WO2020032152A1 - Procédé de synthèse stéréosélective de dérivé nucléosidique à substitution en position 4' - Google Patents

Procédé de synthèse stéréosélective de dérivé nucléosidique à substitution en position 4' Download PDF

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WO2020032152A1
WO2020032152A1 PCT/JP2019/031293 JP2019031293W WO2020032152A1 WO 2020032152 A1 WO2020032152 A1 WO 2020032152A1 JP 2019031293 W JP2019031293 W JP 2019031293W WO 2020032152 A1 WO2020032152 A1 WO 2020032152A1
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methyl
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mmol
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向後　悟
智子 松浦
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ヤマサ醤油株式会社
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • 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
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
    • 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 method for stereoselective synthesis of 4'-substituted nucleoside derivatives.
  • nucleoside derivatives for pharmaceuticals has been studied for a long time, and many compounds have already been used as antitumor drugs, antiviral drugs, and immunosuppressive drugs.
  • 4'-substituted nucleoside derivatives in which the 4-position of the ribose sugar of the nucleoside is substituted with a specific functional group are a useful group of compounds in the field of antiviral agents and the like, and have attracted attention in recent years.
  • hepatitis B virus HBV
  • HBV hepatitis B virus
  • 4'-chloromethyl-2'-deoxy-3 ', 5'-di-O-isobutyryl-2'-fluorocytidine (also known as ALS-8176, Patent Document 2 and Non-Patent Document 1) Acts as a polymerase inhibitor of respiratory tract inclusion virus (RSV) and is being developed as a first-in-class anti-RSV agent.
  • RSV respiratory tract inclusion virus
  • a problem encountered with the currently reported methods for synthesizing 4'-substituted nucleoside derivatives is that they involve a step of generating stereoisomers.
  • the synthesis is performed by the following reaction steps.
  • a diastereomer represented by the formula (2 ′) is generated in the conversion of the compound represented by the formula (1) into the compound represented by the formula (2).
  • the reaction is carried out without separating the diastereomer represented by (2 '), the diastereomer of the target compound is by-produced. For this reason, not only is the yield of the target compound reduced, but also a separation step is required to separate the diastereomer. It has been considered a problem that the purification process is difficult and complicated.
  • Non-Patent Document 2 discloses the following method for introducing a 4'-substituent in the synthesis of 4'-methyluridine.
  • the above-mentioned reactions include a reaction step in which a protecting group is not introduced at a target position and a by-product is generated. That is, one equivalent of sodium hydride and benzyl bromide are allowed to act on 3-O-benzyl-4-C-hydroxymethyl-1,2-O-isopropylidene- ⁇ -D-ribofuranose, and selectively to the 5-position In this step, only the hydroxyl group is protected with benzyl. In this reaction, a stereoselective protecting group could not be introduced. As a result, 66% of the benzyl compound at the 5-position was obtained, while 11% of the benzyl compound at the 6-position as a by-product were obtained.
  • Non-Patent Document 2 requires purification by chromatography in order to separate by-products in which a protecting group has not been introduced at the target position.
  • the separation of the by-product or the stereoisomer is difficult because the structure is similar to the target product, and there is a problem that the purification step is complicated.
  • the present invention relates to a method for synthesizing a 4′-substituted nucleoside intermediate represented by the formula (6), which comprises the following steps 1 to 3.
  • Step 1 using the compound of formula (3) as a starting material, reacting the compound of formula (3) with a nucleophile to obtain a compound of formula (4) in which a substituent is stereoselectively introduced
  • Step 2 hydrolyzing the compound of formula (4) to obtain a compound of formula (5)
  • step 3 maintaining the compound of formula (5) under acidic conditions to obtain a compound represented by formula (6)
  • Process 1 using the compound of formula (3) as a starting material, reacting the compound of formula (3) with a nucleophile to obtain a compound of formula (4) in which a substituent is stereoselectively introduced
  • Step 2 hydrolyzing the compound of formula (4) to obtain a compound of formula (5)
  • step 3 maintaining the compound of formula (5) under acidic conditions to obtain a compound represented by formula (6)
  • Process 1 using the compound of formula (3) as
  • R 1 represents a hydroxyl-protecting group
  • Me represents a methyl group
  • X represents a substituent.
  • the present invention also relates to a method for synthesizing a 4′-substituted nucleoside derivative comprising the following steps 1 to 7.
  • Step 1 using the compound of formula (3) as a starting material, reacting the compound of formula (3) with a nucleophile to obtain a compound of formula (4) in which a substituent is stereoselectively introduced
  • Step 2 hydrolyzing the compound of formula (4) to obtain a compound of formula (5)
  • Step 3 a step of maintaining the compound of the formula (5) under acidic conditions to obtain a compound of the formula (6)
  • Step 4 a step of introducing protecting groups R 2 and R 2 ′ into a hydroxyl group of the compound of the formula (6) to obtain a compound represented by the formula (7)
  • Step 5 a step of introducing a protecting group R 3 into the compound of the formula (7) to obtain a compound of the formula (8)
  • Step 6 condensing the compound of the formula (8) with a base represented by Y to obtain a compound of the formula (9),
  • R 1 , R 2 , R 2 ′ and R 3 are hydroxyl-protecting groups, Me is a methyl group, X is a substituent, and Y is a nucleic acid base.
  • the present invention can be applied not only to the natural D-form but also to a method for synthesizing a non-natural L-form 4′-substituted nucleoside derivative.
  • a method for synthesizing an L-form 4′-substituted nucleoside intermediate represented by the formula (6 ′) consisting of Step 1: a step of obtaining a compound of formula (4 ′) in which a substituent is stereoselectively introduced by reacting a compound of formula (3 ′) with a nucleophile using a compound of formula (3 ′) as a starting material; Step 2: hydrolyzing the compound of the formula (4 ') to obtain a compound of the formula (5'), and step 3: maintaining the compound of the formula (5 ') under acidic conditions and represented by the formula (6') For obtaining a compound
  • R 1 represents a hydroxyl-protecting group
  • Me represents a methyl group
  • X represents a substituent.
  • the present invention relates to a method for synthesizing an L-type 4′-substituted nucleoside derivative comprising the following steps 1 to 7.
  • Step 1 a step of obtaining a compound of formula (4 ′) in which a substituent is stereoselectively introduced by reacting a compound of formula (3 ′) with a nucleophile using a compound of formula (3 ′) as a starting material;
  • Step 2 hydrolyzing the compound of the formula (4 ′) to obtain a compound of the formula (5 ′)
  • Step 3 a step of maintaining the compound of the formula (5 ′) under acidic conditions to obtain a compound of the formula (6 ′)
  • Step 4 a step of introducing a protecting group R 2 and R 2 ′ into a hydroxyl group of the compound of the formula (6 ′) to obtain a compound represented by the formula (7 ′)
  • Step 5 introducing a protecting group R 3 into the compound of the formula (7 ′) to obtain a compound of the formula (8 ′);
  • R 1 , R 2 , R 2 ′ and R 3 are hydroxyl-protecting groups, Me is a methyl group, X is a substituent, and Y is a nucleic acid base.
  • the stereoselective introduction of the substituent X in the step 1 and the re-rolling to a five-membered ring in the step 3 can be easily performed.
  • Synthesis of substituted nucleoside derivatives has become possible.
  • the gist of the reaction step of the present invention is that a scheme via a compound of formula (6) or (6 ') as an intermediate could be constructed.
  • the desired 4′-substituted nucleoside derivative can be synthesized in good yield without by-producing a stereoisomer. It is possible to solve the problem of by-products of stereoisomers, reduction in yield, and complication of the purification process.
  • FIG. 1 shows methyl 4-C-methyl-2,3-O-isopropylidene- ⁇ -L, a stereoisomer of methyl 4-C-methyl-2,3-O-isopropylidene- ⁇ -D-ribopyranoside.
  • 1 shows a 1 H-NMR spectrum of -lixopyranoside.
  • FIG. 2 shows a 1 H-NMR spectrum of a synthesized solution of methyl 4-C-methyl-2,3-isopropylidene- ⁇ -D-ribopyranoside obtained in Example 1.
  • the present invention provides a method for synthesizing a 4′-substituted nucleoside intermediate represented by the formula (6) comprising steps 1 to 3, and a method for synthesizing a 4′-substituted nucleoside derivative comprising steps 1 to 7. It is about the law.
  • the reaction steps are shown in the scheme below. Since the D-form and the L-form have the same reaction conditions and the same reagents, the D-form is described below as an example.
  • R 1 , R 2 , R 2 ′ and R 3 are hydroxyl-protecting groups, Me is a methyl group, X is a substituent, and Y is a nucleic acid base.
  • the starting material is a compound of formula (3).
  • the hydroxyl-protecting group for R 1 may be any group usually used for protecting a hydroxyl group, such as methyl ether, ethyl ether, tertiary butyl ether, trityl ether, dimethoxytrityl ether, benzyl ether, methoxy benzyl ether, An ether-based protecting group such as allyl ether and a silyl-based protecting group such as t-butyldimethylsilyl and t-butyldiphenylsilyl can be used.
  • methyl ⁇ 2,3-O-isopropylidene- ⁇ -L-ribopyranoside-4-ulose can be exemplified. can do.
  • Step 1 is a step of stereoselectively introducing a substituent X.
  • the compound of formula (4) can be synthesized by reacting the compound of formula (3) with an alkylating agent in the presence of a nucleophile or a base. .
  • Examples of the substituent represented by X include a linear, branched, or cyclic alkyl group, alkenyl group, aryl group, 1,3-dithiane, dioxolan ring, dioxane ring, and the like.
  • examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an i-propyl group, a cyclopropyl group, and a cyclopentyl group.
  • Examples of the alkenyl group include a vinyl group and an allyl group.
  • an aryl group for example, a heteroaryl group such as a phenyl group, a naphthyl group, and a thienyl group.
  • substituents may be further branched.
  • the branched substituent include an alkyl group such as a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an i-propyl group, a cyclopropyl group and a cyclopentyl group; a halogen such as chlorine and fluorine;
  • Examples include an alkylsilyl group such as a cyano group, a nitro group, and a trimethylsilyl group, and an alkoxy group such as a phenyl group, a methoxy group, and an ethoxy group that may be substituted with an alkyl group, a halogen atom, and an alkoxy group.
  • the introduced substituent X can be converted to another substituent in the following intermediate step and final step. Further, the substituent converted from the X group can be appropriately subjected to protection and deprotection.
  • the nucleophilic agent used in the reaction includes an organomagnesium reagent (Grignard reagent), an organolithium reagent, an organozinc reagent, an organocopper reagent, an organotin reagent, an organoaluminum reagent, an organotitanium reagent, an organosilicon compound, an organocopper art reagent, Various metal reagents such as magnesium-lithium can be used.
  • a Grignard reagent in addition to the Grignard reagent, zinc (II) chloride, magnesium chloride, magnesium bromide, copper (I) chloride, copper (II) chloride, copper cyanide (I) ), Tetrabutylammonium bromide, sodium methoxide, potassium methoxide, lithium methoxide, cerium (III) chloride, lithium perchlorate, lithium chloride, iron (II) chloride, lanthanum (III) bislithium chloride complex, t
  • the yield is improved by adding 0.1 to 3 equivalents of potassium butoxide, lithium t-butoxy, aluminum chloride, indium (III) chloride, manganese (II) chloride and the like.
  • zinc chloride (II), magnesium bromide, copper chloride (I), cerium chloride (III), and tetrabutylammonium butamide are preferably used, and zinc chloride (II), copper chloride ( It is particularly preferred to use I).
  • a nucleophile is allowed to act at -78 to 25 ° C for 15 minutes to 3 hours.
  • Appropriate conditions can be appropriately selected as the working conditions depending on the combination of the substituent X, the nucleophile, and other reagents to be used.
  • the compound of formula (4) can also be synthesized by reacting a base or a reagent serving as a fluorine anion source with an alkylating agent and reacting with the generated alkyl anion.
  • Examples of the reagent serving as a fluorine anion source include fluorides such as tetraammonium fluoride, potassium fluoride, cesium fluoride, and silver fluoride.
  • Examples of the alkylating agent include (trifluoromethyl) trimethylsilane, (difluoromethyl) trimethylsilane, (trimethylsilyl) acetonitrile, acetonitrile, chloroacetonitrile, bromoacetonitrile, iodoacetonitrile, 2-trimethylsilyl-1,3-dithiane, and 1,3.
  • -Alkyl dihalides such as dithiane, nitromethane, chloroiodomethane and chlorobromomethane.
  • X is a trifluoromethyl group or a difluoromethyl group
  • (trifluoromethyl) trimethylsilane or (difluoromethyl) trimethylsilane is used as an alkylating agent
  • tetrabutylammonium fluoride, potassium fluoride, and fluorine are used as a fluorine anion source.
  • Cesium oxide or the like can be used.
  • an organic solvent such as an alcoholic solvent such as tetrahydrofuran, dimethylformamide, acetonitrile, toluene, and methanol can be used as the solvent, and the reaction is performed at 0 to 25 ° C. for 1 hour to overnight.
  • (trimethylsilyl) acetonitrile can be used as an alkylating agent, tetrabutylammonium fluoride as a fluorine anion source, and lithium acetate as a base.
  • an organic solvent such as an alcoholic solvent such as tetrahydrofuran, dimethylformamide, acetonitrile, toluene, and methanol can be used as a solvent, and the reaction is performed at 0 to 25 ° C. for 1 hour to overnight.
  • a cyanomethyl anion generated by treating acetonitrile with a strong base such as butyllithium or treating haloacetonitrile such as iodoacetonitrile with a turbogrignard reagent or the like is also suitable.
  • an organic solvent such as diethyl ether, tetrahydrofuran, dioxane, acetonitrile, and toluene can be used, and the reaction is carried out at -78 ° C to 25 ° C for 1 hour to overnight.
  • X is 1,3-dithiane
  • 2-trimethylsilyl-1,3-dithiane is an alkylating agent and tetrabutylammonium phenoxide as a base.
  • an anion generated by treating 1,3-dithiane with a strong base such as butyllithium may be used.
  • an organic solvent such as an alcoholic solvent such as tetrahydrofuran, dimethylformamide, acetonitrile, toluene, and methanol can be used as the solvent, and the reaction is performed at 0 to 25 ° C. for 1 hour to overnight.
  • nitromethane can be used as the alkylating agent, and sodium hydroxide, potassium fluoride, sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like can be used as the alkylating agent.
  • an alcoholic solvent such as methanol or an organic solvent such as tetrahydrofuran can be used, and the reaction is carried out at 0 to 25 ° C. for 1 hour to overnight.
  • alkylating agents include dihalogenated alkyls such as chloroiodomethane, chlorobromomethane and dichloromethane; bases such as alkyllithiums such as methyllithium, sec-butyllithium and n-butyllithium; turbo Grignard reagents; Can be used.
  • An organic solvent such as tetrahydrofuran or dimethyl ether can be used, and the reaction is carried out at -78 to 0 ° C for 30 minutes to 2 hours.
  • the compound of the formula (4) is incubated in an aqueous solvent such as water or dioxane using an acid such as hydrochloric acid or trifluoroacetic acid under acidic conditions, for example, at 80 ° C. for about 24 to 48 hours. (4) a step of hydrolyzing the compound to obtain a compound of the formula (5).
  • step 3 the compound of formula (5) is incubated at 0 to 25 ° C. for about 24 to 72 hours in a hydrogen chloride alcohol solution prepared by adding acetyl chloride to an alcohol solvent such as methanol to generate hydrogen chloride.
  • a hydrogen chloride alcohol solution prepared by adding acetyl chloride to an alcohol solvent such as methanol to generate hydrogen chloride.
  • Step 4 is a step of introducing protecting groups R 2 and R 2 ′ into the hydroxyl group of the compound of formula (6) to obtain a compound of formula (7).
  • R 2 an acyl group such as an acetyl group, a propionyl group, and a benzoyl group can be used.
  • R 2 ′ an acyl group such as an acetyl group, a propionyl group, and a benzoyl group, or a hydrogen atom can be used.
  • R 2 ′ when the substituent X is bulky, for example, a vinyl group, a cyanomethyl group, or the like, R 2 ′ may be a hydrogen atom H, but this does not hinder the subsequent steps.
  • R 2 ′ is not hydrogen atom H
  • R 2 ′ is the same type of acyl group as R 2 .
  • this step can be carried out by adding the compound of formula (6) to pyridine and 3 to 20 equivalents of acetic anhydride and reacting for about 12 to 24 hours.
  • Step 5 is a step of introducing a protecting group R 3 into the compound of the formula (7) to obtain a compound of the formula (8).
  • R 3 an acyl group such as an acetyl group, a propionyl group, and a benzoyl group can be used.
  • the reaction can be carried out by adding 1 to 20 equivalents of acetic anhydride in acetic acid in the presence of a catalytic amount of sulfuric acid and allowing it to act for 1 to 24 hours.
  • step 5 When R 2 ′ is a hydrogen atom H, in step 5, the hydrogen atom H of R 2 ′ is converted to a protecting group R 2 .
  • Step 6 is a step of condensing the compound of formula (8) with a nucleobase represented by Y (pyrimidine, purine, azapyrimidine, azapurine, deazapurine, or a derivative thereof) to obtain a compound of formula (9). .
  • Y pyrimidine, purine, azapyrimidine, azapurine, deazapurine, or a derivative thereof
  • Base derivatives include halogen atoms, alkyl groups, haloalkyl groups, alkenyl groups, haloalkenyl groups, alkynyl groups, amino groups, alkylamino groups, hydroxyl groups, hydroxyamino groups, aminoxy groups, alkoxy groups, mercapto groups, alkylmercapto groups , An aryl group, an aryloxy group, a cyano group or the like having a substituent, and the number and position of the substituent are not particularly limited.
  • halogen atom as a substituent include chlorine, fluorine, iodine, and bromine.
  • alkyl group include lower alkyl groups having 1 to 7 carbon atoms such as methyl, ethyl and propyl.
  • haloalkyl group include haloalkyl groups having an alkyl having 1 to 7 carbon atoms, such as fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, and bromoethyl.
  • alkenyl group include alkenyl groups having 2 to 7 carbon atoms such as vinyl and allyl.
  • haloalkenyl group examples include haloalkenyl groups having 2 to 7 carbon atoms, such as bromovinyl and chlorovinyl.
  • alkynyl group examples include alkynyl groups having 2 to 7 carbon atoms such as ethynyl and propynyl.
  • alkylamino group examples include alkylamino groups having 1 to 7 carbon atoms such as methylamino and ethylamino.
  • the condensation reaction can be performed by reacting the compound of the formula (8) with a base represented by Y in the presence of a Lewis acid.
  • the bases may be used in a silylated form.
  • Such silylated bases may be prepared by a known method, for example, in hexamethyldisilazane and trichlorosilane, or in an organic solvent such as acetonitrile, toluene and 1,2-dichloroethane. , N, O-bis (trimethylsilyl) acetamide and heating under reflux.
  • the Lewis acid used include tin tetrachloride and trimethylsilyl trifluoromethanesulfonate.
  • Step 7 is a step of deprotecting R 2 by a commonly used method.
  • the compound of formula (10) can be obtained by removing R 2 by ammonolysis or hydrolysis of the compound of formula (9).
  • the reaction can be carried out by reacting the compound of the formula (9) in aqueous ammonia at room temperature for about 1 to 4 hours.
  • Steps 1 to 7 the steps can be continuously performed without performing isolation and purification as appropriate depending on the situation.
  • the sugar compound of the compound of the formula (10) obtained by the above-mentioned steps is modified by a known method to convert the target compound. Can be obtained.
  • the obtained 4'-substituted nucleoside derivative and intermediate of each step can be isolated and purified by a known method. Examples include, but are not limited to, various types of chromatography and crystallization such as ion exchange and adsorption.
  • the method for synthesizing the stereoselective 4'-substituted nucleoside derivative of the present invention can also be applied to the synthesis of an unnatural L-form nucleoside. That is, by reacting a compound represented by the formula (3 ′) obtained from D-lyxose with a nucleophile, a compound represented by the formula (4 ′) having a stereoselectively introduced substituent can be obtained. Thereafter, through the same steps as described above, the L-nucleoside derivative (10 ′) can be obtained.
  • R 1 , R 2 , R 2 ′ and R 3 are hydroxyl-protecting groups, Me is a methyl group, X is a substituent, and Y is a nucleic acid base.
  • the residue was purified with a medium pressure fractionator (YAMAZEN UNIVERSAL PREMIUM Silicagel 30 ⁇ m, 7 g, 12-30% ethyl acetate / n-hexane), and methyl 4-C-methyl-2,3-O-isopropylidene- ⁇ - D-ribopyranoside (310 mg, 1.42 mmol, 89%) was obtained.
  • a medium pressure fractionator YAMAZEN UNIVERSAL PREMIUM Silicagel 30 ⁇ m, 7 g, 12-30% ethyl acetate / n-hexane
  • stereoisomers were synthesized by the method shown in the following scheme.
  • cerium chloride (120.8 mg, 0.490 mmol) was added. After cooling to 0 ° C., a tetrahydrofuran solution of methylmagnesium bromide (3.0 mol / L, 0.17 mL) was added, and the mixture was stirred for 2 hours and 45 minutes, and then heated to room temperature. The mixture was stirred overnight, quenched with a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated.
  • the residue was purified with a medium pressure fractionator (YAMAZEN UNIVERSAL PREMIUM Silicagel 30 ⁇ m, 7 g, 12-30% ethyl acetate / n-hexane), and methyl 4-C-methyl-2,3-O-isopropylidene- ⁇ - D-ribopyranoside (40.6 mg, 0.186 mmol, 75%) was obtained.
  • a medium pressure fractionator YAMAZEN UNIVERSAL PREMIUM Silicagel 30 ⁇ m, 7 g, 12-30% ethyl acetate / n-hexane
  • the residue was purified with a medium pressure fractionator (YAMAZEN UNIVERSAL PREMIUM Silicagel 30 ⁇ m, 7 g, 12-30% ethyl acetate / n-hexane), and methyl 4-C-methyl-2,3-O-isopropylidene- ⁇ - D-ribopyranoside (25.0 mg, 0.115 mmol, 47%) was obtained.
  • a medium pressure fractionator YAMAZEN UNIVERSAL PREMIUM Silicagel 30 ⁇ m, 7 g, 12-30% ethyl acetate / n-hexane
  • X phenyl group
  • R 1 methyl group
  • dehydrated tetrahydrofuran (10 mL)
  • zinc chloride (II) 14.7 mg, 0.108 mmol
  • iodoacetonitrile (0.16 ml, 2.16 mol
  • the temperature was raised to room temperature, and the mixture was stirred for 18 hours and 20 minutes.
  • the reaction was stopped by adding ice, and ethyl acetate and deionized water were added to carry out liquid separation. Further, the organic layer was washed with saturated sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated.
  • trimethylsilyl trifluoromethanesulfonate (223 ⁇ L, 1.23 mmol) was added, and the mixture was stirred at 50 ° C. for 17 hours and 30 minutes. The temperature was raised to 60 ° C., and the mixture was further stirred for 4 hours. After cooling to 0 ° C., the reaction was stopped by adding a saturated aqueous solution of sodium hydrogen carbonate, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated.
  • the residue was purified with a medium pressure fractionator (SNAP Ultra 10 g, 0-2% methanol / chloroform), and 2 ′, 3 ′, 5′-tri-O-acetyl-4′-C-chloromethyl-D-uridine. (126.4 mg, 0.302 mmol, 98%).
  • SNAP Ultra 10 g 0-2% methanol / chloroform
  • 2 ′, 3 ′, 5′-tri-O-acetyl-4′-C-chloromethyl-D-uridine (126.4 mg, 0.302 mmol, 98%).
  • the organic layer was dried over anhydrous magnesium carbonate, filtered and concentrated. It was dissolved in acetic acid (8 mL) and acetic anhydride (1.81 mL), and sulfuric acid (150 ⁇ L) was added under ice-cooling. After 20 minutes, the temperature was raised to room temperature, and the mixture was stirred for 18 hours. The reaction was stopped by adding ice water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and deionized water, and dried over anhydrous magnesium sulfate.
  • methyl 2,3-O-isopropylidene- ⁇ -D-lyxopyranoside (1.30 g, 6.38 mmol) was dissolved in dehydrated dichloromethane (19 mL) and added dropwise, followed by stirring for 1 hour.
  • Triethylamine (5.3 mL, 38.0 mmol) was added and the temperature was raised to room temperature.
  • the reaction was stopped by adding a saturated aqueous solution of sodium chloride, and extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated.
  • X methyl group
  • R 1 methyl group
  • Argon Atmosphere methyl 2,3-O-isopropylidene- ⁇ -L-ribopyranoside-4-ulose (48.2 mg, 0.238 mmol) was dissolved in dehydrated tetrahydrofuran (2 mL), and zinc (II) chloride (3.2 mg) was dissolved. , 23.5 ⁇ mol).
  • the organic layer was dried over anhydrous magnesium carbonate, filtered and concentrated. It was dissolved in acetic acid (5 mL) and acetic anhydride (1.4 mL), and sulfuric acid (100 ⁇ L) was added under ice-cooling. After 20 minutes, the temperature was raised to room temperature, and the mixture was stirred for 18 hours. The reaction was stopped by adding ice water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and deionized water, and dried over anhydrous magnesium sulfate.
  • Methyl 4-C-vinyl-2,3-O-isopropylidene- ⁇ -D -Ripopyranoside (1.19 g, 5.14 mmol) was dissolved in a 1 mol / L trifluoroacetic acid aqueous solution (5.14 mL), and the mixture was heated with stirring at 80 ° C for 2 hours. After concentration and azeotropic distillation with acetonitrile, the residue was suspended in methanol.
  • X aminoethyl group
  • R 1 methyl group
  • methyl 4-C-cyanomethyl-2,3-O-isopropylidene- ⁇ -D-ribopyranoside 409 mg, 1.68 mmol
  • the mixture was heated to reflux at 90 ° C. and stirred for 4 hours. After completion of the reaction, the reaction solution was filtered through celite, and the obtained filtrate was concentrated.
  • dichloroethane 5.1 mL
  • uracil 114 mg, 1.02 mmol
  • BSA 0.75 mL, 3.06 mmol

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Abstract

Le problème à résoudre par la présente invention concerne la fourniture de procédés de synthèse de dérivés nucléosidiques à substitution en position 4' qui comprennent une étape selon laquelle des stéréoisomères sont produits et, qui présentent des problèmes tels qu'un faible rendement et une complication d'une étape de raffinement. Ainsi, l'objet de la présente invention est de fournir un procédé de synthèse plus simple et ne produisant pas de stéréoisomères. La présente invention concerne un procédé de synthèse d'un intermédiaire nucléosidique à susbstitution en position 4' représenté par la formule (6), le procédé comprenant les étapes suivantes 1 à 3 : étape 1 selon laquelle un composé de formule (3) est utilisé en tant que matière première de départ, et un nucléophile est amené à agir sur le composé de formule (3) pour obtenir le composé de formule (4), un groupe substituant étant introduit de manière stéréosélective ; étape 2 selon laquelle le composé de formule (4) est hydrolysé pour obtenir le composé de formule (5) ; et l'étape 3 selon laquelle le composé de formule (5) est maintenu dans des conditions acides pour obtenir le composé représenté par la formule (6). Dans les formules, R1 représente un groupe protecteur d'un groupe hydroxyle, Me représente un groupe méthyle, et X représente un groupe substituant.
PCT/JP2019/031293 2018-08-09 2019-08-08 Procédé de synthèse stéréosélective de dérivé nucléosidique à substitution en position 4' WO2020032152A1 (fr)

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US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
US11767337B2 (en) 2020-02-18 2023-09-26 Gilead Sciences, Inc. Antiviral compounds
US12030903B2 (en) 2020-02-18 2024-07-09 Gilead Sciences, Inc. Antiviral compounds
US12054507B2 (en) 2020-02-18 2024-08-06 Gilead Sciences, Inc. Antiviral compounds
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11767337B2 (en) 2020-02-18 2023-09-26 Gilead Sciences, Inc. Antiviral compounds
US12030903B2 (en) 2020-02-18 2024-07-09 Gilead Sciences, Inc. Antiviral compounds
US12054507B2 (en) 2020-02-18 2024-08-06 Gilead Sciences, Inc. Antiviral compounds
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
US12116380B2 (en) 2021-08-18 2024-10-15 Gilead Sciences, Inc. Phospholipid compounds and methods of making and using the same

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