WO2016115962A1 - 一种奈必洛尔中间体的制备方法及奈必洛尔的制备方法 - Google Patents

一种奈必洛尔中间体的制备方法及奈必洛尔的制备方法 Download PDF

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WO2016115962A1
WO2016115962A1 PCT/CN2015/099448 CN2015099448W WO2016115962A1 WO 2016115962 A1 WO2016115962 A1 WO 2016115962A1 CN 2015099448 W CN2015099448 W CN 2015099448W WO 2016115962 A1 WO2016115962 A1 WO 2016115962A1
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formula
compound
group
nebivolol
benzopyran
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PCT/CN2015/099448
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English (en)
French (fr)
Inventor
李洪明
褚长虎
吉都明
缪存铅
毕建豪
杨国胜
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浙江海翔药业股份有限公司
上海海翔医药科技发展有限公司
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Publication of WO2016115962A1 publication Critical patent/WO2016115962A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a process for the preparation of a nebivolol intermediate, and to a process for the preparation of nebivolol or a pharmaceutically acceptable salt thereof using the intermediate.
  • the drug nebivolol is a third-generation adrenergic beta-blocker, a mixture of equimolar amounts of levorotatory and dextro-isomers, in which the dextro-isomer has a strong ⁇ 1 receptor blockade, left-handed
  • the isomers have endothelial cell-dependent vasodilating effects.
  • Nebivolol's chemical structure has four chiral centers with ten chiral isomers.
  • the marketed drug is a racemic composition of equimolar RSSS configuration and the RRRS configuration of nebivolol hydrochloride. body.
  • Patent document WO2008/010022A2 discloses a process for the preparation of nebivolol, a compound of the formula RS/SR-IV (a mixture of a RS-IV compound and an SR-IV compound) and a compound of the formula R/S-I (R-I)
  • the compound is coupled with the S-I compound) to obtain a key intermediate formula RS#S/SR#R-V compound (a mixture of a compound of the formula RS#S-V and a compound of the formula SR#R-V, wherein # represents a compound
  • the carbonyl carbon atom as a latent chiral center is subjected to selective reduction reaction and amino hydrogenation deprotection to obtain nebivolol of the type RSSS/RRRS.
  • the method directly couples the compound of the formula RS/SR-IV with the compound of the formula R/S-I, and the synthesis efficiency is high.
  • the compound of the formula RS#S/SR#R-V produced in this method is mixed with a large proportion of unusable by-products, the formula RS#R/SR#S-V compound, which requires cumbersome derivatization.
  • the recrystallization step is carried out to purify and remove the by-product; at the same time, the generated compound of the formula RS#S/SR#R-V cannot be resolved, and the subsequent reduction reaction is more demanding for the reaction conditions.
  • a first object of the present invention is to provide a process for preparing a nebivolol intermediate compound V which is simple in operation, good in atom economy, high in yield, and low in cost.
  • Another object of the present invention is to provide a process for the preparation of nebivolol or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for preparing a nebivolol intermediate formula RS#S-V compound and a compound of the formula RR#S-V, comprising:
  • X 1 and X 2 each represent a hydrogen atom or a halogen atom attached at any position of the benzene ring; and X 1 and X 2 may be the same group or different;
  • LG is an easy leaving group selected from the group consisting of bromine, chlorine, and sulfonate groups
  • PG is hydrogen or a removable amino protecting group, and the removable amino protecting group is selected from the group consisting of methyl, allyl, tert-butyl, benzyl, benzhydryl, trityl, fluorenyl, a 9,10-dihydroanthracene-9-yl group, wherein when an aromatic ring is present in the protecting group, the aromatic ring may have a substituent selected from the group consisting of halogen, nitro, C 1 -C 4 alkane a group of -CF 3 , -CHF 2 , -OR 2 wherein R 2 is selected from hydrogen, a mono- or di-substituted C 1 -C 4 alkyl group; PG is preferably a benzyl group;
  • the compound of the formula RS/RR-IV refers to a mixture of the compound of the formula RS-IV and the compound of the formula RR-IV, and the molar ratio of the two is not specifically limited.
  • the compound of formula RS/RR-IV is a substantially equimolar amount of a mixture of a compound of formula RS-IV and a compound of formula RR-IV.
  • the hydroxyl group in the structural formula of the compound of the formula RS/RR-IV is connected to the adjacent chiral carbon by a curve, and the curve indicates that the chiral carbon may be of the R type or the S type.
  • the "#" in the compound of the formula RS#S-V and the compound of the formula RR#S-V represents a carbonyl carbon atom as a latent chiral center in the compound.
  • step (1) the chemical reaction of step (1) is carried out under basic conditions, in an inert solvent, under catalyst catalysis.
  • the base in the basic condition is selected from the group consisting of carbonates, hydrogencarbonates, organic bases such as triethylamine, diisopropylethylamine.
  • the base is sodium hydrogencarbonate or potassium hydrogencarbonate.
  • the inert solvent is selected from any one or more of acetone, tetrahydrofuran, acetonitrile, toluene, dichloromethane, ethyl acetate, dimethylformamide, preferably acetonitrile or tetrahydrofuran.
  • the catalyst is selected from any one or more of potassium bromide, potassium iodide, sodium bromide, and sodium iodide, preferably potassium bromide or sodium bromide.
  • the molar ratio of the compound of the formula RS/RR-IV to the compound of the formula S-I is (1.0-2.5):1, preferably (1.0-1.5):1.
  • the compound of the formula RS/RR-IV the compound of the formula S-I: base: the molar ratio of the catalyst is 1.0: (1.0-2.5): (1.0-4.0): (0.05-0.3), preferably 1.0 :(1.0-1.5): 2.0: (0.1-0.15).
  • the temperature of the reaction is from 10 to 80 ° C, preferably from 10 to 50 ° C.
  • the reaction is carried out for a period of from 10 to 60 hours, preferably from 10 to 24 hours.
  • the chiral center of the pyran ring of the compound of formula RS/RR-IV has a purity greater than 90%, preferably greater than 95%, more preferably greater than 99%.
  • the percentage of enantiomeric excess of the compound of formula S-I is greater than 90%, preferably greater than 95%, more preferably greater than 99%.
  • the compound of the formula S-I can be produced by a method known from the prior art, for example, the method disclosed in WO2008/010022A2 or CN102164906A.
  • the compound of the formula RS/RR-IV can be produced by the following method:
  • the compound of the formula RS/RR-III refers to a mixture of the compound of the formula RS-III and the compound of the formula RR-III, and the molar ratio of the two is not particularly limited.
  • the compound of formula RS/RR-III is an equimolar amount of a mixture of a compound of formula RS-III and a compound of formula RR-III.
  • the RS/RR-III compound can be prepared by a method disclosed in, for example, the patent document CN102164906A or WO2008/010022A2, and the specific reaction conditions of the preparation method disclosed in the literature can be appropriately adjusted to obtain different molar ratios.
  • the obtained compound of the formula RS/RR-IV can also be isolated according to the method reported in WO2008/010022A2 to obtain a compound of the formula RR-IV and the formula RS-IV in a single configuration, respectively, which are then combined in any ratio.
  • the compound of the formula RS#S-V can be separated from the compound of the formula RR#S-V by, for example, filtration and/or further recrystallization.
  • the separating step of the step (2) is: the material obtained by the reaction of the step (1) is separated by filtration, and the obtained filter cake is a solid mainly composed of the compound of the formula RS#S-V; The obtained filtrate was concentrated to obtain a solid or a concentrate mainly composed of the compound of the formula RR #S-V.
  • the solid or concentrate of the above formula RS#S-V compound-based solid and the formula RR#S-V compound may be used for the preparation of nebivolol or its hydrochloride salt either directly or after further purification.
  • the method for purifying the solid of the formula RS#S-V compound may be: adding a solid of the formula RS#S-V compound to a solvent, stirring, filtering, removing the residue, and concentrating the filtrate. A solid was obtained.
  • This purification step can be carried out once or repeatedly to obtain a higher purity formula RS#S-V compound.
  • the solvent is selected from the group consisting of acetone, tetrahydrofuran, acetonitrile, toluene, dichloromethane, ethyl acetate or dimethylformamide or any mixture thereof, preferably dichloromethane.
  • the method for purifying the solid or concentrated liquid of the formula RR#S-V compound may be: adding a solid or a concentrated liquid of the formula RR#S-V compound to a poor solvent, stirring, and filtering.
  • the obtained solid is a compound of the formula RS#S-V
  • the filtrate is concentrated to give a compound of the formula RR#S-V.
  • This purification step can be carried out once or repeatedly to obtain a purified compound of the formula RR#S-V.
  • the obtained RS#S-V compound can be combined with the above purified RS#S-V compound with or without further purification.
  • the poor solvent is selected from the group consisting of an alkane, an ether, an alcohol, a nitrile, and an ester solvent, and is preferably an ether solvent.
  • the filtrate obtained by the filtration of the material obtained in the step (1) may be directly added to the poor solvent without concentration or concentration, stirred, and filtered, and the obtained solid is a compound of the formula RS#S-V.
  • the filtrate was concentrated to give the compound of formula RR#S-V.
  • the poor solvent is selected from the group consisting of an alkane, an ether, an alcohol, a nitrile, and an ester solvent, and is preferably an ether solvent.
  • the present invention also provides a method for preparing a nebivolol intermediate formula SR#R-V compound and a compound of the formula SS#R-V, comprising:
  • X 1 and X 2 each represent a hydrogen atom or a halogen atom attached at any position of the benzene ring; and X 1 and X 2 may be the same group or different;
  • LG is an easy leaving group selected from the group consisting of bromine, chlorine, and sulfonate groups
  • PG is hydrogen or a removable amino protecting group
  • the removable amino protecting group is selected from the group consisting of methyl, allyl, tert-butyl, benzyl, benzhydryl, trityl, decyl, 9, a 10-dihydropurin-9-yl group, wherein when an aromatic ring is present in the protecting group, the aromatic ring may have a substituent selected from the group consisting of a halogen, a nitro group, and a C 1 -C 4 alkyl chain.
  • R 2 is selected from hydrogen, a mono- or di-substituted C 1 -C 4 alkyl group;
  • PG is preferably a benzyl group;
  • the compound of the formula SR/SS-IV refers to a mixture of the compound of the formula SR-IV and the compound of the formula SS-IV, and the molar ratio of the two is not particularly limited.
  • the compound of formula SR/SS-IV is a substantially equimolar amount of a mixture of a compound of formula SR-IV and a compound of formula SS-IV.
  • the hydroxyl group in the structural formula of the compound of the formula SR/SS-IV is connected to the adjacent chiral carbon by a curve, and the curve indicates that the chiral carbon may be R type or S type.
  • the "#" in the compound of the formula RS#S-V and the compound of the formula RR#S-V represents a carbonyl carbon atom as a latent chiral center in the compound.
  • step (1) the chemical reaction of step (1) is carried out under basic conditions, in an inert solvent, under catalyst catalysis.
  • the base is selected from the group consisting of carbonates, hydrogencarbonates, organic bases such as triethylamine, diisopropylethylamine, preferably sodium hydrogencarbonate or potassium hydrogencarbonate.
  • the inert solvent is selected from any one or more of acetone, tetrahydrofuran, acetonitrile, toluene, dichloromethane, ethyl acetate, dimethylformamide, preferably acetonitrile or tetrahydrofuran.
  • the catalyst is selected from any one or more of potassium bromide, potassium iodide, sodium bromide, and sodium iodide, preferably potassium bromide or sodium bromide.
  • the molar ratio of the compound of the formula SR/SS-IV to the compound of the formula R-I is from 1.0 to 2.5:1, preferably from 1.0 to 1.5:1.
  • the compound of formula SR/SS-IV compound R-I: base: catalyst is charged in a molar ratio of 1.0: 1.0-2.5: 1.0-4.0: 0.05-0.3, preferably 1.0: 1.0-1.5: 2.0: 0.1-0.15.
  • the temperature of the reaction is from 10 to 80 ° C, preferably from 10 to 50 ° C.
  • the reaction is carried out for a period of from 10 to 60 hours, preferably from 10 to 24 hours.
  • the chiral center of the pyran ring of the compound of formula SR/SS-IV has a purity greater than 90%, preferably greater than 95%, more preferably greater than 99%.
  • the percentage of enantiomeric excess of the compound of formula R-I is greater than 90%, preferably greater than 95%, more preferably greater than 99%.
  • the compound of the formula R-I can be produced by a method known from the prior art, for example, the method disclosed in WO2008/010022A2 or CN102164906A.
  • the compound of the formula SR/SS-IV can be produced by the following method:
  • the compound SR/SS-III is a mixture of a compound of the formula SR-III and a compound of the formula SS-III, both There are no specific restrictions on the molar ratio.
  • the compound of formula SR/SS-III is an equimolar amount of a mixture of a compound of formula SR-III and a compound of formula SS-III.
  • the compound of the formula SR/SS-III can be prepared by a method disclosed in, for example, the patent document CN102164906A or WO2008/010022A2, and the specific reaction conditions of the preparation methods disclosed in the above documents can be appropriately adjusted to obtain different moles.
  • SR/SS-IV can also be isolated according to the method reported in WO2008/010022A2 to obtain SS-IV and SR-IV compounds in a single configuration, respectively, which are then combined in any ratio.
  • the compound of the formula SR#R-V can be separated from the compound of the formula SS#R-V by, for example, filtration and/or further recrystallization.
  • the separating step of the step (2) is an operation of separating the material obtained by the reaction of the step (1), and the obtained filter cake is a solid mainly composed of the compound SR#R-V.
  • the filtrate is concentrated to give a solid or concentrate based on the compound SS#R-V.
  • the solid or concentrate based on the above formula SR#R-V compound and the solid or concentrated SS#R-V compound can be used for the preparation of nebivolol or its hydrochloride salt either directly or after further purification.
  • the method for purifying the solid of the formula SR#R-V compound may be: adding a solid mainly composed of the formula SR#R-V to a solvent, stirring, filtering, removing the residue, and concentrating the filtrate. A solid was obtained.
  • the purification step can be carried out once or repeatedly to obtain a higher purity formula SR#R-V compound.
  • the solvent may be selected from the group consisting of acetone, tetrahydrofuran, acetonitrile, toluene, dichloromethane, ethyl acetate or dimethylformamide or any mixture thereof, preferably dichloromethane.
  • the solid or concentrated liquid of the formula SS#R-V compound may be purified by adding the solid aerosol concentrate of the formula SS#R-V compound to a poor solvent, stirring, and filtering.
  • the obtained solid was a compound of the formula SR#R-V, and the filtrate was concentrated to give a compound of the formula SS#R-V.
  • This purification step can be carried out once or repeatedly to obtain a purified compound of the formula SS#R-V.
  • the obtained formula SR#R-V compound can be combined with the above purified formula SR#R-V compound with or without further purification.
  • the poor solvent is selected from the group consisting of an alkane, an ether, an alcohol, a nitrile, and an ester solvent, and is preferably an ether solvent.
  • the filtrate obtained by the filtration of the material obtained in the step (1) may be directly added to the poor solvent without concentration or concentration, stirred, and filtered, and the obtained solid is a compound of the formula SR#R-V.
  • the filtrate was concentrated to give the compound SS#R-V.
  • the poor solvent is selected from the group consisting of an alkane, an ether, an alcohol, a nitrile, and an ester solvent, and is preferably an ether solvent.
  • the present invention provides a method of preparing nebivolol or a pharmaceutically acceptable salt thereof, comprising:
  • the compound of the formula RS#S-V and the compound of the formula RR#S-V in the step (2) are in a mixture, preferably in a substantially equimolar amount, for example, in a molar ratio. Selective reduction was carried out in the form of a mixture of 1.05:1 to 1:1.05.
  • step (2) is reacted to obtain a mixture of a compound of the formula RSSS-VI and a compound of the formula RRRS-VI, which may be purified or unpurified into the next step to give RSSS-nepirol and RRRS. a mixture of nebivolol and other molar ratios.
  • the reaction obtained in the step (2) can also be separated to obtain a compound of the formula RSSS-VI and a compound of the formula RRRS-VI, respectively, and the PG group and the X 1 and X 2 substituents are respectively removed to obtain an independent RSSS- Nebivolol and RRRS- Nebivolol, then RSSS-Nebivolol and RRRS-Nebivolol were mixed in equimolar amounts to give the product.
  • a small amount of by-products - a compound of the formula RSRS-VI and a compound of the formula RRSS-VI are formed, and the by-product can be directly removed into the next reaction without being removed; or can be removed by a separation and purification method commonly used in the art, such as column chromatography.
  • the recrystallization method or the like is preferably a recrystallization method.
  • the compound of the formula RS#S-V and the compound of the formula RR#S-V in the step (2) are substantially equimolar, for example, in a molar ratio of 1.05:1 to 1:1.05, respectively. Perform a selective reduction.
  • step (2) yields a separate compound of the formula RSSS-VI and a compound of the formula RRRS-VI.
  • An equimolar ratio of the compound of the formula RSSS-VI and the compound of the formula RRRS-VI was mixed, and the next reaction was carried out to obtain a mixture of RSSS-nepirol and RRRS-nepirol in a molar ratio.
  • the compound of the formula RSSS-VI and the compound of the formula RRRS-VI obtained in the step (2) can respectively remove the PG group and the X 1 and X 2 substituents, and obtain independent RSSS- Nebivolol and RRRS-Niebi. Lol, then RSSS-nepirol and RRRS-nepirol are mixed in equimolar amounts to obtain a product.
  • the selective reduction reaction in the step (2) is carried out in the presence of a reducing reagent under Lewis acid catalysis.
  • the reducing agent is selected from the group consisting of sodium borohydride, potassium borohydride, lithium borohydride, calcium borohydride, zinc borohydride, sodium triacetoxyborohydride, lithium aluminum hydride, red aluminum and borane.
  • One or more kinds are preferably sodium borohydride, potassium borohydride or lithium borohydride.
  • the Lewis acid is selected from the group consisting of boron trifluoride, calcium chloride, magnesium chloride, lithium chloride, potassium chloride, barium chloride, manganese chloride, titanium tetrachloride, zinc chloride, copper sulfate, palladium sulfate , one or more of zinc bromide, calcium acetate, palladium chloride, manganese chloride, anhydrous aluminum chloride, aluminum isopropoxide, cesium chloride, magnesium perchlorate and alkoxy titanate, Preferred is palladium chloride, Zinc chloride or alkoxy titanate.
  • the reaction is carried out in a solvent, preferably the solvent is selected from the group consisting of tetrahydrofuran, isopropanol, acetonitrile, diisopropyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, cyclohexane, xylene, toluene, dichloro One or more of methane.
  • a solvent preferably the solvent is selected from the group consisting of tetrahydrofuran, isopropanol, acetonitrile, diisopropyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, cyclohexane, xylene, toluene, dichloro One or more of methane.
  • the reaction temperature is from -40 ° C to 50 ° C and the reaction time is from 0.5 to 40 hours.
  • the reducing agent is sodium borohydride
  • the Lewis acid is zinc chloride or tetraisopropyl titanate
  • the solvent is ethylene glycol dimethyl ether
  • the reaction temperature is -10 ° C -10 °C
  • the reaction time is 15-20 hours.
  • the selective reduction reaction in the step (2) also generates a small amount of by-products - a compound of the formula RSRS-VI and a compound of the formula RRSS-VI, which may be directly removed into the next reaction without being removed;
  • the separation and purification method is removed, for example, column chromatography, recrystallization, or the like, and is preferably a recrystallization method.
  • the solvent used in the recrystallization method is selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, tetrahydrofuran, diisopropyl ether, toluene, acetone, cyclohexane or any mixture thereof, more preferably methanol, Isopropyl alcohol, ethyl acetate or a mixture thereof.
  • the recrystallization removal step results in an HPLC chiral purity of the formula RSSS/RRRS-VI compound of the material greater than 98%, preferably greater than 99%.
  • step (3) is carried out in the presence of a Pd/C catalyst.
  • the Pd/C catalyst has a Pd content of 5 to 10% by weight, preferably 5% by weight or 10% by weight.
  • the reaction is carried out in a solvent.
  • the solvent is an alcohol solvent, more preferably any one of methanol, ethanol, and isopropanol, and more preferably methanol.
  • the temperature of the reaction is from 25 to 85 ° C, preferably from 30 to 60 ° C; and the reaction time is from 1 to 30 hours, preferably from 2 to 10 hours.
  • the product obtained in the step (3) contains a by-product, it can be removed by a conventional method.
  • the present invention provides a second method for preparing nebivolol or a pharmaceutically acceptable salt thereof, comprising:
  • the compound of the formula SR#R-V and the compound of the formula SS#R-V in the step (2) are in a mixture, preferably in a substantially equimolar amount, for example, in a molar ratio.
  • 1.05 Mix of 1 to 1:1.05 The way of the object, selective reduction.
  • the step (2) is reacted to obtain a mixture of the compound of the formula SRRR-VI and the compound of the formula SSSR-VI, and the mixture can be subjected to impurity removal or no impurity removal to the next reaction to obtain SRRR-nepirol.
  • reaction obtained in the step (2) can also be separated to obtain a compound of the formula SRRR-VI and a compound of the formula SSSR-VI, respectively, and the PG group and the X 1 and X 2 substituents are respectively removed to obtain an independent SRRR- Nebivolol and SSSR- Nebivolol, and then SRRR-Nebivolol and SSSR-Nebivolol were mixed in equimolar amounts to obtain a product.
  • a small amount of by-products, a compound of the formula SRSR-VI and a compound of the formula SSRR-VI, are produced, and the by-products may be directly removed into the next reaction without being removed; or may be removed by a separation and purification method commonly used in the art, such as column chromatography.
  • the recrystallization method or the like is preferably a recrystallization method.
  • the compound of the formula SR#R-V and the compound of the formula SS#R-V in the step (2) are substantially equimolar ratio, for example, in a molar ratio of 1.05:1 to 1:1.05, respectively. Perform a selective reduction.
  • step (2) yields a separate compound of the formula SRRR-VI and a compound of the formula SSSR-VI.
  • An equimolar ratio of the compound of the formula SRRR-VI and the compound of the formula SSSR-VI was carried out, and the next reaction was carried out to obtain a mixture of SRRR-nepirol and SSSR-nepirol in an equimolar ratio.
  • the compound of the formula SRRR-VI and the compound of the formula SSSR-VI obtained in the step (2) can respectively remove the PG group and the X 1 and X 2 substituents to obtain independent SRRR-nepirol and SSSR-naibi. Lol, then SRRR-nepirol and SSSR-nepirol are mixed in equimolar amounts to obtain a product.
  • the selective reduction reaction of step (2) is carried out in the presence of a reducing reagent under Lewis acid catalysis.
  • the reducing agent is selected from the group consisting of sodium borohydride, potassium borohydride, lithium borohydride, calcium borohydride, zinc borohydride, sodium triacetoxyborohydride, lithium aluminum hydride, red aluminum and borane.
  • One or more kinds are preferably sodium borohydride, potassium borohydride or lithium borohydride.
  • the Lewis acid is selected from the group consisting of boron trifluoride, calcium chloride, magnesium chloride, lithium chloride, potassium chloride, barium chloride, manganese chloride, titanium tetrachloride, zinc chloride, copper sulfate, palladium sulfate , one or more of zinc bromide, calcium acetate, palladium chloride, manganese chloride, anhydrous aluminum chloride, aluminum isopropoxide, cesium chloride, magnesium perchlorate and alkoxy titanate, Preference is given to palladium chloride, zinc chloride or alkoxy titanates.
  • the reaction is carried out in a solvent, preferably the solvent is selected from the group consisting of tetrahydrofuran, isopropanol, acetonitrile, diisopropyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, cyclohexane, xylene, toluene, dichloro One or more of methane.
  • a solvent preferably the solvent is selected from the group consisting of tetrahydrofuran, isopropanol, acetonitrile, diisopropyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, cyclohexane, xylene, toluene, dichloro One or more of methane.
  • the reaction temperature is from -40 ° C to 50 ° C and the reaction time is from 0.5 to 40 hours.
  • the reducing agent is sodium borohydride
  • the Lewis acid is calcium chloride or lithium chloride
  • the solvent is tetrahydrofuran
  • the reaction temperature is -5 ° C - 20 ° C
  • the reaction time is 8-12. hour.
  • the selective reduction reaction in the step (2) generates a small amount of a by-product SRSR-VI compound and a compound of the formula SSRR-VI, and the by-product can be removed by a separation and purification method commonly used in the art, for example, column chromatography, recrystallization.
  • the method or the like is preferably a recrystallization method.
  • the solvent used in the recrystallization method is selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, tetrahydrogen Furan, diisopropyl ether, toluene, acetone, cyclohexane or any mixture thereof, more preferably methanol, isopropanol, ethyl acetate or a mixture thereof.
  • the recrystallization removal step results in an HPLC chiral purity of the SRRR/SSSR-VI compound in the material of greater than 99%.
  • step (3) is carried out in the presence of a Pd/C catalyst.
  • the Pd/C catalyst has a Pd content of 5 to 10% by weight, preferably 5% by weight or 10% by weight.
  • the reaction is carried out in a solvent.
  • the solvent is an alcohol solvent, more preferably any one of methanol, ethanol, and isopropanol, and more preferably methanol.
  • the temperature of the reaction is from 25 to 85 ° C, preferably from 30 to 60 ° C; and the reaction time is from 1 to 30 hours, preferably from 2 to 10 hours.
  • the product obtained in the step (3) contains a by-product, it can be removed by a conventional method.
  • the present invention provides a third method of preparing nebivolol or a pharmaceutically acceptable salt thereof, comprising:
  • a compound of the formula RS#S-V, a compound of the formula RR#S-V, a compound of the formula SR#R-V and a compound of the formula SS#R-V are prepared by the above method;
  • RSSS-VI compound and the formula SRRR-VI compound are removed from the PG group, and when X 1 and X 2 are not H, the X 1 and X 2 groups are removed to obtain an equimolar amount.
  • the compound of the formula RS#S-V and the compound of the formula SR#R-V in the step (2) are in a mixture, preferably in a substantially equimolar amount, for example, in a molar ratio. Selective reduction was carried out in the form of a mixture of 1.05:1 to 1:1.05.
  • the step (2) is reacted to obtain a mixture of the compound of the formula RSSS-VI and the compound of the formula SRRR-VI, and the mixture can be subjected to impurity removal or no impurity removal to the next reaction to obtain RSSS-nepirol. a mixture with an equimolar ratio of SRRR-nepirol.
  • the reaction obtained in the step (2) can also be separated to obtain a compound of the formula RSSS-VI and a compound of the formula SRRR-VI, respectively, and the PG group and the X 1 and X 2 substituents are respectively removed to obtain an independent RSSS- Nebivolol and SRRR- Nebivolol, then RSSS- Nebivolol and SRRR-Nebivolol are mixed in equimolar amounts to obtain a product.
  • Step (2) simultaneously produces a small amount of by-products - a compound of the formula RSRS-VI and a compound of the formula SRSR-VI, which may be removed without further removal, and may be directly removed by a separation and purification method commonly used in the art, for example, Column chromatography, recrystallization, and the like are preferably recrystallization methods.
  • the compound of the formula RS#S-V and the compound of the formula SR#R-V in the step (2) are substantially equimolar ratio, for example, in a molar ratio of 1.05:1 to 1:1.05, respectively. Perform a selective reduction.
  • step (2) yields a separate compound of the formula RSSS-VI and a compound of the formula SRRR-VI.
  • An equimolar ratio of the RSSS-VI compound and the compound of the formula SRRR-VI were mixed, and the next reaction was carried out to obtain a mixture of RSSS-nepirol and SRRR-nepirol in a molar ratio.
  • the compound of the formula RSSS-VI and the compound of the formula SRRR-VI obtained in the step (2) can respectively remove the PG group and the X 1 and X 2 substituents, and obtain independent RSSS-nepirol and SRRR-nai Lol, then RSSS-nepirol and SRRR-nepirol are mixed in equimolar amounts to obtain a product.
  • the selective reduction reaction of step (2) is carried out in the presence of a reducing reagent under Lewis acid catalysis.
  • the reducing agent is selected from the group consisting of sodium borohydride, potassium borohydride, lithium borohydride, calcium borohydride, zinc borohydride, sodium triacetoxyborohydride, lithium aluminum hydride, red aluminum and borane.
  • One or more kinds are preferably sodium borohydride, potassium borohydride or lithium borohydride.
  • the Lewis acid is selected from the group consisting of boron trifluoride, calcium chloride, magnesium chloride, lithium chloride, potassium chloride, barium chloride, manganese chloride, titanium tetrachloride, zinc chloride, copper sulfate, palladium sulfate , one or more of zinc bromide, calcium acetate, palladium chloride, manganese chloride, anhydrous aluminum chloride, aluminum isopropoxide, cesium chloride, magnesium perchlorate and alkoxy titanate, Preference is given to palladium chloride, zinc chloride or alkoxy titanates.
  • the reaction is carried out in a solvent, preferably the solvent is selected from the group consisting of tetrahydrofuran, isopropanol, acetonitrile, diisopropyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, cyclohexane, xylene, toluene, dichloro One or more of methane.
  • a solvent preferably the solvent is selected from the group consisting of tetrahydrofuran, isopropanol, acetonitrile, diisopropyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, cyclohexane, xylene, toluene, dichloro One or more of methane.
  • the reaction temperature is from -40 ° C to 50 ° C and the reaction time is from 0.5 to 40 hours.
  • the reducing agent is sodium borohydride
  • the Lewis acid is zinc chloride or tetraisopropyl titanate
  • the solvent is ethylene glycol dimethyl ether
  • the reaction temperature is -10 ° C -10 °C
  • the reaction time is 15-20 hours.
  • the selective reduction reaction in the step (2) also generates a small amount of a by-product RSRS-VI compound and a compound of the formula SRSR-VI, and the by-product can be removed by a separation and purification method commonly used in the art, such as column chromatography, heavy
  • the crystallization method or the like is preferably a recrystallization method.
  • the solvent used in the recrystallization method is selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, tetrahydrofuran, diisopropyl ether, toluene, acetone, cyclohexane or any mixture thereof, more preferably methanol, Isopropyl alcohol, ethyl acetate or a mixture thereof.
  • the recrystallization removal step results in an HPLC chiral purity of the RSSS/SRRR-VI compound in the material of greater than 99%.
  • step (3) is carried out in the presence of a Pd/C catalyst.
  • the Pd/C catalyst has a Pd content of 5 to 10% by weight, preferably 5% by weight or 10% by weight.
  • the reaction is carried out in a solvent.
  • the solvent is an alcohol solvent, more preferably any one of methanol, ethanol, and isopropanol, and more preferably methanol.
  • the temperature of the reaction is from 25 to 85 ° C, preferably from 30 to 60 ° C; and the reaction time is from 1 to 30 hours, preferably from 2 to 10 hours.
  • the product obtained in the step (3) contains a by-product, it can be removed by a conventional method.
  • the present invention provides a fourth method for preparing nebivolol or a pharmaceutically acceptable salt thereof, comprising:
  • a compound of the formula RS#S-V, a compound of the formula RR#S-V, a compound of the formula SR#R-V and a compound of the formula SS#R-V are prepared by the above method;
  • the compound of the formula RR#S-V and the compound of the formula SS#R-V in the step (2) are in a mixture, preferably in a substantially equimolar amount, for example, in a molar ratio. Selective reduction was carried out in the form of a mixture of 1.05:1 to 1:1.05.
  • the step (2) is reacted to obtain a mixture of the compound of the formula RRRS-VI and the compound of the formula SSSR-VI, and the mixture can be subjected to impurity removal or no impurity removal to the next reaction to obtain RRRS-nepirol.
  • reaction obtained in the step (2) can also be separated to obtain a compound of the formula RRRS-VI and a compound of the formula SSSR-VI, respectively, and the PG group and the X 1 and X 2 substituents are respectively removed to obtain an independent RRRS- Nebivolol and SSSR- Nebivolol, then RRRS-Nebivolol and SSSR-Nebivolol were mixed in equimolar amounts to give the product.
  • Step (2) simultaneously generates a small amount of by-products - a compound of the formula RRSS-VI and a compound of the formula SSRR-VI, which may be directly removed into the next reaction without being removed; or may be removed by a separation and purification method commonly used in the art, for example Column chromatography, recrystallization, and the like are preferably recrystallization methods.
  • the compound of the formula RR#S-V and the compound of the formula SS#R-V in the step (2) are in a substantially equimolar ratio, for example, in a molar ratio of 1.05:1 to 1:1.05, respectively. Perform a selective reduction.
  • step (2) yields a separate compound of the formula RRRS-VI and a compound of the formula SSSR-VI.
  • An equimolar ratio of the RRRS-VI compound and the compound of the formula SSSR-VI were mixed, and the next reaction was carried out to obtain a mixture of RRRS-nepirol and SSSR-nepirol in a molar ratio.
  • the compound of the formula RRRS-VI and the compound of the formula SSSR-VI obtained in the step (2) can respectively remove the PG group and the X 1 and X 2 substituents to obtain independent RRRS-nepirol and SSSR-naibi. Lol, then RRRS-nepirol and SSSR-nepirol are mixed in equimolar amounts to obtain a product.
  • the selective reduction reaction of step (2) is carried out in the presence of a reducing reagent under Lewis acid catalysis.
  • the reducing agent is selected from the group consisting of sodium borohydride, potassium borohydride, lithium borohydride, calcium borohydride, zinc borohydride, sodium triacetoxyborohydride, lithium aluminum hydride, red aluminum and borane.
  • One or more kinds are preferably sodium borohydride, potassium borohydride or lithium borohydride.
  • the Lewis acid is selected from the group consisting of boron trifluoride, calcium chloride, magnesium chloride, lithium chloride, potassium chloride, barium chloride, manganese chloride, titanium tetrachloride, zinc chloride, copper sulfate, palladium sulfate , one or more of zinc bromide, calcium acetate, palladium chloride, manganese chloride, anhydrous aluminum chloride, aluminum isopropoxide, cesium chloride, magnesium perchlorate and alkoxy titanate, Preference is given to palladium chloride, zinc chloride or alkoxy titanates.
  • the reaction is carried out in a solvent, preferably the solvent is selected from the group consisting of tetrahydrofuran, isopropanol, acetonitrile, diisopropyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, cyclohexane, xylene, toluene, dichloro One or more of methane.
  • a solvent preferably the solvent is selected from the group consisting of tetrahydrofuran, isopropanol, acetonitrile, diisopropyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, cyclohexane, xylene, toluene, dichloro One or more of methane.
  • the reaction temperature is from -40 ° C to 50 ° C and the reaction time is from 0.5 to 40 hours.
  • the reducing agent is sodium borohydride
  • the Lewis acid is calcium chloride or lithium chloride
  • the solvent is tetrahydrofuran
  • the reaction temperature is -5 ° C - 20 ° C
  • the reaction time is 8-12. hour.
  • the selective reduction reaction in the step (2) generates a small amount of a by-product, a compound of the formula RRSS-VI and a compound of the formula SSRR-VI, which can be removed by a separation and purification method commonly used in the art, such as column chromatography.
  • the recrystallization method or the like is preferably a recrystallization method.
  • the solvent used in the recrystallization method is selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, tetrahydrofuran, diisopropyl ether, toluene, acetone, cyclohexane or any mixture thereof, more preferably methanol, Isopropyl alcohol, ethyl acetate or a mixture thereof.
  • the recrystallization removal step results in an HPLC chiral purity of the formula RRRS/SSSR-VI compound of the material greater than 99%.
  • step (3) is carried out in the presence of a Pd/C catalyst.
  • the Pd/C catalyst has a Pd content of 5 to 10% by weight, preferably 5% by weight or 10% by weight.
  • the reaction is carried out in a solvent.
  • the solvent is an alcohol solvent, more preferably any one of methanol, ethanol, and isopropanol, and more preferably methanol.
  • the temperature of the reaction is from 25 to 85 ° C, preferably from 30 to 60 ° C; and the reaction time is from 1 to 30 hours, preferably from 2 to 10 hours.
  • the product obtained in the step (3) contains a by-product, it can be removed by a conventional method.
  • nebivolol has a symmetrical chemical structure
  • the formula SRRR-nepirol and the formula RRRS- nebivolol are the same compound
  • the formula SSSR-nepirol and the formula RSSS- Nebiolo Is the same compound.
  • the nebivolol preparation method of the present invention adopts a new synthetic idea, that is, a three-dimensional structure-fixed intermediate compound V which first forms a chiral carbon on a pyran ring at both ends, and then uses chirality.
  • the stereochemistry induced to control the position of the hydroxyl group.
  • the RS/RR-IV compound is synthesized by using the RI compound as a raw material, and then the intermediate compound of the formula V is synthesized by using the RS/RR-IV compound and the compound of the formula SI as a raw material, whereby the compound of the formula V is on the pyran ring at both ends.
  • the stereostructure of the chiral carbon is fixed to the R and S types respectively; or, first, the SR compound is synthesized using the SI compound as a raw material, and then the intermediate compound V is synthesized using the SR/SS-IV compound and the RI compound as raw materials.
  • the stereostructure of the chiral carbon on the pyran ring of the compound of formula V is fixed to S and R, respectively; then the chiral induction is used to control the stereochemistry of the hydroxyl position, and the compound of formula V above is selectively reduced to obtain RSSS/ The SRRR-VI compound-based product, through subsequent operations, finally obtained RSSS/SRRR- nebivolol.
  • the method for preparing RSSS/SRRR- Nebivolol of the present invention avoids the formation of a large amount of isomer waste in the prior art such as a compound of the formula RR/SS-IV and a compound of the formula RS#R/SR#SV, thereby greatly improving Raw material utilization rate and RSSS/SRRR- Nebivolol's synthesis efficiency reduces costs.
  • the method of the invention avoids the cumbersome separation operation and the waste recycling problem required for separating the above-mentioned isomer waste in the prior art, the operation steps are greatly simplified, the cost is reduced, and the industrial production is more suitable.
  • the white solid A was dissolved in ethyl acetate at 0 ° C, and then added to a NaOH solution and the mixture was evaporated to ethyl acetate. Concentration gave 91 g of a white solid, which had a HPLC purity of 97.6% of the compound of the formula RSSS/SRRR-VI.
  • Recrystallization refining The white solid obtained in the above step was added to isopropanol (600 ml), and the solution was dissolved under reflux. The mixture was crystallized at room temperature for 15 h, and filtered to give a white solid (75.6 g). The HPLC purity of the formula RSSS/SRRR-VI was 99.3. %.
  • the RSSS-VI compound was prepared by using the compound of the formula RS#S-V prepared by the method of Example 5 as a raw material.
  • the SRRR-VI compound was prepared by the procedure of Example 7 by the procedure of Example 7 to prepare the compound of the formula SR#R-V.
  • Example 10 the compound of the formula RR#S-V prepared by the method of Example 5 was used as a starting material to prepare the title compound.
  • the obtained SRRR/RSSS-Nebivolol was dissolved in 300 ml of methanol, and hydrogen chloride gas was passed at a low temperature to prepare nebivolol hydrochloride.
  • the activated carbon was decolorized, the activated carbon was removed by hot filtration, and the filtrate was stirred and cooled to form a white crystal.
  • the solid nebivolol hydrochloride was 13.8 g, and the HPLC purity was 99.5%.
  • R-6-fluoro-8-bromo-(2R/S)-2-epoxyethyl-1-benzopyran (1.45 g, 5.3 mmol) obtained according to the procedure of Example 14.2.
  • Benzylamine (1.99 g, 18.6 mmol) and isopropanol (10 mL) were refluxed for 3 h and the reaction was completed.
  • the solvent was evaporated, the ⁇ 2R)-1-benzopyran-2-yl]-(1R/S)-1-ethanol 1.3 g, yield 63%.
  • R-6-fluoro-1-benzopyran-2-carboxylic acid methyl ester (5 g, 23.8 mmol), NCS (4.76 g, 35.3 mmol), FeCl 3 (0.384 g, 2.38 mmol), was placed in a 100 mL three-neck flask. Chloroform (50 mL) was heated to reflux. After the reaction was completed, it was cooled to room temperature, and the mixture was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Methyl benzopyran-2-carboxylate 4.91 g, yield 84%, HPLC purity 98.73%.
  • R-6-fluoro-8-chloro-1-benzopyran-2-carboxylic acid methyl ester (3.0 g, 12.2 mmol) was placed in a 100 mL three-necked flask, and anhydrous tetrahydrofuran (35 mL) was added under a nitrogen atmosphere. (2.35 g, 18.4 mmol). After cooling to -70 ° C or less, n-butyllithium n-hexane solution (2.5 M, 7.4 mL, 18.4 mmol) was added dropwise, and the mixture was stirred and stirred for 0.5 h.
  • the R-2-chloro-1-(6-fluoro-8-chloro-1-benzopyran-2-yl)-ethanone prepared by the method of Example 21.2 was placed in a 100 mL single-necked flask (2.3 g, 8.74 mmol). ,2-[(Benzyl)amino]-1-[6-fluoro-(2S)-1-benzopyran-2-yl]-(1R/S)-1-ethanol (2.39 g, 7.94) mmol), NaHCO 3 (1.33g, 15.89mmol), KBr (0.104g, 0.874mmol), in acetonitrile (15mL).
  • SRRR- nebivolol hydrochloride and RSSS-nepirol hydrochloride prepared by the methods of Examples 19 and 20 were mixed in an equimolar amount to obtain SRRR/RSSS-nepirol hydrochloride exotherm. Spin body.

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Abstract

本发明提供一种奈必洛尔中间体式V化合物的制备方法，包括如下方法之一：(1)将RS/RR-IV化合物与式S-I化合物进行偶联对接反应，得到含有式RS#S-V化合物和式RR#S-V化合物的物料，将两种构型的式V化合物进行分离；(2)将SR/SS-IV化合物与式R-I化合物进行偶联对接反应，得到含有式SR#R-V化合物和式SS#R-V化合物的物料，将两种构型的式V化合物进行分离。进一步地，本发明还提供由上述式V化合物制备奈必洛尔或其药学上可接受的盐的方法。本发明所述方法具有操作简便、反应条件温和、原子经济性好、收率高、成本低等特点，适合工业化生产。

Description

一种奈必洛尔中间体的制备方法及奈必洛尔的制备方法 技术领域
本发明涉及一种奈必洛尔中间体的制备方法，以及应用该中间体制备奈必洛尔或其药学上可接受的盐的方法。
背景技术
药品奈必洛尔是第三代肾上腺素β受体阻滞剂，是等摩尔量的左旋和右旋异构体的混合物，其中右旋异构体有强大的β1受体阻滞作用，左旋异构体具有内皮细胞依赖性血管扩张作用。奈必洛尔的化学结构具有四个手性中心，共十个手性异构体，上市药品是等摩尔量的RSSS构型和RRRS构型的奈必洛尔盐酸盐组成的外消旋体。
专利文献WO2008/010022A2公开了一种奈必洛尔的制备方法，将式RS/SR-Ⅳ化合物(RS-Ⅳ化合物与SR-Ⅳ化合物的混合物)与式R/S-Ⅰ化合物(R-Ⅰ化合物与S-Ⅰ化合物的混合物)偶联对接，得到关键中间体式RS#S/SR#R-Ⅴ化合物(式RS#S-Ⅴ化合物与式SR#R-Ⅴ化合物的混合物，其中#表示化合物中作为潜手性中心的羰基碳原子)，经选择性还原反应、氨基氢化脱保护，获得RSSS/RRRS型奈必洛尔。
Figure PCTCN2015099448-appb-000001
该方法直接以式RS/SR-Ⅳ化合物与式R/S-I化合物偶联对接，合成效率较高。然而，该方法中生成的式RS#S/SR#R-Ⅴ化合物中混有较大比例的无法应用的副产物——式RS#R/SR#S-Ⅴ化合物，需要采用繁琐的衍生化和/或重结晶步骤进行纯化除去所述副产物；而同时，生成的式RS#S/SR#R-Ⅴ化合物无法进行拆分，进行后续还原反应时对于反应条件要求较为苛刻。
此外，该方法在合成式RS/SR-Ⅳ化合物的过程中也同时生成了较大比例的无法应用的 副产物——式RR/SS-Ⅳ化合物，同样需要采用繁琐的分步重结晶步骤除去所述副产物。
由于上述副产物不能得到有效利用，导致目标产物的收率较低，原子经济性差，同时这些副产物的回收处理也需要消耗一定的成本。
因此，需要一种操作简单、原料经济性好、收率高、成本低的制备所述奈必洛尔中间体式V化合物的方法，以及应用该中间体制备奈必洛尔的方法。
发明内容
本发明的第一个目的在于提供一种操作简单、原子经济性好、收率高、成本低的制备奈必洛尔中间体式Ⅴ化合物的方法。
本发明的另一目的在于提供一种制备奈必洛尔或其药学上可接受的盐的方法。
本发明的目的是通过如下技术方案实现的：
本发明提供一种制备奈必洛尔中间体式RS#S-Ⅴ化合物和式RR#S-Ⅴ化合物的方法，包括：
(1)将式RS/RR-Ⅳ化合物与式S-I化合物进行偶联对接反应，得到含有式RS#S-Ⅴ化合物和式RR#S-Ⅴ化合物的物料，
Figure PCTCN2015099448-appb-000002
其中，X1和X2各自代表苯环任意位置上连接的氢原子或卤素原子；X1与X2可以为相同的基团，也可以不同；
LG为易于离去基团，选自溴、氯、磺酸酯基；
PG为氢或可脱除的氨基保护基，所述可脱除的氨基保护基选自甲基、烯丙基、叔丁基、苄基、二苯甲基、三苯甲基、芴基、9,10-二氢蒽-9-基，其中在所述保护基中存在芳环时，芳环上可以带有取代基，所述取代基选自卤素、硝基、C1-C4烷基、-CF3、-CHF2、-OR2基团，其中R2选自氢、单一取代或二取代的C1-C4烷基；PG优选为苄基；
(2)将步骤(1)所得物料分离，分别得到式RS#S-Ⅴ化合物和式RR#S-Ⅴ化合物。
其中，所述式RS/RR-Ⅳ化合物是指式RS-Ⅳ化合物与式RR-Ⅳ化合物的混合物，且对二者的摩尔比没有具体限制。
在本发明一种实施方式中，所述式RS/RR-Ⅳ化合物为基本上等摩尔量的式RS-Ⅳ化合物与式RR-Ⅳ化合物的混合物。
需要说明的是，本发明中，式RS/RR-Ⅳ化合物的结构式中羟基与相邻的手性碳以曲线连接，该曲线表示所述手性碳可以为R型或S型。式RS#S-Ⅴ化合物和式RR#S-Ⅴ化合物中的“#”表示化合物中作为潜手性中心的羰基碳原子。
优选地，步骤(1)的化学反应在碱性条件下，惰性溶剂中，催化剂催化下进行。
优选地，所述碱性条件中的碱选自碳酸盐、碳酸氢盐、有机碱，所述有机碱例如三乙基胺、二异丙基乙基胺。优选地，所述碱为碳酸氢钠或碳酸氢钾。
优选地，所述惰性溶剂选自丙酮、四氢呋喃、乙腈、甲苯、二氯甲烷、乙酸乙酯、二甲基甲酰胺中任意一种或多种，优选为乙腈或四氢呋喃。
优选地，所述的催化剂选自溴化钾、碘化钾、溴化钠、碘化钠中的任意一种或多种，优选为溴化钾或溴化钠。
优选地，所述式RS/RR-Ⅳ化合物与所述式S-Ⅰ化合物的摩尔比为(1.0-2.5):1，优选为(1.0-1.5):1。
优选地，所述式RS/RR-Ⅳ化合物:式S-Ⅰ化合物:碱:催化剂的投料摩尔比为1.0:(1.0-2.5):(1.0-4.0):(0.05-0.3)，优选为1.0:(1.0-1.5):2.0:(0.1-0.15)。
优选地，所述反应的温度为10-80℃，优选10-50℃。
优选地，所述反应的时间为10-60小时，优选10-24小时。
优选地，所述式RS/RR-Ⅳ化合物的吡喃环上手性中心的纯度大于90％，优选大于95％，更优选大于99％。
优选地，所述式S-Ⅰ化合物的对映体过量百分比大于90％，优选大于95％，更优选大于99％。
上述反应中，所述式S-Ⅰ化合物可通过现有方法，例如文献WO2008/010022A2或CN102164906A公开的方法进行制备。
上述反应中，式RS/RR-Ⅳ化合物可以通过如下方法制备：
使式RS/RR-Ⅲ化合物与NH2PG反应生成式RS/RR-Ⅳ化合物
Figure PCTCN2015099448-appb-000003
其中所述式RS/RR-Ⅲ化合物是指式RS-Ⅲ化合物与式RR-Ⅲ化合物的混合物，对二者的摩尔比没有具体限制。
在本发明一种实施方式中，所述式RS/RR-Ⅲ化合物为等摩尔量的式RS-Ⅲ化合物与式RR-Ⅲ化合物的混合物。
所述RS/RR-Ⅲ化合物可以通过例如专利文献CN102164906A或WO2008/010022A2公开的方法进行制备，且本领域技术人员可对该文献公开的制备方法的具体反应条件进行适当调整，以获得不同摩尔比的式RS-Ⅲ化合物与式RR-Ⅲ化合物的混合物。
制得的式RS/RR-Ⅳ化合物也可以根据WO2008/010022A2报道的方法进行分离，分别得到单一构型的式RR-Ⅳ和式RS-Ⅳ化合物，然后二者配成任意比例的混合物。
步骤(2)中，可通过例如过滤和/或进一步重结晶的方式将式RS#S-Ⅴ化合物与式RR#S-Ⅴ化合物分离。
在本发明的一种实施方式中，步骤(2)所述分离步骤的操作为：将步骤(1)反应所得的物料过滤分离，所得滤饼为式RS#S-Ⅴ化合物为主的固体；所得滤液浓缩，得到式RR#S-Ⅴ化合物为主的固体或浓缩液。
上述式RS#S-Ⅴ化合物为主的固体和式RR#S-Ⅴ化合物为主的固体或浓缩液可以直接、或经过进一步纯化后用于制备奈必洛尔或其盐酸盐。
优选地，所述式RS#S-Ⅴ化合物为主的固体的纯化方法可以为：将所述式RS#S-Ⅴ化合物为主的固体加入溶剂中，搅拌，过滤，除去滤渣，滤液浓缩，得到固体。该纯化步骤可进行一次或重复多次，得到较高纯度的式RS#S-Ⅴ化合物。所述溶剂选自丙酮、四氢呋喃、乙腈、甲苯、二氯甲烷、乙酸乙酯或二甲基甲酰胺或其任意混合物，优选为二氯甲烷。采用这样的纯化方法能够除去所述式RS#S-Ⅴ化合物为主的固体中含有的无机盐等杂质，从而得到纯度更高的式RS#S-Ⅴ化合物。
优选地，所述式RR#S-Ⅴ化合物为主的固体或浓缩液的纯化方法可以为：将所述式RR#S-Ⅴ化合物为主的固体或浓缩液加入不良溶剂中，搅拌，过滤，所得固体为式RS#S-Ⅴ化合物，滤液浓缩得到式RR#S-Ⅴ化合物。该纯化步骤可进行一次或重复多次，得到纯化的式RR#S-Ⅴ化合物。其中，所得式RS#S-Ⅴ化合物可以经过或不经过进一步纯化，与上述纯化的式RS#S-Ⅴ化合物合并。所述不良溶剂选自烷烃、醚、醇、腈、酯类溶剂，优选为醚类溶剂。通过采用该方法，可以得到纯化的式RR#S-Ⅴ化合物，同时可以将滤液中溶解的式RS#S-Ⅴ化合物充分分离出来，避免浪费。
在本发明的另一种实施方式中，步骤(1)所得物料过滤所得的滤液也可以不经浓缩或经浓缩后直接加入不良溶剂，搅拌，过滤，所得固体为式RS#S-Ⅴ化合物，滤液浓缩得到式RR#S-Ⅴ化合物。所述不良溶剂选自烷烃、醚、醇、腈、酯类溶剂，优选为醚类溶剂。
本发明还提供一种制备奈必洛尔中间体式SR#R-Ⅴ化合物和式SS#R-Ⅴ化合物的方法，包括：
(1)将式SR/SS-Ⅳ化合物与式R-Ⅰ化合物进行偶联对接反应，得到含有式SR#R-Ⅴ化合物和式SS#R-Ⅴ化合物的物料，
Figure PCTCN2015099448-appb-000004
其中，X1和X2各自代表苯环任意位置上连接的氢原子或卤素原子；X1与X2可以为相同的基团，也可以不同；
LG为易于离去基团，选自溴、氯、磺酸酯基；
PG为氢或可脱除的氨基保护基，可脱除的氨基保护基选自甲基、烯丙基、叔丁基、苄基、二苯甲基、三苯甲基、芴基、9,10-二氢蒽-9-基，其中在所述保护基中存在芳环时，芳环上可以带有取代基，所述取代基选自卤素、硝基、C1-C4烷基链、-CF3、-CHF2、-OR2基 团，其中R2选自氢、单一取代或二取代的C1-C4烷基；PG优选为苄基；
(2)将步骤(1)所得物料分离，分别得到式SR#R-Ⅴ化合物和式SS#R-Ⅴ化合物。
其中，所述式SR/SS-Ⅳ化合物是指式SR-Ⅳ化合物与式SS-Ⅳ化合物的混合物，且对二者的摩尔比没有具体限制。
在本发明一种实施方式中，所述式SR/SS-Ⅳ化合物为基本上等摩尔量的式SR-Ⅳ化合物与式SS-Ⅳ化合物的混合物。
需要说明的是，本发明中，式SR/SS-Ⅳ化合物的结构式中羟基与相邻的手性碳以曲线连接，该曲线表示所述手性碳可以为R型或S型。式RS#S-Ⅴ化合物和式RR#S-Ⅴ化合物中的“#”表示化合物中作为潜手性中心的羰基碳原子。
优选地，步骤(1)的化学反应在碱性条件下，惰性溶剂中，催化剂催化下进行。
优选地，所述碱选自碳酸盐、碳酸氢盐、有机碱如三乙基胺、二异丙基乙基胺，优选碳酸氢钠或碳酸氢钾。
优选地，所述惰性溶剂选自丙酮、四氢呋喃、乙腈、甲苯、二氯甲烷、乙酸乙酯、二甲基甲酰胺中任意一种或多种，优选为乙腈或四氢呋喃。
优选地，所述的催化剂选自溴化钾、碘化钾、溴化钠、碘化钠中的任意一种或多种，优选为溴化钾或溴化钠。
优选地，所述式SR/SS-Ⅳ化合物与所述式R-Ⅰ化合物的摩尔比为1.0-2.5:1，优选为1.0-1.5:1。
优选地，所述的式SR/SS-Ⅳ化合物:式R-Ⅰ化合物:碱:催化剂的投料摩尔比为1.0:1.0-2.5:1.0-4.0:0.05-0.3，优选为1.0:1.0-1.5:2.0:0.1-0.15。
优选地，所述反应的温度为10-80℃，优选10-50℃。
优选地，所述反应的时间为10-60小时，优选10-24小时。
优选地，所述式SR/SS-Ⅳ化合物的吡喃环上手性中心的纯度大于90％，优选大于95％，更优选大于99％。
优选地，所述式R-Ⅰ化合物的对映体过量百分比大于90％，优选大于95％，更优选大于99％。
上述反应中，所述式R-Ⅰ化合物可通过现有方法，例如文献WO2008/010022A2或CN102164906A公开的方法进行制备。
上述反应中，式SR/SS-Ⅳ化合物可通过如下方法制备：
使SR/SS-Ⅲ化合物与NH2PG反应生成式SR/SS-Ⅳ化合物
Figure PCTCN2015099448-appb-000005
其中所述式SR/SS-Ⅲ化合物是指式SR-Ⅲ化合物与式SS-Ⅲ化合物的混合物，对二者的 摩尔比没有具体限制。
在本发明一种实施方式中，所述式SR/SS-Ⅲ化合物为等摩尔量的式SR-Ⅲ化合物与式SS-Ⅲ化合物的混合物。
所述式SR/SS-Ⅲ化合物可通过例如专利文献CN102164906A或WO2008/010022A2公开的方法进行制备，且本领域技术人员可对上述文献公开的制备方法的具体反应条件进行适当调整，以获得不同摩尔比的式SR-Ⅲ化合物与式SS-Ⅲ化合物的混合物。
制得的式SR/SS-Ⅳ化合物也可以根据WO2008/010022A2报道的方法进行分离，分别得到单一构型的SS-Ⅳ和SR-Ⅳ化合物,然后二者配成任意比例的混合物。
步骤(2)中，可通过例如过滤和/或进一步重结晶的方式将式SR#R-V化合物与式SS#R-Ⅴ化合物分离。
在本发明的一种实施方式中，步骤(2)所述分离步骤的操作为：将步骤(1)反应所得的物料过滤分离，所得滤饼为式SR#R-Ⅴ化合物为主的固体，滤液浓缩得到式SS#R-Ⅴ化合物为主的固体或浓缩液。
上述式SR#R-Ⅴ化合物为主的固体和式SS#R-Ⅴ化合物为主的固体或浓缩液可以直接、或经过进一步纯化后用于制备奈必洛尔或其盐酸盐。
优选地，所述式SR#R-Ⅴ化合物为主的固体的纯化方法可以为：将所述式SR#R-Ⅴ化合物为主的固体加入溶剂中，搅拌，过滤，除去滤渣，滤液浓缩，得到固体。所述纯化步骤可进行一次或重复多次，得到较高纯度的式SR#R-Ⅴ化合物。所述溶剂可选自丙酮、四氢呋喃、乙腈、甲苯、二氯甲烷、乙酸乙酯或二甲基甲酰胺或其任意混合物，优选为二氯甲烷。采用这样的纯化方法能够除去所述式SR#R-Ⅴ化合物为主的固体中含有的无机盐等杂质，从而得到纯度更高的式SR#R-Ⅴ化合物。
优选地，所述式SS#R-Ⅴ化合物为主的固体或浓缩液的纯化方法可以为：将所述式SS#R-Ⅴ化合物为主的固体火炮浓缩液加入不良溶剂，搅拌，过滤，所得固体为式SR#R-Ⅴ化合物，滤液浓缩得到式SS#R-Ⅴ化合物。该纯化步骤可进行一次或重复多次，得到纯化的式SS#R-Ⅴ化合物。其中，所得式SR#R-Ⅴ化合物可以经过或不经过进一步纯化，与上述纯化的式SR#R-Ⅴ化合物合并。所述不良溶剂选自烷烃、醚、醇、腈、酯类溶剂，优选为醚类溶剂。通过采用该方法，可以得到纯化的式SS#R-Ⅴ化合物，同时可以将滤液中溶解的式SR#R-Ⅴ化合物充分分离出来，从而避免产物的浪费。
在本发明的另一种实施方式中，步骤(1)所得物料过滤所得的滤液也可以不经浓缩或经浓缩后直接加入不良溶剂，搅拌，过滤，所得固体为式SR#R-Ⅴ化合物，滤液浓缩得到式SS#R-Ⅴ化合物。所述不良溶剂选自烷烃、醚、醇、腈、酯类溶剂，优选为醚类溶剂。
进一步地，本发明提供一种制备奈必洛尔或其药学上可接受的盐的方法，包括：
(1)采用上述方法制备式RS#S-Ⅴ化合物和式RR#S-Ⅴ化合物；
(2)将所得式RS#S-Ⅴ化合物和式RR#S-Ⅴ化合物进行选择性还原，得到式RSSS-Ⅵ 化合物和式RRRS-Ⅵ化合物，
Figure PCTCN2015099448-appb-000006
(3)将所得式RSSS-Ⅵ化合物和式RRRS-Ⅵ化合物脱除PG基团，以及当X1、X2不为H时，脱除X1、X2基团，得到等摩尔量的RSSS-奈必洛尔和RRRS-奈必洛尔，或进一步制备其药学上可接受的盐。
在本发明的一种优选的实施方式中，步骤(2)中式RS#S-Ⅴ化合物和式RR#S-Ⅴ化合物以混合物的方式，优选以基本等摩尔量的混合物，例如以摩尔比为1.05:1～1:1.05的混合物的方式，进行选择性还原。
采用该种实施方式时，步骤(2)反应得到式RSSS-Ⅵ化合物和式RRRS-Ⅵ化合物的混合物，该混合物可以经过纯化或不经纯化进入下一步反应，得到RSSS-奈必洛尔和RRRS-奈必洛尔等摩尔比的混合物。
另外，步骤(2)反应得到所述混合物也可以经过分离，分别得到式RSSS-Ⅵ化合物和式RRRS-Ⅵ化合物，二者分别脱除PG基团和X1、X2取代基，得到独立的RSSS-奈必洛尔和RRRS-奈必洛尔，然后将RSSS-奈必洛尔和RRRS-奈必洛尔以等摩尔量混合，得到产品。
同时生成少量副产物——式RSRS-Ⅵ化合物和式RRSS-Ⅵ化合物，所述副产物可以不除去，直接进入下一步反应；也可以采用本领域常用的分离纯化方法除去，例如柱层析法、重结晶法等，优选为重结晶法。
在本发明的另一种实施方式中，步骤(2)中式RS#S-Ⅴ化合物和式RR#S-Ⅴ化合物以基本等摩尔比，例如以摩尔比为1.05:1～1:1.05，分别进行选择性还原。
采用该种实施方式时，步骤(2)得到独立的式RSSS-Ⅵ化合物和式RRRS-Ⅵ化合物。取等摩尔比的式RSSS-Ⅵ化合物和式RRRS-Ⅵ化合物混合，进入下一步反应，得到RSSS-奈必洛尔和RRRS-奈必洛尔等摩尔比的混合物。
另外，步骤(2)得到的式RSSS-Ⅵ化合物和式RRRS-Ⅵ化合物，可以分别脱除PG基团和X1、X2取代基，得到独立的RSSS-奈必洛尔和RRRS-奈必洛尔，然后将RSSS-奈必洛尔和RRRS-奈必洛尔以等摩尔量混合，得到产品。
优选地，步骤(2)中所述选择性还原反应在还原试剂存在下、路易斯酸催化下进行。
优选地，所述的还原试剂选自硼氢化钠，硼氢化钾，硼氢化锂、硼氢化钙、硼氢化锌、三乙酰氧基硼氢化钠、氢化锂铝、红铝和硼烷中的一种或多种，优选为硼氢化钠、硼氢化钾或硼氢化锂。
优选地，所述路易斯酸选自三氟化硼，氯化钙，氯化镁，氯化锂，氯化钾，氯化钡，氯化锰，四氯化钛，氯化锌，硫酸铜，硫酸钯，溴化锌，乙酸钙，氯化钯，氯化锰，无水氯化铝，异丙醇铝，氯化铋，高氯酸镁和烷氧基钛酸酯中的一种或多种，优选为氯化钯， 氯化锌或烷氧基钛酸酯。
所述反应在溶剂中进行，优选地，所述溶剂选自四氢呋喃，异丙醇，乙腈，异丙醚，叔丁基甲醚，乙二醇二甲醚、环己烷，二甲苯，甲苯，二氯甲烷中的一种或多种。
优选地，所述反应温度为-40℃-50℃，反应时间为0.5-40小时。
在本发明一种优选的实施方式中，还原剂采用硼氢化钠，路易斯酸采用氯化锌或四异丙基钛酸酯，溶剂采用乙二醇二甲醚，反应温度为-10℃-10℃，反应时间为15-20小时。
步骤(2)所述选择性还原反应还会生成少量副产物——式RSRS-Ⅵ化合物和式RRSS-Ⅵ化合物，所述副产物可以不除去，直接进入下一步反应；也可以采用本领域常用的分离纯化方法除去，例如柱层析法、重结晶法等，优选为重结晶法。
优选地，所述重结晶法采用的溶剂选自甲醇、乙醇、异丙醇、乙酸乙酯、乙腈、四氢呋喃、异丙醚、甲苯、丙酮、环己烷或其任意混合物，更优选为甲醇、异丙醇、乙酸乙酯或其混合物。
优选地，所述重结晶除杂步骤使物料中式RSSS/RRRS-Ⅵ化合物的HPLC手性纯度大于98％，优选大于99％。
优选地，步骤(3)所述反应在Pd/C催化剂存在下进行。
所述的Pd/C催化剂中为Pd含量为5-10wt％，优选为5wt％或10wt％。
所述反应在溶剂中进行，优选地，所述溶剂为醇类溶剂，更优选为甲醇、乙醇、异丙醇中的任意一种，更优选为甲醇。
优选地，所述反应的温度为25-85℃，优选为30-60℃；反应时间为1-30小时，优选为2-10小时。
当步骤(3)所得产物中含有副产物时，可通过常规方法除去。
进一步地，本发明还提供第二种制备奈必洛尔或其药学上可接受的盐的方法，包括：
(1)采用上述方法制备式SR#R-Ⅴ化合物和式SS#R-Ⅴ化合物；
(2)将所得式SR#R-Ⅴ化合物和式SS#R-Ⅴ化合物进行选择性还原，得到式SRRR-Ⅵ化合物和式SSSR-Ⅵ化合物；
Figure PCTCN2015099448-appb-000007
(3)将所得式SRRR-Ⅵ化合物和式SSSR-Ⅵ化合物脱除PG基团，以及当X1、X2不为H时，脱除X1、X2基团，得到等摩尔量的式SRRR-奈必洛尔和式SSSR-奈必洛尔，或进一步制备其药学上可接受的盐。
在本发明的一种优选的实施方式中，步骤(2)中式SR#R-Ⅴ化合物和式SS#R-Ⅴ化合物以混合物的方式，优选以基本等摩尔量的混合物，例如以摩尔比为1.05:1～1:1.05的混合 物的方式，进行选择性还原。
采用该种实施方式时，步骤(2)反应得到式SRRR-Ⅵ化合物和式SSSR-Ⅵ化合物的混合物，该混合物可以经过除杂或不经除杂进入下一步反应，得到SRRR-奈必洛尔和SSSR-奈必洛尔等摩尔比的混合物。
另外，步骤(2)反应得到所述混合物也可以经过分离，分别得到式SRRR-Ⅵ化合物和式SSSR-Ⅵ化合物，二者分别脱除PG基团和X1、X2取代基，得到独立的SRRR-奈必洛尔和SSSR-奈必洛尔，然后将SRRR-奈必洛尔和SSSR-奈必洛尔以等摩尔量混合，得到产品。
同时生成少量副产物——式SRSR-Ⅵ化合物和式SSRR-Ⅵ化合物，所述副产物可以不除去，直接进入下一步反应；也可以采用本领域常用的分离纯化方法除去，例如柱层析法、重结晶法等，优选为重结晶法。
在本发明的另一种实施方式中，步骤(2)中式SR#R-Ⅴ化合物和式SS#R-Ⅴ化合物以基本等摩尔比，例如以摩尔比为1.05:1～1:1.05，分别进行选择性还原。
采用该种实施方式时，步骤(2)得到独立的式SRRR-Ⅵ化合物和式SSSR-Ⅵ化合物。取等摩尔比的式SRRR-Ⅵ化合物和式SSSR-Ⅵ化合物混合，进入下一步反应，得到SRRR-奈必洛尔和SSSR-奈必洛尔等摩尔比的混合物。
另外，步骤(2)得到的式SRRR-Ⅵ化合物和式SSSR-Ⅵ化合物，可以分别脱除PG基团和X1、X2取代基，得到独立的SRRR-奈必洛尔和SSSR-奈必洛尔，然后将SRRR-奈必洛尔和SSSR-奈必洛尔以等摩尔量混合，得到产品。
优选地，步骤(2)所述选择性还原反应在还原试剂存在下、路易斯酸催化下进行。
优选地，所述的还原试剂选自硼氢化钠，硼氢化钾，硼氢化锂、硼氢化钙、硼氢化锌、三乙酰氧基硼氢化钠、氢化锂铝、红铝和硼烷中的一种或多种，优选为硼氢化钠、硼氢化钾或硼氢化锂。
优选地，所述路易斯酸选自三氟化硼，氯化钙，氯化镁，氯化锂，氯化钾，氯化钡，氯化锰，四氯化钛，氯化锌，硫酸铜，硫酸钯，溴化锌，乙酸钙，氯化钯，氯化锰，无水氯化铝，异丙醇铝，氯化铋，高氯酸镁和烷氧基钛酸酯中的一种或多种，优选为氯化钯，氯化锌或烷氧基钛酸酯。
所述反应在溶剂中进行，优选地，所述溶剂选自四氢呋喃，异丙醇，乙腈，异丙醚，叔丁基甲醚，乙二醇二甲醚、环己烷，二甲苯，甲苯，二氯甲烷中的一种或多种。
优选地，所述反应温度为-40℃-50℃，反应时间为0.5-40小时。
在本发明一种优选的实施方式中，还原剂采用硼氢化钠，路易斯酸采用氯化钙或者氯化锂，溶剂采用四氢呋喃，反应温度为-5℃-20℃下，反应时间为8-12小时。
步骤(2)所述选择性还原反应会生成少量副产物式SRSR-Ⅵ化合物和式SSRR-Ⅵ化合物，所述副产物可采用本领域常用的分离纯化方法除去，例如柱层析法、重结晶法等，优选为重结晶法。
优选地，所述重结晶法采用的溶剂选自甲醇、乙醇、异丙醇、乙酸乙酯、乙腈、四氢 呋喃、异丙醚、甲苯、丙酮、环己烷或其任意混合物，更优选为甲醇、异丙醇、乙酸乙酯或其混合物。
优选地，所述重结晶除杂步骤使物料中SRRR/SSSR-Ⅵ化合物的HPLC手性纯度大于99％。
优选地，步骤(3)所述反应在Pd/C催化剂存在下进行。
所述的Pd/C催化剂中为Pd含量为5-10wt％，优选为5wt％或10wt％。
所述反应在溶剂中进行，优选地，所述溶剂为醇类溶剂，更优选为甲醇、乙醇、异丙醇中的任意一种，更优选为甲醇。
优选地，所述反应的温度为25-85℃，优选为30-60℃；反应时间为1-30小时，优选为2-10小时。
当步骤(3)所得产物中含有副产物时，可通过常规方法除去。
进一步地，本发明提供第三种制备奈必洛尔或其药学上可接受的盐的方法，包括：
(1)采用上述方法制备得到式RS#S-Ⅴ化合物、式RR#S-Ⅴ化合物、式SR#R-Ⅴ化合物和式SS#R-Ⅴ化合物；
(2)取其中式RS#S-Ⅴ化合物和式SR#R-Ⅴ化合物，进行选择性还原，得到式RSSS-Ⅵ化合物和式SRRR-Ⅵ化合物；
(3)将所得式RSSS-Ⅵ化合物和式SRRR-Ⅵ化合物脱除PG基团，以及当X1、X2不为H时，脱除X1、X2基团，得到等摩尔量的式SRRR-奈必洛尔和式SSSR-奈必洛尔，或进一步制备其药学上可接受的盐。
在本发明的一种优选的实施方式中，步骤(2)中式RS#S-Ⅴ化合物和式SR#R-Ⅴ化合物以混合物的方式，优选以基本等摩尔量的混合物，例如以摩尔比为1.05:1～1:1.05的混合物的方式，进行选择性还原。
采用该种实施方式时，步骤(2)反应得到式RSSS-Ⅵ化合物和式SRRR-Ⅵ化合物的混合物，该混合物可以经过除杂或不经除杂进入下一步反应，得到RSSS-奈必洛尔和SRRR-奈必洛尔等摩尔比的混合物。
另外，步骤(2)反应得到所述混合物也可以经过分离，分别得到式RSSS-Ⅵ化合物和式SRRR-Ⅵ化合物，二者分别脱除PG基团和X1、X2取代基，得到独立的RSSS-奈必洛尔和SRRR-奈必洛尔，然后将RSSS-奈必洛尔和SRRR-奈必洛尔以等摩尔量混合，得到产品。
步骤(2)同时生成少量副产物——式RSRS-Ⅵ化合物和式SRSR-Ⅵ化合物，所述副产物可以不除去，直接进入下一步反应；也可以采用本领域常用的分离纯化方法除去，例如柱层析法、重结晶法等，优选为重结晶法。
在本发明的另一种实施方式中，步骤(2)中式RS#S-Ⅴ化合物和式SR#R-Ⅴ化合物以基本等摩尔比，例如以摩尔比为1.05:1～1:1.05，分别进行选择性还原。
采用该种实施方式时，步骤(2)得到独立的式RSSS-Ⅵ化合物和式SRRR-Ⅵ化合物。 取等摩尔比的式RSSS-Ⅵ化合物和式SRRR-Ⅵ化合物混合，进入下一步反应，得到RSSS-奈必洛尔和SRRR-奈必洛尔等摩尔比的混合物。
另外，步骤(2)得到的式RSSS-Ⅵ化合物和式SRRR-Ⅵ化合物，可以分别脱除PG基团和X1、X2取代基，得到独立的RSSS-奈必洛尔和SRRR-奈必洛尔，然后将RSSS-奈必洛尔和SRRR-奈必洛尔以等摩尔量混合，得到产品。
优选地，步骤(2)所述选择性还原反应在还原试剂存在下、路易斯酸催化下进行。
优选地，所述的还原试剂选自硼氢化钠，硼氢化钾，硼氢化锂、硼氢化钙、硼氢化锌、三乙酰氧基硼氢化钠、氢化锂铝、红铝和硼烷中的一种或多种，优选为硼氢化钠、硼氢化钾或硼氢化锂。
优选地，所述路易斯酸选自三氟化硼，氯化钙，氯化镁，氯化锂，氯化钾，氯化钡，氯化锰，四氯化钛，氯化锌，硫酸铜，硫酸钯，溴化锌，乙酸钙，氯化钯，氯化锰，无水氯化铝，异丙醇铝，氯化铋，高氯酸镁和烷氧基钛酸酯中的一种或多种，优选为氯化钯，氯化锌或烷氧基钛酸酯。
所述反应在溶剂中进行，优选地，所述溶剂选自四氢呋喃，异丙醇，乙腈，异丙醚，叔丁基甲醚，乙二醇二甲醚、环己烷，二甲苯，甲苯，二氯甲烷中的一种或多种。
优选地，所述反应温度为-40℃-50℃，反应时间为0.5-40小时。
在本发明一种优选的实施方式中，还原剂采用硼氢化钠，路易斯酸采用氯化锌或四异丙基钛酸酯，溶剂采用乙二醇二甲醚，反应温度为-10℃-10℃，反应时间为15-20小时。
步骤(2)所述选择性还原反应还会生成少量副产物式RSRS-Ⅵ化合物和式SRSR-Ⅵ化合物，所述副产物可采用本领域常用的分离纯化方法除去，例如柱层析法、重结晶法等，优选为重结晶法。
优选地，所述重结晶法采用的溶剂选自甲醇、乙醇、异丙醇、乙酸乙酯、乙腈、四氢呋喃、异丙醚、甲苯、丙酮、环己烷或其任意混合物，更优选为甲醇、异丙醇、乙酸乙酯或其混合物。
优选地，所述重结晶除杂步骤使物料中RSSS/SRRR-Ⅵ化合物的HPLC手性纯度大于99％。
优选地，步骤(3)所述反应在Pd/C催化剂存在下进行。
所述的Pd/C催化剂中为Pd含量为5-10wt％，优选为5wt％或10wt％。
所述反应在溶剂中进行，优选地，所述溶剂为醇类溶剂，更优选为甲醇、乙醇、异丙醇中的任意一种，更优选为甲醇。
优选地，所述反应的温度为25-85℃，优选为30-60℃；反应时间为1-30小时，优选为2-10小时。
当步骤(3)所得产物中含有副产物时，可通过常规方法除去。
进一步地，本发明还提供第四种制备奈必洛尔或其药学上可接受的盐的方法，包括：
(1)采用上述方法制备得到式RS#S-Ⅴ化合物、式RR#S-Ⅴ化合物、式SR#R-Ⅴ化合物和式SS#R-Ⅴ化合物；
(2)将所得式RR#S-Ⅴ化合物和式SS#R-Ⅴ化合物进行选择性还原，得到式RRRS-Ⅵ化合物和式SSSR-Ⅵ化合物；
(3)将所得式RRRS-Ⅵ化合物和式SSSR-Ⅵ化合物脱除PG基团，以及当X1、X2不为H时，脱除X1、X2基团，得到等摩尔量的式SRRR-奈必洛尔和式SSSR-奈必洛尔，或进一步制备其药学上可接受的盐。
在本发明的一种优选的实施方式中，步骤(2)中式RR#S-Ⅴ化合物和式SS#R-Ⅴ化合物以混合物的方式，优选以基本等摩尔量的混合物，例如以摩尔比为1.05:1～1:1.05的混合物的方式，进行选择性还原。
采用该种实施方式时，步骤(2)反应得到式RRRS-Ⅵ化合物和式SSSR-Ⅵ化合物的混合物，该混合物可以经过除杂或不经除杂进入下一步反应，得到RRRS-奈必洛尔和SSSR-奈必洛尔等摩尔比的混合物。
另外，步骤(2)反应得到所述混合物也可以经过分离，分别得到式RRRS-Ⅵ化合物和式SSSR-Ⅵ化合物，二者分别脱除PG基团和X1、X2取代基，得到独立的RRRS-奈必洛尔和SSSR-奈必洛尔，然后将RRRS-奈必洛尔和SSSR-奈必洛尔以等摩尔量混合，得到产品。
步骤(2)同时生成少量副产物——式RRSS-Ⅵ化合物和式SSRR-Ⅵ化合物，所述副产物可以不除去，直接进入下一步反应；也可以采用本领域常用的分离纯化方法除去，例如柱层析法、重结晶法等，优选为重结晶法。
在本发明的另一种实施方式中，步骤(2)中式RR#S-Ⅴ化合物和式SS#R-Ⅴ化合物以基本等摩尔比，例如以摩尔比为1.05:1～1:1.05，分别进行选择性还原。
采用该种实施方式时，步骤(2)得到独立的式RRRS-Ⅵ化合物和式SSSR-Ⅵ化合物。取等摩尔比的式RRRS-Ⅵ化合物和式SSSR-Ⅵ化合物混合，进入下一步反应，得到RRRS-奈必洛尔和SSSR-奈必洛尔等摩尔比的混合物。
另外，步骤(2)得到的式RRRS-Ⅵ化合物和式SSSR-Ⅵ化合物，可以分别脱除PG基团和X1、X2取代基，得到独立的RRRS-奈必洛尔和SSSR-奈必洛尔，然后将RRRS-奈必洛尔和SSSR-奈必洛尔以等摩尔量混合，得到产品。
优选地，步骤(2)所述选择性还原反应在还原试剂存在下、路易斯酸催化下进行。
优选地，所述的还原试剂选自硼氢化钠，硼氢化钾，硼氢化锂、硼氢化钙、硼氢化锌、三乙酰氧基硼氢化钠、氢化锂铝、红铝和硼烷中的一种或多种，优选为硼氢化钠、硼氢化钾或硼氢化锂。
优选地，所述路易斯酸选自三氟化硼，氯化钙，氯化镁，氯化锂，氯化钾，氯化钡，氯化锰，四氯化钛，氯化锌，硫酸铜，硫酸钯，溴化锌，乙酸钙，氯化钯，氯化锰，无水氯化铝，异丙醇铝，氯化铋，高氯酸镁和烷氧基钛酸酯中的一种或多种，优选为氯化钯，氯化锌或烷氧基钛酸酯。
所述反应在溶剂中进行，优选地，所述溶剂选自四氢呋喃，异丙醇，乙腈，异丙醚，叔丁基甲醚，乙二醇二甲醚、环己烷，二甲苯，甲苯，二氯甲烷中的一种或多种。
优选地，所述反应温度为-40℃-50℃，反应时间为0.5-40小时。
在本发明一种优选的实施方式中，还原剂采用硼氢化钠，路易斯酸采用氯化钙或氯化锂，溶剂采用四氢呋喃，反应温度为-5℃-20℃下，反应时间为8-12小时。
步骤(2)所述选择性还原反应会生成少量副产物——式RRSS-Ⅵ化合物和式SSRR-Ⅵ化合物，所述副产物可采用本领域常用的分离纯化方法除去，例如柱层析法、重结晶法等，优选为重结晶法。
优选地，所述重结晶法采用的溶剂选自甲醇、乙醇、异丙醇、乙酸乙酯、乙腈、四氢呋喃、异丙醚、甲苯、丙酮、环己烷或其任意混合物，更优选为甲醇、异丙醇、乙酸乙酯或其混合物。
优选地，所述重结晶除杂步骤使物料中式RRRS/SSSR-Ⅵ化合物的HPLC手性纯度大于99％。
优选地，步骤(3)所述反应在在Pd/C催化剂存在下进行。
所述的Pd/C催化剂中为Pd含量为5-10wt％，优选为5wt％或10wt％。
所述反应在溶剂中进行，优选地，所述溶剂为醇类溶剂，更优选为甲醇、乙醇、异丙醇中的任意一种，更优选为甲醇。
优选地，所述反应的温度为25-85℃，优选为30-60℃；反应时间为1-30小时，优选为2-10小时。
当步骤(3)所得产物中含有副产物时，可通过常规方法除去。
需要说明的是，由于奈必洛尔具有对称的化学结构，因此式SRRR-奈必洛尔和式RRRS-奈必洛尔为同一化合物，式SSSR-奈必洛尔与式RSSS-奈必洛尔为同一化合物。
与现有技术相比，本发明的奈必洛尔制备方法采用了新的合成思路，即首先生成两端吡喃环上的手性碳的立体结构固定的中间体式V化合物，然后利用手性诱导来控制羟基位置的立体化学。具体来说，首先采用R-I化合物作为原料合成RS/RR-IV化合物，然后以RS/RR-IV化合物和式S-I化合物作为原料合成中间体式V化合物，由此式V化合物两端吡喃环上的手性碳的立体结构被分别固定为R和S型；或者，首先采用S-I化合物作为原料合成SR/SS-IV化合物，然后以SR/SS-IV化合物和式R-I化合物作为原料合成中间体式V化合物，由此式V化合物两端吡喃环上手性碳的立体结构被分别固定为S和R型；然后利用手性诱导来控制羟基位置的立体化学，将上述式V化合物选择性还原得到RSSS/SRRR-VI化合物为主的产物，通过后续操作，最终得到RSSS/SRRR-奈必洛尔。
可见，本发明的RSSS/SRRR-奈必洛尔制备方法避免了现有技术中大量异构体废料如式RR/SS-IV化合物、式RS#R/SR#S-V化合物的生成，从而大大提高了原料的利用率和 RSSS/SRRR-奈必洛尔的合成效率，降低了成本。同时，本发明方法避免了现有技术中分离上述异构体废料所需的繁琐的重结晶等分离操作及废料回收利用的问题，操作步骤大大简化，成本降低，更适合工业化生产。
具体实施方式
以下以具体实施例对本发明的技术方案进行详细说明，但本发明的保护范围不限于此。
实施例1 2-氯-1-[6-氟-(2R)-1-苯并吡喃-2-基]-(1R/S)-1-乙醇(式RS/RR-Ⅱ化合物)的制备
Figure PCTCN2015099448-appb-000008
室温下，向1L的三口烧瓶内加入2-氯-1-((R)-6-氟-1-苯并吡喃-2-基)-乙酮(50g，0.21mol)(即式R-Ⅰ化合物，该化合物可参照CN102164906A实施例6公开的方法制备)，无水乙醇(300mL)，分批加入NaBH4(9.9g,0.26mol)，反应30min，加饱和氯化铵溶液淬灭反应，过滤，滤液蒸除乙醇，残渣加水(300mL)和乙酸乙酯(600mL)分液，乙酸乙酯层以无水硫酸钠干燥，过滤，滤液浓缩得2-氯-1-[6-氟-(2R)-1-苯并吡喃-2-基]-(1S)-1-乙醇与2-氯-1-[6-氟-(2R)-1-苯并吡喃-2-基]-(1R)-1-乙醇的混合物(49.4g，收率98.0％)。
实施例2 R-6-氟-(2R/S)-2-环氧乙基-1-苯并吡喃(式RS/RR-Ⅲ化合物)的制备
Figure PCTCN2015099448-appb-000009
室温下，向500mL三口烧瓶中加入按照实施例1的方法制备得到的2-氯-1-[6-氟-(2R)-1-苯并吡喃-2-基]-(1R/S)-1-乙醇(51.5g,0.22mol)、氢氧化钠溶液(2M,0.44mol)，反应18h，反应液用乙酸乙酯萃取，乙酸乙酯层用无水硫酸钠干燥，过滤，滤液浓缩得油状液体R-6-氟-(2S)-2-环氧乙基-1-苯并吡喃与R-6-氟-(2R)-2-环氧乙基-1-苯并吡喃的混合物(43.1g,收率98％)。
实施例3 2-[(苯甲基)氨基]-1-[6-氟-(2R)-1-苯并吡喃-2-基]-(1R/S)-1-乙醇(式RS/RR-Ⅳ化合物)的制备
Figure PCTCN2015099448-appb-000010
向500mL单口烧瓶中加入根据实施例2的方法制备得到的R-6-氟-(2R/S)-2-环氧乙基-1- 苯并吡喃(50.36g，0.26mol)，苄胺(97g，0.90mol)和异丙醇(150mL)，回流反应3h，减压蒸除异丙醇，残渣加入环己烷(500mL),室温搅拌2h,过滤得到白色固体，干燥，得到2-[(苯甲基)氨基]-1-[6-氟-(2R)-1-苯并吡喃-2-基]-(1S)-1-乙醇与2-[(苯甲基)氨基]-1-[6-氟-(2R)-1-苯并吡喃-2-基]-(1R)-1-乙醇的混合物(51.6g(0.17mol)，收率为66％)。
实施例4 2-[(苯甲基)氨基]-1-[6-氟-(2S)-1-苯并吡喃-2-基]-(1R/S)-1-乙醇(式SR/SS-Ⅳ)的制备
以式S-I化合物(其中X2为H，LG为Cl，参照CN102164906A实施例7公开的方法制备)为原料，参照实施例1-3的操作步骤合成2-[(苯甲基)氨基]-1-[6-氟-(2S)-1-苯并吡喃-2-基]-(1R/S)-1-乙醇。
实施例5 2-{苄基-[2-(6-氟-(2R)-1-苯并吡喃-2-基)-(2R/S)-羟基-乙基]-氨基}-1-(6-氟-2(S)-1-苯并吡喃-2-基)-乙酮(式RS#S-Ⅴ化合物与式RR#S-Ⅴ化合物)的合成
Figure PCTCN2015099448-appb-000011
向500mL的三口烧瓶内加入按照实施例3的方法制备得到的2-[(苯甲基)氨基]-1-[6-氟-(2R)-1-苯并吡喃-2-基]-(1R/S)-1-乙醇(29.98g，0.99mol，RR/RS＝48/52)，2-氯-1-((S)-6-氟-1-苯并吡喃-2-基)-乙酮(27.2g，0.119mol)(S-Ⅰ，可参照CN102164906A实施例7公开的方法制备)，KBr(1.17g，9.9mmol)，NaHCO3(12.4g，0.148mol,1.5eq.)，乙腈(250mL)，室温搅拌18h后，升温至40℃至反应完全，过滤得白色固体和滤液A。
白色固体用二氯甲烷溶解，抽滤,滤液浓缩得2-{苄基-[2-(6-氟-2(R)-1-苯并吡喃-2-基)-(2S)-羟基-乙基]-氨基}-1-(6-氟-2(S)-1-苯并吡喃-2-基)-乙酮(RS#S-V)23.5g，收率91％，纯度99.3％。
滤液A减压浓缩，得2-{苄基-[2-(6-氟-2(R)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-2(S)-1-苯并吡喃-2-基)-乙酮(RR#S-V)，初产物40.5g，纯度84％，直接下一步用于选择性还原。
实施例6 2-{苄基-[2-(6-氟-(2S)-1-苯并吡喃-2-基)-(2R/S)-羟基-乙基]-氨基}-1-(6-氟-2(R)-1-苯并吡喃-2-基)-乙酮(式SR#R-Ⅴ化合物和式SS#R-Ⅴ化合物)的合成
以实施例4方法制备得到的2-[(苯甲基)氨基]-1-[6-氟-(2S)-1-苯并吡喃-2-基]-(1R/S)-1-乙醇和2-氯-1-((R)-6-氟-1-苯并吡喃-2-基)-乙酮(参照CN102164906A实施例6公开的方法制备)作为原料，参照实施例5的操作步骤，制备得到2-{苄基-[2-(6-氟-(2S)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-2(R)-1-苯并吡喃-2-基)-乙酮(SR#R-V)和2-{苄基-[2-(6-氟-(2S)-1-苯并吡喃-2-基)-(2S)-羟基-乙基]-氨基}-1-(6-氟-2(R)-1-苯并吡喃-2-基)-乙酮 (SS#R-V)。
实施例7 2-R[S[S(S)]]-[[苄基亚胺]双-(亚甲基)]双]-6-氟-1-苯并吡喃-2-甲醇和2-S[R[R(R)]]-[[苄基亚胺]双-(亚甲基)]双]-6-氟-1-苯并吡喃-2-甲醇(式RSSS-Ⅵ化合物和式SRRR-Ⅵ化合物)消旋体的合成
Figure PCTCN2015099448-appb-000012
3L三口烧瓶中，加入实施例5方法制备得到的式RS#S-Ⅴ化合物(49.2g，0.1mol)，实施例6方法制备得到的式SR#R-Ⅴ化合物(49.2g，0.1mol)和乙二醇二甲醚(1460ml)，室温下搅拌溶清，降温至-5℃，快速滴加四异丙基氧基钛酸酯(113.6g，0.4mol)，搅拌1h后分批加入NaBH4(15.2g，0.4mol)，继续反应15h，原料反应完全，降温至-15℃，滴加4N盐酸(800ml)，滴毕继续搅拌2h，过滤得白色固体A；
0℃下，将白色固体A用乙酸乙酯溶解，加入NaOH溶液中和至乙酸乙酯层pH约12，分液得到乙酸乙酯层，以饱和食盐水洗涤两次，无水硫酸钠干燥，浓缩得到白色固体91g，其中式RSSS/SRRR-Ⅵ化合物的HPLC纯度97.6％。
重结晶精制：将上步所得白色固体加入异丙醇(600ml)，回流下溶清，室温下机械搅拌充分析晶15h，滤得白色固体75.6g，式RSSS/SRRR-Ⅵ化合物的HPLC纯度99.3％。
手性分析：正相HPLC条件：Chiracel AD-H Column(250mm)；流动相：正己烷：异丙醇：二乙胺＝80：20：0.1；检测波长：UV280nm；流速：0.8mL/min；出峰时间分别为16min(SRSR-Ⅵ)，25min(SRRR-Ⅵ)，31min(RSSS-Ⅵ)，39min(SSRR-Ⅵ)。
实施例8 2-R[S[S(S)]]-[[苄基亚胺]双-(亚甲基)]双]-6-氟-1-苯并吡喃-2-甲醇((式RSSS-Ⅵ化合物)的合成
Figure PCTCN2015099448-appb-000013
参照实施例7的操作步骤，以实施例5方法制备得到的式RS#S-Ⅴ化合物为原料，制备RSSS-Ⅵ化合物。
实施例9 2-S[R[R(R)]]-[[苄基亚胺]双-(亚甲基)]双]-6-氟-1-苯并吡喃-2-甲醇(式SRRR-Ⅵ化合物)的合成
Figure PCTCN2015099448-appb-000014
参照实施例7的操作步骤，以实施例6方法制备得到的式SR#R-Ⅴ化合物制备SRRR-Ⅵ化合物。
实施例10 2-S[R[R(R)]]-[[苄基亚胺]双-(亚甲基)]双]-6-氟-1-苯并吡喃-2-甲醇和2-R[S[S(S)]]-[[苄基亚胺]双-(亚甲基)]双]-6-氟-1-苯并吡喃-2-甲醇合成及其盐酸盐的制备
Figure PCTCN2015099448-appb-000015
以CaCl2(6.5g，58.4mmol)和NaBH4(4.43g，116.8mmol)在四氢呋喃(150ml)下回流2h；冷却至室温，将实施例5方法制备得到的式RR#S-Ⅴ化合物(12g，24.34mmol)，实施例6方法制备得到的式SS#R-Ⅴ化合物(12g，24.34mmol)的THF(50ml)溶液缓慢滴入，反应2h，TLC检测原料反应完全，RRSS/(RRRS+SSSR)-Ⅵ＝40/60。
将反应液倒入冰水中，加入乙酸乙酯萃取，分别以1N HCl和饱和氯化钠溶液洗涤，无水硫酸钠干燥，室温搅拌4h，析出RSSS/RRRS-Ⅵ盐酸盐13g,手性纯度为RRSS/(RRRS+SSSR)-Ⅵ盐酸盐＝5/95，且式RRRS-Ⅵ盐酸盐化合物与式SSSR-Ⅵ盐酸盐化合物摩尔比为1：1。
实施例11 2-S[R[R(R)]]-[[苄基亚胺]双-(亚甲基)]双]-6-氟-1-苯并吡喃-2-甲醇其盐酸盐的制备
Figure PCTCN2015099448-appb-000016
参照实施例10的操作步骤，以实施例5方法制备得到的式RR#S-Ⅴ化合物为原料，制备题述化合物。
实施例12 2-R[S[S(S)]]-[[苄基亚胺]双-(亚甲基)]双]-6-氟-1-苯并吡喃-2-甲醇其盐酸盐的制备
Figure PCTCN2015099448-appb-000017
参照实施例10的操作步骤，以实施例6方法制备得到的式SS#R-Ⅴ化合物制备题述化合物。
实施例13 [亚胺]双-(亚甲基)双[6-氟-1-苯并吡喃]-2-甲醇(SRRR/RSSS-奈必洛尔)及其盐酸盐的制备
Figure PCTCN2015099448-appb-000018
向250mL高压釜内，投入实施例11的方法制备得到的2-S[R[R(R)]]-[[苄基亚胺]双-(亚甲基)]双]6-氟-1-苯并吡喃-2-甲醇和实施例12的方法制备得到的2-R[S[S(S)]]-[[苄基亚胺]双-(亚甲基)]双]6-氟-1-苯并吡喃-2-甲醇各18g(36.4mmol)，Pd/C 1.8g,甲醇320mL,加氢，压力0.8MPa,加热至50℃，反应2h，TLC检测反应完全后，过滤除去Pd/C,浓缩，得到SRRR/RSSS-奈必洛尔14.7g。
将所得SRRR/RSSS-奈必洛尔加甲醇300ml溶解，低温下通氯化氢气体，制成奈必洛尔盐酸盐，加入活性炭脱色，趁热滤除活性炭，滤液搅拌降温析晶，滤得白色固体奈必洛尔盐酸13.8g，HPLC纯度99.5％。
实施例14 2-{苄基-[2-(6-氟-8-溴-2(R)-1-苯并吡喃-2-基)-(2S)-羟基-乙基]-氨基}-1-(6-氟-2(S)-1-苯并吡喃-2-基)-乙酮和2-{苄基-[2-(6-氟-8-溴-2(R)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-2(S)-1-苯并吡喃-2-基)-乙酮，以及
2-{苄基-[2-(6-氟-8-溴-2(S)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-2(R)-1-苯并吡喃-2-基)-乙酮和2-{苄基-[2-(6-氟-8-溴-2(S)-1-苯并吡喃-2-基)-(2S)-羟基-乙基]-氨基}-1-(6-氟-2(R)-1-苯并吡喃-2-基)-乙酮的制备
实施例14.1 2-氯-1-[6-氟-8-溴-(2R)-1-苯并吡喃-2-基]-(1R/S)-1-乙醇(式RS/RR-Ⅱ化合物)制备
Figure PCTCN2015099448-appb-000019
向50mL三口烧瓶中加入2-氯-1-[6-氟-(2R)-1-苯并吡喃-2-基]-(1R/S)-1-乙醇(1.4g,6mmol)、三氟乙酸(8mL),NBS(1.62g,9mmol)，室温反应1h，GC跟踪反应，反应完全后蒸除三氟乙酸，残渣用二氯甲烷(20mL)萃取,饱和NaHCO3(10mL)洗涤，饱和氯化钠洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到2-氯-1-[6-氟-8-溴-(2R)-1-苯并吡喃-2-基]-(1R/S)-1-乙醇1.8g，直接下一步反应。
产物结构确认：1H NMR(CDCl3,400MHz)δ＝7.09-7.12(m,1H),6.74-6.77(m,1H),3.73-4.29(m,4H)，2.77-2.98(m,2H),1.99-2.05(m,1H),1.77-1.87(m,1H)。
实施例14.2 R-6-氟-8-溴-(2R/S)-2-环氧乙基-1-苯并吡喃(式RS/RR-Ⅲ化合物)制备
Figure PCTCN2015099448-appb-000020
室温下，向50mL三口烧瓶中加入实施例14.1的方法制备得到的2-氯-1-[6-氟-8-溴-(2R)-1-苯并吡喃-2-基]-(1R/S)-1-乙醇(1.8g,6mol)、预先配置的氢氧化钠溶液(氢氧化钠0.48g，12mmol,水6mL)，反应18h，TLC监测原料转化完毕，乙酸乙酯萃取，干燥，浓缩得R-6-氟-8-溴-(2R/S)-2-环氧乙基-1-苯并吡喃1.45g，溴代-成环氧两步收率为88％。
产物结构确认：1H NMR(CDCl3,400MHz)δ＝7.08-7.12(m,1H),6.71-6.75(m,1H),3.90-4.14(m,1H),3.16-3.23(m,1H),2.78-2.98(m,4H),2.06-2.18(m,1H),1.85-1.99(m,1H)。
实施例14.3 2-[(苯甲基)氨基]-1-[6-氟-8-溴-(2R)-1-苯并吡喃-2-基]-(1R/S)-1-乙醇(式RS/RR-Ⅳ化合物)制备
Figure PCTCN2015099448-appb-000021
向100ml单口烧瓶中加入按照实施例14.2方法制备得到的R-6-氟-8-溴-(2R/S)-2-环氧乙基-1-苯并吡喃(1.45g,5.3mmol)，苄胺(1.99g，18.6mmol)和异丙醇(10mL)，回流反应3h，反应完毕。蒸除溶剂，残渣加入环己烷(15mL),室温搅拌2h,过滤得到白色固体，干燥，得到白色固体2-[(苯甲基)氨基]-1-[6-氟-8-溴-(2R)-1-苯并吡喃-2-基]-(1R/S)-1-乙醇1.3g，收率63％。
产物结构确认数据：1H NMR(CDCl3,400MHz)δ＝7.26-7.34(m,5H),7.06-7.08(m,1H),6.72-6.74(m,1H),3.08-4.04(m,4H),2.75-3.09(m,4H),1.94-2.04(m,2H)。
实施例14.4 2-[(苯甲基)氨基]-1-[6-氟-8-溴-(2S)-1-苯并吡喃-2-基]-(1R/S)-1-乙醇(式SR/SS-Ⅳ化合物)的制备
以2-氯-1-[6-氟-(2S)-1-苯并吡喃-2-基]-(1R/S)-1-乙醇(1.4g,6mmol)作为原料，参照实施例14.1-14.3的方法制备2-[(苯甲基)氨基]-1-[6-氟-8-溴-(2S)-1-苯并吡喃-2-基]-(1R/S)-1-乙醇。
实施例14.5 2-{苄基-[2-(6-氟-8-溴-2(R)-1-苯并吡喃-2-基)-(2S)-羟基-乙基]-氨基}-1-(6-氟-2(S)-1-苯并吡喃-2-基)-乙酮，和2-{苄基-[2-(6-氟-8-溴-2(R)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-2(S)-1-苯并吡喃-2-基)-乙酮(式RS#S-Ⅴ化合物与式RR#S-Ⅴ化合物)的制备
Figure PCTCN2015099448-appb-000022
室温下，向50mL三口烧瓶中投入按照实施例14.3的方法制备得到的2-[(苯甲基)氨 基]-1-[6-氟-8-溴-(2R)-1-苯并吡喃-2-基]-(1R/S)-1-乙醇(8.2g,21mmol),S-2-氯-1-((R)-6-氟-1-苯并吡喃-2-基)-乙酮(5.44g,23mmol)，NaHCO3(5.29g,63mmol)，KBr(0.25g,2.1mol)，乙腈(80mL)，磁力搅拌，TLC跟踪反应。反应完全后，过滤得白色固体和滤液B。
白色固体用二氯甲烷溶解，抽滤,滤液浓缩得2-{苄基-[2-(6-氟-8-溴-2(R)-1-苯并吡喃-2-基)-(2S)-羟基-乙基]-氨基}-1-(6-氟-2(S)-1-苯并吡喃-2-基)-乙酮2.25g。
滤液B减压浓缩，得2-{苄基-[2-(6-氟-8-溴-2(R)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-2(S)-1-苯并吡喃-2-基)-乙酮4.2g。
实施例14.6 2-{苄基-[2-(6-氟-8-溴-2(S)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-2(R)-1-苯并吡喃-2-基)-乙酮，和2-{苄基-[2-(6-氟-8-溴-2(S)-1-苯并吡喃-2-基)-(2S)-羟基-乙基]-氨基}-1-(6-氟-2(R)-1-苯并吡喃-2-基)-乙酮(式SR#R-Ⅴ化合物与式SS#R-Ⅴ化合物)的制备
Figure PCTCN2015099448-appb-000023
室温下，向50mL三口烧瓶中投入按照实施例14.4方法制备得到的2-[(苯甲基)氨基]-1-[6-氟-8-溴-(2S)-1-苯并吡喃-2-基]-(1R/S)-1-乙醇(11.18g,29.4mmol)，R-2-氯-1-((R)-6-氟-1-苯并吡喃-2-基)-乙酮(7.41g,32.4mmol),NaHCO3(7.4g,88.2mol),KBr(0.35g,2.94mmol)，乙腈(120mL)，磁力搅拌，TLC跟踪反应。反应完全后，过滤得白色固体和滤液C。
白色固体用二氯甲烷溶解，抽滤,滤液浓缩得2-{苄基-[2-(6-氟-8-溴-2(S)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-2(R)-1-苯并吡喃-2-基)-乙酮5g。
滤液C减压浓缩，得2-{苄基-[2-(6-氟-8-溴-2(S)-1-苯并吡喃-2-基)-(2S)-羟基-乙基]-氨基}-1-(6-氟-2(R)-1-苯并吡喃-2-基)-乙酮8.61g。
产物2-{苄基-[2-(6-氟-8-溴-2(S)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-2(R)-1-苯并吡喃-2-基)-乙酮:1H NMR(CDCl3,400MHz)δ＝7.29-7.37(m,5H),7.06-7.08(m,1H),6.71-6.75(m,4H),4.02-4.08(m,1H),3.92-3.97(m,1H),3.83-3.86(m,1H),3.62-3.69(m,2H),3.31-3.34(m,1H),3.17-3.20(m,1H),2.75-2.82(m,4H),2.09-2.26(m,4H),1.91-2.02(m,1H),1.70-1.80(m,1H)。
产物2-{苄基-[2-(6-氟-8-溴-2(S)-1-苯并吡喃-2-基)-(2S)-羟基-乙基]-氨基}-1-(6-氟-2(R)-1-苯并吡喃-2-基)-乙酮:1H NMR(CDCl3,400MHz)δ＝7.29-7.35(m,5H),7.04-7.07(m,1H),6.68-6.75(m,4H),4.26-4.30(m,1H),3.92-3.97(m,1H),3.83-3.86(m,1H),3.63(S,2H),3.31-3.34(m,1H),3.17-3.20(m,1H),2.75-2.82(m,4H),2.09-2.26(m,4H),1.91-2.02(m,1H),1.70-1.80(m,1H)。
实施例15 2-{苄基-[2-(6-氟-2(S)-1-苯并吡喃-2-基)-(2S)-羟基-乙基]-氨基}-1-(6-氟-8-溴 -2(R)-1-苯并吡喃-2-基)-1(S)-乙醇(式RSSS-Ⅵ化合物)的制备
Figure PCTCN2015099448-appb-000024
向100mL单口烧瓶内投入2-{苄基-[2-(6-氟-8-溴-2(R)-1-苯并吡喃-2-基)-(2S)-羟基-乙基]-氨基}-1-(6-氟-2(S)-1-苯并吡喃-2-基)-乙酮(4.0g,7mmol),乙二醇二甲醚25mL,冷却至-10℃,加入Ti(Oi-Pr)4(3.97g.14mmol,NaBH4(0.53g,14mmol),-10℃下反应18h，TLC跟踪反应，反应完全。加入冰的氯化铵水溶液淬灭反应，二氯甲烷(30mL)萃取，0.5M氢氧化钠溶液(5mL)洗涤，饱和氯化钠洗涤，柱层析纯化(P:E＝10:1)，得2-{苄基-[2-(6-氟-2(S)-1-苯并吡喃-2-基)-(2S)-羟基-乙基]-氨基}-1-(6-氟-8-溴-2(R)-1-苯并吡喃-2-基)-1(S)-乙醇3.6g，收率89％，RSSS/RSRS＝92.7/7.3。
产物结构确认：1H NMR(CDCl3,400MHz)δ＝7.25-7.35(m,5H)，7.06-7.09(m,1H)，6.67-6.78(m,4H),3.68-3.94(m,6H)，2.70-3.14(m,10H)，2.20-2.25(m,1H)，1.76-1.86(m,3H)。
实施例16 2-{苄基-[2-(6-氟-2(R)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-8-溴-2(S)-1-苯并吡喃-2-基)-1(R)-乙醇(式SRRR-Ⅵ化合物)的制备
Figure PCTCN2015099448-appb-000025
向100mL单口烧瓶内投入2-{苄基-[2-(6-氟-8-溴-2(R)-1-苯并吡喃-2-基)-(2S)-羟基-乙基]-氨基}-1-(6-氟-2(S)-1-苯并吡喃-2-基)-乙酮(1.85g,3.2mmol)，乙二醇二甲醚25mL,冷却至-10℃,加入Ti(Oi-Pr)4(3.97g，14mmol),NaBH4(0.53g,14mmol)，-10℃下反应18h，TLC跟踪反应，反应完全。加入冰的氯化铵水溶液淬灭反应，二氯甲烷(30mL)萃取，0.5M氢氧化钠溶液(5mL)洗涤，饱和氯化钠洗涤，柱层析纯化(P:E＝10:1)，得2-{苄基-[2-(6-氟-2(S)-1-苯并吡喃-2-基)-(2S)-羟基-乙基]-氨基}-1-(6-氟-8-溴-2(R)-1-苯并吡喃-2-基)-1(S)-乙醇1g，收率54％，SRRR/SRSR＝92.1/7.9。
产物结构确认：1H NMR(CDCl3,400MHz)δ＝7.25-7.35(m,5H)，7.06-7.09(m,1H)，6.66-6.78(m,4H)，3.68-3.94(m,6H)，2.64-3.13(m,10H)，2.20-2.23(m,1H)，1.76-1.86(m,3H)。
实施例17 2-{苄基-[2-(6-氟-2(S)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-8-溴-2(R)-1-苯并吡喃-2-基)-1(R)-乙醇(式RRRS-Ⅵ化合物)的制备
Figure PCTCN2015099448-appb-000026
向100mL单口烧瓶内投入2-{苄基-[2-(6-氟-8-溴-2(R)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-2(S)-1-苯并吡喃-2-基)-乙酮(4.1g，7.16mmol)，四氢呋喃(50mL)，冷却至-10℃，加入无水LiCl(1.2g，28.6mmol)，KBH4(0.58，10.7mmol)，TLC跟踪反应。反应完全后，氯化铵水溶液淬灭反应，二氯甲烷(30mL)萃取，氢氧化钠溶液(0.5M，5mL)和饱和氯 化钠洗涤，无水硫酸钠干燥，过滤，滤液浓缩，柱层析纯化，得2-{苄基-[2-(6-氟-2(S)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-8-溴-2(R)-1-苯并吡喃-2-基)-1(R)-乙醇2g,收率为60％，RRRS/RRSS＝54/45。
产物结构确认：1H NMR(CDCl3,400MHz)δ＝7.24-7.35(m,5H),7.04-7.08(m,1H),6.65-6.78(m,4H),3.80-3.96(m,6H),2.69-3.07(m,10H),2.11-2.14(m,1H),1.83-1.93(m,3H)。
实施例18 2-{苄基-[2-(6-氟-2(R)-1-苯并吡喃-2-基)-(2S)-羟基-乙基]-氨基}-1-(6-氟-8-溴-2(S)-1-苯并吡喃-2-基)-1(S)-乙醇(式SSSR-Ⅵ化合物)的制备
Figure PCTCN2015099448-appb-000027
向100mL单口烧瓶内投入2-{苄基-[2-(6-氟-8-溴-2(S)-1-苯并吡喃-2-基)-(2S)-羟基-乙基]-氨基}-1-(6-氟-2(R)-1-苯并吡喃-2-基)-乙酮(8.2g,14.3mmol)和四氢呋喃(50mL),冷却至-10℃,加入无水LiCl(2.41g，57.3mmol),KBH4(1.15g，21.4mmol)，TLC跟踪反应。反应完全后，加入氯化铵水溶液淬灭反应，二氯甲烷(40mL)萃取，氢氧化钠溶液(0.5M，5mL)和饱和氯化钠洗涤，无水硫酸钠干燥，过滤，滤液浓缩，柱层析纯化，得2-{苄基-[2-(6-氟-2(R)-1-苯并吡喃-2-基)-(2S)-羟基-乙基]-氨基}-1-(6-氟-8-溴-2(S)-1-苯并吡喃-2-基)-1(S)-乙醇初产物4.2g，收率为51％，SSSR/SSRR＝56/44。
产物结构确认：1H NMR(CDCl3,400MHz)δ＝7.24-7.34(m,5H),7.04-7.08(m,1H),6.65-6.76(m,4H),3.80-3.97(m,6H),2.69-3.07(m,10H),2.11-2.15(m,1H),1.86-1.96(m,3H)。
实施例19 (2S[R[R(R)]]]-[[亚胺]双-(亚甲基)]双[6-氟-1-苯并吡喃-2-甲醇)盐酸盐(SRRR-奈必洛尔盐酸盐)的合成
Figure PCTCN2015099448-appb-000028
向高压氢化反应釜内投入实施例17的方法制备得到的2-{苄基-[2-(6-氟-2(S)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-8-溴-2(R)-1-苯并吡喃-2-基)-1(R)-乙醇(1.1g,1.9mmol),Pd/C 0.11g，甲醇20mL,碳酸钾(0.53g,3.8mmol，2eq.),油浴50℃,H2压力0.7Mpa,磁力搅拌过夜，TLC跟踪反应,反应完全后，过滤除去Pd/C及盐，滤液浓缩除溶剂，残渣加入异丙醇溶解后再次过滤，异丙醇母液内通入HCl气体，搅拌2h,过滤，干燥得RRRS-奈必洛尔盐酸盐0.55g。
实施例20 RRRS-奈必洛尔盐酸盐、SSSR-奈必洛尔盐酸盐的制备
分别采用实施例15的方法制备的2-{苄基-[2-(6-氟-2(S)-1-苯并吡喃-2-基)-(2S)-羟基-乙基]-氨基}-1-(6-氟-8-溴-2(R)-1-苯并吡喃-2-基)-1(S)-乙醇、实施例16的方法制备的2-{苄基-[2-(6-氟-2(R)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-8-溴-2(S)-1-苯并吡喃-2-基)-1(R)-乙醇、实施例18的方法制备的2-{苄基-[2-(6-氟-2(R)-1-苯并吡喃-2-基)-(2S)-羟基- 乙基]-氨基}-1-(6-氟-8-溴-2(S)-1-苯并吡喃-2-基)-1(S)-乙醇作为反应物，采用实施例19的方法，分别制备得到RSSS-奈必洛尔盐酸盐、RRRS-奈必洛尔盐酸盐、SSSR-奈必洛尔盐酸盐(其中RSSS-奈必洛尔盐酸盐与SSSR-奈必洛尔盐酸盐为相同化合物)。
实施例21 2-{苄基-[2-(6-氟-2(R)-1-苯并吡喃-2-基)-(2S)-羟基-乙基]-氨基}-1-(6-氟-8-氯-2(S)-1-苯并吡喃-2-基)-乙酮，和2-{苄基-[2-(6-氟-2(R)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-8-氯-2(S)-1-苯并吡喃-2-基)-乙酮的制备
实施例21.1 R-6-氟-8-氯-1-苯并吡喃-2-甲酸甲酯的制备
Figure PCTCN2015099448-appb-000029
向100mL三口烧瓶内投入R-6-氟-1-苯并吡喃-2-甲酸甲酯(5g，23.8mmol),NCS(4.76g，35.3mmol),FeCl3(0.384g，2.38mmol),氯仿(50mL)，加热至回流。反应完全后，冷却至室温，反应液以饱和氯化钠洗涤，无水硫酸钠干燥，过滤，滤液浓缩，用硅胶柱层析分离纯化得到白色固体R-6-氟-8-氯-1-苯并吡喃-2-甲酸甲酯4.91g，收率84％，HPLC纯度为98.73％。
产物结构确认数据：1H NMR(400MHz,CDCl3)δ＝6.98(dd,J＝8.1,3.0Hz,1H),6.68(dd,J＝8.4,3.0Hz,1H),4.89(t,J＝5.1Hz,1H),3.79(s,3H),2.87–2.67(m,2H),2.32–2.21(m,2H)。
实施例21.2 R-2-氯-1-(6-氟-8-氯-1-苯并吡喃-2-基)-乙酮(式R-Ⅰ化合物)的制备
Figure PCTCN2015099448-appb-000030
向100mL三口烧瓶内投入R-6-氟-8-氯-1-苯并吡喃-2-甲酸甲酯(3.0g,12.2mmol),氮气保护下加入无水四氢呋喃(35mL)，溴氯甲烷(2.35g，18.4mmol)。冷却至-70℃以下，滴加正丁基锂正己烷溶液(2.5M，7.4mL，18.4mmol)，滴加完毕，搅拌0.5h。滴加冰乙酸(3mL)，继续搅拌0.5h后加入水(15mL)，并控制温度在-30℃以下。在水滴加完毕后，升至室温，加入乙酸乙酯(50mL)萃取，饱和氯化钠洗涤，无水硫酸钠干燥，过滤，滤液浓缩，得微黄色固体，再用正己烷-乙酸乙酯混合溶剂重结晶，得到白色固体R-2-氯-1-(6-氟-8-氯-1-苯并吡喃-2-基)-乙酮2.3g，收率71％。
产物结构确认：1H NMR(400MHz,CDCl3)δ7.03(dd,J＝8.0,3.0Hz,1H),6.75(dd,J＝8.3,3.0Hz,1H),4.73(dd,J＝8.0,4.0Hz,1H),4.72(d,J＝17.4Hz,1H),4.57(d,J＝17.4Hz,1H),2.99-2.71(m,2H),2.43-2.36(m,1H),2.12-2.03(m,1H)。
实施例21.3 2-{苄基-[2-(6-氟-2(S)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-8-氯-2(R)-1-苯并吡喃-2-基)-乙酮和2-{苄基-[2-(6-氟-2(S)-1-苯并吡喃-2-基)-(2S)-羟基-乙基]-氨基}-1-(6-氟-8-氯-2(R)-1-苯并吡喃-2-基)-乙酮(式SR#R-Ⅴ化合物和式SS#R-Ⅴ化合物)的制备
Figure PCTCN2015099448-appb-000031
向100mL单口烧瓶内投入实施例21.2方法制备得到的R-2-氯-1-(6-氟-8-氯-1-苯并吡喃-2-基)-乙酮(2.3g，8.74mmol)，2-[(苯甲基)氨基]-1-[6-氟-(2S)-1-苯并吡喃-2-基]-(1R/S)-1-乙醇(2.39g，7.94mmol)，NaHCO3(1.33g，15.89mmol),KBr(0.104g，0.874mmol)，乙腈(15mL)。室温搅拌至反应完成，直接柱层析，分离得到白色固体2-{苄基-[2-(6-氟-2(S)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-8-氯-2(R)-1-苯并吡喃-2-基)-乙酮1.24g，收率为24％，和黄色粘稠液体2-{苄基-[2-(6-氟-2(S)-1-苯并吡喃-2-基)-(2S)-羟基-乙基]-氨基}-1-(6-氟-8-氯-2(R)-1-苯并吡喃-2-基)-乙酮2.1g，收率为46％。
实施例22 2-{苄基-[2-(6-氟-2(S)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-8-氯-2(R)-1-苯并吡喃-2-基)-1(R)-乙醇(式SRRR-Ⅵ化合物)的制备
Figure PCTCN2015099448-appb-000032
向100mL单口烧瓶内投入2-{苄基-[2-(6-氟-2(S)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-8-氯-2(R)-1-苯并吡喃-2-基)-乙酮(1.04g,1.97mmol)，乙二醇二甲醚(15mL)，Ti(Oi-Pr)4(1.12g，3.94mmol)，冷却至-10℃，继续加入NaBH4(0.149g，3.94mmol)，-10℃下反应18h，TLC跟踪反应，反应完全后，饱和氯化铵水溶液淬灭反应，二氯甲烷(30mL)萃取，分别以0.5M氢氧化钠水溶液(5mL)和饱和氯化钠洗涤，无水硫酸钠干燥，过滤，滤液浓缩，硅胶柱层析纯化得2-{苄基-[2-(6-氟-2(S)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-8-氯-2(R)-1-苯并吡喃-2-基)-1(R)-乙醇初产物0.76g,收率为72％，SRRR/SRSR＝86/14。
实施例23 (2S[R[R(R)]]-[[亚胺]双-(亚甲基)]双]6-氟-1-苯并吡喃-2-甲醇)盐酸盐(SRRR-奈必洛尔盐酸盐)的合成
Figure PCTCN2015099448-appb-000033
向高压氢化反应釜内投入2-{苄基-[2-(6-氟-2(S)-1-苯并吡喃-2-基)-(2R)-羟基-乙基]-氨基}-1-(6-氟-8-氯-2(R)-1-苯并吡喃-2-基)-1(R)-乙醇(1.0g,1.9mmol)，Pd/C 0.11g，甲醇20mL，碳酸钾(0.53g,3.8mmol，2eq.)，油浴50℃，H2压力0.7Mpa,磁力搅拌过夜，TLC跟踪反应,反应完全后，过滤除Pd/C及盐，滤液浓缩除去溶剂，加入异丙醇溶解后再次过滤，异丙醇母液内通入HCl气体，搅拌2h,过滤，干燥得SRRR-奈必洛尔盐酸盐0.54g。
实施例24 等摩尔比SRRR/RSSS-奈必洛尔盐酸盐的制备
将实施例19、20方法分别制得的SRRR-奈必洛尔盐酸盐和RSSS-奈必洛尔盐酸盐以等摩尔量混合，得到SRRR/RSSS-奈必洛尔盐酸盐外消旋体。
需要说明的是，以上实施例仅是示例性的，而非穷尽性的，并不对本发明保护范围的构成限制。本领域技术人员可以根据上述实施例的方法，可选择采用多种变化方式，制备SRRR-奈必洛尔盐酸盐与RSSS-奈必洛尔盐酸盐外消旋体。

Claims (15)

  1. 一种奈必洛尔中间体式RS#S-V和式RR#S-Ⅴ化合物的制备方法，包括：
    (1)将式RS/RR-Ⅳ化合物与式S-I化合物进行偶联对接反应，得到含有式RS#S-V和式RR#S-Ⅴ化合物的物料，
    Figure PCTCN2015099448-appb-100001
    其中，X1和X2各自代表苯环任意位置连接的氢原子或卤素原子；X1与X2为相同或不同的基团；
    LG为易于离去基团，选自溴、氯、磺酸酯基；
    PG为氢或可脱除的氨基保护基，所述可脱除的氨基保护基选自甲基、烯丙基、叔丁基、苄基、二苯甲基、三苯甲基、芴基、9,10-二氢蒽-9-基，其中在所述保护基中存在芳环时，芳环上可以带有取代基，所述取代基选自卤素、硝基、C1-C4烷基、-CF3、-CHF2、-OR2基团，其中R2选自氢、单一取代或二取代的C1-C4烷基；PG优选为苄基；
    (2)从步骤(1)所得的物料中分离得到式RS#S-Ⅴ化合物和式RR#S-Ⅴ化合物。
  2. 根据权利要求1所述的制备方法，其特征在于，步骤(1)所述反应在碱性条件下、惰性溶剂中、催化剂催化下进行。
  3. 根据权利要求2所述的制备方法，其特征在于，所述碱性条件中的碱选自碳酸盐、碳酸氢盐、有机碱；优选为三乙基胺、二异丙基乙基胺、碳酸氢钠或碳酸氢钾；所述惰性溶剂选自丙酮、四氢呋喃、乙腈、甲苯、二氯甲烷、乙酸乙酯、二甲基甲酰胺中任意一种或多种；所述的催化剂选自溴化钾、碘化钾、溴化钠、碘化钠中的任意一种或多种。
  4. 根据权利要求3所述的制备方法，其特征在于，所述步骤(1)中，式RS/RR-Ⅳ化合物:式S-Ⅰ化合物:碱:催化剂的投料摩尔比为1.0:(1.0-2.5):(1.0-4.0):(0.05-0.3)，优选为1.0:(1.0-1.5):2.0:(0.1-0.15)。
  5. 根据权利要求1-4任一项所述的制备方法，其特征在于，式RS/RR-Ⅳ化合物为式RS-Ⅳ化合物与式RR-Ⅳ化合物的混合物。
  6. 根据权利要求1-5任一项所述的制备方法，其特征在于，步骤(2)通过过滤和/或分步重结晶的方式将式RS#S-Ⅴ化合物和式RR#S-Ⅴ化合物分离。
  7. 一种奈必洛尔中间体的式SR#R-V和式SS#R-Ⅴ化合物的制备方法，包括：
    (1)将式SR/SS-Ⅳ化合物与式R-Ⅰ化合物进行偶联对接反应，得到含有式SR#R-V和式SS#R-Ⅴ化合物的物料，
    Figure PCTCN2015099448-appb-100002
    其中，X1和X2各自代表苯环任意位置连接的氢原子或卤素原子；X1与X2为相同或不同的基团；
    LG为易于离去基团，选自溴、氯、磺酸酯基；
    PG为氢或可脱除的氨基保护基，所述可脱除的氨基保护基选自甲基、烯丙基、叔丁基、苄基、二苯甲基、三苯甲基、芴基、9,10-二氢蒽-9-基，其中在所述保护基中存在芳环时，芳环上可以带有取代基，所述取代基选自卤素、硝基、C1-C4烷基、-CF3、-CHF2、-OR2基团，其中R2选自氢、单一取代或二取代的C1-C4烷基；PG优选为苄基；
    (2)从步骤(1)所得的物料中分离得到式SR#R-Ⅴ化合物和式SS#R-Ⅴ化合物。
  8. 根据权利要求4所述的制备方法，其特征在于，步骤(1)所述反应在碱性条件下、惰性溶剂中、催化剂催化下进行。
  9. 根据权利要求8所述的制备方法，其特征在于，所述碱性条件中的碱选自碳酸盐、碳酸氢盐、有机碱；优选为三乙基胺、二异丙基乙基胺、碳酸氢钠或碳酸氢钾；所述惰性溶剂选自丙酮、四氢呋喃、乙腈、甲苯、二氯甲烷、乙酸乙酯、二甲基甲酰胺中任意一种或多种；所述的催化剂选自溴化钾、碘化钾、溴化钠、碘化钠中的任意一种或多种。
  10. 根据权利要求9所述的制备方法，其特征在于，所述步骤(1)中，式SR/SS-Ⅳ化合物:式R-Ⅰ化合物:碱:催化剂的投料摩尔比为1.0:(1.0-2.5):(1.0-4.0):(0.05-0.3)，优选为1.0:(1.0-1.5):2.0:(0.1-0.15)。
  11. 根据权利要求7-10任一项所述的制备方法，其特征在于，式SR/SS-Ⅳ化合物为式SR-Ⅳ化合物与式SS-Ⅳ化合物的混合物。
  12. 根据权利要求7-11任一项所述的制备方法，其特征在于，步骤(2)通过过滤和/或分步重结晶的方式将式SR#R-Ⅴ化合物和式SS#R-Ⅴ化合物分离。
  13. 一种制备奈必洛尔或其药学上可接受的盐的方法，包括：
    (1)采用权利要求1-6任一项所述的方法制备式RS#S-V和式RR#S-Ⅴ化合物；
    (2)将所得的式RS#S-Ⅴ化合物和式RR#S-Ⅴ化合物进行选择性还原，得到式RSSS-Ⅵ化合物和式RRRS-Ⅵ化合物，
    Figure PCTCN2015099448-appb-100003
    (3)将所得式RSSS-Ⅵ化合物和式RRRS-Ⅵ化合物脱除PG基团，以及当X1、X2不为H时，脱除X1、X2基团，得到等摩尔量的式RSSS-奈必洛尔和式RRRS-奈必洛尔，或进一步制备其药学上可接受的盐。
  14. 一种制备奈必洛尔或其药学上可接受的盐的方法，包括：
    (1)采用权利要求7-12任一项所述的方法制备式SR#R-V和式SS#R-Ⅴ化合物；
    (2)将所得式SR#R-Ⅴ化合物和式SS#R-Ⅴ化合物进行选择性还原，得到式SRRR-Ⅵ 化合物和式SSSR-Ⅵ化合物；
    Figure PCTCN2015099448-appb-100004
    (3)将所得式SRRR-Ⅵ化合物和式SSSR-Ⅵ化合物脱除PG基团，以及当X1、X2不为H时，脱除X1、X2基团，得到等摩尔量的式SRRR-奈必洛尔和式SSSR-奈必洛尔，或进一步制备其药学上可接受的盐。
  15. 一种制备奈必洛尔或其药学上可接受的盐的方法，包括：
    (1)采用权利要求1-6任一项所述的方法制备式RS#S-V和式RR#S-Ⅴ化合物，采用权利要求7-12任一项所述的方法制备式SR#R-V和式SS#R-Ⅴ化合物；
    (2)取式RS#S-Ⅴ化合物和式SR#R-Ⅴ化合物，进行选择性还原，得到式RSSS-Ⅵ化合物和式SRRR-Ⅵ化合物；或者，取式RR#S-Ⅴ化合物和式SS#R-Ⅴ化合物进行选择性还原，得到式RRRS-Ⅵ化合物和式SSSR-Ⅵ化合物；
    (3)将所得式RSSS-Ⅵ化合物和式SRRR-Ⅵ化合物脱除PG基团，以及当X1、X2不为H时，脱除X1、X2基团，得到等摩尔量的式SRRR-奈必洛尔和式SSSR-奈必洛尔，或进一步制备其药学上可接受的盐；或者，将所得式RRRS-Ⅵ化合物和式SSSR-Ⅵ化合物脱除PG基团，以及当X1、X2不为H时，脱除X1、X2基团，得到等摩尔量的式SRRR-奈必洛尔和式SSSR-奈必洛尔，或进一步制备其药学上可接受的盐。
PCT/CN2015/099448 2015-01-19 2015-12-29 一种奈必洛尔中间体的制备方法及奈必洛尔的制备方法 WO2016115962A1 (zh)

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