WO2020050411A1 - 配糖体化合物の製造方法 - Google Patents
配糖体化合物の製造方法 Download PDFInfo
- Publication number
- WO2020050411A1 WO2020050411A1 PCT/JP2019/035241 JP2019035241W WO2020050411A1 WO 2020050411 A1 WO2020050411 A1 WO 2020050411A1 JP 2019035241 W JP2019035241 W JP 2019035241W WO 2020050411 A1 WO2020050411 A1 WO 2020050411A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- acid
- compound represented
- general formula
- formula
- Prior art date
Links
- 0 CCOCC(C(*(*(*)N)O*)C1OCC(C)(C)OCC(C)(C)OCC*)OC1=C Chemical compound CCOCC(C(*(*(*)N)O*)C1OCC(C)(C)OCC(C)(C)OCC*)OC1=C 0.000 description 2
Classifications
-
- 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
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
-
- 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
- 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
-
- 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 present invention relates to a method for producing a glycoside compound and an amidite compound.
- RNA is a useful material that can be used as an RNA probe, antisense RNA, ribozyme, siRNA, aptamer, and the like.
- RNA can be synthesized by a solid phase synthesis method or the like.
- a nucleoside phosphoramidite hereinafter, referred to as “amidite”
- examples of such a protecting group for the hydroxyl group at the 2′-position of the amidite include TBDMS (t-butyldimethylsilyl), TOM (triisopropylsilyloxymethyl), ACE (bis (2-acetoxyethoxy) methyl) and the like. Have been.
- TBDMS t-butyldimethylsilyl
- TOM triisopropylsilyloxymethyl
- ACE bis (2-acetoxyethoxy
- An object of the present invention is to provide a method for producing a glycoside compound and an amidite compound that enable synthesis of a target compound (amidite compound) with high purity.
- the present inventors have conducted intensive studies to achieve the above object, and as a result, when producing a glycoside compound represented by the general formula (3) in a synthesis reaction of an amidite compound, an oxidizing agent was contained in the reaction system. It has been found that by adding (N-iodosuccinimide) and then adding an acid (trifluoromethanesulfonic acid), it is possible to suppress the generation of impurities having the same molecular weight as the target product. As a result, it is possible to synthesize a target compound (amidite compound) with high purity.
- the present invention has been completed based on these findings and further studied, and provides a method for producing the following glycoside compound and amidite compound.
- the invention includes, but is not limited to, the embodiments described in the following sections.
- a method for producing a glycoside compound represented by the general formula (3) Step A: The glycoside compound represented by the general formula (1) is reacted with the ether compound represented by the formula (2) in the presence of an oxidizing agent and an acid to be represented by the general formula (3).
- a step of producing a glycoside compound which comprises adding an oxidizing agent to the reaction system and then adding an acid.
- B a represents optionally cytosine group optionally substituted by an acyl group, or a uracil group
- R 1 represents a C1-C6 alkyl group or a phenyl group
- n represents 0 or 1.
- the oxidizing agent is selected from the group consisting of N-halogenated succinimides and N-halogenated hydantoins; and
- the acid is selected from the group consisting of perfluoroalkylcarboxylic acids and salts thereof, alkylsulfonic acids and salts thereof, arylsulfonic acids and salts thereof, perfluoroalkylsulfonic acids and salts thereof, and combinations of two or more of these. , The method. Item 2. Item 2. The production method according to Item 1, wherein n is 1. Item 3. Item 2. The method according to Item 1, wherein n is 0. Item 4. Item 4.
- Item 9 The production method according to any one of Items 1 to 7, wherein tetrahydrofuran is used as a solvent.
- Item 9. The production method according to any one of Items 1 to 8, wherein R 1 is a methyl group.
- Item 10. The method according to any one of Items 1 to 9, wherein B a is a cytosine group substituted with an acetyl group or an unsubstituted uracil group.
- Item 11 A method for producing an amidite compound represented by the general formula (I), (Wherein, Ba and n are the same as described above; G 1 and G 2 are the same or different and each represent a hydroxyl-protecting group; G 3 is the same or different and represents an alkyl group.
- Step A reacting the glycoside compound represented by the general formula (1) with the ether compound represented by the formula (2) by the production method according to any one of the above items 1 to 10, The method, comprising the step of producing the glycoside compound represented by (3).
- Step B glycoside compound represented by general formula (4) obtained by deprotecting the 3′-position and 5′-position hydroxyl group of glycoside compound represented by general formula (3) obtained in step A
- the process of manufacturing (Wherein, Ba and n are the same as described above.) Item 12.
- Item 13 further comprising: Item 13.
- Step C Step B obtained in the general formula (4) 'introducing a protecting group G 1 to the position of the hydroxyl group, 3' 5 of glycoside compounds represented by position hydroxyl group with phosphoramidite of formula Step of producing an amidite compound represented by (I) (Wherein, B a , n, G 1 , G 2 and G 3 are the same as described above.) Item 14.
- the production method of the present invention generation of impurities of the intermediate compound can be suppressed in the synthesis reaction of the amidite compound, and as a result, the target compound (amidite compound) can be produced with high purity.
- the present invention is a method for producing an amidite compound represented by the general formula (I), and comprises the following step A, steps A and B, or steps A to C.
- B a represents an optionally substituted cytosine group with an acyl group, or a uracil group
- n represents 0 or 1
- G 1 and G 2 are the same or different and each represent a hydroxyl-protecting group
- G 3 is the same or different and represents an alkyl group.
- Step A The glycoside compound represented by the general formula (1) is reacted with the ether compound represented by the formula (2) in the presence of an oxidizing agent and an acid to be represented by the general formula (3).
- a process for producing a glycoside compound which comprises adding an oxidizing agent to a reaction system and then adding an acid. (Wherein, B a and n are the same as described above, and R 1 represents a C1-C6 alkyl group or a phenyl group.)
- Step B glycoside compound represented by general formula (4) obtained by deprotecting the 3′- and 5′-position hydroxyl groups of glycoside compound represented by general formula (3) obtained in step A
- the process of manufacturing In the formula, Ba and n are the same as described above.
- Step C Step B obtained in the general formula (4) 'introducing a protecting group G 1 to the position of the hydroxyl group, 3' 5 of glycoside compounds represented by position hydroxyl group with phosphoramidite of formula Step of producing an amidite compound represented by (I) (Wherein, B a , n, G 1 , G 2 and G 3 are the same as described above.)
- R 1 is preferably a methyl group.
- Nucleobases in B a is a cytosine group, or uracil group shown below.
- R 2 represents a hydrogen atom, an acetyl group, an isobutyryl group, or a benzoyl group.
- G 1 can be used without any particular limitation as long as it can function as a protecting group, and known protecting groups used in amidite compounds can be widely used.
- G 1 is preferably the following groups. (In the formula, R 3 , R 4 and R 5 are the same or different and represent hydrogen or an alkoxy group.)
- R 3 , R 4 and R 5 is preferably hydrogen and the remaining two are preferably alkoxy groups, and particularly preferably an alkoxy group is a methoxy group.
- the G 2 as long as it can function as a protecting group can be used without particular limitation, can be widely used known protecting groups used in amidite compound.
- Examples of G 2 include a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a hydrocarbon group other than the above-described alkyl groups, a haloalkyl group, an aryl group, a heteroaryl group, an arylalkyl group, and a cycloalkenyl group.
- G 2 is preferably an alkyl group substituted with an electron withdrawing group.
- the electron withdrawing group include a cyano group, a nitro group, an alkylsulfonyl group, a halogen, an arylsulfonyl group, a trihalomethyl group, and a trialkylamino group, and a cyano group is preferable.
- G 2 is particularly preferably the following groups.
- G 3 is the same or different and is an alkyl group, and two G 3 may be bonded to each other to form a cyclic structure.
- the alkyl group may be linear or branched, and is preferably an alkyl group having 1 to 12 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms.
- Alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, and hexyl.
- the alkyl group herein includes an alkyl moiety such as an alkoxy group.
- the acyl group represents a linear or branched aliphatic acyl group or an aromatic acyl group, and has a total carbon number of 2 to 12 including carbonyl carbon, and preferably 2 to 12 carbon atoms.
- the acyl group include an aliphatic acyl group (for example, acetyl group, propionyl group, butanoyl group (butyryl group), isobutanoyl group (isobutyryl group), pentanoyl group, hexanoyl group, heptanoyl group, octanoyl group, A nonanoyl group, a decanoyl group, an undecanoyl group and the like; and an aromatic acyl group (eg, a benzoyl group, a 1-naphthoyl group and a 2-naphthoyl group), preferably an acetyl group, an isobutyryl group or a benzoyl group.
- the amidite compound of the present invention includes a free state and a salt state.
- the salt of the amidite compound of the present invention is not particularly limited, and may be a base addition salt, for example, a salt with an inorganic base such as a sodium salt, a magnesium salt, a potassium salt, a calcium salt, an aluminum salt; methylamine Salts with organic bases such as salts, ethylamine salts and ethanolamine salts; salts with basic amino acids such as lysine salts, ornithine salts and arginine salts, and base addition salts such as ammonium salts.
- a base addition salt for example, a salt with an inorganic base such as a sodium salt, a magnesium salt, a potassium salt, a calcium salt, an aluminum salt; methylamine Salts with organic bases such as salts, ethylamine salts and ethanolamine salts; salts with basic amino acids such as lysine salts, ornithine salts and
- the salt may be an acid addition salt, and specific examples of such salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; formic acid, Organic acids such as acetic acid, propionic acid, oxalic acid, malonic acid, malic acid, tartaric acid, fumaric acid, succinic acid, lactic acid, maleic acid, citric acid, methanesulfonic acid, trifluoromethanesulfonic acid and ethanesulfonic acid; aspartic acid, Acid addition salts with acidic amino acids such as glutamic acid are mentioned.
- mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid
- formic acid Organic acids such as acetic acid, propionic acid, oxalic acid, malonic acid, malic acid, tartaric acid, fumaric acid, succinic acid
- Step A In this reaction, a glycoside compound represented by the general formula (1) is reacted with an ether compound represented by the formula (2) (coupling reaction) in the presence of an oxidizing agent and an acid to form a compound represented by the general formula (1).
- the glycoside compound represented by (3) can be obtained, and in particular, an oxidizing agent is added to the reaction system, and then an acid is added.
- the oxidizing agent examples include N-halogenated succinimides such as N-chlorosuccinimide, N-bromosuccinimide and N-iodosuccinimide, and N-halogenated hydantoins such as 1,3-diiodo-5,5-dimethylhydantoin.
- N-halogenated succinimide is preferably used, and N-iodosuccinimide is more preferably used.
- Examples of the diacid include perfluoroalkylcarboxylic acids and salts thereof, alkylsulfonic acids and salts thereof, arylsulfonic acids and salts thereof, perfluoroalkylsulfonic acids and salts thereof, and combinations of two or more of these.
- Examples of the salt include a metal salt (for example, a copper salt and a silver salt).
- Specific examples of the acid include methanesulfonic acid, paratoluenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, silver trifluoromethanesulfonic acid, and the like, and a combination of two or more thereof. In the present invention, trifluoromethanesulfonic acid is preferably used.
- the solvent for this reaction is not particularly limited, and examples thereof include diethyl ether, tetrahydrofuran (THF), cyclopentyl methyl ether, 2-methyltetrahydrofuran, ethers such as dimethoxyethane, dioxane, hydrocarbons such as toluene, nitriles such as acetonitrile, and the like. And halogenated hydrocarbons such as chlorobenzene and dichloromethane.
- the amount of the ether compound represented by the formula (2) is usually 1 to 5 mol, preferably 1 to 3 mol, more preferably 1 to 1 mol per 1 mol of the glycoside compound represented by the general formula (1). 1.51.5 mol.
- the amount of the oxidizing agent is usually 1 to 3 mol, preferably 1 to 2 mol, more preferably 1 to 1.5 mol, per 1 mol of the glycoside compound represented by the general formula (1).
- the amount of the acid is usually 0.1 to 5 mol, preferably 0.5 to 3 mol, more preferably 0.5 to 1.5 mol, per 1 mol of the ether compound represented by the general formula (1). It is.
- the reaction temperature of this reaction is generally -80 to 0 ° C, preferably -60 to -10 ° C, more preferably -50 to -40 ° C.
- the reaction time of this reaction is generally 1 to 12 hours, preferably 1 to 8 hours, more preferably 1 to 4 hours.
- the glycoside compound represented by the general formula (1) can be produced by a known method, or a commercially available product can be obtained.
- the ether compound represented by the formula (2) can be produced by a known method (see Patent Documents 1, 2, and 3).
- an oxidizing agent is added to a mixture of a glycoside compound represented by the general formula (1) and an ether compound represented by the formula (2), and then the resulting mixture is added to the mixture. It can be performed by adding an acid. For example, it can be carried out by sequentially dropping a glycoside compound represented by the general formula (1), an ether compound of the formula (2), N-iodosuccinimide, and trifluoromethanesulfonic acid.
- Step B In this reaction, the 3′- and 5′-hydroxyl groups of the glycoside compound represented by the general formula (3) obtained in Step A are deprotected to thereby remove the glycoside represented by the general formula (4). A somatic compound can be obtained.
- the deprotection reaction can be appropriately changed depending on the protecting group, and can be carried out, for example, by using a known deprotecting agent.
- the deprotecting agent is not particularly limited, and examples thereof include pyridine hydrogen fluoride, triethylamine trihydrofluoride, pyridine hydrofluoride, ammonium fluoride, hydrofluoric acid, and tetrabutylammonium fluoride. .
- the amount of the deprotecting agent is usually 0.1 to 20 mol, preferably 0.2 to 10 mol, more preferably 1 to 5 mol, per 1 mol of the glycoside compound represented by the general formula (3). is there.
- the solvent for this reaction is not particularly limited, and examples thereof include ketones such as acetone, ethers such as diethyl ether and tetrahydrofuran (THF), hydrocarbons such as toluene, alcohols such as methanol and ethanol, and nitriles such as acetonitrile.
- ketones such as acetone
- ethers such as diethyl ether and tetrahydrofuran (THF)
- hydrocarbons such as toluene
- alcohols such as methanol and ethanol
- nitriles such as acetonitrile.
- the reaction temperature of this reaction is usually 0 to 100 ° C, preferably 10 to 60 ° C, more preferably 10 to 30 ° C.
- the reaction time of this reaction is usually 30 minutes to 72 hours, preferably 2 to 24 hours.
- Step C In this reaction, 'and introducing a protective group G 1 to the position of the hydroxyl group, 3' 5 of glycoside compounds represented by the obtained formula (4) in the step B-position of the hydroxyl group to a phosphoramidite of
- the amidite compound represented by the general formula (I) can be obtained.
- introducing a phosphoramidite of protecting group G 1 may also be can either be carried out simultaneously (in one step), the phosphoramidite of after introducing the protecting group G 1, or phospho it is also possible to introduce the protecting group G 1 after the Roamidaito of. Among them, it is preferable to perform the phosphoramidite of after introducing the protecting group G 1.
- the protecting group introducing agent may be appropriately selected according to G 1, for example, 4,4'-dimethoxytrityl chloride.
- the solvent is not particularly limited, and examples thereof include aromatic solvents such as toluene and pyridine, nitriles such as acetonitrile, and ethers such as tetrahydrofuran.
- the reaction temperature is usually 0-100 ° C, preferably 10-60 ° C, more preferably 20-30 ° C.
- the reaction time is generally 30 minutes to 24 hours, preferably 1 to 8 hours.
- the amount of the protecting group-introducing agent is generally 1 to 100 mol, preferably 1 to 20 mol, more preferably 1 to 5 mol, per 1 mol of the glycoside compound represented by the general formula (4).
- phosphoramidite reagent can be appropriately selected depending on the G 2 and G 3, for example, 2-cyanoethyl -N, N, N ', N'- tetraisopropylphosphorodiamidite And the like.
- the solvent is not particularly restricted but includes, for example, nitriles such as acetonitrile, ethers such as tetrahydrofuran, halogenated solvents such as dichloromethane and the like.
- the reaction temperature is generally 0-40 ° C, preferably 20-40 ° C.
- the reaction time is generally 30 minutes to 24 hours, preferably 1 to 6 hours.
- the amount of the phosphoramidite-forming reagent is usually 1 to 20 mol, preferably 1 to 5 mol, more preferably 1 to 1.5 mol, per 1 mol of the glycoside compound represented by the general formula (4).
- reaction product obtained in any of the steps A to C can be subjected to purification, washing, concentration and other treatments by a known method.
- the production method of the present invention in the process of producing the glycoside compound represented by the general formula (3), generation of impurities having the same molecular weight can be suppressed. As a result, it becomes possible to produce the target compound, an amidite compound represented by the general formula (I), with high purity.
- Example 1 N 4 -acetyl-3 ′, 5′-O- (tetraisopropyldisiloxane-1,3-diyl) cytidine (TIPS-C) (10.0 g, 19.0 mmol) and toluene (50 ml) were added to the flask, The solution was concentrated to 30 ml. After adding tetrahydrofuran (22 ml), the reaction solution was cooled to ⁇ 50 ° C., and 2-cyanoethoxymethylmethylthiomethyl ether (hereinafter referred to as an EMM agent) (4.58 g, 28.4 mmol), N was added thereto.
- EMM agent 2-cyanoethoxymethylmethylthiomethyl ether
- the organic layer was further washed with a solution consisting of sodium bicarbonate (1.75 g), sodium thiosulfate pentahydrate (5.0 g) and water (32.5 ml). The organic layer was concentrated to obtain a crude product containing the target compound.
- Example 2 3 ′, 5′-O- (tetraisopropyldisiloxane-1,3-diyl) uridine (TIPS-U) (5.0 g, 10.0 mmol) and toluene (25 ml) were added to the flask, and concentrated to 15 ml. After adding tetrahydrofuran (3.5 ml), the solution was cooled to ⁇ 50 ° C., and there was added an EMM agent (2.48 g, 15.4 mmol) and N-iodosuccinimide (3.18 g, 14.1 mmol) in tetrahydrofuran.
- TIPS-U 5′-O- (tetraisopropyldisiloxane-1,3-diyl) uridine
- Example 3 The above crude EMM C-1 was dissolved in tetrahydrofuran (40 ml), hydrogen trifluoride / triethylamine (3.36 g, 20.8 mmol) was added, and the mixture was stirred at 20 ° C. for 16 hours. The reaction solution was cooled to 0 ° C., and tert-butyl methyl ether (60 ml) was added dropwise. The resulting solid was collected by filtration and dried to obtain the target compound (7.95 g).
- Example 4 The above crude EMM C-2 (7.0 g, 17.6 mmol) was dissolved in pyridine (35 ml), acetonitrile (14 ml), and toluene (35 ml), and cooled to 0 ° C. 4,4′-Dimethoxytrityl chloride (7.14 g, 21.1 mmol) was added thereto, and the mixture was stirred at 20 ° C. for 4 hours. Methanol (3.5 ml) was added and the mixture was stirred for 5 minutes. The reaction solution was washed with a solution of sodium hydrogen carbonate (1.75 g) and water (35 ml) with toluene (7 ml), and the mixture was separated at room temperature. did.
- Example 5 Acetonitrile (18 ml) was added to the above-mentioned EMM C-3 (6.0 g, 8.6 mmol), and diisopropylamine tetrazolide (1.68 g, 9.8 mmol), 2-cyanoethyl N, N, at 25 ° C. N ′, N′-Tetraisopropyl phosphorodiamidite (3.09 g, 10.3 mmol) was added and the mixture was stirred at 35 ° C. for 2 hours. The reaction solution was poured into a solution composed of toluene (60 ml), water (30 ml) and sodium hydrogen carbonate (1.5 g), and the mixture was separated at room temperature.
- the organic layer was washed four times with a solution composed of DMF (30 ml) and water (30 ml), twice with water (30 ml), and once with a solution composed of sodium chloride (3.0 g) and water (30 ml).
- Example 6 N 4 -acetyl-3 ′, 5′-O- (tetraisopropyldisiloxane-1,3-diyl) cytidine (TIPS-C) (1.0 g, 1.9 mmol) was dissolved in tetrahydrofuran (10 ml). And methylthiomethyl 2-cyanoethyl ether (hereinafter referred to as CEM agent) (0.37 g, 2.8 mmol) and Molecular Sieves 4A (0.8 g) were added to the mixture, and the mixture was stirred at -45 ° C. under a nitrogen atmosphere at 30 ° C. Stirred for minutes.
- CEM agent methylthiomethyl 2-cyanoethyl ether
- Molecular Sieves 4A 0.8 g
- Example 7 N4-acetyl-3 ′, 5′-O- (tetraisopropyldisiloxane-1,3-diyl) cytidine (TIPS-C) (3.0 g, 5.7 mmol) was azeotroped three times with toluene (15 ml). The solvent was distilled off with a vacuum pump. The residue was dissolved in tetrahydrofuran (30 ml) under a nitrogen atmosphere, and the solution was cooled to -45 ° C.
- TIPS-C tetraisopropyldisiloxane-1,3-diyl
- EMM agent (2.8 g, 18 mmol), N-iodosuccinimide (2.0 g, 9.0 mmol), and trifluoromethanesulfonic acid (1.3 g, 8.8 mmol) were added dropwise to this solution in this order. After stirring at ⁇ 45 ° C. for 5 hours, the reaction solution was quenched by adding triethylamine. The reaction solution was added to an ice-cooled solution consisting of ethyl acetate (30 ml), sodium hydrogen carbonate (1.5 g), sodium thiosulfate pentahydrate (3.0 g) and water (30 ml), and the mixture was added at room temperature. Separated. The organic layer was concentrated to obtain a crude product containing the target compound.
- Example 8 3 ′, 5′-O- (Tetraisopropyldisiloxane-1,3-diyl) uridine (TIPS-U) (3.0 g, 6.0 mmol) was dissolved in tetrahydrofuran (30 ml) under a nitrogen atmosphere, and the solution was dissolved. Cooled to -45 ° C. To this solution, an EMM agent (1.56 g, 9.7 mmol), N-iodosuccinimide (2.16 g, 9.7 mmol) and trifluoromethanesulfonic acid (1.44 g, 9.7 mmol) were added dropwise in this order. After stirring at ⁇ 45 ° C.
- reaction solution was quenched by adding triethylamine.
- EMM agent (2.8 g, 18 mmol), trifluoromethanesulfonic acid (1.3 g, 8.8 mmol), and N-iodosuccinimide (2.0 g, 9.0 mmol) were added dropwise to this solution in this order. After stirring at -45 ° C for 5 hours, the mixture was quenched by adding triethylamine. The reaction solution was added to an ice-cooled solution consisting of ethyl acetate (30 ml), sodium hydrogen carbonate (1.5 g), sodium thiosulfate pentahydrate (3.0 g) and water (30 ml), and the mixture was added at room temperature. Separated. The organic layer was concentrated to obtain a crude product containing the target compound.
- Reagent addition order 1 EMM agent or CEM agent, N-iodosuccinimide, trifluoromethanesulfonic acid EMM agent or CEM agent, trifluoromethanesulfonic acid, N-iodosuccinimide in order As shown in Table 1 above, by adding trifluoromethanesulfonic acid after N-iodosuccinimide, generation of impurities is suppressed, The target product could be obtained with higher purity.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Abstract
Description
本発明は、配糖体化合物及びアミダイト化合物の製造方法に関する。
工程A:酸化剤及び酸の存在下で、一般式(1)で表される配糖体化合物と式(2)で表されるエーテル化合物とを反応させて一般式(3)で表される配糖体化合物を製造する工程であって、反応系内に酸化剤を添加し、次いで酸を添加する、該工程
Baは、アシル基により置換されていてもよいシトシン基、又はウラシル基を表し、
R1はC1~C6アルキル基、又はフェニル基を表し、そして、
nは0又は1を表す。)を含み、
ここで、
酸化剤は、N-ハロゲン化スクシンイミドおよびN-ハロゲン化ヒダントインからなる群から選ばれ、そして、
酸は、パーフルオロアルキルカルボン酸およびその塩、アルキルスルホン酸およびその塩、アリールスルホン酸およびその塩、パーフルオロアルキルスルホン酸およびその塩、およびこれらの2種類以上の組み合わせ、からなる群から選ばれる、該方法。
項2. nが1である、項1に記載の製造方法。
項3. nが0である、項1に記載の製造方法。
項4. 酸化剤がN-ハロゲン化スクシンイミドである、項1~3のいずれか1つに記載の製造方法。
項5. 酸化剤がN-ヨードスクシンイミドである、項1~4のいずれか1つに記載の製造方法。
項6. 酸がトリフルオロメタンスルホン酸、トリフルオロメタンスルホン酸銀、およびメタンスルホン酸からなる群から選ばれる少なくとも1つである、項1~5のいずれか1つに記載の製造方法。
項7. 酸がトリフルオロメタンスルホン酸である、項1~6のいずれか1つに記載の製造方法。
項8. 溶媒としてテトラヒドロフランを用いる、項1~7のいずれか1つに記載の製造方法。
項9. R1がメチル基である、項1~8のいずれか1つに記載の製造方法。
項10. Baがアセチル基で置換されたシトシン基、又は無置換のウラシル基である、項1~9のいずれか1つに記載の製造方法。
項11. 一般式(I)で表されるアミダイト化合物を製造する方法であって、
G1及びG2は同一又は相異なって水酸基の保護基を示し、そして、
G3は同一又は相異なってアルキル基を示す。)
工程A:項1~10のいずれか1つに記載の製造方法によって、一般式(1)で表される配糖体化合物と式(2)で表されるエーテル化合物とを反応させて一般式(3)で表される配糖体化合物を製造する工程を含む、該方法。
項12. 工程B:工程Aで得られた一般式(3)で表される配糖体化合物の3’位と5’位の水酸基を脱保護して一般式(4)で表される配糖体化合物を製造する工程
を更に含む、項11に記載の方法。
項13. 脱保護剤としてトリエチルアミン3フッ化水素酸塩又はピリジンフッ化水素酸塩を用いる、項12に記載の方法。
項14. 工程C:工程Bで得られた一般式(4)で表される配糖体化合物の5’位の水酸基に保護基G1を導入し、3’位の水酸基をホスホロアミダイト化して一般式(I)で表されるアミダイト化合物を製造する工程
を更に含む、項12又は13に記載の方法。
項15. 5’位水酸基の保護基導入試薬として4,4’-ジメトキシトリチルクロリドを用いる、項14に記載の方法。
項16. 3’位水酸基のホスホロアミダイト化試薬として2-シアノエチル-N,N,N’,N’-テトライソプロピルホスホロジアミダイトを用いる、項14又は15に記載の方法。
Baはアシル基により置換されていてもよいシトシン基、又はウラシル基を表し、
nは0又は1を表し、
G1及びG2は同一又は相異なって水酸基の保護基を示し、そして、
G3は同一又は相異なってアルキル基を示す。)
本反応では、酸化剤及び酸の存在下で、一般式(1)で表される配糖体化合物と式(2)で表されるエーテル化合物とを反応(カップリング反応)させることで一般式(3)で表される配糖体化合物を得ることができ、特に、反応系内に酸化剤を添加し、次いで酸を添加することを特徴とする。
本反応では、工程Aで得られた一般式(3)で表される配糖体化合物の3’位と5’位の水酸基を脱保護することで一般式(4)で表される配糖体化合物を得ることができる。
本反応では、工程Bで得られた一般式(4)で表される配糖体化合物の5’位の水酸基に保護基G1を導入し、3’位の水酸基をホスホロアミダイト化することで一般式(I)で表されるアミダイト化合物を得ることができる。
Claims (16)
- 一般式(3)で表される配糖体化合物を製造する方法であって、
工程A:酸化剤及び酸の存在下で、一般式(1)で表される配糖体化合物と式(2)で表されるエーテル化合物とを反応させて一般式(3)で表される配糖体化合物を製造する工程であって、反応系内に酸化剤を添加し、次いで酸を添加する、該工程
Baは、アシル基により置換されていてもよいシトシン基、又はウラシル基を表し、
R1はC1~C6アルキル基、又はフェニル基を表し、そして、
nは0又は1を表す。)を含み、
ここで、
酸化剤は、N-ハロゲン化スクシンイミドおよびN-ハロゲン化ヒダントインからなる群から選ばれ、そして、
酸は、パーフルオロアルキルカルボン酸およびその塩、アルキルスルホン酸およびその塩、アリールスルホン酸およびその塩、パーフルオロアルキルスルホン酸およびその塩、およびこれらの2種類以上の組み合わせ、からなる群から選ばれる、該方法。 - nが1である、請求項1に記載の製造方法。
- nが0である、請求項1に記載の製造方法。
- 酸化剤がN-ハロゲン化スクシンイミドである、請求項1~3のいずれか1つに記載の製造方法。
- 酸化剤がN-ヨードスクシンイミドである、請求項1~4のいずれか1つに記載の製造方法。
- 酸がトリフルオロメタンスルホン酸、トリフルオロメタンスルホン酸銀、およびメタンスルホン酸からなる群から選ばれる少なくとも1つである、請求項1~5のいずれか1つに記載の製造方法。
- 酸がトリフルオロメタンスルホン酸である、請求項1~6のいずれか1つに記載の製造方法。
- 溶媒としてテトラヒドロフランを用いる、請求項1~7のいずれか1つに記載の製造方法。
- R1がメチル基である、請求項1~8のいずれか1つに記載の製造方法。
- Baがアセチル基で置換されたシトシン基、又は無置換のウラシル基である、請求項1~9のいずれか1つに記載の製造方法。
- 脱保護剤としてトリエチルアミン3フッ化水素酸塩又はピリジンフッ化水素酸塩を用いる、請求項12に記載の方法。
- 5’位水酸基の保護基導入試薬として4,4’-ジメトキシトリチルクロリドを用いる、請求項14に記載の方法。
- 3’位水酸基のホスホロアミダイト化試薬として2-シアノエチル-N,N,N’,N’-テトライソプロピルホスホロジアミダイトを用いる、請求項14又は15に記載の方法。
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201980058307.8A CN112638926A (zh) | 2018-09-07 | 2019-09-06 | 糖苷化合物的制造方法 |
KR1020217009766A KR20210058865A (ko) | 2018-09-07 | 2019-09-06 | 배당체 화합물의 제조 방법 |
US17/273,988 US20210355153A1 (en) | 2018-09-07 | 2019-09-06 | Method for producing glycoside compound |
EP19856557.4A EP3848381A4 (en) | 2018-09-07 | 2019-09-06 | METHOD OF PREPARING A GLYCOSIDE COMPOUND |
JP2020541322A JP7423533B2 (ja) | 2018-09-07 | 2019-09-06 | 配糖体化合物の製造方法 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2018168135 | 2018-09-07 | ||
JP2018-168135 | 2018-09-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2020050411A1 true WO2020050411A1 (ja) | 2020-03-12 |
Family
ID=69723235
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2019/035241 WO2020050411A1 (ja) | 2018-09-07 | 2019-09-06 | 配糖体化合物の製造方法 |
Country Status (6)
Country | Link |
---|---|
US (1) | US20210355153A1 (ja) |
EP (1) | EP3848381A4 (ja) |
JP (1) | JP7423533B2 (ja) |
KR (1) | KR20210058865A (ja) |
CN (1) | CN112638926A (ja) |
WO (1) | WO2020050411A1 (ja) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0578381A (ja) * | 1991-02-28 | 1993-03-30 | Nisshin Oil Mills Ltd:The | シアログリコシル化合物の製造方法 |
WO2007097447A1 (ja) | 2006-02-27 | 2007-08-30 | Nippon Shinyaku Co., Ltd. | 核酸保護基の脱離方法 |
WO2013027843A1 (ja) * | 2011-08-25 | 2013-02-28 | 株式会社ボナック | 配糖体化合物、チオエーテルの製造方法、エーテル、エーテルの製造方法、配糖体化合物の製造方法、核酸の製造方法 |
JP5157168B2 (ja) | 2004-08-26 | 2013-03-06 | 日本新薬株式会社 | ホスホロアミダイト化合物及びオリゴrnaの製法 |
WO2016159374A1 (ja) * | 2015-04-02 | 2016-10-06 | 株式会社ボナック | 配糖体化合物の製造方法 |
JP2018168135A (ja) | 2017-03-30 | 2018-11-01 | 三菱ケミカル株式会社 | 置換テトラヒドロフランの製造方法 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5554881Y2 (ja) | 1977-02-03 | 1980-12-19 | ||
JPWO2007097446A1 (ja) * | 2006-02-27 | 2009-07-16 | 日本新薬株式会社 | オリゴ核酸のキャッピング法 |
EP1995253B1 (en) * | 2006-02-27 | 2016-12-21 | Nippon Shinyaku Co., Ltd. | Method for detaching protecting group on nucleic acid |
JP5168145B2 (ja) * | 2006-08-02 | 2013-03-21 | 日本新薬株式会社 | 核酸保護基の導入方法 |
JP5138527B2 (ja) * | 2008-09-29 | 2013-02-06 | 株式会社日立ソリューションズ | ポリシーベースのファイルサーバアクセス制御方法及びシステム |
WO2011125943A1 (ja) * | 2010-04-01 | 2011-10-13 | 日本新薬株式会社 | 修飾オリゴヌクレオチド |
KR20190059971A (ko) * | 2016-10-14 | 2019-05-31 | 가부시키가이샤 보낙 | 신규 글리코시드 화합물 및 그의 제조 방법 |
KR102670605B1 (ko) * | 2018-04-24 | 2024-05-29 | 스미또모 가가꾸 가부시끼가이샤 | 아미다이트 화합물 및 그 화합물을 사용한 폴리뉴클레오티드의 제조 방법 |
-
2019
- 2019-09-06 WO PCT/JP2019/035241 patent/WO2020050411A1/ja unknown
- 2019-09-06 JP JP2020541322A patent/JP7423533B2/ja active Active
- 2019-09-06 EP EP19856557.4A patent/EP3848381A4/en active Pending
- 2019-09-06 US US17/273,988 patent/US20210355153A1/en active Pending
- 2019-09-06 KR KR1020217009766A patent/KR20210058865A/ko unknown
- 2019-09-06 CN CN201980058307.8A patent/CN112638926A/zh active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0578381A (ja) * | 1991-02-28 | 1993-03-30 | Nisshin Oil Mills Ltd:The | シアログリコシル化合物の製造方法 |
JP5157168B2 (ja) | 2004-08-26 | 2013-03-06 | 日本新薬株式会社 | ホスホロアミダイト化合物及びオリゴrnaの製法 |
WO2007097447A1 (ja) | 2006-02-27 | 2007-08-30 | Nippon Shinyaku Co., Ltd. | 核酸保護基の脱離方法 |
WO2013027843A1 (ja) * | 2011-08-25 | 2013-02-28 | 株式会社ボナック | 配糖体化合物、チオエーテルの製造方法、エーテル、エーテルの製造方法、配糖体化合物の製造方法、核酸の製造方法 |
JP5554881B2 (ja) | 2011-08-25 | 2014-07-23 | 株式会社ボナック | 配糖体化合物、チオエーテルの製造方法、エーテル、エーテルの製造方法、配糖体化合物の製造方法、核酸の製造方法 |
WO2016159374A1 (ja) * | 2015-04-02 | 2016-10-06 | 株式会社ボナック | 配糖体化合物の製造方法 |
JP2018168135A (ja) | 2017-03-30 | 2018-11-01 | 三菱ケミカル株式会社 | 置換テトラヒドロフランの製造方法 |
Non-Patent Citations (3)
Title |
---|
PETERSEN, SCOTT G. ET AL.: "o-Nitrobenzenesulfonamides in Nucleoside Synthesis: Efficient 5' -Aziridination of Adenosine", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 70, no. 15, 2005, pages 5833 - 5839, XP055297467, ISSN: 0022-3263, DOI: 10.1021/jo050205w * |
See also references of EP3848381A4 |
VERDEGAAL, C. H. M. ET AL.: "Acid-catalyzed isomerization of the tetraisopropyldisiloxane-1,3-diyl group. Simultaneous protection of two secondary alcoholic functions", TETRAHEDRON LETTERS, vol. 21, no. 16, 1980, pages 1571 - 1574, XP055692553, ISSN: 0040-4039 * |
Also Published As
Publication number | Publication date |
---|---|
CN112638926A (zh) | 2021-04-09 |
EP3848381A4 (en) | 2022-05-11 |
JP7423533B2 (ja) | 2024-01-29 |
EP3848381A1 (en) | 2021-07-14 |
US20210355153A1 (en) | 2021-11-18 |
JPWO2020050411A1 (ja) | 2021-08-30 |
KR20210058865A (ko) | 2021-05-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7280248B2 (ja) | アミダイト化合物及び該化合物を用いたポリヌクレオチドの製造方法 | |
JP6281599B2 (ja) | 擬似固相保護基およびヌクレオチド | |
JP7484951B2 (ja) | オリゴヌクレオチドの製造方法 | |
US9834577B2 (en) | Process for the preparation of gemcitabine-[phenyl(benzoxy-L-alaninyl)] phosphate | |
JP5322940B2 (ja) | (Rp)−8−置換cAMPSを製造する方法 | |
JP2020523381A (ja) | 3’−デオキシアデノシン−5’−o−[フェニル(ベンジルオシキ−l−アラニニル)]ホスフェート(nuc−7738)の合成 | |
US11414451B2 (en) | Floxuridine synthesis | |
EP3473637A1 (en) | Method for synthesizing ribonucleic acid h-phosphonate monomer, and oligonucleotide synthesis in which said monomer is used | |
US11661406B2 (en) | Method for producing intermediate useful for synthesis of SGLT inhibitor | |
JP7423533B2 (ja) | 配糖体化合物の製造方法 | |
EP4049996A1 (en) | Glycoside compound, amidite compound, and production method for polynucleotide using said compounds | |
EP1186612B1 (en) | Process for the preparation of cytidine derivatives | |
WO2021070507A1 (ja) | 配糖体化合物の製造方法 | |
WO2020246443A1 (ja) | 二分岐脂質結合オリゴヌクレオチドの製造方法及び中間体 | |
JPWO2010079813A1 (ja) | イノシン誘導体の製造方法 | |
EP0523080A1 (en) | TOSYLCYTIDINE-3'-0 AND CYTOSINE COMPOUNDS, AND THEIR PRODUCTION METHOD. | |
JP4627625B2 (ja) | N−アセチルシチジン類の製造方法 | |
JP4402951B2 (ja) | エリスロマイシン化合物の製造方法 | |
JP2011148738A (ja) | リボヌクレオシド誘導体またはその塩の製造方法 | |
JP2001354692A (ja) | シチジン誘導体の製造法 | |
WO2009082844A1 (fr) | Dérivé hydroxyle de la capécitabine, ses procédés de préparation et ses utilisations pour préparer la capécitabine |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 19856557 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2020541322 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 20217009766 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2019856557 Country of ref document: EP Effective date: 20210407 |