WO2015188782A1 - 索非布韦的制备方法 - Google Patents

索非布韦的制备方法 Download PDF

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WO2015188782A1
WO2015188782A1 PCT/CN2015/081368 CN2015081368W WO2015188782A1 WO 2015188782 A1 WO2015188782 A1 WO 2015188782A1 CN 2015081368 W CN2015081368 W CN 2015081368W WO 2015188782 A1 WO2015188782 A1 WO 2015188782A1
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compound
alkyl
formula
potassium
sodium
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French (fr)
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张寅生
敖汪伟
王庆璘
林志强
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正大天晴药业集团股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/02—Phosphorylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • the invention belongs to the field of drug synthesis, in particular to a preparation method of the hepatitis C drug sofosbuvir.
  • sofosbuvir After the acquisition of Famous, Gilead developed and launched sofosbuvir (PSI-7977, GS-7977, ).
  • sofosbuvir and ribavirin (RBV) for oral treatment of HCV genotype 2 and type 3 patients; and approval of peginterferon (pegIFN) and ribba for injection Weilin (RBV) is a combination therapy for the first time patients with HCV gene type 1 and 4.
  • pegIFN peginterferon
  • Soufebuvir has a longer treatment cycle and usually requires 12 weeks to 24 weeks of treatment. The cost of treatment is extremely expensive, and only a very small number of patients worldwide can afford the treatment and benefit.
  • the current route for synthesizing sofosbuvir mainly includes the following two methods:
  • the nucleophilic substitution reaction of the phosphorus chiral center results in complete conversion of the configuration if the two diastereomeric mixtures 1-Sp and 1-Rp can be separated by conventional chemistry.
  • 1-Sp will be a relatively inexpensive reagent for the synthesis of a single desired isomer product, sofosbuvir.
  • intermediate 1 is not sufficiently stable, and it is possible to obtain a single acid chloride isomer by silica gel chiral column chromatography under anhydrous alcohol-free conditions, but this is not realistic.
  • Usually a crude mixture is used as the phosphation reagent and the resulting product is also a 1:1 mixture of diastereomers.
  • pentafluorophenol is used as a reaction reagent, and nitrophenol is also reported to participate in the reaction in the prior art.
  • the desired S configuration diastereomer can be separated and then subjected to selective nucleophilic substitution reaction with the 5'-hydroxyl group on the nucleoside to prepare a phosphonate single enantiomeric product.
  • the process has certain advantages, but the total yield of the reaction reagent is only 15% with a single nitrophenol instead of the phosphate ester, and the cost of the single pentafluorophenol-substituted phosphate ester is too high.
  • the invention provides a process for the preparation of a compound of formula I, which comprises reacting a compound of formula II with a compound of formula III in the presence of a base and a metal ion,
  • ring A is aryl or heteroaryl
  • R 1 is independently selected from halogen, hydroxy, nitro, C 1-4 alkyl, -OC 1-4 alkyl, halo C 1-4 alkyl, - C(O)OC 1-4 alkyl, -C 1-4 alkyl C(O)O C 1-4 alkyl, -C 1-4 alkyl C(O) C 1-4 alkyl, -OC ( O) C 1-4 alkyl
  • R 2 is selected from unsubstituted or substituted phenyl, heteroaryl, -SC 1-4 alkyl, -C (O) O C 1-4 alkyl-substituted C 1-4 Alkyl
  • R 3 is selected from C 1-6 alkyl
  • R 4 is selected from -F, -OH or -H
  • R 5 and R 6 are each independently selected from -F, -CH 3 or -H
  • R 7 is selected From a purine base or a pyrimidine base
  • the base includes an inorganic base and an organic base, and examples thereof include sodium hydride, t-butylmagnesium chloride, lithium hydride, lithium t-butoxide, potassium t-butoxide, sodium t-butoxide, NaHMDS, LiHMDS, methylimidazole ( For example, 1-methylimidazole, 2-methylimidazole, 4-methylimidazole, DBU.
  • the base used is t-butyl magnesium chloride.
  • the metal ion is magnesium ion, lithium ion or copper ion, preferably magnesium ion or lithium ion.
  • lithium chloride, magnesium chloride or copper chloride is directly added; it will be understood by those skilled in the art that as long as a reagent capable of generating magnesium ions, lithium ions or copper ions is added to the reaction system. It is not limited to lithium chloride, magnesium chloride or copper chloride.
  • the solvent used in the reaction is not limited as long as it can dissolve the reactants.
  • the organic solvent used is tetrahydrofuran.
  • anhydrous tetrahydrofuran is used.
  • Ring A is phenyl, naphthyl, benzopyridinyl.
  • R 1 is independently selected from -Cl, -OH, -NO 2 , -CH 3 , -OCH 3 , -C(O)OCH 3 , -C 2 H 4 C(O)OCH 3 , -C 2 H 4 C(O)CH 3 , -OC(O)CH 2 CH 3 .
  • R 2 is selected from the group consisting of -CH 3 , -CH 2 CH 3 , -CH 2 phenyl, -SCH 3 , -C(O)OC 2 H 5 .
  • R 3 is selected from the group consisting of -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 .
  • R 4 is selected from the group consisting of -OH.
  • R 5 and R 6 are each independently selected from -F, -CH 3 .
  • R 7 is selected from uracil.
  • n is zero.
  • ring A is phenyl, n is 0, R 2 is methyl, R 3 is isopropyl, R 4 is -OH, and R 5 and R 6 are -F and -CH 3 , respectively.
  • R 7 is a uracil group.
  • the compound of formula III-1 can be prepared according to the methods disclosed in the prior art, or can be prepared as follows, including: a compound of formula IV and a compound of formula V in the presence of an organic base Reaction wherein the definitions of Ring A, R 1 , R 2 , R 3 and n are the same as defined in Formula III.
  • the organic base is selected from the group consisting of triethylamine, DBU, methylimidazole (for example, 1-methylimidazole, 2-methylimidazole, 4-methylimidazole).
  • the organic base used It is triethylamine.
  • the organic solvent used in the reaction is not limited, and in one embodiment of the present invention, the organic solvent used is dichloromethane.
  • the compound of formula III-2 can be prepared as follows, comprising: reacting a compound of formula III-1 with a nucleophile in the presence of a phase transfer catalyst, wherein The definitions of ring A, R 1 , R 2 , R 3 and n are the same as defined in formula III.
  • the phase transfer catalyst comprises TBAB, TBAI, 18-crown-6-ether, and the nucleophilic reagent includes sodium azide, potassium azide, sodium cyanide, potassium cyanide, sodium thiocyanate, sulfur. Potassium cyanate, TMSN 3 (azidotrimethylsilane), TMSCN (cyanotrimethylsilane).
  • sofosbuvir comprising: reacting a compound of formula 3 with a compound of formula 2 in the presence of a base and a metal ion to prepare sofosbuvir, wherein X is selected from -CN, -SCN, -Cl or -N 3.
  • the base includes an inorganic base and an organic base, and examples thereof include sodium hydride, t-butyl magnesium chloride, lithium hydride, lithium t-butoxide, potassium t-butoxide, sodium t-butoxide, NaHMDS, LiHMDS, methylimidazole, DBU.
  • the base used is t-butyl magnesium chloride.
  • the metal ion is magnesium ion, lithium ion or copper ion, preferably magnesium ion or lithium ion.
  • lithium chloride, magnesium chloride or copper chloride is directly added; it will be understood by those skilled in the art that as long as a reagent capable of generating magnesium ions, lithium ions or copper ions is added to the reaction system. It is not limited to lithium chloride, magnesium chloride or copper chloride.
  • the solvent used in the reaction is not limited as long as it can dissolve the reactants.
  • the solvent used is tetrahydrofuran.
  • anhydrous tetrahydrofuran is used.
  • the compound of the formula 3-1 can be produced according to a known method disclosed in the prior art. It can also be prepared by a method comprising reacting a compound of the formula 4-1 with a compound of the formula 5 in the presence of an organic base.
  • the organic base is selected from the group consisting of triethylamine, DBU, methylimidazole (for example, 1-methylimidazole, 2-methylimidazole, 4-methylimidazole).
  • the organic base used It is triethylamine.
  • the organic solvent used in the reaction is not limited, and in one embodiment of the present invention, the organic solvent used is dichloromethane.
  • the phase transfer catalyst comprises TBAB, TBAI, 18-crown-6-ether, and the nucleophilic reagent includes sodium azide, potassium azide, sodium cyanide, potassium cyanide, sodium thiocyanate, sulfur. Potassium cyanate, TMSN3 (azidotrimethylsilane), TMSCN (cyanotrimethylsilane).
  • a process for the preparation of a compound of formula 3-2 which comprises reacting a compound of formula 3-1 with a nucleophile in the presence of a phase transfer catalyst to prepare a compound of formula 3-2, wherein X is selected from -N 3 , -SCN, -CN.
  • the phase transfer catalyst comprises TBAB, TBAI, 18-crown-6-ether, and the nucleophilic reagent includes sodium azide, potassium azide, sodium cyanide, potassium cyanide, sodium thiocyanate, sulfur. Potassium cyanate, TMSN3 (azidotrimethylsilane), TMSCN (cyanotrimethylsilane).
  • a compound of formula 3-2 is provided.
  • a method for preparing sofosbuvir comprising: (a) reacting a compound of formula 3-1 with a nucleophile in the presence of a phase transfer catalyst to prepare a compound of formula 3-2; (b) The compound of formula 3-2 is reacted with a compound of formula 2 in the presence of a base and a metal ion to prepare sofosbuvir.
  • the phase transfer catalyst comprises TBAB, TBAI, 18-crown-6-ether
  • the nucleophilic reagent comprises sodium azide, potassium azide, sodium cyanide, potassium cyanide, Sodium thiocyanate, potassium thiocyanate, TMSN 3 (azidotrimethylsilane), TMSCN (cyanotrimethylsilane).
  • the base described in the step (b) includes an inorganic base and an organic base, and examples thereof include sodium hydride, t-butyl magnesium chloride, lithium hydride, lithium t-butoxide, potassium t-butoxide, sodium t-butoxide, NaHMDS, LiHMDS. , methylimidazole, DBU.
  • the base used is t-butyl magnesium chloride.
  • the metal ion is magnesium ion, lithium ion or copper ion, preferably magnesium ion, lithium ion.
  • lithium chloride, magnesium chloride or copper chloride is directly added; as will be understood by those skilled in the art. Yes, as long as a reagent capable of generating magnesium ions, lithium ions or copper ions is added to the reaction system, it is not limited to lithium chloride, magnesium chloride or copper chloride.
  • the solvent used in the reaction is not limited as long as it can dissolve the reactants.
  • the organic solvent used is tetrahydrofuran.
  • anhydrous tetrahydrofuran is used.
  • the compounds of the invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers.
  • the compound containing an asymmetric carbon atom and/or a phosphorus atom of the present invention can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using a chiral starting material or a chiral reagent.
  • the compounds of the invention also include tautomeric forms.
  • the tautomeric form is derived from the exchange of a single bond with an adjacent double bond and accompanied by a proton transfer.
  • halogen means fluoro, chloro, bromo or iodo, preferably fluoro, chloro or bromo.
  • hydroxy refers to -OH.
  • DBU refers to 1,8-diazabicycloundec-7-ene.
  • NaHMDS sodium bis(trimethylsilyl)amide
  • LiHMDS refers to lithium bis(trimethylsilyl)amide.
  • TBAB refers to tetrabutylammonium bromide
  • TBAI refers to tetrabutylammonium iodide.
  • alkyl refers to a straight or branched saturated hydrocarbon group consisting of a carbon atom and a hydrogen atom, such as a C 1-20 alkyl group, preferably a C 1-6 alkyl group, such as methyl, ethyl, or propyl.
  • Base eg n-propyl and isopropyl
  • butyl eg n-butyl, isobutyl, sec-butyl or tert-butyl
  • pentyl eg n-pentyl, isopentyl, neopentyl
  • aryl refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system having from 6 to 14 carbon atoms, preferably from 6 to 12 carbon atoms, and most preferably having 6 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
  • heteroaryl refers to a monocyclic or fused ring of 5 to 12 ring atoms having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms containing 1, 2, 3 or Four ring atoms selected from N, O, and S, the remaining ring atoms are C, and have a fully conjugated ⁇ -electron system.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , tetrazolyl, triazinyl, benzopyridinyl.
  • purine base and "pyrimidine base” include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine, N 6 -alkylhydrazine, N 6 -benzylhydrazine, N 6 -halogenated hydrazine (eg 6-chloropurine), thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, uracil, 5-halouracil (eg 5 -Fluorouracil).
  • HPLC detection conditions are: column: Sunfire C18 5.0um, 4.6*150mm; mobile phase: phase A: 0.01M phosphate buffer salt (pH 7.2), phase B: methanol; mobile phase A and B ratio is 1:1, total flow rate: 1 mL/min; detection wavelength: 260 nm; retention time (min): Rp isomer: 11.13 min, Sp isomer: 15.38 min.
  • the Sp or Rp described herein means that the configuration of the P atom is the S configuration or the R configuration, respectively.
  • the carbonyl group on the compound of formula III may chelate with the metal ion, resulting in steric hindrance, allowing the compound of formula II to selectively attack from the less sterically hindered site, thereby enriching the desired isomer.
  • the preparation method of the invention is more stereoselective, and the desired isomers prepared are more enriched without separating the intermediates, thereby greatly reducing the production cost and being suitable for industrial production.
  • the compound of the formula 2 (5.20 g, 20.0 mmol) was obtained from EtOAc (EtOAc m.
  • EtOAc EtOAc m.
  • the reaction temperature was raised to 25 ° C, and the mixture was stirred for 30 minutes.
  • lithium chloride (21.0 mmol)
  • a mixed solution of Compound 3-1 (about 28.4 mmol) and THF (30 ml) was slowly added dropwise while maintaining the temperature at 5 °C. After the dropwise addition, the mixture was stirred for 15 hours.
  • the reaction solution was quenched with 1N aqueous HCl (25 mL) (Sp:Rp ratio: 4:1). Further toluene (100 ml) was added and the temperature was raised to room temperature.
  • the nucleophile is NaSCN and the phase transfer catalyst is TBAB
  • the nucleophile is NaSCN
  • the phase transfer catalyst is 18-crown-6
  • the nucleophile is NaSCN
  • the phase transfer catalyst is TBAB and 18-crown-6
  • the compound of the formula 3-1 (the product of the step (a) of Example 1) was dissolved in dichloromethane (20 ml), and TBAB (2.8 mmol) and 18-crown-6 (2.8 mmol) were added to NaSCN.
  • the nucleophile is NaN 3 and the phase transfer catalyst is TBAB
  • the nucleophile is KCN and the phase transfer catalyst is TBAB
  • the compound of formula 2 (5.20 g, 20.0 mmol) was taken in anhydrous THF (30 mL).
  • tert-Butylmagnesium chloride (1.0 M in THF, 42 mL, 42.0 mmol) was added with stirring. The reaction temperature was raised to 25 ° C, and the mixture was stirred for 30 minutes. After lithium chloride (21.0 mmol) was added, a mixed solution of the compound of the formula 3-2 (about 28.4 mmol, obtained in Example 2) and THF (30 ml) was slowly added dropwise while maintaining the temperature at 5 °C. After the completion of the dropwise addition, the mixture was stirred for 15 hours.
  • reaction solution was quenched with 1N aqueous HCl (25 mL) (Sp: Rp ratio: 6:1). After further adding toluene (100 ml), the temperature was raised to room temperature. After the organic layer with 1N HCl, washed with water, 5% Na 2 CO 3 and brine, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to give a solid after solvent, added dichloromethane (20ml), stirred for 5 minutes plus The mixture was stirred for 2 hours with isopropyl ether, and the precipitated solid was filtered. The solid was dissolved in dichloromethane (60 ml) by heating and cooled to room temperature to precipitate a needle-like solid. If necessary, the crystallization was repeated to obtain pure sofosbuvir (3.6 g, yield 34%, HPLC purity 98.7%).
  • the compound of formula 2 (5.20 g, 20.0 mmol) was taken in anhydrous THF (30 mL).
  • tert-Butylmagnesium chloride (1.0 M in THF, 42 mL, 42.0 mmol) was added with stirring.
  • the reaction temperature was raised to 25 ° C, and the mixture was stirred for 30 minutes.
  • Lithium chloride (21.0 mmol) was added, and then a mixed solution of the compound of the formula 3-2 (about 28.4 mmol) obtained in Example 2 and THF (30 ml) was slowly added dropwise while maintaining the temperature at 5 °C. After the dropwise addition, the mixture was stirred for 15 hours.
  • reaction solution was quenched with 1N aqueous HCl (25 mL) (Sp: Rp ratio: 7:1). After further adding toluene (100 ml), the temperature was raised to room temperature. After the organic layer with 1N HCl, washed with water, 5% Na 2 CO 3 and brine, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to give a solid after solvent, added dichloromethane (20ml), stirred for 5 minutes plus The mixture was stirred for 2 hours with isopropyl ether, and the precipitated solid was filtered. The solid was dissolved in dichloromethane (60 ml) by heating and cooled to room temperature to precipitate a needle-like solid. If necessary, the crystallization was repeated to obtain pure sofosbuvir (4.2 g, yield 40%, HPLC purity 98.8%).
  • the compound of formula 2 (5.20 g, 20.0 mmol) was taken in anhydrous THF (30 mL).
  • tert-Butylmagnesium chloride (1.0 M in THF, 42 mL, 42.0 mmol) was added with stirring. The reaction temperature was raised to 25 ° C, and the mixture was stirred for 30 minutes.
  • lithium chloride (21.0 mmol)
  • a mixed solution of the compound of the formula 3-2 (about 28.4 mmol) obtained in Example 2 and THF (30 ml) was slowly added dropwise while maintaining the temperature at 5 °C. After the dropwise addition, the mixture was stirred for 15 hours.
  • reaction solution was quenched with 1N aqueous HCl (25 mL) (Sp: Rp ratio: 6:1). After further adding toluene (100 ml), the temperature was raised to room temperature. After the organic layer with 1N HCl, washed with water, 5% Na 2 CO 3 and brine, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to give a solid after solvent, added dichloromethane (20ml), stirred for 5 minutes plus The mixture was stirred for 2 hours with isopropyl ether, and the precipitated solid was filtered. The solid was dissolved in dichloromethane (60 ml) by heating and cooled to room temperature to precipitate a needle-like solid. If necessary, repeated crystallization can be carried out to obtain pure sofosbuvir (4.02 g, yield 40%, HPLC purity 98.8%).

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Abstract

本发明涉及索非布韦的制备方法，具体而言，本发明提供了一种更具立体选择性的制备方法，在不分离中间体的前提下，制备得到的所需异构体更为富集，从而大大降低生产成本，适合于工业化生产。

Description

索非布韦的制备方法
相关申请的引用
本申请要求于2014年6月12日向中华人民共和国国家知识产权局提交的第201410260643.X号中国发明专利申请的权益，在此将其全部内容以援引的方式整体并入本文中。
技术领域
本发明属于药物合成领域，具体而言涉及丙肝药物索非布韦的制备方法。
背景技术
吉利德在收购法莫赛特后，开发并上市了索非布韦(sofosbuvir，PSI-7977，GS-7977，
Figure PCTCN2015081368-appb-000001
)。2013年，FDA批准索非布韦与利巴韦林(RBV)联用，用于HCV基因2型和3型病人的口服治疗；并批准与注射用乙二醇干扰素(pegIFN)和利巴韦林(RBV)联合用药，用于治疗HCV基因1和4型的初次患者。索非布韦的治疗周期较长，通常需要12周-24周的疗程，治疗费用极其昂贵，目前全球仅有极少数患者能够承受该治疗并获益。
目前用于合成索非布韦的路线主要包括以下两种方法：
Figure PCTCN2015081368-appb-000002
其中方法Ⅰ，磷手性中心的亲核取代反应会导致构型的完全转换，如果能用常规化学将两种非对映体混合物1-Sp及1-Rp分开。1-Sp将是相对便宜的试剂，用来合成单一的所需异构体产物sofosbuvir。然而,中间体1不够稳定，在无水无醇的条件下，用硅胶手性柱层析分离获得单一的酰氯异构体是可能的，但不现实。通常是用粗品混合物作为磷酸酯化试剂，生成的产物也为1：1的非对映体混和物。
方法Ⅱ以五氟苯酚作为反应试剂，现有技术中也有报道使用硝基苯酚参与反应。所需的S构型非对映异构体能够分离出来，然后与核苷上的5'-羟基发生选择性亲核取代反应，制备得到膦酸酯单一对映体产品。该工艺有一定的优越性，但以单一的硝基苯酚取代磷酸酯为反应试剂总收率只有15％，以单一的五氟苯酚取代的磷酸酯为反应试剂成本太高。
尽管索非布韦的疗效显著，但目前仍需开发出更适合工业化生产的工艺，以降低生产成本，进而降低药品价格，让更多的患者受益。
发明内容
一方面，本发明提供了一种式Ⅰ化合物的制备方法，包括：在碱和金属离子存在下，式Ⅱ化合物和式Ⅲ化合物反应，
Figure PCTCN2015081368-appb-000003
其中，环A为芳基或杂芳基，R1独立地选自卤素、羟基、硝基、C1-4烷基、-OC1-4烷基、卤代C1-4烷基、-C(O)O C1-4烷基、-C1-4烷基C(O)O C1-4烷基、-C1-4烷基C(O) C1-4烷基、-OC(O) C1-4烷基，R2选自未取代的或被苯基、杂芳基、-SC1-4烷基、-C(O)O C1-4烷基取代的C1-4烷基，R3选自C1-6烷基，R4选自-F、-OH或-H，R5和R6各自独立地选自-F、-CH3或-H，R7选自嘌呤碱基或嘧啶碱基，n为0-4的整数，X选自-Cl、-N3、-SCN、-CN。
所述的碱包括无机碱和有机碱，可列举的实例包括氢化钠、叔丁基氯化镁、氢化锂、叔丁醇锂、叔丁醇钾、叔丁醇钠、NaHMDS、LiHMDS、甲基咪唑(例如1-甲基咪唑、2-甲基咪唑、4-甲基咪唑)、DBU。在本发明的一个实施方案中，使用的碱为叔丁基氯化镁。
所述的金属离子为镁离子、锂离子或铜离子，优选镁离子、锂离子。在本发明的一些实施方案中，直接加入氯化锂、氯化镁或氯化铜；本领域技术人员可以理解的是，只要在反应体系中加入能产生镁离子、锂离子或铜离子的试剂即可，并不限于氯化锂、氯化镁或氯化铜。
反应中使用的溶剂不受限制，只要能溶解反应物即可。在本发明的一些实施方案中，使用的有机溶剂为四氢呋喃。在本发明的一个实施方案中，使用的是无水四氢呋喃。
在一些实施方案中，环A为苯基、萘基、苯并吡啶基。在一些实施方案中，R1独立地选自-Cl、-OH、-NO2、-CH3、-OCH3、-C(O)OCH3、-C2H4C(O)OCH3、-C2H4C(O)CH3、-OC(O)CH2CH3。在一些实施方案中，R2选自-CH3、-CH2CH3、-CH2苯基、-SCH3、-C(O)OC2H5。在一些实施方案中，R3选自-CH3、-CH2CH3、-CH(CH3)2。在一些实施方案中，R4选自-OH。在一些实施方案中，R5和R6各自独立地选自-F、-CH3。在一些实施方案中，R7选自尿嘧啶基。在一些实施方案中，n为0。在一个优选的实施方案中，环A为苯基，n为0，R2为甲基，R3为异丙基，R4为-OH，R5和R6分别为-F和-CH3，R7为尿嘧啶基。
当X为-Cl时，所述式Ⅲ-1化合物可按照现有技术中公开的方法来制备，也可以按照下述方法制备，包括：在有机碱的存在下，式Ⅳ化合物和式Ⅴ化合物反应，其中环A、R1、R2、R3和n的定义与式Ⅲ中的定义相同。
Figure PCTCN2015081368-appb-000004
所述的有机碱选自三乙胺、DBU、甲基咪唑(例如1-甲基咪唑、2-甲基咪唑、4-甲基咪唑)，在本发明的一个实施方案中，使用的有机碱为三乙胺。反应时使用的有机溶剂不受限制，在本发明的一个实施方案中，使用的有机溶剂为二氯甲烷。
当X为-N3、-SCN、-CN时，所述式Ⅲ-2化合物可以按照下述方法制备，包括：在相转移催化剂的存在下，式Ⅲ-1化合物与亲核试剂反应，其中环A、R1、R2、R3和n的定义与式Ⅲ中的定义相同。
Figure PCTCN2015081368-appb-000005
所述的相转移催化剂包括TBAB、TBAI、18-冠-6-醚，所述的亲核试剂包括叠氮化钠、叠氮化钾、氰化钠、氰化钾、硫氰酸钠、硫氰酸钾、TMSN3(叠氮基三甲基硅烷)、TMSCN(氰基三甲基硅烷)。
本发明的一些具体实施方案中，提供了一种索非布韦的制备方法，所述方法包括：在碱和金属离子存在下，式3化合物和式2化合物反应，制备得到索非布韦，其中X选自-CN、-SCN、-Cl或-N3。
Figure PCTCN2015081368-appb-000006
所述的碱包括无机碱和有机碱，可列举的实例包括氢化钠、叔丁基氯化镁、氢化锂、叔丁醇锂、叔丁醇钾、叔丁醇钠、NaHMDS、LiHMDS、甲基咪唑、DBU。在本发明的一个实施方案中，使用的碱为叔丁基氯化镁。
所述的金属离子为镁离子、锂离子或铜离子，优选镁离子、锂离子。在本发明的一些实施方案中，直接加入氯化锂、氯化镁或氯化铜；本领域技术人员可以理解的是，只要在反应体系中加入能产生镁离子、锂离子或铜离子的试剂即可，并不限于氯化锂、氯化镁或氯化铜。
反应中使用的溶剂不受限制，只要能溶解反应物即可。在本发明的一些实施方案中，使用的溶剂为四氢呋喃。在本发明的一个实施方案中，使用的是无水四氢呋喃。
其中当X为Cl时，式3-1的化合物可以按照现有技术中公开的已知方法来制备。也可以按照下述方法来制备，包括在有机碱的存在下，式4-1化合物和式5化合物反应。
Figure PCTCN2015081368-appb-000007
所述的有机碱选自三乙胺、DBU、甲基咪唑(例如1-甲基咪唑、2-甲基咪唑、4-甲基咪唑)，在本发明的一个实施方案中，使用的有机碱为三乙胺。反应时使用的有机溶剂不受限制，在本发明的一个实施方案中，使用的有机溶剂为二氯甲烷。
另一方面，提供了通式化合物Ⅲ-2的制备方法，其中X选自-N3、-SCN、-CN，包括：在相转移催化剂存在下，式Ⅲ-1化合物与亲核试剂反应，其中环A、R1、R2、R3和n的定义与式Ⅲ中的定义相同。
Figure PCTCN2015081368-appb-000008
所述的相转移催化剂包括TBAB、TBAI、18-冠-6-醚，所述的亲核试剂包括叠氮化钠、叠氮化钾、氰化钠、氰化钾、硫氰酸钠、硫氰酸钾、TMSN3(叠氮基三甲基硅烷)、TMSCN(氰基三甲基硅烷)。
在本发明的一些实施方案中，提供了式3-2化合物的制备方法，包括：在相转移试催化剂存在下，式3-1化合物与亲核试剂反应，制备得到式3-2化合物，其中X选自-N3、-SCN、-CN。
Figure PCTCN2015081368-appb-000009
所述的相转移催化剂包括TBAB、TBAI、18-冠-6-醚，所述的亲核试剂包括叠氮化钠、叠氮化钾、氰化钠、氰化钾、硫氰酸钠、硫氰酸钾、TMSN3(叠氮基三甲基硅烷)、TMSCN(氰基三甲基硅烷)。
再一方面，提供了通式化合物Ⅲ-2，其中X选自-N3、-SCN、-CN，环A、 R1、R2、R3和n的定义与式Ⅲ中的定义相同。
Figure PCTCN2015081368-appb-000010
在一个具体的实施方案中，提供式3-2的化合物。
Figure PCTCN2015081368-appb-000011
再一方面，提供了一种索非布韦的制备方法，所述方法包括：(a)在相转移催化剂存在下，式3-1化合物与亲核试剂反应，制备得到式3-2化合物；(b)在碱和金属离子的存在下，式3-2化合物与式2化合物反应，制备得到索非布韦。
Figure PCTCN2015081368-appb-000012
步骤(a)中，所述的相转移催化剂包括TBAB、TBAI、18-冠-6-醚，所述的亲核试剂包括叠氮化钠、叠氮化钾、氰化钠、氰化钾、硫氰酸钠、硫氰酸钾、TMSN3(叠氮基三甲基硅烷)、TMSCN(氰基三甲基硅烷)。
步骤(b)中所述的碱包括无机碱和有机碱，可列举的实例包括氢化钠、叔丁基氯化镁、氢化锂、叔丁醇锂、叔丁醇钾、叔丁醇钠、NaHMDS、LiHMDS、甲基咪唑、DBU。在本发明的一个实施方案中，使用的碱为叔丁基氯化镁。
所述的金属离子为镁离子、锂离子或铜离子，优选镁离子、锂离子，在本发明的一些实施方案中，直接加入氯化锂、氯化镁或氯化铜；本领域技术人员可以理解的是，只要在反应体系中加入能产生镁离子、锂离子或铜离子的试剂即可，并不限于氯化锂、氯化镁或氯化铜。
反应中使用的溶剂不受限制，只要能溶解反应物即可。在本发明的一些实施方案中，使用的有机溶剂为四氢呋喃。在本发明的一个实施方案中，使用的是无水四氢呋喃。
本发明化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本发明的含有不对称碳原子和/或磷原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
本发明化合物还包括互变异构体形式。互变异构体形式来源于一个单键与相邻的双键交换并一起伴随一个质子的迁移。
本文中所用的术语具有如下含义：
术语“卤素”是指氟、氯、溴或碘，优选氟、氯或溴。
术语“羟基”指-OH。
术语“DBU”指1,8-二氮杂二环十一碳-7-烯。
术语“NaHMDS”指二(三甲基硅基)氨基钠。
术语“LiHMDS”指二(三甲基硅基)氨基锂。
术语“TBAB”指四丁基溴化铵。
术语“TBAI”指四丁基碘化铵。
术语“烷基”是指由碳原子和氢原子组成的直链或支链的饱和烃基团，如C1-20烷基，优选为C1-6烷基，例如甲基、乙基、丙基(例如正丙基和异丙基)、丁基(例如正丁基、异丁基、仲丁基或叔丁基)、戊基(例如正戊基、异戊基、新戊基)、正己基、2-甲基己基等。
术语“芳基”是指具有完全共轭的π电子体系的全碳单环或稠合环，其具有6-14个碳原子，优选具有6-12个碳原子，最优选具有6个碳原子。芳基的非限制性实例包括但不限于苯基、萘基和蒽基。
术语“杂芳基”是指5-12个环原子的单环或稠合环，具有5、6、7、8、9、10、11或12个环原子，其中含有1、2、3或4个选自N、O、S的环原子，其余环原子为C，且具有完全共轭的π-电子体系。杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三嗪基、苯并吡啶基。
术语“嘌呤碱基”和“嘧啶碱基”，包括但不限于鸟嘌呤、腺嘌呤、次黄嘌呤、2,6-二氨基嘌呤、N6-烷基嘌呤、N6-苄基嘌呤、N6-卤代嘌呤(例如6-氯嘌呤)、 胸腺嘧啶、胞嘧啶、5-氟胞嘧啶、5-甲基胞嘧啶、6-氮杂嘧啶、尿嘧啶、5-卤代尿嘧啶(例如5-氟尿嘧啶)。
本文中，HPLC的检测条件为：色谱柱：Sunfire C18 5.0um,4.6*150mm；流动相：A相：0.01M 磷酸缓冲盐(pH 7.2)，B相：甲醇；流动相A和B的比例为1:1，总流速：1mL/min；检测波长：260nm；保留时间(min)：Rp异构体:11.13min，Sp 异构体:15.38min。
本文中所述的Sp或者Rp分别是指P原子的构型为S构型或R构型。
发明人发现，制备式Ⅰ化合物时，在金属离子的存在下，式Ⅲ化合物以非对映体混和物的形式(例如Sp/Rp＝1:1)参与反应时，可以得到Sp富集的式Ⅰ化合物。当式Ⅲ-1化合物以非对映异构体混合物的形式(例如Sp/Rp＝1:1)制备得到中间体式Ⅲ-2化合物，接着与式Ⅱ化合物反应时，在一些实施方案中，可得到Sp富集程度更高的式Ⅰ化合物。推测金属离子存在下，式Ⅲ化合物上的羰基可能与金属离子螯合，产生空间位阻,使式Ⅱ化合物选择性从位阻较小的部位进攻,从而使得所需的异构体富集。
本发明的制备方法更具立体选择性，在不分离中间体的前提下，制备得到的所需异构体更为富集，从而大大降低生产成本，适合于工业化生产。
具体实施方式
实施例1 索非布韦的制备
Figure PCTCN2015081368-appb-000013
步骤(a)：
0℃下，二氯磷酸苯酯(6.0g，28.4mmol)于无水二氯甲烷(30ml)中，搅拌下加入丙氨酸异丙基酯盐酸盐(4.8g，28.4mmol)，将混合物搅拌并冷却至-55℃后，缓慢滴加三乙胺(6.5g，64mmol)和二氯甲烷(30ml)的混合溶液，期间保持温度于-55℃，滴毕，继续搅拌60分钟，后升至-5℃搅拌2小时，TLC监测反应完成。过滤除去三乙胺盐酸盐，滤液减压蒸除溶剂，得化合物3-1，为无色油状物(Sp/Rp＝1/1)。
31PNMR(CDCl3,300Hz,H3PO4为内标):δ8.25&7.94(1:1)；
1HNMR(CDCl3,300MHz):δ7.39-7.34(m,2H),7.27-7.18(m,3H),5.10-5.02(m,1H),4.51(br,1H),4.11(m,1H),1.49(d,3H),1.29-1.24(m,6H)；
13CNMR(CDCl3,300MHz):δ172.1(Rp),196.3(Sp),129.8,129.6(d),125.9,120.5(d),69.7(d),50.7(d),21.6(d),20.4(d)。
步骤(b)：
5℃下，式2化合物(5.20g，20.0mmol)于无水THF(30ml)中，搅拌下加入叔丁基氯化镁(1.0M THF溶液，42ml，42.0mmol)。反应温度上升至25℃，将混合物搅拌30分钟。加入氯化锂(21.0mmol)后，缓慢滴加化合物3-1(约28.4mmol)和THF(30ml)的混合溶液，期间保持温度于5℃。滴毕，搅拌15小时。用1N HCl水溶液(25ml)淬灭反应液(HPLC测定Sp:Rp比例为4:1)。再加入甲苯(100ml)，温度上升至室温。有机层用1N HCl、水、5％Na2CO3及食盐水洗涤，无水硫酸镁干燥，过滤，减压蒸除溶剂后得固体，加入二氯甲烷(20ml)，搅拌5分钟后再加异丙醚，继续搅拌2小时，过滤出析出的固体。将固体加热溶解于二氯甲烷中(60ml)，慢慢冷却至室温析出针状固体。必要时重复结晶可获得纯的索非布韦(2.6g，收率25％，HPLC测定纯度达98.8％)。
31PNMR(CDCl3,300Hz,H3PO4为内标):δ3.54ppm；
13CNMR(CDCl3,300Hz):δ173.1(d),162.7(s),150.2(d),139.3(d),129.6(q)；
MS(M+H):530.1。
实施例2 式3-2所示化合物的制备
Figure PCTCN2015081368-appb-000014
(1)亲核试剂为NaSCN，相转移催化剂为TBAB
将式3-1所示的化合物(实施例1步骤(a)的产物)溶于二氯甲烷(20ml)中，加入TBAB(2.8mmol)，将NaSCN(35mmol)的水(2.0ml)溶液滴加到上述反应液中。滴毕，继续搅拌60分钟，过滤除去固体。滤液用水洗后，加MgSO4干燥24小时。过滤，滤液减压蒸除溶剂，得如式3-2所示的化合物(其中X＝SCN)。
1HNMR(CDCl3,500Hz):δ7.32-7.13(m,3H),7.08-7.02(m,2H),5.0-4.9(m,1H),3.92(m,1H),1.49(m,3H),1.23-1.17(m,6H)；
31PNMR(CDCl3,300Hz,H3PO4为内标):δ-18.16/-18.26。
(2)亲核试剂为NaSCN，相转移催化剂为18-冠醚-6
将式3-1所示的化合物(实施例1步骤(a)的产物)溶于醋酸乙酯(20ml)中，加入18-冠醚-6(2.8mmol)，将NaSCN(35mmol)加到上述反应液中。滴毕，继续搅拌60分钟，过滤除去固体。过滤液用水洗后，加MgSO4干燥24小时。过滤，滤液减压蒸除溶剂，得如式3-2所示的化合物(其中X＝SCN)。
(3)亲核试剂为NaSCN，相转移催化剂为TBAB和18-冠醚-6
将式3-1所示的化合物(实施例1步骤(a)的产物)溶于二氯甲烷(20ml)中，加入TBAB(2.8mmol)及18-冠醚-6(2.8mmol)，将NaSCN(35mmol)的水(2.0ml)溶液加到上述反应液中。滴毕，继续搅拌60分钟，过滤除去固体。滤液用水洗后，加MgSO4干燥24小时。过滤，滤液减压蒸除溶剂，得如式3-2所示的化合物(其中X＝SCN)。
(4)亲核试剂为NaN3，相转移催化剂为TBAB
将式3-1所示的化合物(实施例1步骤(a)的产物)溶于二氯甲烷(20ml)中，加入TBAB(2.8mmol)，将NaN3(35mmol)的水(2.0ml)溶液滴加到上述反应液中。滴毕，继续搅拌60分钟，过滤除去固体。滤液用水洗后，加MgSO4干燥24小时。过滤，滤液减压蒸除溶剂，得如式3-2所示的化合物(其中X＝N3)。
1HNMR(CDCl3,500Hz):δ7.30-7.33(m,2H),7.27-7.21(m,3H),5.10-5.05(m,1H),4.12-4.00(m,1H),1.43(d,3H),1.28-1.17(m,6H)；
31PNMR-(CDCl3,300Hz,H3PO4内标):δ2.04/2.19。
(5)亲核试剂为KCN，相转移催化剂为TBAB
将如式3-1所示的化合物溶于二氯甲烷(20ml)中，加入TBAB(2.8mmol)，将KCN(35mmol)的水(2.0ml)溶液滴加到上述反应液中。滴毕，继续搅拌60分钟，过滤除去固体。滤液用水洗后，加MgSO4干燥24小时。过滤，滤液减压蒸除溶剂，得如式3-2所示的化合物(其中X＝CN)。
1HNMR(CDCl3,300Hz):δ7.22-7.13(m,3H),7.09-7.02(m,2H),5.01-4.95(m,1H),4.08-3.93(m,1H),1.43-1.35(m,3H),1.20-1.17(m,6H)；
31PNMR(CDCl3,300Hz,H3PO4内标):δ-2.71/-2.93。
实施例3 索非布韦的制备
Figure PCTCN2015081368-appb-000015
(1)X为SCN
5℃下，将式2所示的化合物(5.20g，20.0mmol)于无水THF(30ml)中。搅拌下加入叔丁基氯化镁(1.0M THF溶液，42ml，42.0mmol)。反应温度上升至25℃，将混合物搅拌30分钟。加入氯化锂(21.0mmol)后，缓慢滴加式3-2的化合物(约28.4毫摩尔，实施例2制备得到)和THF(30ml)的混合溶液，期间保持温度于5℃。滴毕后，搅拌15小时。用1N HCl水溶液(25ml)淬灭反应液(HPLC测定Sp:Rp比例为6:1)。再加入甲苯(100ml)后，温度上升至室温。有机层用1N HCl、水、5％Na2CO3及食盐水洗涤，无水硫酸镁干燥，过滤，减压蒸除溶剂后得固体，加入二氯甲烷(20ml)，搅拌5分钟后再加异丙醚，继续搅拌2小时，过滤出析出的固体。将固体加热溶解于二氯甲烷中(60ml)，慢慢冷却至室温析出针状固体。必要时重复结晶可获得纯索非布韦(3.6g，收率34％，HPLC测定纯度达98.7％)。
1HNMR(CDCl3,300MHz):δ8.63(s，1H，NH)，7.46(d,1H,C6-H),7.36(t,2H,o-aromatic),7.18-7.24(m,3H,m,p-aromatic)，6.20-6.14(d，1H，Cl’-H)，5.70-5.68(d，1H，C5-H)，5.05-4.97(m，1H，CH-(CH3)2),4.57-4.41(m，2H，C5’-H2)，4.12-4.09(d，1H，C3’-H)，4.06-3.79(m，3H，C3’-OH，C4’-H，Ala-CH-CH3)，3.79(s，1H，Ala-NH)，1.44(d，3H，C2’-H3)，1.36-1.34(d，3H，Ala-CH3)，1.25-1.23(t，6H，CH-(CH3)2)；
P31NMR(CDCl3,300Hz,H3PO4内标):δ3.56。
(2)X为N3
5℃下，将式2所示的化合物(5.20g，20.0mmol)于无水THF(30ml)中。搅拌下加入叔丁基氯化镁(1.0M THF溶液，42ml，42.0mmol)。反应温度上升 至25℃，将混合物搅拌30分钟。加入氯化锂(21.0mmol)，后缓慢滴加实施例2制备得到的式3-2的化合物(约28.4毫摩尔)和THF(30ml)的混合溶液，期间保持温度于5℃。滴毕，搅拌15小时。用1N HCl水溶液(25ml)淬灭反应液(HPLC测定Sp:Rp比例为7:1)。再加入甲苯(100ml)后，温度上升至室温。有机层用1N HCl、水、5％Na2CO3及食盐水洗涤，无水硫酸镁干燥，过滤，减压蒸除溶剂后得固体，加入二氯甲烷(20ml)，搅拌5分钟后再加异丙醚，继续搅拌2小时，过滤出析出的固体。将固体加热溶解于二氯甲烷中(60ml)，慢慢冷却至室温析出针状固体。必要时重复结晶可获得纯索非布韦(4.2g，收率40％，HPLC测定纯度达98.8％)。
1HNMR(CDCl3,300MHz):δ8.63(s，1H，NH)，7.46(d,1H,C6-H),7.36(t,2H,o-aromatic),7.18-7.24(m,3H,m,p-aromatic)，6.20-6.14(d，1H，Cl’-H)，5.70-5.68(d，1H，C5-H)，5.05-4.97(m，1H，CH-(CH3)2),4.57-4.41(m，2H，C5’-H2)，4.12-4.09(d，1H，C3’-H)，4.06-3.79(m，3H，C3’-OH，C4’-H，Ala-CH-CH3)，3.79(s，1H，Ala-NH)，1.44(d，3H，C2’-H3)，1.36-1.34(d，3H，Ala-CH3)，1.25-1.23(t，6H，CH-(CH3)2)；
P31NMR(CDCl3,300Hz,H3PO4内标):δ3.56。
(3)X为CN
5℃下，将式2所示的化合物(5.20g，20.0mmol)于无水THF(30ml)中。搅拌下加入叔丁基氯化镁(1.0M THF溶液，42ml，42.0mmol)。反应温度上升至25℃，将混合物搅拌30分钟。加入氯化锂(21.0mmol)后，缓慢滴加实施例2制备得到的式3-2的化合物(约28.4毫摩尔)和THF(30ml)的混合溶液，期间保持温度于5℃。滴毕，搅拌15小时。用1N HCl水溶液(25ml)淬灭反应液(HPLC测定Sp:Rp比例为6:1)。再加入甲苯(100ml)后，温度上升至室温。有机层用1N HCl、水、5％Na2CO3及食盐水洗涤，无水硫酸镁干燥，过滤，减压蒸除溶剂后得固体，加入二氯甲烷(20ml)，搅拌5分钟后再加异丙醚，继续搅拌2小时，过滤出析出的固体。将固体加热溶解于二氯甲烷中(60ml)，慢慢冷却至室温析出针状固体。必要时重复结晶可获得纯索非布韦(4.02g，收率40％，HPLC测定纯度达98.8％)。
1HNMR(CDCl3,300MHz):δ8.63(s，1H，NH)，7.46(d,1H,C6-H),7.36(t,2H, o-aromatic),7.18-7.24(m,3H,m,p-aromatic)，6.20-6.14(d，1H，Cl’-H)，5.70-5.68(d，1H，C5-H)，5.05-4.97(m，1H，CH-(CH3)2),4.57-4.41(m，2H，C5’-H2)，4.12-4.09(d，1H，C3’-H)，4.06-3.79(m，3H，C3’-OH，C4’-H，Ala-CH-CH3)，3.79(s，1H，Ala-NH)，1.44(d，3H，C2’-H3)，1.36-1.34(d，3H，Ala-CH3)，1.25-1.23(t，6H，CH-(CH3)2)；
P31NMR(CDCl3,300Hz,H3PO4内标):δ3.56。

Claims (10)

  1. 式Ⅰ化合物的制备方法，包括：在碱和金属离子存在下，式Ⅱ化合物和式Ⅲ化合物反应，
    Figure PCTCN2015081368-appb-100001
    其中，环A为芳基或杂芳基，R1独立地选自卤素、羟基、硝基、C1-4烷基、-OC1-4烷基、卤代C1-4烷基、-C(O)O C1-4烷基、-C1-4烷基C(O)O C1-4烷基、-C1-4烷基C(O)C1-4烷基、-OC(O)C1-4烷基，R2选自未取代的或被苯基、杂芳基、-SC1-4烷基、-C(O)O C1-4烷基取代的C1-4烷基，R3选自C1-6烷基，R4选自-F、-OH或-H，R5和R6各自独立地选自-F、-CH3或-H，R7选自嘌呤或嘧啶碱基，n为0-4的整数，X选自-Cl、-N3、-SCN、-CN。
  2. 权利要求1的制备方法，其中所述的金属离子为镁离子、锂离子或铜离子。
  3. 权利要求1的制备方法，当X选自-N3、-SCN或-CN时，还包括：
    Figure PCTCN2015081368-appb-100002
    在相转移催化剂存在下，式Ⅲ-1化合物与亲核试剂反应，其中环A、R1、R2、R3和n的定义与权利要求1中的定义相同，制备得到式Ⅲ-2化合物。
  4. 权利要求3的制备方法，其中相转移试剂包括TBAB、TBAI、18-冠-6-醚，所述的亲核试剂包括叠氮化钠、叠氮化钾、氰化钠、氰化钾、硫氰酸钠、硫氰酸钾、叠氮基三甲基硅烷、氰基三甲基硅烷。
  5. 化合物Ⅲ-2的制备方法，其中X选自-N3、-SCN、-CN，包括：在相转移催化剂存在下，
    Figure PCTCN2015081368-appb-100003
    式Ⅲ-1化合物与亲核试剂反应，其中环A、R1、R2、R3和n的定义与权利要求1中式Ⅲ中的定义相同。
  6. 权利要求5的制备方法，其中所述的相转移催化剂包括TBAB、TBAI、18-冠-6-醚，所述的亲核试剂包括叠氮化钠、叠氮化钾、氰化钠、氰化钾、硫氰酸钠、硫氰酸钾、叠氮基三甲基硅烷、氰基三甲基硅烷。
  7. 式Ⅲ-2的化合物，
    Figure PCTCN2015081368-appb-100004
    其中X选自-N3、-SCN、-CN，环A、R1、R2、R3和n的定义与权利要求1中式Ⅲ中的定义相同。
  8. 式3-2的化合物，
    Figure PCTCN2015081368-appb-100005
    其中X为-SCN、-CN或-N3。
  9. 索非布韦的制备方法，包括：(a)在相转移催化剂存在下，式3-1化合物与亲核试剂反应，制备得到式3-2化合物，其中X为-SCN、-CN或-N3；(b)在碱和金属离子的存在下，式3-2化合物与式2化合物反应，制备得到索非布韦
    Figure PCTCN2015081368-appb-100006
  10. 权利要求9的制备方法，其中步骤(a)中，相转移催化剂包括TBAB、TBAI、18-冠-6-醚，所述的亲核试剂包括叠氮化钠、叠氮化钾、氰化钠、氰化钾、 硫氰酸钠、硫氰酸钾、叠氮基三甲基硅烷、氰基三甲基硅烷；步骤(b)中金属离子为镁离子、锂离子或铜离子。
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