CN106588831B - A kind of preparation method of Furanones compound - Google Patents

A kind of preparation method of Furanones compound Download PDF

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CN106588831B
CN106588831B CN201611008713.8A CN201611008713A CN106588831B CN 106588831 B CN106588831 B CN 106588831B CN 201611008713 A CN201611008713 A CN 201611008713A CN 106588831 B CN106588831 B CN 106588831B
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compound
preparation
solvent
furanones
iii
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CN106588831A (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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  • 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 kind of preparation methods of Furanones compound.The present invention provides the preparation methods of Furanones compound III a kind of, the following steps are included: in solvent, under the conditions of inorganic salts are existing, compound II and reducing agent are subjected to reduction reaction, Furanones compound III is obtained, solvent is the mixed solvent of aliphatic alcohols solvent or aliphatic alcohols solvent and water.Using Furanones compound III, only Bu Waxitan can be made in three steps, and synthetic route is short；Compound II ee value is greater than 99.0%, and racemization does not occur for reaction process, and obtained Bu Waxitan I crude product de value is greater than 99.0%；By crystallization rather than Chiral high pressure liquid phase prepares column is further purified, the chiral purity of Bu Waxitan I can be further increased to 99.80% or more de value, other of Bu Waxitan I simultaneously are single miscellaneous less than 0.1%, and it is other to reach api class, are suitable for industrialized production.

Description

A kind of preparation method of Furanones compound
Technical field
The present invention relates to a kind of preparation methods of Furanones compound.
Background technique
Bu Waxitan I is western smooth analog derivative, has extensive antiepileptic activity and higher safety, which can pass through With synaptic vesicle proteins 2A (SV2A) in conjunction with and play antiepileptic action.The Belgian excellent when ratio (UCB) of pharmacy giant is announced insane It is that the 12 weeks by a definite date III phases of epilepsy agent Bu Waxitan mono- are studied statistics indicate that, Bu Waxitan can significantly reduce partial seizures Frequency simultaneously improves reactivity.Bu Waxitan tolerance and the past are studied consistent in research.When excellent ratio in 2015 respectively to FDA and European drug administration (EMA) submits the New Drug Application of Bu Waxitan and listing license application simultaneously granted, Bu Waxitan at For the 3rd commercialized product in UCB landmark epilepsy exclusive right, the said firm is carrying out later period research, seeks to ratify this medicinal In pediatric patients, while single medication as 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. are usually synthesized Route is five to ten multisteps, but is finally required to progress Chiral high pressure liquid phase and prepares column fractionation, and yield is low, loss is big, cost It is high, can not be mass produced, therefore, find a kind of high income, reaction step is short, post-processing is simple, product purity obtained height, The synthetic method for the Bu Waxitan I that production cost is low, is suitable for industrialized production is current technical problem urgently to be solved.
Summary of the invention
The technical problem to be solved by the present invention is to walk to overcome the synthetic method of Bu Waxitan in the prior art to react Rapid length, total recovery is low, post-processing step is cumbersome, obtained product purity is low, high production cost, is not suitable for industrialized production etc. Defect and provide a kind of preparation method of Furanones compound.Use Furanones compound of the invention for intermediate system Standby Bu Waxitan reaction step is short, overall yield of reaction is high, post-processing step is simple, product purity obtained is high, production cost is low, It is suitable for industrialized production.
The present invention provides the preparation methods of Furanones compound III a kind of comprising following steps: in solvent, nothing Under the conditions of machine salt is existing, compound II is reacted with reducing agent, obtains 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 the Furanones compound III can be the conventional method of such reaction in this field, this Particularly preferred following reaction condition in invention:
In the preparation method of the Furanones compound III, the preferred methanol of aliphatic alcohols solvent and/ Or ethyl alcohol.When making solvent using the mixed solvent of aliphatic alcohols solvent and water, the 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 the Furanones compound III, the preferred sodium borohydride of the reducing agent, hydroboration One of lithium, potassium borohydride, 3-sec-butyl lithium borohydride and lithium triethylborohydride are a variety of.
In the preparation method of the Furanones compound III, the reducing agent is with the compound II's Molar ratio preferably 1~5, further preferred 1.5~2, such as 1.6.
In the preparation method of the Furanones compound III, the inorganic salts preferably calcium chloride, iron chloride, One of zinc chloride and zinc sulfate are a variety of, further preferred calcium chloride.The preferably powdered calcium chloride of the calcium chloride.
In the preparation method of the Furanones compound III, the inorganic salts are with the compound II's Molar ratio preferably 1~5, further preferred 1.1~2, such as 1.1.
In the preparation method of the Furanones compound III, preferably 20 DEG C~30 DEG C of the temperature of the reaction.
In the preparation method of the Furanones compound III, the process of the reaction can use this field In routine monitoring method (such as TLC, HPLC or NMR) be monitored, generally using compound II disappear when as the terminal of reaction, The time of the reaction preferably 1 hour~24 hours, further preferred 8 hours~12 hours, such as 12 hours.
The preparation method of the Furanones compound III preferably uses 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 and solvent are formed, and is reacted to obtain furan Mutter ketone compounds III.
The preparation method of the Furanones compound III preferably uses following post-processing step: after reaction, quenching Go out reaction, remove solvent, be diluted with water, extract, drying, filtering, removing solvent and obtain Furanones compound III.Described Quenching reaction preferably uses hydrochloric acid, and the hydrochloric acid can rub for conventional commercial hydrochloric acid reagent in this field, the hydrochloric acid You are the preferred 5mol/L~6mol/L of concentration, such as 6mol/L, the molar concentration refer to that the mole of hydrogen chloride and hydrochloric acid are total The ratio of volume.Extraction, drying, filtering and the removing solvent can be using the conventional method of the generic operation in this field. The preferred halogenated hydrocarbon solvent of solvent that the extraction uses, the preferred chlorinated hydrocarbon solvent of the halogenated hydrocarbon solvent are described The preferred methylene chloride of chlorinated hydrocarbon solvent.The drying preferably uses desiccant dryness；The desiccant is preferably anhydrous Sodium sulphate and/or anhydrous magnesium sulfate.The mode that the mode of the removing solvent is preferably concentrated under reduced pressure.
The present invention also provides the preparation methods of compound IV a kind of comprising following steps: is made according to the method described above The Furanones compound III and then in polar non-proton organic solvent, will be described under inert gas shielding Furanones compound III and iodination reagent carry out nucleophilic substitution, obtain compound IV；
The preparation method of the compound IV can be the conventional method of such nucleophilic substitution in this field, this hair Particularly preferred following reaction condition in bright:
In the preparation method of the compound IV, the preferred nitrogen of the inert gas and/or argon gas.
In the preparation method of the compound IV, the preferred ether solvent of the polar non-proton organic solvent, nitrile One of class solvent, amide solvent, sulfoxide type solvents and halogenated hydrocarbon solvent are a variety of.The ether solvent preferably four Hydrogen furans and/or methyltetrahydrofuran.The preferred acetonitrile of the nitrile solvents.The preferred N of the amide solvent, N- dimethyl Formamide.The preferred dimethyl sulfoxide of sulfone class solvent.The preferred chlorinated hydrocarbon solvent of the halogenated hydrocarbon solvent, it is described The preferred methylene chloride of chlorinated hydrocarbon solvent.
In the preparation method of the compound IV, the polar non-proton organic solvent and the Furanones Volume mass ratio preferred 1mL/g~100mL/g, further preferred 6mL/g~10mL/g, such as the 7.8mL/ of compound III g。
In the preparation method of the compound IV, the preferred iodine of the iodination reagent, N- iodo succinyl are sub- One of amine and Iodotrimethylsilane are a variety of, further preferred Iodotrimethylsilane.
In the preparation method of the compound IV, the iodination reagent and the Furanones compound III Molar ratio preferably 1~5, further preferred 1~2, such as 1.
In the preparation method of the compound IV, preferably 20 DEG C~30 DEG C of the temperature of the nucleophilic substitution.
In the preparation method of the compound IV, the process of the nucleophilic substitution can be using in this field Routine monitoring method (such as TLC, HPLC or NMR) be monitored, when generally being disappeared with the Furanones compound III For the terminal of reaction, the time of the nucleophilic substitution preferably 1 hour~10 hours, further preferred 2 hours~6 is small When, such as 2 hours.
The preparation method of the compound IV preferably uses following steps: -5~0 DEG C, iodination reagent being added to furans In the mixture that ketone compounds III and polar non-proton organic solvent are formed, carries out nucleophilic substitution and obtain the change Close object IV.
The preparation method of the compound IV preferably uses following post-processing step: after reaction, sequentially adding salt Acid and sodium thiosulfate solution, washing, drying, filtering, remove solvent at extraction, obtain compound IV after purification.Described Hydrochloric acid can be conventional commercial hydrochloric acid reagent in this field, the preferred 1mol/L~2mol/L of the molar concentration of the hydrochloric acid, institute The molar concentration stated refers to the mole of hydrogen chloride and the ratio of hydrochloric acid total volume.The preferred matter of the sodium thiosulfate solution Measuring percentage is 5%~20%, such as 10%, and the mass percent refers to the quality and sodium thiosulfate of sodium thiosulfate The percentage of aqueous solution gross mass.Extraction, washing, drying, filtering and the removing solvent can be using such in this field The conventional method of operation.The preferred halogenated hydrocarbon solvent of solvent that the extraction uses, the preferred chlorine of the halogenated hydrocarbon solvent For hydrocarbon solvent, the preferred methylene chloride of the chlorinated hydrocarbon solvent.The washing preferably uses saturated common salt water washing, institute The number for the washing stated preferably 1~3 time, such as 2 times.The desiccant is preferably dried using desiccant, and described is dry Drying prescription anhydrous sodium sulfate and/or anhydrous magnesium sulfate.The mode that the mode of the removing solvent is preferably concentrated under reduced pressure.
The present invention also provides the preparation methods of compound V a kind of comprising following steps: institute being made according to the method described above The compound IV that states and then in organic solvent, by the compound IV and dehydrating agent carry out dehydration obtain it is described Compound V；
The preparation method of the compound V can be the conventional method of such dehydration in this field, in the present invention Particularly preferred following reaction condition:
In the preparation method of the compound V, the preferred ether solvent of organic solvent, aromatic hydrocarbon solvent and nitrile solvents One of or it is a variety of.The preferred tetrahydrofuran of the ether solvent and/or 2- methylfuran.The preferred second of the nitrile solvents Nitrile.The preferred toluene of the aromatic hydrocarbon solvent.
In the preparation method of the compound V, the volume mass of the organic solvent and the compound IV Ratio preferred 0.1mL/g~10mL/g, further preferred 1mL/g~3mL/g, such as 1.17mL/g.
In the preparation method of the compound V, the preferred thionyl chloride of the dehydrating agent, oxalyl chloride and tertiary valeric chloride One of or it is a variety of.
In the preparation method of the compound V, the dehydrating agent and the compound IV molar ratio preferably 1 ~5, further preferred 1.5~2.5, such as 2.
In the preparation method of the compound V, preferably 20 DEG C~30 DEG C of the temperature of the dehydration.
In the preparation method of the compound V, the process of the dehydration can be using normal in this field Rule monitoring method (such as TLC, HPLC or NMR) are monitored, described as the terminal of reaction when generally being disappeared using compound IV The time of dehydration preferably 20 hours~30 hours, further preferred 22 hours~26 hours, such as 24 hours.
The preparation method of the compound V preferably carries out under inert gas protection, and the inert gas can be Inert gas conventional in the art, preferably nitrogen and/or argon gas.
The preparation method of the compound V preferably uses following steps: under inert gas shielding, dehydrating agent being added to In the mixture that compound IV and organic solvent are formed, carries out dehydration and obtain the compound V.The addition Mode be preferably added dropwise, the speed of the dropwise addition is subject to system temperature no more than 30 DEG C.
The preparation method of the compound V preferably includes following post-processing step: removing solvent, essence after reaction It evaporates, obtains the compound V.The removing solvent and rectifying can use the conventional method of the generic operation in this field, The mode of the removing solvent is preferably evaporated under reduced pressure.
In the present invention, preferably after reaction, solvent, rectifying are removed, obtained after the compound V without further pure Change the reaction for directly carrying out preparing the Bu Waxitan I.
The present invention also provides the preparation methods of Bu Waxitan I a kind of comprising following steps: is made according to the method described above Compound V and then in organic solvent, under conditions of anhydrous and inert gas shielding, by the compound V and L-2- ammonia Base butyramide carries out condensation reaction and obtains Bu Waxitan I；
The preparation method of the Bu Waxitan I can be the conventional method of such condensation reaction in this field, the present invention In particularly preferably following reaction condition:
In the preparation method of the Bu Waxitan I, the anhydrous condition, which preferably passes through, is added desiccant realization, institute One of desiccant preferred molecular sieve, anhydrous sodium sulfate and anhydrous magnesium sulfate for stating are a variety of, further preferred molecular sieve and Anhydrous sodium sulfate.The preferred 4A molecular sieve of the molecular sieve.
In the preparation method of the Bu Waxitan I, the preferred nitrogen of the inert gas and/or argon gas.
In the preparation method of the Bu Waxitan I, the preferred halogenated hydrocarbon solvent of the organic solvent；The halogen For the preferred chlorinated hydrocarbon solvent of hydrocarbon solvent；The preferred methylene chloride of the chlorinated hydrocarbon solvent.
In the preparation method of the Bu Waxitan I, the volume mass of the organic solvent and the compound V Ratio preferred 1mL/g~100mL/g, further preferred 8mL/g~15mL/g, such as 11.5mL/g.
In the preparation method of the Bu Waxitan I, the L-2- amino-butanamide can be with the shape of its hydrochloride Formula uses, when the L-2- amino-butanamide is in the form of the hydrochloride salt in use, the condensation reaction needs to deposit in alkali It carries out under the conditions；The preferred inorganic base of the alkali, the preferred potassium hydroxide of the inorganic base and/or sodium hydroxide.It is described Inorganic base and the L-2- amino-butanamide acid salt molar ratio preferably 1~5, further preferred 2~3, such as 2.1.The preferred L-2- amino-butanamide hydrochloride of L-2- amino-butanamide acid salt.
In the preparation method of the Bu Waxitan I, the L-2- amino-butanamide rubs with the compound V's That ratio preferably 1~2, further preferred 1~1.05.
In the preparation method of the Bu Waxitan I, preferably 20 DEG C~30 DEG C of the temperature of the condensation reaction.
In the preparation method of the Bu Waxitan I, the process of the condensation reaction can be using in this field Routine monitoring method (such as TLC, HPLC or NMR) is monitored, described as the terminal of reaction when generally being disappeared using compound V Time preferably 15 hours~25 hours of condensation reaction, such as 18 hours.
The preparation method of the Bu Waxitan I preferably existing for the phase transfer catalyst under the conditions of carry out, the phase The preferred tetrabutylammonium bromide of transfer catalyst.The molar ratio of the phase transfer catalyst and the compound V is preferred 0.01~0.05, further preferred 0.03~0.04, such as 0.035.
The preparation method of the Bu Waxitan I preferably includes following post-processing step: after reaction, filtering removes Solvent obtains the crude product of Bu Waxitan I.The filtering, remove solvent can be using the routine side of the generic operation in this field Method, the filtering preferably use diatomite to filter, and the removing solvent is preferably using the method being concentrated under reduced pressure.
The crude product of the Bu Waxitan I is preferably through being beaten, be recrystallized to give Bu Waxitan I.The mashing and again The preferred esters solvent of solvent and alcohols that crystallization can be used using the conventional method of the generic operation in this field, the mashing The mixed solvent of solvent, the preferred 6:1~12:1 of volume ratio of the esters solvent and the alcohols solvent, such as 9:1. The esters solvent ethyl acetate；The preferred isopropanol of the alcohols solvent.The solvent that the recrystallization uses is excellent Select the mixed solvent of polar non-proton organic solvent or polar non-proton organic solvent and fatty alcohols solvent.The polarity is non- One of the preferred esters solvent of proton-organic solvent, ether solvent, ketones solvent and nitrile solvents are a variety of, further preferably Ether solvent.The esters solvent ethyl acetate.The preferred tetrahydrofuran of the ether solvent and/or isopropyl ether.Institute The preferred acetone of the ketones solvent stated.The preferred acetonitrile of the nitrile solvents.The preferred isopropanol of fatty alcohols solvent, methanol With one of ethyl alcohol or a variety of, further preferred isopropanol.
The HPLC purity of the Bu Waxitan I is more than or equal to 99.80%.
The preparation method of the Bu Waxitan I preferably uses following synthetic route:
Heretofore described raw material or reagent are commercially available in addition to special instruction.
In the present invention, the room temperature refers to environment temperature, is 10 DEG C~35 DEG C.
The positive effect of the present invention is that:
Using Furanones compound III of the invention, only Bu Waxitan can be prepared in three steps, and synthetic route is short；Instead Answer process that racemization does not occur, the chiral purity of obtained Bu Waxitan I crude product is also high；By crystallization rather than Chiral high pressure liquid phase It prepares column to be further purified, the chiral purity of Bu Waxitan I being further increased to 99.80% or more, (de value is big In 99.80%), at the same Bu Waxitan I other are single miscellaneous less than 0.1%, it is other to reach api class, is 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 the reality It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient The selection of product specification.
Embodiment 1:
By (R) -3- methoxycarbonyl caproic acid, (174.1g, 1mol, ee value are 99.2%) to be dissolved in 500mL methanol, are cooled down To 0 DEG C, 500mL water is added, is cooled to 0 DEG C, sequentially adds the second of powdered calcium chloride (115.8g, 1.1mol) and sodium borohydride Alcoholic solution (2M, 800mL).Reaction solution is stirred overnight (about 12 hours) under (20 DEG C~30 DEG C) and hydrochloric acid reaction is added afterwards (6M, 1000mL) is concentrated under reduced pressure, and the dilution of 500mL water is added, and methylene chloride extracts (3 × 150mL), merges organic phase, anhydrous sulphur Sour sodium dries, filters, and Furanones compound III 108.9g, yield 85.0%, purity: 97.2% are obtained after reduced pressure (GC)。
R-3- methoxycarbonyl caproic acid can according to Angewandte Chemie International Edition, The preparation of method described in 1998,37 (13-14), 1931-1933, ee value are greater than 99.0%.
Embodiment 2:
Under nitrogen protection, Furanones compound III (128.1g, 1mol) is dissolved in 1L methylene chloride, is cooled to 0 DEG C, it is added Iodotrimethylsilane (150mL), reaction solution stirs 2 hours at 20~30 DEG C.Then sequentially add hydrochloric acid solution (mass percent 10%, the mass percent refer to sodium thiosulfate for (1M, 800mL) and sodium thiosulfate solution Quality and sodium thiosulfate solution gross mass percentage, 400mL.), water phase is extracted with 1L methylene chloride, and organic phase is used Saturated common salt is washed twice, and anhydrous sodium sulfate dries, filters, and Bu Waxitan intermediate compound IV (254.6g) is obtained after reduced pressure, Yield 99.5%, purity: 95.6% (GC).
Embodiment 3:
Under nitrogen protection, Bu Waxitan intermediate compound IV (1280.4g, 4mol) is dissolved in 1500mL toluene, is slowly added Enter thionyl chloride (951.8g, 8mol), reaction solution stirs 24 hours at (20 DEG C~30 DEG C) of room temperature, and solvent is concentrated under reduced pressure.It is remaining Object vacuum pump pressure rectifying (0.32mmHg, 90-95 DEG C) obtains flaxen transparency liquid compound V 1310g.
Obtained compound V 1310g is dissolved in 2.5L dichloromethane solution.The addition of above-mentioned solution is then contained into L-2- Amino-butanamide hydrochloride (428.9g, 4.2mol), 4A molecular sieve (500g), potassium hydroxide (500g), anhydrous sodium sulfate In the dichloromethane solution (12.5L) of (500g), tetrabutylammonium bromide (49g, 0.14mol), reaction solution stirs at 20~30 DEG C Diatomite filtering is added after mixing 18 hours, filtrate decompression is concentrated to dryness to obtain Bu Waxitan (I) crude product.With ethyl acetate and isopropyl Mixed liquor (ethyl acetate/isopropanol volume ratio is 90:10) mashing filtering of alcohol, isopropyl ether recrystallize get Bu Waxitan (543.5g, two step total recoverys 64%).HPLC:99.86%, largest single impurity 0.08%, de value: 99.84%.
Comparative example 1:(bibliography WO2007031263A1)
The chiral preparation liquid phase separation of 11.7g Bu Waxitan mixed body (1:1) progress, 20 μm of Chiralpak AD, 100* 500mm column, mobile phase be normal heptane, ethyl alcohol (volume ratio 50:50), available Bu Waxitan 5.20g, yield 44%, HPLC purity: 99.26%, largest single impurity 0.20%, de value: 98.60%.

Claims (56)

1. a kind of preparation method of Furanones compound III, it is characterised in that it is the following steps are included: -5 DEG C~0 DEG C, Xiang Hua The mixture for sequentially adding that inorganic salts and reducing agent and solvent are formed in the mixture that object II and solvent are formed is closed, react To Furanones compound III；The solvent is the mixed of aliphatic alcohols solvent or aliphatic alcohols solvent and water Bonding solvent；The aliphatic alcohols solvent is methanol and/or ethyl alcohol；The reducing agent is sodium borohydride, lithium borohydride, boron One of hydrofining, 3-sec-butyl lithium borohydride and lithium triethylborohydride are a variety of；The inorganic salts are calcium chloride；Institute The molar ratio of the reducing agent and the compound II stated is 1.5~2；The inorganic salts rub with the compound II's Your ratio is 1.1~2；When the mixed solvent using aliphatic alcohols solvent and water makees solvent, the aliphatic alcohols is molten The volume ratio of agent and the water is 1~5；
2. the preparation method of Furanones compound III as described in claim 1, it is characterised in that:
In the preparation method of the Furanones compound III, the temperature of the reaction is 20 DEG C~30 DEG C.
3. the preparation method of Furanones compound III as described in claim 1, it is characterised in that:
In the preparation method of the Furanones compound III, the time of the reaction is 1 hour~24 hours.
4. the preparation method of Furanones compound III as described in claim 1, it is characterised in that:
The preparation method of the Furanones compound III uses following post-processing step: after reaction, quenching reaction, Solvent is removed, is diluted with water, extracts, drying, filtering, removing solvent and obtain Furanones compound III.
5. the preparation method of Furanones compound III as described in claim 1, it is characterised in that:
In the preparation method of the Furanones compound III, when the mixed solvent using aliphatic alcohols solvent and water When making solvent, the volume ratio of the aliphatic alcohols solvent and the water is 2~3.
6. the preparation method of Furanones compound III as claimed in claim 3, it is characterised in that:
In the preparation method of the Furanones compound III, the time of the reduction reaction is 8 hours~12 small When.
7. the preparation method of Furanones compound III as claimed in claim 4, it is characterised in that:
In the post-processing step that the preparation method of the Furanones compound III uses, the quenching reaction uses salt Acid.
8. the preparation method of Furanones compound III as claimed in claim 4, it is characterised in that:
In the post-processing step that the preparation method of the Furanones compound III uses, the solvent of the extraction use For halogenated hydrocarbon solvent.
9. the preparation method of Furanones compound III as claimed in claim 4, it is characterised in that:
In the post-processing step that the preparation method of the Furanones compound III uses, the drying uses desiccant It is dry.
10. the preparation method of Furanones compound III as claimed in claim 4, it is characterised in that:
In the post-processing step that the preparation method of the Furanones compound III uses, the mode of the removing solvent For the mode of reduced pressure.
11. a kind of preparation method of compound IV, it is characterised in that the following steps are included: according to any one of claim 1~10 After Furanones compound III is made in the preparation method, then in polar non-proton organic solvent, inert gas shielding Under, the Furanones compound III and iodination reagent are subjected to nucleophilic substitution, obtain compound IV；
12. the preparation method of compound IV as claimed in claim 11, it is characterised in that:
In the preparation method of the compound IV, the inert gas is nitrogen and/or argon gas.
13. the preparation method of compound IV as claimed in claim 11, it is characterised in that:
In the preparation method of the compound IV, the polar non-proton organic solvent be ether solvent, nitrile solvents, One of amide solvent, sulfoxide type solvents and halogenated hydrocarbon solvent are a variety of.
14. the preparation method of compound IV as claimed in claim 11, it is characterised in that:
In the preparation method of the compound IV, the polar non-proton organic solvent is with the compound III's Volume mass ratio is 1mL/g~100mL/g.
15. the preparation method of compound IV as claimed in claim 11, it is characterised in that:
In the preparation method of the compound IV, the iodination reagent is iodine, N-iodosuccinimide and three One of methyl iodide silane is a variety of.
16. the preparation method of compound IV as claimed in claim 11, it is characterised in that:
In the preparation method of the compound IV, the iodination reagent and the compound III molar ratio be 1~ 5。
17. the preparation method of compound IV as claimed in claim 11, it is characterised in that:
In the preparation method of the compound IV, the temperature of the nucleophilic substitution is 20 DEG C~30 DEG C.
18. the preparation method of compound IV as claimed in claim 11, it is characterised in that:
In the preparation method of the compound IV, the time of the nucleophilic substitution is 1 hour~10 hours.
19. the preparation method of compound IV as claimed in claim 11, it is characterised in that:
The preparation method of the compound IV uses following steps: -5~0 DEG C, iodination reagent being added to Furanones chemical combination In the mixture that object III and polar non-proton organic solvent are formed, carries out nucleophilic substitution and obtain compound IV.
20. the preparation method of compound IV as claimed in claim 11, it is characterised in that:
The preparation method of the compound IV uses following post-processing step: after reaction, sequentially adding hydrochloric acid and thio Aqueous sodium persulfate solution, washing, drying, filtering, removes solvent at extraction, obtains compound IV after purification.
21. the preparation method of compound IV as claimed in claim 13, it is characterised in that:
In the preparation method of the compound IV, the ether solvent is tetrahydrofuran and/or methyltetrahydrofuran.
22. the preparation method of compound IV as claimed in claim 13, it is characterised in that: in the preparation of the compound IV In method, the nitrile solvents are acetonitrile.
23. the preparation method of compound IV as claimed in claim 13, it is characterised in that:
In the preparation method of the compound IV, the amide solvent is n,N-Dimethylformamide.
24. the preparation method of compound IV as claimed in claim 13, it is characterised in that:
In the preparation method of the compound IV, the sulfoxide type solvents are dimethyl sulfoxide.
25. the preparation method of compound IV as claimed in claim 13, it is characterised in that:
In the preparation method of the compound IV, the halogenated hydrocarbon solvent is chlorinated hydrocarbon solvent.
26. the preparation method of compound IV as claimed in claim 14, it is characterised in that:
In the preparation method of the compound IV, the polar non-proton organic solvent and the Furanones chemical combination The volume mass ratio of object III is 6mL/g~10mL/g.
27. the preparation method of compound IV as claimed in claim 16, it is characterised in that:
In the preparation method of the compound IV, the iodination reagent and III moles of the Furanones compound Ratio is 1~2.
28. the preparation method of compound IV as claimed in claim 18, it is characterised in that:
In the preparation method of the compound IV, the time of the nucleophilic substitution is 2 hours~6 hours.
29. the preparation method of compound IV as claimed in claim 20, it is characterised in that:
In the post-processing step that the preparation method of the compound IV uses, the molar concentration of the hydrochloric acid be 1mol/L~ 2mol/L, the molar concentration refer to the mole of hydrogen chloride and the ratio of hydrochloric acid total volume.
30. the preparation method of compound IV as claimed in claim 20, it is characterised in that:
In the post-processing step that the preparation method of the compound IV uses, the quality hundred of the sodium thiosulfate solution Divide than being 5%~20%, the mass percent refers to the quality and sodium thiosulfate solution gross mass of sodium thiosulfate Percentage.
31. the preparation method of compound IV as claimed in claim 20, it is characterised in that:
In the post-processing step that the preparation method of the compound IV uses, the solvent that the extraction uses is halogenated hydrocarbon Solvent.
32. the preparation method of compound IV as claimed in claim 20, it is characterised in that:
In the post-processing step that the preparation method of the compound IV uses, the washing is to be washed using saturated common salt It washs.
33. the preparation method of compound IV as claimed in claim 20, it is characterised in that:
In the post-processing step that the preparation method of the compound IV uses, the number of the washing is 1~3 time.
34. the preparation method of compound IV as claimed in claim 20, it is characterised in that:
In the post-processing step that the preparation method of the compound IV uses, the drying is dried using desiccant.
35. the preparation method of compound IV as claimed in claim 20, it is characterised in that:
In the post-processing step that the preparation method of the compound IV uses, the mode of the removing solvent is to be concentrated under reduced pressure Mode.
36. a kind of preparation method of compound V, it is characterised in that it is the following steps are included: any according to claim 11~35 The compound IV and then in organic solvent is made in preparation method described in, by the compound IV and dehydration Agent carries out dehydration and obtains compound V；
37. the preparation method of compound V as claimed in claim 36, it is characterised in that:
In the preparation method of the compound V, organic solvent is one in ether solvent, aromatic hydrocarbon solvent and nitrile solvents Kind is a variety of.
38. the preparation method of compound V as claimed in claim 36, it is characterised in that:
In the preparation method of the compound V, the volume mass ratio of the organic solvent and the compound IV For 0.1mL/g~10mL/g.
39. the preparation method of compound V as claimed in claim 36, it is characterised in that:
In the preparation method of the compound V, the dehydrating agent is one in thionyl chloride, oxalyl chloride and tertiary valeric chloride Kind is a variety of.
40. the preparation method of compound V as claimed in claim 36, it is characterised in that:
In the preparation method of the compound V, the dehydrating agent and the compound IV molar ratio are 1~5.
41. the preparation method of compound V as claimed in claim 36, it is characterised in that:
In the preparation method of the compound V, the temperature of the dehydration is 20 DEG C~30 DEG C.
42. the preparation method of compound V as claimed in claim 36, it is characterised in that:
In the preparation method of the compound V, the time of the dehydration is 20 hours~30 hours.
43. the preparation method of compound V as claimed in claim 36, it is characterised in that:
The preparation method of the compound V carries out under inert gas protection.
44. the preparation method of compound V as claimed in claim 36, it is characterised in that:
The preparation method of the compound V uses following steps: under inert gas shielding, dehydrating agent being added to compound IV In the mixture formed with organic solvent, carries out dehydration and obtain the compound V.
45. the preparation method of compound V as claimed in claim 36, it is characterised in that:
The preparation method of the compound V includes following post-processing step: removing solvent, rectifying after reaction, obtains institute The compound V stated.
46. the preparation method of compound V as claimed in claim 37, it is characterised in that:
In the preparation method of the compound V, the ether solvent is tetrahydrofuran and/or 2- methylfuran.
47. the preparation method of compound V as claimed in claim 37, it is characterised in that:
In the preparation method of the compound V, the aromatic hydrocarbon solvent is toluene.
48. the preparation method of compound V as claimed in claim 37, it is characterised in that:
In the preparation method of the compound V, the nitrile solvents are acetonitrile.
49. the preparation method of compound V as claimed in claim 38, it is characterised in that:
In the preparation method of the compound V, the volume mass ratio of the organic solvent and the compound IV For 1mL/g~3mL/g.
50. the preparation method of compound V as claimed in claim 40, it is characterised in that:
In the preparation method of the compound V, the dehydrating agent and the compound IV molar ratio be 1.5~ 2.5。
51. the preparation method of compound V as claimed in claim 42, it is characterised in that:
In the preparation method of the compound V, the time of the dehydration is 22 hours~26 hours.
52. the preparation method of compound V as claimed in claim 43, it is characterised in that:
When the preparation method of the compound V carries out under inert gas protection, the inert gas be nitrogen and/or Argon gas.
53. the preparation method of compound V as claimed in claim 44, it is characterised in that:
In the step of preparation method of the compound V uses, the mode of the addition is to be added dropwise, the dropwise addition Speed is subject to system temperature no more than 30 DEG C.
54. the preparation method of compound V as claimed in claim 45, it is characterised in that:
In the post-processing step that the preparation method of the compound V includes, the mode of the removing solvent is vacuum distillation.
55. the preparation method of compound V as claimed in claim 45, it is characterised in that:
After reaction, solvent, rectifying are removed, directly carries out preparation institute without further purification after obtaining the compound V The reaction of the Bu Waxitan I stated.
56. a kind of preparation method of Bu Waxitan I, it is characterised in that it is the following steps are included: according to claim 36~55 times The compound V and then in organic solvent is made in preparation method described in one, and anhydrous and inert gas shielding exists Under conditions of, the compound V and L-2- amino-butanamide are subjected to condensation reaction and obtain 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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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
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CN109828049A (en) * 2019-03-04 2019-05-31 成都美域高制药有限公司 A kind of enantiomter (S)-furanone detection method of (R)-furanone
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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