temperature was raised to 130°C and refluxed with water for 16 h. The reaction was stopped when the content of compound I was less than 1% by HPLC. The temperature was lowered to room temperature. 10% sodium carbonate (200 ml) was added to the reaction system to wash the reaction solution. The liquids were separated, and the organic phase was desolventized to recover toluene to obtain a brown oil. Vacuum distillation was performed under reduced pressure in an oil pump. The fractions collected at an oil temperature of 120°C and a top temperature of 70°C yielded 37 g of L-menthol. The fractions collected at an oil temperature of 180-200°C and a top temperature of 158-160°C yielded 266.7 g of a crude vortex of Compound II (a pale yellow oil). This crude vortex of Compound II was added to 5% n-hexane, cooled to -20°C, and allowed to stand for 24 hours to crystallize. A white needle-like solid, i.e., chiral Compound II, was filtered out. The filtrate was recovered, racemized again, and crystallized a second time to obtain chiral Compound II. The total yield was 73.6%, with a HPLC purity of 99.2% and a chiral ee of 99.2%.

[0060] Synthesis of compound III

[0061] Chiral compound II (28 g, 0.1 mol), 5% palladium on carbon (2.8 g, 10% w / w), triethylamine (10.1 g, 0.1 mol), and ethyl acetate (280 g) were added to a 500 ml hydrogenation reactor. The atmosphere was purged with nitrogen three times and hydrogen once, followed by a flow of 0.4 MPa hydrogen. The reaction was continued at 30°C for 8 h. HPLC analysis indicated that the content of compound II was less than 1%, and the reaction was stopped. The palladium on carbon was filtered and recycled for the next reaction. The filtrate was filtered through diatomaceous earth again, and the filtrate was desolvated to obtain 28.4 g of compound III (a colorless oily liquid). The crude product was used directly in the next reaction.

[0062] Synthesis of compound IV

[0063] Potassium hydroxide (6.7 g, 0.12 mol) was added to methanol (140 g) at room temperature and stirred to dissolve. After the temperature dropped to room temperature, a methanol solution of Compound III (28.4 g, 0.1 mol) was slowly added to the reaction system. The system was cooled to 0°C and sodium borohydride (3.78 g, 0.1 mol) was added portionwise. After addition, the temperature was naturally raised to room temperature and the reaction was allowed to react for 3-4 hours. After the disappearance of Compound III by TLC, the reaction was stopped and the pH was adjusted to neutral with 1N hydrochloric acid. The methanol was evaporated under reduced pressure at 40°C. The residue was dissolved in 150 g of water and adjusted to pH 14 with 14 g of potassium hydroxide. The mixture was extracted with dichloromethane (100 ml x 2) and dried to remove the solvent to recover L-menthol. The aqueous phase was adjusted to pH 2-3 with concentrated hydrochloric acid, stirred for 8 h, extracted with dichloromethane (150 ml * 2), and the dichloromethane was combined and dried to remove the solvent to obtain a crude product, which was purified by vacuum distillation to obtain 10.2 g of compound IV (colorless oily liquid) with a yield of 79.7%, a GC purity of 99.4%, and an ee value of 99.2%.

[0064] Example 2

[0065] The synthesis of (R)-4-propyl-dihydrofuran-2-one includes the following four steps:

[0066] Synthesis of Compound I

[0067] To a 500ml four-necked flask, add n-hexane (190ml) and morpholine (60.1g, 0.69mol) with stirring. The system was cooled to 0-10°C, and 50% glyoxylic acid (93.5g, 0.63mol) was added dropwise, maintaining the internal temperature below 40°C. The reaction was stirred at 25-30°C for 2h. Then, n-valeraldehyde (57.7g, 0.67mol) was added dropwise at 25°C, maintaining the reaction at 40-42°C for 18h. The system was cooled to 25°C, and the mixture separated into three layers. The middle layer was separated and dissolved in 116ml of hydrochloric acid. Impurities were extracted once with 100ml of n-hexane. The aqueous phase was then extracted with 100g of isopropyl ether (3 times). The combined isopropyl ethers were dried over anhydrous sodium sulfate, and filtered to remove the solvent, yielding 83.2g of Compound I (brown oily liquid) with a yield of 92.85%. GC analysis revealed 96.5%.

[0068] Synthesis of Compound II

[0069] To a 2000ml four-necked flask with a water separator, xylene (1000ml), compound I (142g, 1.0mol), p-toluenesulfonic acid (1.42g, 1% W / W) and L-menthol (187.5g, 1.2mol) were added, and the internal temperature was raised to 150°C and refluxed with water to react for 12h. The reaction was stopped when the content of compound I was less than 1% by HPLC. The temperature was lowered to room temperature, and 10% sodium bicarbonate (300ml) was added to the reaction system to wash the reaction solution. The liquids were separated, and the organic phase was desolventized to recover xylene to obtain a brown oil. Vacuum distillation was performed under reduced pressure in an oil pump. The fractions at 120°C and 70°C were collected to yield 35.4 g of L-menthol. The fractions at 180-200°C and 158-160°C were then collected to yield 270.3 g of crude compound II (a pale yellow oil). This crude compound II was added to 5% n-hexane, cooled to -20°C, and allowed to stand for 24 hours to crystallize. A white needle-like solid, i.e., chiral compound II, was filtered out. The filtrate was recovered, racemized again, and crystallized a second time to yield chiral compound II. The total yield was 74.2%, the HPLC purity was 99.1%, and the chiral ee value was 99.0%.

[0070] Synthesis of compound III

[0071] Chiral Compound II (28 g, 0.1 mol), 5% palladium on carbon (2.8 g, 10% w / w), triethylamine (10.1 g, 0.1 mol), and ethyl acetate (280 g) were added to a 500 ml hydrogenation reactor. The atmosphere was purged with nitrogen three times and hydrogen once. Hydrogen was then introduced at 0.4 MPa and the reaction was continued at 30°C for 8 h. HPLC analysis indicated that the content of Compound II was less than 1%, at which point the reaction was terminated. The palladium on carbon was filtered and recycled for the next reaction. The filtrate was filtered through diatomaceous earth again, and the solvent was removed to obtain 28.4 g of a colorless oily liquid. The crude product was used directly in the next reaction.

[0072] Synthesis of compound IV

[0073] Sodium hydroxide (24 g, 0.6 mol) was added to methanol (700 g) at room temperature and stirred to dissolve. After the temperature dropped to room temperature, a methanol solution of Compound III (140 g, 0.5 mol) was slowly added to the reaction system. The system was cooled to 0°C and sodium borohydride (18.9 g, 0.5 mol) was added portionwise. After addition, the temperature was naturally raised to room temperature and the reaction was allowed to proceed for 3-4 hours. TLC analysis confirmed the complete reaction of Compound III. The reaction was stopped and the pH was adjusted to neutral with 1N hydrochloric acid. The methanol was evaporated under reduced pressure at 40°C. The residue was dissolved in 700 g of water and adjusted to pH 14 with 50 g of potassium hydroxide. The mixture was extracted with dichloromethane (500 ml x 2) and dried to remove the solvent to recover L-menthol. The aqueous phase was adjusted to pH 2-3 with concentrated hydrochloric acid, stirred for 14 h, extracted with dichloromethane (700 ml*2), the dichloromethanes were combined, dried and desolvated to obtain a crude product, which was purified by vacuum distillation to obtain 52.5 g of compound IV (colorless oily liquid) with a yield of 81.6%, a GC purity of 99.2%, and an ee value of 99.0%.

[0074] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the present invention. Anyone skilled in the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by one of ordinary skill in the art without departing from the spirit and technical principles disclosed herein are intended to be covered by the claims of the present invention.

Claims

1. A method for synthesizing a brivaracetam intermediate, characterized in that: The following steps are involved: Step 1: Glyoxylic acid reacts with n-valeraldehyde to obtain compound I; Step 2: reacting the compound I with L-menthol to obtain a chiral compound II; Step 3: Reduction of the double bond of the chiral compound II to obtain compound III; Step 4: Compound III is subjected to reduction reaction to obtain compound IV; 2. The method for synthesizing the brivaracetam intermediate according to claim 1, wherein In step 1, glyoxylic acid reacts with n-valeraldehyde under alkaline conditions to obtain compound I; The molar ratio of the base to glyoxylic acid is 1:(1-1.1).

3. The method for synthesizing the brivaracetam intermediate according to claim 1, wherein In step 1, the molar ratio of glyoxylic acid to n-valeraldehyde is 1:(1-1.1); and / or, In step 1, n-hexane is used as the reaction solvent, and the volume ratio of n-valeraldehyde to the reaction solvent is 1:3-5.

4. The method for synthesizing the brivaracetam intermediate according to claim 1, wherein In step 2, the compound I reacts with L-menthol in the presence of a catalyst to obtain a chiral compound II; The weight ratio of the compound I to the catalyst is 1:0.01-0.05; and / or, In the step 2, the molar ratio of compound I to L-menthol is 1:(1-1.2).

5. The method for synthesizing the brivaracetam intermediate according to claim 1, wherein In step 2, the catalyst is p-toluenesulfonic acid; and / or, In step 2, toluene or xylene is used as the reaction solvent, and the volume ratio of compound I to the reaction solvent is 1:8-10.

6. The method for synthesizing the brivaracetam intermediate according to claim 1, wherein: In step 3, the chiral compound II is reduced to a double bond under alkaline conditions to generate compound III, wherein the molar ratio of compound II to the base is 1:1 to 1.1; In step 3, palladium carbon is used as a catalyst; and / or, In step 3, ethyl acetate is used as the reaction solvent, and the weight ratio of compound II to the reaction solvent is 1:5-10.

7. The method for synthesizing the brivaracetam intermediate according to claim 1, wherein: In step 4, sodium borohydride or lithium aluminum hydride is used as a reducing agent, and the molar ratio of compound III to the reducing agent is 1:1 to 1.1; In step 4, the compound III undergoes a reduction reaction under alkaline conditions, and the molar ratio of the compound III to the base is 1:1 to 1.2; and / or, In step 4, methanol is used as the reaction solvent, and the weight ratio of compound III to the reaction solvent is 1:5-6.

8. The method for synthesizing the brivaracetam intermediate according to claim 1, wherein The reaction temperature of step 1 is 0-45°C; The reaction temperature of step 2 is 120-150°C; The reaction temperature of step 3 is 0-30°C; and / or, In step 3, double bonds are reduced by hydrogenation, wherein the hydrogen pressure is 0.2-0.4 MPa.

9. The method for synthesizing the brivaracetam intermediate according to claim 1, wherein: The following steps are involved: Step 1: Add a base to the reaction solvent, add glyoxylic acid dropwise at a temperature of 0-45°C, stir for 1.8-2.2 hours, add n-valeraldehyde dropwise at a temperature of 0-45°C, react at a temperature of 0-45°C for 18-24 hours, and separate the system into three layers. Separate the middle layer, dissolve it with hydrochloric acid, extract, dry, and desolventize to obtain Compound I; Step 2: Add compound I, catalyst and L-menthol to the reaction solvent, heat, reflux with water at a temperature of 120-150°C for 12-16 hours, stop the reaction when the content of compound I is less than 1%, cool to room temperature, wash the reaction solution with alkaline water, desolventize and recover the reaction solvent, and distill the residue under reduced pressure using an oil pump to obtain a crude product of compound II. Add the crude product of compound II to a crystallization solvent, cool to -15--20°C for crystallization for 20-24 hours, and filter out a white needle-shaped solid to obtain chiral compound II; The filtrate is recovered and crystallized again for racemization to obtain chiral compound II, and chiral compound II is combined; Step 3: Add chiral compound II, palladium carbon, base and reaction solvent to the reaction kettle, replace the hydrogen atmosphere three times, introduce pressurized hydrogen, and react at 0-30°C for 6-8 hours. When the content of chiral compound II is less than 1%, stop the reaction, filter out the palladium carbon, and recover it for reuse. The filtrate is desolvated to obtain compound III; Step 4: Add alkali to the reaction solvent and stir, then add compound III to the alkali solution, add the reducing agent in batches, stop the reaction after the addition is complete, adjust the pH to neutral with hydrochloric acid, remove the reaction solvent, dissolve the residue in water, adjust the pH to 14 with alkali, extract with an organic solvent, dry and desolventize to recover L-menthol; adjust the pH of the aqueous phase to 2-3 with concentrated hydrochloric acid, stir for 6-8 hours, extract with an organic solvent, combine the organic solvent layers, dry and desolventize, and purify to obtain compound IV.

10. The method for synthesizing the brivaracetam intermediate according to claim 9, wherein: The base in step 1 is morpholine; The alkaline water in step 2 is an aqueous solution of sodium carbonate, potassium carbonate or sodium bicarbonate; The crystallization solvent in step 2 is n-hexane or n-heptane; the volume ratio of the crude product of compound II to the crystallization solvent is 1:5; The base in step 3 is triethylamine; and / or, The base in step 4 is sodium hydroxide or potassium hydroxide.

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