WO2018045997A1 - 作为索非布韦中间体的2-氟-2-甲基脱氧核苷的制备方法 - Google Patents

作为索非布韦中间体的2-氟-2-甲基脱氧核苷的制备方法 Download PDF

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WO2018045997A1
WO2018045997A1 PCT/CN2017/101078 CN2017101078W WO2018045997A1 WO 2018045997 A1 WO2018045997 A1 WO 2018045997A1 CN 2017101078 W CN2017101078 W CN 2017101078W WO 2018045997 A1 WO2018045997 A1 WO 2018045997A1
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compound
formula
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methyl
phenyl
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French (fr)
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孔锐
袁哲东
郭猛
胡明通
王笃政
强斌
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Shanghai Dude Medical Science And Technology Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Shanghai Dude Medical Science And Technology Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C07H13/06—Fatty acids

Definitions

  • the present application belongs to the field of pharmaceutical synthesis, and in particular to a method for preparing 2-fluoro-2-methyldeoxynucleoside as an intermediate of sofosbuvir.
  • Sofosbuvir chemical name (S)-2- ⁇ (S)- ⁇ (2R,3R,4R,5R)-5-[2,4-dioxo-3,4-di Hydrogen pyrimidine-1(2H)-yl]-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl ⁇ methoxy ⁇ (phenoxy)phosphorylamino ⁇ propionic acid isopropyl ester, CAS registration No.: 1190307-88-0, trade name Sovaldi, is a new drug developed by Gilead for the treatment of chronic hepatitis C. It was approved for marketing in the United States on December 6, 2013 by the US Food and Drug Administration (FDA).
  • FDA Food and Drug Administration
  • sofosbuvir is generally (2'R)-2'-deoxy-2'-fluoro-2' - Phosphorylation of methyl uridine (Formula 1) with phosphorus oxychloride or phosphate of phenoxyphosphoramidopropionate as shown below:
  • the addition reaction in this route requires the use of methyl lithium at -78 ° C, the conditions are harsh, the side reaction is more, and the DAST fluorination reaction step is low, only 15%.
  • the synthetic route is simple and convenient, wherein the ratio of the beta isomer to the alpha isomer in the coupling product of the five carbon sugar ring nucleus and the cytosine side chain significantly affects the yield of the route.
  • the present application provides a method of preparing a compound of formula V from a compound of formula II as shown below, comprising the steps of:
  • R 1 or R 2 are each independently selected from H, C 1-6 alkyl, 5- to 6-membered aryl or 5- to 6-membered heteroaryl, said C 1-6 alkyl, five to six
  • the aryl or 5- to 6-membered heteroaryl is optionally 1 , 2 or 3 selected from the group consisting of hydroxyl, amino, nitro, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy Substituted with a substituent of a C 1-6 acyl group, a C 1-6 acyloxy group or a C 1-6 acylamino group.
  • Another aspect of the present application provides a process for the preparation of a compound of Formula 1, comprising the preparation of a compound of Formula II as described above.
  • the method for preparing the compound of Formula 1 optionally includes the following steps:
  • R 1 or R 2 is as defined above.
  • Another aspect of the present application provides a method of preparing a compound of formula II, comprising the steps of:
  • R 1 and R 2 are as defined above and R 3 is selected from methyl, ethyl or propyl.
  • R 1 , R 2 and R 3 are as defined above.
  • said R 1 or R 2 are each independently selected from H, methyl or phenyl, and R 3 is selected from methyl, ethyl or propyl.
  • said R 1 or R 2 are each independently selected from H, methyl or phenyl and are not simultaneously phenyl; in Formula IV and Formula 5, said R 1 or R 2 are each independently selected from H, methyl or phenyl, R 3 is selected from methyl, ethyl or propyl; in formula 6 R 2 is selected from H or methyl.
  • Another aspect of the present application provides the use of a compound as shown below for the preparation of a compound of formula 1:
  • R 1 , R 2 and R 3 are as defined above.
  • the R 1 or R 2 are each independently selected from the group consisting of H, methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl, 4-hydroxybenzene.
  • a compound of formula II is converted to a compound of formula III by a reducing agent selected from the group consisting of lithium tri-tert-butoxyaluminum hydride and dihydro bis(2-methoxyB).
  • a reducing agent selected from the group consisting of lithium tri-tert-butoxyaluminum hydride and dihydro bis(2-methoxyB).
  • Sodium oxy)aluminate (red aluminum) is preferably lithium tri-tert-butoxyaluminum hydride.
  • a compound of formula III is converted to a compound of formula IV by an acetylating agent and a base selected from the group consisting of acetic anhydride, acetyl chloride or glacial acetic acid, preferably acetic anhydride.
  • a compound of formula III is converted to a compound of formula IV by an acetylating agent and a base selected from the group consisting of triethylamine, pyridine, N,N-diisopropylethylamine. Or 4-dimethylaminopyridine, preferably 4-dimethylaminopyridine.
  • a compound of formula IV is converted to a compound of formula V by a Lewis acid under the action of a Lewis acid, the Lewis acid being selected from the group consisting of tin tetrachloride, aluminum trichloride, and the like.
  • a Lewis acid being selected from the group consisting of tin tetrachloride, aluminum trichloride, and the like.
  • a compound of formula V is converted to a compound of formula VI by the action of an acid selected from the group consisting of glacial acetic acid, formic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid, preferably glacial acetic acid.
  • an acid selected from the group consisting of glacial acetic acid, formic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid, preferably glacial acetic acid.
  • a compound of formula VI is converted to a compound of formula 1 by the action of ammonia, said ammonia
  • the form of existence is selected from the group consisting of ammonia methanol solution, ammonia ethanol solution, ammonia water or ammonia gas, preferably ammonia methanol solution.
  • a compound of formula 2 is converted to a compound of formula 3, the fluorinating agent being selected from the group consisting of tetraethylammonium fluoride hydrate or triethylamine trihydrofluoride, preferably tetraethyl fluoride Ammonium hydrate.
  • a compound of formula 2 is converted to a compound of formula 3 selected from the group consisting of hydrochloric acid, sulfuric acid or methanesulfonic acid, preferably hydrochloric acid.
  • a compound of Formula 3 and a compound of Formula 4 are converted to a compound of Formula 5 under the action of a base selected from the group consisting of triethylamine, pyridine, N,N-diisopropylethylamine. Or 4-dimethylaminopyridine, preferably triethylamine; the catalyst is selected from the group consisting of 4-dimethylaminopyridine.
  • a compound of formula 5 is converted to a compound of formula 6 by the action of an acid selected from the group consisting of hydrochloric acid, sulfuric acid, trifluoroacetic acid or acetic acid, preferably trifluoroacetic acid.
  • a compound of Formula 6 and a compound of Formula 7 are converted to a compound of Formula II under the action of a base and a catalyst selected from the group consisting of triethylamine, pyridine, N,N-diisopropyl B.
  • a catalyst selected from the group consisting of triethylamine, pyridine, N,N-diisopropyl B.
  • An amine or 4-dimethylaminopyridine, preferably triethylamine; the catalyst is selected from the group consisting of 4-dimethylaminopyridine.
  • the compound of the formula 2 used in the present application can be synthesized by a method known in the art, for example, by Wittig condensation reaction of (R)-glyceraldehyde acetal with methyl 2-(triphenylphosphine) propionate, followed by bishydroxyl
  • Wittig condensation reaction of (R)-glyceraldehyde acetal with methyl 2-(triphenylphosphine) propionate
  • bishydroxyl The steps of sulfonylation, oxidation, etc. are available, and the specific synthetic route is as follows:
  • compound as used herein includes all stereoisomeric forms, geometric isomer forms, tautomeric forms, and isotopic forms of the compounds.
  • an ethyl group “optionally” substituted with halo refers to an ethyl group may be unsubstituted (CH 2 CH 3), monosubstituted (e.g., CH 2 CH 2 F), polysubstituted (e.g. CHFCH 2 F, CH 2 CHF 2, etc.) or completely substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or which cannot be synthesized is introduced.
  • C mn means that there are m to n integer carbon atoms in the moiety.
  • C1-6 alkyl means that the alkyl group has 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • substituted means that any one or more hydrogen atoms on a particular atom are substituted with a substituent as long as the valence of the particular atom is normal and the substituted compound is stable.
  • halogen means fluoro, chloro, bromo or iodo.
  • amino refers to a -NH 2 group, a -NH(C 1-6 alkyl) group or a -N(C 1-6 alkyl) 2 group. Specific examples of the amino group include, but are not limited to, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHC 2 H 5 , -N(C 2 H 5 ) 2 , -N(C 3 H 7 ) 2 , -N(CH 3 )C 2 H 5 and the like.
  • alkyl refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, which is attached to the remainder of the molecule by a single bond.
  • Non-limiting examples of the term include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, -CH (CH 3) 2, -CH (CH 3 (CH 2 CH 3 ), -CH(CH 2 CH 3 ) 2 , -C(CH 3 ) 3 , -C(CH 2 CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH (CH 3 )(CH 2 CH 3 ) or the like.
  • propyl includes CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-; 2) Butyryl includes CH 3 CH 2 CH 2 CO-, (CH 3 ) 2 CHCO-.
  • alkoxy refers to -O-alkyl
  • acyl refers to an alkyl group -CO- (or H), e.g., "C 3 acyl” refers to -CO-C 2 H 5.
  • acyloxy refers to -O-CO- alkyl (or H), e.g., "C 3 acyloxy” refers to -O-CO-C 2 H 5 .
  • acylamino refers to -NH-CO- alkyl (or H), e.g., "C 3 acyloxy” refers to -NH-CO-C 2 H 5 .
  • the stereo direction of the chemical bond is not limited, for example, include Two isomers.
  • the 1-membered substituent of the oxa 5-membered ring is on the same side as the 4-substituent, and is the ⁇ isomer; the substituent at the 1-position of the oxa 5-membered ring is not on the same side as the 4-substituent, and is the ⁇ -isomer:
  • the chiral compound is in enantiomeric excess
  • the enantiomeric excess means that the content of the chiral isomer (the amount of the substance) is equal to or greater than about 10 %, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, About 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or about 99.99%.
  • the compounds may exist in specific geometric or stereoisomeric forms.
  • This application contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomeric or diastereomeric excess mixtures, all of which belong to the present Within the scope of the application. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • reaction is optionally carried out in a solvent. All solvents used in the present application are commercially available and can be used without further purification.
  • the reaction is generally carried out under inert nitrogen in an anhydrous solvent. .
  • the reaction yield per step is high, the operation is simple, and the compound of the formula IV and the O-trimethylsilyl-N4-benzoylcytosine condensation product, the ⁇ isomer
  • the ratio with the alpha isomer is as high as 5/1, and the yield is greatly improved compared with the method reported in the literature, which significantly improves the synthesis of sofosbuvir and its intermediates.
  • the compound of formula 2-1 (6.0 g, 19.34 mmol) was dissolved in anhydrous dioxane (60 mL), tetraethyl ammonium fluoride hydrate (4.85 g, 29 mmol) was added, and the mixture was stirred at 100 ° C for 1 h, cooled to At room temperature, 2,2-dimethoxypropane (60 mL) was added, and concentrated hydrochloric acid (4.84 mL, 58.03 mmol) was added dropwise at room temperature, and the mixture was stirred at room temperature for 3 h, and diluted with ethyl acetate (60 mL).
  • the compound of the formula 5-1 (100 mg, 0.26 mmol) was dissolved in anhydrous dichloromethane (5 mL), trifluoroacetic acid (60 mg, 0.53 mmol) was added, and the reaction was stirred at room temperature for 48 h, and the mixture was diluted with DCM The solution was washed, separated, and the organic phase was evaporated to dryness to give a semi-solid 50 mg, yield 65%.
  • the compound of the formula 5-2 (100 mg, 0.33 mmol) was dissolved in anhydrous dichloromethane (5 mL), trifluoroacetic acid (75 mg, 0.66 mmol) was added, and the reaction was stirred at room temperature for 48 h, the reaction mixture was diluted with DCM, and saturated sodium hydrogen carbonate was added. The solution was washed, separated, and the organic phase was evaporated to dryness to give a semi-solid 46 mg.
  • the compound of the formula 6-1 (50 mg, 0.17 mmol), DMAP (2 mg, 0.017 mmol) was dissolved in anhydrous THF (5 mL), reduced to 0 ° C, triethylamine (0.094 mL, 0.68 mmol) was added, and cinnamoyl chloride was added dropwise. (56.6 mg, 0.34 mmol) in THF, the mixture was stirred for 12h, and the mixture was evaporated to dryness. .
  • the compound of the formula 6-2 (50 mg, 0.23 mmol), DMAP (2.8 mg, 0.023 mmol) was dissolved in anhydrous THF (5 mL), then reduced to 0 ° C, triethylamine (0.13 mL, 0.92 mmol) was added, and propylene was added dropwise.
  • the solution of the acid chloride (41.5 mg, 0.46 mmol) in THF was stirred for 12h, and the reaction mixture was filtered to remove solids.
  • the compound of formula II-1 (5 g, 11.78 mmol) was dissolved in THF (50 mL), cooled to -30 ° C, and tri-tert-butoxy hydrogen was added dropwise.
  • a solution of lithium aluminum in THF (16.5 mL, 16.5 mmol) was gradually warmed to -15 ° C and stirred for 2 h.
  • EA 50 mL was added, and a saturated aqueous solution of ammonium chloride (50 mL) was added dropwise, and the mixture was stirred for 1 hour, filtered over sodium sulfate decahydrate, and the filter cake was washed three times with EA.
  • the filtrate was separated and the organic phase was washed with dilute hydrochloric acid and purified water.
  • the organic layer was combined, washed with brine, dried over anhydrous sodium sulfate.
  • the compound of the formula II-2 (5 g, 14.35 mmol) was dissolved in THF (50 mL), cooled to -30 ° C, and a solution of lithium tri-tert-butoxyaluminum hydride (20.1 mL, 20.1 mmol) was added dropwise. The reaction was stirred for 2 h at -15 °C. EA (50 mL) was added, and a saturated aqueous solution of ammonium chloride (50 mL) was added dropwise, and the mixture was stirred for 1 hour, filtered over sodium sulfate decahydrate, and the filter cake was washed three times with EA. The filtrate was separated and the organic phase was washed with dilute hydrochloric acid and purified water. The organic layer was combined, washed with brine, dried over anhydrous sodium sulfate.
  • the compound of formula II-3 (5 g, 18.37 mmol) was dissolved in THF (50 mL), cooled to -30 ° C, and tri-tert-butoxy hydrogen was added dropwise.
  • a solution of lithium aluminum in THF (25.7 mL, 25.7 mmol) was gradually warmed to -15 ° C and stirred for 2 h.
  • EA 50 mL was added, and a saturated aqueous solution of ammonium chloride (50 mL) was added dropwise, and the mixture was stirred for 1 hour, filtered over sodium sulfate decahydrate, and the filter cake was washed three times with EA.
  • the filtrate was separated and the organic phase was washed with dilute hydrochloric acid and purified water.
  • the organic layer was combined, washed with brine, dried over anhydrous sodium sulfate
  • the compound of the formula II-4 (5 g, 14.35 mmol) was dissolved in THF (50 mL), cooled to -30 ° C, and a solution of lithium tri-tert-butoxy aluminum hydride (20.1 mL, 20.1 mmol) was added dropwise. The reaction was stirred for 2 h at -15 °C. EA (50 mL) was added, and a saturated aqueous solution of ammonium chloride (50 mL) was added dropwise, and the mixture was stirred for 1 hour, filtered over sodium sulfate decahydrate, and the filter cake was washed three times with EA. The filtrate was separated and the organic phase was washed with dilute hydrochloric acid and purified water. The organic layer was combined, washed with brine, dried over anhydrous sodium sulfate.
  • the compound of the formula III-1 (3.75 g, 8.79 mmol) was dissolved in anhydrous THF (20 mL), and DMAP (1.07 g, 8. The temperature was lowered to -20 ° C, acetic anhydride (1.66 mL, 17.59 mmol) was added dropwise, and the mixture was stirred for 2 h. The EA and water were added to the reaction mixture. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. It was evaporated to dryness to give 3.86 g of white solid.
  • the compound of the formula III-2 (3 g, 8.56 mmol) was dissolved in anhydrous THF (20 mL), DMAP (1.04 g, 8.56 mmol) was added, and the mixture was cooled to -20 ° C, and acetic anhydride (1.62 mL, 17.13 mmol) was added dropwise. After stirring for 2 h, EA and a water solution were added to the reaction mixture, and the organic phase was washed successively with water and brine, dried over anhydrous sodium sulfate and evaporated to dryness
  • the compound of the formula III-3 (3.5 g, 12.76 mmol) was dissolved in anhydrous THF (20 mL), EtOAc (EtOAc, EtOAc, The reaction mixture was stirred for 2 h, and EA (50 mL) and water (50 mL) were added to the mixture, and the mixture was stirred and extracted, and the organic phase was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The white solid was dried over 3.81 g, yield 94.4%.
  • the compound of the formula III-4 (3 g, 8.56 mmol) was dissolved in anhydrous THF (20 mL), DMAP (1.04 g, 8.56 mmol) was added, and the temperature was lowered to -20 ° C, and acetic anhydride was added dropwise at t ⁇ 20 ° C (1.62).
  • N-benzoylcytosine (0.92g, 4.27mmol), ammonium sulfate (11.3mg, 0.085mmol) was suspended in HMDS (10mL) in a nitrogen atmosphere and in a dry environment. The temperature was raised to 130 ° C and refluxed for 2 h. The HMDS was evaporated to give a pale yellow syrup at room temperature, and a solution of the compound of formula IV-1 (1 g, 2.13 mmol) in chlorobenzene (10 mL) was added to the syrup, and the mixture was dropped to 0 ° C, and slowly added dropwise to SnCl.
  • N-benzoylcytosine (1.1 g, 5.1 mmol) and ammonium sulfate (13.5 mg, 0.10 mmol) were suspended in HMDS (10 mL) under nitrogen atmosphere and in a dry atmosphere. The mixture was heated to 130 ° C and refluxed for 2 h. The HMDS was evaporated to give a pale yellow syrup at room temperature, and a solution of the compound of formula IV-2 (1 g, 2.55 mmol) of chlorobenzene (10 mL) was added to the syrup, and the mixture was dropped to 0 ° C.
  • N-benzoylcytosine (1.36 g, 6.32 mmol) and ammonium sulfate (16.71 mg, 0.126 mmol) were suspended in HMDS (10 mL) under nitrogen atmosphere and in a dry atmosphere. The mixture was heated to 130 ° C and refluxed for 2 h. The HMDS was removed by rotary evaporation at room temperature to obtain a pale yellow syrup. A solution of the compound of formula IV-3 (1 g, 3.16 mmol) of chlorobenzene (10 mL) was added to the syrup, and the mixture was dropped to 0 ° C, slowly dropping.
  • N-benzoylcytosine (1.1 g, 5.1 mmol) and ammonium sulfate (13.5 mg, 0.10 mmol) were suspended in HMDS (10 mL) under nitrogen atmosphere and in a dry atmosphere. The mixture was heated to 130 ° C and refluxed for 2 h. The HMDS was removed by rotary evaporation at room temperature to obtain a pale yellow syrup.
  • the compound of formula V-1 (0.4 g, 0.64 mmol) was suspended in 70% aqueous acetic acid (10 mL), and the mixture was stirred and refluxed for 6h. The reaction mixture was cooled to room temperature, and a white solid was precipitated. After filtration and drying, 0.29 g of a white powder was obtained in a yield of 86.86%.
  • the compound of formula V-2 (0.4 g, 0.73 mmol) was suspended in 70% aqueous acetic acid (10 mL), and the mixture was stirred and refluxed for 6 h. The reaction mixture was cooled to room temperature, and a white solid was precipitated. After filtration and drying, 0.26 g of a white powder was obtained in a yield of 80.08%.
  • the compound of formula V-3 (0.4 g, 0.85 mmol) was suspended in 70% aqueous acetic acid (10 mL), and the mixture was stirred and refluxed for 6 h. The reaction mixture was cooled to room temperature, and a white solid was formed. After filtration and drying, 0.27 g of a white powder was obtained in a yield of 86.23%.
  • the compound of formula V-4 (0.4 g, 0.73 mmol) was suspended in 70% aqueous acetic acid (10 mL), and the mixture was stirred and refluxed for 6 h. The reaction mixture was cooled to room temperature, and a white solid was formed. , filtered and dried to get white The powder was 0.28 g, and the yield was 86.24%.
  • the VI-4 compound (0.2 g, 0.45 mmol) was added to a solution of ammonia in methanol (6.43 mL, 45 mmol). The reaction was stirred for 3 h, then gradually warmed to room temperature. The reaction was stirred for 20 h. The rate is 76.85% and the purity is 98.6%.

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Abstract

本申请属于药物合成领域，涉及作为索非布韦中间体的2-氟-2-甲基脱氧核糖的制备方法。具体而言，本申请提供一种的由式Ⅱ化合物制备式V化合物的方法，以及所用中间体。本申请的制备方法在缩合反应中立体选择性地得到作为β异构体的式V化合物，可用于索非布韦中间体式1化合物合成路线的收率，低工艺路线成本，更适合于工业化放大。

Description

作为索非布韦中间体的2-氟-2-甲基脱氧核苷的制备方法 技术领域
本申请属于药物合成领域，具体而言，涉及作为索非布韦中间体的2-氟-2-甲基脱氧核苷的制备方法。
背景技术
索非布韦(Sofosbuvir)，化学名为(S)-2-{(S)-{{(2R,3R,4R,5R)-5-[2,4-二氧代-3,4-二氢嘧啶-1(2H)-基]-4-氟-3-羟基-4-甲基四氢呋喃-2-基}甲氧基}(苯氧基)磷酰基氨基}丙酸异丙酯，CAS登记号：1190307-88-0，商品名为Sovaldi，是由吉利德公司开发用于治疗慢性丙肝的新药，于2013年12月6日经美国食品药品监督管理局(FDA)批准在美国上市。2014年1月16日经欧洲药品管理局(EMEA)批准在欧盟各国上市。临床试验证明，索非布韦针对1～4型丙肝，该药联合聚乙二醇干扰素或利巴韦林的总体持续病毒学应答率分别高达90％、89-95％、61-63％和90％。另外对一些丙肝并肝硬化的患者，疗效也非常显著。
WO2012012465、US20140219958、J.Org.Chem,2011,76(20):8311-8319等文献报道索非布韦的合成一般是将(2'R)-2'-脱氧-2'-氟-2'-甲基脲苷(式1)与苯氧基磷酰胺基丙酸异丙酯的磷酰氯或磷酸酯发生磷酰化反应得到，如下所示：
Figure PCTCN2017101078-appb-000001
针对式1化合物的合成方法，现有文献的报道可归类为两条合成路线：
文献J.Med.Chem.,2005,48(17):5504-5508报道以胞嘧啶核苷为原料，经过官能团保护、氧化、加成、二乙胺基三氟化硫(DAST)氟化、脱保护等步骤制备：
Figure PCTCN2017101078-appb-000002
该路线中加成反应需要使用甲基锂在-78℃反应，条件苛刻，副反应多，同时DAST氟化反应这一步收率低，只有15％。
WO2006031725、WO2008045419、WO2013178571、J.Org.Chem.,2009,74(17):6819-6824等文献报道：以(2R)-2-脱氧-2-氟-2-甲基-D-赤式戊糖酸-γ-内酯-3,5-二苯甲酸酯为原料，将羰基还原成醇，再转变成卤素或羧酸酯衍生物，用Vorbrüggen合成法与胞嘧啶衍生物反应生成核苷，最后脱掉保护基得到式1化合物：
Figure PCTCN2017101078-appb-000003
该合成路线操作简便，其中五碳糖环母核与胞嘧啶侧链的偶联产物中β异构体与α异构体比例显著影响该路线收率。
文献Organic Process Research & Development 2008,12,888–891报道一种吉西他滨的合成 方法，该方法中，式10a/b核糖衍生化合物与胞嘧啶衍生物发生缩合反应得到β异构体与α异构体比例为1:1的式13a/b化合物，β异构体没有呈现富集现象，显著降低整条路线的收率。
因此需要开发一条使得偶联产物的β异构体得到富集合成路线，以提高路线总收率，降低工艺路线成本，更适合于工业化放大。
发明内容
本申请提供一种如下所示的由式Ⅱ化合物制备式V化合物的方法，包括如下步骤：
a)将式Ⅱ化合物在还原剂的作用下转变为式Ⅲ化合物，
Figure PCTCN2017101078-appb-000004
b)式Ⅲ化合物在乙酰化试剂和碱的作用下转变为式Ⅳ化合物，
Figure PCTCN2017101078-appb-000005
c)式Ⅳ化合物在路易斯酸作用下与式Ⅶ化合物偶联转变为式Ⅴ所示化合物，
Figure PCTCN2017101078-appb-000006
其中，所述R1或R2各自独立地选自H、C1-6烷基、五～六元芳基或五～六元杂芳基，所述C1-6烷基、五～六元芳基或五～六元杂芳基任选地被1个、2个或3个选自羟基、氨基、硝基、氰基、卤素、C1-6烷基、C1-6烷氧基、C1-6酰基、C1-6酰氧基或C1-6酰氨基的取代基取代。
本申请另一方面提供一种式1所示化合物的制备方法，包括前述所述的由式Ⅱ化合物制 备式V化合物的方法。
在本申请的部分实施方式中，所述一种式1所示化合物的制备方法可选地包括如下步骤：
d)式Ⅴ化合物通过酸的作用转变为式Ⅵ化合物，
Figure PCTCN2017101078-appb-000007
e)式Ⅵ化合物在氨的作用下转变为式1化合物，
Figure PCTCN2017101078-appb-000008
所述R1或R2如前述所定义。
本申请另一方面提供一种式Ⅱ化合物的制备方法，包括如下步骤：
f)式2化合物先发生氟化反应，再在酸和2,2-二甲氧基丙烷存在下脱去磺酸基转变为式3化合物，
Figure PCTCN2017101078-appb-000009
g)式3化合物与式4化合物在碱和催化剂的作用下转变为式5化合物，
Figure PCTCN2017101078-appb-000010
h)式5化合物与酸作用转变为式6化合物，
Figure PCTCN2017101078-appb-000011
i)式6化合物与式7化合物在碱和催化剂作用下转变为式Ⅱ化合物，
Figure PCTCN2017101078-appb-000012
所述R1和R2如前述所定义，R3选自甲基、乙基或丙基。
本申请另一方面提供如下所示化合物：
Figure PCTCN2017101078-appb-000013
所述R1、R2和R3如前述所定义。优选，所述R1或R2各自独立地选自H、甲基或苯基，R3选自甲基、乙基或丙基。更优选，在式Ⅱ和式Ⅲ中，所述R1或R2各自独立地选自H、甲基或苯基且二者不同时为苯基；在式Ⅳ和式5中，所述R1或R2各自独立地选自H、甲基或苯基，R3选自甲基、乙基或丙基；在式6中R2选自H或甲基。
本申请另一方面提供如下所示化合物在制备式1化合物中的用途：
Figure PCTCN2017101078-appb-000014
所述R1、R2和R3如前述所定义。
在本申请的部分实施方式中，优选地，所述R1或R2各自独立地选自H、甲基、乙基、丙基、丁基、戊基、己基、苯基、4-羟基苯基、4-氨基苯基、4-二甲基氨基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-甲基苯基、4-乙基苯基、4-甲氧基苯基、4-乙氧基苯基、4-甲基氨基苯基、4-乙基氨基苯基、4-甲酰基苯基、4-乙酰基苯基、4-甲酰氧基苯基、4-乙酰氧基苯基、4-甲酰氨基苯基、4-乙酰氨基苯基、2-羟基苯基、2-氨基苯基、2-二甲基氨基苯基、2-氟苯基、2-氯苯基、2-溴苯基、2-甲基苯基、2-乙基苯基、2-甲氧基苯基、2-乙氧基苯基、2-甲基氨基苯基、2-乙基氨基苯基、2-甲酰基苯基、2-乙酰基苯基、2-甲酰氧基苯基、2-乙酰氧基苯基、2-甲酰氨基苯基、2-乙酰氨基苯基、2,4-二甲基苯基、2,4-二氟苯基、2,4-二氯苯基、2,4-二溴苯基、吡咯-2-基、吡咯-3-基、吡啶-2-基、吡啶-3-基或吡啶-4-基，优选的，所述R1或R2各自独立地选自H、甲基或苯基。
在本申请的部分实施方式中，由式Ⅱ化合物在还原剂的作用下转变为式Ⅲ化合物中，所述还原剂选自三叔丁氧基氢化铝锂、二氢双(2-甲氧乙氧基)铝酸钠(红铝)，优选为三叔丁氧基氢化铝锂。
在本申请的部分实施方式中，由式Ⅲ化合物在乙酰化试剂和碱的作用下转变为式Ⅳ化合物中，所述乙酰化试剂选自乙酸酐、乙酰氯或冰乙酸，优选乙酸酐。
在本申请的部分实施方式中，由式Ⅲ化合物在乙酰化试剂和碱的作用下转变为式Ⅳ化合物中，所述碱选自三乙胺、吡啶、N,N-二异丙基乙胺或4-二甲氨基吡啶，优选4-二甲氨基吡啶。
在本申请的部分实施方式中，由式Ⅳ化合物在路易斯酸作用下与式Ⅶ化合物偶联转变为式Ⅴ所示化合物中，所述路易斯酸选自四氯化锡、三氯化铝、三氯化铁、四氯化钛或三氟化硼乙醚，优选四氯化锡。
在本申请的部分实施方式中，由式Ⅴ化合物通过酸的作用转变为式Ⅵ化合物中，所述酸选自冰乙酸、甲酸、三氟乙酸、盐酸、硫酸或甲磺酸，优选冰乙酸。
在本申请的部分实施方式中，由式Ⅵ化合物在氨的作用下转变为式1化合物中，所述氨 的存在形式选自氨甲醇溶液、氨乙醇溶液、氨水或氨气，优选氨甲醇溶液。
在本申请的部分实施方式中，由式2化合物转变为式3化合物中，所述氟化试剂选自四乙基氟化铵水合物或三乙胺三氢氟酸盐，优选四乙基氟化铵水合物。
在本申请的部分实施方式中，由式2化合物转变为式3化合物中，所述酸选自盐酸、硫酸或甲磺酸，优选盐酸。
在本申请的部分实施方式中，由式3化合物与式4化合物在碱的作用下转变为式5化合物中，所述碱选自三乙胺、吡啶、N,N-二异丙基乙胺或4-二甲氨基吡啶，优选三乙胺；所述催化剂选自4-二甲氨基吡啶。
在本申请的部分实施方式中，由式5化合物与酸作用转变为式6化合物中，所述酸选自盐酸、硫酸、三氟乙酸或乙酸，优选三氟乙酸。
在本申请的部分实施方式中，由式6化合物与式7化合物在碱和催化剂作用下转变为式Ⅱ化合物中，所述碱选自三乙胺、吡啶、N,N-二异丙基乙胺或4-二甲氨基吡啶，优选三乙胺；所述催化剂选自4-二甲氨基吡啶。
本申请所用原料式2化合物可由本领域公知的方法合成得到，例如，由(R)-甘油醛缩丙酮与2-(三苯基膦烯)丙酸甲酯通过Wittig缩合反应，再经双羟基化、亚磺酰化、氧化等步骤可获得，具体合成路线如下所示：
Figure PCTCN2017101078-appb-000015
说明和定义
除非另有说明，本文所用的下列术语和短语具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
本文所用的术语“化合物”包括化合物的所有立体异构体形式、几何异构体形式、互变异构体形式和同位素形式。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括 发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH2CH3)、单取代的(如CH2CH2F)、多取代的(如CHFCH2F、CH2CHF2等)或完全被取代的(CF2CF3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
本文所用的Cm-n指该部分中具有m～n个整数碳原子。例如，“C1-6烷基”指该烷基具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的即可。
术语“卤素”是指氟、氯、溴或碘。
术语“氨基”指-NH2基团、-NH(C1～6烷基)基团或-N(C1～6烷基)2基团。氨基的具体例子包括但不限于-NH2、-NHCH3、-N(CH3)2、-NHC2H5、-N(C2H5)2、-N(C3H7)2、-N(CH3)C2H5等。
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的脂肪烃基团，其通过单键与分子的其余部分连接。该术语的非限制性实例包括甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、-CH(CH3)2、-CH(CH3)(CH2CH3)、-CH(CH2CH3)2、-C(CH3)3、-C(CH2CH3)3、-CH2CH(CH3)2、-CH2CH(CH3)(CH2CH3)等。
术语“丙、丁、戊”表示碳原子数量的文字与官能团形成的基团包括其所有同分异构体形式，例如：1)丙基包括CH3CH2CH2-、(CH3)2CH-；2)丁酰基包括CH3CH2CH2CO-、(CH3)2CHCO-。
术语“烷氧基”指-O-烷基。
术语“酰基”指-CO-烷基(或H)，例如，“C3酰基”指-CO-C2H5。
术语“酰氧基”指-O-CO-烷基(或H)，例如，“C3酰氧基”指-O-CO-C2H5。
术语“酰氨基”指-NH-CO-烷基(或H)，例如，“C3酰氧基”指-NH-CO-C2H5。
在本申请中，在本申请中，当化学键用
Figure PCTCN2017101078-appb-000016
表示时，指不限定该化学键的立体方向，例如式
Figure PCTCN2017101078-appb-000017
包括
Figure PCTCN2017101078-appb-000018
两种异构体。其中，氧杂五元环1位取代基与4位取代基在同侧，为β异构体；氧杂五元环1位取代基与4位取代基不 在同侧，为α异构体：
Figure PCTCN2017101078-appb-000019
在本申请中，在一些实施例中，所述手性化合物是对映体过量的，所述对映体过量是指其中的手性异构体的含量(物质的量)等于或大于约10％、约20％、约30％、约40％、约50％、约60％、约70％、约80％、约90％、约95％、约96％、约97％、约98％、约99％、约99.1％、约99.2％、约99.3％、约99.4％、约99.5％、约99.6％、约99.7％、约99.8％、约99.9％或约99.99％。
在本申请中，消旋体、ambiscalemic and scalemic或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
在本申请中，化合物可以存在特定的几何或立体异构体形式。本申请设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体过量的混合物，所有这些混合物都属于本申请的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
在本申请中，所述反应可选地在溶剂中进行，本申请中所使用的所有溶剂是市售的，无需进一步纯化即可使用，反应一般是在惰性氮气下、无水溶剂中进行的。
在本申请所述合成路线中，每步反应收率高，操作简单，且式Ⅳ所示化合物与O‐三甲基硅基‐N4‐苯甲酰基胞嘧啶缩合产物中，β异构体的与α异构体的比例高达5/1，相比于文献报道的方法，收率有了较大提高，为索非布韦及其中间体的合成作出了显著改进。
具体实施方式
以下实施例对本发明技术方案作进一步非限制性的详细说明。它们不应该被认为是对本发明范围的限制，而只是本发明的示例性说明和典型代表。本发明中使用的溶剂、试剂和原料等均为市售化学纯或分析纯产品。
实施例1
Figure PCTCN2017101078-appb-000020
将式2‐1化合物(6.0g，19.34mmol)溶于无水二噁烷(60mL)，加入四乙基氟化铵水合物(4.85g，29mmol)，升至100℃搅拌反应1h，冷却至室温，加入2,2‐二甲氧基丙烷(60mL)，室温下滴加入浓盐酸(4.84mL，58.03mmol)，滴毕保持室温搅拌反应3h，向反应液中加入乙酸乙酯(60mL)稀释，以饱和碳酸氢钠溶液(60mL)洗涤，旋蒸除去大部分有机溶剂，再加入乙酸乙酯萃取分液，有机相以饱和食盐水洗涤两次，水相合并以乙酸乙酯提取一次，有机相合并，并以无水硫酸钠干燥，过滤，滤液蒸干得无色油状物4.3g，粗品收率88.8％。
实施例2
Figure PCTCN2017101078-appb-000021
将式3‐1化合物(0.5g，2mmol)、DMAP(24mg，0.2mmol)溶于无水THF(5mL)，降至0℃，加入三乙胺(0.66mL，4.79mmol)，滴加入肉桂酰氯(0.67g，4mmol)的THF溶液，滴毕搅拌反应3h，反应混合物过滤，滤液蒸干得黄色油状物，通过硅胶柱进行纯化，收集含目标产物洗脱液并蒸干得淡黄色油状物0.65g，收率85.5％。
MS：[M+H]+＝367。
1H NMR(400MHz，CDCl3)：δ0.98(s，6H)，1.42-1.45(d，3H)，2.20(s，3H)，3.66-3.92(m，4H)，4.96-5.03(d，1H)，5.22-5.31(d，1H)，7.20-7.43(m，5H)。
实施例3
Figure PCTCN2017101078-appb-000022
将式3‐1化合物(0.5g，2mmol)、DMAP(24mg，0.2mmol)溶于无水THF(5mL)，降至0℃，加入三乙胺(1.11mL，8mmol)，滴加入丙烯酰氯(0.36g，4mmol)的THF溶液，滴毕 搅拌反应24h，反应混合物过滤，滤液蒸干得黄色油状物，通过硅胶柱进行纯化，收集含目标产物洗脱液并蒸干得淡黄色油状物0.46g，收率75.6％。
MS：[M+H]+＝291。
1H NMR(400MHz，CDCl3)：δ0.99(s，6H)，1.43-1.46(d，3H)，2.12(s，3H)，3.61-3.88(m，4H)，4.68-4.74(m，2H)，5.11-5.16(m，1H)。
实施例4
Figure PCTCN2017101078-appb-000023
将式5‐1化合物(100mg，0.26mmol)溶于无水二氯甲烷(5mL)，加入三氟乙酸(60mg，0.53mmol)，室温搅拌反应48h，反应液以DCM稀释，加入饱和碳酸氢钠溶液洗涤，分液，有机相蒸干得半固体状物50mg，收率65％。
MS：[M+H]+＝295。
1H NMR(400MHz，CDCl3)：δ1.46-1.51(d，3H)，3.61-3.93(m，4H)，4.12(brs，1H)，4.88-4.93(d，1H)，5.19-5.27(d，1H)，7.21-7.40(m，5H)。
实施例5
Figure PCTCN2017101078-appb-000024
将式5‐2化合物(100mg，0.33mmol)溶于无水二氯甲烷(5mL)，加入三氟乙酸(75mg，0.66mmol)，室温搅拌反应48h，反应液以DCM稀释，加入饱和碳酸氢钠溶液洗涤，分液，有机相蒸干得半固体状物46mg，收率64％。
MS：[M+H]+＝219。
1H NMR(400MHz，CDCl3)：δ1.43-1.49(d，3H)，3.56-3.90(m，4H)，4.08(brs，1H)，4.71-4.78(m，2H)，5.13-5.18(m，1H)。
实施例6
Figure PCTCN2017101078-appb-000025
将式6‐1化合物(50mg，0.17mmol)、DMAP(2mg，0.017mmol)溶于无水THF(5mL)，降至0℃，加入三乙胺(0.094mL，0.68mmol)，滴加入肉桂酰氯(56.6mg，0.34mmol)的THF溶液，滴毕搅拌反应12h，反应液过滤除去固体，滤液蒸干得淡黄色油状物，以乙酸乙酯/石油醚重结晶得白色粉末52mg，收率72.1％。
MS：[M+H]+＝425。
1H NMR(400MHz，CDCl3)：δ1.71-1.77(d，3H)，4.44-4.48(d，2H)，4.84-4.88(m，1H)，5.3-5.4(m，1H)，6.42-6.53(m，2H)，7.34-7.45(m，6H)，7.49-7.55(m，4H)，7.71-7.83(m，2H)。
实施例7
Figure PCTCN2017101078-appb-000026
将式6‐1化合物(50mg，0.17mmol)、DMAP(2mg，0.017mmol)溶于无水THF(5mL)，降至0℃，加入三乙胺(0.094mL，0.68mmol)，滴加入丙烯酰氯(30.76mg，0.34mmol)的THF溶液，滴毕搅拌反应12h，反应液过滤除去固体，滤液蒸干得淡黄色油状物，以乙酸乙酯/石油醚重结晶得白色粉末43mg，收率72.7％。
MS：[M+H]+＝349。
1H NMR(400MHz，CDCl3)：δ1.66-1.73(d，3H)，4.38-4.42(d，2H)，4.82-4.86(m，1H)，5.26-5.42(m，1H)，5.96-6.11(m，2H)，6.39-6.50(m，2H)，7.46-7.57(m，6H)。
实施例8
Figure PCTCN2017101078-appb-000027
将式6‐2化合物(50mg，0.23mmol)、DMAP(2.8mg，0.023mmol)溶于无水THF(5mL)，降至0℃，加入三乙胺(0.13mL，0.92mmol)，滴加入丙烯酰氯(41.5mg，0.46mmol)的THF溶液，滴毕搅拌反应12h，反应液过滤除去固体，滤液蒸干得淡黄色油状物48mg，收率76.9％。
MS：[M+H]+＝273。
1H NMR(400MHz，CDCl3)：δ1.65-1.71(d，3H)，4.33-4.45(d，2H)，4.79-4.81(m，1H)，5.23-5.34(m，1H)，5.56-5.78(m，4H)，6.22-6.51(m，2H)。
实施例9
Figure PCTCN2017101078-appb-000028
将式6‐2化合物(50mg，0.23mmol)、DMAP(2.8mg，0.023mmol)溶于无水THF(5mL)，降至0℃，加入三乙胺(0.13mL，0.92mmol)，滴加入肉桂酰氯(76mg，0.46mmol)的THF(1mL)组成的溶液，滴毕搅拌反应12h，反应液过滤除去固体，滤液蒸干得淡黄色油状物，以乙酸乙酯/石油醚重结晶得白色粉末56mg，收率70.2％。
MS：[M+H]+＝349。
1H NMR(400MHz，CDCl3)：δ1.70-1.75(d，3H)，4.43-4.51(d，2H)，4.86-4.93(m，1H)，5.23-5.44(m，1H)，6.05-6.17(m，2H)，6.43-6.55(m，2H)，7.43-7.66(m，6H)。
实施例10
Figure PCTCN2017101078-appb-000029
将式Ⅱ‐1化合物(5g，11.78mmol)溶于THF(50mL)，降温至‐30℃，滴加三叔丁氧基氢 化铝锂的THF溶液(16.5mL，16.5mmol)，滴毕逐渐升温至‐15℃，搅拌反应2h。加入EA(50mL)，滴加饱和氯化铵溶液(50mL)，继续搅拌1h，通过十水合硫酸钠过滤，滤饼以EA洗涤三次，滤液分液，有机相依次以稀盐酸、纯水洗涤，合并有机层，以饱和食盐水洗涤，无水硫酸钠干燥过夜，蒸干得淡黄色油状物4.5g，收率89.6％。
MS：[M+Na]+＝449。
1H NMR(400MHz，CDCl3)：δ1.51-1.60(d，3H)，3.63(brs，1H)，4.15-4.34(d，2H)，4.75-4.83(m，1H)，5.18-5.39(m，1H)，5.43(s，1H)，6.33-6.50(m，2H)，7.25-7.41(m，6H)，7.53-7.67(m，4H)，7.78-7.89(m，2H)。
实施例11
Figure PCTCN2017101078-appb-000030
将式Ⅱ‐2化合物(5g，14.35mmol)溶于THF(50mL)，降温至‐30℃，滴加三叔丁氧基氢化铝锂的THF溶液(20.1mL，20.1mmol)，滴毕逐渐升温至‐15℃，搅拌反应2h。加入EA(50mL)，滴加饱和氯化铵溶液(50mL)，继续搅拌1h，通过十水合硫酸钠过滤，滤饼以EA洗涤三次，滤液分液，有机相依次以稀盐酸、纯水洗涤，合并有机层，以饱和食盐水洗涤，无水硫酸钠干燥过夜，蒸干得淡黄色油状物4.7g，收率93.5％。
MS：[M+Na]+＝373。
1H NMR(400MHz，CDCl3)：δ1.44-1.61(d，3H)，3.59(brs，1H)，4.19-4.32(d，2H)，4.68-4.77(m，1H)，5.18-5.39(m，1H)，5.43(s，1H)，5.36-5.47(m，1H)，5.89-5.97(m，2H)，6.25-6.41(m，2H)，7.41-7.66(m，6H)。
实施例12
Figure PCTCN2017101078-appb-000031
将式Ⅱ‐3化合物(5g，18.37mmol)溶于THF(50mL)，降温至‐30℃，滴加三叔丁氧基氢 化铝锂的THF溶液(25.7mL，25.7mmol)，滴毕逐渐升温至‐15℃，搅拌反应2h。加入EA(50mL)，滴加饱和氯化铵溶液(50mL)，继续搅拌1h，通过十水合硫酸钠过滤，滤饼以EA洗涤三次，滤液分液，有机相依次以稀盐酸、纯水洗涤，合并有机层，以饱和食盐水洗涤，无水硫酸钠干燥过夜，蒸干得淡黄色油状物4.5g，收率89.3％。
MS：[M+Na]+＝397。
1H NMR(400MHz，CDCl3)：δ1.53-1.66(d，3H)，3.63(brs，1H)，4.21-4.29(d，2H)，4.55-4.71(m，1H)，5.20-5.36(m，1H)，5.55(s，1H)，5.83-6.01(m，4H)，6.15-6.40(m，2H)。
实施例13
Figure PCTCN2017101078-appb-000032
将式Ⅱ‐4化合物(5g，14.35mmol)溶于THF(50mL)，降温至‐30℃，滴加三叔丁氧基氢化铝锂的THF溶液(20.1mL，20.1mmol)，滴毕逐渐升温至‐15℃，搅拌反应2h。加入EA(50mL)，滴加饱和氯化铵溶液(50mL)，继续搅拌1h，通过十水合硫酸钠过滤，滤饼以EA洗涤三次，滤液分液，有机相依次以稀盐酸、纯水洗涤，合并有机层，以饱和食盐水洗涤，无水硫酸钠干燥过夜，蒸干得淡黄色油状物4.3g，收率85.5％。
MS：[M+Na]+＝373。
1H NMR(400MHz，CDCl3)：δ1.47-1.63(d，3H)，3.63(brs，1H)，4.22-4.38(d，2H)，4.65-4.79(m，1H)，5.28-5.44(m，1H)，5.56(s，1H)，5.62-5.87(m，1H)，5.93-6.10(m，2H)，6.29-6.45(m，2H)，7.40-7.68(m，6H)。
实施例14
Figure PCTCN2017101078-appb-000033
将式Ⅲ‐1化合物(3.75g，8.79mmol)溶于无水THF(20mL)，加入DMAP(1.07g，8.79mmol)， 降温至‐20℃，滴加乙酸酐(1.66mL，17.59mmol)，滴毕搅拌反应2h，反应液中加入EA和水分液，有机相依次以水和饱和食盐水洗涤，无水硫酸钠干燥，蒸干得白色固体3.86g，收率93.7％。
MS：[M+Na]+＝491。
1H NMR(400MHz，CDCl3)：δ1.48-1.53(d，3H)，2.11(s，3H)，4.11-4.31(d，2H)，4.70-4.82(m，1H)，5.20-5.36(m，1H)，5.50(s，1H)，6.27-6.52(m，2H)，7.23-7.46(m，6H)，7.58-7.72(m，4H)，7.81-7.97(m，2H)。
实施例15
Figure PCTCN2017101078-appb-000034
将式Ⅲ‐2化合物(3g，8.56mmol)溶于无水THF(20mL)，加入DMAP(1.04g，8.56mmol)，降温至‐20℃，滴加乙酸酐(1.62mL，17.13mmol)，滴毕搅拌反应2h，反应液中加入EA和水分液，有机相依次以水和饱和食盐水洗涤，无水硫酸钠干燥，蒸干得白色固体3.21g，收率95.5％。
MS：[M+Na]+＝415。
1H NMR(400MHz，CDCl3)：δ1.43-1.50(d，3H)，2.13(s，3H)，4.16-4.37(d，2H)，4.68-4.80(m，1H)，5.23-5.39(m，1H)，5.47(s，1H)，5.66-5.72(m，1H)，5.92-6.10(m，2H)，6.29-6.43(m，2H)，7.30-7.49(m，6H)。
实施例16
Figure PCTCN2017101078-appb-000035
将式Ⅲ‐3化合物(3.5g，12.76mmol)溶于无水THF(20mL)，加入DMAP(1.55g，12.76mmol)，降温至‐20℃，滴加乙酸酐(2.41mL，25.52mmol)，滴毕搅拌反应2h，反应液中加入EA(50mL)和水(50mL)，搅拌萃取后分液，有机相依次以水和饱和食盐水洗涤，无水硫酸钠干燥，蒸 干得白色固体3.81g，收率94.4％。
MS：[M+Na]+＝339。
1H NMR(400MHz，CDCl3)：δ1.53-1.59(d，3H)，2.14(s，3H)，4.20-4.33(d，2H)，4.50-4.67(m，1H)，5.20-5.34(m，1H)，5.51(s，1H)，5.89-6.03(m，4H)，6.25-6.40(m，2H)。
实施例17
Figure PCTCN2017101078-appb-000036
将式Ⅲ‐4化合物(3g，8.56mmol)溶于无水THF(20mL)，加入DMAP(1.04g，8.56mmol)，降温至‐20℃，保持t≤‐20℃下滴加入乙酸酐(1.62mL，17.13mmol)，滴毕搅拌反应2h，反应液中加入EA和水分液，有机相依次以水和饱和食盐水洗涤，无水硫酸钠干燥，蒸干得白色固体3.13g，收率93.2％。
MS：[M+Na]+＝415。
1H NMR(400MHz，CDCl3)：δ1.52-1.57(d，3H)，2.01(s，3H)，4.18-4.35(d，2H)，4.59-4.75(m，1H)，5.18-5.36(m，1H)，5.53(s，1H)，5.61-5.68(m，1H)，5.90-6.13(m，2H)，6.27-6.40(m，2H)，7.28-7.46(m，6H)。
实施例18
Figure PCTCN2017101078-appb-000037
氮气保护及干燥环境中，N‐苯甲酰基胞嘧啶(0.92g，4.27mmol)，硫酸铵(11.3mg，0.085mmol)悬浮于HMDS(10mL)中，升温至130℃回流搅拌反应2h，降至室温，旋蒸除去HMDS，得淡黄色糖浆状物，向该糖浆状物中加入由式Ⅳ‐1化合物(1g，2.13mmol)的氯苯(10mL)溶液，降至0℃，缓慢滴加入SnCl4(1.1mL，9.39mmol)，升至70℃搅拌反应20h， HPLC测得反应液中产物的β构型和α构型含量依次为60.25％和11.90％，异构体比例β/α＝5.06。降至室温，加入二氯甲烷、碳酸氢钠和硅藻土，搅拌均匀，降至0℃，滴加纯水，滴毕升至室温搅拌反应2h，大量气泡冒出，将所得混合物过滤，滤液以饱和食盐水洗涤两次，无水硫酸钠干燥过夜，蒸干得黄色固体粗品，以甲醇/氯苯重结晶得白色粉末0.91g，收率68.36％，纯度96.81％(HPLC)。
MS：[M+H]+＝624。
1H NMR(400MHz，CDCl3)：δ1.56-1.66(d，3H)，4.40-4.45(d，2H)，4.81-4.89(m，1H)，5.25-5.36(m，1H)，5.40(s，1H)，6.41-6.52(m，2H)，7.29-7.49(m，8H)，7.56-7.69(m，8H)，7.73-7.88(m，2H)，8.16(d，1H)，8.37(d，1H)。
实施例19
Figure PCTCN2017101078-appb-000038
氮气保护及干燥环境中，N‐苯甲酰基胞嘧啶(1.1g，5.1mmol)，硫酸铵(13.5mg，0.10mmol)悬浮于HMDS(10mL)中，升温至130℃回流搅拌反应2h，降至室温，旋蒸除去HMDS，得淡黄色糖浆状物，向该糖浆状物中加入由式Ⅳ‐2化合物(1g，2.55mmol)的氯苯(10mL)组成的溶液，降至0℃，缓慢滴加入SnCl4(1.31mL，11.21mmol)，升至70℃搅拌反应20h，HPLC测得反应液中产物的β构型和α构型含量依次为62.31％和12.56％，异构体比例β/α＝4.96。降至室温，加入二氯甲烷、碳酸氢钠和硅藻土，搅拌均匀，降至0℃，滴加纯水，滴毕升至室温搅拌反应2h，大量气泡冒出，将所得混合物过滤，滤液以饱和食盐水洗涤两次，无水硫酸钠干燥过夜，蒸干得黄色固体粗品，以甲醇/氯苯重结晶得白色粉末1.08g，收率77.42％，纯度96.77％(HPLC)。
MS：[M+H]+＝547。
1H NMR(400MHz，CDCl3)：δ1.61-1.70(d，3H)，4.39-4.42(d，2H)，4.80-4.88(m，1H)，5.19-5.33(m，1H)，5.35(s，1H)，5.55-5.67(m，2H)，,5.91-6.08(m，3H)，7.22-7.71m，10H)，8.10(d，1H)，8.33(d，1H)。
实施例20
Figure PCTCN2017101078-appb-000039
氮气保护及干燥环境中，N‐苯甲酰基胞嘧啶(1.36g，6.32mmol)，硫酸铵(16.71mg，0.126mmol)悬浮于HMDS(10mL)中，升温至130℃回流搅拌反应2h，降至室温，旋蒸除去HMDS，得淡黄色糖浆状物，向该糖浆状物中加入由式Ⅳ‐3化合物(1g，3.16mmol)的氯苯(10mL)组成的溶液，降至0℃，缓慢滴加入SnCl4(1.63mL，13.91mmol)，升至70℃搅拌反应20h，HPLC测得反应液中产物的β构型和α构型含量依次为58.26％和12.33％，异构体比例β/α＝4.73。降至室温，加入二氯甲烷、碳酸氢钠和硅藻土，搅拌均匀，降至0℃，滴加纯水，滴毕升至室温搅拌反应2h，大量气泡冒出，将所得混合物过滤，滤液以饱和食盐水洗涤两次，无水硫酸钠干燥过夜，蒸干得黄色固体粗品，以甲醇/氯苯重结晶得白色粉末1.23g，收率82.64％，纯度96.67％(HPLC)。
MS：[M+H]+＝471。
1H NMR(400MHz，CDCl3)：δ1.55-1.69(d，3H)，4.36-4.40(d，2H)，4.76-4.83(m，1H)，5.10-5.29(m，1H)，5.33(s，1H)，5.66-5.78(m，4H)，5.99-6.18(m，2H)，7.12-7.35(m，5H)，8.11(d，1H)，8.30(d，1H)。
实施例21
Figure PCTCN2017101078-appb-000040
氮气保护及干燥环境中，N‐苯甲酰基胞嘧啶(1.1g，5.1mmol)，硫酸铵(13.5mg，0.10mmol)悬浮于HMDS(10mL)中，升温至130℃回流搅拌反应2h，降至室温，旋蒸除去HMDS，得淡黄色糖浆状物，向该糖浆状物中加入由式Ⅳ‐4化合物(1g，2.55mmol)的氯苯(10mL)组 成的溶液，降至0℃，缓慢滴加入SnCl4(1.31mL，11.21mmol)，升至70℃搅拌反应20h，HPLC测得反应液中产物的β构型和α构型含量依次为61.98％和12.84％，异构体比例β/α＝4.82。降至室温，加入二氯甲烷、碳酸氢钠和硅藻土，搅拌均匀，降至0℃，滴加纯水，滴毕升至室温搅拌反应2h，大量气泡冒出，将所得混合物过滤，滤液以饱和食盐水洗涤两次，无水硫酸钠干燥过夜，蒸干得黄色固体粗品，以甲醇/氯苯重结晶得白色粉末1.01g，收率72.41％，纯度96.08％(HPLC)。
MS：[M+H]+＝547。
1H NMR(400MHz，CDCl3)：δ1.61-1.70(d，3H)，4.39-4.42(d，2H)，4.80-4.88(m，1H)，5.19-5.33(m，1H)，5.35(s，1H)，5.55-5.67(m，2H)，,5.91-6.08(m，3H)，7.22-7.71m，10H)，8.10(d，1H)，8.33(d，1H)。
实施例22
Figure PCTCN2017101078-appb-000041
将式Ⅴ‐1化合物(0.4g，0.64mmol)悬浮于70％醋酸水溶液(10mL)中，升至回流搅拌反应6h，反应液降至室温，析出白色固体，加入冰水，冰浴下搅拌1h，过滤干燥后得到白色粉末0.29g，收率86.86％。
MS：[M+H]+＝521。
1H NMR(400MHz，CDCl3)：δ1.44-1.49(d，3H)，4.51-4.56(d，2H)，4.88-4.92(m，1H)，5.26-5.37(m，1H)，5.44(s，1H)，6.23-6.46(m，2H)，7.20-7.41(m，6H)，7.52-7.70(m，4H)，7.77-7.92(m，2H)，8.02(d，1H)，8.26(d，1H)，9.17(s，1H)。
实施例23
Figure PCTCN2017101078-appb-000042
将式Ⅴ‐2化合物(0.4g，0.73mmol)悬浮于70％醋酸水溶液(10mL)中，升至回流搅拌反应6h，反应液降至室温，析出白色固体，加入冰水，冰浴下搅拌1h，过滤干燥后得到白色粉末0.26g，收率80.08％。
MS：[M+H]+＝444。
1H NMR(400MHz，CDCl3)：δ1.46-1.52(d，3H)，4.49-4.53(d，2H)，4.86-4.90(m，1H)，5.22-5.39(m，1H)，5.49(s，1H)，5.65-5.72(m，1H)，5.88-6.05(m，2H)，6.26-6.44(m，2H)，7.25-7.47(m，6H)8.05(d，1H)，8.23(d，1H)，9.20(s，1H)。
实施例24
Figure PCTCN2017101078-appb-000043
将式Ⅴ‐3化合物(0.4g，0.85mmol)悬浮于70％醋酸水溶液(10mL)中，升至回流搅拌反应6h，反应液降至室温，析出白色固体，加入冰水，冰浴下搅拌1h，过滤干燥后得到白色粉末0.27g，收率86.23％。
MS：[M+H]+＝368。
1H NMR(400MHz，CDCl3)：δ1.49-1.55(d，3H)，4.47-4.56(d，2H)，4.80-4.87(m，1H)，5.19-5.35(m，1H)，5.45(s，1H)，5.69-5.80(m，4H)，5.96-6.25(m，2H)，8.00(d，1H)，8.22(d，1H)，9.15(s，1H)。
实施例25
Figure PCTCN2017101078-appb-000044
将式Ⅴ‐4化合物(0.4g，0.73mmol)悬浮于70％醋酸水溶液(10mL)中，升至回流搅拌反应6h，反应液降至室温，析出白色固体，加入冰水，冰浴下搅拌1h，过滤干燥后得到白色 粉末0.28g，收率86.24％。
MS：[M+H]+＝444。
1H NMR(400MHz，CDCl3)：δ1.41-1.50(d，3H)，4.45-4.52(d，2H)，4.83-4.92(m，1H)，5.26-5.41(m，1H)，5.44(s，1H)，5.67-5.75(m，1H)，5.86-6.09(m，2H)，6.27-6.48(m，2H)，7.20-7.45(m，6H)8.01(d，1H)，8.24(d，1H)，9.18(s，1H)。
实施例26
Figure PCTCN2017101078-appb-000045
于0℃下，将Ⅵ‐1化合物(0.2g，0.384mmol)加入至氨甲醇溶液(5.5mL，38.42mmol)中，搅拌反应3h，后逐渐升至室温持续搅拌反应20h，将反应液旋干除去溶剂得到黄色油状物，加入异丙醚，室温搅拌3h，析出白色固体，过滤，烘干，得白色粉末81mg，收率81％，纯度98.5％。
MS：[M+H]+＝261。
1H NMR(400MHz，CDCl3)：δ1.24-1.29(d，3H)，3.63-3.66(m，1H)，3.81-3.90(m，3H)，5.29(s，1H)，5.66-5.68(m，2H)，5.98-6.03(d，1H)，7.97-7.99(d，1H)，11.47(s，1H)。
实施例27
Figure PCTCN2017101078-appb-000046
于0℃下，将Ⅵ‐2化合物(0.2g，0.45mmol)加入至氨甲醇溶液(6.43mL，45mmol)中，搅拌反应3h，后逐渐升至室温持续搅拌反应20h，将反应液旋干除去溶剂得到黄色油状物， 加入异丙醚，室温搅拌3h，析出白色固体，过滤，烘干，得白色粉末92mg，收率78.6％，纯度97.9％。
MS：[M+H]+＝261。
1H NMR(400MHz，CDCl3)：δ1.24-1.29(d，3H)，3.63-3.66(m，1H)，3.81-3.90(m，3H)，5.29(s，1H)，5.66-5.68(m，2H)，5.98-6.03(d，1H)，7.97-7.99(d，1H)，11.47(s，1H)。
实施例28
Figure PCTCN2017101078-appb-000047
于0℃下，将Ⅵ‐3化合物(0.2g，0.543mmol)加入至氨甲醇溶液(7.8mL，38.42mmol)中，搅拌反应3h，后逐渐升至室温持续搅拌反应20h，将反应液旋干除去溶剂得到黄色油状物，加入异丙醚，室温搅拌3h，析出白色固体，过滤，烘干，得白色粉末110mg，收率77.85％，纯度98.2％。
MS：[M+H]+＝261。
1H NMR(400MHz，CDCl3)：δ1.24-1.29(d，3H)，3.63-3.66(m，1H)，3.81-3.90(m，3H)，5.29(s，1H)，5.66-5.68(m，2H)，5.98-6.03(d，1H)，7.97-7.99(d，1H)，11.47(s，1H)。
实施例29
Figure PCTCN2017101078-appb-000048
于0℃下，将Ⅵ‐4化合物(0.2g，0.45mmol)加入至氨甲醇溶液(6.43mL，45mmol)中， 搅拌反应3h，后逐渐升至室温持续搅拌反应20h，将反应液旋干除去溶剂得到黄色油状物，加入异丙醚，室温搅拌3h，析出白色固体，过滤，烘干，得白色粉末90mg，收率76.85％，纯度98.6％。
MS：[M+H]+＝261。
1H NMR(400MHz，CDCl3)：δ1.24-1.29(d，3H)，3.63-3.66(m，1H)，3.81-3.90(m，3H)，5.29(s，1H)，5.66-5.68(m，2H)，5.98-6.03(d，1H)，7.97-7.99(d，1H)，11.47(s，1H)。

Claims (9)

  1. 一种由式II化合物制备式V化合物的方法，包括如下步骤：
    a)将式II化合物在还原剂的作用下转变为式III化合物，
    Figure PCTCN2017101078-appb-100001
    b)式III化合物在乙酰化试剂和碱的作用下转变为式IV化合物，
    Figure PCTCN2017101078-appb-100002
    c)式IV化合物在路易斯酸作用下与式VII化合物偶联转变为式Ⅴ所示化合物，
    Figure PCTCN2017101078-appb-100003
    其中，所述R1或R2各自独立地选自H、C1-6烷基、五～六元芳基或五～六元杂芳基，所述C1-6烷基、五～六元芳基或五～六元杂芳基任选地被1个、2个或3个选自羟基、氨基、硝基、氰基、卤素、C1-6烷基、C1-6烷氧基、C1-6酰基、C1-6酰氧基或C1-6酰氨基的取代基取代。
  2. 根据权利要求1所述的方法，其特征在于，所述R1或R2各自独立地选自H、甲基、乙基、丙基、丁基、戊基、己基、苯基、4-羟基苯基、4-氨基苯基、4-二甲基氨基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-甲基苯基、4-乙基苯基、4-甲氧基苯基、4-乙氧基苯基、4-甲基氨基苯基、4-乙基氨基苯基、4-甲酰基苯基、4-乙酰基苯基、4-甲酰氧基苯基、4-乙 酰氧基苯基、4-甲酰氨基苯基、4-乙酰氨基苯基、2-羟基苯基、2-氨基苯基、2-二甲基氨基苯基、2-氟苯基、2-氯苯基、2-溴苯基、2-甲基苯基、2-乙基苯基、2-甲氧基苯基、2-乙氧基苯基、2-甲基氨基苯基、2-乙基氨基苯基、2-甲酰基苯基、2-乙酰基苯基、2-甲酰氧基苯基、2-乙酰氧基苯基、2-甲酰氨基苯基、2-乙酰氨基苯基、2,4-二甲基苯基、2,4-二氟苯基、2,4-二氯苯基、2,4-二溴苯基、吡咯-2-基、吡咯-3-基、吡啶-2-基、吡啶-3-基或吡啶-4-基，优选的，所述R1或R2各自独立地选自H、甲基或苯基。
  3. 一种式1所示化合物的制备方法，包括权利要求1所述的由式II化合物制备式V化合物的方法，
    Figure PCTCN2017101078-appb-100004
  4. 根据权利要求3所述的式1所示化合物的制备方法，其特征在于，还包括如下步骤：
    d)式Ⅴ化合物通过酸的作用转变为式VI化合物，
    Figure PCTCN2017101078-appb-100005
    e)式VI化合物在氨的作用下转变为式1化合物，
    Figure PCTCN2017101078-appb-100006
    其中，所述R1或R2各自独立地选自H、C1-6烷基、五～六元芳基或五～六元杂芳基，所述C1-6烷基、五～六元芳基或五～六元杂芳基任选地被1个、2个或3个选自羟基、氨基、硝基、氰基、卤素、C1-6烷基、C1-6烷氧基、C1-6酰基、C1-6酰氧基或C1-6酰氨基的取代基取代。
  5. 根据权利要求3或4任一项所述的制备方法，其特征在于，所述R1或R2各自独立地选自H、甲基、乙基、丙基、丁基、戊基、己基、苯基、4-羟基苯基、4-氨基苯基、4-二甲基氨基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-甲基苯基、4-乙基苯基、4-甲氧基苯基、4-乙氧基苯基、4-甲基氨基苯基、4-乙基氨基苯基、4-甲酰基苯基、4-乙酰基苯基、4-甲酰氧基苯基、4-乙酰氧基苯基、4-甲酰氨基苯基、4-乙酰氨基苯基、2-羟基苯基、2-氨基苯基、2-二甲基氨基苯基、2-氟苯基、2-氯苯基、2-溴苯基、2-甲基苯基、2-乙基苯基、2-甲氧基苯基、2-乙氧基苯基、2-甲基氨基苯基、2-乙基氨基苯基、2-甲酰基苯基、2-乙酰基苯基、2-甲酰氧基苯基、2-乙酰氧基苯基、2-甲酰氨基苯基、2-乙酰氨基苯基、2,4-二甲基苯基、2,4-二氟苯基、2,4-二氯苯基、2,4-二溴苯基、吡咯-2-基、吡咯-3-基、吡啶-2-基、吡啶-3-基或吡啶-4-基，优选的，所述R1或R2各自独立地选自H、甲基或苯基。
  6. 一种式II化合物的制备方法，包括如下步骤：
    f)式2化合物先发生氟化反应，再在酸和2,2-二甲氧基丙烷存在下脱去磺酸基转变为式3化合物，
    Figure PCTCN2017101078-appb-100007
    g)式3化合物与式4化合物在碱和催化剂的作用下转变为式5化合物，
    Figure PCTCN2017101078-appb-100008
    h)式5化合物与酸作用转变为式6化合物，
    Figure PCTCN2017101078-appb-100009
    i)式6化合物与式7化合物在碱和催化剂作用下转变为式II化合物，
    Figure PCTCN2017101078-appb-100010
    其中，所述R1或R2各自独立地选自H、C1-6烷基、五～六元芳基或五～六元杂芳基，所述C1-6烷基、五～六元芳基或五～六元杂芳基任选地被1个、2个或3个选自羟基、氨基、硝基、氰基、卤素、C1-6烷基、C1-6烷氧基、C1-6酰基、C1-6酰氧基或C1-6酰氨基的取代基取代，R3选自甲基、乙基或丙基。
  7. 根据权利要求6所述的制备方法，其特征在于，所述R1或R2各自独立地选自H、甲基、乙基、丙基、丁基、戊基、己基、苯基、4-羟基苯基、4-氨基苯基、4-二甲基氨基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-甲基苯基、4-乙基苯基、4-甲氧基苯基、4-乙氧基苯基、4-甲基氨基苯基、4-乙基氨基苯基、4-甲酰基苯基、4-乙酰基苯基、4-甲酰氧基苯基、4-乙酰氧基苯基、4-甲酰氨基苯基、4-乙酰氨基苯基、2-羟基苯基、2-氨基苯基、2-二甲基氨基苯基、2-氟苯基、2-氯苯基、2-溴苯基、2-甲基苯基、2-乙基苯基、2-甲氧基苯基、2-乙氧基苯基、2-甲基氨基苯基、2-乙基氨基苯基、2-甲酰基苯基、2-乙酰基苯基、2-甲酰氧基苯基、2-乙酰氧基苯基、2-甲酰氨基苯基、2-乙酰氨基苯基、2,4-二甲基苯基、2,4-二 氟苯基、2,4-二氯苯基、2,4-二溴苯基、吡咯-2-基、吡咯-3-基、吡啶-2-基、吡啶-3-基或吡啶-4-基，优选的，所述R1或R2各自独立地选自H、甲基或苯基。
  8. 如下所示化合物：
    Figure PCTCN2017101078-appb-100011
    其中，所述R1或R2各自独立地选自H、甲基或苯基，R3选自甲基、乙基或丙基。
  9. 如权利要求8所述的化合物在制备式1化合物中的用途
    Figure PCTCN2017101078-appb-100012
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