A process for the preparation of brivaracetam

Abstract

The present disclosure relates to a preparation method of brivaracetam or a pharmaceutically acceptable salt thereof, which has short reaction time, good yield and high purity, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a method for preparing buvastan or a pharmaceutically acceptable salt thereof. Background Technology

[0002] Brivaracetam is a third-generation antiepileptic drug developed by UCB (UCB) of Belgium. Its structure is shown in formula (I).

[0003]

[0004] Bricetan is a derivative of levetiracetam, with a binding affinity 10 times greater than levetiracetam. It boasts higher bioavailability, a shorter time to peak absorption, and is unaffected by food. Due to its improved safety profile and potential for use in a wider range of epilepsy conditions, bricetan is considered one of the most promising third-generation antiepileptic drugs and is expected to become another blockbuster drug to replace levetiracetam.

[0005] Numerous synthetic processes for buvasidan have been disclosed, as described in patent applications CN106279074A, CN111892526A, CN105646319A, and WO2020148787A. However, these processes suffer from various drawbacks, including low yields, long reaction times, high production costs, and poor industrial feasibility. Therefore, there is an urgent need to develop a more economical and industrially viable method for preparing buvasidan. Summary of the Invention

[0006] This disclosure provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the step of reacting a compound of formula (III) with a compound of formula (II) or a pharmaceutically acceptable salt thereof under an alkaline reagent to form a compound of formula (I).

[0007]

[0008] The alkaline reagent is sodium carbonate; the reaction solvent is dioxane; and X is selected from halogens.

[0009] In some embodiments, the preparation method of the compound of formula (I) or a pharmaceutically acceptable salt thereof provided in this disclosure, wherein X is selected from chlorine, bromine or iodine, and optionally, X is bromine.

[0010] In some embodiments, the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is a hydrochloride salt.

[0011] In some embodiments, the molar ratio of the compound represented by formula (III) to the basic reagent is selected from 1:1 to 1:10.

[0012] In an optional embodiment, the molar ratio of the compound represented by formula (III) to the basic reagent is selected from 1:2 to 1:5.

[0013] In an optional embodiment, the molar ratio of the compound shown in formula (III) to the basic reagent is selected from 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5 or 1:10, or a value between any two points.

[0014] In an optional embodiment, the molar ratio of the compound represented by formula (III) to the basic reagent is 1:2.5.

[0015] In some embodiments, the molar ratio of the compound represented by formula (III) to the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 1:1 to 1:5.

[0016] In an optional embodiment, the molar ratio of the compound represented by formula (III) to the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5 or any value between two points.

[0017] In an optional embodiment, the molar ratio of the compound of formula (III) to the compound of formula (II) or a pharmaceutically acceptable salt thereof is 1:2.

[0018] In some embodiments, the method for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof provided in this disclosure uses a reaction temperature selected from 80-160°C.

[0019] In an optional embodiment, the method for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof provided in this disclosure, wherein the reaction temperature is selected from 100-150°C.

[0020] In an optional embodiment, the method for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof provided in this disclosure uses a reaction temperature selected from 120-140°C.

[0021] In an optional embodiment, the method for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof provided in this disclosure uses a reaction temperature selected from 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, 125°C, 130°C, 135°C, 140°C, 145°C, 150°C, 155°C, or 160°C, or any value between any two points.

[0022] In some embodiments, the method for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof provided in this disclosure, wherein the reaction occurs in a closed reactor, i.e., a closed-tube reaction.

[0023] In some embodiments, the method of this disclosure is carried out under pressure. In some embodiments, the reactor pressure can be maintained at 0–10 MPa, i.e., 0–100 atmospheres. In some embodiments, the reactor pressure is maintained at, for example, 1–2 MPa, i.e., 10–20 atmospheres, including 1 MPa, 1.1 MPa, 1.2 MPa, 1.3 MPa, 1.4 MPa, 1.5 MPa, 1.6 MPa, 1.7 MPa, 1.8 MPa, 1.9 MPa, or 2 MPa.

[0024] In some embodiments, the method for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof provided in this disclosure further includes the step of recrystallizing the compound of formula (I) or a pharmaceutically acceptable salt thereof in an ether solvent selected from diethyl ether, isopropyl ether or methyl tert-butyl ether.

[0025] In an optional embodiment, the ether solvent is isopropyl ether.

[0026] In some embodiments, the method for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof provided in this disclosure further includes the step of reacting the compound of formula (V) with a ring-opening reagent to obtain the compound of formula (IV) or the compound of formula (III), wherein X is as defined in the compound of formula (III) and may be chlorine, bromine or iodine.

[0027]

[0028] In an optional embodiment, the ring-opening reagent is selected from hydrobromic acid or its acetic acid solvent, trimethyliodosilane, trimethylbromosilane, trimethylchlorosilane, and phosphorus trihalomethane.

[0029] In an optional embodiment, the ring-opening reagent is hydrobromic acid or its acetic acid solvent.

[0030] In some embodiments, the preparation methods of the compound of formula (I) or its pharmaceutically acceptable salts provided in this disclosure, wherein the compound of formula (IV) is reacted with methanol to obtain the compound of formula (III).

[0031] This disclosure further provides a compound of formula (I) obtained by the aforementioned preparation method.

[0032] In an optional embodiment, the compound of formula (I) obtained by the aforementioned preparation method provided in this disclosure has a chiral purity greater than 99.5%, and optionally, a chiral purity greater than 99.9%.

[0033] This disclosure further provides a pharmaceutical composition comprising a compound of formula (I) prepared by the aforementioned method and one or more pharmaceutically acceptable excipients.

[0034] This disclosure further provides the use of the compound of formula (I) obtained by the aforementioned preparation method or the aforementioned composition in the preparation of a medicament for treating epilepsy, migraine, bipolar disorder, chronic pain, neuropathic pain, bronchitis, asthma or allergic diseases.

[0035] Optionally, this disclosure provides the use of the compound of formula (I) obtained by the aforementioned preparation method or the aforementioned composition in the preparation of a medicament for treating epilepsy.

[0036] The terms "to form" and "to form" in this disclosure do not specifically refer to a single-step conversion reaction between two substrates; they can be a single-step or multi-step reaction between two substrates. If the intermediate contains an amino protecting group, the intermediate undergoes a deamination step with a protecting agent before reacting with the corresponding substrate to obtain the desired product.

[0037] The pharmaceutically acceptable salts of the compounds described in this disclosure are selected from inorganic or organic salts.

[0038] The “medicinal excipients” disclosed herein include, but are not limited to, any adjuvant, carrier, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration (FDA) for use in humans or livestock.

[0039] The values ​​in this disclosure are instrument measurements or calculated values ​​after instrument measurement, and are subject to a certain degree of error. Generally speaking, ±10% is within the reasonable error range. Of course, the context in which the value is used needs to be considered. For example, for the content of total impurities, the value is defined as having an error variation of no more than ±10% after measurement, and can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%. Detailed Implementation

[0040] The present invention will be explained in more detail below with reference to embodiments or experimental examples. The embodiments or experimental examples in the present invention are only used to illustrate the technical solutions of the present invention and are not intended to limit the substance and scope of the present invention.

[0041] The raw materials and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products.

[0042] Related substances HPLC detection method:

[0043] Column: Waters BEH shield RP18 (4.6mm × 100mm, 2.5μm)

[0044] Mobile phase:

[0045] A: 10mM potassium dihydrogen phosphate aqueous solution (pH 7.0) - acetonitrile (95:5)

[0046] B: Acetonitrile

[0047] Gradient elution: (A:B, 0-12min:90:10; 12-22min:82:18; 22-31min:25:75; 31-40min:90:10).

[0048] Flow rate: 1 ml / min

[0049] Column temperature: 25℃

[0050] Wavelength: 210nm

[0051] Injection volume: 5 μl

[0052] Chiral HPLC detection method:

[0053] Chromatographic column: Chiralpak IC (4.6 mm × 250 mm, 5 μm)

[0054] Mobile phase: hexane-isopropanol (45:55) isocratic elution

[0055] Flow rate: 1 ml / min

[0056] Column temperature: 30℃

[0057] Wavelength: 210nm

[0058] Injection volume: 10 μl

[0059] Example 1. Preparation of methyl R-3-bromomethylhexanoate

[0060]

[0061] Step 1: Weigh 50 g of (R)-dihydro-4-propyl-2(3H)-furanone (0.39 mol) into a 500 mL three-necked reaction flask. Add 191.5 g of 33% HBr acetic acid solution (0.78 mol) dropwise at 0 °C. After the addition is complete, raise the temperature to 50 °C and stir the reaction for 4–5 h. After the reaction is complete, add 500 mL of dichloromethane and 1000 mL of water to the system. Stir and extract, then allow to stand and separate the layers. Concentrate the organic phase to dryness under reduced pressure to obtain 78.2 g of (R)-3-bromomethylhexanoic acid, with an HPLC purity of 98.8% and a yield of 95.8%.

[0062] Step 2: Weigh 50g of (R)-3-bromomethylhexanoic acid (0.24mol) into a 250mL three-necked reaction flask, add 200mL of anhydrous methanol and stir to dissolve. Cool to 0℃ and slowly add 34.2g of thionyl chloride (0.29mol). After the addition is complete, allow the temperature to rise naturally to room temperature. Stir the reaction for 2 hours, then slowly add 600mL of water to the system and extract with dichloromethane. Combine the organic phases and concentrate under reduced pressure to obtain 52.5g of (R)-3-bromomethylhexanoate methyl ester with an HPLC purity of 98.4% and a yield of 98%.

[0063] Example 2. Preparation of buvasidan

[0064]

[0065] 20 g of methyl R-3-bromomethylhexanoate (0.09 mol), 24.9 g of (S)-2-aminobutyrate (0.18 mol), and 23.9 g of anhydrous sodium carbonate (0.225 mol) were weighed and placed in a 250 mL stainless steel reactor. 200 mL of 1,4-dioxane was added. The mixture was stirred, the reactor was sealed, and the temperature was raised to 140 °C. After reacting for 4 hours, a sample was taken. HPLC showed that the starting material was almost completely converted. The reactor was cooled to room temperature, and then the gas valve was opened to allow atmospheric flow. The reaction solution was filtered to remove inorganic salts. The filtrate was concentrated to dryness under reduced pressure at 60 °C to obtain 18.4 g of waxy crude buvacertane, with a yield of 96.8%. The HPLC chemical purity was 98.6%, and the Chiral HPLC chiral purity was 99.93%.

[0066] The obtained waxy crude buvacerostat was recrystallized from isopropyl ether to give 17.5 g of white needle-like crystals, with a yield of 95.1%. The HPLC chemical purity was 99.8%, and the Chiral HPLC chiral purity was 99.9%.

[0067] Comparative Example 1. Preparation of Bisvastatin

[0068] 20 g of methyl R-3-bromomethylhexanoate (0.09 mol), 24.9 g of (S)-2-aminobutyrate (0.18 mol), and 23.9 g of anhydrous sodium carbonate (0.225 mol) were weighed and placed in a 250 mL stainless steel reactor. 200 mL of LDM was added. The reactor was stirred, sealed, and heated to 180 °C. After 4 hours of reaction, a sample was taken. HPLC showed that the starting material was almost completely converted. The reactor was cooled to room temperature, and then the gas valve was opened to allow atmospheric flow. The reaction solution was filtered to remove inorganic salts. 600 mL of water was added to the filtrate. The aqueous layer was extracted with 100 mL of ethyl acetate each time, for a total of three extractions. The combined ethyl acetate was concentrated to dryness under reduced pressure at 45 °C to obtain 9.8 g of waxy crude buvacerostatin, with a yield of 51.6%. The HPLC chemical purity was 97.1%, and the Chiral HPLC chiral purity was 99.0%.

[0069] Comparative Example 2. Preparation of buvasidan

[0070] 20 g of methyl R-3-bromomethylhexanoate (0.09 mol), 24.9 g of (S)-2-aminobutyrate (0.18 mol), and 23.9 g of anhydrous sodium carbonate (0.225 mol) were weighed and placed in a 250 ml stainless steel reactor. 200 ml of isopropyl acetate was added. The mixture was stirred, the reactor was sealed, and the temperature was raised to 140 °C. After 4 hours of reaction, a sample was taken. HPLC showed that a significant amount of the raw material remained. The reaction was extended to 16 hours, and HPLC showed that the raw material was almost completely converted. The reactor was cooled to ambient temperature, and then the gas valve was opened to allow atmospheric flow. The reaction solution was filtered to remove inorganic salts. The filtrate was concentrated to dryness under reduced pressure at 45 °C to obtain 15.4 g of waxy crude buvascarbate, with a yield of 80.9%. The HPLC chemical purity was 96.4%, and the Chiral HPLC chiral purity was 99.2%. The crude product was recrystallized from methyl tert-butyl ether to obtain 12.5 g of white needle-like crystals of buvascarbate, with a yield of 81.2%. HPLC chemical purity 99.2%, Chiral HPLC chiral purity 99.6%.

[0071] Comparative Examples 3-5. Preparation of Bisvastatin

[0072] Weigh 20g of (R)-3-bromomethylhexanoate methyl ester (0.09mol), 24.9g of (S)-2-aminobutyramide hydrochloride (0.18mol), and 23.9g of anhydrous sodium carbonate (0.225mol), and place them into a 250ml glass reaction flask. Add the materials as shown in the table below.

[0073] Table 1. Reaction conditions and results

[0074] solvent temperature result Comparative Example 3 Acetonitrile 80℃ Samples were taken after 22 hours of reaction, and HPLC showed that a significant amount of the starting material remained. Comparative Example 4 Tetrahydrofuran reflux HPLC analysis after 22 hours showed that more than 20% of the active pharmaceutical ingredient was unreacted. Comparative Example 5 Ethyl acetate reflux HPLC analysis after 22 hours showed that more than 20% of the active pharmaceutical ingredient was unreacted.

[0075] Comparative Example 6. Preparation of Bisvastatin

[0076]

[0077] Weigh 20g of methyl R-3-bromomethylhexanoate (0.09mol), 24.9g of (S)-2-aminobutyrate (0.18mol), and 23.9g of anhydrous potassium carbonate (31g), and place them into a 250mL stainless steel reactor. Add 200mL of 1,4-dioxane. Stir, seal the reactor, and heat to 95℃. After reacting for 22 hours, take a sample. HPLC analysis showed that 90% of the raw materials did not react.

[0078] Comparative Example 7. Preparation of Bisvastatin

[0079]

[0080] Weigh 20 g of methyl R-3-bromomethylhexanoate (0.09 mol), 24.9 g of (S)-2-aminobutyrate (0.18 mol), and 23.9 g of triethylamine (22.7 g), and place them in a 250 mL stainless steel reactor. Add 200 mL of 1,4-dioxane. Stir, seal the reactor, and heat to 95 °C. After reacting for 10 h, take a sample. Cool the glass reaction flask to room temperature, add 200 mL of water and 50 mL of ethyl acetate, stir and extract. Allow to stand and separate the layers. Extract the aqueous layer again with 50 mL of ethyl acetate. Combine the ethyl acetate phases and concentrate to dryness under reduced pressure at 60 °C to obtain 13.2 g of waxy crude buvacerostatin, yield 70%. HPLC chemical purity was 95.5%, and Chiral HPLC chiral purity was 97.8%.

[0081] Comparative Example 8. Preparation of Bisvastatin

[0082] Weigh 5.92 g of ethyl R-3-bromomethylhexanoate (0.025 mol), 2.55 g of (S)-2-aminobutyramide hydrochloride (0.025 mol), and 3.03 g of triethylamine (0.03 mol), and place them in a 250 ml glass reaction flask. Add 50 ml of DMF. Stir and heat to 140 °C, react for 2 hours, add water and toluene to separate the layers, discard the aqueous phase, concentrate the toluene layer to obtain crude brivacertan, and then recrystallize from isopropyl ether to obtain brivacertan. The ee value was 95% as determined by HPLC.

[0083] Comparative Example 9. Preparation of Bisvastatin

[0084] Weigh 5.92 g of ethyl R-3-bromomethylhexanoate (0.025 mol), 2.55 g of (S)-2-aminobutyramide hydrochloride (0.025 mol), and 3.03 g of triethylamine (0.03 mol), and place them in a 250 ml glass reaction flask. Add 50 ml of DMF. Stir and heat to 70 °C, react for 8 hours, add water and toluene to separate the layers, concentrate the toluene layer to obtain crude brivacertan, and then recrystallize from isopropyl ether to obtain brivacertan. The ee value was 96% as determined by HPLC.

[0085] Comparative Example 10. Preparation of Bisvastatin

[0086] 20 g of ethyl R-3-bromomethylhexanoate (0.085 mol), 24.9 g of (S)-2-aminobutyramide hydrochloride (0.18 mol), and 23.9 g of anhydrous sodium carbonate (0.225 mol) were weighed and placed in a 250 ml glass reaction flask. 200 ml of 1,4-dioxane was added. The mixture was stirred and heated to 95 °C. After reacting for 22 h, HPLC showed that the starting material was almost completely converted. The glass reaction flask was cooled to room temperature, and the reaction solution was filtered to remove inorganic salts. The filtrate was concentrated to dryness under reduced pressure at 60 °C to obtain 13.6 g of waxy crude buvacertane, with a yield of 72.5%. The HPLC chemical purity was 95.8%, and the Chiral HPLC chiral purity was 99.6%.

[0087] Comparative Example 11. Preparation of Bisvastatin

[0088] Weigh 11.8 g of ethyl R-3-bromomethylhexanoate, 5.6 g of (S)-2-aminobutyramide, and 4 g of anhydrous sodium carbonate, and place them in a 100 ml glass reaction flask. Add 50 ml of ethanol. Stir and heat to 60 °C. After reacting for 8 hours, take a sample. HPLC showed that the starting material did not react much, and no brivaceran was produced.

[0089] Comparative Example 12. Preparation of Bisvastatin

[0090] The base and solvent in Comparative Example 11 were replaced with potassium carbonate and ethanol, and the reaction was carried out at 60°C. After 8 hours of reaction, a sample was taken for HPLC detection, and there were basically no product peaks.

[0091] Comparative Example 13. Preparation of Bisvastatin

[0092] The base and solvent in Comparative Example 11 were replaced with sodium bicarbonate and methanol, and the reaction was carried out at 70°C. After 8 hours of reaction, a sample was taken for HPLC analysis, and almost no product peaks were found.

[0093] Comparative Example 14. Preparation of Bisvastatin

[0094] The base and solvent in Comparative Example 11 were replaced with sodium phosphate and tetrahydrofuran, and the reaction was carried out at 50°C. After 8 hours of reaction, a sample was taken for HPLC analysis, and almost no product peaks were found.

[0095] Example 3. Preparation of buvasidan

[0096]

[0097] 1 kg of methyl R-3-bromomethylhexanoate (4.5 mol), 1245 g of (S)-2-aminobutyrate (9 mol), and 1195 g of anhydrous sodium carbonate (11.25 mol) were weighed and placed in a 20 L stainless steel reactor. 10 L of 1,4-dioxane was added. The mixture was stirred, the reactor was sealed, and the temperature was raised to 140 °C. After reacting for 4 hours, a sample was taken. HPLC showed that the raw materials were almost completely converted. The reactor was cooled to room temperature, and then the gas valve was opened to allow atmospheric flow. The reaction solution was filtered to remove inorganic salts. The filtrate was concentrated under reduced pressure at 60 °C to dryness, yielding 926 g of waxy crude buvascarb. The obtained waxy crude buvascarb was recrystallized from isopropyl ether to obtain 886 g of white needle-like crystals, with a yield of 95.8%. The HPLC chemical purity was 99.7%, and the Chiral HPLC chiral purity was 99.9%.

Claims

1. A method for preparing a compound of formula (I), comprising the step of reacting a compound of formula (III) with the hydrochloride salt of a compound of formula (II) under an alkaline reagent to form a compound of formula (I), wherein the reaction occurs in a closed reactor, the alkaline reagent is sodium carbonate, the molar ratio of the compound of formula (III) to the alkaline reagent is selected from 1:2.5, the molar ratio of the compound of formula (III) to the hydrochloride salt of the compound of formula (II) is selected from 1:2, the reaction temperature is selected from 140°C, and the reaction solvent is dioxane, further comprising the step of recrystallizing the compound of formula (I) in an ether solvent, wherein the ether solvent is isopropyl ether, and the chiral purity of the compound of formula (I) is greater than 99.9%. ； in, X is selected from bromine.

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