WO2024169490A1 - 布立西坦中间体的不对称催化氢化合成方法 - Google Patents

布立西坦中间体的不对称催化氢化合成方法 Download PDF

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WO2024169490A1
WO2024169490A1 PCT/CN2024/072430 CN2024072430W WO2024169490A1 WO 2024169490 A1 WO2024169490 A1 WO 2024169490A1 CN 2024072430 W CN2024072430 W CN 2024072430W WO 2024169490 A1 WO2024169490 A1 WO 2024169490A1
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formula
synthesis method
catalytic hydrogenation
catalyst
ruthenium
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French (fr)
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张万斌
王国平
刘德龙
王光杰
丁正东
芦雨菲
于振鹏
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Yangzhou Aurisco Pharmaceutical Co Ltd
Shanghai Jiao Tong University
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Yangzhou Aurisco Pharmaceutical Co Ltd
Shanghai Jiao Tong University
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Definitions

  • the present invention relates to the field of organic compound synthesis, and in particular to a method for synthesizing (2S)-2-[(4R)-2-oxo-4-propyl-1-pyrrolidinyl]butyric acid by asymmetric catalytic hydrogenation.
  • Brivaracetam chemically known as (2S)-2-[(4R)-2-oxo-4-propyl-1-pyrrolidinyl]butanamide, has the following structure:
  • Brivaracetam is a third-generation anti-epileptic drug developed by UCB of Belgium. It was approved for marketing by EMEA and FDA in January and February 2016, respectively. It is used as an adjunctive treatment for partial seizures with or without secondary systemic seizures in adults and adolescents with epilepsy over 16 years old.
  • UCB a company originally researched, disclosed a method for preparing (2S)-2-[(4R)-2-oxo-4-propyl-1-pyrrolidinyl]butanamide in WO01/62726.
  • the method used Pd/C as a catalyst and hydrogenated and reduced compound 374 in the presence of NH 4 COOH to obtain two enantiomers 158 and 159, and the ratio of the two was close to 1:1.
  • WO2017/076738A1 improves the scheme described in WO01/62726, specifically: the compound represented by formula (III) is catalytically hydrogenated using Pt/C as a catalyst in the presence of formic acid or citric acid to generate compounds represented by formula (Ia) and (Ib), and the reaction formula is as follows.
  • the chiral purity of the target compound in the crude product is improved, and the DE value of the obtained product is about 61%.
  • a chromatographic column is required to separate enantiomers, which makes it difficult to achieve mass production.
  • Guangzhou Saifeng Pharmaceutical Technology Co., Ltd. attempted to prepare brivaracetam with high optical purity by asymmetric reduction to address this problem, and disclosed a method for preparing 2-oxo-1-pyrrolidine chiral derivatives.
  • the method uses transition metals as catalysts, in the presence of phosphorus ligands, and silane as a hydrogen source at low temperature to prepare brivaracetam with high optical purity.
  • the method uses chiral ligands with complex structures, which are difficult to obtain in large quantities and expensive, which seriously restricts its industrial application.
  • chiral induced catalysis often has relatively strict requirements on reaction conditions, and a relatively serious amplification effect often occurs in production, which further brings difficulties to its subsequent application.
  • CN107513031A discloses a method for preparing a chiral 2-oxo-1-pyrrolidine derivative, which involves using palladium carbon, palladium aluminum oxide, palladium silicon dioxide, palladium barium carbonate, palladium calcium carbonate, palladium hydroxide carbon, ruthenium carbon, Raney nickel, platinum dioxide and rhodium carbon to catalyze the compound shown in formula VI to produce the compound shown in formula I ( R 1 is hydrogen or alkyl).
  • (2S)-2-(4-propyl-1,5-dihydropyrrole-2-one)butyric acid is used as a substrate, and catalytic hydrogenation is performed to obtain (2S)-2-[(4R)-2-oxo-4-propyl-1-pyrrolidinyl]butyric acid.
  • the yield of the product obtained by recrystallization twice is 80%, and the de value is 95%. The conversion rate is not disclosed.
  • WO2019/157856A1 discloses a method for preparing a high chiral purity lactam intermediate, which involves hydrogenating and reducing compound C in the presence of a heavy metal catalyst (palladium carbon, palladium, platinum carbon, platinum, ruthenium carbon, rhodium carbon, palladium aluminum oxide, palladium silicon dioxide, palladium barium carbonate, palladium calcium carbonate, palladium hydroxide carbon, palladium dioxide) and a chiral inducing agent (formic acid, citric acid, malonic acid, succinic acid, hydrochloric acid, hydrobromic acid, etc.) to obtain compound D:
  • the product yield after crystallization is 77-96%, the de value is 99.0-99.6%, and the conversion rate is not disclosed.
  • the inventors of the present application found in actual scale-up production that although the de value of the product obtained by catalytic hydrogenation of (2S)-2-(4-propyl-1,5-dihydropyrrole-2-one)butyric acid using a heavy metal catalyst (e.g., palladium on carbon) is high, the conversion rate of the substrate is not high enough, unreacted raw materials exist in the target product, and it is difficult to remove the raw materials from the target product by either recrystallization or column chromatography, resulting in high product purification costs and low quality.
  • a heavy metal catalyst e.g., palladium on carbon
  • the present invention provides, on one hand, a method for synthesizing a compound represented by formula II by asymmetric catalytic hydrogenation, the method comprising: in a hydrogen atmosphere, in a solvent, the compound represented by formula I is subjected to asymmetric hydrogenation reduction in the presence of a catalyst generated by the reaction of a planar chiral metallocene ligand and a ruthenium salt and a base to form a compound represented by formula II, and the reaction formula is shown as follows:
  • planar chiral metallocene ligand is selected from the compounds shown in the following formulas III to VI:
  • R is selected from H, a straight or branched alkyl group containing 1 to 8 carbon atoms, a cycloalkyl group containing 1 to 8 carbon atoms, a substituted or unsubstituted aryl group or a benzyl group containing 6 to 10 carbon atoms.
  • Ar is a substituted or unsubstituted aryl group containing 6 to 10 carbon atoms.
  • substitution means that one or more hydrogen atoms on the aryl or benzyl group may be optionally replaced by an alkyl group, a haloalkyl group, an alkoxy group, a cycloalkyl group, an aryl group, a benzyl group or a halogen group.
  • the ruthenium salt is selected from tris(triphenylphosphine)ruthenium dichloride, dichloro(p-methylisopropylphenyl)ruthenium(II) dimer, phenylruthenium(II) chloride dimer, bis(2,2'-bipyridine)ruthenium dichloride, (1,5-cyclooctadiene)ruthenium dichloride, phenylmethylenebis(tricyclohexylphosphine)ruthenium(II) dichloride, p-isopropylphenyltriphenylphosphine ruthenium dichloride, bis(triphenylphosphine)cyclopentadienylruthenium(II) chloride, chloro(indenyl)bis(triphenylphosphine)ruthenium(II), pentamethylcyclopentadienylbis(triphenylphosphine)chloride, dichlorodicarbon
  • substituted means that one or more hydrogen atoms on the aryl or benzyl group may be optionally replaced by an alkyl group having 1 to 8 carbon atoms, a haloalkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a cycloalkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, a benzyl group or a halogen.
  • R is selected from methyl, ethyl, isopropyl, tert-butyl, substituted or unsubstituted aryl or benzyl containing 6 to 10 carbon atoms.
  • R is selected from isopropyl or tert-butyl.
  • Ar is phenyl, or phenyl substituted by methyl or trifluoromethyl.
  • the planar chiral metallocene ligand is selected from the compounds shown in formula IV or VI.
  • the ruthenium salt is selected from tris(triphenylphosphine)ruthenium dichloride, dichloro(p-methylisopropylphenyl)ruthenium(II) dimer, phenylchloride ruthenium(II) dimer.
  • the catalyst is selected from the compounds shown in the following structures:
  • the catalyst is selected from the compounds shown in the following structures:
  • the catalyst is selected from the compounds shown in the following structures:
  • the solvent is selected from methanol, ethanol, isopropanol, propanol, butanol, isobutanol, acetone, 1,4-dioxane, tetrahydrofuran, dichloromethane, acetonitrile, toluene, xylene, or a combination thereof.
  • the solvent is selected from methanol, ethanol, and isopropanol.
  • the base is selected from LiOH, NaOH, KOH, Li 2 CO 3 , Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , LiHCO 3 , NaHCO 3 , KHCO 3 , CsHCO 3 , Na 3 PO 4 , Na 2 HPO 4 , NaH 2 PO 4 , triethylamine, pyridine, 2,6-methylpyridine, 1,8-diazabicycloundec-7-ene, 1,4-diazabicyclo[2.2.2]octane, or a combination thereof.
  • the base is selected from NaOH and/or KOH.
  • the molar ratio of the compound represented by formula I to the base is 1:0.1 to 3. In another more preferred embodiment of the present invention, the molar ratio of the compound represented by formula I to the base is 1:0.8 to 1.5. In another more preferred embodiment of the present invention, the molar ratio of the compound represented by formula I to the base is 1:1.
  • the reaction temperature of the asymmetric catalytic hydrogenation synthesis method is -20 to 60° C. In another more preferred embodiment of the present invention, the reaction temperature of the asymmetric catalytic hydrogenation synthesis method is 15 to 50° C., for example, 25 to 35° C.
  • the hydrogen pressure of the asymmetric catalytic hydrogenation synthesis method is 1 to 80 bar, more preferably 40 to 60 bar, for example, 40 bar, 45 bar, 50 bar, 55 bar, 60 bar.
  • the molar ratio of the reaction substrate to the catalyst in the asymmetric catalytic hydrogenation synthesis method is 10000:1 to 10:1, more preferably, 3000:1 to 100:1.
  • the method for reacting a planar chiral metallocene ligand with a ruthenium salt to generate a catalyst comprises the steps of: reacting the planar chiral metallocene ligand with a ruthenium salt in a solvent at 60 to 120° C. to generate a catalyst.
  • the reaction temperature in the method for reacting a planar chiral metallocene ligand with a ruthenium salt to generate a catalyst is 70 to 100° C.
  • the solvent used in the method for reacting a planar chiral metallocene ligand with a ruthenium salt to generate a catalyst is selected from methanol, ethanol, isopropanol, propanol, butanol, isobutanol, acetone, 1,4-dioxane, tetrahydrofuran, dichloromethane, acetonitrile, toluene, xylene, or a combination.
  • the asymmetric catalytic hydrogenation synthesis method of the compound represented by the above formula II comprises the following steps:
  • the solvents used in steps (1) and (2) may be the same or different.
  • the asymmetric catalytic hydrogenation synthesis method of the compound represented by the above formula II comprises the following steps:
  • planar chiral ferrocene ligand reacts with the ruthenium salt in a solvent to generate a catalyst to obtain a reaction solution containing the catalyst
  • step (1) adding the compound of formula I, a base and a solvent to the reaction solution containing the catalyst in step (1), and asymmetric hydrogenation reduction of the compound of formula I in a hydrogen atmosphere to form a compound of formula II,
  • the solvents used in steps (1) and (2) are preferably the same.
  • Another aspect of the present invention provides a method for synthesizing brivaracetam, which comprises the following steps:
  • R' is selected from aliphatic or aromatic hydrocarbon groups.
  • the esterification reaction of step (1) is carried out in methanol or ethanol solvent in the presence of thionyl chloride.
  • the amount of raw materials and the reaction temperature are in accordance with the conventional amount and temperature of this type of reaction, for example, thionyl chloride is added dropwise to methanol at -10-0°C, stirred at -15 to -5°C for 0.5 to 1.5 hours, the compound shown in formula II is stirred at -15 to -5°C for 0.5 to 1.5 hours, the temperature is raised to 0 to 10°C, stirred for 1.5 to 3 hours, and the reaction is detected by TLC until the reaction is complete.
  • the amination reaction in step (2) is carried out in a mixed solvent of aqueous ammonia and alcohol with a mass concentration of 15 to 28% under the condition of passing ammonia gas at -10 to 5°C, wherein the alcohol is methanol and/or ethanol.
  • Another aspect of the present invention provides the use of the compound shown in the following structure in the asymmetric catalytic hydrogenation of 1,5-dihydropyrrole-2-one and its derivatives, wherein 1,5-dihydropyrrole-2-one and its derivatives are hydrogenated and reduced to generate 2-pyrrolidone and its derivatives,
  • Another aspect of the present invention provides the use of the compound shown in the following structure in the asymmetric catalytic hydrogenation of 1,5-dihydropyrrol-2-one and its derivatives to generate 2-pyrrolidone and its derivatives,
  • the present invention provides a catalyst for asymmetric hydrogenation reduction, the structure of which is as follows:
  • FIG1 is a hydrogen nuclear magnetic resonance spectrum of (2S)-2-[(4R)-2-oxo-4-propyl-1-pyrrolidinyl]butyric acid obtained in Example 1.
  • the synthesis method uses a catalyst formed by a planar chiral metallocene ligand and a ruthenium salt to catalyze the asymmetric hydrogenation of 2S-2-(4-propyl-1,5-dihydropyrrole-2-one)butyric acid (compound shown in Formula I), and the final product obtained has a high conversion rate and a high dr value.
  • the method for generating a catalyst by reacting a planar chiral ruthenocene ligand with a ruthenium salt comprises reacting the planar chiral ruthenocene ligand with the ruthenium salt in a solvent at 60 to 120° C. for 4 to 8 hours, treating and separating the reaction solution to obtain a catalyst, and more preferably the reaction temperature is 70 to 100° C. for 5 to 7 hours.
  • the solvent used includes but is not limited to methanol, ethanol, isopropanol, propanol, butanol, isobutanol, acetone, 1,4-dioxane, tetrahydrofuran, dichloromethane, acetonitrile, toluene, and xylene.
  • the method for generating a catalyst by reacting a planar chiral ferrocene ligand with a ruthenium salt comprises reacting the planar chiral ferrocene ligand with a ruthenium salt in a solvent at 60 to 120° C. for 0.3 to 1 hour to generate a catalyst and obtain a reaction solution containing the catalyst. More preferably, the reaction temperature is 70 to 100° C. and the reaction time is 0.4 to 0.6 hours.
  • the solvent used includes but is not limited to methanol, ethanol, isopropanol, propanol, butanol, isobutanol, acetone, 1,4-dioxane, tetrahydrofuran, dichloromethane, acetonitrile, toluene, and xylene.
  • the catalyst is formed by a planar chiral metallocene ligand molecule and two ruthenium salts
  • the molar ratio of the planar chiral metallocene ligand to the ruthenium salt is 1:2 to 3, more preferably 1:2 to 2.5.
  • the catalyst is formed by a planar chiral metallocene ligand molecule and a ruthenium salt
  • the molar ratio of the planar chiral metallocene ligand to the ruthenium salt is 1:1 to 2, more preferably 1:1 to 1.5.
  • the asymmetric catalytic hydrogenation synthesis method of the compound represented by Formula II of the present invention comprises: in a hydrogen atmosphere, in a solvent, the compound represented by Formula I is subjected to asymmetric hydrogenation reduction in the presence of a catalyst formed by a planar chiral metallocene ligand and a ruthenium salt and a base to generate the compound represented by Formula II.
  • the reaction formula is shown below:
  • planar chiral metallocene ligand is selected from the compounds shown in the following formula III or IV:
  • R is selected from H, a straight or branched alkyl group containing 1 to 8 carbon atoms, a substituted or unsubstituted aryl group or a benzyl group containing 6 to 10 carbon atoms; and in formula VI, Ar is a substituted or unsubstituted aryl group containing 6 to 10 carbon atoms.
  • Ruthenium salts include but are not limited to tris(triphenylphosphine)ruthenium dichloride, dichloro(p-methylisopropylphenyl)ruthenium(II) dimer, phenylruthenium chloride(II) dimer, bis(2,2'-bipyridine)ruthenium dichloride, (1,5-cyclooctadiene)ruthenium dichloride, phenylmethylenebis(tricyclohexylphosphine)ruthenium dichloride, p-isopropylphenyltriphenylphosphine ruthenium dichloride, bis(triphenylphosphine)cyclopentadienylruthenium chloride, chloro(indenyl)bis(triphenylphosphine)ruthenium, pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium chloride, dichlorodicarbonylbis(tripheny
  • the catalyst is a compound formed by the compound shown in formula IV or VI and the above ruthenium salt. More preferably, the catalyst is a catalyst formed by a compound shown in formula VI and tris(triphenylphosphine)ruthenium dichloride, dichloro(p-methylisopropylphenyl)ruthenium dimer or phenylruthenium chloride dimer.
  • the structure of the catalyst used in the present invention is as follows:
  • the solvent used in the synthesis reaction includes but is not limited to methanol, ethanol, isopropanol, propanol, butanol, isobutanol, acetone, 1,4-dioxane, tetrahydrofuran, dichloromethane, acetonitrile, toluene, xylene, and more preferably a protic solvent such as methanol, ethanol, isopropanol.
  • the base used in the synthesis reaction includes but is not limited to LiOH, NaOH, KOH, Li 2 CO 3 , Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , LiHCO 3 , NaHCO 3 , KHCO 3 , CsHCO 3 , Na 3 PO 4 , Na 2 HPO 4 , NaH 2 PO 4 , triethylamine, pyridine, 2,6-methylpyridine, 1,8-diazabicycloundec-7-ene, 1,4-diazabicyclo[2.2.2]octane, more preferably, a cheap inorganic base, such as NaOH and KOH.
  • the molar ratio of the base to the catalytic substrate is preferably 0.1 to 3:1, more preferably 0.8 to 1.5:1.
  • the reaction temperature of the asymmetric hydrogenation is preferably -20 to 60°C, more preferably 15 to 50°C, and the hydrogen pressure during the reaction is preferably 1 to 80 bar, more preferably 40 to 60 bar.
  • the amount of the catalyst is not particularly limited, as long as it can significantly promote the asymmetric catalytic hydrogenation reaction. From the perspective of efficiency and cost of the actual experiment, the molar ratio of the reaction substrate to the catalyst can be 10000:1 to 10:1, preferably 3000:1 to 100:1, more preferably 2000:1 to 100:1, for example 2000:1, 1500:1, 1000:1, 500:1, 100:1.
  • the catalyst used can be generated by reacting a chiral metallocene ligand with a ruthenium salt before the hydrogenation reaction, and separated and purified, and used for the asymmetric hydrogenation catalysis of the compound shown in Formula I.
  • the compound shown in Formula I can also be added to a reaction system containing a catalyst generated by reacting a chiral metallocene ligand with a ruthenium salt, and an asymmetric hydrogenation catalytic reaction is carried out in situ (the obtained catalyst is not separated and purified), that is, the asymmetric hydrogenation of the catalyst prepared by reacting a chiral metallocene ligand with a ruthenium salt with a substrate can be carried out by a "one-pot method".
  • “one-pot method” means that in a two-step reaction, the product obtained by the first step reaction does not need to be purified, and the raw materials, other additives and solvents of the second step reaction are directly added to the reaction solution obtained by the first step reaction.
  • substituted means that one or more hydrogen atoms on the group can be optionally replaced by an alkyl group, a haloalkyl group (e.g., trifluoromethyl), an alkoxy group, a cycloalkyl group, an aryl group, a benzyl group, or a halogen (e.g., fluorine, chlorine, bromine, iodine).
  • a haloalkyl group e.g., trifluoromethyl
  • an alkoxy group e.g., a cycloalkyl group, an aryl group, a benzyl group
  • a halogen e.g., fluorine, chlorine, bromine, iodine
  • substituted means that one or more hydrogen atoms on an aryl group or a benzyl group can be optionally replaced by an alkyl group having 1 to 8 carbon atoms, a haloalkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a cycloalkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, a benzyl group, or a halogen.
  • aryl refers to a monocyclic or bicyclic hydrocarbon ring system containing at least one unsaturated aromatic ring, for example, phenyl, naphthyl, indolyl, indenyl, etc.
  • the catalyst used in the asymmetric catalytic hydrogenation synthesis method of the present invention has a good catalytic effect, especially when a catalyst formed by a planar chiral ruthenocene ligand and a ruthenium salt is used, the substrate conversion rate is high, the stereoselectivity is good, and the dr value is high;
  • the cost of the catalyst used is lower than that of the palladium catalyst commonly used in the prior art.
  • the reagents and raw materials used in the present invention are commercially available.
  • the raw materials used in the following examples such as the compound represented by formula I, have an ee value greater than 99%.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • the compound of formula I (1.0 g, 4.7 mmol), NaOH (0.2 g, 5.2 mmol, 1.1 equiv) and catalyst 1 (4.1 mg, 2.35 ⁇ mol, 0.05 mol%) were added to a 50 mL dry round-bottom flask equipped with a magnetic stirrer. After vacuuming and replacing nitrogen, degassed isopropanol (10 mL) was added, and after stirring evenly (the solution was green), the round-bottom flask was placed in a hydrogenation reactor. After replacing the gas in the reactor with hydrogen three times, hydrogen was added until the pressure was 50 bar.
  • the crude product was purified by recrystallization from methyl tert-butyl ether: cyclohexane (volume ratio of 1:5) to obtain a pure product.
  • the H NMR spectrum of the pure product is as follows:
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Ru(II)Cl 2 (PPh 3 ) 3 (4.5 mg, 0.1 mol%) and ligand V-1 (2.3 mg, 0.06 mol%) were added to a 50 mL two-necked flask, and isopropanol (5 mL) was added under nitrogen atmosphere. The liquid nitrogen was frozen and vacuumed and replaced with nitrogen three times, and then refluxed for 0.5 h. During this process, the brown insoluble matter gradually dissolved to form a uniform solution, and catalyst 3 was obtained.
  • the compound of formula I (1.0 g, 4.7 mmol), NaOH (0.2 g, 5.2 mmol, 1.1 equiv), and degassed isopropanol (10 mL) were added to the reaction system containing catalyst 3. After stirring evenly, the round-bottom flask was placed in a hydrogenation reactor. After replacing the gas in the reactor three times with hydrogen, hydrogen was added to a pressure of 50 bar.
  • the preparation method of the catalyst formed by the planar chiral ruthenocene ligand and the ruthenium salt used in the following Examples 4 to 33 is similar to that of Example 1 (the molar ratio of the ligand to the ruthenium salt is adjusted according to the ratio of the number of molecules of the two in the catalyst structure), and these catalysts catalyze the hydrogenation of the compound shown in Formula I in a similar manner to Example 1.
  • the preparation method of the catalyst formed by the planar chiral ferrocene ligand and the ruthenium salt used is similar to that of Example 3 (the molar ratio of the ligand to the ruthenium salt is adjusted according to the ratio of the number of molecules of the two in the catalyst structure), and these catalysts catalyze the hydrogenation of the compound shown in Formula I in a similar manner to Example 3.
  • Catalyst 5 catalyzes the hydrogenation of the compound represented by formula I in a similar manner to Example 1.
  • Ru(II)Cl 2 (PPh 3 ) 3 (4.5 mg, 0.1 mol%) and ligand III-1 (2.3 mg, 0.1 mol%) were added to a 50 mL two-necked flask, and isopropanol (2 mL) was added under nitrogen atmosphere. The liquid nitrogen was refrigerated and vacuumed and replaced with nitrogen three times, and then refluxed for 0.5 h. During this process, the brown insoluble matter gradually dissolved to form a uniform solution, and a solution containing catalyst 12 was obtained.
  • Catalyst 12 catalyzes the hydrogenation of the compound represented by formula I in a similar manner to Example 3.
  • the catalyst formed by the planar chiral ruthenocene ligand and the ruthenium salt has a better selective catalytic effect than the catalyst formed by the planar chiral ferrocene ligand and the ruthenium salt.
  • Catalyst 1 was used as a catalyst to catalyze the asymmetric hydrogenation of the compound represented by formula I, and the temperature, time, hydrogen pressure, solvent, etc. of the catalytic reduction were screened.
  • Examples 36 to 71 utilize catalyst 1 to asymmetric catalytic hydrogenate the compound represented by formula I to synthesize the compound represented by formula II, wherein the molar ratio of substrate to catalyst is about 2000:1, and the solvent, base, reaction system temperature (solvent temperature), hydrogen pressure, reaction time and reaction results (substrate conversion rate, dr value) used are shown in Table 3 below (the dr values in Table 3 are all dr values of the crude product).
  • catalyst 1 has a good selective catalytic effect when reacted for about 48 hours with an inorganic base as the base, an alcohol as the reaction solvent, a temperature of about 35° C. and a hydrogen pressure of about 50 bar.
  • Example 72 The preparation of Examples 72 to 77 was carried out according to the description of 1.2 in Example 1, except that the molar ratio of the substrate (compound represented by Formula I) to the catalyst (catalyst 1) was different.
  • the specific molar ratio of the substrate to the catalyst and the reaction results are shown in Table 4 below.
  • the conversion rate of 84% can be achieved when the molar ratio of substrate to catalyst is 10000:1. After the molar ratio of the two is greater than 1000:1, the conversion rate does not increase significantly.
  • the molar ratio of substrate to catalyst is 10000:1, and complete conversion and excellent dr value can be achieved, and the ratio can still be further increased.
  • the molar ratio of substrate to catalyst is preferably 2000 to 100:1.
  • Amination reaction Add 25 mL of concentrated ammonia water to the reaction bottle, add 2.5 mL of ethanol, cool to 0 ° C, add 2.5 g of the above yellow oil until it is completely dissolved, pass ammonia gas at -5 to 0 ° C for amination, after the TLC reaction is completed, add ethyl acetate and water, and adjust the system pH to 6 to 8 with hydrochloric acid, and separate the organic phase. The organic phase is dried with anhydrous magnesium sulfate, filtered, and the filtrate is concentrated to dryness. Isopropyl ether is refined to obtain 2.2 g of brivaracetam. The mass yield is 88%. The HPLC purity is 100%, and the optical purity is 99.93%.

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Abstract

本发明涉及一种布立西坦中间体的不对称催化氢化合成方法，该合成方法包括步骤：在氢气氛围下，在溶剂中，式I所示化合物在面手性二茂金属配体与钌盐形成的催化剂和碱存在下，发生不对称氢化还原，形成式II所示化合物，反应式如下所示。本发明的不对称催化氢化合成方法所用催化剂成本低，原料的转化率高，得到的最终产物的DR值可达到大于99:1，适合于工业化生产。

Description

布立西坦中间体的不对称催化氢化合成方法
本申请要求申请日为2021年2月10日的中国专利申请号CN202110185444.7的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及有机化合物合成领域，具体地说，涉及(2S)-2-[(4R)-2-氧代-4-丙基-1-吡咯烷基]丁酸的不对称催化氢化合成方法。
背景技术
布立西坦(Brivaracetam)，化学名为(2S)-2-[(4R)-2-氧代-4-丙基-1-吡咯烷基]丁酰胺，其结构如下：
布立西坦是由比利时UCB公司开发的第三代抗癫痫药物，分别于2016年1月和2月获EMEA和FDA批准上市，用于治疗成人和16岁以上青少年癫痫患者的部分发作，伴有或不伴有继发性全身发作的辅助治疗。
原研UCB公司在WO01/62726公开了(2S)-2-[(4R)-2-氧代-4-丙基-1-吡咯烷基]丁酰胺的制备方法，所述方法利用Pd/C为催化剂，在NH4COOH存在下，加氢还原化合物374，得到两种对映异构体158和159，两者的比例接近1：1。
WO2017/076738A1对WO01/62726记载的方案进行了改进，具体为：将式(III)所示化合物利用Pt/C为催化剂，在甲酸或柠檬酸存在下，催化加氢生成式(Ia)和(Ib)所示化合物，反应式如下。粗品中目标化合物的手性纯度得到提高，得到的产物的DE值约为61％。
上述两种方法制备布立西坦的过程中均需要用到色谱柱分离对映异构，难于实现批量生产。广州赛烽医药技术有限公司在CN104892483A中，针对此问题，尝试通过不对称还原制备光学纯度较高的布立西坦，公开了2-氧代-1吡咯烷手性衍生物的制备方法，该方法是以过渡金属为催化剂，在磷配体存在下，以硅氢烷为氢源，低温下，制备得到高光学纯度的布立西坦，但是该方法使用到结构复杂，难于大量获得且价格昂贵的手性配体，严重制约了其工业化应用，此外，手性诱导催化往往对反应条件要求比较苛刻，在生产中往往出现比较严重的放大效应，进一步对其后续应用带来了困难。
CN107513031A公开了一种2-氧代-1-吡咯烷手性衍生物的制备方法，该方法涉及利用钯炭、钯氧化铝、钯二氧化硅、钯碳酸钡、钯碳酸钙、氢氧化钯碳、钉碳、雷尼镍、二氧化铂及铑炭等催化剂催化式VI所示化合物生成式I所示化合物(R1为氢或烷基)。该现有技术中，以(2S)-2-(4-丙基-1,5-二氢吡咯-2-酮)丁酸为底物，催化加氢得到(2S)-2-[(4R)-2-氧代-4-丙基-1-吡咯烷基]丁酸，重结晶2次得到的产物的收率为80％，de值为95％，没有公开转化率。WO2019/157856A1公开了一种高手性纯度内酰胺中间体的制备方法，该方法涉及将化合物C在重金属催化剂(钯炭、钯、铂炭、铂、钌炭、铑炭、钯氧化铝、钯二氧化硅、钯碳酸钡、钯碳酸钙、氢氧化钯碳、二氧化钯)以及手性诱导剂(甲酸、柠檬酸、丙二酸、丁二酸、盐酸、氢溴酸等)存在下，加氢还原得到化合物D：经析晶体后的产品收率为77～96％，de值为99.0～99.6％，也没有公开转化率。本申请发明人在实际放大生产中发现虽然利用重金属催化剂(例如，钯炭)催化氢化(2S)-2-(4-丙基-1,5-二氢吡咯-2-酮)丁酸得到的产物的de值较高，但是底物的转化率不够高，目标产品中存在未反应的原料，而且无论是通过重结晶还是通过柱层析都很难将原料从目标产品中除去，导致产品纯化成本高，质量低。
综上所述，通过催化氢化得到布立西坦或其中间体的现有方案均不理想。因此，本领域需要一种成本低，操作简单且可得到高手性纯度产品的布立西坦中间体的制备工艺。
发明内容
针对现有技术中布立西坦及其中间体制备过程中存在的缺陷，本发明一方面提供了一种式II所示化合物的不对称催化氢化合成方法，所述合成方法包括：在氢气氛围下，在溶剂中，式I所示化合物在面手性二茂金属配体与钌盐反应生成的催化剂以及碱存在下，进行不对称氢化还原，形成式II所示化合物，反应式如下所示：
所述面手性二茂金属配体选自如下式III～VI所示的化合物：
中，R选自H、含1～8个碳的直链或支链烷基、含1～8个碳的环烷基、含6～10个碳的取代的或未被取代的芳基或苄基，式VI中Ar为含6～10个碳的取代的或未被取代的芳基，“取代”指芳基或苄基上的一个或多个氢原子可任选地被烷基、卤代烷基、烷氧基、环烷基、芳基、苄基或卤素所取代，
所述钌盐选自三(三苯基膦)二氯化钌、二氯(对甲基异丙基苯基)钌(II)二聚体、苯基氯化钌(Ⅱ)二聚体、双(2,2'-联吡啶)二氯化钌、(1,5-环辛二烯)二氯化钌、苯基亚甲基双(三环己基磷)二氯化钌(II)、对异丙苯基三苯基膦二氯化钌、二(三苯基膦)环戊二烯基氯化钌(II)、氯(茚基)双(三苯基膦)合钌(II)、五甲基环戊二烯基双(三苯基膦)氯化钌(II)、二氯二羰基双(三苯基膦)钌、二氯双[(2-丙基膦)乙基胺]钌(II)、三(三苯基膦)羰基氢氯化钌(II)，或其组合。
在本发明的另一优选例中，“取代”指芳基或苄基上的一个或多个氢原子可任选地被1～8个碳的烷基、1～8个碳的卤代烷基、1～8个碳的烷氧基、1～8个碳的环烷基、6～10个碳的芳基、苄基或卤素所取代。
在本发明的另一优选例中，上述式III～VI中，R选自甲基、乙基、异丙基，叔丁基、含6～10个碳的取代的或未被取代的芳基或苄基。在本发明的另一优选例中，上述式III～VI中，R选自异丙基或叔丁基。在本发明的另一优选例中，Ar为苯基，或者为被甲基或三氟甲基取代的苯基。
在本发明的另一优选例中，所述面手性茂金属配体选自式IV或VI所示的化合物。在本发明的另一优选例中，所述钌盐选自三(三苯基膦)二氯化钌、二氯(对甲基异丙基苯基)钌(II)二聚体、苯基氯化钌(Ⅱ)二聚体。
在本发明的另一优选例中，所述催化剂选自以下结构所示的化合物：

在本发明的另一更优选例中，所述催化剂选自以下结构所示的化合物：
在本发明的另一更优选例中，所述催化剂选自以下结构所示的化合物：
在本发明的另一优选例中，所述溶剂选自甲醇、乙醇、异丙醇、丙醇、丁醇、异丁醇、丙酮、1，4-二氧六环、四氢呋喃、二氯甲烷、乙腈，甲苯、二甲苯、或组合。在本发明的另一更优选例中，所述溶剂选自甲醇、乙醇、异丙醇。
在本发明的另一优选例中，所述碱选自LiOH、NaOH、KOH、Li2CO3、Na2CO3、K2CO3、Cs2CO3、LiHCO3、NaHCO3、KHCO3、CsHCO3、Na3PO4、Na2HPO4、NaH2PO4、三乙胺、吡啶、2,6-甲基吡啶、1,8-二氮杂二环十一碳-7-烯、1,4-二氮杂二环[2.2.2]辛烷，或其组合。在本发明的另一更优选例中，所述碱选自NaOH和/或KOH。
在本发明的另一优选例中，式I所示化合物与所述碱的摩尔为1:0.1～3。在本发明的另一更优选例中，式I所示化合物与所述碱的摩尔为1:0.8～1.5。在本发明的另一更优选例中，式I所示化合物与所述碱的摩尔为1:1。
在本发明的另一优选例中，不对称催化氢化合成方法的反应温度为-20～60℃。在本发明的另一更优选例中，不对称催化氢化合成方法的反应温度为15～50℃，例如，25～35℃。
在本发明的另一优选例中，不对称催化氢化合成方法的氢气压力为1～80bar，更优选40～60bar，例如，40bar、45bar、50bar、55bar、60bar。
在本发明的另一优选例中，不对称催化氢化合成方法中反应底物与催化的摩尔比为10000:1～10:1，更优选，3000:1～100:1。
在本发明的另一优选例中，面手性二茂金属配体与钌盐反应生成催化剂的方法包括步骤：将面手性二茂金属配体与钌盐在溶剂中，在60～120℃反应，生成催化剂。在本发明的另一更优选例中，面手性二茂金属配体与钌盐反应生成催化剂的方法中反应温度为70～100℃。
在本发明的另一优选例中，面手性二茂金属配体与钌盐反应生成催化剂的方法所用溶剂选自甲醇、乙醇、异丙醇、丙醇、丁醇、异丁醇、丙酮、1，4-二氧六环、四氢呋喃、二氯甲烷、乙腈，甲苯、二甲苯、或组合。
在本发明的另一优选例中，上述式II所示化合物的不对称催化氢化合成方法包括以下步骤：
(1)所述面手性二茂钌配体与所述钌盐在溶剂中进行反应，反应完毕，对反应液进行处理分离得到催化剂；
(2)将式I所示化合物、步骤(1)得到的催化剂、碱和溶剂加入反应容器中，在氢气氛围下发生不对称氢化还原，形成式II所示化合物，
步骤(1)和(2)所用溶剂可以相同，也可以不同。
在本发明的另一优选例中，上述式II所示化合物的不对称催化氢化合成方法包括以下步骤：
(1)所述面手性二茂铁配体与所述钌盐在溶剂中进行反应生成催化剂，得到含催化剂的反应液，
(2)向步骤(1)的含催化剂的反应液中加入式I所示化合物、碱和溶剂，在氢气氛围中，式I所示化合物发生不对称氢化还原，形成式II所示化合物，
步骤(1)和(2)所用溶剂优选是相同的。
本发明另一方面提供了布立西坦的合成方法，该合成方法包括以下步骤：
(1)将上述不对称催化氢化合成方法得到的式II所示化合物进行酯化反应，得到式II-1所示化合物，
(2)II-1所示化合物进行氨基化反应得到布立西坦，反应式如下：
式II-1中，R’选自脂肪族或芳香烃基。
在另一优选例中，步骤(1)的酯化反应在甲醇或乙醇溶剂中，在氯化亚砜存在下进行。原料用量和反应温度按照此类反应的常规用量和温度，例如，在-10-0℃将氯化亚砜滴加到甲醇中，-15～-5℃搅拌0.5～1.5小时，式II所示化合物，-15～-5℃搅拌0.5～1.5小时，升温至0～10℃，搅拌1.5～3小时，TLC检测反应至反应完全。
在另一优选例中，步骤(2)的氨基化反应在质量浓度为15～28％的氨水和醇的混合溶剂中，-10～5℃通入氨气条件下进行，其中，所述醇为甲醇和/或乙醇。
本发明另一方面提供了以下结构所示的化合物在不对称催化氢化1,5-二氢吡咯-2-酮及其衍生物中的用途，其中1,5-二氢吡咯-2-酮及其衍生物加氢还原生成2-吡咯烷酮及其衍生物，

本发明的另一方面提供了以下结构所示的化合物在不对称催化氢化1,5-二氢吡咯-2-酮及其衍生物，生成2-吡咯烷酮及其衍生物中的用途，
本发明再一方面提供了用于不对称氢化还原的催化剂，其结构如下：

应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
下列附图用于说明本发明的具体实施方案，而不用于限定由权利要求书所界定的本发明范围。
图1是实施例1得到的(2S)-2-[(4R)-2-氧代-4-丙基-1-吡咯烷基]丁酸的核磁共振氢谱。
图2是实施例1得到的(2S)-2-[(4R)-2-氧代-4-丙基-1-吡咯烷基]丁酸的HPLC图谱。其中99:1dr；HPLC[DAICEL CHIRALPAK IK-H,n-hexane/EtOH/MeOH/HCOOH＝94/5/1/0.1,210nm,1.0mL/min,30℃,tR1＝13.1min(major),tR2＝16.9min(minor)]。
图3是实施例2得到的(2S)-2-[(4R)-2-氧代-4-丙基-1-吡咯烷基]丁酰胺的HPLC图谱。
具体实施方式
针对现有技术中布立西坦及其中间体制备过程中存在的缺陷，本申请发明人经过广泛而深入的研究，研发了一种新的(2S)-2-[(4R)-2-氧代-4-丙基-1-吡咯烷基]丁酸(式II所示化合物)的不对称催化氢化合成方法，该合成方法使用面手性二茂金属配体与钌盐形成的催化剂催化2S-2-(4-丙基-1,5-二氢吡咯-2-酮)丁酸(式I所示化合物)进行不对称氢化，得到的最终产物转化率高，dr值高。
催化剂的制备
面手性二茂钌配体与钌盐反应生成催化剂的方法包括将面手性二茂钌配体与钌盐在溶剂中，在60～120℃，反应4～8小时，对反应液进行处理分离得到催化剂，更优选反应温度为70～100℃，时间为5～7小时。所用溶剂包括但不局限于甲醇、乙醇、异丙醇、丙醇、丁醇、异丁醇、丙酮、1，4-二氧六环、四氢呋喃、二氯甲烷、乙腈，甲苯、二甲苯。
面手性二茂铁配体与钌盐反应生成催化剂的方法包括将面手性二茂铁配体与钌盐在溶剂中，在60～120℃，反应0.3～1小时，生成催化剂，得到含催化剂的反应液。更优选反应温度为70～100℃，时间为0.4～0.6小时。所用溶剂包括但不局限于甲醇、乙醇、异丙醇、丙醇、丁醇、异丁醇、丙酮、1，4-二氧六环、四氢呋喃、二氯甲烷、乙腈，甲苯、二甲苯。
催化剂由一个面手性二茂金属配体分子与两个钌盐形成时，面手性二茂金属配体与钌盐反应生成催化剂的反应体系中，面手性二茂金属配体与钌盐的摩尔比为1:2～3，更优选1:2～2.5。
催化剂由一个面手性二茂金属配体分子与一个钌盐形成时，面手性二茂金属配体与钌盐反应生成催化剂的反应体系中，面手性二茂金属配体与钌盐的用量摩尔比为1:1～2，更优选1:1～1.5。
式II所示化合物的不对称催化氢化合成方法
本发明中式II所示化合物的不对称催化氢化合成方法包括：在氢气氛围下，在溶剂中，式I所示化合物在面手性二茂金属配体与钌盐形成的催化剂以及碱存在下，发生不对称氢化还原，生成式II所示化合物，反应式如下所示：
面手性二茂金属配体选自如下式III或IV所示的化合物：
中R选自H、含1～8个碳的直链或支链烷基、含6～10个碳的取代的或未被取代的芳基或苄基；式VI中，Ar为含6～10个碳的取代的或未被取代的芳基。钌盐包括但不局限于三(三苯基膦)二氯化钌、二氯(对甲基异丙基苯基)钌(II)二聚体、苯基氯化钌(Ⅱ)二聚体、双(2,2'-联吡啶)二氯化钌、(1,5-环辛二烯)二氯化钌、苯基亚甲基双(三环己基磷)二氯化钌、对异丙苯基三苯基膦二氯化钌、二(三苯基膦)环戊二烯基氯化钌、氯(茚基)双(三苯基膦)合钌、五甲基环戊二烯基双(三苯基膦)氯化钌、二氯二羰基双(三苯基膦)钌、二氯双[(2-丙基膦)乙基胺]钌、三(三苯基膦)羰基氢氯化钌。较佳地，催化剂为式IV或VI所示化合物与上述钌盐形成的化合物。更佳地，催化剂为式VI所示化合物与三(三苯基膦)二氯化钌、二氯(对甲基异丙基苯基)钌二聚体或苯基氯化钌二聚体形成的催化剂。最佳地，用于本发明的催化剂的结构如下：
合成反应所用溶剂包括但不局限于甲醇、乙醇、异丙醇、丙醇、丁醇、异丁醇、丙酮、1,4-二氧六环、四氢呋喃、二氯甲烷、乙腈，甲苯、二甲苯，更优选质子性溶剂，例如甲醇、乙醇、异丙醇。合成反应所用碱包括但不局限于LiOH、NaOH、KOH、Li2CO3、Na2CO3、K2CO3、Cs2CO3、LiHCO3、NaHCO3、KHCO3、CsHCO3、Na3PO4、Na2HPO4、NaH2PO4、三乙胺、吡啶、2,6-甲基吡啶、1,8-二氮杂二环十一碳-7-烯、1,4-二氮杂二环[2.2.2]辛烷，更优选，价格便宜的无机碱，例如，NaOH、KOH。碱的用量为其与催化底物的摩尔比优选为0.1～3:1，更优选为0.8～1.5:1。不对称氢化的反应温度优选为-20～60℃，更优选为15～50℃，反应过程中的氢气压力优选为1～80bar，更优选为40～60bar。催化剂的用量没有特别限定，只要能明显促进不对称催化氢化反应即可，从实际实验的效率和成本角度考虑，反应底物与催化剂的摩尔比可以为10000:1～10:1，较佳地，3000:1～100:1，更较佳地，2000:1～100:1，例如2000:1、1500:1、1000:1、500:1、100:1。
本发明的(2S)-2-[(4R)-2-氧代-4-丙基-1-吡咯烷基]丁酸的不对称催化氢化合成方法中，所用催化剂可以在氢化反应前预先由面手性二茂金属配体与钌盐反应生成，并分离纯化，用于式I所示化合物的不对称氢化催化，也可以将式I所示化合物加入到含手性二茂金属配体与钌盐反应生成的催化剂的反应体系中，原位进行不对称氢化催化反应(得到的催化剂不进行分离纯化)，即，面手性二茂金属配体与钌盐反应制备催化剂的与底物的不对称氢化可通过“一锅法”进行。此处，“一锅法”是指两步反应中，第一步反应得到的产品不需要纯化，直接在第一步反应得到的反应液中加入第二步反应的原料、其他添加剂和溶剂。
本发明的描述中，术语，“取代”指基团上的一个或多个氢原子可任选地被烷基、卤代烷基(例如，三氟甲基)、烷氧基、环烷基、芳基、苄基或卤素(例如，氟、氯、溴、碘)所取代。更佳地“取代”指芳基或苄基上的一个或多个氢原子可任选地被1～8个碳的烷基、1～8个碳的卤代烷基、1～8个碳的烷氧基、1～8个碳的环烷基、6～10个碳的芳基、苄基或卤素所取代。
术语“芳基”指单环或双环烃环体系，所述烃环体系含有至少一个不饱和芳香环。例如，苯基、萘基、吲哚基、茚基等。
相对于现有技术，本发明的优势效果在于：
1.本发明的不对称催化氢化合成方法所用的催化剂的催化效果好，尤其是利用面手性二茂钌配体和钌盐形成的催化剂时，底物转化率高，立体选择性好，dr值高；
2.所用的催化剂的成本比现有技术中常用钯催化剂的成本低。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
本发明所用试剂，原料如未特别说明，均市售可得。
下列实施例1～34所用催化剂，以及用于形成该催化剂的面手性二茂金属配体和钌盐见表1。
表1





下列实施例中所用的原料，例如式I所示化合物的ee值大于99％。
实施例1：
1.1催化剂的制备典型操作
配体VI-1(69.5mg)和三(三苯基膦)二氯化钌(156.8mg)溶于甲苯(25mL)中，在90℃条件下加热搅拌6h。冷却至室温，减压除去溶剂，柱层析分离[洗脱剂:V(石油醚)∶V(乙酸乙酯)＝5∶1]，得到深绿色固体(136.0mg,96.8％)，即，催化剂1。
催化剂1的核磁共振氢谱的结果如下：
1H NMR(500MHz,CDCl3)δ:7.66-6.75(m,50H),5.60-5.50(m,2H),5.43(s,2H),4.93(t,J＝10.0Hz,2H),4.70-4.63(m,2H),4.45(s,2H),4.40(t,J＝9.0Hz,2H),0.79(s,18H)；31PNMR(162MHz,CDCl3)δ:67.53,42.63。
1.2(2S)-2-[(4R)-2-氧代-4-丙基-1-吡咯烷基]丁酸的制备
将式I所示化合物(1.0g,4.7mmol)、NaOH(0.2g,5.2mmol,1.1equiv)和催化剂1(4.1mg,2.35μmol,0.05mol％)依次加入装有磁性搅拌子的50mL干燥圆底烧瓶中。抽真空置换氮气后加入脱气的异丙醇(10mL)，搅拌均匀(溶液呈绿色)后将圆底烧瓶置于氢化反应釜中。氢气置换釜内气体三次后加入氢气至压力为50bar。反应于35℃油浴中搅拌48小时后，冷却至室温，缓慢释放氢气，减压蒸发溶剂，加入水(10mL)稀释后用稀盐酸调至pH＝1，乙酸乙酯萃取(20mL×3)，有机相经无水硫酸钠干燥后过滤，蒸发溶剂得到(2S)-2-[(4R)-2-氧代-4-丙基-1-吡咯烷基]丁酸粗品(>1.0g,dr值大于99:1)。
粗品利用甲基叔丁基醚:环己烷(体积比为1:5)重结晶纯化，得到纯品。纯品的核磁共振氢谱如下：
1H NMR(400MHz,CDCl3)δ:4.63(dd,J＝10.8,5.2Hz,1H),3.44(dd,J＝9.4,7.8Hz,1H),3.18(dd,J＝9.4,7.2Hz,1H),2.60(dd,J＝16.8,8.4Hz,1H),2.42-2.28(m,1H),2.17(dd,J＝16.8,8.4Hz,1H),2.11-1.99(m,1H),1.79-1.65(m,1H),1.51-1.43(m,2H),1.39-1.29(m,2H),0.98-0.88(m,6H)。
粗品进行HPLC检测，HPLC信息如下：
[DAICEL CHIRALPAK IK-Hcolumn,n-hexane/EtOH/MeOH/HCOOH＝94/5/1/0.1,210nm,1.0mL/min,30℃,tR1＝13.1min(major),tR2＝16.9min(minor)],dr>99:1。
实施例2：
(2S)-2-[(4R)-2-氧代-4-丙基-1-吡咯烷基]丁酰胺的制备
将2S-2-(4-丙基-1,5-二氢吡咯-2-酮)丁酰胺(1.0g,4.7mmol,ee大于99％)、Cs2CO3(3.1g,9.4mmol,2.0equiv)和催化剂1(4.1mg,2.35μmol,0.05mol％)依次加入装有磁性搅拌子的50mL干燥圆底烧瓶中。抽真空置换氮气后加入脱气的异丙醇(10mL)，搅拌均匀(溶液呈绿色)后将圆底烧瓶置于氢化反应釜中。氢气置换釜内气体三次后加入氢气至压力为40bar。在室温下搅拌48小时后，反应液冷却至室温，缓慢释放氢气，减压蒸发溶剂，加入水(10mL)稀释后用稀盐酸调至pH＝1，乙酸乙酯萃取(20mL×3)，有机相经无水硫酸钠干燥后过滤，蒸发溶剂得到残留物(底物转化率为>99％conv.,>1.0g,dr值为1.2:1)。
上述残留物经手性柱分离得到(2S)-2-[(4R)-2-氧代-4-丙基-1-吡咯烷基]丁酰胺。其核磁共振氢谱如下：
1H NMR(400MHz,CDCl3)δ:6.44(s,1H),5.78(s,1H),4.45-4.42(m,1H),3.49(dd,J＝9.6,7.6Hz,1H),3.05(dd,J＝9.6,6.8Hz,1H),2.55(dd,J＝16.8,8.4Hz,1H),2.40-2.28(m,1H),2.12-2.07(m,1H),1.99-1.88(m,1H),1.73-1.62(m,1H),1.46-1.38(m,2H),1.37-1.29(m,2H),0.95-0.86(m,6H)。
粗品进行HPLC检测，结果参见图3。
实施例3
3.1催化剂的制备
在50mL的二口瓶中加入Ru(II)Cl2(PPh3)3(4.5mg,0.1mol％)，配体V-1(2.3mg,0.06mol％)，氮气氛下加入异丙醇(5mL)。液氮冷冻抽真空换氮气三次，然后回流0.5h，在此过程中，棕色不溶物渐渐地溶解形成均一溶液，得到催化剂3。
3.2式II所示化合物的制备
向上述含催化剂3的反应体系中加入式I所示化合物(1.0g,4.7mmol)、NaOH(0.2g,5.2mmol,1.1equiv)，和脱气的异丙醇(10mL)，搅拌均匀后，将圆底烧瓶置于氢化反应釜中。氢气置换釜内气体三次后加入氢气至压力为50bar。反应于50℃油浴中搅拌48小时后，冷却至室温，缓慢释放氢气，减压蒸发溶剂，加入水(10mL)稀释后用稀盐酸调至pH＝1，乙酸乙酯萃取(20mL×3)，有机相经无水硫酸钠干燥后过滤，蒸发溶剂得到式II所示化合物粗品(底物转化率为>1.0g，dr值为7:1)。
粗品进行HPLC检测，HPLC信息如下：
[DAICEL CHIRALPAK IK-Hcolumn,n-hexane/EtOH/MeOH/HCOOH＝94/5/1/0.1,210nm,1.0mL/min,30℃,tR1＝13.1min(major),tR2＝16.9min(minor)],dr约为7:1。
实施例4～33
下列实施例4～33中所用的面手性二茂钌配体与钌盐形成的催化剂的制备方法与实施例1类似(配体与钌盐的摩尔比根据催化剂结构中的两种的分子数比例进行调整)，这些催化剂按照实施例1的类似方式催化式I所示化合物进行氢化。所用的面手性二茂铁配体与钌盐形成的催化剂的制备方法与实施例3类似，(配体与钌盐的摩尔比根据催化剂结构中的两种的分子数比例进行调整)，这些催化剂按照实施例3的类似方式催化式I所示化合物进行氢化。
催化剂5的制备典型操作
配体IV-1(540mg)和三(三苯基膦)二氯化钌(1054mg)溶于甲苯(25mL)中，在90℃条件下加热搅拌6h。冷却至室温，减压除去溶剂，柱层析分离[洗脱剂:V(石油醚)∶V(乙酸乙酯)＝5∶1]，得到深绿色固体(935mg,95％yield)，即，催化剂5。
催化剂5按照实施例1的类似方式催化式I所示化合物进行氢化。
催化剂12的制备典型操作
在50mL的二口瓶中加入Ru(II)Cl2(PPh3)3(4.5mg,0.1mol％)，配体III-1(2.3mg,0.1mol％)，氮气氛下加入异丙醇(2mL)。液氮冷冻抽真空换氮气三次，然后回流0.5h，在此过程中，棕色不溶物渐渐地溶解形成均一溶液，得到含催化剂12的溶液。
催化剂12按照实施例3的类似方式催化式I所示化合物进行氢化。
下列实施例4～33中所用催化剂与反应结果见下表2，其中底物(式I所示化合物)与催化剂的摩尔比约为2000:1(表2中的dr值均为粗品的dr值)。
表2

上述实施例4～35可以看出，面手性二茂钌配体与钌盐形成的催化剂比面手性二茂铁配体与钌盐形成的催化剂选择性催化效果更好。
实施例36～71
以催化剂1为催化剂催化式I所示化合物进行不对称氢化，对催化还原的温度、时间，氢气压力、溶剂等进行了筛选。
下列实施例36～71利用催化剂1不对称催化氢化式I所示化合物合成式II所示化合物，其中底物与催化剂的摩尔比约为2000:1，所用溶剂、碱、反应体系温度(溶剂温度)、氢气压力、反应时间以及反应结果(底物转化率、dr值)见下表3(表3中的dr值均为粗品的dr值)。
表3

从上述实施例36～71可以看出，催化剂1在无机碱作为碱，醇作为反应溶剂，约35℃的温度和约50bar的氢气压力下反应约48小时，选择性催化效果较好。
实施例72～77
(2S)-2-[(4R)-2-氧代-4-丙基-1-吡咯烷基]丁酸的制备
实施例72～77的制备按照实施例1中1.2的记载，不同之处仅在于底物(式I所示化合物)与催化剂(催化剂1)的摩尔比例不同。底物与催化剂的具体摩尔比以及反应结果见下表4。
表4
从上述实施例60～65可以看出，催化剂1在NaOH作为碱，异丙醇为反应溶剂，35℃的温度和50bar的氢气压力下反应48小时，底物与催化剂的摩尔比为10000:1时也可以达到84％的转化率，两者摩尔比大于1000:1以后，转化率没有明显增加。另外，实际实验过程中发现只要适当延长反应足够的时间，底物与催化剂的摩尔比为10000:1时也能达到完全转化以及优异的dr值，且该比例仍可以进一步上升。但从合成成本考虑，底物与催化剂的摩尔比优选2000～100:1。
实施例78
从式II所示化合物合成布立西坦
酯化反应：向反应瓶中加入33mL甲醇，氮气保护，降温至-10℃，加入1.8g氯化亚砜，控温-10-0℃滴加完毕，加入2.2g式II所示化合物，-5℃～0℃反应3小时，TLC检测至反应完全，浓缩至干，加入乙酸乙酯和水，碳酸钠水溶液调节pH＝6～8，分液，有机相用无水硫酸镁干燥，过滤，滤液浓缩至干，得到2.5g黄色油状物，即，(2S)-2-[(4R)-2-氧代-4-丙基-1-吡咯烷基]丁酸甲酯。质量收率113.63％。HPLC纯度为98.22％。
氨化反应：向反应瓶中加入25mL浓氨水，加入2.5mL乙醇，降温至0℃，加入2.5g上述黄色油状物至完全溶解，-5～0℃通入氨气氨化，TLC反应完成后，加入乙酸乙酯和水，并用盐酸调节体系pH＝6～8，分出有机相。有机相利用无水硫酸镁干燥，过滤，滤液浓缩至干，异丙醚精制得布立西坦2.2g。质量收率88％。HPLC纯度为100％，光学纯度为99.93％。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (17)

  1. 一种式II所示化合物的不对称催化氢化合成方法，其特征在于，所述合成方法包括步骤：在氢气氛围下，在溶剂中，式I所示化合物在面手性二茂金属配体与钌盐形成的催化剂以及碱存在下，进行不对称氢化还原，形成式II所示化合物，反应式如下所示：
    所述面手性二茂金属配体选自如下式III～VI所示的化合物：
    式III～VI中，R选自H、含1～8个碳的直链或支链烷基、含1～8个碳的环烷基、含6～10个碳的取代的或未被取代的芳基或苄基，式VI中，Ar为含6～10个碳的取代的或未被取代的芳基，“取代”指芳基或苄基上的一个或多个氢原子可任选地被烷基、卤代烷基、烷氧基、环烷基、芳基、苄基或卤素所取代，
    所述钌盐选自三(三苯基膦)二氯化钌、二氯(对甲基异丙基苯基)钌(II)二聚体、苯基氯化钌(Ⅱ)二聚体、双(2,2'-联吡啶)二氯化钌、(1,5-环辛二烯)二氯化钌、苯基亚甲基双(三环己基磷)二氯化钌、对异丙苯基三苯基膦二氯化钌、二(三苯基膦)环戊二烯基氯化钌、氯(茚基)双(三苯基膦)合钌、五甲基环戊二烯基双(三苯基膦)氯化钌、二氯二羰基双(三苯基膦)钌、二氯双[(2-丙基膦)乙基胺]钌、三(三苯基膦)羰基氢氯化钌，或其组合。
  2. 根据权利要求1所述的不对称催化氢化合成方法，其特征在于，式III～VI中，R选自甲基、乙基、异丙基，叔丁基、含6～10个碳的取代的或未被取代的芳基或苄基，更优选异丙基或叔丁基，和/或
    式VI中，Ar为苯基，或者为被甲基或三氟甲基取代的苯基。
  3. 根据权利要求1所述的不对称催化氢化合成方法，其特征在于，所述面手性二茂金属配体选自式IV或VI所示的化合物，其中R选自甲基、乙基、异丙基，叔丁基、含6～10个碳的芳基或苄基，和/或
    所述钌盐选自三(三苯基膦)二氯化钌、二氯(对甲基异丙基苯基)钌二聚体、苯基氯化钌二聚体。
  4. 根据权利要求1或2所述的不对称催化氢化合成方法，其特征在于，所述催化剂选自以下结构所示的化合物：

  5. 根据权利要求4所述的不对称催化氢化合成方法，其特征在于，所述催化剂选自以下结构所示的化合物：
  6. 根据权利要求5所述的不对称催化氢化合成方法，其特征在于，所述催化剂选自以下结构所示的化合物：
  7. 根据权利要求1至4任一项所述的不对称催化氢化合成方法，其特征在于，所述溶剂选自甲醇、乙醇、异丙醇、丙醇、丁醇、异丁醇、丙酮、1，4-二氧六环、四氢呋喃、二氯甲烷、乙腈，甲苯、二甲苯、或组合，和/或
    所述碱选自LiOH、NaOH、KOH、Li2CO3、Na2CO3、K2CO3、Cs2CO3、LiHCO3、NaHCO3、KHCO3、CsHCO3、Na3PO4、Na2HPO4、NaH2PO4、三乙胺、吡啶、2,6-甲基吡啶、1,8-二氮杂二环十一碳-7-烯、1,4-二氮杂二环[2.2.2]辛烷，或其组合，更优选NaOH和/或KOH；和/或
    式I所示化合物与所述碱的摩尔为1:0.1～3。
  8. 根据权利要求1至4任一项所述的不对称催化氢化合成方法，其特征在于，所述不对称催化氢化合成方法的反应温度为-20～60℃，和/或
    所述不对称催化氢化合成方法的氢气压力为1～80bar，和/或
    所述不对称催化氢化合成方法中反应底物与催化的摩尔比为10000:1～10:1。
  9. 根据权利要求8所述的不对称催化氢化合成方法，其特征在于，
    所述不对称催化氢化合成方法的反应温度为15～50℃，和/或
    所述不对称催化氢化合成方法的氢气压力为40～60bar，和/或
    所述不对称催化氢化合成方法中反应底物与催化的摩尔比为3000:1～100:1。
  10. 根据权利要求1至4任一项所述的不对称催化氢化合成方法，其特征在于，所述面手性二茂金属配体与所述钌盐反应生成催化剂的方法包括步骤：将面手性茂金属配体与钌盐在溶剂中，在60～120℃反应，生成催化剂，
    优选地，所述面手性二茂金属配体与所述钌盐反应所用溶剂选自甲醇、乙醇、异丙醇、丙醇、丁醇、异丁醇、丙酮、1，4-二氧六环、四氢呋喃、二氯甲烷、乙腈，甲苯、二甲苯，或组合。
  11. 根据权利要求10所述的不对称催化氢化合成方法，其特征在于，所述不对称催化氢化合成方法包括以下步骤：
    (1)所述面手性二茂钌配体与所述钌盐在溶剂中进行反应，反应完毕，对反应液进行处理分离得到催化剂；
    (2)将式I所示化合物、步骤(1)得到的催化剂、碱和溶剂加入反应容器中，在氢气氛围下发生不对称氢化还原，形成式II所示化合物，
    步骤(1)和(2)所用溶剂可以相同，也可以不同。
  12. 根据权利要求10所述的不对称催化氢化合成方法，其特征在于，所述不对称催化氢化合成方法包括以下步骤：
    (1)所述面手性二茂铁配体与所述钌盐在溶剂中进行反应生成催化剂，得到含催化剂的反应液，
    (2)向步骤(1)的含催化剂的反应液中加入式I所示化合物、碱和溶剂，在氢气氛围中，式I所示化合物发生不对称氢化还原，形成式II所示化合物，
    步骤(1)和(2)所用溶剂优选是相同的。
  13. 布立西坦的合成方法，其特征在于，所述合成方法包括以下步骤：
    (1)将权利要求1至12任一项所述的不对称催化氢化合成方法得到的式II所示化合物进行酯化反应，合成式II-1所示化合物，
    (2)II-1所示化合物进行氨基化反应合成布立西坦，反应式如下：
    式II-1中，R’选自脂肪烃基或芳香烃基。
  14. 根据权利要求11所述的合成方法，其特征在于，步骤(1)的酯化反应在甲醇或乙醇溶剂中，在氯化亚砜存在下进行，和/或
    步骤(2)的氨基化反应在质量浓度为15-28％的氨水和醇的混合溶剂中，-10～5℃通入氨气条件下进行，其中，所述醇为甲醇和/或乙醇。
  15. 以下结构所示的化合物在不对称催化氢化1,5-二氢吡咯-2-酮及其衍生物中的用途，其中1,5-二氢吡咯-2-酮及其衍生物加氢还原生成2-吡咯烷酮及其衍生物，

  16. 以下结构所示的化合物在不对称催化氢化1,5-二氢吡咯-2-酮及其衍生物中的用途，其中1,5-二氢吡咯-2-酮及其衍生物加氢还原生成2-吡咯烷酮及其衍生物，
  17. 用于不对称氢化还原的催化剂，其结构如下：

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