CN115784959A - Preparation method of brivaracetam - Google Patents
Preparation method of brivaracetam Download PDFInfo
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- CN115784959A CN115784959A CN202111055384.3A CN202111055384A CN115784959A CN 115784959 A CN115784959 A CN 115784959A CN 202111055384 A CN202111055384 A CN 202111055384A CN 115784959 A CN115784959 A CN 115784959A
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Abstract
The invention designs a method for preparing and synthesizing a key intermediate of brivaracetam, namely a chiral pyrrolidone derivative through catalytic hydrogenation. In particular to the method which utilizes substrate chirality induction to complete asymmetric catalytic hydrogenation of dihydropyrrolone by a metal catalyst by adjusting substituent groups of a modified substrate. The invention has the advantages of simple and easy process route, high yield, low cost, easy industrial production and the like.
Description
Technical Field
The invention belongs to the field of medicinal chemical synthesis, and particularly relates to a method for preparing a key intermediate of brivaracetam by metal-catalyzed asymmetric hydrogenation through substrate chiral induction. The method has simple steps and high stereoselectivity, can efficiently synthesize the brivaracetam, and has great industrial application value.
Background
Brivaracetam (Brivaracetam), chemical name: (2S) -2- [ (4R) -2-oxo-4-n-propyl-1-pyrrolidinyl)]Butyramide, CAS:357336-20-0, molecular formula: c 11 H 20 N 2 O 2 Molecular weight: 317.38, the structural formula is:
brivaracetam was developed by UCB and approved by the united states Food and Drug Administration (FDA) and European Medical Administration (EMA) in 2016 for the adjuvant treatment of partial seizures, with or without secondary generalized seizures, in adolescent and adult patients with epilepsy at age 16 and older.
International patent WO01/62726 first discloses a synthetic route for brivaracetam, and the specific method is as follows:
the process first prepares an oxopyrroline intermediate (II) by reductive amination of 5-hydroxy-4-n-propyl-2-furanone and (S) -2-aminobutanamide, followed by palladium/carbon catalyzed hydrogenation of intermediate (II) to prepare a mixture of diastereomers having a ratio (Ia)/(Ib) of 50/50. Finally, obtaining the brivaracetam (Ia) by chiral chromatographic column resolution. Since the other diastereomer (Ib) is completely inactive in the treatment of epilepsy (known from EP 1659191B), the synthesis of Buwa by this route produces by-products (Ib) which greatly reduce the overall yield, increase the production costs and are disadvantageous for scale-up.
The same problem is encountered with the synthesis of bravaracetam reported in patents US8338621B2, WO2005028435, WO2017076738, WO01/62726a2, wo2018042393, US20080009638a1, wo2007065634a1, as well as in the Journal of Medicinal Chemistry,2004,47,530 and Tetrahedron Letters,2019,60,46,151249, i.e. either the chiral intermediate or the final product needs to be obtained by chiral column resolution, thus greatly reducing the industrial application value of these methods.
The synthesis of chiral lactone intermediates by enzymatic chiral resolution was reported in org. Process res. Dev.2016,20,1566 and completed the synthesis of brivaracetam. However, the enzyme-catalyzed chiral resolution wastes half of the material, so that the yield is low, the synthetic route is long, and the industrial production cannot be realized.
Patent CN104892483A reports the preparation of brivaracetam by copper-hydrogen catalyzed asymmetric hydrogenation of intermediate (III), the specific method is as follows:
however, the in-situ preparation of the copper-hydrogen catalyst and the subsequent hydrogenation reaction both require extremely severe reaction conditions, have high requirements on chemical processes, and are not suitable for industrial production. Secondly, the use of expensive chiral ligands adds significantly to the cost of production.
Patent WO2016191435A1 reports a route to the synthesis of brivaracetam starting from cheap chiral epichlorohydrin. However, some steps in the synthetic route involve the use of relatively severe reaction conditions such as strong alkali or heat, resulting in increased reaction by-products, low reaction yield, and partial racemization of chiral intermediates.
Because the existing process for preparing the brivaracetam is complex, and the preparation method of the medicament mainly adopts chiral resolution of racemate, the preparation time and cost are greatly increased, and the increase of waste materials is not environment-friendly. Therefore, the method which is simple and feasible and is suitable for industrial production needs to be developed in the field to efficiently prepare the brivaracetam.
Disclosure of Invention
The invention aims to solve the problem of the synthesis process, provides a method for preparing a key intermediate of the brivaracetam with high optical purity by using an asymmetric palladium catalytic hydrogenation method induced by substrate chirality, and prepares the brivaracetam (Ia) by using a simple and easy synthesis route with high yield.
Specifically, the invention is realized by the following technical scheme, and the preparation method of the brivaracetam comprises the following synthetic route:
the method comprises the following steps:
reaction a: dihydropyrrolones (III) and primary amines (IV) form amides (V);
and b, reaction: carrying out reduction reaction on the amide (V) and a hydrogen source in the presence of a metal catalyst to generate pyrrolidone (VI);
reaction c: the R group in the pyrrolidone (VI) is removed under proper conditions to generate the brivaracetam (Ia).
In a preferred embodiment of the present invention, the compounds of formulae (V) and (VI) are represented by the following formulae:
the R group is tert-butyloxycarbonyl, fluorenyl methoxycarbonyl, trimethylsiloxyethyl carbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, benzenesulfonyl, trifluoroacetyl, methanesulfonyl, trifluoromethanesulfonyl, 2-nitrobenzenesulfonyl and 4-nitrobenzenesulfonyl, preferably p-toluenesulfonyl.
First-step reaction (reaction a): (S) -2- (4-n-propyl-1, 5-dihydropyrrol-2-one) butanoic acid (III) was coupled with the primary amine (IV) under the action of EDCI and DMAP. After the reaction solution was washed with 1M HCl, the aqueous phase was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Recrystallizing and purifying the crude product by ethyl acetate to obtain the dihydropyrrolone intermediate (V).
According to the preparation method of the dihydropyrrolone Intermediate (IV), the R group in the general formula is selected from tert-butyloxycarbonyl, fluorenyl methoxycarbonyl, trimethyl silicon ethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, benzenesulfonyl, trifluoroacetyl, methanesulfonyl, trifluoromethanesulfonyl, 2-nitrobenzenesulfonyl and 4-nitrobenzenesulfonyl, and is preferably p-toluenesulfonyl.
According to the process for the preparation of the dihydropyrrolone Intermediate (IV) of the present invention, the molar ratio of (S) -2- (4-n-propyl-1, 5-dihydropyrrol-2-one) butanoic acid (III) to primary amine (IV) is 1:1 to 1:1.5, preferably 1:1.
second-step reaction (reaction b): adding the dihydropyrrolone Intermediate (IV), a solvent and a metal catalyst into a reactor, and cooling. Stirring in the presence of a hydrogen source, and filtering and recrystallizing after complete reaction to obtain a pure pyrrolidone (VI).
According to the process for preparing pyrrolidone (VI), in the general formula, R is selected from tert-butyloxycarbonyl, fluorenyl methoxycarbonyl, trimethyl silylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, benzenesulfonyl, trifluoroacetyl, methanesulfonyl, trifluoromethanesulfonyl, 2-nitrobenzenesulfonyl and 4-nitrobenzenesulfonyl, preferably p-toluenesulfonyl.
According to the preparation method of the pyrrolidone (VI), the metal catalyst is selected from palladium carbon, palladium chloride, palladium bromide, palladium alumina, palladium tetrakis (triphenylphosphine) palladium, palladium acetate, palladium oxide, palladium trifluoroacetate, palladium sulfate, palladium silicon dioxide, palladium nitrate, palladium barium carbonate, palladium calcium carbonate, palladium carbon hydroxide, bis (triphenylphosphine) palladium dichloride, allyl palladium chloride dimer, ruthenium carbon, raney nickel, platinum dioxide and rhodium carbon, and preferably palladium carbon.
According to the process for preparing 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.
according to the process for the preparation of pyrrolidone (VI) of the present invention, the solvent is selected from the group consisting of methanol, ethanol, isopropanol, dichloromethane, acetone, toluene, tetrahydrofuran, dimethyltetrahydrofuran, methyl tert-butyl ether, cyclopentylmethyl ether, 1, 4-dioxane, diisopropyl ether, di-n-butyl ether, ethylene glycol dimethyl ether, ethyl acetate and trifluoroethanol, preferably tetrahydrofuran.
According to the process for the preparation of pyrrolidone (VI) according to the present invention, said hydrogen source is selected from hydrogen, ammonium formate, silane and sodium borohydride, preferably hydrogen.
According to the process for the preparation of pyrrolidone (VI) of the present invention, the reaction temperature is from-20 ℃ to room temperature, preferably-20 ℃.
The applicant of the present invention unexpectedly finds that the chiral induction capability of the substrate can be greatly improved by adjusting the modification group R of the amide in the dihydropyrrolone Intermediate (IV), so that the asymmetric hydrogenation of the dihydropyrrolone Intermediate (IV) can be completed simply by using an achiral catalyst, the pyrrolidone (VI) can be prepared with high optical purity and high yield, and the method is easy to operate, simple in reaction conditions, and suitable for industrial production.
The third reaction (reaction c): removing the tosyl group from the pyrrolidone intermediate (VIa) under proper conditions, filtering and concentrating to obtain a crude product, and recrystallizing to obtain a pure product of the Buvalacetam (Ia).
According to the preparation method of the present invention, the reaction conditions are selected from magnesium/methanol/heating reflux, magnesium/methanol/ultrasonic treatment, hydrobromic acid/phenol/heating reflux and hydrobromic acid/acetic acid/heating reflux, preferably magnesium/methanol/ultrasonic treatment.
The present invention further provides an intermediate compound selected from compounds represented by the following formulae:
it should be noted that, in the scope of the method of the present invention, the above technical processes and the technical processes expressed in the following embodiments may be combined with each other to form a new technical solution. For reasons of space, they are not described in detail here.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of (Va);
FIG. 2 is a nuclear magnetic hydrogen spectrum of (VIa).
Detailed Description
The present invention will be described below with reference to specific embodiments and drawings, but the present invention is not limited thereto.
The starting material (S) -2- (4-n-propyl-1, 5-dihydropyrrol-2-one) butyric acid (III) is prepared according to patent CN 107513031A.
The following provides specific embodiments of the present invention for the preparation of brivaracetam (Ia).
Example 1: preparation of dihydropyrrolone intermediate (Va)
(S) -2- (4-n-propyl-1, 5-dihydropyrrol-2-one) butanoic acid (III) (21.1g, 100mmol), p-toluenesulfonamide (17.1g, 100mmol) and DMAP (13.4g, 110mmol) were dissolved in dichloromethane (500 mL), cooled to 0 ℃ and EDCI (21.1g, 110mmol) was added. After the addition was complete, the reaction was slowly warmed to room temperature and stirred overnight. The reaction mixture was adjusted to pH 5 to 6 by adding 1M HCl, then the aqueous phase was extracted with dichloromethane (3 × 100ml), the organic phases were combined, washed with saturated brine (100ml × 3), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate to dryness gave crude solid which was recrystallized from ethyl acetate (150 mL) to give 32.8g of white solid in 90% yield.
MS(m/z)：[M+H] + ＝365.20
1 H NMR(600MHz,CDCl 3 )δ7.91(d,J＝7.7Hz,2H),7.30(d,J＝8.4Hz,2H),5.97(s,1H),4.90(s,1H),4.65(t,J＝7.7Hz,1H),3.81(s,2H),2.42(s,3H),2.31(t,J＝7.6Hz,2H),1.89(dp,J＝14.4,7.2Hz,1H) 1.68 (tt, J =15.2,7.7hz, 1h), 1.57 (p, J =7.4hz, 2h), 0.96 (t, J =7.3hz, 3h), 0.82 (t, J =7.3hz, 3h) ppm, as shown in particular in fig. 1.
Example 2: preparation of pyrrolidone intermediate (VIa)
Dihydropyrrolidone intermediate (Va) (90mmol, 32.8g) was dissolved in tetrahydrofuran in an autoclave, cooled to-20 ℃ H 2 Replacing three times and filling with H 2 Stirring at-20 deg.C for 8h under 20 atm. Filtration and concentration of the filtrate to dryness gave 32.7g of off-white solid in 99% yield (de = 96. Recrystallization from methyl tert-butyl ether/n-heptane gave pure 30.9g (de) as a white solid>99％)。
MS(m/z)：[M+H] + ＝367.18
1 H NMR(600MHz,CDCl 3 ) δ 7.91 (d, J =8.0hz, 2h), 7.29 (d, J =7.3hz, 2h), 4.86 (s, 1H), 4.41 (t, J =7.9hz, 1h), 3.36 (t, J =8.8hz, 1h), 2.76 (t, J =8.5hz, 1h), 2.59 (dd, J =17.3,8.5hz, 1h), 2.42 (s, 3H), 2.28-2.26 (m, 1H), 2.07-2.03 (m, 1H), 1.84 (dp, J =14.4,7.3hz, 1h), 1.62 (tt, J =15.3,7.5hz, 1h), 1.25 (dt, J =12.0,6.6hz, 4h), 0.88 (t, J =6.3hz, 3h), 0.81 (t, J =7.4hz, 3h) ppm.
Example 3: preparation of brivaracetam (Ia)
Pyrrolidone intermediate (VIa) (5.83g, 15.9mmol) was dissolved in methanol (80 mL), magnesium strips (1.91g, 79.5mmol) were added, and sonication was carried out for 1h. Filtration was performed, 1M HCl was slowly added dropwise to the filtrate to pH <6, and concentrated to dryness. The resulting crude solid was redissolved in dichloromethane (100 mL), washed with saturated brine (20ml _ 3), and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate to dryness and recrystallization of the crude solid from methyl tert-butyl ether gave 2.79g of a white solid in 83% yield (de > 99%).
The above examples merely represent preferred embodiments of the present invention, and it should be noted that those skilled in the art should also understand that the modifications and amendments made by the conception and method of the present invention should also be considered as within the scope of the present invention.
Claims (10)
1. A preparation method of the brivaracetam is characterized by comprising the following steps:
the method comprises the following steps:
reaction a: dihydropyrrolones (III) and primary amines (IV) form amides (V);
reaction b: carrying out reduction reaction on amide (V) and a hydrogen source in the presence of a metal catalyst to generate pyrrolidone (VI);
and c, reaction: the R group in the pyrrolidone (VI) is removed under proper conditions to generate the brivaracetam (Ia).
2. The process according to claim 1, wherein the compounds represented by the formulae (V) and (VI):
the R group is tert-butyloxycarbonyl, fluorenyl methoxycarbonyl, trimethylsiloxyethyl carbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, benzenesulfonyl, trifluoroacetyl, methylsulfonyl, trifluoromethanesulfonyl, 2-nitrobenzenesulfonyl and 4-nitrobenzenesulfonyl, preferably p-toluenesulfonyl.
3. The process of claim 1, wherein in step a, the molar ratio of dihydropyrrolones (III) to primary amines (IV) is 1:1 to 1:1.5, preferably 1:1.
4. the method according to claim 1, wherein 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 on carbon hydroxide, bis (triphenylphosphine) palladium dichloride, allylpalladium chloride dimer, ruthenium on carbon, raney nickel, platinum dioxide, and rhodium on carbon, preferably palladium on carbon.
5. The process according to claim 1, wherein in step b, the molar ratio of catalyst to compound (V) is 1:0.01 to 1:0.2, preferably 1:0.1.
6. the process according to claim 1, wherein in step b, the hydrogen source is selected from hydrogen, ammonium formate, silane and sodium borohydride, preferably hydrogen.
7. The method according to claim 1, wherein in the step b, the solvent for the reduction reaction is selected from the group consisting of methanol, ethanol, isopropanol, dichloromethane, acetone, toluene, tetrahydrofuran, dimethyltetrahydrofuran, methyl tert-butyl ether, cyclopentylmethyl ether, 1, 4-dioxane, diisopropyl ether, di-n-butyl ether, ethylene glycol dimethyl ether, ethyl acetate and trifluoroethanol, preferably tetrahydrofuran.
8. The method according to claim 1, wherein in step b, the reduction reaction temperature is from-20 ℃ to room temperature, preferably-20 ℃.
9. The method according to claim 1, wherein in step c, the reaction conditions are selected from the group consisting of magnesium/methanol/heat reflux, magnesium/methanol/sonication, hydrobromic acid/phenol/heat reflux, and hydrobromic acid/acetic acid/heat reflux, preferably magnesium/methanol/sonication.
10. A compound characterized by: selected from the group consisting of compounds represented by the following formulae:
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