阅读说明：本技术 一种布瓦西坦的制备方法 (Preparation method of brivaracetam ) 是由 颜剑波 陈洪斌 杨成钰 林义 于 2020-05-27 设计创作，主要内容包括：本发明公开了一种布瓦西坦的制备方法,属于药物合成化学领域。针对现有目标化合物合成路线复杂、收率低、成本高等问题,提出了一种新的制备方法,该方法包括如下步骤:1)化合物II在手性催化剂作用下进行不对称还原,得到化合物III；2)化合物III与卤代试剂反应,得到中间体化合物IV；3)化合物IV与L-氨基丁酰胺反应,得到化合物I。本发明具有工艺简单、生产成本低和易于工业化生产等优点。(The invention discloses a preparation method of brivaracetam, belonging to the field of pharmaceutical synthetic chemistry. Aiming at the problems of complex synthetic route, low yield, high cost and the like of the existing target compound, the method provides a new preparation method, which comprises the following steps of 1) carrying out asymmetric reduction on a compound II under the action of a chiral catalyst to obtain a compound III; 2) reacting the compound III with a halogenating reagent to obtain an intermediate compound IV; 3) and reacting the compound IV with L-aminobutanamide to obtain a compound I. The invention has the advantages of simple process, low production cost, easy industrial production and the like.)

1. A preparation method of brivaracetam (compound I), which is characterized by comprising the following steps:

1) reacting the compound II in the presence of a chiral metal catalyst and hydrogen to obtain a compound III;

2) reacting the compound III with a halogenating reagent in the presence of a solvent to generate an intermediate compound IV;

3) reacting the compound IV with L-aminobutanamide (compound V) under the action of a solvent and alkali, and recrystallizing the obtained crude product to obtain a compound I;

2. the method according to claim 1, wherein the central metal of the chiral catalyst in step 1) is one of (1, 5-cyclooctadiene) ruthenium (II) dichloride, bis (cyclopentadiene) ruthenium (II), tetrakis (dimethyl sulfoxide) ruthenium (II) chloride, bis (1, 5-cyclooctadiene) rhodium tetrafluoroborate (I), bis (norbornene) rhodium (I) tetrafluoroborate, 1, 5-cyclooctadiene (acetylacetonato) rhodium (I), bis (1, 5-cyclooctadiene) iridium (I) chloride dimer, 1, 5-cyclooctadiene (acetylacetonato) iridium (I); the chiral ligand of the chiral catalyst is one of (R, R) - (+) -2,2' -isopropylidene bis (4-phenyl-2-oxazoline), (R, R) - (+) -2,2' -isopropylidene bis (4-tert-butyl-2-oxazoline), (R, R) - (+) -2,2' -isopropylidene bis (4-isopropyl-2-oxazoline), bis [ (R) -4-isopropyl-4, 5-dihydrooxazol-2-yl ] methane, bis [ (R) -4-phenyl-4, 5-dihydrooxazol-2-yl ] methane and bis [ (R) -4-tert-butyl-4, 5-dihydrooxazol-2-yl ] methane.

3. The preparation method according to claim 1, wherein the molar ratio of the chiral catalyst to the compound II in the step 1) is 1:500 to 1:10000, and the reaction temperature is 0 ℃ to 60 ℃.

4. The method according to claim 1 or 3, wherein the pressure of the reaction in the step 1) is 0.5 to 3 MPa.

5. The method according to claim 1, wherein the halogenating agent in step 2) is selected from the group consisting of trimethylbromosilane, hydrobromic acid-thionyl chloride/ethanol; the reaction solvent is one or more of ethanol, dichloromethane, toluene and tetrahydrofuran.

6. The method according to claim 1, wherein the molar ratio of the compound III to the halogenating agent in step 2) is from 1:1.5 to 1: 4; the temperature of the reaction is between 0 ℃ and 50 ℃.

7. The method of claim 1, wherein the base in step 3) is one of sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate; the reaction solvent is one of methanol, ethanol, isopropanol, tetrahydrofuran and dioxane.

8. The process according to claim 1, wherein the molar ratio of compound IV to base in step 3) is between 1:1 and 1: 3; the temperature of the reaction of the compound IV with L-aminobutanamide is between 20 ℃ and 90 ℃.

9. The method according to claim 1, wherein the solvent for recrystallization in step 3) is one or more selected from the group consisting of ethyl acetate, isopropyl acetate, methyl tert-ether, n-hexane and n-heptane.

Technical Field

The invention relates to a preparation method of an antiepileptic drug, namely, busulfacetam, and particularly relates to a preparation method of (S) -2- ((R) -2-oxo-4-propylpyrrolidine-1-yl) butanamide. The invention belongs to the field of pharmaceutical synthetic chemistry.

Background

Brivaracetam is a third-generation antiepileptic drug developed by UCB corporation, belgium, and is used to treat patients with partial seizures aged 16 years and older, with or without secondary systemic seizures as an adjunct therapy. Compared with the second-generation antiepileptic drug levetiracetam, the brivaracetam has higher drug effect and safety. Therefore, the development of the bulk drug of the brivaracetam has better market prospect.

The chemical name of the brivaracetam is (S) -2- ((R) -2-oxo-4-propyl pyrrolidine-1-yl) butyramide, and the chemical structure is shown as follows:

the original patent US6784197B2 reported a route to the synthesis of bravaracetam. Although the route is short, the optically stored brivaracetam must be separated by chiral chromatography, which requires high equipment and therefore is costly to produce.

Patent CN108658831A reports a route for synthesizing bravaracetam based on palladium chloride catalytic hydrogenation. Although the diastereoselectivity of hydrogenation reaches 98:2, the consumption of palladium chloride reaches 10%, the price is high, and the production cost is high.

Patent US8957226B2 reports a route to the synthesis of bravaracetam based on Michael addition of ethyl 2-hexenoate to nitromethane. The intermediate and the final product of the route both need chiral chromatographic separation, have high production cost and are difficult to produce in a large scale.

Patents WO2018042393a1, WO2018220646a1 and CN107216276A each report a route to the asymmetric induction of bravaracetam based on chiral oxazolidinones. The route has more steps, some steps have more severe reaction conditions, some reagents are expensive, and the overall production cost is high.

Patents US20190152908a1, CN105646319B and CN106365986B respectively report asymmetric synthesis routes of bravaracetam with R-epichlorohydrin as chiral source. Some reaction steps of the synthetic route have harsh conditions, expensive reagents and high production cost.

Patent US8076493B2 reports a route to the synthesis of bravaracetam based on the asymmetric dihydroxylation of 1-pentene. The route has many steps, some reagents are expensive, the operation is complicated, and the method is not suitable for mass production.

The literature org. Process Res. Dev.2016,20,1566-1575 and patent CN109266630A respectively report a route for the synthesis of bravaracetam based on enzymatic kinetic resolution. The process has more steps, and the purity and the yield can not meet the use requirements in kilogram-level scale production.

In summary, although the synthesis of the bravaracetam has been reported, a simple and reliable synthesis route of the bravaracetam with low cost and suitable for industrial production needs to be developed in the field.

Disclosure of Invention

The invention aims to provide a preparation method of the brivaracetam, which has simple steps, simple and reliable process and easy industrial production.

The synthetic route of the invention is as follows:

the invention comprises the following steps:

1) and reacting the compound II in the presence of a chiral metal catalyst and hydrogen to obtain a compound III.

2) Compound III is reacted with a halogenating agent in the presence of a solvent to form intermediate compound IV.

3) Reacting the compound IV with aminobutanamide in a solvent under the action of alkali, and recrystallizing the obtained crude product in a solvent to obtain the compound I.

In the step 1), the central metal of the chiral catalyst is one of (1, 5-cyclooctadiene) ruthenium dichloride (II), bis (cyclopentadiene) ruthenium (II), tetrakis (dimethyl sulfoxide) ruthenium chloride (II), bis (1, 5-cyclooctadiene) rhodium tetrafluoroborate (I), bis (norbornene) rhodium (I) tetrafluoroborate, 1, 5-cyclooctadiene (acetylacetone) rhodium (I), bis (1, 5-cyclooctadiene) iridium chloride (I) dimer, 1, 5-cyclooctadiene (acetylacetone) iridium (I) and the like; the chiral ligand of the chiral catalyst is one of (R, R) - (+) -2,2' -isopropylidenebis (4-phenyl-2-oxazoline), (R, R) - (+) -2,2' -isopropylidenebis (4-tert-butyl-2-oxazoline), (R, R) - (+) -2,2' -isopropylidenebis (4-isopropyl-2-oxazoline), bis [ (R) -4-isopropyl-4, 5-dihydrooxazol-2-yl ] methane, bis [ (R) -4-phenyl-4, 5-dihydrooxazol-2-yl ] methane, bis [ (R) -4-tert-butyl-4, 5-dihydrooxazol-2-yl ] methane and the like.

Further, in the step 1), the molar ratio of the chiral catalyst to the compound II is 1: 500-1: 10000, and the reaction temperature is 0-60 ℃; the reaction pressure is 0.5-3 Mpa.

In step 2), the halogenating agent is selected from one of trimethyl bromosilane, hydrobromic acid-thionyl chloride/ethanol; the reaction solvent is one or more of ethanol, dichloromethane, toluene and tetrahydrofuran.

Further, the molar ratio of said compound III to the halogenating agent in step 2) is between 1:1.5 and 1:4, preferably 1: 2.

Further, the temperature at which said III is reacted with the halogenating agent in step 2) is between 0 ℃ and 50 ℃.

In the step 3), the alkali is one of sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, sodium phosphate and the like; the reaction solvent is one of methanol, ethanol, isopropanol, tetrahydrofuran, dioxane and other solvents; the solvent for recrystallization is one of ethyl acetate, isopropyl acetate, methyl tert-ether, n-hexane, n-heptane and the like or a mixed solvent of the ethyl acetate, the isopropyl acetate, the methyl tert-ether, the n-hexane and the n-heptane.

Further, the molar ratio of the compound IV to the base in step 3) is between 1:1 and 1:3, preferably 1: 1.5.

Further, the temperature of the reaction of the compound IV with L-aminobutanamide in step 3) is between 20 ℃ and 90 ℃.

Compared with the prior art, the invention has the following remarkable advantages:

1) because the invention adopts the asymmetric catalysis mode to realize the high stereoselectivity synthesis of the compound III, the defect that the original grinding process needs chiral resolution or chiral auxiliary group to induce asymmetric synthesis is avoided, the preparation process is more environment-friendly, and the cost is lower;

2) because the inorganic base is adopted in the API preparation step, the method avoids using a large amount of organic base, reduces the cost of ammonia nitrogen post-treatment, greatly reduces the generation of byproducts and improves the reaction yield.

3) Compared with the prior art, the total production cost of the invention is 40-50% lower than that of the original process, and the purity of the compound I reaches more than 99%, thus completely meeting the requirements of API production.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be noted that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention, and it should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.