CN106588831A - Method for preparing furanone compounds - Google Patents

Method for preparing furanone compounds Download PDF

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Publication number
CN106588831A
CN106588831A CN201611008713.8A CN201611008713A CN106588831A CN 106588831 A CN106588831 A CN 106588831A CN 201611008713 A CN201611008713 A CN 201611008713A CN 106588831 A CN106588831 A CN 106588831A
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preparation
compound
solvent
furanones
iii
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CN106588831B (en
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应述欢
皮红军
陈健
周威
张爵明
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Shanghai Yunshengyan Neoplasm Technology Co ltd
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Shanghai Bocimed Pharmaceutical Co Ltd
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/58—Preparation of carboxylic acid halides
    • C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a method for preparing furanone compounds, and provides a method for preparing a furanone compound III. The method includes the following steps that in a solvent, in the presence of inorganic salt, a compound II and a reducing agent are subjected to a reduction reaction, and the furanone compound III is obtained; the solvent is a fatty alcohol solvent or a mixed solvent of a fatty alcohol solvent and water. The brivaracetam can be prepared with the furanone compound III only with the three steps, and the synthetic route is short; the ee value of the compound II is larger than 99.0%, racemization does not occur in the reaction process, and the de value of a brivaracetam I crude product is larger than 99.0%; the brivaracetam I crude product is further purified through a crystal instead of a chirality high-pressure-liquid-phase preparing column, and the chirality purity of brivaracetam I can be further increased to be the de value of 99.80% or above; meanwhile, the content of other individual impurities of the brivaracetam I is smaller than 0.1%, and reaches the API level, and the method is suitable for industrial production. The formula is defined in the description.

Description

A kind of preparation method of Furanones compound
Technical field
The present invention relates to a kind of preparation method of Furanones compound.
Background technology
Bu Waxitan I are western smooth analog derivatives, and with extensive antiepileptic activity and higher security, the medicine can pass through Combine with synaptic vesicle proteins 2A (SV2A) and play antiepileptic action.It is insane that the excellent when ratio (UCB) of Belgian pharmacy giant is announced The as shown by data that the III phases of 12 weeks by a definite date of epilepsy agent Bu Waxitan mono- are studied, Bu Waxitan can significantly reduce partial seizures Frequency simultaneously improves reactivity.Bu Waxitan tolerances are consistent with previously research in research.When excellent ratio in 2015 respectively to FDA and European drug administration (EMA) submits the NDA of Bu Waxitan and listing license application and granted to, Bu Waxitan into For the 3rd commercialized product in UCB landmark epilepsy exclusive rights, the said firm is carrying out the later stage and is studying, and this is medicinal to seek approval In pediatric patients, while as single medication of adult patient.
Bu Waxitan I can be prepared by various ways, such as document Journal of Medical Chemistry, 2004,47 (3), 530-549 and patent document WO2005028435, WO2007031263, WO2007065634 etc., generally synthesis Route is five to ten multisteps, but is finally required to carry out Chiral high pressure liquid phase and prepares post fractionation, and yield is low, loss is big, cost It is high, cannot mass produce, therefore, find a kind of high income, reactions steps are short, post processing is simple, obtained product purity height, Low production cost, the synthetic method of the Bu Waxitan I for being suitable for industrialized production are the technical problems for being badly in need of solving at present.
The content of the invention
The technical problem to be solved be in order to overcome prior art in Bu Waxitan synthetic method reaction step Suddenly grow, total recovery is low, post-processing step is loaded down with trivial details, obtained product purity is low, production cost is high, be not suitable for industrialized production etc. Defect and provide a kind of preparation method of Furanones compound.The Furanones compound of the present invention is adopted for middle system Standby Bu Waxitan reactions steps are short, overall yield of reaction is high, post-processing step is simple, obtained product purity height, low production cost, It is suitable for industrialized production.
The invention provides a kind of preparation method of Furanones compound III, it is comprised the following steps：In solvent, nothing Under conditions of machine salt is present, compound II is reacted with reducing agent, obtained Furanones compound III, it is described Solvent is the mixed solvent of aliphatic alcohols solvent or aliphatic alcohols solvent and water；
The preparation method of described Furanones compound III can be the conventional method of such reaction in this area, this Particularly preferred following reaction condition in invention：
In the preparation method of described Furanones compound III, the described preferred methyl alcohol of aliphatic alcohols solvent and/ Or ethanol.When solvent is made using the mixed solvent of aliphatic alcohols solvent and water, described aliphatic alcohols solvent with it is described Water volume ratio preferably 1～5, further preferred 2～3, such as 2.6.
In the preparation method of described Furanones compound III, the preferred sodium borohydride of described reducing agent, hydroboration One or more in lithium, potassium borohydride, 3-sec-butyl lithium borohydride and lithium triethylborohydride.
In the preparation method of described Furanones compound III, described reducing agent is with described compound II's Molar ratio preferably 1～5, further preferred 1.5～2, such as 1.6.
In the preparation method of described Furanones compound III, described inorganic salts preferably calcium chloride, iron chloride, One or more in zinc chloride and zinc sulfate, further preferred calcium chloride.The preferred powder calcium chloride of described calcium chloride.
In the preparation method of described Furanones compound III, described inorganic salts are with described compound II's Molar ratio preferably 1～5, further preferred 1.1～2, such as 1.1.
In the preparation method of described Furanones compound III, preferably 20 DEG C～30 DEG C of the temperature of described reaction.
In the preparation method of described Furanones compound III, the process of described reaction can adopt this area In routine monitoring method (such as TLC, HPLC or NMR) be monitored, when typically being disappeared with compound II as react terminal, Preferably 1 hour～24 hours, further preferred 8 hours～12 hours, such as 12 hours time of described reaction.
The preparation method of described Furanones compound III preferably adopts following steps：- 5 DEG C～0 DEG C, to compound The mixture that inorganic salts, reducing agent and solvent are formed is sequentially added in the mixture that II is formed with solvent, reaction is carried out and is obtained furan Mutter ketone compounds III.
The preparation method of described Furanones compound III preferably adopts following post-processing step：After reaction terminates, quench Go out reaction, remove solvent, be diluted with water, extract, being dried, filtering, removing solvent and obtain Furanones compound III.Described Reaction is quenched preferably using hydrochloric acid, described hydrochloric acid can be conventional commercial hydrochloric acid reagent in this area, described hydrochloric acid rubs Preferred 5mol/L～the 6mol/L of your concentration, such as 6mol/L, described molar concentration refers to that the mole of hydrogen chloride is total with hydrochloric acid The ratio of volume.Described extraction, drying, filtration and remove solvent and can adopt the conventional method of the generic operation in this area. The preferred halogenated hydrocarbon solvent of solvent that described extraction is adopted, the preferred chlorinated hydrocarbon solvent of described halogenated hydrocarbon solvent is described The preferred dichloromethane of chlorinated hydrocarbon solvent.Described drying preferably adopts desiccant dryness；Described drier is preferably anhydrous Sodium sulphate and/or anhydrous magnesium sulfate.The mode of the preferred reduced pressure concentration of mode of described removing solvent.
Present invention also offers a kind of preparation method of compound IV, it is comprised the following steps：It is obtained according to the method described above After described Furanones compound III, then in polar non-proton organic solvent, under inert gas shielding, will be described Furanones compound III carries out nucleophilic substitution with iodination reagent, obtains compound IV；
The preparation method of described compound IV can be the conventional method of such nucleophilic substitution in this area, this Particularly preferred following reaction condition in bright：
In the preparation method of described compound IV, the preferred nitrogen of described inert gas and/or argon gas.
In the preparation method of described compound IV, the preferred ether solvent of described polar non-proton organic solvent, nitrile One or more in class solvent, amide solvent, sulfoxide type solvents and halogenated hydrocarbon solvent.Described ether solvent preferably four Hydrogen furans and/or methyltetrahydrofuran.The preferred acetonitrile of described nitrile solvents.The preferred N of described amide solvent, N- dimethyl Formamide.The described preferred dimethyl sulfoxide (DMSO) of sulfone class solvent.The preferred chlorinated hydrocarbon solvent of described halogenated hydrocarbon solvent, it is described The preferred dichloromethane of chlorinated hydrocarbon solvent.
In the preparation method of described compound IV, described polar non-proton organic solvent and described Furanones Preferred 1mL/g～the 100mL/g of volume mass ratio of compound III, such as further preferred 6mL/g～10mL/g, 7.8mL/ g。
In the preparation method of described compound IV, the preferred iodine of described iodination reagent, N- iodos succinyl are sub- One or more in amine and Iodotrimethylsilane, further preferred Iodotrimethylsilane.
In the preparation method of described compound IV, described iodination reagent and described Furanones compound III Molar ratio preferably 1～5, further preferred 1～2, such as 1.
In the preparation method of described compound IV, preferably 20 DEG C～30 DEG C of the temperature of described nucleophilic substitution.
In the preparation method of described compound IV, the process of described nucleophilic substitution can be using in this area Routine monitoring method (such as TLC, HPLC or NMR) be monitored, when typically being disappeared with described Furanones compound III For the terminal of reaction, preferably 1 hour～10 hours time of described nucleophilic substitution, further preferred 2 hours～6 is little When, such as 2 hours.
The preparation method of described compound IV preferably adopts following steps：- 5～0 DEG C, iodination reagent is added to into furans In the mixture that ketone compounds III is formed with polar non-proton organic solvent, carry out nucleophilic substitution and obtain described change Compound IV.
The preparation method of described compound IV preferably adopts following post-processing step：After reaction terminates, salt is sequentially added Acid and sodium thiosulfate solution, extraction, washing, drying, filtration, removing solvent, obtain compound IV after purification.Described Hydrochloric acid can be conventional commercial hydrochloric acid reagent in this area, the preferred 1mol/L～2mol/L of molar concentration of described hydrochloric acid, institute The molar concentration stated refers to the mole of hydrogen chloride and the ratio of hydrochloric acid cumulative volume.The preferred matter of described sodium thiosulfate solution Amount percentage is 5%～20%, such as 10%, and described mass percent refers to the quality and sodium thiosulfate of sodium thiosulfate The percentage of aqueous solution gross mass.Described extraction, washing, drying, filter and remove solvent can using in this area such The conventional method of operation.The preferred halogenated hydrocarbon solvent of solvent that described extraction is adopted, the preferred chlorine of described halogenated hydrocarbon solvent For varsol, the preferred dichloromethane of described chlorinated hydrocarbon solvent.Described washing preferably adopts saturated common salt water washing, institute The number of times of the washing stated preferably 1～3 time, such as 2 times.Described drier is preferably dried using drier, and described is dry Drying prescription anhydrous sodium sulfate and/or anhydrous magnesium sulfate.The mode of the preferred reduced pressure concentration of mode of described removing solvent.
Present invention also offers a kind of preparation method of compound V, it is comprised the following steps：Institute is obtained according to the method described above After the compound IV for stating, then in organic solvent, described compound IV and dehydrating agent are carried out into dehydration and obtains described Compound V；
The preparation method of described compound V can be the conventional method of such dehydration in this area, in the present invention Particularly preferred following reaction condition：
In the preparation method of described compound V, the preferred ether solvent of organic solvent, aromatic hydrocarbon solvent and nitrile solvents In one or more.The preferred tetrahydrofuran of described ether solvent and/or 2- methylfurans.The preferred second of described nitrile solvents Nitrile.The preferred toluene of described aromatic hydrocarbon solvent.
In the preparation method of described compound V, the volume mass of described organic solvent and described compound IV Preferred 0.1mL/g～the 10mL/g of ratio, such as further preferred 1mL/g～3mL/g, 1.17mL/g.
In the preparation method of described compound V, the preferred thionyl chloride of described dehydrating agent, oxalyl chloride and tertiary valeric chloride In one or more.
In the preparation method of described compound V, described dehydrating agent and described compound IV molar ratios preferably 1 ～5, further preferred 1.5～2.5, such as 2.
In the preparation method of described compound V, preferably 20 DEG C～30 DEG C of the temperature of described dehydration.
In the preparation method of described compound V, the process of described dehydration can adopt normal in this area Rule monitoring method (such as TLC, HPLC or NMR) are monitored, described as the terminal for reacting when typically being disappeared with compound IV Preferably 20 hours～30 hours, further preferred 22 hours～26 hours, such as 24 hours time of dehydration.
The preparation method of described compound V is preferably carried out under inert gas shielding, and described inert gas can be Inert gas conventional in the art, preferred nitrogen and/or argon gas.
The preparation method of described compound V preferably adopts following steps：Under inert gas shielding, dehydrating agent is added to In the mixture that compound IV is formed with organic solvent, carry out dehydration and obtain described compound V.Described addition Mode be preferably added dropwise, the speed of described dropwise addition is defined by system temperature less than 30 DEG C.
The preparation method of described compound V preferably includes following post-processing step：Reaction removes solvent, essence after terminating Evaporate, obtain described compound V.Described removing solvent and rectifying can adopt the conventional method of the generic operation in this area, The preferred vacuum distillation of mode of described removing solvent.
In the present invention, after preferred reaction terminates, solvent, rectifying are removed, obtained after described compound V without further pure Change is directly prepared the reaction of described Bu Waxitan I.
Present invention also offers a kind of preparation method of Bu Waxitan I, it is comprised the following steps：It is obtained according to the method described above After compound V, then in organic solvent, under conditions of anhydrous and inert gas shielding, by described compound V and L-2- ammonia Base butyramide carries out condensation reaction and obtains Bu Waxitan I；
The preparation method of described Bu Waxitan I can be the conventional method of such condensation reaction in this area, of the invention In particularly preferred following reaction condition：
In the preparation method of described Bu Waxitan I, described anhydrous condition is preferably realized by adding drier, institute One or more in drier preferred molecular sieve, anhydrous sodium sulfate and the anhydrous magnesium sulfate stated, further preferred molecular sieve and Anhydrous sodium sulfate.The preferred 4A molecular sieves of described molecular sieve.
In the preparation method of described Bu Waxitan I, the preferred nitrogen of described inert gas and/or argon gas.
In the preparation method of described Bu Waxitan I, the preferred halogenated hydrocarbon solvent of described organic solvent；Described halogen For the preferred chlorinated hydrocarbon solvent of varsol；The preferred dichloromethane of described chlorinated hydrocarbon solvent.
In the preparation method of described Bu Waxitan I, the volume mass of described organic solvent and described compound V Preferred 1mL/g～the 100mL/g of ratio, such as further preferred 8mL/g～15mL/g, 11.5mL/g.
In the preparation method of described Bu Waxitan I, described L-2- amino-butanamides can be with the shape of its hydrochloride Formula is used, and when described L-2- amino-butanamides are used in the form of the hydrochloride salt, described condensation reaction needs to be deposited in alkali Carry out under the conditions；The preferred inorganic base of described alkali, the preferred potassium hydroxide of described inorganic base and/or NaOH.It is described Inorganic base and described L-2- amino-butanamide acid salt molar ratio preferably 1～5, further preferred 2～3, for example 2.1.The described preferred L-2- amino-butanamide hydrochlorides of L-2- amino-butanamide acid salt.
In the preparation method of described Bu Waxitan I, described L-2- amino-butanamides rub with described compound V's That ratio preferably 1～2, further preferred 1～1.05.
In the preparation method of described Bu Waxitan I, preferably 20 DEG C～30 DEG C of the temperature of described condensation reaction.
In the preparation method of described Bu Waxitan I, the process of described condensation reaction can be using in this area Routine monitoring method (such as TLC, HPLC or NMR) is monitored, described as the terminal for reacting when typically being disappeared with compound V Condensation reaction preferably 15 hours～25 hours, such as 18 hours time.
The preparation method of described Bu Waxitan I is preferably carried out under conditions of phase transfer catalyst presence, described phase The preferred TBAB of transfer catalyst.Described phase transfer catalyst is preferred with the molar ratio of described compound V 0.01～0.05, further preferred 0.03～0.04, such as 0.035.
The preparation method of described Bu Waxitan I preferably includes following post-processing step：After reaction terminates, filter, remove Solvent obtains the crude product of Bu Waxitan I.Described filtration, remove solvent and can adopt the routine side of the generic operation in this area Method, described filtration is preferably filtered using diatomite, and described removes solvent preferably using the method for reduced pressure concentration.
The crude product of described Bu Waxitan I is preferably through being beaten, be recrystallized to give Bu Waxitan I.Described beating and weight Crystallization can adopt the conventional method of the generic operation in this area, the preferred esters solvent of solvent and alcohols that described beating is adopted The mixed solvent of solvent, the volume ratio preferably 6 of described esters solvent and described alcohols solvent：1～12：1, such as 9：1. Described esters solvent ethyl acetate；The preferred isopropanol of described alcohols solvent.The solvent that described recrystallization is adopted is excellent Select the mixed solvent of polar non-proton organic solvent or polar non-proton organic solvent and aliphatic alcohols solvent.Described polarity is non- One or more in the preferred esters solvent of proton-organic solvent, ether solvent, ketones solvent and nitrile solvents, further preferably Ether solvent.Described esters solvent ethyl acetate.The preferred tetrahydrofuran of described ether solvent and/or isopropyl ether.Institute The preferred acetone of ketones solvent stated.The preferred acetonitrile of described nitrile solvents.The described preferred isopropanol of aliphatic alcohols solvent, methyl alcohol With one or more in ethanol, further preferred isopropanol.
The HPLC purity of described Bu Waxitan I is more than or equal to 99.80%.
The preparation method of described Bu Waxitan I preferably adopts following synthetic route：
Heretofore described raw material or reagent are commercially available in addition to special instruction.
In the present invention, described room temperature refers to environment temperature, is 10 DEG C～35 DEG C.
The present invention positive effect be：
Bu Waxitan can be prepared using Furanones compound III only three steps of the present invention, synthetic route is short；Instead Answer process that racemization does not occur, the chiral purity of the Bu Waxitan I crude products for obtaining is also high；By crystallization rather than Chiral high pressure liquid phase Prepare post to be further purified, (de values are big the chiral purity of Bu Waxitan I can be further increased to into more than 99.80% In 99.80%), at the same Bu Waxitan I other it is single it is miscellaneous be less than 0.1%, reach api class not, be suitable for industrialized production.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality Among applying a scope.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to business Product specification is selected.
Embodiment 1：
By (R) -3- methoxycarbonyl caproic acids, (174.1g, 1mol, ee value is lowered the temperature 99.2%) to be dissolved in 500mL methyl alcohol To 0 DEG C, 500mL water is added, be cooled to 0 DEG C, sequentially add the second of powder calcium chloride (115.8g, 1.1mol) and sodium borohydride Alcoholic solution (2M, 800mL).Reactant liquor is stirred overnight (about 12 hours) under (20 DEG C～30 DEG C) and adds hydrochloric acid reaction afterwards (6M, 1000mL), reduced pressure concentration adds the dilution of 500mL water, dichloromethane extraction (3 × 150mL) to merge organic phase, anhydrous sulphur Sour sodium is dried, and filters, and Furanones compound III 108.9g, yield 85.0%, purity are obtained after reduced pressure concentration：97.2% (GC)。
R-3- methoxycarbonyls caproic acid can according to Angewandte Chemie International Edition, Prepared by 1998,37 (13-14), the method described by 1931-1933, ee values are more than 99.0%.
Embodiment 2：
Under nitrogen protection, Furanones compound III (128.1g, 1mol) are dissolved in 1L dichloromethane, are cooled to 0 DEG C, add Iodotrimethylsilane (150mL), reactant liquor to stir 2 hours at 20～30 DEG C.Subsequently sequentially add hydrochloric acid solution (mass percent is 10%, and described mass percent refers to sodium thiosulfate for (1M, 800mL) and sodium thiosulfate solution Quality and sodium thiosulfate solution gross mass percentage, 400mL.), water is mutually extracted with 1L dichloromethane, and organic phase is used Saturated common salt is washed twice, anhydrous sodium sulfate drying, is filtered, and Bu Waxitan intermediate compound IVs (254.6g) are obtained after reduced pressure concentration, Yield 99.5%, purity：95.6% (GC).
Embodiment 3：
Under nitrogen protection, Bu Waxitan intermediate compound IVs (1280.4g, 4mol) are dissolved in 1500mL toluene, it is slow to add Enter thionyl chloride (951.8g, 8mol), reactant liquor is stirred 24 hours for (20 DEG C～30 DEG C) in room temperature, reduced pressure concentration solvent.It is remaining Thing vacuum pump pressure rectifying (0.32mmHg, 90-95 DEG C) obtains flaxen transparency liquid compound V 1310g.
The compound V 1310g for obtaining are dissolved in into 2.5L dichloromethane solutions.Subsequently above-mentioned solution is added and contains L-2- Amino-butanamide hydrochloride (428.9g, 4.2mol), 4A molecular sieves (500g), potassium hydroxide (500g), anhydrous sodium sulfate (500g), in the dichloromethane solution (12.5L) of TBAB (49g, 0.14mol), reactant liquor is stirred at 20～30 DEG C Diatomite is added to filter after mixing 18 hours, filtrate reduced in volume obtains Bu Waxitan (I) crude product to dry.With ethyl acetate and isopropyl (ethyl acetate/isopropanol volume ratio is 90 to the mixed liquor of alcohol：10) beating is filtered, isopropyl ether recrystallization get Bu Waxitan (543.5g, two step total recoverys 64%).HPLC：99.86%, maximum single miscellaneous 0.08%, de values：99.84%.
Comparative example 1：(bibliography WO2007031263A1)
11.7g Bu Waxitan DLs body (1:1) chiral preparation liquid phase separation, 20 μm of Chiralpak AD, 100* are carried out 500mm posts, mobile phase is normal heptane, (volume ratio is 50 to ethanol:50) Bu Waxitan 5.20g, can be obtained, yield is 44%, HPLC purity：99.26%, maximum single miscellaneous 0.20%, de values：98.60%.

Claims (10)

1. a kind of preparation method of Furanones compound III, it is characterised in that it is comprised the following steps：In solvent, inorganic salts Under conditions of presence, compound II is reacted with reducing agent, obtained Furanones compound III, described solvent For aliphatic alcohols solvent or the mixed solvent of aliphatic alcohols solvent and water；
2. the preparation method of Furanones compound III as claimed in claim 1, it is characterised in that：
In the preparation method of described Furanones compound III, described aliphatic alcohols solvent is methyl alcohol and/or second Alcohol；
And/or,
In the preparation method of described Furanones compound III, when the mixed solvent using aliphatic alcohols solvent and water When making solvent, described aliphatic alcohols solvent and the volume ratio of described water is 1～5；
And/or,
In the preparation method of described Furanones compound III, described reducing agent is sodium borohydride, lithium borohydride, boron One or more in hydrofining, 3-sec-butyl lithium borohydride and lithium triethylborohydride；
And/or,
In the preparation method of described Furanones compound III, described reducing agent and described compound II mole Ratio is 1～5；
And/or,
In the preparation method of described Furanones compound III, described inorganic salts are calcium chloride, iron chloride, zinc chloride With one or more in zinc sulfate；
And/or,
In the preparation method of described Furanones compound III, described inorganic salts and described compound II mole Ratio is 1～5；
And/or,
In the preparation method of described Furanones compound III, the temperature of described reaction is 20 DEG C～30 DEG C；
And/or,
In the preparation method of described Furanones compound III, the time of described reaction is 1 hour～24 hours；
And/or,
The preparation method of described Furanones compound III adopts following steps：- 5 DEG C～0 DEG C, to compound II and solvent The mixture that inorganic salts and reducing agent are formed with solvent is sequentially added in the mixture of formation, reaction is carried out and is obtained Furanones Compound III；
And/or,
The preparation method of described Furanones compound III adopts following post-processing step：Reaction terminate after, be quenched reaction, Solvent is removed, is diluted with water, extracted, being dried, filtering, removing solvent and obtain Furanones compound III.
3. the preparation method of Furanones compound III as claimed in claim 2, it is characterised in that：
In the preparation method of described Furanones compound III, when the mixed solvent using aliphatic alcohols solvent and water When making solvent, described aliphatic alcohols solvent and the volume ratio of described water is 2～3；
And/or,
In the preparation method of described Furanones compound III, described reducing agent and described compound II mole Ratio is 1.5～2；
And/or,
In the preparation method of described Furanones compound III, described inorganic salts and described compound II mole Ratio is 1.1～2；
And/or,
In the preparation method of described Furanones compound III, the time of described reduction reaction is 8 hours～12 little When；
And/or,
In the post-processing step that the preparation method of described Furanones compound III is adopted, the described reaction that is quenched adopts salt Acid；
And/or,
In the post-processing step that the preparation method of described Furanones compound III is adopted, the solvent that described extraction is adopted For halogenated hydrocarbon solvent；
And/or,
In the post-processing step that the preparation method of described Furanones compound III is adopted, described drying adopts drier It is dried；
And/or,
In the post-processing step that the preparation method of described Furanones compound III is adopted, the described mode for removing solvent For the mode of reduced pressure concentration.
4. a kind of preparation method of compound IV, it is characterised in that comprise the following steps：According to any one of claims 1 to 3 institute The preparation method stated is obtained after Furanones compound III, then in polar non-proton organic solvent, under inert gas shielding, Described Furanones compound III and iodination reagent are carried out into nucleophilic substitution, compound IV is obtained；
5. the preparation method of compound IV as claimed in claim 4, it is characterised in that：
In the preparation method of described compound IV, described inert gas is nitrogen and/or argon gas；
And/or,
In the preparation method of described compound IV, described polar non-proton organic solvent be ether solvent, nitrile solvents, One or more in amide solvent, sulfoxide type solvents and halogenated hydrocarbon solvent；
And/or,
In the preparation method of described compound IV, described polar non-proton organic solvent is with described compound III's Volume mass ratio is 1mL/g～100mL/g；
And/or,
In the preparation method of described compound IV, described iodination reagent is iodine, N-iodosuccinimide and three One or more in methyl iodide silane；
And/or,
In the preparation method of described compound IV, described iodination reagent and described compound III molar ratios be 1～ 5；
And/or,
In the preparation method of described compound IV, the temperature of described nucleophilic substitution is 20 DEG C～30 DEG C；
And/or,
In the preparation method of described compound IV, the time of described nucleophilic substitution is 1 hour～10 hours；
And/or,
The preparation method of described compound IV adopts following steps：- 5～0 DEG C, iodination reagent is added to into Furanones chemical combination In the mixture that thing III is formed with polar non-proton organic solvent, carry out nucleophilic substitution and obtain compound IV；
And/or,
The preparation method of described compound IV adopts following post-processing step：After reaction terminates, hydrochloric acid and thio is sequentially added Aqueous sodium persulfate solution, extraction, washing, drying, filtration, removing solvent, obtain compound IV after purification.
6. the preparation method of compound IV as claimed in claim 5, it is characterised in that：
In the preparation method of described compound IV, described ether solvent is tetrahydrofuran and/or methyltetrahydrofuran；
And/or,
In the preparation method of described compound IV, described nitrile solvents are acetonitrile；
And/or,
In the preparation method of described compound IV, described amide solvent is DMF；
And/or,
In the preparation method of described compound IV, described sulfoxide type solvents are dimethyl sulfoxide (DMSO)；
And/or,
In the preparation method of described compound IV, described halogenated hydrocarbon solvent is chlorinated hydrocarbon solvent；
And/or,
In the preparation method of described compound IV, described polar non-proton organic solvent and described Furanones chemical combination The volume mass ratio of thing III is 6mL/g～10mL/g；
And/or,
In the preparation method of described compound IV, described iodination reagent and III mole described of Furanones compound Ratio is 1～2；
And/or,
In the preparation method of described compound IV, the time of described nucleophilic substitution is 2 hours～6 hours；
And/or,
In the post-processing step that the preparation method of described compound IV is adopted, the molar concentration of described hydrochloric acid be 1mol/L～ 2mol/L, described molar concentration refers to the mole of hydrogen chloride and the ratio of hydrochloric acid cumulative volume；
And/or,
In the post-processing step that the preparation method of described compound IV is adopted, the quality hundred of described sodium thiosulfate solution Divide than being 5%～20%, described mass percent refers to the quality and sodium thiosulfate solution gross mass of sodium thiosulfate Percentage；
And/or,
In the post-processing step that the preparation method of described compound IV is adopted, the solvent that described extraction is adopted is for halogenated hydrocarbon Solvent；
And/or,
In the post-processing step that the preparation method of described compound IV is adopted, described washing is to be washed using saturated common salt Wash；
And/or,
In the post-processing step that the preparation method of described compound IV is adopted, the number of times of described washing is 1～3 time；
And/or,
In the post-processing step that the preparation method of described compound IV is adopted, described drying is dried using drier；
And/or,
In the post-processing step that the preparation method of described compound IV is adopted, the mode of described removing solvent is reduced pressure concentration Mode.
7. a kind of preparation method of compound V, it is characterised in that it is comprised the following steps：According to any one of claim 4～6 institute The preparation method stated is obtained after described compound IV, then in organic solvent, described compound IV is entered with dehydrating agent Row dehydration obtains compound V；
8. the preparation method of compound V as claimed in claim 7, it is characterised in that：
In the preparation method of described compound V, organic solvent is in ether solvent, aromatic hydrocarbon solvent and nitrile solvents Plant or various；
And/or,
In the preparation method of described compound V, the volume mass ratio of described organic solvent and described compound IV For 0.1mL/g～10mL/g；
And/or,
In the preparation method of described compound V, described dehydrating agent is in thionyl chloride, oxalyl chloride and tertiary valeric chloride Plant or various；
And/or,
In the preparation method of described compound V, described dehydrating agent and described compound IV molar ratios is 1～5；
And/or,
In the preparation method of described compound V, the temperature of described dehydration is 20 DEG C～30 DEG C；
And/or,
In the preparation method of described compound V, the time of described dehydration is 20 hours～30 hours；
And/or,
The preparation method of described compound V is carried out under inert gas shielding；
And/or,
The preparation method of described compound V adopts following steps：Under inert gas shielding, dehydrating agent is added to into compound IV In the mixture formed with organic solvent, carry out dehydration and obtain described compound V；
And/or,
The preparation method of described compound V includes following post-processing step：Reaction removes solvent, rectifying after terminating, and obtains institute The compound V for stating.
9. the preparation method of compound V as claimed in claim 8, it is characterised in that：
In the preparation method of described compound V, described ether solvent is tetrahydrofuran and/or 2- methylfurans；
And/or,
In the preparation method of described compound V, described aromatic hydrocarbon solvent is toluene；
And/or,
In the preparation method of described compound V, described nitrile solvents are acetonitrile；
And/or,
In the preparation method of described compound V, the volume mass ratio of described organic solvent and described compound IV For 1mL/g～3mL/g；
And/or,
In the preparation method of described compound V, described dehydrating agent and described compound IV molar ratios be 1.5～ 2.5；
And/or,
In the preparation method of described compound V, the time of described dehydration is 22 hours～26 hours；
And/or,
When the preparation method of described compound V is carried out under inert gas shielding, described inert gas be nitrogen and/or Argon gas；
And/or,
In the step of preparation method of described compound V is adopted, the mode of described addition to be added dropwise, described dropwise addition Speed is defined by system temperature less than 30 DEG C；
And/or,
In the post-processing step that the preparation method of described compound V includes, the mode of described removing solvent is vacuum distillation；
And/or,
After reaction terminates, solvent, rectifying are removed, obtain directly being prepared institute without further purification after described compound V The reaction of the Bu Waxitan I for stating.
10. a kind of preparation method of Bu Waxitan I, it is characterised in that it is comprised the following steps：A kind of preparation side of Bu Waxitan I Method, it is characterised in that it is comprised the following steps：Described change is obtained according to the preparation method described in any one of claim 7～9 After compound V, then in organic solvent, under conditions of anhydrous and inert gas shielding is present, by described compound V and L-2- Amino-butanamide carries out condensation reaction and obtains Bu Waxitan I；
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CN107216276A (en) * 2017-06-29 2017-09-29 爱斯特（成都）生物制药股份有限公司 A kind of new Bu Waxitan synthetic method
CN107604018A (en) * 2017-10-17 2018-01-19 重庆迪维斯生物科技有限公司 A kind of preparation method of Bu Waxitan intermediates
IT201800006320A1 (en) * 2018-06-14 2019-12-14 PROCESS FOR THE ASYMMETRIC SYNTHESIS OF (R) -4-PROPYLDIHYDROFURAN-2 (3H) -ONE
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CN110790730A (en) * 2018-08-01 2020-02-14 北京万全德众医药生物技术有限公司 Preparation method of (R) -4-propyl-dihydrofuran-2-ketone
CN110824093A (en) * 2018-08-13 2020-02-21 北京海晶生物医药科技有限公司 Method for detecting brivaracetam and related substances thereof
CN110824093B (en) * 2018-08-13 2023-08-22 北京海晶生物医药科技有限公司 Method for detecting brivaracetam and related substances thereof
CN111170881A (en) * 2018-11-09 2020-05-19 上海医药集团股份有限公司 Preparation method of brivaracetam intermediate
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CN110128377A (en) * 2019-04-17 2019-08-16 石家庄手性化学有限公司 A kind of (R) -4- propyl-dihydrofuran -2- ketone preparation method of optical purity

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