A method for preparing brivaracetam

Abstract

The present invention designs a method for preparing a key intermediate of synthetic boceprevir, namely a chiral pyrrolidone derivative, through catalytic hydrogenation. Specifically, it involves the use of substrate chiral induction by adjusting and modifying the substituents of the substrate to achieve the asymmetric catalytic hydrogenation of dihydropyrrolidone by a metal catalyst. The advantages of the present invention are that the process route is simple and feasible, the yield is high, the cost is low, and it is easy to industrialize production, etc.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemical synthesis, and particularly relates to a method for preparing a key intermediate of brivaracetam by metal-catalyzed asymmetric hydrogenation through substrate chiral induction. This method has simple steps and high stereoselectivity, can efficiently synthesize brivaracetam, and has great industrial application value. Background Art

[0002] Brivaracetam, chemically named: (2S)-2-[(4R)-2-oxo-4-propyl-1-pyrrolidinyl]butyramide, CAS: 357336-20-0, molecular formula: C 11 H 20 N 2 O 2 , molecular weight: 317.38, and the structural formula is:

[0003]

[0004] Brivaracetam was developed by UCB and was approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2016 for the adjunctive treatment of partial seizures in adolescents and adults 16 years of age and older with or without secondary generalized seizures.

[0005] International Patent WO01 / 62726 first disclosed the synthetic route of brivaracetam, and the specific method is as follows:

[0006]

[0007] This method first prepares an oxopyrroline intermediate (II) by the reductive amination reaction of 5-hydroxy-4-propyl-2-furanone and (S)-2-aminobutyramide, and then prepares a mixture of diastereoisomers with a ratio of (Ia) / (Ib) of 50 / 50 by the palladium / carbon-catalyzed hydrogenation reaction of intermediate (II). Finally, brivaracetam (Ia) is obtained by chiral column chromatography separation. Since the other diastereoisomer (Ib) has no activity at all in the treatment of epilepsy (known from EP1659191B), the by-product (Ib) generated by synthesizing brivaracetam using this route greatly reduces the total yield, increases the production cost, and is not conducive to scale-up production.

[0008] The synthesis methods of bucindolol reported in patents US8338621B2, WO2005028435, WO2017076738, WO01 / 62726A2, WO2018042393, US20080009638A1, WO2007065634A1, as well as the literature Journal of Medicinal Chemistry, 2004, 47, 530 and Tetrahedron Letters, 2019, 60, 46, 151249 all encounter the same problem, that is, chiral intermediates or the final product need to be obtained by chiral column chromatography separation, thus greatly reducing the industrial application value of these methods.

[0009] The literature Org.Process Res.Dev. 2016, 20, 1566 reported the synthesis of chiral lactone intermediates by enzyme-catalyzed chiral resolution, and then completed the synthesis of bucindolol. However, due to the fact that enzyme-catalyzed chiral resolution will waste half of the materials, resulting in low yield, and the synthesis route is long, it is impossible to achieve industrial production.

[0010]

[0011] Patent CN104892483A reported the preparation of bucindolol by the copper hydride-catalyzed asymmetric hydrogenation reaction of intermediate (III), and the specific method is as follows:

[0012]

[0013] However, both the in-situ preparation of the copper hydride catalyst and the subsequent hydrogenation reaction require extremely harsh reaction conditions, with very high chemical process requirements and are not suitable for industrial production. Secondly, the use of expensive chiral ligands greatly increases the production cost.

[0014] Patent WO2016191435A1 reported a route for synthesizing bucindolol starting from inexpensive chiral epichlorohydrin. However, some steps in the synthesis route involve relatively harsh reaction conditions such as the use of strong bases or heating, resulting in an increase in reaction by-products, low reaction yield, and partial racemization of chiral intermediates.

[0015]

[0016] Due to the complexity of the existing processes for preparing bucindolol, and the fact that the preparation methods of this drug still mainly rely on the chiral resolution of racemates, the preparation time and cost are greatly increased, and the increase in waste materials is also not environmentally friendly. Therefore, there is a need in this field to develop a simple and feasible method suitable for industrial production to efficiently prepare bucindolol. Summary of the Invention

[0017] The object of the present invention is to solve the above synthetic process problems, and to provide a method for preparing a key intermediate of boceprevir with high optical purity by an asymmetric palladium-catalyzed hydrogenation method induced by substrate chirality, and to prepare boceprevir (Ia) through a simple and feasible synthetic route with high yield.

[0018] Specifically, the present invention is achieved through the following technical solutions. A method for preparing boceprevir, the synthetic route is as follows:

[0019]

[0020] Including:

[0021] Reaction a: Dihydropyrrolidone (III) reacts with primary amine (IV) to form amide (V);

[0022] Reaction b: Amide (V) undergoes a reduction reaction with a hydrogen source in the presence of a metal catalyst to form pyrrolidone (VI);

[0023] Reaction c: The R group in pyrrolidone (VI) is removed under appropriate conditions to form boceprevir (Ia).

[0024] As a preferred technical solution of the present invention, wherein, formula (V) and (VI) are compounds represented by the following formula:

[0025]

[0026] The R group is tert-butoxycarbonyl, fluorenylmethoxycarbonyl, trimethylsilylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, benzenesulfonyl, trifluoroacetyl, methanesulfonyl, trifluoromethanesulfonyl, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, preferably p-toluenesulfonyl.

[0027] The first step reaction (Reaction a): (S)-2-(4-n-propyl-1,5-dihydropyrrol-2-one) butyric acid (III) is coupled with primary amine (IV) under the action of EDCI and DMAP. After the reaction solution is pickled with 1M HCl, the aqueous phase is extracted with dichloromethane, and the organic phase is concentrated after drying over anhydrous sodium sulfate. The crude product is purified by recrystallization from ethyl acetate to obtain the dihydropyrrolidone intermediate (V).

[0028]

[0029] According to the preparation method of the dihydropyrrolidone intermediate (IV) of the present invention, the R group in the general formula is selected from tert-butoxycarbonyl, fluorenylmethoxycarbonyl, trimethylsilylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, benzenesulfonyl, trifluoroacetyl, methanesulfonyl, trifluoromethanesulfonyl, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, preferably p-toluenesulfonyl.

[0030] According to the preparation method of the pyrrolidone intermediate (IV) of the present invention, the molar ratio of (S)-2-(4-n-propyl-1,5-dihydropyrrol-2-one) butyric acid (III) to the primary amine (IV) is 1:1 to 1:1.5, preferably 1:1.

[0031] The second reaction (reaction b): Add the pyrrolidone intermediate (IV), a solvent, and a metal catalyst to the reactor and cool. Stir in the presence of a hydrogen source. After the reaction is complete, filter and recrystallize to obtain the pure product of pyrrolidone (VI).

[0032]

[0033] According to the preparation method of pyrrolidone (VI) of the present invention, the R group in the general formula is selected from tert-butoxycarbonyl, fluorenylmethoxycarbonyl, trimethylsilylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, benzenesulfonyl, trifluoroacetyl, methanesulfonyl, trifluoromethanesulfonyl, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, preferably p-toluenesulfonyl.

[0034] According to the preparation method of pyrrolidone (VI) of the present invention, the metal catalyst is selected from palladium on carbon, palladium chloride, palladium bromide, palladium on alumina, tetrakis(triphenylphosphine)palladium, palladium acetate, palladium oxide, palladium trifluoroacetate, palladium sulfate, palladium on silica, palladium nitrate, palladium carbonate barium, palladium carbonate calcium, palladium hydroxide on carbon, bis(triphenylphosphine)palladium dichloride, allylpalladium chloride dimer, ruthenium on carbon, Raney nickel, platinum dioxide, and rhodium on carbon, preferably palladium on carbon.

[0035] According to the preparation method of pyrrolidone (VI) of the present invention, the molar ratio of the catalyst to the compound (V) is 1:0.01 to 1:0.2, preferably 1:0.1.

[0036] According to the preparation method of pyrrolidone (VI) of the present invention, the solvent is selected from methanol, ethanol, isopropanol, dichloromethane, acetone, toluene, tetrahydrofuran, dimethyltetrahydrofuran, methyl tert-butyl ether, cyclopentylhexylmethyl ether, 1,4-dioxane, diisopropyl ether, di-n-butyl ether, ethylene glycol dimethyl ether, ethyl acetate, and trifluoroethanol, preferably tetrahydrofuran.

[0037] According to the preparation method of pyrrolidone (VI) of the present invention, the hydrogen source is selected from hydrogen, ammonium formate, silane, and sodium borohydride, preferably hydrogen.

[0038] According to the preparation method of pyrrolidone (VI) of the present invention, the reaction temperature is from -20°C to room temperature, preferably -20°C.

[0039] The applicant of the present invention unexpectedly found that by adjusting the modifying group R of the amide in the dihydropyrrolone intermediate (IV), the chiral induction ability of the substrate can be greatly improved. Therefore, the asymmetric hydrogenation of the dihydropyrrolone intermediate (IV) can be completed simply by using an achiral catalyst, and pyrrolidone (VI) can be prepared with high optical purity and high yield, and it is easy to operate, the reaction conditions are simple and suitable for industrial production.

[0040] The third-step reaction (Reaction c): The pyrrolidone intermediate (VIa) is de-tosylated under appropriate conditions, and after filtration and concentration, a crude product is obtained, and the pure product of brivaracetam (Ia) is obtained after recrystallization.

[0041]

[0042] According to the preparation method of brivaracetam (Ia) of the present invention, the reaction conditions are selected from magnesium / methanol / heating under reflux, magnesium / methanol / ultrasonic treatment, hydrobromic acid / phenol / heating under reflux, and hydrobromic acid / acetic acid / heating under reflux, and magnesium / methanol / ultrasonic treatment is preferred.

[0043] The present invention further provides an intermediate compound, which is a compound represented by the following formula:

[0044] It should be noted that within the scope of the method of the present invention, the above-mentioned various technical processes and the technical processes expressed in the following examples can be combined with each other to form new technical solutions. Due to space limitations, they will not be elaborated here. Description of the Drawings

[0045] Figure 1 It is a schematic diagram of the 1H NMR spectrum of (Va);

[0046] Figure 2 It is a schematic diagram of the 1H NMR spectrum of (VIa). Detailed Embodiments

[0047] The present invention will be described below in conjunction with specific examples and drawings, but the present invention is not limited thereto.

[0048] The reaction starting material (S)-2-(4-n-propyl-1,5-dihydropyrrol-2-one) butyric acid (III) was prepared with reference to Patent CN107513031A.

[0049] The following provides a specific implementation method of the present invention for the preparation of brivaracetam (Ia).

[0050] Example 1: Preparation of Dihydropyrrolone Intermediate (Va)

[0051]

[0052] (S)-2-(4-Propyl-1,5-dihydropyrrol-2-one)butyric acid (III) (21.1 g, 100 mmol), p-toluenesulfonamide (17.1 g, 100 mmol) and DMAP (13.4 g, 110 mmol) were dissolved in dichloromethane (500 mL). After cooling to 0 °C, EDCI (21.1 g, 110 mmol) was added. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred overnight. 1M HCl was added to the reaction mixture to adjust the pH to 5 - 6, then the aqueous phase was extracted with dichloromethane (3 × 100 mL). The combined organic phases were washed with saturated brine (100 mL × 3) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness, and the resulting crude solid was recrystallized from ethyl acetate (150 mL) to give 32.8 g of a white solid in 90% yield.

[0053] MS (m / z): [M + H] + = 365.20

[0054] 1 H NMR (600 MHz, CDCl 3 ) δ 7.91 (d, J = 7.7 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 5.97 (s, 1H), 4.90 (s, 1H), 4.65 (t, J = 7.7 Hz, 1H), 3.81 (s, 2H), 2.42 (s, 3H), 2.31 (t, J = 7.6 Hz, 2H), 1.89 (dp, J = 14.4, 7.2 Hz, 1H), 1.68 (tt, J = 15.2, 7.7 Hz, 1H), 1.57 (p, J = 7.4 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H), 0.82 (t, J = 7.3 Hz, 3H) ppm., as shown specifically Figure 1 as follows.

[0055] Example 2: Preparation of pyrrolidone intermediate (VIa)

[0056]

[0057] In an autoclave, the dihydropyrrolone intermediate (Va) (90 mmol, 32.8 g) was dissolved in tetrahydrofuran. After cooling to -20 °C, H 2 was displaced three times and H 2 was charged until the pressure reached 20 atm, and the mixture was stirred at -20 °C for 8 h. After filtration, the filtrate was concentrated to dryness to give 32.7 g of an off-white solid in 99% yield (de = 96:4). Recrystallization from methyl tert-butyl ether / n-heptane gave 30.9 g of a white solid pure product (de > 99%).

[0058] MS (m / z): [M+H] + = 367.18

[0059] 1 H NMR (600 MHz, CDCl 3 ) δ 7.91 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 7.3 Hz, 2H), 4.86 (s, 1H), 4.41 (t, J = 7.9 Hz, 1H), 3.36 (t, J = 8.8 Hz, 1H), 2.76 (t, J = 8.5 Hz, 1H), 2.59 (dd, J = 17.3, 8.5 Hz, 1H), 2.42 (s, 3H), 2.28–2.26 (m, 1H), 2.07–2.03 (m, 1H), 1.84 (dp, J = 14.4, 7.3 Hz, 1H), 1.62 (tt, J = 15.3, 7.5 Hz, 1H), 1.25 (dt, J = 12.0, 6.6 Hz, 4H), 0.88 (t, J = 6.3 Hz, 3H), 0.81 (t, J = 7.4 Hz, 3H) ppm., as specifically shown in Figure 2 shown below.

[0060] Example 3: Preparation of Brivaracetam (Ia)

[0061]

[0062] Dissolve pyrrolidone intermediate (VIa) (5.83 g, 15.9 mmol) in methanol (80 mL), add magnesium strip (1.91 g, 79.5 mmol), and sonicate for 1 h. Filter, slowly add 1 M HCl to the filtrate until pH < 6, and concentrate to dryness. The obtained crude solid is redissolved in dichloromethane (100 mL), washed with saturated brine (20 mL * 3), and dried over anhydrous sodium sulfate. Filter, concentrate the filtrate to dryness, and recrystallize the obtained crude solid with methyl tert-butyl ether to obtain 2.79 g of white solid with a yield of 83% (de > 99%).

[0063] The above-described embodiments only represent the preferred embodiments of the present invention. It should be noted that for those skilled in the technical field of this technology, the improvements and refinements made using the concept and method of the present invention should also be regarded as within the protection scope of the present invention.

Claims

1. A preparation method of bucindolol, characterized in that: It includes: Reaction a: Dihydropyrrolidone (III) reacts with primary amine (IV) to form amide (V); Reaction b: Amide (V) undergoes a reduction reaction with a hydrogen source in the presence of a metal catalyst to form pyrrolidone (VI); Reaction c: The R group in pyrrolidone (VI) is removed under magnesium / methanol / heating under reflux, magnesium / methanol / ultrasonic treatment, hydrobromic acid / phenol / heating under reflux, or hydrobromic acid / acetic acid / heating under reflux to form bucindolol (Ia); The R group is tert-butoxycarbonyl, fluorenylmethoxycarbonyl, trimethylsilylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, benzenesulfonyl, trifluoroacetyl, methanesulfonyl, trifluoromethanesulfonyl, 2-nitrobenzenesulfonyl, or 4-nitrobenzenesulfonyl.

2. The preparation method according to claim 1, characterized in that, The R group is p-toluenesulfonyl.

3. The preparation method according to claim 1, characterized in that, In step a, through EDCI / DMAP coupling, the molar ratio of dihydropyrrolidone (III) to primary amine (IV) is 1:1 to 1:1.

5.

4. The preparation method according to claim 1 or 3, characterized in that, The molar ratio of dihydropyrrolidone (III) to primary amine (IV) is 1:

1.

5. The preparation method according to claim 1, characterized in that, In step b, the metal catalyst is selected from palladium on carbon, palladium chloride, palladium bromide, palladium alumina, tetrakis(triphenylphosphine)palladium, palladium acetate, palladium oxide, palladium trifluoroacetate, palladium sulfate, palladium silica, palladium nitrate, palladium barium carbonate, palladium calcium carbonate, palladium hydroxide on carbon, bis(triphenylphosphine)palladium dichloride, allylpalladium chloride dimer, ruthenium on carbon, Raney nickel, platinum dioxide, and rhodium on carbon.

6. The preparation method according to claim 1 or 5, characterized in that, The metal catalyst is palladium on carbon.

7. The preparation method according to claim 1, characterized in that, In step b, the molar ratio of the catalyst to compound (V) is 1:0.01 to 1:0.

2.

8. The preparation method according to claim 1 or 7, characterized in that, The molar ratio of the metal catalyst to compound (V) is 1:0.

1.

9. The preparation method according to claim 1, characterized in that, In step b, the hydrogen source is selected from hydrogen, ammonium formate, silane, and sodium borohydride.

10. The preparation method according to claim 1 or 9, characterized in that, The hydrogen source is hydrogen.

11. The preparation method according to claim 1, characterized in that, In step b, the reduction reaction solvent is selected from methanol, ethanol, isopropanol, dichloromethane, acetone, toluene, tetrahydrofuran, dimethyltetrahydrofuran, methyl tert-butyl ether, cyclopentylhexylmethyl ether, 1,4-dioxane, diisopropyl ether, di-n-butyl ether, ethylene glycol dimethyl ether, ethyl acetate, and trifluoroethanol.

12. The preparation method according to claim 1 or 11, characterized in that, The reduction reaction solvent is tetrahydrofuran.

13. The preparation method according to claim 1, characterized in that, In step b, the reduction reaction temperature is -20°C to room temperature.

14. The preparation method according to claim 1 or 13, characterized in that, the reduction reaction temperature is -20 °C.

15. A compound, characterized by: selected from the compounds represented by the following formula:

Images