Preparation method of briracetam

Abstract

The invention belongs to the field of chemical medicine preparation, and relates to a preparation method of briracetam. The preparation method comprises the following steps: by taking 3-alkenylpyrrolidone as a raw material, carrying out asymmetric Michael addition reaction, substitution reaction, ammonolysis reaction and the like to prepare the briracetam. The method disclosed by the invention is high in stereoselectivity, chiral raw materials do not need to be purchased, and high-yield and high-purity briracetam can be obtained by using common raw materials.

Description

Technical Field

[0001] The invention belongs to the field of chemical drug preparation and relates to a preparation method of brivaracetam and (S)-2-((R)-3-propylpyrrolidin-1-yl)butanamide. Background Art

[0002]

[0003] Brivaracetam is a third-generation anti-epileptic drug developed by UCB of Belgium. It is used to treat partial seizures in adults and adolescents over 16 years of age with epilepsy, with or without secondary generalized seizures. It has entered the Phase III clinical stage in China. Compared with other anti-epileptic drugs, Brivaracetam has a low dosage and good tolerance. Brivaracetam can selectively bind to synaptic vesicle protein 2A (SV2A) located in the presynaptic membrane, thereby reducing the release of excitatory neurotransmitters and controlling epileptic seizures by regulating the balance of excitatory and inhibitory neurotransmitters in the brain. Brivaracetam is a derivative of levetiracetam. However, its affinity is 15-30 times that of levetiracetam, which allows its clinical dosage to be reduced by about 10 times.

[0004] The previously reported synthetic route of brivaracetam has two very obvious shortcomings. First, the synthetic route is long and complicated, and the total yield is low. For example, CN108503610A and CN108503609A mentioned that (R)-4-propyl-dihydrofuran-2-one is used as a key intermediate, and then brivaracetam is obtained through several steps of reaction. In this type of preparation method, the preparation of the intermediate alone is extremely complicated, and it is necessary to purchase high-purity chiral raw materials to obtain qualified products. Second, it involves the problem of chiral separation, and the separation is carried out using a chiral resolving agent, such as reported in CN113582902 and CN111333563, which uses a resolving agent for separation. Such a separation method has a low yield and high cost, which is not conducive to industrial production. Summary of the invention

[0005] In view of the deficiencies of the prior art, the present invention provides a method for preparing brivaracetam, which has high stereoselectivity, does not require the purchase of chiral raw materials, and uses common raw materials to asymmetrically synthesize brivaracetam with high yield and high purity twice.

[0006] In order to achieve the above objectives, the technical solution adopted by the present invention is as follows: A method for preparing brivaracetam comprises the following steps:

[0007]

[0008] S1, using 3-vinylpyrrolidone (Formula I) as a raw material, and reacting it with dipropylzinc in a solvent under the catalysis of a chiral ligand and a Cu catalyst to produce R-4-propylpyrrolidone (Formula II);

[0009] This step is to obtain the intermediate of formula II with high selectivity through asymmetric reaction, wherein dipropyl zinc provides a propyl side chain, and the propyl group is transferred from Zn to Cu through an organic copper catalyst to produce a more active organic copper reagent. The alkyl zinc fragment is complexed with the carbonyl of the enone, and the alkyl copper forms a π complex with the enone to obtain a bimetallic complex, resulting in a fixed conformation, thereby obtaining high stereoselectivity. The ability of organic zinc reagents to undergo metal transformation to convert them into more active organic metal reagents has been demonstrated by Ni, Cu, Pd, and Ti.

[0010]

[0011] Monodentate phosphoramide ligands have extremely high catalytic activity in asymmetric Michael addition reactions. Different groups have different stereoselectivities. The stronger the electron-donating ability of the group, the higher the catalytic activity. Among the following three phosphoramide ligands screened in this patent, compound A has the highest catalytic stereoselectivity and the product has a high ee value. The amount of chiral ligand added should not be too much, otherwise it will affect the reaction rate and chiral selectivity.

[0012]

[0013] S2, R-4-propylpyrrolidone (Formula II) undergoes a substitution reaction with tert-butyl bromoacetate (Formula III) in a solvent in the presence of a base and an iodine salt to obtain tert-butyl α-((R)-3-propylpyrrolidin-1-yl)acetate (Formula IV);

[0014] In nucleophilic substitution reaction, the base removes the hydrogen on nitrogen. The alkalinity cannot be too strong, otherwise the tert-butyl ester will be hydrolyzed. Weak bases such as Na2CO3, K2CO3, etc. are used. Iodine salt is used to increase the activity of bromide by halogen substitution.

[0015] S3, tert-butyl α-((R)-3-propylpyrrolidin-1-yl)acetate (Formula IV) reacts with ethyl bromide in the presence of a base, a solvent and a ligand to obtain tert-butyl (S)-2-((R)-3-propylpyrrolidin-1-yl)butyrate (Formula V);

[0016] The chiral ligand is a compound (R,R)-bis(2-naphthyl)-NAS bromide, which negatively complexes with oxygen, thereby affecting the chiral selectivity. The amount of ligand added should not be too much, otherwise it will affect the reaction rate and the chiral selectivity of the ligand. The structure is shown below:

[0017]

[0018] (R,R)-bis(2-naphthyl)-NASbromide

[0019] The reaction mechanism is as follows:

[0020]

[0021] S4, (S)-2-((R)-3-propylpyrrolidin-1-yl)butyric acid tert-butyl ester (Formula V) undergoes aminolysis reaction with ammonia to obtain (S)-2-((R)-3-propylpyrrolidin-1-yl)butyramide, i.e., brivaracetam (Formula VI).

[0022] Specifically, the reaction process is:

[0023]

[0024] Preferably, in S1, the chiral ligand is one of compounds A, B, and C, preferably compound A;

[0025] Preferably, in S1, the molar ratio of compound I to the chiral ligand is 1:0.34-0.45, preferably 1:0.4;

[0026] Preferably, in S1, the Cu catalyst is Cu(OTf)2, CuI, CuTC, copper acetate, preferably CuTC;

[0027] Preferably, in S1, the molar ratio of the chiral ligand to the Cu catalyst is 2:1;

[0028] Preferably, in S1, the molar ratio of compound I to dipropyl zinc is 1:1.0-3.0, preferably 1:2.0;

[0029] Preferably, in S1, the solvent is toluene, ethylbenzene, DMF, THF, DCM, acetone, preferably toluene.

[0030] Preferably, in S2, the reaction temperature is 60-100°C, preferably 85-90°C;

[0031] Preferably, in S2, the base is a mixture of one or more of Na2CO3, K2CO3, LDA, tBuOK, tBuONa, KOH, triethylamine, cesium carbonate, and sodium hydride;

[0032] Preferably, in S2, the solvent is selected from a mixture of one or more of isopropyl acetate, isopropyl ether, dioxane, DMF, THF, DCM, chloroform, methanol, ethanol, and acetonitrile;

[0033] Preferably, in S2, the molar ratio of compound II to compound III is 1:1.02-1.05;

[0034] Preferably, in S3, the molar ratio of compound IV to ethyl bromide is 1:1.0-1.3, preferably 1:1.1; the molar ratio of compound IV to the ligand is 45-55:1, preferably 50:1.

[0035] Preferably, in S3, the base may be a mixture of one or more of potassium carbonate, sodium carbonate, cesium carbonate, KOH, NaOH, cesium carbonate, tBuOK, and tBuONa;

[0036] Preferably, in S3, the solvent is selected from a mixture of one or more of DMF, DMSO, DMA, THF, DCM, toluene and tert-butanol;

[0037] Preferably, in S3, the ligand is R,R-bis(2-naphthyl)-NASbromide;

[0038] Preferably, in S4, the reaction temperature is 0-80°C, preferably 50-60°C.

[0039] The advantages of the present invention are: the method of the present invention has high stereoselectivity, and there is no need to purchase chiral raw materials. Brivaracetam with high yield and high purity can be obtained by using common raw materials. DETAILED DESCRIPTION

[0040] The following specific examples are provided to further illustrate the present invention and should not be construed as limiting the present invention.

[0041] The yields in the following examples are calculated based on the molar number of the substrate fed in each specific step.

[0042]

[0043] Example 1

[0044] 1) Preparation of R-4-propylpyrrolidone (Formula II):

[0045] Add dry toluene to the reaction flask, add compound I (4.15g, 50mmol), CuTC (1.9g, 10mmol), compound A (10.79g, 20mmol) in sequence, and stir at room temperature for 40min. Add 2M (Pr)2Zn toluene solution (50ml, 100mmol) under stirring, stir and react for 2h, quench the mixture with NH4Cl saturated aqueous solution after completion, and extract with DCM. The combined organic layer is dried (Na2SO4), concentrated and chromatographed (n-hexane-EA) to obtain 5.41g compound II, with a yield of 85%, a purity of 99.2%, and an ee of 98.0%.

[0046] 2) Preparation of tert-butyl α-((R)-3-propylpyrrolidin-1-yl)acetate (Formula IV):

[0047] In a reaction flask, a mixture of R-4-propylpyrrolidone (Formula II) (5.1 g, 40 mmol), compound III (8.04 g, 41.2 mmol), sodium iodide (0.6 g, 4 mmol), and sodium carbonate (0.06 g, 80 mmol) was refluxed at 88°C in 60 ml of isopropyl acetate for 10 h. After cooling, the mixture was washed with 8% sodium bicarbonate solution, the organic layer was separated, and washed three times with saturated brine. The organic layer was dried over anhydrous MgSO4 and evaporated to dryness, 30 ml of isopropyl ether was added, concentrated, heated, and crystallized to obtain 7.72 g of compound IV with a yield of 80%, a purity of 99.0%, and an optical purity of ee 98.5%.

[0048] 3) Preparation of tert-butyl (S)-2-((R)-3-propylpyrrolidin-1-yl)butyrate (Formula V)

[0049] Compound IV (7.24 g, 30 mmol), bromoethane (3.6 g, 33 mmol), (R, R)-bis(2-naphthyl)-NAS bromide (0.5 g, 0.6 mmol) in toluene (30 mL) were added to the reaction flask. A 50 wt% aqueous potassium hydroxide solution (30 mL) was added, and the mixture was stirred at room temperature for 1 h, and quenched with a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, the combined extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 6:1 as eluent) to give 7.50 g of compound V, with a yield of 93%, a purity of 99.2%, and ee 99.0%.

[0050] 4) Preparation of Brivaracetam (Formula VI)

[0051] Compound V (7.5 g, 27.9 mmol) and methanol (50 ml) were added to a pressure reactor. After stirring and dissolving, the reactor was evacuated and ammonia gas was introduced until the pressure in the reactor reached 0.6 MPa. The pressure was maintained during the process and the temperature was raised to 55 ° C and stirred for 10 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dry methanol. Isopropyl ether (80 ml) was added to the residue and the temperature was raised to 48 ° C. Stirring until completely dissolved, cooling to 0 ° C and stirring to crystallize, filtering and drying to obtain 5.32 g of brivaracetam with a yield of 90% and a purity of 99.4%.

[0052] Example 2

[0053] 1) Preparation of R-4-propylpyrrolidone (Formula II):

[0054] Add dry toluene to the reaction flask, add compound I (4.15g, 50mmol), CuTC (1.9g, 10mmol), compound A (10.79g, 20mmol) in sequence, and stir at room temperature for 40min. Add 2M (Pr)2Zn toluene solution (50ml, 100mmol) under stirring, stir and react for 2h, then quench the mixture with NH4Cl saturated aqueous solution, and extract with DCM. The combined organic layer is dried (Na2SO4), concentrated and chromatographed (n-hexane-EA) to obtain 5.15g of compound II, with a yield of 81%, a purity of 99.1%, and an ee of 98.2%.

[0055] 2) Preparation of tert-butyl α-((R)-3-propylpyrrolidin-1-yl)acetate (Formula IV):

[0056] In a reaction flask, a mixture of R-4-propylpyrrolidone (Formula II) (5.1 g, 40 mmol), compound III (8.04 g, 41.2 mmol), sodium iodide (0.6 g, 4 mmol), and sodium carbonate (0.06 g, 80 mmol) was refluxed at 85°C in 60 ml of isopropyl acetate for 10 h. After cooling, the mixture was washed with 8% sodium bicarbonate solution, the organic layer was separated, and washed three times with saturated brine. The organic layer was dried over anhydrous MgSO4 and evaporated to dryness, 30 ml of isopropyl ether was added, concentrated, heated, and crystallized to obtain 7.55 g of compound IV. The yield was 78%, the purity was 99.0%, and the optical purity ee was 98.6%.

[0057] 3) Preparation of tert-butyl (S)-2-((R)-3-propylpyrrolidin-1-yl)butyrate (Formula V)

[0058] Compound IV (7.24 g, 30 mmol), ethyl bromide (3.6 g, 33 mmol), (R,R)-bis(2-naphthyl)-NAS bromide (0.5 g, 0.6 mmol) in toluene (30 mL) were added to the reaction flask. A 50 wt% aqueous potassium hydroxide solution (30 mL) was added, and the mixture was stirred at room temperature for 1 h, and quenched with a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the combined extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 5:1 as eluent) to obtain 7.65 g of compound V. The yield was 95%, the purity was 99.3%, and the ee was 99.1%.

[0059] 4) Preparation of Brivaracetam (Formula VI)

[0060] Compound V (7.5 g, 27.9 mmol) and methanol (50 ml) were added to a pressure reactor. After stirring and dissolving, the reactor was evacuated and ammonia gas was introduced until the pressure in the reactor reached 0.6 MPa. The pressure was maintained during the process. The temperature was raised to 50 ° C and the reaction was stirred for 10 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dry methanol. Isopropyl ether (80 ml) was added to the residue and the temperature was raised to 45 ° C. Stirring until completely dissolved, cooling to 5 ° C and stirring to crystallize, filtering and drying to obtain 5.36 g of brivaracetam with a yield of 91% and a purity of 99.3%.

[0061] Example 3

[0062] 1) Preparation of R-4-propylpyrrolidone (Formula II):

[0063] Add dry toluene to the reaction flask, add compound I (4.15g, 50mmol), CuTC (1.9g, 10mmol), compound A (10.79g, 20mmol) in sequence, and stir at room temperature for 40min. Add 2M (Pr)2Zn toluene solution (50ml, 100mmol) under stirring, stir and react for 2h, quench the mixture with NH4Cl saturated aqueous solution after completion, and extract with DCM. The combined organic layer is dried (Na2SO4), concentrated and chromatographed (n-hexane-EA) to obtain 5.16g of compound II, with a yield of 81%, a purity of 99.0%, and an ee of 98.3%.

[0064] 2) Preparation of tert-butyl α-((R)-3-propylpyrrolidin-1-yl)acetate (Formula IV):

[0065] In a reaction flask, a mixture of R-4-propylpyrrolidone (Formula II) (5.1 g, 40 mmol), compound III (8.04 g, 41.2 mmol), sodium iodide (0.6 g, 4 mmol), and sodium carbonate (0.06 g, 80 mmol) was refluxed at 90°C in 60 ml of isopropyl acetate for 10 h. After cooling, the mixture was washed with 8% sodium bicarbonate solution, the organic layer was separated, and washed three times with saturated brine. The organic layer was dried over anhydrous MgSO4 and evaporated to dryness, 30 ml of isopropyl ether was added, concentrated, heated, and crystallized to obtain 7.90 g of compound IV, with a yield of 82%, a purity of 99.2%, and an optical purity of ee 98.5%.

[0066] 3) Preparation of tert-butyl (S)-2-((R)-3-propylpyrrolidin-1-yl)butyrate (Formula V)

[0067] Compound IV (7.24 g, 30 mmol), ethyl bromide (3.6 g, 33 mmol), (R, R)-bis(2-naphthyl)-NAS bromide (0.5 g, 0.6 mmol) in toluene (30 mL) were added to the reaction flask. A 50 wt% aqueous potassium hydroxide solution (30 mL) was added, and the mixture was stirred at room temperature for 1 h, and quenched with a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, the combined extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 7:1 as eluent) to obtain 7.53 g of compound V, with a yield of 93%, a purity of 99.1%, and ee 99.2%.

[0068] 4) Preparation of Brivaracetam (Formula VI)

[0069] Compound V (7.5 g, 27.9 mmol) and methanol (50 ml) were added to a pressure reactor. After stirring and dissolving, the reactor was evacuated and ammonia gas was introduced until the pressure in the reactor reached 0.6 MPa. The pressure was maintained during the process. The temperature was raised to 60 ° C and the reaction was stirred for 10 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dry methanol. Isopropyl ether (80 ml) was added to the residue and the temperature was raised to 50 ° C. Stirring until completely dissolved, cooling to 0 ° C and stirring to crystallize, filtering and drying to obtain 5.47 g of brivaracetam with a yield of 93% and a purity of 99.1%.

[0070] Example 4

[0071] Preparation of R-4-propylpyrrolidone (Formula II):

[0072] Add dry toluene to the reaction flask, add compound I (4.15g, 50mmol), CuTC (1.9g, 10mmol), compound B (8.31g, 20mmol) in sequence, and stir at room temperature for 40min. Add 2M (Pr) 2Zn toluene solution (50ml, 100mmol) under stirring, stir and react for 2h, quench the mixture with NH 4 Cl saturated aqueous solution after completion, and extract with DCM. The combined organic layer is dried (Na 2 SO 4), concentrated and chromatographed (n-hexane-EA) to obtain 5.02g of compound II, with a yield of 79%, a purity of 99.2%, and ee 95.0%.

[0073] Example 5

[0074] Preparation of R-4-propylpyrrolidone (Formula II):

[0075] Add dry toluene to the reaction flask, add compound I (4.15g, 50mmol), CuTC (1.9g, 10mmol), compound C (7.19g, 20mmol) in sequence, and stir at room temperature for 40min. Add 2M (Pr)2Zn toluene solution (50ml, 100mmol) under stirring, stir and react for 2h, then quench the mixture with NH4Cl saturated aqueous solution, and extract with DCM. The combined organic layer is dried (Na2SO4), concentrated and chromatographed (n-hexane-EA) to obtain 5.21g of compound II, with a yield of 82%, a purity of 99.0%, and an optical purity of ee 94.0%.

[0076] It can be seen from Examples 1, 4 and 5 that the chiral ligand compound A, compared with compounds B and C, can prepare R-4-propylpyrrolidone with higher optical purity.

[0077] Comparative Example 1

[0078] Preparation of R-4-propylpyrrolidone (Formula II):

[0079] Add dry toluene to the reaction flask, add compound I (4.15g, 50mmol), CuTC (1.9g, 10mmol), compound A (16.19g, 30mmol) in sequence, and stir at room temperature for 40min. Add 2M (Pr)2Zn toluene solution (50ml, 100mmol) under stirring, stir and react for 2h, then quench the mixture with NH4Cl saturated aqueous solution, and extract with DCM. The combined organic layer is dried (Na2SO4), concentrated and chromatographed (n-hexane-EA) to obtain 4.64g of compound II, with a yield of 73%, a purity of 99.0%, and an optical purity of ee 90.5%.

[0080] Compared with Example 1, the ratio of compound A in Comparative Example 1 was increased, and the yield and optical purity were significantly reduced.

[0081] Comparative Example 2

[0082] Preparation of tert-butyl (S)-2-((R)-3-propylpyrrolidin-1-yl)butyrate (Formula V)

[0083] Compound IV (7.24 g, 30 mmol), ethyl bromide (3.6 g, 33 mmol), (R, R)-bis(2-naphthyl)-NAS bromide (0.83 g, 1.0 mmol) in toluene (30 mL) were added to the reaction flask. A 50 wt% aqueous potassium hydroxide solution (30 mL) was added, and the mixture was stirred at room temperature for 1 h, and quenched with a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, the combined extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 6:1 as eluent) to give 6.47 g of compound V, with a yield of 80%, a purity of 99.0%, and ee 86.0%.

[0084] Compared with Example 1, in Comparative Example 2, the ratio of (R,R)-bis(2-naphthyl)-NAS bromide was increased, and the yield and optical purity were significantly reduced.

[0085] It can be seen from Comparative Examples 1 and 2 that the proportion of chiral ligands is critical to the reaction yield and optical purity.

[0086] The above embodiments are only used to illustrate the technical solutions of the present invention. Those skilled in the art should understand that the above embodiments do not limit the present invention in any form, and any technical solutions obtained by equivalent replacement or equivalent transformation shall fall within the protection scope of the present invention.

Claims

1. A method for preparing brivaracetam, characterized in that: The steps include: S1, using 3-vinylpyrrolidone (Formula I) as a raw material, and reacting it with dipropylzinc in a solvent under the catalysis of a chiral ligand and a Cu catalyst to produce R-4-propylpyrrolidone (Formula II); S2, R-4-propylpyrrolidone (Formula II) undergoes a substitution reaction with tert-butyl bromoacetate (Formula III) in a solvent in the presence of a base and an iodine salt to obtain tert-butyl α-((R)-3-propylpyrrolidin-1-yl)acetate (Formula IV); S3, tert-butyl α-((R)-3-propylpyrrolidin-1-yl)acetate (Formula IV) reacts with ethyl bromide in the presence of a base, a solvent and a chiral ligand to obtain tert-butyl (S)-2-((R)-3-propylpyrrolidin-1-yl)butyrate (Formula V); S4, (S)-2-((R)-3-propylpyrrolidin-1-yl)butyric acid tert-butyl ester (Formula V) undergoes aminolysis reaction with ammonia to obtain (S)-2-((R)-3-propylpyrrolidin-1-yl)butyramide, i.e., brivaracetam (Formula VI).

2. The method for preparing brivaracetam according to claim 1, characterized in that: The reaction process is:

3. The method for preparing brivaracetam according to claim 1, characterized in that: In S1, the chiral ligand is at least one of compounds A, B, and C; 4. The method for preparing brivaracetam according to claim 3, characterized in that: In S1, the molar ratio of compound I to the chiral ligand is 1:0.35-0.45, preferably 1:0.4; the Cu catalyst is at least one of Cu(OTf)2, CuOTf, CuI, CuTC, and copper acetate; the molar ratio of the chiral ligand to the Cu catalyst is 2:

1.

5. The method for preparing brivaracetam according to claim 3, characterized in that: In S1, the molar ratio of compound I to the dipropyl zinc is 1:2.0-3.0, preferably 1:2.0; and the solvent is at least one of toluene, ethylbenzene, DMF, THF, DCM, and acetone.

6. The method for preparing brivaracetam according to claim 1, characterized in that: In S2, the reaction temperature is 85-90°C; the base is a mixture of one or more of Na2CO3, K2CO3, LDA, tBuOK, tBuONa, KOH, triethylamine, cesium carbonate, and sodium hydride.

7. The method for preparing brivaracetam according to claim 1, characterized in that: In S2, the solvent is selected from a mixture of one or more of isopropyl acetate, isopropyl ether, dioxane, DMF, THF, DCM, chloroform, methanol, ethanol, and acetonitrile; and the molar ratio of compound II to compound III is 1:1.02-1.

05.

8. The method for preparing brivaracetam according to claim 1, characterized in that: In S3, the molar ratio of compound IV to ethyl bromide is 1:1.0-1.3 or 1:1.1; the molar ratio of compound IV to the ligand is 45-55:1, preferably 50:

1.

9. The method for preparing brivaracetam according to claim 1, characterized in that: In S3, the base is a mixture of one or more of potassium carbonate, sodium carbonate, cesium carbonate, KOH, NaOH, cesium carbonate, tBuOK, and tBuONa; the solvent is a mixture of one or more of DMF, DMSO, DMA, THF, DCM, toluene, and tert-butanol; and the ligand is R,R-bis(2-naphthyl)-NAS bromide.

10. The method for preparing brivaracetam according to claim 1, characterized in that: In S4, the reaction temperature is 50-60°C.

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