WO2020168510A1 - Procédé de préparation de butyrolactone chirale - Google Patents

Procédé de préparation de butyrolactone chirale Download PDF

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WO2020168510A1
WO2020168510A1 PCT/CN2019/075688 CN2019075688W WO2020168510A1 WO 2020168510 A1 WO2020168510 A1 WO 2020168510A1 CN 2019075688 W CN2019075688 W CN 2019075688W WO 2020168510 A1 WO2020168510 A1 WO 2020168510A1
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compound
reaction
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preparation
inert solvent
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PCT/CN2019/075688
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郭朋
朱文峰
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上海博璞诺科技发展有限公司
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Publication of WO2020168510A1 publication Critical patent/WO2020168510A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form

Definitions

  • This application belongs to the field of medicinal chemistry, and specifically relates to a preparation method of the chiral butyrolactone intermediate of Buwaxitan.
  • Brivaracetam the chemical name is (S)-2-(R)-3-propylpyrrolidin-1-ylbutanamide.
  • Buwaxitan is a third-generation anti-epileptic drug newly developed by the Belgian pharmaceutical giant (UCB). This drug can exert anti-epileptic effects by combining with synaptic vesicle protein 2A (SV2A). The results of clinical trials have shown that Buwaxitan can significantly reduce the frequency of partial seizures and improve the response rate. It has extensive anti-epileptic activity and high safety.
  • Buwaxitan API There are two chiral centers in the Buwaxitan structure, which is difficult to synthesize.
  • the Buwaxitan API can be obtained by simple synthesis in 2 to 3 steps.
  • (S)-2-Aminobutanamide is the main raw material of the marketed drug levetiracetam, and the market supply is sufficient. Therefore, chiral butyrolactone (I) has become a key intermediate in the synthesis of Buwaxitan.
  • WO2016191435 discloses a synthetic method for preparing optically pure Buwaxitan, wherein the chirality of the n-propyl group on the butyrolactone is introduced by using chiral epichlorohydrin as a starting material, and the route cost is relatively low.
  • the chiral epoxy raw materials have two reaction sites, the synthesis of a five-membered ring and a three-membered ring requires strict control of the chirality; the entire route requires two high vacuum distillation operations. Therefore, there are certain difficulties in the actual enlargement of the route.
  • Huasheng Pharmaceutical discloses a synthetic method for preparing chiral butyrolactone intermediate I (CN107827844).
  • the highly toxic sodium cyanide and the relatively expensive titanium triisopropoxy chloride are used in the route, and the route is not of high industrial value.
  • Ma Liang et al. (CN108503610) used a chiral auxiliary method to construct a butyrolactone chiral center, but other reaction steps used metal oxidation, and the atom utilization rate was not high.
  • Liu Xingxin et al. (CN107216276) also used a chiral auxiliary method to construct a butyrolactone chiral center, which also has the problem of low atom utilization and complicated steps.
  • the purpose of the present invention is to provide a method for synthesizing chiral butyrolactone (I) with high yield, simple method, high chiral purity, low production cost and suitable for industrial production.
  • the first aspect of the present invention provides a method for preparing chiral butyrolactone represented by formula (I), the method comprising the steps:
  • L is a C 1-4 alkyl sulfonate group or a halogenated C 1-4 alkyl sulfonate group; R is a C 1-6 alkyl group.
  • R is methyl, ethyl, propyl, isopropyl or tert-butyl.
  • L is a triflate group.
  • the ethyl Grignard reagent is ethyl magnesium bromide or ethyl magnesium chloride.
  • reaction molar ratio of the compound (II) and the ethyl Grignard reagent is 1: (1 to 2.0); preferably 1: (1.2 to 1.6).
  • the catalyst in step (1), is cuprous iodide, ketone bromide, cuprous cyanide or ketone dimethyl sulfide bromide.
  • step (1) the reaction molar ratio of the compound (II) and the catalyst is 1:(0.01-0.2); preferably 1:(0.05-0.15).
  • the reaction temperature is -80 to 0°C; preferably -78 to -60°C or -40 to -20°C.
  • the reaction time is 0.5 to 5 hours.
  • the inert solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and toluene.
  • step (1) in an inert solvent, first add compound (II) and a catalyst, and then add (preferably dropwise) a solution of ethyl Grignard reagent, and then perform a ring-opening reaction to form Compound (III).
  • the reaction temperature is -78 to -60°C.
  • step (1) in an inert solvent, first add a solution of ethyl Grignard reagent and a catalyst, and then add (preferably dropwise) compound (II), and then perform a ring-opening reaction to form Compound (III).
  • the reaction temperature is -40 to -20°C.
  • step (1) after the ring-opening reaction is completed, the reaction mixture is quenched, separated, extracted and concentrated to obtain compound (III), which is directly used in the next reaction.
  • step (1) after the ring-opening reaction is completed, a saturated aqueous ammonium chloride solution is added dropwise to the reaction mixture, and an organic solvent (such as methyl tert-butyl ether, petroleum ether, etc.) is used for the aqueous phase. ) Extraction, the organic phase is washed with water, dried and concentrated to obtain compound (III), which is directly used in the next reaction.
  • an organic solvent such as methyl tert-butyl ether, petroleum ether, etc.
  • step (2) in an inert solvent, first add compound (III) and a base; then add (preferably dropwise) a sulfonylation reagent for sulfonylation reaction, thereby forming compound (IV) Or a mixture containing compound (IV).
  • step (2) first dissolve compound (III) in an inert solution, and then add a base and a sulfonylation reagent in sequence.
  • step (2) the reaction molar ratio of compound (III) to the sulfonylating reagent is 1:(1 to 1.2).
  • step (2) the reaction molar ratio of compound (III) and base is 1:(1 ⁇ 1.5).
  • the reaction temperature is -20 to 30°C; preferably -10 to 0°C.
  • reaction time is 1 to 24 hours; preferably 1 to 2 hours.
  • the base is one or more of triethylamine, pyridine, diisopropylethylamine, and 4-dimethylaminopyridine (DMAP).
  • the inert solvent is one of dichloromethane, ethyl acetate, dichloroethane, isopropyl acetate, tetrahydrofuran, methyl tert-butyl ether or Many kinds.
  • step (2) after the sulfonylation reaction is completed, the reaction mixture is filtered to obtain a filtrate containing compound (IV), and the filtrate is directly used in the next reaction.
  • the sulfonylation reagent is selected from the group consisting of C 1-4 alkyl sulfonate chloride, halogenated C 1-4 alkyl sulfonate chloride, C 1- 4 alkyl sulfonic anhydride, halogenated C 1-4 alkyl sulfonic anhydride, or a combination thereof.
  • the sulfonylation reagent is selected from the group consisting of trifluoromethanesulfonic acid chloride, trifluoromethanesulfonic anhydride or a combination thereof.
  • the alkaline conditions are conditions in the presence of organic bases.
  • the organic base is one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.
  • the acidic conditions are conditions in which an acidic solution exists.
  • the acidic solution is one or more of sulfuric acid solution, hydrochloric acid solution, phosphoric acid solution, and trifluoroacetic acid solution.
  • the acidic solution is an acidic aqueous solution.
  • step (3) the time for carrying out the substitution reaction under alkaline conditions is 2-24 hours; preferably 10-14 hours.
  • the temperature for the substitution reaction under alkaline conditions is 0 to 70°C; preferably 0 to 5°C.
  • the time for the ring-closure reaction under acidic conditions is 12 to 36 hours; preferably 20 to 25 hours.
  • the temperature for the ring closure reaction under acidic conditions is 80-100°C; preferably 90-100°C.
  • the inert solvent is ethylene glycol dimethyl ether or tetrahydrofuran.
  • step (3) the reaction molar ratio of the compound (IV) to the compound (V) is 1: (1 to 1.2).
  • step (3) after the ring-closure reaction is completed, the reaction mixture is extracted (for example, with an organic solvent such as methylene chloride), and the organic phase is washed with water, dried and concentrated to obtain compound (I) Crude product: The crude product is distilled under reduced pressure to obtain pure compound (I).
  • step (3) the filtrate containing compound (IV) obtained in step (2) is reacted with compound (V) in an inert solvent under alkaline conditions for substitution reaction; After completion, the reaction mixture is subjected to a ring-closure reaction under acidic conditions, thereby forming compound (I).
  • step (3) the organic base and compound (V) are first added to an inert solvent, and then compound (IV) or a mixture containing compound (IV) is added (preferably dropwise) to perform substitution reaction ; After the substitution reaction is over, an acidic solution is added to carry out a ring-closure reaction to form compound (I).
  • step (3) the organic base and compound (V) are first added to the inert solvent, and then (preferably added dropwise) the filtrate containing compound (IV) obtained in step (2) is added for substitution.
  • the time for the substitution reaction is 2-24 hours; preferably 10-14 hours.
  • the temperature of the substitution reaction is 0-30°C; preferably 0-5°C.
  • the time for the ring closure reaction is 12 to 36 hours; preferably 20 to 25 hours.
  • the temperature of the ring closure reaction is 80-100°C; preferably 90-100°C.
  • the organic base is one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.
  • the acidic solution is one or more of sulfuric acid solution, hydrochloric acid solution, phosphoric acid solution, and trifluoroacetic acid solution.
  • the acidic solution is an acidic aqueous solution.
  • the present invention provides a new method for preparing chiral butyrolactone (I), an intermediate compound of Buwaxitan.
  • the raw materials used are cheap and easily available, the synthesis route is short, the operation is simple, the reaction process is safe and environmentally friendly, the chirality retention performance is good, and the overall process is very suitable for industrial production.
  • the inventor unexpectedly discovered a method for preparing chiral butyrolactone (I), an intermediate of Buwaxitan.
  • the method uses (R)-2-(tert-butoxymethyl) oxirane Alkane (compound (II)) is used as a raw material, and high-purity chiral butyrolactone (I) is obtained through ring opening, sulfonylation, substitution and ring closing reactions.
  • Each step of the reaction involved in the method has simple operation and simple post-treatment, and finally high-purity chiral butyrolactone (I) can be obtained in a higher yield.
  • the entire route is very conducive to industrial amplification. On this basis, the present invention has been completed.
  • C 1-6 alkyl means a linear or branched alkyl group having 1 to 6 carbon atoms.
  • C 1-4 alkyl means a straight or branched alkyl group having 1 to 4 carbon atoms. For example, but not limited to, methyl, ethyl, propyl, isopropyl, tert-butyl, etc.
  • halo refers to iodo, bromo, chloro or fluoro.
  • the "halogenation” can be monohalogenation, polyhalogenation (such as dihalogenation, trihalogenation, etc.) or perhalogenation (that is, all hydrogen atoms of the group are replaced by halogen atoms).
  • halogen atom refers to an iodine atom, a bromine atom, a chlorine atom, or a fluorine atom.
  • the chiral butyrolactone an intermediate of Buwaxitan of the present invention, is named (R)-4-n-propyl-dihydro-3H-furan-2-one, and its structure is as shown in formula (I). It can be represented by formula (I'), and formula (I) and formula (I') can be used interchangeably.
  • the chiral center exists in the R configuration, and the R configuration is determined according to the rules described in Pure. Appl. Chem. 45 (1976) 11-30.
  • the present invention provides an intermediate compound for preparing chiral butyrolactone (I), the structure of which is shown in formula (A).
  • R 1 is hydrogen, C 1-4 alkylsulfonyl or halogenated C 1-4 alkylsulfonyl.
  • the intermediate compound is compound (III);
  • the intermediate compound is compound (IV);
  • L is a C 1-4 alkylsulfonate group or a halogenated C 1-4 alkylsulfonate group.
  • the present invention provides a method for preparing compound (III), which includes step (1).
  • Step (1) At a certain temperature (for example -80 ⁇ 0°C; preferably -78 ⁇ -60°C or -40 ⁇ -20°C), in an inert solvent, in an ethyl Grignard reagent (for example, ethyl bromide In the presence of magnesium or ethyl magnesium chloride) and a catalyst (such as cuprous iodide, ketone bromide, cuprous cyanide or ketone dimethyl sulfide bromide), compound (II) is subjected to a ring-opening reaction for a period of time (such as 0.5 to 5 hours), thereby forming compound (III);
  • a certain temperature for example -80 ⁇ 0°C; preferably -78 ⁇ -60°C or -40 ⁇ -20°C
  • an ethyl Grignard reagent for example, ethyl bromide In the presence of magnesium or ethyl magnesium chloride
  • a catalyst such as cuprous iodide, ketone
  • reaction molar ratio of the compound (II) and the ethyl Grignard reagent is 1: (1 to 2.0); preferably 1: (1.2 to 1.6).
  • step (1) the reaction molar ratio of the compound (II) and the catalyst is 1:(0.01-0.2); preferably 1:(0.05-0.15).
  • the inert solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and toluene.
  • the inert solvent is preferably an anhydrous solvent.
  • step (1) in an inert solvent, first add compound (II) and a catalyst, and then add (preferably dropwise) a solution of ethyl Grignard reagent, and then perform a ring-opening reaction to form Compound (III).
  • the reaction temperature is -78 to -60°C.
  • step (1) in an inert solvent, first add a solution of ethyl Grignard reagent and a catalyst, and then add (preferably dropwise) compound (II), and then perform a ring-opening reaction to form Compound (III).
  • the reaction temperature is -40 to -20°C.
  • step (1) after the ring-opening reaction is completed, the reaction mixture is quenched, separated, extracted and concentrated to obtain compound (III), which is directly used in the next reaction.
  • step (1) after the ring-opening reaction is completed, a saturated aqueous ammonium chloride solution is added dropwise to the reaction mixture, and an organic solvent (such as methyl tert-butyl ether, petroleum ether, etc.) is used for the aqueous phase. ) Extraction, the organic phase is washed with water, dried and concentrated to obtain compound (III), which is directly used in the next reaction.
  • an organic solvent such as methyl tert-butyl ether, petroleum ether, etc.
  • the present invention provides a method for preparing compound (IV), which includes step (2).
  • Step (2) At a certain temperature (for example, -20 ⁇ 30°C; preferably -10 ⁇ 0°C), in an inert solvent, in the presence of a base, the compound (III) is subjected to a sulfonylation reaction with a sulfonylation reagent A period of time (for example, 1 to 24 hours; preferably 1 to 2 hours) to form compound (IV) or a mixture containing compound (IV);
  • a certain temperature for example, -20 ⁇ 30°C; preferably -10 ⁇ 0°C
  • a sulfonylation reagent A period of time (for example, 1 to 24 hours; preferably 1 to 2 hours) to form compound (IV) or a mixture containing compound (IV);
  • L is a C 1-4 alkylsulfonate group or a halogenated C 1-4 alkylsulfonate group.
  • the base is an organic base (for example, one or more of triethylamine, pyridine, diisopropylethylamine, 4-dimethylaminopyridine (DMAP) ).
  • organic base for example, one or more of triethylamine, pyridine, diisopropylethylamine, 4-dimethylaminopyridine (DMAP) ).
  • step (2) in an inert solvent, first add compound (III) and a base; then add (preferably dropwise) a sulfonylation reagent for sulfonylation reaction, thereby forming compound (IV) Or a mixture containing compound (IV).
  • step (2) first dissolve compound (III) in an inert solution, and then add a base and a sulfonylating reagent in sequence.
  • step (2) the reaction molar ratio of compound (III) to the sulfonylating reagent is 1:(1 to 1.2).
  • step (2) the reaction molar ratio of compound (III) and base is 1:(1 ⁇ 1.5).
  • the inert solvent is one of dichloromethane, ethyl acetate, dichloroethane, isopropyl acetate, tetrahydrofuran, methyl tert-butyl ether or Many kinds.
  • the mixture containing compound (IV) may be a filtrate containing compound (IV).
  • step (2) after the sulfonylation reaction is completed, the reaction mixture is filtered to obtain a filtrate containing compound (IV), and the filtrate is directly used in the next reaction.
  • the sulfonylation reagent is selected from the group consisting of C 1-4 alkyl sulfonate chloride, halogenated C 1-4 alkyl sulfonate chloride, C 1- 4 alkyl sulfonic anhydride, halogenated C 1-4 alkyl sulfonic anhydride, or a combination thereof.
  • the sulfonylation reagent is selected from the group consisting of trifluoromethanesulfonic acid chloride, trifluoromethanesulfonic anhydride or a combination thereof.
  • the present invention provides a preparation method of chiral butyrolactone, which comprises step (3).
  • Step (3) At a certain temperature (for example, 0 ⁇ 70°C; preferably 0 ⁇ 5°C), in an inert solvent, under alkaline conditions, compound (IV) or a mixture containing compound (IV) and compound (V)
  • the reaction proceeds for a period of time (for example, 2-24 hours; preferably 10-14 hours); after the completion of the substitution reaction, the reaction mixture is heated at a certain temperature (for example, 80-100°C; preferably 90-100°C) Carry out the ring closure reaction for a period of time (for example, 12 to 36 hours; preferably 20 to 25 hours) under acidic conditions to form compound (I);
  • L is a C 1-4 alkylsulfonate group or a halogenated C 1-4 alkylsulfonate group (preferably a trifluoromethanesulfonate group);
  • R is a C 1-6 alkyl group (preferably methyl , Ethyl, propyl, isopropyl or tert-butyl).
  • the alkaline conditions are conditions in the presence of organic bases.
  • the organic base is one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.
  • the acidic conditions are conditions in which an acidic solution exists.
  • the acidic solution is one or more of sulfuric acid solution, hydrochloric acid solution, phosphoric acid solution, and trifluoroacetic acid solution.
  • the acidic solution is an acidic aqueous solution.
  • the inert solvent is ethylene glycol dimethyl ether or tetrahydrofuran.
  • step (3) the reaction molar ratio of the compound (IV) to the compound (V) is 1: (1 to 1.2).
  • step (3) after the ring-closure reaction is completed, the reaction mixture is extracted (for example, with an organic solvent such as methylene chloride), and the organic phase is washed with water, dried and concentrated to obtain compound (I) Crude product: The crude product is distilled under reduced pressure to obtain pure compound (I).
  • step (3) the filtrate containing compound (IV) obtained in step (2) is reacted with compound (V) in an inert solvent under alkaline conditions for substitution reaction; After completion, the reaction mixture is subjected to a ring-closure reaction under acidic conditions, thereby forming compound (I).
  • step (3) the organic base and compound (V) are first added to an inert solvent, and then compound (IV) or a mixture containing compound (IV) is added (preferably dropwise) to carry out the substitution reaction ; After the substitution reaction is over, an acidic solution is added to carry out a ring-closure reaction to form compound (I).
  • step (3) the organic base and compound (V) are first added to the inert solvent, and then (preferably added dropwise) the filtrate containing compound (IV) obtained in step (2) is added for substitution.
  • the method for preparing the compound (II) in the present invention can be prepared by any method known in the art.
  • the method shown in the following step (4) can also be used.
  • Step (4) At a certain temperature (for example, 0 ⁇ 35°C; preferably 10 ⁇ 30°C), in an inert solvent, in a catalyst (for example, boron trifluoride, boron trifluoride tetrahydrofuran, boron trifluoride acetonitrile) In the presence of one or more), the compound (VI) is reacted with tert-butanol for a period of time (for example, 1 to 24 hours; preferably 1 to 5 hours) to form compound (II);
  • a catalyst for example, boron trifluoride, boron trifluoride tetrahydrofuran, boron trifluoride acetonitrile
  • step (4) includes the steps: in an inert solvent, first add tert-butanol and a catalyst; then add (preferably dropwise) compound (VI) for substitution reaction, thereby forming compound (II).
  • the inert solvent is one or more of dichloromethane, dichloroethane, tetrahydrofuran, and acetonitrile.
  • step (4) after the reaction is completed, the reaction mixture is separated into layers, and the organic phase is washed with water, dried and concentrated to obtain compound (II).
  • the chiral butyrolactone prepared by the invention has high chemical purity and can be used as a pharmaceutical intermediate to prepare the drug Buwaxitan.
  • the method for preparing Buwaxitan from chiral butyrolactone can be any method known in the art.
  • the detection method of the compound of the present invention includes the following:
  • NMR spectra were recorded on a BRUKER AC 250 Fourier transform NMR spectrometer equipped with an Aspect 3000 computer and a 5mm 1 H/ 13 C dual probe.
  • the compound was studied in DMSO-d 6 (or CDCl 3 ) solution at a probe temperature of 313K. Lock the instrument on the deuterium signal of DMSO-d 6 (or CDCl 3 ).
  • the chemical shift is expressed in ppm from the magnetic field downstream of the TMS as the internal standard.
  • GC conditions Chromatographic column Agilent HP-5 (30m*320um*0.25um) detector FID temperature is 180°C, inlet temperature is 150°C, carrier gas is nitrogen, column constant flow rate is 1ml/min, split ratio is 20:1; running time is 18.83min, of which the initial temperature is 30°C, keep for 5 minutes, at a rate of 15°C/min from 30°C to 145°C, keep for 0min, at a rate of 30°C/min, from 145°C to 180 °C, keep for 5min.
  • Chiral GC conditions (Compound I): Chromatographic column Macherey-Nagel Lipodex E type (25m*250um), detector FID temperature is 220°C, inlet temperature is 200°C, carrier gas is helium, column constant pressure is 60kPa , The split ratio is 100:1; the running time is 68min, in which the initial temperature is 70°C, keep for 1 minute, and at a rate of 1°C/min from 70°C to 122°C, keep for 15min.
  • HPLC conditions Chromatographic column Agilent Eclipse plus-C18, 4.6*50mm, 5um; in 3.5 minutes, 95% 0.1% H 3 PO 4 aqueous solution and 5% acetonitrile to 5% 0.1% H 3 PO 4 aqueous solution and 95 Gradient elution of% acetonitrile, 5% 0.1% H 3 PO 4 aqueous solution and 95% acetonitrile continue to elute for 1.5 minutes.
  • the flow rate is set to 2.0 mL/min.
  • the column temperature was set at 35°C.
  • the detection wavelength is 210nm.
  • the reaction solution was extracted twice with 300 ml of dichloromethane, the organic phases were combined, washed with water, dried, and concentrated to obtain a crude product.
  • the crude product was subjected to vacuum distillation to collect fractions at 45-55°C to obtain 11 g of the target product, with a GC purity of 97%, an ee value of 98%, and a yield of 46%.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation de butyrolactone chirale. Spécifiquement, selon le procédé, le composé (II) est utilisé en tant que matière première pour réaliser de manière séquentielle des réactions d'ouverture de boucle, de sulfonylation, de substitution et de fermeture de boucle pour obtenir un composé de butyrolactone chirale (I). Dans un procédé de synthèse de la présente invention, les matières premières utilisées sont bon marché et facilement disponibles, le processus de synthèse est court, l'opération est simple, le processus de réaction est sûr et respectueux de l'environnement, la propriété de maintien de chiralité est bonne, et le processus global est très approprié pour une production industrielle.
PCT/CN2019/075688 2019-02-21 2019-02-21 Procédé de préparation de butyrolactone chirale WO2020168510A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113717132A (zh) * 2021-08-31 2021-11-30 珠海润都制药股份有限公司 一种抗癫痫药物的关键中间体及其制备方法

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Publication number Priority date Publication date Assignee Title
CN101528721A (zh) * 2006-11-06 2009-09-09 霍夫曼-拉罗奇有限公司 用于制备(s)-4-氟甲基-二氢-呋喃-2-酮的方法
CN105481801A (zh) * 2015-12-11 2016-04-13 惠州市莱佛士制药技术有限公司 一种普瑞巴林手性中间体的制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101528721A (zh) * 2006-11-06 2009-09-09 霍夫曼-拉罗奇有限公司 用于制备(s)-4-氟甲基-二氢-呋喃-2-酮的方法
CN105481801A (zh) * 2015-12-11 2016-04-13 惠州市莱佛士制药技术有限公司 一种普瑞巴林手性中间体的制备方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113717132A (zh) * 2021-08-31 2021-11-30 珠海润都制药股份有限公司 一种抗癫痫药物的关键中间体及其制备方法
CN113717132B (zh) * 2021-08-31 2023-03-03 珠海润都制药股份有限公司 一种抗癫痫药物的关键中间体及其制备方法

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