WO2020143674A1

WO2020143674A1 - Compounds and their use in the synthesis of brivaracetam apis

Info

Publication number: WO2020143674A1
Application number: PCT/CN2020/070948
Authority: WO
Inventors: Ruyong WANG; Yizhang YE; Xuan GONG; Fengsen ZHANG; Zhonghong WANG; Dandan Li; Yueli FU; Yan Feng; Xinshan Kang
Original assignee: Fujian Haixi Pharmaceuticals Co., Ltd; Xinshan Kang
Priority date: 2019-01-09
Filing date: 2020-01-08
Publication date: 2020-07-16
Also published as: CN112154140A; CN112154140B

Abstract

Provided is a compound of formula III, and also provided are its use and method in the synthesis of Brivaracetam APIs. The raw materials involved in the method are cheap and easy to obtain, and can prepare Brivaracetam APIs with high optical, which avoids chiral separation and tedious separation and purification steps, reduces cost and is more suitable for industrial production.

Description

Compounds and their use in the synthesis of Brivaracetam APIs

This application claims benefit of priority to Chinese Patent Application Serial No. 201910018911. X filed on January 9, 2019, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The invention relates to the field of API synthesis, and in particular to the synthesis of Brivaracetam intermediates and APIs. The information provided is intended solely to assist the understanding of the reader. None of the information provided nor references cited is admitted to be prior art to the present invention. Each of the references cited is incorporated herein in its entirety and for any purpose.

BACKGROUND OF THE INVENTION

Brivaracetam belongs to the third generation antiepileptic drug and is a novel high-affinity ligand for synaptophysin 2A (SV2A) , which also inhibits voltage-dependent sodium channels. In 2016, Brivaracetam was approved by the FDA for the treatment of seizures, and the results showed that Brivaracetam has a good effect on generalized seizures.

Many synthetic routes have been reported in the literature and patents of Brivaracetam, which are summarized as follows:

For example, the original patent CN1882535A discloses a preparation method of Brivaracetam, and the synthesis route is as follows:

The final product of this synthesis route is the mixture of Brivaracetam and its diastereomer (2S) -2- ( (4S) -2-oxo-4-propyl-1-pyrrolidine) butylamide. It is necessary to use (chiralpak ad 20μm) chiral solid phase and n-hexane/ethanol (45/55, V/V) as eluent at 25±2℃ to separate the above mixture by chromatography, so as to obtain a high purity Brivaracetam. This method has the disadvantages of low separation efficiency and high production cost, and the second step uses catalytic hydrogenation, which requires higher synthesis equipment.

Benoit M. (J. Med. chem. 2004, 47, 530-549) provided another synthetic route for Brivaracetam. This preparation method also uses chiral chromatography to separate Brivaracetam and its diastereoisomer:

The crude Brivaracetam obtained by this method needs to be separated by a silica gel column before crystal separation to obtain a pure product, and the high-performance liquid chromatography analysis finds that the purity is 83-88%and the impurity content is high.

WO2007065634A1 provides another synthetic route for the preparation of Brivaracetam, which requires the use of a relatively expensive metal catalyst RuCl ₃, and the preparation method also uses a chiral column to separate Brivaracetam and its diastereomer

CN106365986A provides another synthetic route for the preparation of Brivaracetam. The route is novel, with high chiral purity and low production cost. However, the UV absorption of the reaction intermediate is relatively weak, which makes it difficult to detect and control the quality. Many intermediates are liquid and need to be used for vacuum distillation, which requires high equipment.

In view of the above known synthetic methods, most of the intermediates involved are liquid without ultraviolet absorption, which are difficult to purify, detect and quality control, or costly to synthesize, or require special equipment to complete the isomer separation and purification by column chromatography. So they are not suitable for large-scale industrial production. In order to overcome the problems existing in the reported routes, the purpose of the present invention is to provide a method for preparing a compound such as formula III, and its use in the synthesis of Brivaracetam APIs. This method achieves creative breakthroughs. It has the advantages of short synthetic routes, easy-to-obtain raw materials, simple process, easy detection and quality control of intermediates, etc. Compared with the existing synthetic technology, it has very obvious cost and process advantages, which is very suitable for the industrial production of Brivaracetam APIs.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula III, which is applicable to the preparation of Brivaracetam APIs.

A compound for the preparation of Brivaracetam has the structure of formula III:

Wherein:

R is selected from optionally substituted or unsubstituted C ₁-C ₅ alkyl, optionally substituted or unsubstituted C ₆-C ₁₂ Aryl, and optionally susbstituted or unsubstituted 5-12 membered heteroaryl;

R ² is selected from OH, NH ₂, NHBn, NBn ₂ or optionally susbstituted or unsubstituted alkoxy;

R ³ is selected from hydrogen, OH, optionally substituted or unsubstituted C ₁-C ₄ alkoxy, optionally substituted or unsubstituted OC (O) (C ₁-C ₄) alkyl or OBz.

In any and all embodiments, the substituents may be selected from a subset of the listed alternative items. For example, in some embodiments, R ¹ is selected from an optionally substituted or unsubstituted phenyl group, an optionally substituted or unsubstituted naphthyl group, an optionally substituted or unsubstituted pyridyl or quinolyl group; in further embodiments, R ¹ is selected from arbitrarily substituted or unsubstituted phenyl.

In some embodiments, R ¹ is selected from an optionally substituted or unsubstituted phenyl group, an optionally substituted or unsubstituted naphthyl group, an optionally substituted or unsubstituted pyridyl or quinolyl group, and the hydrogen on R ¹ may be substituted by one or more R ⁴ groups, R ⁴ is selected from halogen, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, nitro, cyano. In still other embodiments, R ¹ is selected from an optionally substituted or unsubstituted phenyl group, the hydrogen on R ¹ may be substituted by one or more R ⁴ groups, and R ⁴ is selected halogen, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, nitro, cyano.

In some preferred embodiments, R ¹ is selected from:

Wherein,

In some embodiments, R ² is selected from OH or NH ₂.

In some further preferred embodiments, R ² is selected from OH or NH ₂; R ³ is selected from OH. In some further preferred embodiments, R ² is selected from NH ₂, and R ³ is selected from OH. In some further preferred embodiments, R ² and R ³ are selected from OH.

In some further preferred embodiments, R ² is selected from OH or NH ₂; R ³ is selected from hydrogen. In some further preferred embodiments, R ² is selected from NH ₂, and R ³ is selected from hydrogen. In some further preferred embodiments, R ² is selected from OH and R ³ is selected from hydrogen.

The application provides a method for preparing a compound of formula III-1, which method comprises the following steps:

wherein, R ² is selected from OH or NH ₂.

The application provides a method for preparing a compound of formula III-2, which method comprises the following steps:

wherein, R ² is selected from OH or NH ₂.

It will also be understood by those skilled in the field that, according to the synthetic route described above, those skilled in the field can obtain the desired products by reasonably selecting the raw materials and synthetic methods known in the field according to their technical knowledge and conventional technical means.

In a specific embodiment, the reaction conditions of each reaction step may be:

preparation of the compound of formula II from the compound of formula I,

The compound of formula II is prepared by reacting a compound of formula I with compound A in a solvent or solvent free condition.

In a more specific embodiment, the aforementioned compound A includes L-2-aminobutanamide, L-2-aminobutanamide hydrochloride, L-2-aminobutyric acid or L-2-aminobutyric acid hydrochloride.

In some embodiments, the compound of formula I is reacted with compound A under the action of a base to prepare a compound of formula II. Preferably, the base is selected from one or more of sodium methoxide, potassium methoxide, magnesium methoxide, sodium ethoxide, potassium ethoxide, sodium t-butoxide, potassium t-butoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, Sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine or 1, 8-Diazabicyclo [5.4.0] undec-7-ene (DBU) . More preferably, the equivalent of alkali is between 0.01 and 10. In some more specific preferred embodiments, the solvent is selected from one or more of water, methanol, ethanol, propanol, isopropanol, tert-butanol, n-butanol, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, toluene, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methylpyrrolidone.

In some preferred embodiments, the compound of formula I is reacted with compound A under the action of a base to prepare a compound of formula II, wherein the compound A is selected from L-2-aminobutanamide, L-2-aminobutanamide hydrochloride, L-2-aminobutyric acid or L-2-aminobutyric acid hydrochloride; the base is selected from one or more of sodium methoxide, potassium methoxide, magnesium methoxide, sodium ethoxide, potassium ethoxide, sodium t-butoxide, potassium t-butoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, Sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine or 1, 8-Diazabicyclo [5.4.0] undec-7-ene (DBU) , and the equivalent of alkali is between 0.01 and 10; the solvent is selected from one or more of water, methanol, ethanol, propanol, isopropanol, tert-butanol, n-butanol, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, toluene, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methylpyrrolidone.

Preparation of the compound of formula III-1 from the compound of formula II:

The compound of formula III-1 is prepared by reacting a compound of formula II in oxidation system in a solvent.

In some specific embodiments, method for preparing compound of formula III-1 from compound of formula II, wherein the solvent is selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, acetone, acetonitrile, toluene, dichloromethane, tetrahydrofuran or DMF, N-methylpyrrolidone or DMSO. Preferably, the oxidation system is selected from 4-Methylmorpholine N-oxide/Tetrapropylammonium perruthenate (NMO/TPAP) , DMSO/ (COCl) ₂/TEA, Dess-Martin periodinane (DMP) , DMSO/Sulfur trioxide pyridine complex (DMSO/Py·SO ₃) , NaIO ₄/TEMPO/NaBr, NaIO ₄/TEMPO/KBr, KIO ₄/TEMPO/NaBr, KIO ₄/TEMPO/KBr, NaClO/TEMPO/NaBr or NaClO/TEMPO/KBr, KMnO ₄, NaMnO ₄, KMnO ₄/TEMPO or NaMnO ₄/TEMPO.

In some specific preferred embodiments, the compound of formula III-1 is prepared by reacting a compound of formula II in oxidation system in a solvent, wherein the solvent is selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, n-butanol, acetone, acetonitrile, toluene, dichloromethane, tetrahydrofuran or DMF, N-methylpyrrolidone or DMSO; the oxidation system is selected from 4-Methylmorpholine N-oxide/Tetrapropylammonium perruthenate (NMO/TPAP) , DMSO/ (COCl) ₂/TEA, Dess-Martin periodinane (DMP) , DMSO/Sulfur trioxide pyridine complex (DMSO/Py·SO ₃) , NaIO ₄/TEMPO/NaBr, NaIO ₄/TEMPO/KBr, KIO ₄/TEMPO/NaBr, KIO ₄/TEMPO/KBr, NaClO/TEMPO/NaBr or NaClO/TEMPO/KBr, KMnO ₄, NaMnO ₄, KMnO ₄/TEMPO or NaMnO ₄/TEMPO.

Preparation of the compound of formula III-2 from the compound of formula II,

In a solvent, a product of a compound of formula II reacted with an oxidizing agent system is then reacted with a reducing agent to prepare a compound of formula III-2.

In some specific embodiments, method for preparing compound of formula III-2 from compound of formula II, wherein the solvent is selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, acetone, acetonitrile, toluene, dichloromethane, tetrahydrofuran or DMF, N-methylpyrrolidone or DMSO. Preferably, the oxidation system is selected from 4-Methylmorpholine N-oxide/Tetrapropylammonium perruthenate (NMO/TPAP) , DMSO/ (COCl) ₂/TEA, Dess-Martin periodinane (DMP) , DMSO/Sulfur trioxide pyridine complex (DMSO/Py·SO ₃) , NaIO ₄/TEMPO/NaBr, NaIO ₄/TEMPO/KBr, KIO ₄/TEMPO/NaBr, KIO ₄/TEMPO/KBr, NaClO/TEMPO/NaBr or NaClO/TEMPO/KBr, KMnO ₄, NaMnO ₄, KMnO ₄/TEMPO or NaMnO ₄/TEMPO. More preferably, the reducing agent includes sodium borohydride, sodium cyanoborohydride, sodium triacetylborohydride, triethylsilane/trifluoroacetic acid, Pd/H ₂, Pt/H ₂, Ni/H ₂, Pd (OH) ₂/H ₂ or Pd/ammonium formate.

In some specific preferred embodiments, in a solvent, a product of a compound of formula II reacted with an oxidizing agent system is then reacted with a reducing agent to prepare a compound of formula III-2, wherein the solvent is selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, n-butanol, acetone, acetonitrile, toluene, dichloromethane, tetrahydrofuran or DMF, N-methylpyrrolidone or DMSO; the oxidation system is selected from 4-Methylmorpholine N-oxide/Tetrapropylammonium perruthenate (NMO/TPAP) , DMSO/ (COCl) ₂/TEA, Dess-Martin periodinane (DMP) , DMSO/Sulfur trioxide pyridine complex (DMSO/Py·SO ₃) , NaIO ₄/TEMPO/NaBr, NaIO ₄/TEMPO/KBr, KIO ₄/TEMPO/NaBr, KIO ₄/TEMPO/KBr, NaClO/TEMPO/NaBr or NaClO/TEMPO/KBr, KMnO ₄, NaMnO ₄, KMnO ₄/TEMPO or NaMnO ₄/TEMPO; the reducing agent includes sodium borohydride, sodium cyanoborohydride, sodium triacetylborohydride, triethylsilane/trifluoroacetic acid, Pd/H ₂, Pt/H ₂, Ni/H ₂, Pd (OH) ₂/H ₂ or Pd/ammonium formate.

Use of a compound of formula III and a subset thereof as described above for the preparation of Brivaracetam VI.

Preferably, a compound of formula III-1-1 is used in a method of preparing Brivaracetam VI, which method comprises the steps of preparing formula VI by a compound of formula III-1-1:

In a specific embodiment, preparation of the compound of formula IV-1 from the compound of formula III-1-1, removing the sulfonyl group on compound of formula III-1-1 by a reducing agent in an organic solvent to prepare a compound of formula IV-1.

In some embodiments, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water.

In some further embodiments, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water; and the reducing agent is selected from active metals and salts thereof, tin hydride or transition metals.

In some further embodiments, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water; and the reducing agent is selected from Mg, Ca, Al, Zn, Ni, Sm, SmI ₂.

In some further embodiments, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water; the reducing agent is selected from active metals and salts thereof, tin hydride or transition metals, and is used in combination with one or more ofHg, I ₂, Lewis acid or base.

In some further specific embodiments, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water; and the reducing agent is selected from Mg, Ca, Al, Zn, Ni, Sm, SmI ₂, and is used in combination with one or more ofHg, I ₂, Lewis acid or base.

In some further specific embodiments, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water; the reducing agent is selected from active metals and salts thereof, tin hydride or transition metals, and is used in combination with one or more of Hg, I ₂, Lewis acid or base, wherein the Lewis acid and the Lewis base are selected from one or more of hydrochloric acid, ammonium chloride, trimethylchlorosilane, titanium tetrachloride, nickel chloride, nickel bromide, nickel iodide, acetic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, citric acid, ammonia, methylmagnesium bromide, tetramethylethylenediamine, sodium acetate, potassium acetate, etc.

In some further specific embodiments, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water; and the reducing agent is selected from Mg, Ca, Al, Zn, Ni, Sm, SmI ₂, and is used in combination with one or more of Hg, I ₂, Lewis acid or base, wherein the Lewis acid and the Lewis base are selected from one or more of hydrochloric acid, ammonium chloride, trimethylchlorosilane, titanium tetrachloride, nickel chloride, nickel bromide, nickel iodide, acetic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, citric acid, ammonia, methylmagnesium bromide, tetramethylethylenediamine, sodium acetate, potassium acetate, etc.

In some further specific embodiments, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water; the reducing agent is selected from active metals and salts thereof, tin hydride or transition metals, and is used in a molar equivalent of between 1 and 30; the reducing agent is used in combination with one or more of Hg, I ₂, Lewis acid or base, wherein the Lewis acid and the Lewis base are selected from one or more of hydrochloric acid, ammonium chloride, trimethylchlorosilane, titanium tetrachloride, nickel chloride, nickel bromide, nickel iodide, acetic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, citric acid, ammonia, methylmagnesium bromide, tetramethylethylenediamine, sodium acetate, potassium acetate, etc.

In some further specific embodiments, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water; and the reducing agent is selected from Mg, Ca, Al, Zn, Ni, Sm, SmI ₂, and is used in a molar equivalent of between 1 and 30; the reducing agent is used in combination with one or more of Hg, I ₂, Lewis acid or base, wherein the Lewis acid and the Lewis base are selected from one or more of hydrochloric acid, ammonium chloride, trimethylchlorosilane, titanium tetrachloride, nickel chloride, nickel bromide, nickel iodide, acetic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, citric acid, ammonia, methylmagnesium bromide, tetramethylethylenediamine, sodium acetate, potassium acetate, etc.

More specifically, in some preferred embodiments, preparation of the compound of formula IV-1 from the compound of formula III-1-1:

removing the sulfonyl group on compound of formula III-1-1 by a reducing agent in an organic solvent to prepare a compound of formula IV-1, wherein the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water; the reducing agent is Mg, which is used in a molar equivalent of between 1 and 30, and the reducing agent is used in combination with one or more of hydrochloric acid, trimethyl chlorosilane, nickel chloride, nickel bromide, nickel iodide, acetic acid, propionic acid, methylmagnesium bromide, tetramethylethylenediamine, sodium acetate or potassium acetate.

Preparation of the compound of formula VI from the compound of formula IV-1,

A compound of formula IV-1 is reacted with a reducing agent in a solvent to prepare a compound of formula VI.

In some specific embodiments, method for preparing compound of formula VI from compound of formula IV-1, wherein the solvent is selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, acetonitrile, toluene, dichloromethane or tetrahydrofuran. Preferably, the reducing agent includes sodium borohydride, sodium cyanoborohydride, sodium triacetylborohydride, triethylsilane/trifluoroacetic acid, Pd/H ₂, Pt/H ₂, Ni/H ₂, Pd (OH) ₂/H ₂ or Pd/ammonium formate.

In some specific embodiments, A compound of formula IV-1 is reacted with a reducing agent in a solvent to prepare a compound of formula VI, wherein the solvent is selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, acetonitrile, toluene, dichloromethane or tetrahydrofuran. Preferably, the reducing agent includes sodium borohydride, sodium cyanoborohydride, sodium triacetylborohydride, triethylsilane/trifluoroacetic acid, Pd/H ₂, Pt/H ₂, Ni/H ₂, Pd (OH) ₂/H ₂ or Pd/ammonium formate.

Preferably, a compound of formula III-1-1 is used in a method of preparing Brivaracetam VI, which method comprises the step of preparing formula VI by a compound of formula III-1-1:

Preferably, a compound of formula III-2-1 is used in a method of preparing Brivaracetam VI, which method comprises the step of preparing formula VI by a compound of formula III-2-1:

The method for preparing Brivaracetam VI from compound of formula III-2-1 includes the step of removing the sulfonyl group on compound of formula III-2-1 by a reducing agent in an organic solvent.

In some preferred embodiments, the method for the preparation of Brivaracetam VI by using the compounds of formula III-1-2 includes the steps of preparing a compound of formula VI by a compound of formula III-1-2.

In other preferred embodiments, the method for the preparation of Brivaracetam VI by using the compounds of formula III-1-2 includes the steps of preparing a compound of formula VI by a compound of formula III-1-2.

In some preferred embodiments, the method for the preparation of Brivaracetam VI by using the compounds of formula III-2-2 includes the steps of preparing a compound of formula VI by a compound of formula III-2-2.

In other preferred embodiments, the method for the preparation of Brivaracetam VI by using the compounds of formula III-2-2 includes the steps of preparing a compound of formula VI by a compound of formula III-2-2.

More specifically, in some embodiments, by virtue of the above scheme, the present invention has the following advantages over the prior art: The present invention provides a method for preparing a compound of formula III, which is used to synthesize Brivaracetam APIs. The synthetic route of this method is short, the raw materials are easy to obtain, the whole process is simple, and the operability is strong. It has potential industrial value and is suitable for industrial production.

DEFINITIONS

Unless otherwise stated, the following terms used in the specification and claims have the meanings discussed below. Variables defined in this section, such as A, R, X, Z and the like, are for reference within this section only, and are not meant to have the save meaning as may be used outside of this definitions section. Further, many of the groups defined herein can be optionally substituted. The listing in this definitions section of typical substituents is exemplary and is not intended to limit the substituents defined elsewhere within this specification and claims.

represents the position of the substituent.

"C _m-C _n" refers to the carbon atoms contained in m-n.

"Alkyl" refers to a saturated aliphatic hydrocarbon radical or linker including straight chain and branched chain groups of 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms. "Lower alkyl" refers specifically to an alkyl group with 1 to 4 carbon atoms. Examples of alkyl groups include- (CH ₂) ₃-, methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and the like. Alkyl may be substituted or unsubstituted. Typical substituent groups include cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, nitro, silyl, amino and-NR ^xR ^y, where R ^x and R ^y are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, acetyl, sulfonyl, trifluoromethanesulfonyl and, combined, a five- or six-member heteroalicyclic ring.

"Cycloalkyl" refers to a 3 to 8 member all-carbon monocyclic ring, an all-carbon 5-member/6-member or 6-member/6-member fused bicyclic ring, or a multicyclic fused ring (a "fused" ring system means that each ring in the system shares at least an adjacent carbon atom with each other ring in the system) group wherein one or more of the rings may contain one or more double bonds but none of the rings has a completely conjugated pi-electron system. Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene, and the like. A cycloalkyl group may be substituted or unsubstituted. Typical substituent groups include alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, Camido, N-amido, nitro, amino and–NRxRy, with Rx and Ry as defined above.

"Aryl" refers to an all-carbon monocyclic or fused-ring polycyclic groups of 6 to 12 carbon atoms having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted. Typical substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, Ocarbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, sulfonyl, amino and-NR ^xR ^y, with R ^x and R ^y as defined above.

"Heteroaryl" refers to a monocyclic or fused ring group of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from N, O, and S, the remaining ring atoms being C, and, in addition, having a completely conjugated π-electron system. Examples, without limitation, of unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine, tetrazole, triazine, and carbazole. The heteroaryl group may be substituted or unsubstituted. Typical substituents include alkyl, cycloalkyl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, sulfonamido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, amino and–NR ^xR ^y with R ^x and R ^y as defined above.

"heteroalkyl" include optionally substituted alkyl radicals in which one or more skeletal chain atoms is a heteroatom, e.g., oxygen, nitrogen, sulfur, silicon, phosphorus or combinations thereof. The heteroatom (s) may be placed at any interior position of the heteroalkyl group or at the position at which the heteroalkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH ₂-O-CH ₃, -CH ₂-CH ₂-O-CH ₃, -OCH ₂-, -CH ₂-NH-CH ₃, -CH ₂-CH ₂-NH-CH ₃, -CH ₂-N (CH ₃) -CH ₃, -NCH ₂CH ₂-, -CH ₂-CH ₂-NH-CH ₃, -CH ₂-CH ₂-N (CH ₃) -CH ₃, -CH ₂-S-CH ₂-CH ₃, -CH ₂-CH ₂-S (O) -CH ₃, -CH ₂-CH ₂-S (O) ₂-CH ₃. In addition, up to two heteroatoms may be consecutive, such as, by way of example, -CH ₂-NH-OCH ₃.

"Acyl" or "carbonyl" refers to a -C (O) R" group, where R" is selected from the group consisting of hydrogen, lower alkyl, trihalomethyl, unsubstituted cycloalkyl, aryl optionally substituted with one or more, preferably one, two, or three substituents selected from the group consisting of lower alkyl, trihalomethyl, lower alkoxy, halo and-NRxRy groups, heteroaryl (bonded through a ring carbon) optionally substituted with one or more, preferably one, two, or three substitutents selected from the group consisting of lower alkyl, trihaloalkyl, lower alkoxy, halo and-NRxRy groups and heteroalicyclic (bonded through a ring carbon) optionally substituted with one or more, preferably one, two, or three substituents selected from the group consisting of lower alkyl, trihaloalkyl, lower alkoxy, halo and-NRxRy groups. Representative acyl groups include, but are not limited to, acetyl, trifluoroacetyl, benzoyl, and the like.

"Alkoxy" refers to both an -O- (alkyl) or an -O- (unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkyl or cycloalkyl group may be substituted or unsubstituted, and typical substituents include a halogen group and the like. Representative examples include, but are not limited to, trifluoromethoxy, difluoromethoxy, and the like.

"Aryloxy" refers to an -O-aryl or an -O-heteroaryl group, as defined herein. Representative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof.

An "O-carboxy" group refers to a -OC (O) R" group, with R" as defined above.

"Acetyl" group refers to a -C (O) CH ₃ group.

"Cyano" refers to a -C≡N group.

"Nitro" refers to a -NO ₂ group.

"Aldehyde" refers to an acyl group in which R" is hydrogen.

"Hydroxy" refers to an -OH group.

"Halo" group refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

A "sulfonyl" group refers to a -S (O) ₂R" group wherein, in addition to being as defined above. Typical examples are methanesulfonyl (Ms) , benzenesulfonyl (Bs) , p-toluenesulfonyl (Ts) , and p-nitrobenzenesulfonyl (Ns) .

The term "heteroatom" refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from among oxygen, sulfur, nitrogen, silicon and phosphorus, but are not limited to these atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms can all be the same as one another, or some or all of the two or more heteroatoms can each be different from the others.

The term "optionally substituted" or "substituted" means that the referenced group may be substituted with one or more additional group (s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, acyl, nitro, haloalkyl, fluoroalkyl, amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "heterocycle group optionally substituted with an alkyl group" means that the alkyl may but need not be present, and the description includes situations where the heterocycle group is substituted with an alkyl group and situations where the heterocycle group is not substituted with the alkyl group.

As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. The compounds of the present disclosure may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers) , enantiomers or diastereomers. Accordingly, any chemical structures within the scope of the specification depicted, in whole or in part, with a relative configuration encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into the component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.

Compounds of Formula III include, but are not limited to optical isomers of compounds of Formula I, racemates, and other mixtures thereof. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column. In addition, compounds of Formula III include Z- and E- forms (or cis- and trans- forms) of compounds with double bonds. Where compounds of Formula I exist in various tautomeric forms, chemical entities of the present invention include all tautomeric forms of the compound.

EXAMPLES

The invention includes, but is not limited to, the following examples to further illustrate the preparation of the compounds described herein.

The following embodiments are only used to illustrate the specific embodiments of the invention, which can enable the professional and technical personnel to understand the invention more comprehensively, but can not limit the invention in any way. In the specific embodiments of the present invention, the technical means or methods not specifically described are conventional technical means or methods in the technical field, etc.

The chemical reagents used in the following examples are all commercially available chemical reagents.

Typical exemplary embodiments of the present invention are as follows:

Example 1 Synthesis of (3S) -N- ( (S) -1-amino-1-oxobutan-2-yl) -3- (hydroxymethyl) -2-tosylhexanamide

To a 100ml three-necked flask with mechanical stirring function was added a 30%solution of sodium methoxide in methanol (7.20g, 40.0mmol) , followed by (S) -2-aminobutyramide hydrochloride (5.50g, 40.0mmol) . After stirring at room temperature for 0.5 h, (4S) -4-propyl-3-tosyldihydrofuran-2 (3H) -one (5.65 g, 20.0 mmol) was added. The resulting mixture was heated to reflux and stirred for 24 h. Then 50 ml of water was added, and the mixture was stirred for 1 h. After cooling to room temperature, the solid was collected by filtration, and washed with water, and dried to obtain 7.12 g of crude product. The crude product was slurried with DCM to obtain pure product 5.81 g, yield: 75.3%. LC-MS [M+H] -m/z: 385.

Example 2 Synthesis of (3S) -N- ( (S) -1-amino-1-oxobutan-2-yl) -3- (hydroxymet hyl) -2-tosylhexanamide

To a 100ml three-necked flask with mechanical stirring function was added (S) -2-aminobutyramide (4.10g, 40.0mmol) and MeOH (4 ml) , followed by (4S) -4-propyl-3-tosyldihydrofuran-2 (3H) -one (5.65g, 20.0mmol) . The resulting mixture was heated to reflux and stirred for 24 h. Then 50 ml 10%brine was added, and the mixture was stirred for 1 h. After cooling to room temperature, the solid was collected by filtration, and washed with water, and dried to obtain 6.86 g of crude product. The crude product was slurried with DCM to obtain pure product 5.22 g, yield: 67.5%. LC-MS [M+H] -m/z: 385.

Example 3 Synthesis of (3S) -N- ( (S) -1-amino-1-oxobutan-2-yl) -3- (hydroxymethyl) -2-tosylhexanamide

To a 100ml three-necked flask with mechanical stirring function was added a 30%solution of Sodium ethoxide in ethanol (9.10g, 40.0mmol) , followed by (S) -2-aminobutyramide hydrochloride (5.50g, 40.0mmol) . After stirring at room temperature for 0.5 h, (4S) -4-propyl-3-tosyldihydrofuran-2 (3H) -one (5.65 g, 20.0 mmol) was added. The resulting mixture was heated to reflux and stirred for 24 h. Then 50 ml of water was added, and the mixture was stirred for 1 h. After cooling to room temperature, the solid was collected by filtration, and washed with water, and dried to obtain 6.67 g of crude product. The crude product was slurried with DCM to obtain pure product 5.10 g, yield: 66.0%. LC-MS [M+H] -m/z: 385.

Example 4 Synthesis of (3S) -N- ( (S) -1-amino-1-oxobutan-2-yl) -3- (hydroxymethyl) -2-tosylhexanamide

To a 100ml three-necked flask with mechanical stirring function was added (S) -2-aminobutyramide hydrochloride (5.50g, 40.0mmol) , TEA (4.05g, 40.0mmol) and MeOH (40 ml) . The mixture was stirred for 0.5h, then (4S) -4-propyl-3-tosyldihydrofuran-2 (3H) -one (5.65 g, 20.0 mmol) was added. The resulting mixture was heated to reflux and stirred for 24 h. Then 50 ml of water was added, and the mixture was stirred for 1 h. After cooling to room temperature, the solid was collected by filtration, and washed with water, and dried to obtain 6.32 g of crude product. The crude product was slurried with DCM to obtain pure product 4.65 g, yield: 60.5%. LC-MS [M+H] -m/z: 385.

Example 5 The synthesis of compounds II-1～II-19 is similar to example 1

Table 1

Example 6 Synthesis of (2S) -2- ( (3S) -2-hydroxy-5-oxo-3-propyl-4-tosylpyrrolidin-1-yl) butanamide

To a 250 ml three-necked flask with mechanical stirring function was added (3S) -N- ( (S) -1-amino-1-oxobutan-2-yl) -3- (hydroxymethyl) -2-tosylhexanamide (5.00g, 13.0mmol) , tempo (100mg, 0.65mmol) , KBr (150mg, 1.3mmol) and DCM (20 ml) , followed by NaIO ₄ (6.95g, 32.5mmol) at room temperature. The resulting mixture was heated to 45℃ and stirred for 24h. After the reaction was completed by TLC monitoring, water (35 ml) and NaOH (520 mg) were added, and the mixture was stirred for 4h. The organic phase was collected after standing a while, washed with saturated brine (20ml*2) , dried with anhydrous Na ₂SO ₄, and concentrated. The residue was purified by column chromatography to obtain the desired product (3.82 g, 77.0%) . LC-MS [M+H] -m/z: 383.

Example 7 Synthesis of (2S) -2- ( (3S) -2-hydroxy-5-oxo-3-propyl-4-tosylpyrrolidin-1-yl) butanamide

To a 250 ml three-necked flask with mechanical stirring function was added (3S) -N- ( (S) -1-amino-1-oxobutan-2-yl) -3- (hydroxymethyl) -2-tosylhexanamide (5.00g, 13.0mmol) , tempo (100mg, 0.65mmol) , KBr (150mg, 1.3mmol) and DCM (20 ml) , followed by 8%aqueous NaClO (24.18g, 26.0mmol) at room temperature. The resulting mixture was heated to 45℃ and stirred for 24h. After the reaction was completed by TLC monitoring, water (35 ml) and NaOH (520 mg) were added, and the mixture was stirred for 4h. The organic phase was collected after standing a while, washed with saturated brine (20ml*2) , dried with anhydrous Na ₂SO ₄, and concentrated. The residue was purified by column chromatography to obtain the desired product (1.25 g, 25.1%) . LC-MS [M+H] -m/z: 383.

Example 8 Synthesis of (2S) -2- ( (3S) -2-hydroxy-5-oxo-3-propyl-4-tosylpyrrolidin-1-yl) butanamide

To a 250 ml three-necked flask with mechanical stirring function was added (3S) -N- ( (S) -1-amino-1-oxobutan-2-yl) -3- (hydroxymethyl) -2-tosylhexanamide (5.00g, 13.0mmol) , Dess-Martin Periodinane (11.02g, 26.0mmol) and DCM (20 ml) . The resulting mixture was stirred at room temperature for 24h. After the reaction was completed by TLC monitoring, the solid was removed by filtration. Then water (35 ml) and NaOH (520 mg) were added, and the mixture was stirred for 4h. The organic phase was collected after standing a while, washed with saturated brine (20ml*2) , dried with anhydrous Na ₂SO ₄, and concentrated. The residue was purified by column chromatography to obtain the desired product (1.86 g, 37.4%) . LC-MS [M+H] -m/z: 383.

Example 9 Synthesis of (2S) -2- ( (3S) -2-hydroxy-5-oxo-3-propyl-4-tosylpyrrolidin-1-yl) butanamide

To a 250 ml three-necked flask with mechanical stirring function was added (3S) -N- ( (S) -1-amino-1-oxobutan-2-yl) -3- (hydroxymethyl) -2-tosylhexanamide (5.00g, 13.0mmol) , Py·SO ₃ (6.20g, 39.0mmol) , TEA (5.25g, 42.0 mmol) , DCM (20 ml) and DMSO (20ml) . The resulting mixture was stirred at room temperature for 24h. After the reaction was completed by TLC monitoring, water was added, and extracted with DCM(20ml*2) . The combined organic phase was added water (35 ml) and NaOH (520 mg) , and stirred for 4h. The organic phase was collected after standing a while, washed with saturated brine (20ml*2) , dried with anhydrous Na ₂SO ₄, and concentrated. The residue was purified by column chromatography to obtain the desired product (2.14 g, 43.1%) . LC-MS [M+H] -m/z: 383.

Example 10 Synthesis of (2S) -2- ( (3S) -2-hydroxy-5-oxo-3-propyl-4-tosylpyrrolidin-1-yl) butanamide

To a 100 ml three-necked flask with mechanical stirring function was added (3S) -N- ( (S) -1-amino-1-oxobutan-2-yl) -3- (hydroxymethyl) -2-tosylhexanamide (5.00g, 13.0mmol) , NMO (3.04g, 26.0mmol) , TPAP (23mg, 0.065 mmol) and DCM (20 ml) . The resulting mixture was stirred at room temperature for 24h. After the reaction was completed by TLC monitoring, water was added, and extracted with DCM (20ml*2) . The combined organic phase was added water (35 ml) and NaOH (520 mg) , and stirred for 4h. The organic phase was collected after standing a while, washed with saturated brine (20ml*2) , dried with anhydrous Na ₂SO ₄, and concentrated. The residue was purified by column chromatography to obtain the desired product (1.42 g, 28.5%) . LC-MS [M+H] -m/z: 383.

Example 11 The synthesis ofcompounds III-1-1～III-1-19 is similar to example 6

Table 2

Example 12 Synthesis of (2S) -2- ( (4S) -2-oxo-4-propyl-3-tosylpyrrolidin-1-yl) butanamide

To a 250 ml three-necked flask with mechanical stirring function was added (3S) -N- ( (S) -1-amino-1-oxobutan-2-yl) -3- (hydroxymethyl) -2-tosylhexanamide (5.00g, 13.0mmol) , tempo (100mg, 0.65mmol) , KBr (150mg, 1.3mmol) and DCM (50 ml) , followed by NaIO ₄ (7.00g, 32.5mmol) at room temperature. The resulting mixture was heated to 45℃ and stirred for 24h. The organic phase was collected, added water (35 ml) and NaOH (500 mg) , and stirred for 4h. The organic phase was collected after standing a while, washed with saturated brine (20ml*2) , dried with anhydrous Na ₂SO ₄, and filtered. To the filtrate was added triethylsilane (4.50g, 39.2mmol) with stirring, then cooled to 0 ℃ and was added TFA (25 ml) dropwise within 1min. The resulting mixture was stirred for 30 min at 0 ℃, then warmed to room temperature and stirred for another 4h. Concentrated and the residue was redissolved with DCM (50 ml) . The solution was washed with saturated aqueous NaHCO ₃ (50ml*2) , dried with anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to obtain the desired product as white solid (2.8g, 58.7%) . LC-MS [M+H] -m/z: 367.

Example 13 The synthesis ofcompounds III-1-1～III-1-19 is similar to example 6

Table 3

Example 14 Synthesis of (2S) -2- ( (3R) -2-hydroxy-5-oxo-3-propylpyrrolidin-1-yl) butanamide

To a 250 ml three-necked flask with mechanical stirring function was added (2S) -2- ( (3S) -2-hydroxy-5-oxo-3-propyl-4-tosylpyrrolidin-1-yl) butanamide (3.80g, 10.0mmol) , magnesium chips (2.4g, 100.0mmol) and MeOH (50ml) , followed by 0.1ml TMSCl. The resulting mixture was stirred for 24h, then concentrated in vacuo. The residue was poured into saturated brine, and extracted with EA (3*50ml) . The combined organic phases were dried with anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to obtain the desired product (641mg, 28.0%) . LC-MS [M+H] -m/z: 229.

Example 15 Synthesis of (2S) -2- ( (3R) -2-hydroxy-5-oxo-3-propylpyrrolidin-1-yl) butanamide

To a 250 ml three-necked flask with mechanical stirring function was added (2S) -2- ( (3S) -2-hydroxy-5-oxo-4- (phenylsulfonyl) -3-propylpyrrolidin-1-yl) butanamide (2.6g, 7.06mmol) , magnesium chips (1.72g, 70.57mmol) and MeOH (40ml) , followed by 0.1ml TMSCl. The resulting mixture was stirred for 24h, then concentrated in vacuo. The residue was poured into saturated brine (45ml) , and extracted with EA (3*45ml) . The combined organic phases were dried with anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to obtain the desired product (312mg, 19.3%) . LC-MS [M+H] -m/z: 229.

Example 16 Synthesis of (2S) -2- ( (3R) -2-hydroxy-5-oxo-3-propylpyrrolidin-1-yl) butanamide

To a 250 ml three-necked flask with mechanical stirring function was added (2S) -2- ( (3S) -2-hydroxy-4- (naphthalen-1-ylsulfonyl) -5-oxo-3-propylpyrrolidin-1-yl) bu tanamide (2.3g, 5.50mmol) , magnesium chips (1.34g, 54.96mmol) and MeOH (40ml) , followed by 0.1ml TMSCl. The resulting mixture was stirred for 24h, then concentrated in vacuo. The residue was poured into saturated brine (45ml) , and extracted with EA (3*45ml) . The combined organic phases were dried with anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to obtain the desired product (168mg, 13%) . LC-MS [M+H] -m/z: 229.

Example 17 Preparation of Brivaracetam

To a 250 ml three-necked flask with mechanical stirring function was added (2S) -2- ( (3R) -2-hydroxy-5-oxo-3-propylpyrrolidin-1-yl) butanamide (600mg, 2.6mmol) , DCM (15ml) and triethylsilane (907mg, 7.8mmol) . The resulting mixture was cooled to -25 ℃, and added TFA (25 ml) dropwise within 1min. After being stirred for 30 min at -25 ℃, the reaction mixture was warmed to room temperature and stirred for another 4h. The solution was washed with saturated aqueous NaHCO ₃ (20ml*3) , dried with anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to obtain the desired product as white solid (318mg, 81.3%) . LC-MS [M+H] -m/z: 213.

Example 18 Preparation of Brivaracetam

To a 250 ml three-necked flask with mechanical stirring function was added (2S) -2- ( (4S) -2-oxo-3- (phenylsulfonyl) -4-propylpyrrolidin-1-yl) butanamide (3.3g, 9.36mmol) , magnesium chips (2.28g, 93.63mmol) and MeOH (50ml) , followed by 0.1ml TMSCl. The resulting mixture was stirred for 24h, then concentrated in vacuo. The residue was poured into saturated brine (50ml) , and extracted with EA (50ml*3) . The combined organic phases were dried with anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to obtain the desired product (337mg, 17%) . LC-MS [M+H] -m/z: 213.

Example 19 Preparation of Brivaracetam

To a 250 ml three-necked flask with mechanical stirring function was added (2S) -2- ( (4S) -3- ( (4-methoxyphenyl) sulfonyl) -2-oxo-4-propylpyrrolidin-1-yl) butanamide (2.9g, 7.58mmol) , magnesium chips (1.84g, 75.82mmol) and MeOH (50ml) , followed by 0.1ml TMSCl. The resulting mixture was stirred for 24h, then concentrated in vacuo. The residue was poured into saturated brine (50ml) , and extracted with EA (50ml*3) . The combined organic phases were dried with anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to obtain the desired product (416mg, 26%) . LC-MS [M+H] -m/z: 213.

Example 20 Preparation of Brivaracetam

To a 250 ml three-necked flask with mechanical stirring function was added (2S) -2- ( (4S) -2-oxo-4-propyl-3-tosylpyrrolidin-1-yl) butanamide (3.6g, 10.0mmol) , magnesium chips (2.4g, 100.0mmol) and MeOH (50ml) . The resulting mixture was stirred for 1h at 50℃, then CH ₃COONa (8.2g, 100.0mmol) was added, and stirred for overnight. The reaction mixture was poured into cold aqueous HCl solution (50ml) , and extracted with EA (50ml*3) . The combined organic phases were dried with anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to obtain the desired product (256mg, 12%) . LC-MS [M+H] -m/z: 213.

Example 21 Preparation of Brivaracetam

To a 250 ml three-necked flask with mechanical stirring function was added (2S) -2- ( (4S) -2-oxo-4-propyl-3-tosylpyrrolidin-1-yl) butanamide (3.6g, 10.0mmol) , magnesium chips (2.4g, 100.0mmol) , MeOH (50ml) and DMF (50 ml) , followed by 0.2ml TMSCl. The resulting mixture was stirred for 24h at 50℃, then poured into cold aqueous HCl solution (50ml) , and extracted with DCM (50ml*3) . The combined organic phases were washed with water (3*100ml) , dried with anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to obtain the desired product (229mg, 10.8%) . LC-MS [M+H] -m/z: 213.

Example 22 Preparation of Brivaracetam

To a 250 ml three-necked flask with mechanical stirring function was added (2S) -2- ( (4S) -2-oxo-4-propyl-3-tosylpyrrolidin-1-yl) butanamide (3.6g, 10.0mmol) , magnesium chips (1.8g, 50.0mmol) , and MeOH (50ml) , followed by 0.1ml TMSCl. The resulting mixture was stirred for 24h at room temperature, then then concentrated in vacuo. To the residue was added HCl solution (50ml) , and extracted with EA (50ml*3) . The combined organic phases were washed with water (3*100ml) , dried with anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to obtain the desired product (1.01g, 47.6%) . LC-MS [M+H] -m/z: 213.

Example 23 Preparation of Brivaracetam

To a 250 ml three-necked flask with mechanical stirring function was added (2S) -2- ( (4S) -2-oxo-4-propyl-3-tosylpyrrolidin-1-yl) butanamide (3.6g, 10.0mmol) , Sodium amalgam (2.23g) , and MeOH (50ml) . The resulting mixture was stirred for 24h at 50℃, then then concentrated in vacuo. To the residue was added HCl solution (50ml) , and extracted with EA (50ml*3) . The combined organic phases were washed with water (3*100ml) , dried with anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to obtain the desired product (182mg, 8.6%) .

Example 24 Preparation of Brivaracetam

To a 250 ml three-necked flask with mechanical stirring function was added (2S) -2- ( (4S) -2-oxo-4-propyl-3-tosylpyrrolidin-1-yl) butanamide (3.6g, 10.0mmol) , magnesium chips (7.2g, 300.0mmol) , and MeOH (50ml) . The resulting mixture was stirred for 48h at 50℃, then then concentrated in vacuo. To the residue was added HCl solution (50ml) , and extracted with EA (50ml*3) . The combined organic phases were washed with water (3*100ml) , dried with anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to obtain the desired product (850mg, 40.1%) .

Example 25 Synthesis of (2S) -2- ( (3S) -3- (hydroxymethyl) -2-tosylhexanamido) butanoic acid

To a 100ml three-necked flask with mechanical stirring function was added a 30%solution of sodium methoxide in methanol (7.20g, 40.0mmol) , followed by (S) -2-aminobutyric acid (4.12g, 40.0mmol) . After stirring at room temperature for 0.5 h, (4S) -4-propyl-3-tosyldihydrofuran-2 (3H) -one (5.65 g, 20.0 mmol) was added. The resulting mixture was heated to reflux and stirred for overnight. Then 50 ml of water was added, and the mixture was stirred for 1 h. After cooling to room temperature, the solution was adjusted to pH～3. The solid was collected by filtration, and washed with water, and dried to obtain 5.55 g of crude product, yield: 73%. LC-MS [M+H] -m/z: 386.

Example 26 Synthesis of (2S) -2- ( (3S) -2-hydroxy-5-oxo-3-propyl-4-tosylpyrrolidin-1-yl) butanoic acid

To a 250 ml three-necked flask with mechanical stirring function was added (2S) -2- ( (3S) -3- (hydroxymethyl) -2-tosylhexanamido) butanoic acid (5.01g, 13.0mmol) , tempo (100mg, 0.65mmol) , KBr (150mg, 1.3mmol) and DCM (20 ml) , followed by 8%aqueous NaClO (20 ml) at room temperature. TLC was used to monitor the reaction. After the reaction was completed, the mixture was adjusted to pH～3 with dilute hydrochloric acid. The separated organic phase was washed with saturated brine (20ml*2) , dried with anhydrous Na ₂SO ₄, and concentrated. The residue was purified by column chromatography to obtain the desired product (3.56 g, 71.5%) . LC-MS [M+H] -m/z: 384.

Example 27 Synthesis of (2S) -2- ( (3R) -2-hydroxy-5-oxo-3-propylpyrrolidin-1-yl) butanoic acid

To a 250 ml three-necked flask with mechanical stirring function was added (2S) -2- ( (3S) -2-hydroxy-5-oxo-3-propyl-4-tosylpyrrolidin-1-yl) butanoic acid (1.9g, 5.0mmol) , magnesium chips (2.4g, 100.0mmol) , and MeOH (57ml) , followed by adding 0.2ml TMSCl dropwise. The resulting mixture was stirred for 24h at room temperature. Poured into 6N dilute hydrochloric acid (50ml) , and extracted with DCM (100ml*3) . The combined organic phases were dried with anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to obtain the desired product as white solid (518mg, 45.0%) . LC-MS [M+H] -m/z: 230.

Example 28 Preparation of (S) -2- ( (R) -2-oxo-4-propylpyrrolidin-1-yl) butanoic acid

To a 100 ml three-necked flask was added (2S) -2- ( (3R) -2-hydroxy-5-oxo-3-propylpyrrolidin-1-yl) butanoic acid (2.3g, 10.0mmol) , DCM (50ml) and triethylsilane (4.5g, 39.2mmol) . The mixture was cooled to 0℃, then added BF ₃·Et ₂O (2.8g, 19.7mmol) within 1min. The resulting mixture was allowed to warm to room temperature after stirring at 0℃ for 30min and stirred for another 4h. The reaction mixture was washed with water (50ml*3) , dried with anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to obtain the desired product as white solid (1.6g, 75.0%) . LC-MS [M+H] -m/z: 214.

Example 29 Preparation of Brivaracetam

To a 100 ml three-necked flask was added (S) -2- ( (R) -2-oxo-4-propylpyrrolidin-1-yl) butanoic acid (1.1g, 5.0mmol) , Pyridine (435mg, 5.5mmol) , Boc ₂O (2.2g, 10.0mmol) , NH ₄HCO ₃ (790mg, 10.0mmol) and dioxane (11ml) . The resulting mixture was stirred at room temperature for 12h, then diluted with EA, and washen with water (20ml*3) . The organic phase was dried with anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to obtain the desired product as white solid (671mg, 63.0%) . LC-MS [M+H] -m/z: 213.

Example 30 Preparation of (2S) -2- ( (3S) -2-hydroxy-5-oxo-3-propyl-4-tosylpyr rolidin-1-yl) butanamide

To a 100 ml three-necked flask was added (2S) -2- ( (3S) -2-hydroxy-5-oxo-3-propyl-4-tosylpyrrolidin-1-yl) butanoic acid (3.8g, 10.0mmol) , Pyridine (870mg, 11.0mmol) , Boc ₂O (4.4g, 20.0mmol) , NH ₄HCO ₃ (1.6g, 20.0mmol) and THF (19ml) . The resulting mixture was stirred at room temperature for 12h, then diluted with EA, and washen with water (50ml*3) . The organic phase was dried with anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to obtain the desired product as white solid (2.7g, 71.0%) . LC-MS [M+H] -m/z: 383.

Example Preparation of (2S) -2- ( (4S) -2-oxo-4-propyl-3-tosylpyrrolidin-1-yl) but anoic acid

To a 250 ml three-necked flask with mechanical stirring function was added (2S) -2- ( (3S) -3- (hydroxymethyl) -2-tosylhexanamido) butanoic acid (5.01g, 13.0mmol) , tempo (100mg, 0.65mmol) , KBr (150mg, 1.3mmol) and DCM (50 ml) , followed by NaIO ₄ (7.00g, 32.5mmol) at room temperature. The resulting mixture was heated to 45℃ and stirred for 24h. The organic phase was collected, added water (35 ml) and NaOH (500 mg) , and stirred for 4h, then adjusted to pH～3, and extracted with DCM. The combined organic phases were washed with saturated brine (20ml*2) , dried with anhydrous Na ₂SO ₄, and filtered. To the filtrate was added triethylsilane (4.50g, 39.2mmol) with stirring, then cooled to 0 ℃ and was added TFA (25 ml) dropwise within 1min. The resulting mixture was stirred for 30 min at 0 ℃, then warmed to room temperature and stirred for another 4h. Concentrated and the residue was purified by column chromatography to obtain the desired product as white solid (3.1g, 65.0%) . LC-MS [M+H] -m/z: 368.

Example 32 Preparation of (S) -2- ( (R) -2-oxo-4-propylpyrrolidin-1-yl) butanoic acid

To a 100 ml three-necked flask with mechanical stirring function was added (2S) -2- ( (4S) -2-oxo-4-propyl-3-tosylpyrrolidin-1-yl) butanoic acid (1.8g, 5.0mmol) , magnesium chips (1.2g, 50.0mmol) , and MeOH (57ml) , followed by adding 0.2ml TMSCl dropwise. The resulting mixture was stirred for 24h at room temperature. Poured into 6N dilute hydrochloric acid (50ml) , and extracted with DCM (100ml*3) . The combined organic phases were dried with anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to obtain the desiredproduct as white solid (554mg, 52.0%) . LC-MS [M+H] -m/z: 214.

Example 33 Preparation of (2S) -2- ( (4S) -2-oxo-4-propyl-3-tosylpyrrolidin-1-yl) butanamide

To a 100 ml three-necked flask was added (2S) -2- ( (4S) -2-oxo-4-propyl-3-tosylpyrrolidin-1-yl) butanoic acid (1.8g, 5.0mmol) , Pyridine (435mg, 5.5mmol) , Boc ₂O (2.2g, 10.0mmol) , NH ₄HCO ₃ (0.8g, 10.0mmol) and dioxane (22ml) . The resulting mixture was stirred at room temperature for 12h, then diluted with EA, and washen with water (25ml*3) . The organic phase was dried with anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography to obtain the desired product as white solid (1.5g, 81.9%) . LC-MS [M+H] -m/z: 367.

Although the present invention has been described in considerable detail with reference to certain preferred versions thereof, other versions are possible. Therefore, the spirit and scope of the present invention should not be limited to the description of the preferred versions described herein. All features disclosed in the specification, including the abstract and drawings, and all the steps in any method or process disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. Each feature disclosed in the specification, including abstract and drawings, can be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features. Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in the present application is herein incorporated by reference in its entirety.

Claims

A compound having the structure of formula III:

Wherein:

R ¹ is selected from optionally substituted or unsubstituted C ₁-C ₅ alkyl, optionally substituted or unsubstituted C ₆-C ₁₂ aryl, and optionally susbstituted or unsubstituted 5-12 membered heteroaryl;

R ² is selected from OH, NH ₂, NHBn, NBn ₂ or optionally susbstituted or unsubstituted alkoxy;

R ³ is selected from hydrogen, OH, optionally substituted or unsubstituted C ₁-C ₄ alkoxy, optionally substituted or unsubstituted OC (O) (C ₁-C ₄) alkyl or OBz.
The compound according to claim 1, wherein R ¹ is selected from optionally substituted or unsubstituted phenyl, optionally substituted or unsubstituted naphthyl, and optionally substituted or unsubstituted pyridyl or quinolyl, preferably, R ¹ is selected from optionally substituted or unsubstituted phenyl.
The compound according to claim 2 or 3, wherein the hydrogens of R ¹ could be substituted by one or more R ⁴ groups independently, and R ⁴ is selected from halogen, methyl, ethyl, propyl, isopropyl, t-butyl, trifluoromethyl, methoxy, nitro, cyano.
The compound according to claim 3, wherein R ¹ is selected from:
The compound according to claim 1 or 2, wherein R ²is selected from OH or NH ₂.
The compound according to claim 1 or 2, wherein R ³ is selected from hydrogen or OH, preferably, R ³ is selected from hydrogen.
A method for the preparation of the intermediate III-1 of Brivaracetam, the method comprising the steps of:

wherein, each R ¹ or R ²has the same definition as any of claim 1-5.
A method for the preparation of the intermediate III-2 of Brivaracetam, wherein, the method comprising the steps of:

wherein, each R ¹ or R ²has the same definition as any of claim 1-5.
A method according to claims 7 or 8, wherein includes:

preparation of the compound of formula II from the compound of formula I,

the compound of formula II is prepared by reacting a compound of formula I with compound A in a solvent or solvent free condition, wherein the compound A is selected from L-2-aminobutanamide, L-2-aminobutanamide hydrochloride, L-2-aminobutyric acid or L-2-aminobutyric acid hydrochloride.
The method according to claim 9, wherein the compound of formula I is reacted with compound A under the action of a base to prepare a compound of formula II.
The method according to claim 10, wherein the base is selected from one or more of sodium methoxide, potassium methoxide, magnesium methoxide, sodium ethoxide, potassium ethoxide, sodium t-butoxide, potassium t-butoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, Sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine or 1, 8-Diazabicyclo [5.4.0] undec-7-ene (DBU) .
The method according to claim 11, wherein the equivalent of alkali is between 0.01 and 10.
The method according to claim 9, wherein the solvent is selected from one or more of water, methanol, ethanol, propanol, isopropanol, tert-butanol, n-butanol, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, toluene, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methylpyrrolidone.
The method according to any of claims 7, wherein includes:

preparation of the compound of formula III-1 from the compound of formula II, The compound of formula III-1 is prepared by reacting a compound of formula II in oxidation system in a solvent.
The method according to claim 14, wherein the solvent is selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, acetone, acetonitrile, toluene, dichloromethane, tetrahydrofuran or DMF, N-methylpyrrolidone or DMSO.
The method according to claim 14, wherein the oxidation system is selected from 4-Methylmorpholine N-oxide/Tetrapropylammonium perruthenate (NMO/TPAP) , DMSO/ (COCl) ₂/TEA, Dess-Martin periodinane (DMP) , DMSO/Sulfur trioxide pyridine complex (DMSO/Py·SO ₃) , NaIO ₄/TEMPO/NaBr, NaIO ₄/TEMPO/KBr, KIO ₄/TEMPO/NaBr, KIO ₄/TEMPO/KBr, NaClO/TEMPO/NaBr or NaClO/TEMPO/KBr, KMnO ₄, NaMnO ₄, KMnO ₄/TEMPO or NaMnO ₄/TEMPO.
The method according to claims 8, wherein includes:

preparation of the compound of formula III-2 from the compound of formula II, In a solvent, the product of a compound of formula II reacted with an oxidizing agent system is then reacted with a reducing agent to prepare a compound of formula III-2.
The method according to claim 17, wherein the solvent is selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, n-butanol, acetone, acetonitrile, toluene, dichloromethane, tetrahydrofuran or DMF, N-methylpyrrolidone or DMSO.
The method according to claim 17, wherein the oxidation system is selected from 4-Methylmorpholine N-oxide/Tetrapropylammonium perruthenate (NMO/TPAP) , DMSO/ (COCl) ₂/TEA, Dess-Martin periodinane (DMP) , DMSO/Sulfur trioxide pyridine complex (DMSO/Py·SO ₃) , NaIO ₄/TEMPO/NaBr, NaIO ₄/TEMPO/KBr, KIO ₄/TEMPO/NaBr, KIO ₄/TEMPO/KBr, NaClO/TEMPO/NaBr or NaClO/TEMPO/KBr, KMnO ₄, NaMnO ₄, KMnO ₄/TEMPO or NaMnO ₄/TEMPO.
The method according to claim 17, wherein the reducing agent includes sodium borohydride, sodium cyanoborohydride, sodium triacetylborohydride, triethylsilane/trifluoroacetic acid, Pd/H ₂, Pt/H ₂, Ni/H ₂, Pd (OH) ₂/H ₂ or Pd/ammonium formate.
The use of the compound of claims 1-6 for the preparation of Brivaracetam APIs.
A method for the preparation of Brivaracetam VI, which includes the steps of preparing a compound of formula VI from a compound of formula III-1-1:

wherein, each R ¹ has the same definition as any of claim 1-5.
A method according to claim 22, wherein includes:

preparation of the compound of formula IV-1 from the compound of formula III-1-1,

removing the sulfonyl group on compound of formula III-1-1 by a reducing agent in an organic solvent to prepare a compound of formula IV-1.
The method according to claim 23, wherein the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water.
The method according to claim 23, wherein the reducing agent is selected from active metals and salts thereof, tin hydride or transition metals.
The method according to claim 23, wherein the reducing agent is selected from Mg, Ca, Al, Zn, Ni, Sm, SmI ₂.
The method according to claim 25 or 26, wherein the reducing agent is used in combination with one or more of Hg, I ₂, Lewis acid or base.
The method according to claim 27, wherein the Lewis acid and the Lewis base are selected from one or more of hydrochloric acid, ammonium chloride, trimethylchlorosilane, titanium tetrachloride, nickel chloride, nickel bromide, nickel iodide, acetic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, citric acid, ammonia, methylmagnesium bromide, tetramethylethylenediamine, sodium acetate and potassium acetate.
The method according to any of claim 22-28, wherein the reducing agent is used in a molar equivalent of between 1 and 30.
The method according to claim 23, removing the sulfonyl group on compound of formula III-1-1 by a reducing agent in an organic solvent to prepare a compound of formula IV-1, wherein the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water; the reducing agent is Mg, which is used in a molar equivalent of between 1 and 30, and the reducing agent is used in combination with one or more of hydrochloric acid, trimethyl chlorosilane, nickel chloride, nickel bromide, nickel iodide, acetic acid, propionic acid, methylmagnesium bromide, tetramethylethylenediamine, sodium acetate or potassium acetate.
The method according to any of claims 22-30, wherein includes:

preparation of the compound of formula VI from the compound of formula IV-1,

A compound of formula IV-1 is reacted with a reducing agent in a solvent to prepare a compound of formula VI.
The method according to claim 31, wherein the solvent is selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, acetonitrile, toluene, dichloromethane or tetrahydrofuran.
The method according to claim 31, wherein the reducing agent includes sodium borohydride, sodium cyanoborohydride, sodium triacetylborohydride, triethylsilane/trifluoroacetic acid, Pd/H ₂, Pt/H ₂, Ni/H ₂, Pd (OH) ₂/H ₂ or Pd/ammonium formate.
A method for the preparation of Brivaracetam VI, which includes the step of preparing a compound of formula VI by a compound of formula III-1-1:

wherein, each R ¹ has the same definition as any of claim 1-5.
A method for the preparation of Brivaracetam VI, which includes the step of preparing a compound of formula VI from a compound of formula III-2-1:

wherein, each R ¹ has the same definition as any of claim 1-5.
The method according to claim 35, wherein the method includes the step of removing the sulfonyl group on compound of formula III-2-1 by a reducing agent in an organic solvent to prepare a compound of formula VI.
The method according to claim 36, wherein the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water.
The method according to claim 36, wherein the reducing agent is selected from active metals and salts thereof, tin hydride or transition metals.
The method according to claim 38, wherein the reducing agent is selected from Mg, Ca, Al, Zn, Ni, Sm, SmI ₂.
The method according to claim 38 or 39, wherein the reducing agent is used in combination with one or more of Hg, I ₂, Lewis acid or base.
The method according to claim 40, wherein the Lewis acid and the Lewis base are selected from one or more of hydrochloric acid, ammonium chloride, trimethylchlorosilane, titanium tetrachloride, nickel chloride, nickel bromide, nickel iodide, acetic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, citric acid, ammonia, methylmagnesium bromide, tetramethylethylenediamine, sodium acetate and potassium acetate.
The method according to any of claim 36-41, wherein the reducing agent is used in a molar equivalent of between 1 and 30.
The method according to claim 41, wherein the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water; the reducing agent is Mg, which is used in a molar equivalent of between 1 and 30, and the reducing agent is used in combination with one or more of hydrochloric acid, trimethyl chlorosilane, nickel chloride, nickel bromide, nickel iodide, acetic acid, propionic acid, methylmagnesium bromide, tetramethylethylenediamine, sodium acetate or potassium acetate.
A method for the preparation of Brivaracetam VI, which includes the steps of preparing a compound of formula VI from a compound of formula III-1-2:

wherein, each R ¹ has the same definition as any of claim 1-5.
A method for the preparation of Brivaracetam VI, which includes the steps of preparing a compound of formula VI from a compound of formula III-1-2:

wherein, each R ¹ has the same definition as any of claim 1-5.
A method for the preparation of Brivaracetam VI, which includes the steps of preparing a compound of formula VI from a compound of formula III-2-2:

wherein, each R ¹ has the same definition as any of claim 1-5.
A method for the preparation of Brivaracetam VI, which includes the steps of preparing a compound of formula VI from a compound of formula III-2-2:

wherein, each R ¹ has the same definition as any of claim 1-5.