WO2021095874A1 - オリゴ核酸化合物の製造方法 - Google Patents

オリゴ核酸化合物の製造方法 Download PDF

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WO2021095874A1
WO2021095874A1 PCT/JP2020/042505 JP2020042505W WO2021095874A1 WO 2021095874 A1 WO2021095874 A1 WO 2021095874A1 JP 2020042505 W JP2020042505 W JP 2020042505W WO 2021095874 A1 WO2021095874 A1 WO 2021095874A1
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compound
alkyl
amino
group
chloride
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French (fr)
Japanese (ja)
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純司 浅田
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Nippon Shinyaku Co Ltd
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Nippon Shinyaku Co Ltd
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Priority to CA3161586A priority Critical patent/CA3161586A1/en
Priority to KR1020227019550A priority patent/KR20220098217A/ko
Priority to US17/776,343 priority patent/US12600743B2/en
Priority to CN202080092854.0A priority patent/CN114981281A/zh
Priority to EP20886751.5A priority patent/EP4059944A4/en
Priority to JP2021556191A priority patent/JP7689078B2/ja
Publication of WO2021095874A1 publication Critical patent/WO2021095874A1/ja
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Priority to JP2025087141A priority patent/JP2025128175A/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • 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 producing a novel oligonucleic acid compound.
  • the solid-phase method is a heterogeneous reaction method in which a nucleic acid is extended while contacting a substrate supported on a solid-phase carrier with a solution containing a reaction reagent.
  • a so-called batch method is used in which a reaction vessel with a filter is used to carry out the reaction in the vessel (see, for example, Non-Patent Document 1 and Patent Document 1).
  • a pseudo flow synthesis method is also known, such as an automatic nucleic acid synthesizer (for example, DNA, RNA synthesizer), in which a solid-phase carrier is placed in a column and a solution containing a reaction reagent is allowed to flow through the column to cause a reaction.
  • the liquid phase method is a homogeneous reaction method in which nucleic acid is extended by reacting in a solution containing both a substrate and a reaction reagent.
  • a batch method in which the reaction is carried out in a container is used (see, for example, Patent Document 2 and Patent Document 3).
  • the chemical synthesis method of an oligonucleic acid compound removes the protecting group of an oxygen atom or an amino group on the nucleic acid compound.
  • the nucleic acid is extended by repeating the "deprotection” reaction and the “condensation” reaction of forming a bond between an oxygen atom or a nitrogen atom and a phosphorus atom that have been deprotected and can react.
  • controlling the reaction efficiency and reaction rate in the "condensation" reaction that forms a bond between a phosphorus atom and an oxygen atom or a nitrogen atom is very important in the production of oligonucleic acid compounds, and the conditions for this condensation reaction are It is an element that has a great impact on the production period of oligonucleic acid compounds.
  • the solid-phase method is a heterogeneous reaction between a solid-phase carrier and a solution, it is known that the reactivity of the condensation reaction decreases due to steric hindrance caused by the solid-phase carrier.
  • Polystyrene resin is generally used as the solid-phase carrier, but during the reaction, it swells due to the reaction solvent used, and its volume becomes larger than that in the dry state. The degree of swelling depends on the reaction solvent. Therefore, the reaction efficiency and reaction rate of the condensation reaction in the solid phase method depend on the reaction solvent used.
  • polystyrene resin does not have a large degree of swelling in a polar solvent such as acetonitrile, which is generally used for the synthesis of oligonucleic acid compounds, and the use of a polar solvent in the solid phase method means that the reaction efficiency of the condensation reaction is high. And it cannot be said that it is preferable from the aspect of improving the reaction speed.
  • a polar solvent such as acetonitrile
  • the liquid phase method is a homogeneous reaction method in which a reaction is carried out in a solution containing both a substrate and a reaction reagent. In order to remove the reaction solvent, column purification or the like is required. Similar to the liquid phase method, the synthetic method using a hydrophobic group-bonded nucleoside or a pseudo solid-phase protected nucleoside can react in a uniform system, so that the reaction efficiency is higher and the reaction rate is higher than that of the solid-phase method. fast.
  • non-protic solvents such as chloroform are used in the condensation reaction, as reported, for example, in the synthesis of morpholinon nucleic acids (see, eg, Patent Document 5). Since the condensation reaction in a non-protic solvent requires a very long time, it is preferable to use a non-protic solvent in the reaction of a homogeneous system from the viewpoint of improving the reaction efficiency and reaction rate of the condensation reaction. I can't say.
  • An object of the present invention is to provide a novel production method capable of shortening the production period of an oligonucleic acid compound.
  • the present inventors have found that a phosphorus bond can be efficiently formed by using a reaction accelerator in a condensation reaction of an oligonucleic acid compound, and completed the present invention.
  • substituted [3] represents; and A 2 is C 1-6 alkyl, mono- under basic conditions has been replaced with a leaving group capable of (C 1-6 alkyl) amino-C 1-6 alkyl, di (C 1-6 alkyl) amino-C 1-6 alkyl, tri (C 1-6 alkyl) ammonio-C 1-6 alkyl, under basic conditions Represents a removable group, aryl or heteroaryl. ) Represents a substituent represented by (hereinafter, referred to as "substituent [2]").
  • the compound [B] having a substituent containing a phosphorus atom represented by (hereinafter referred to as “substituent [1]”) is subjected to a condensation reaction, and the following general formula [C]: (During the ceremony, W 0 and X are synonymous with the above; A represents the residue obtained by removing one hydrogen atom of the hydroxyl group or the primary or secondary amino group of the compound from the compound [A]; and B represents the substituent [1] from the compound [B]. Represents the excluded residue.
  • Compound [C] A method for producing a compound represented by (hereinafter referred to as "Compound [C]"), wherein as a reaction accelerator, a quaternary ammonium salt, a quaternary imidazolium salt, or a quaternary morpholinium salt is used.
  • a reaction accelerator a quaternary ammonium salt, a quaternary imidazolium salt, or a quaternary morpholinium salt is used.
  • quaternary phosphonium salts quaternary piperidinium salts, quaternary pyridinium salts, quaternary pyrrolidinium salts, and quaternary sulfonium salts.
  • quaternary phosphonium salts quaternary piperidinium salts
  • quaternary pyridinium salts quaternary pyrrolidinium salts
  • quaternary sulfonium salts The characteristic method can be mentioned.
  • An oligonucleic acid compound is a compound having a structure in which two to a plurality of nucleoside units are linked via a phosphorus bond.
  • a condensation reaction many times to form a phosphorus bond between adjacent nucleoside units.
  • the present invention since phosphorus bonds can be efficiently formed, it can be expected that the production time of the oligonucleic acid compound will be shortened as a result.
  • FIG. 1 illustrates a schematic diagram of a reactor used for a continuous reaction.
  • F-1 to F-5 indicate solution vessels
  • P-1 to P-5 indicate pumps
  • R-1 to R-4 indicate flow reactors
  • S-1 to S-5 indicate supply streams. Show the road.
  • the present invention is a method for producing compound [C] by subjecting compound [A] having a hydroxyl group or a primary or secondary amino group and compound [B] having a substituent [1] to a condensation reaction.
  • a reaction accelerator a quaternary ammonium salt, a quaternary imidazolium salt, a quaternary morpholinium salt, a quaternary phosphonium salt, a quaternary piperidinium salt, a quaternary pyridinium salt, and a quaternary pyrrolidinium are used. It is characterized by being carried out in the presence of at least one selected from the group consisting of salts and quaternary sulfonium salts.
  • a compound containing one to a plurality of nucleoside units in its molecule can be mentioned.
  • a compound containing a nucleoside unit in the range of 1 to 50 is suitable, a compound containing a nucleoside unit in the range of 1 to 30 is preferable, and a compound containing a nucleoside unit in the range of 1 to 25 is preferable.
  • Compounds containing nucleoside units are more preferred.
  • nucleoside unit contained in the compound [A] examples include the following general formulas [4a] to [4d]: [During the ceremony, * Is (1) Bonding position of the phosphorus bond bonded to the oxygen atom at the 5'position of the adjacent nucleoside unit, (2) Bonding position with hydrogen atom or (3) The following general formula [6]: (During the ceremony, * Represents the binding position of compound [A] with a residue; G is (1) Silicon substituent, (2) Long-chain alkyl-carbonyl, (3) 1 to 5 benzoyls substituted with long-chain alkyloxy and / or long-chain alkenyloxy or (4) the following general formula [7]: (During the ceremony, * Represents the connection position with T; Z is (1) (Soluble polymer soluble in organic solvent) -Oxy, (2) (Soluble polymer soluble in organic solvent) -Amino, (3) Long-chain alkyloxy, (4) Solid-phase carrier or (5) The following general formulas [8A] to [
  • Substituents represented by (hereinafter, referred to as “substituent [9A]”, “substituent [9B]”, “substituent [9C]”, “substituent [9D]”, “substituent [9E]", respectively.
  • R 8d is the same or different, each of which is a hydrogen atom, a halogen, a long-chain alkyl optionally substituted with 1 to 13 halogens, or a long-chain alkyl optionally substituted with 1 to 13 halogens.
  • R 8e is (1) Long chain alkyl, Represents (2) long-chain alkyl-carbonyl or (3) benzoyl substituted with 1-5 long-chain alkyloxy and / or long-chain alkenyloxy; and R 8f (1) Long chain alkyl, Represents (2) long-chain alkyl-carbonyl or (3) long-chain alkenyl-carbonyl.
  • Substituents represented by hereinafter, "substituent [8A]”, “substituent [8B]”, “substituent [8C]”, “substituent [8D]", “substituent [8E]", respectively.
  • R 4b1 and R 4b2 represent the same or different hydrogen atoms or C 1-6 alkyl, respectively, or R 4b1 and R 4b2 combine with adjacent carbon atoms to form a carbonyl; and J Represents an oxygen atom or N-R 4b3 (R 4b3 stands for C 1-6 alkyl).
  • Examples thereof include nucleoside units represented by (hereinafter, referred to as “nucleoside unit [4a]”, “nucleoside unit [4b]”, “nucleoside unit [4c]”, and “nucleoside unit [4d]”, respectively).
  • Preferred embodiments of the nucleoside units [4a] to [4d] include, for example, the following general formulas [4a1] to [4d1]: [During the ceremony, d, BP , J, R 4a , R 4b1 and R 4b2 are synonymous with the above; * Is (1) Bonding position of the phosphorus bond bonded to the oxygen atom at the 5'position of the adjacent nucleoside unit, (2) Represents the bond position with a hydrogen atom or (3) the bond position with a substituent [6]; and ** are (1) Bonding position with a phosphorus bond bonded to an oxygen atom at the 3'position or a nitrogen atom at the 3'position of an adjacent nucleoside unit, It represents (2) a bond position with a hydrogen atom or (3) a bond position with a substituent [6].
  • nucleoside unit [4a1] examples of the nucleoside unit represented by (hereinafter, referred to as “nucleoside unit [4b1]”, “nucleoside unit [4c1]”, and “nucleoside unit [4d1]) can be mentioned.
  • nucleoside units in the compound [A] contains a plurality of nucleoside units in its molecule, it is preferable that adjacent nucleoside units in the compound are bonded to each other via a phosphorus bond.
  • the phosphorus bonds between the nucleoside units constituting the compound [A] are the same or different, for example, the following general formula [5]: [During the ceremony, X is synonymous with the above; One of * and ** represents the bond position of the nucleoside unit with the oxygen atom at the 3'position or the nitrogen atom of the 3'position, and the other represents the bond with the oxygen atom of the nucleoside unit at the 5'position different from the nucleoside unit.
  • W represents a lone pair of electrons, an oxygen atom or a sulfur atom.
  • Examples of the bond represented by (hereinafter referred to as “phosphorus bond [5]”) can be mentioned.
  • W preferably represents an oxygen atom or a sulfur atom, and more preferably represents an oxygen atom.
  • (A-1) Compound [A] composed of one to a plurality of nucleoside units [4d]
  • nucleoside unit represented by the general formula [4d] *But, (1) the bond position with the phosphorus bond bonded to the oxygen atom at the 5'position of the adjacent nucleoside unit, or (2) the bond position with the hydrogen atom; **But, (1) The bond position with the phosphorus bond bonded to the nitrogen atom at the 3'position of the adjacent nucleoside unit, or (2) the bond position with the substituent [6].
  • examples of the phosphorus bond between each nucleoside unit constituting the compound [A] include the same or different phosphorus bond [5].
  • the phosphorus bond represented by the general formula [5] one of * and ** represents the bond position of the nucleoside unit with the nitrogen atom at the 3'position, and the other represents the bond position of the nucleoside unit different from the nucleoside unit. It represents the bond position with the oxygen atom at the 5'position.
  • the following general formula [A-1] [During the ceremony, BP , G, T, X and W are synonymous with the above; and n represents an integer from 1 to 50. ]
  • Examples of the compound represented by (hereinafter, referred to as “compound [A-1]”) can be mentioned.
  • An integer of 1 to 50 is suitable for n, an integer of 1 to 30 is preferable, and an integer of 1 to 25 is more preferable.
  • Equation [A-1-2] the following general formula [A-1-2]: Equation [A-1-2]: [During the ceremony, BP is a nucleobase that may be protected; Q 2 is a leaving group capable of either is H, or under acidic conditions; W represents a lone pair of electrons, an oxygen atom, or a sulfur atom, preferably an oxygen atom or a sulfur atom, and more preferably an oxygen atom; X, di (C1-6 alkyl) amino; G is the following formula: [During the ceremony, * Represents the connection position with T. ] Selected from the group consisting of; T is a single bond; n is 1 to 25. ] Compounds include.
  • A-2) Compound [A] composed of one or more nucleoside units selected from the group consisting of nucleoside units [4a], nucleoside units [4b] and nucleoside units [4c]
  • nucleoside unit represented by the general formulas [4a], [4b] and [4c] *But, (1) the bond position with the phosphorus bond bonded to the oxygen atom at the 5'position of the adjacent nucleoside unit, or (2) the bond position with the substituent [6]; **But, It is (1) a bond position with a phosphorus bond bonded to an oxygen atom at the 3'position of an adjacent nucleoside unit, or (2) a bond position with a hydrogen atom.
  • the phosphorus bond [5] is suitable for the phosphorus bond between each nucleoside unit constituting the compound [A].
  • the phosphorus bond represented by the general formula [5] one of * and ** represents the oxygen atom at the 3'position of the nucleoside unit, and the other represents the oxygen atom at the 5'position of the nucleoside unit different from the nucleoside unit. Represents the bond position with an oxygen atom.
  • substituent [7] in the compound [A-1] and the compound [A-2] include the following substituents. [During the ceremony, * Represents the connection position with T. ]
  • a compound containing one to a plurality of nucleoside units in its molecule can be mentioned. More specifically, a compound containing a nucleoside unit in the range of 1 to 10 is suitable, a compound containing a nucleoside unit in the range of 1 to 7 is preferable, and a compound containing a nucleoside unit in the range of 1 to 5 is preferable. Compounds containing the nucleoside unit of are more preferred.
  • nucleoside unit contained in the compound [B] examples include the following general formulas [4e] to [4h]: [During the ceremony, d, BP , J, R 4a , R 4b1 and R 4b2 are synonymous with the above; *** is (1) Bonding position of the phosphorus bond bonded to the oxygen atom at the 5'position of the adjacent nucleoside unit, (2) Represents the bond position with the substituent [1] or (3) the bond position with a group that can be eliminated under acidic conditions; *** is (1) Bonding position with a phosphorus bond bonded to an oxygen atom at the 3'position or a nitrogen atom at the 3'position of an adjacent nucleoside unit, It represents (2) a bond position with a substituent [1] or (3) a bond position with a group that can be eliminated under acidic conditions.
  • nucleoside unit [4e] examples thereof include a nucleoside unit represented by (hereinafter, referred to as “nucleoside unit [4e]”, “nucleoside unit [4f]”, “nucleoside unit [4g]”, and “nucleoside unit [4h]", respectively).
  • Preferred embodiments of the nucleoside units [4e] to [4h] include, for example, the following general formulas [4e1] to [4h1]: [During the ceremony, d, BP , J, R 4a , R 4b1 and R 4b2 are synonymous with the above; *** is (1) Bonding position of the phosphorus bond bonded to the oxygen atom at the 5'position of the adjacent nucleoside unit, (2) Represents a bond position with a substituent [1] or (3) a bond position with a group that can be eliminated under acidic conditions; and *** (1) Bonding position with a phosphorus bond bonded to an oxygen atom at the 3'position or a nitrogen atom at the 3'position of an adjacent nucleoside unit, It represents (2) a bond position with a substituent [1] or (3) a bond position with a group that can be eliminated under acidic conditions.
  • nucleoside unit [4e1] examples of the nucleoside unit represented by (hereinafter, referred to as “nucleoside unit [4e1]”, “nucleoside unit [4f1]”, “nucleoside unit [4g1]”, and “nucleoside unit [4h1]) can be mentioned.
  • nucleoside unit [B] contains a plurality of nucleoside units in its molecule
  • adjacent nucleoside units in the compound are bonded to each other via a phosphorus bond.
  • examples of the phosphorus bond between each nucleoside unit constituting the compound [B] include the same or different phosphorus bond [5].
  • the phosphorus bond represented by the general formula [5] one of * and ** represents the oxygen atom at the 3'position of the nucleoside unit, and the other represents the oxygen atom at the 5'position of the nucleoside unit different from the nucleoside unit. Represents the bond position with an oxygen atom.
  • (B-1) Compound [B] composed of one to a plurality of nucleoside units [4h]
  • nucleoside unit represented by the general formula [4h] ***But, (1) the bond position with the phosphorus bond bonded to the oxygen atom at the 5'position of the adjacent nucleoside unit, or (2) the bond position with the group that can be eliminated under acidic conditions; ****But, (1) The bond position with the phosphorus bond bonded to the nitrogen atom at the 3'position of the adjacent nucleoside unit, or (2) the bond position with the substituent [1].
  • examples of the phosphorus bond between each nucleoside unit constituting the compound [B] include the same or different phosphorus bond [5].
  • the phosphorus bond represented by the general formula [5] one of * and ** represents the nitrogen atom at the 3'position of the nucleoside unit, and the other represents the 5'position of the nucleoside unit different from the nucleoside unit. Represents the bond position with an oxygen atom.
  • the following general formula [1A] [During the ceremony, D, W and X are synonymous with the above; and ** represent the binding position of compound [B] to a residue. ] It is appropriate to have a substituent containing a phosphorus atom represented by.
  • the following general formula [B-1] [During the ceremony, BP , D, X and W are synonymous with the above; p represents an integer from 1 to 10; and Q 1 represents a group that can be eliminated under acidic conditions. ] Examples of the compound represented by (hereinafter, referred to as “compound [B-1]”) can be mentioned.
  • An integer of 1 to 10 is suitable for p, an integer of 1 to 7 is preferable, and an integer of 1 to 5 is more preferable.
  • (B-2) Compound [B] composed of one to a plurality of nucleoside units selected from the group consisting of nucleoside units [4e], nucleoside units [4f] and nucleoside units [4 g].
  • nucleoside unit represented by the general formulas [4e], [4f] and [4g] ***But, (1) the bond position with the phosphorus bond bonded to the oxygen atom at the 3'position of the adjacent nucleoside unit, or (2) the bond position with the substituent [1]; ****But, It is (1) a bond position with a phosphorus bond bonded to an oxygen atom at the 5'position of an adjacent nucleoside unit, or (2) a bond position with a group that can be eliminated under acidic conditions.
  • compound [B] for example, a compound in which the oxygen atom at the 5'position of the nucleoside unit on the 5'-terminal side is replaced with a group that can be eliminated under acidic conditions can be mentioned. ..
  • examples of the phosphorus bond between each nucleoside unit constituting the compound [B] include the same or different phosphorus bond [5].
  • the phosphorus bond represented by the general formula [5] one of * and ** represents the oxygen atom at the 3'position of the nucleoside unit, and the other represents the oxygen atom at the 5'position of the nucleoside unit different from the nucleoside unit. Represents the bond position with an oxygen atom.
  • the following general formula [1B] [During the ceremony, D and X are synonymous with the above; and ** represent the binding position of compound [B] to a residue. ] It is appropriate to have a substituent containing a phosphorus atom represented by.
  • the following general formula [B-2] [During the ceremony, p, BP , D, Q 1 , R 4a , X and W are synonymous with the above. ] Examples of the compound represented by (hereinafter, referred to as “compound [B-2]”) can be mentioned.
  • compound [C] examples include compounds that can be produced by subjecting compound [A] and compound [B] to a condensation reaction.
  • (C-1) Compound [C] composed of one to a plurality of nucleoside units [4d] and one to a plurality of nucleoside units [4h].
  • the compound [C] for example, the following general formula [C-1]: [During the ceremony, n, p, BP , G, Q 1 , T, W and X are synonymous with the above. ]
  • Examples of the compound represented by (hereinafter, referred to as “compound [C-1]”) can be mentioned.
  • examples of the phosphorus bond newly formed in the method for producing the compound [C-1] by reacting the compound [A-1] with the compound [B-1] include a phosphorus bond [5]. Can be mentioned.
  • C-2 One to a plurality of nucleoside units and nucleoside units [4e], nucleoside units [4f] and selected from the group consisting of nucleoside units [4a], nucleoside units [4b] and nucleoside units [4c].
  • Compound [C] composed of one to a plurality of nucleoside units selected from the group consisting of nucleoside units [4 g]
  • examples of the phosphorus bond newly formed in the method for producing the compound [C-2] by reacting the compound [A-2] with the compound [B-2] include the following general formula [ 5a]: [During the ceremony, X is synonymous with the above; and one of * and ** represents the bond position with the oxygen atom at the 3'position of the nucleoside unit, and the other represents the oxygen atom at the 5'position of the nucleoside unit different from the nucleoside unit. Represents the connection position of. ] A bond containing a phosphorus atom represented by (hereinafter, referred to as “phosphorus bond [5a]”) can be mentioned.
  • nucleobase examples include adenine, guanine, hypoxanthine, cytosine, thymine, uracil, and modified bases thereof.
  • modified bases include, for example, pseudouracil, 3-methyluracil, dihydrouracil, 5-alkylcytocin (eg, 5-methylcitosin), 5-alkyluracil (eg, 5-ethyluracil), 5-halouracil (5).
  • 6-azapyrimidine 6-alkylpyrimidine (6-methyluracil), 2-thiouracil, 4-thiouracil, 4-acetylcitosine, 5- (carboxyhydroxymethyl) uracil, 5'-carboxymethylaminomethyl 2-thiouracil, 5-carboxymethyl-aminomethyl uracil, 1-methyl-adenine, 1-methyl-hypoxanthine, 2,2-dimethyl guanine, 3-methylcytosine, 2-methyl-adenine, 2-methylguanine, N 6 - methyl Adenine, 7-methylguanine, 5-methoxyaminomethyl-2-thiouracil, 5-methylaminomethyluracil, 5-methylcarbonylmethyluracil, 5-methyloxyuracil, 5-methyl-2-thiouracil, 2-methylthio-N 6- Isopentenyladenin, uracil-5-oxyacetic acid, 2-thiocitosine, purine, 2,6-diamin
  • nucleobase related to BP may be protected.
  • optionally protected nucleobase includes both unprotected “nucleobase” and protected “nucleobase”, eg, amino groups and / or hydroxyl groups. Includes adenine, guanine, hypoxanthin, cytosine, thymine, uracil, etc., which are unprotected or protected.
  • the protecting group for the amino group is not particularly limited as long as it is used as a protecting group for nucleic acids.
  • examples thereof include phenoxyacetyl, 4-tert-butylphenoxyacetyl, 4-isopropylphenoxyacetyl, and (dimethylamino) methylene.
  • benzoyl, acetyl, phenylacetyl and 4-tert-butylphenoxyacetyl are preferable.
  • the protecting group for the hydroxyl group includes, for example, 2-cyanoethyl, 4-nitrophenethyl, phenylsulfonylethyl, methylsulfonylethyl, trimethylsilylethyl, and 1 to 5 electron-withdrawing groups at arbitrary substitutable positions.
  • As the protecting group for the hydroxyl group 2-cyanoethyl, 4-nitrophenethyl and 4- (tert-butylcarboxy) benzyl are preferable.
  • the protecting group for the 6-position hydroxyl group of guanine is preferably 2-cyanoethyl.
  • the protected nucleobases include, for example, those shown below. [In the formula, Pg represents a protecting group]. More specific protected nucleic acid base embodiments include benzoyl-protected adenine ( ABz ), amino groups benzoyl-protected cytosine ( CBz ), and hydroxyl groups protected by 2-cyanoethyl. And, but not limited to, guanine (GCE, Pac ) in which the amino group is protected with phenoxyacetyl.
  • the "long chain alkyl” refers, for example, to a linear or branched alkyl having 10 to 300 carbon atoms, preferably a linear or branched alkyl having 10 to 100 carbon atoms, and more. Preferred is a linear or branched chain alkyl having 10 to 30 carbon atoms.
  • the "long-chain alkyl” portion of the “long-chain alkyl-carbonyl” and “long-chain alkyloxy” can be the same as the "long-chain alkyl”.
  • “Long-chain alkenyl” For example, a linear or branched alkenyl having 10 to 300 carbon atoms, preferably a linear or branched alkenyl having 10 to 100 carbon atoms, more preferably.
  • the "long-chain alkenyl” portion of the “long-chain alkenyloxy” and the “long-chain alkenyl-carbonyl” can be the same as the "long-chain alkenyl".
  • Examples of the "halogen” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the "5- to 6-membered saturated cyclic amino” includes, for example, a 5- to 6-membered saturated cyclic amino having 1 or 2 N, which may have one O or S as a ring-constituting atom.
  • C 1-6 alkyl indicates a linear or branched alkyl having 1 to 6 carbon atoms, and specifically, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl. , Se-butyl, tert-butyl, n-pentyl, n-hexyl.
  • C 1-6 alkoxy represents a linear or branched chain alkoxy having 1 to 6 carbon atoms, and specifically, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and the like. Examples thereof include isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, and n-hexyloxy.
  • C 1-6 alkoxy moiety of the "C 1-6 alkoxy -C 1-6 alkyl” may include the same ones as the "C 1-6 alkoxy”.
  • di (C 1-6 alkyl) amino mono (amino -C 1-6 alkyl substituted with removable group under basic conditions) amino, di (removable under basic conditions groups
  • the "C 1-6 alkyl” portion of the alkyl) amino and the di (amino-C 1-6 alkyl) amino can be the same as the "C 1-6 alkyl" described above.
  • C 2-10 alkylene is a divalent product produced by removing one hydrogen atom bonded to a different constituent carbon atom from a linear or branched alkyl having 2 to 10 carbon atoms.
  • the group include an ethylene group, a propylene group, an isopropylene group, a butylene group, a pentylene group, and a hexylene group.
  • Such "alkylene” may be substituted with 1 to 12 halogens at any substitutable position. According to L 1 as “alkylene”, ethylene is particularly preferred.
  • C 6-10 arylene removes two hydrogen atoms bonded to two different ring-constituting carbon atoms from a monocyclic or polycyclic aromatic hydrocarbon having 6 to 10 carbon atoms. It is a divalent group produced by, and examples thereof include phenylene and naphthylene. Such “allylen” may be substituted with 1 to 6 halogens at any substitutable position. According to L 1 as “arylene”, phenylene are particularly preferred.
  • Examples of the "group that can be removed under acidic conditions” include trityl, monomethoxytrityl, tert-butyldimethylsilyl, and dimethoxytrityl.
  • Examples of the “group that can be removed under basic conditions” include trifluoroacetyl.
  • Examples of the “group that can be removed under neutral conditions” include a group that can be eliminated by the action of tetrabutylammonium fluoride or a hydrogen trifluoride / triethylamine salt.
  • 2 -Cyanoethoxymethoxy, 2-cyanoethoxy-2-ethoxy, tert-butyldimethylsilyl can be mentioned.
  • Examples of the "silicon substituent” include triphenylsilyl, diisopropylphenylsilyl, tert-butyldimethylsilyl, and tert-butyldiphenylsilyl.
  • Aryl can be, for example, phenyl.
  • Heteroaryl can include, for example, pyridyl, pyrimidyl, pyrariayl, pyrazinyl, thienyl, flanyl.
  • solid phase carrier generally, any substance that can be used for solid phase synthesis of nucleic acids, peptides, peptide nucleic acids, sugars and the like can be used without any particular problem. For example, polystyrene can be used.
  • Polyglass; CPG Oxalylated-Regular Glass (see, eg, Nucleic Acids Research, Vol. 19, 1527 (1991)), TentaGel Support-Aminopolystyrene Glycol Derivatized Support (eg, Tetrahedron Letters, Vol.) .34, 3373 (1993)), Polys-polystyrene / divinylbenzene copolymers, polystyrene-based resins, polyacrylamide-based resins.
  • soluble polymer soluble in an organic solvent include a styrene polymer having no crosslink and a polyethylene glycol derivative.
  • the "soluble polymer soluble in organic solvent” portion of "(soluble polymer soluble in organic solvent) -oxy" and “(soluble polymer soluble in organic solvent) -amino” is the above-mentioned "soluble polymer soluble in organic solvent”.
  • Examples of the “non-crosslinked styrene polymer” include derivatives (TentaGel series, ArgoGel series) of polystyrene not crosslinked with divinylbenzene and having a spacer such as polyethylene glycol.
  • Examples of the "polyethylene glycol derivative” include derivatives having a substituent on polyethylene glycol having a molecular weight of 100 to 40,000 (SUNBRIGHT (registered trademark) series).
  • the solvent that can be used in this production method is not particularly limited as long as it is a solvent usually used in the art, and the solvent may be used alone, or two or more solvents may be mixed and used. You may.
  • the solvent that can be used in this production method include aromatic solvents such as benzene, toluene, xylene, and mesitylene; ester solvents such as ethyl acetate and isopropyl acetate; hexane, pentane, heptane, octane, nonane, cyclohexane, and the like. Examples of the aliphatic solvent of the above. These solvents may be mixed and used. In this production method, a base may be used if necessary.
  • Examples of the "base” that can be used in this production method include diisopropylamine, N, N-diisopropylethylamine, triethylamine, N-ethylmorpholine, and 2,6-lutidine.
  • the amount of the base that can be used in this production method is, for example, appropriately in the range of 1 to 100 times the molar ratio with respect to 1 mol of the compound [A], and 1 to 10 times the amount.
  • the amount is preferably in the range of 1 to 5 times, and more preferably in the range of 1 to 5 times.
  • a reaction accelerator is used.
  • reaction accelerator that can be used in this production method is, for example, a quaternary ammonium salt, a quaternary imidazolium salt, a quaternary morpholinium salt, a quaternary phosphonium salt, a quaternary piperidinium salt, or a quaternary quaternary.
  • a quaternary ammonium salt a quaternary imidazolium salt, a quaternary morpholinium salt, a quaternary phosphonium salt, a quaternary piperidinium salt, or a quaternary quaternary.
  • At least one selected from the group consisting of pyridinium salts, quaternary pyrrolidinium salts, and quaternary sulfonium salts can be used, preferably quaternary ammonium salts, quaternary imidazolium salts, quaternary imidazolium salts.
  • At least one selected from the group consisting of quaternary phosphonium salts, quaternary pyridinium salts, and quaternary pyrrolidinium salts can be used. More preferably, a salt containing a quaternary nitrogen cation selected from the group consisting of a quaternary ammonium salt, a quaternary imidazolium salt, a quaternary pyridinium salt, and a quaternary pyrrolidinium salt, and even more preferably. , At least one selected from the group consisting of quaternary ammonium salts, quaternary imidazolium salts, and quaternary pyrrolidinium salts can be used.
  • the quaternary ammonium salts that can be used in this production method include, for example, amyltriethylammonium bis (trifluoromethanesulfonyl) imide, butyltrimethylammonium bis (trifluoromethanesulfonyl) imide, and benzyl (ethyl) dimethylammonium bis (trifluoromethanesulfonyl).
  • the quaternary ammonium salts that can be used in this production method include, for example, tetra C 1-18 alkyl ammonium salt (for example, tetra C 1-18 alkyl ammonium chloride) and tri C 1-18 alkyl (hydroxy C 1-18 alkyl). ) Ammonium salts, etc. (where C 1-18 alkyl may be the same or different), preferably tetramethylammonium chloride, tetraethylammonium chloride, tetrapropylammonium chloride, tetrabutylammonium chloride, tetrabutyl.
  • Ammonium bromide dodecyltrimethylammonium chloride, choline chloride, N, N, N-trimethylbutane-1-aminochloride.
  • the quaternary imidazolium salt that can be used in this production method is, for example, 1-allyl-3-methylimidazolium chloride, 1-allyl-3-methylimidazolium bis (trifluoromethanesulfonyl) imide, 1-butyl-3.
  • the quaternary imidazolium salt that can be used in this production method is, for example, 1-C 1-18 alkyl-3-C 1-18 alkyl imidazolium chloride, 1-C 1-18 alkyl-3- NC 1 It is -18 alkyl imidazolium chloride, preferably 1-ethyl-3-methyl imidazolium chloride, 1-methyl-3-N-octyl imidazolium chloride.
  • Quaternary phosphonium salts can be used in the present production process may, for example, tetra-C 1-18 alkyl phosphonium salt, a tri C 1-18 alkyl (hydroxy C 1-18 alkyl) phosphonium salts (herein, C 1- 18 Alkyl may be the same or different), preferably trihexyltetradecylphosphonium chloride.
  • the quaternary pyridinium salt that can be used in this production method is, for example, 1-C 1-18 alkylpyridinium salt, preferably 1-ethylpyridinium bromide, 1-ethylpyridinium chloride, 1-butylpyridinium chloride. ..
  • the quaternary pyrrolidinium salt that can be used in this production method is, for example, 1-allyl-1-methylpyrrolidinium bis (trifluoromethanesulfonyl) imide, 1-butyl-1-methylpyrrolidinium bis (trifluoromethanesulfonyl).
  • the quaternary pyrrolidinium salt that can be used in this production method is, for example, 1-C 1-18 alkyl-1-C 1-18 alkyl pyrrolidinium chloride (where C 1-18 alkyl is the same or It may be different), preferably 1-butyl-1-methylpyrrolidinium chloride.
  • Reaction accelerators that can be used in this production method include, for example, Tetramethylammonium chloride, Tetraethylammonium chloride, Tetrapropylammonium chloride, Tetrabutylammonium chloride, Tetraoctylammonium bromide, Dodecyltrimethylammonium chloride, Trioctylmethylammonium chloride, N, N, N-trimethylbutane-1-aminochloride, 1-Ethylpyridinium bromide, 1-Ethylpyridinium chloride, 1-Butylpyridinium chloride, 1-Ethyl-3-methylimidazolium chloride, 1-Methyl-3-N-octylimidazolium chloride, At least one selected from the group consisting of 1-butyl-1-methylpyrrolidinium chloride and trihexyltetradecylphosphonium chloride.
  • preferred reaction accelerators that can be used in this production method include tetra C 1-18 alkylammonium chloride, 1-C 1-18 alkyl-1-C 1-18 alkylpyrrolidinium chloride, 1-.
  • Examples thereof include C 1-18 alkyl-3-C 1-18 alkyl imidazolium chloride, preferably tetrabutyl ammonium chloride, 1-butyl-1-methylpyrrolidinium chloride, and 1-methyl-3-N-octyl imidazole.
  • the amount of the reaction accelerator that can be used in this production method is in the range of 1 to 100 times the molar ratio, preferably 1 to 50 times the amount of 1 mol of compound [A].
  • the range of 1.5 times to 20 times the amount is more preferable.
  • the reaction temperature is, for example, preferably in the range of ⁇ 78 ° C. to 130 ° C., preferably in the range of ⁇ 40 ° C. to 100 ° C., and further preferably in the range of 0 ° C. to 80 ° C.
  • the reaction time varies depending on the type of compound [A] used, the type of compound [B], the type of reaction solvent, the type of base, and the reaction temperature, but for example, the range of 1 minute to 300 minutes is appropriate. It is preferably in the range of 5 minutes to 120 minutes.
  • this production method can be applied by either a batch method or a flow method. Further, this production method can also be applied to a solid-phase method, a liquid-phase method, a liquid-phase method using a hydrophobic group-bonded nucleoside, a pseudo-solid-phase protected nucleoside, or the like, which are known as methods for producing an oligonucleic acid compound.
  • compound [C] which is an oligonucleic acid compound
  • compound [C] can be produced by using the solid phase method, at the oxygen atom at the 3'position of the nucleoside unit on the 3'terminal side of compound [A] or at the 5'of compound [A].
  • the oxygen atom at the 5'position of the nucleoside unit on the terminal side, which is supported on a solid phase carrier, can be used.
  • the oligonucleic acid compound can be produced using the liquid phase method, at the oxygen atom at the 3'position of the nucleoside unit on the 3'end side of compound [A] or on the nucleoside unit on the 5'end side of compound [A].
  • those supported by a soluble polymer that dissolves in an organic solvent can be used.
  • an oligonucleic acid compound can be produced by using a liquid phase method using a hydrophobic group-bonded nucleoside, a pseudo-solid phase-protected nucleoside, or the like
  • the oxygen atom at the 3'position of the nucleoside unit on the 3'terminal side of compound [A] can be produced.
  • one having a hydrophobic group bonded or one supported on a pseudo solid phase can be used (for example,).
  • Compound [C-1] can be produced by subjecting compound [A-1] to a condensation reaction with compound [B-1].
  • the solvent that can be used in this production method is not particularly limited as long as it is a solvent usually used in the art, and the solvent may be used alone, or two or more solvents are mixed. May be used. Examples thereof include aromatic solvents such as benzene, toluene, xylene and mesitylene; ester solvents such as ethyl acetate and isopropyl acetate; aliphatic solvents such as hexane, pentane, heptane, octane, nonane and cyclohexane. Two or more kinds of these solvents may be mixed and used.
  • Examples of the solvent that can be used in this production method include polar solvents and halogen-based solvents.
  • Examples of the polar solvent that can be used in this production method include dimethylacetamide, dimethyl sulfoxide, dimethylformamide, sulfolane, N-methylpiperidone, 1,3-dimethyl-2-imidazolidinone, N, N'-dimethylpropyleneurea or. A mixed solvent thereof can be mentioned. Of these, dimethylacetamide, dimethyl sulfoxide, N-methylpiperidone, 1,3-dimethyl-2-imidazolidinone, and N, N'-dimethylpropylene urea are preferable.
  • halogen-based solvent examples include chloroform, dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,2-trichloroethane, 1,2-dichloroethylene, or a mixed solvent thereof. Can be mentioned. Of these, chloroform, dichloromethane, 1,1-dichloroethane, and 1,2-dichloroethane are preferable.
  • the lower limit of the ratio of the polar solvent in the mixed solvent of the polar solvent and the halogen-based solvent that can be used in this production method is 1.0% by weight, preferably 2.0% by weight, and more preferably 3.0% by weight. , More preferably 5.0% by weight.
  • the upper limit thereof is 90% by weight, preferably 75% by weight, more preferably 50% by weight, still more preferably 40% by weight, and particularly preferably 30% by weight. Further, the upper limit and the lower limit thereof can be used in an appropriate combination, for example, in the range of 1% to 90%, preferably in the range of 5% to 75%, and in the range of 5% to 50%. Is particularly preferable.
  • a base may be used if necessary. Examples of the "base” that can be used in this production method include diisopropylamine, N, N-diisopropylethylamine, triethylamine, N-ethylmorpholine, and 2,6-lutidine.
  • the amount of the base that can be used in this production method is, for example, appropriately in the range of 1 to 100 times the molar ratio with respect to 1 mol of the compound [A], and 1 to 10 times the amount.
  • the amount is preferably in the range of 1 to 5 times, and more preferably in the range of 1 to 5 times.
  • additives may be used if necessary.
  • the "additive" that can be used in this production method for example, LiBr, LiCl, LiI, and NaI are preferable.
  • the amount of the additive that can be used in this production method is, for example, appropriately in the range of 0.2 times to 6.0 times the molar ratio with respect to 1 mol of compound [A], and is 0.
  • the amount is preferably in the range of 4 times to 3.0 times, and more preferably in the range of 1.0 times to 2.5 times.
  • the reaction temperature is, for example, preferably in the range of ⁇ 78 ° C. to 130 ° C., preferably in the range of ⁇ 40 ° C. to 100 ° C., and further preferably in the range of 0 ° C. to 80 ° C.
  • the reaction time varies depending on the type of compound [A] used, the type of compound [B], the type of reaction solvent, the type of base, and the reaction temperature, but for example, the range of 1 minute to 300 minutes is appropriate. It is preferably in the range of 5 minutes to 120 minutes.
  • compound [A-1] has a solid phase carrier in its molecule, that is, when G is a substituent [7] and Z is a solid phase carrier in compound [A-1], for example, ( 1) Fill a suitable column with compound [A-1] and elute the reaction solution containing compound [B-1], or (2) place compound [A-1] and compound [A-1] in a reaction vessel equipped with a filter. This condensation reaction can be carried out by shaking or stirring the reaction solution containing B-1].
  • G is substituted with (1) silicon substituent, (2) long chain alkyl-carbonyl, (3) 1-5 long chain alkyloxy and / or long chain alkenyloxy. If it is a benzoyl or (4) substituent [7] (except when Z is a solid phase carrier), for example, (1) compound [A-1] is placed in a suitable reaction vessel. [A-1] and compound [B-1] are stirred in the reaction solvent, or (2) the solution containing the compound [A-1] and the solution containing the compound [B-1] are independent of each other. This condensation reaction can be carried out by supplying the solution to the flow reactor or the reaction flow path via the supply flow path and mixing the solutions in the flow reactor or the like.
  • the "supply flow path” means a flow path for continuously supplying the solution
  • the “reaction flow path” means a flow path capable of reacting while flowing the solution.
  • the flow reactor means a reactor in which a solution is charged, a reaction is carried out, and a product is recovered at the same time, and the operation is continuous.
  • a pump for supplying a liquid usually used in this field specifically examples include a syringe pump, a plunger pump, a diaphragm pump, and a gear pump.
  • Examples of the distribution reactor include an in-line mixer such as a microreactor and a static mixer.
  • a multi-stage collision type micromixer As a means for guiding the solution containing the compound [A-1] and the solution containing the compound [B-1] from the supply flow path to the reaction flow path, for example, a multi-stage collision type micromixer can be mentioned.
  • the material of the supply channel and the reaction channel is selected from the group consisting of, for example, a fluororesin such as perfluoroalkoxy alkane (PFA), a vinyl chloride resin, a polyamide resin, and an aromatic polyetherketone resin.
  • PFA perfluoroalkoxy alkane
  • Examples include synthetic resin tubing or metal tubing selected from the group consisting of stainless steel, copper and its alloys and titanium and its alloys.
  • the inner diameters of the supply flow path and the reaction flow path may be appropriately selected from, for example, a size within the range of 0.1 mm to 1.0 mm, but for example, a size within the range of 0.2 mm to 1.0 mm. It is preferable to select from.
  • Compound [C-2] can be produced by subjecting compound [A-2] to a condensation reaction with compound [B-2].
  • a base may be used if necessary.
  • Examples of the "base” that can be used in this production method include diisopropylamine, N, N-diisopropylethylamine, triethylamine, N-ethylmorpholine, and 2,6-lutidine.
  • compound [A-2] has a solid phase carrier in its molecule, that is, when G is a substituent [7] and Z is a solid phase carrier in compound [A-2], for example, ( 1) Fill a suitable column with compound [A-1] and elute the reaction solution containing compound [B-2], or (2) place compound [A-2] and compound [A-2] in a reaction vessel with a filter.
  • the condensation reaction can be carried out by shaking or stirring the reaction solution containing B-2].
  • G is substituted with (1) silicon substituent, (2) long chain alkyl-carbonyl, (3) 1-5 long chain alkyloxy and / or long chain alkenyloxy. If it is a benzoyl or (4) substituent [7] (except when Z is a solid phase carrier), for example, (1) compound [A-2] is placed in a suitable reaction vessel. [A-2] and compound [B-2] are stirred in the reaction solvent, or (2) the solution containing the compound [A-2] and the solution containing the compound [B-2] are independent of each other. This condensation reaction can be carried out by supplying the solution to the flow reactor or the reaction flow path via the supply flow path and mixing the solutions in the flow reactor or the like.
  • the compound [C-2] is obtained by purifying the reaction mixture using a column, or (2) a precipitate obtained by adding an appropriate solvent to the reaction mixture is obtained.
  • Compound [C-2] can be obtained by sampling and washing with a suitable solvent.
  • Compound [C-2] is a compound in which each nucleoside unit constituting the compound is a nucleoside unit [4a] and a nucleoside unit [4e], but all or one of the nucleoside unit [4a] or the nucleoside unit [4e]. Even if the part is a compound in which the nucleoside unit [4b], the nucleoside unit [4c], the nucleoside unit [4f] or the nucleoside unit [4g] is replaced, it can be produced by the same method as described above.
  • compound [C] has a solid-phase carrier in its molecule
  • compound [C] is packed in an appropriate column, and compound [C] is washed with an appropriate solvent to remove unnecessary substances.
  • examples of such a compound include compounds in which G is a substituent [7] and Z is a solid phase carrier in the compound [C-1] and the compound [C-2].
  • G is a silicon substituent in compound [C-1] and compound [C-2]
  • the target compound is isolated by performing an operation such as column purification using an appropriate solvent. -Can be purified.
  • n, p, BP , G, Q 1 , T, W and X are synonymous with the above.
  • compound [C-1] when G is a substituent [7] and Z is a solid phase carrier, for example, (1) compound [C-1] is packed in an appropriate column and contains an acid.
  • the elimination reaction can be carried out by eluting the solution or (2) shaking or stirring the solution containing compound [C-1] and an acid in a reaction vessel equipped with a filter.
  • the solvent that can be used in this elimination reaction is not particularly limited as long as it is a solvent usually used in the art, and a single solvent may be used, or two or more solvents are mixed. May be used.
  • Examples thereof include aromatic solvents such as benzene, toluene, xylene and mesitylene; ester solvents such as ethyl acetate and isopropyl acetate; aliphatic solvents such as hexane, pentane, heptane, octane, nonane and cyclohexane. Two or more kinds of these solvents may be mixed and used.
  • the solvent that can be used in this elimination reaction include polar solvents and halogen-based solvents.
  • the solvent that can be used in this elimination reaction is not particularly limited, but for example, a mixed solvent of a polar solvent and a halogen-based solvent can be used.
  • the lower limit of the ratio of the polar solvent in the mixed solvent of the polar solvent and the halogen-based solvent is 1.0% by weight, preferably 2.0% by weight, more preferably 3.0% by weight, still more preferably 5.0. % By weight.
  • the upper limit thereof is 90% by weight, preferably 75% by weight, more preferably 50% by weight, still more preferably 40% by weight, and particularly preferably 30% by weight. Further, the upper limit and the lower limit thereof can be used in an appropriate combination, for example, in the range of 1% to 50%, preferably in the range of 1% to 40%, and in the range of 1% to 30%. Is particularly preferable.
  • Examples of the "acid” that can be used in this desorption reaction include trifluoroacetic acid, cyanopyridine trifluoroacetic acid, triethylamine trifluoroacetic acid, cyanoacetic acid, trichloroacetic acid, phosphoric acid, methanesulfonic acid, and p-toluenesulfone. Acids and hydrochloric acids can be mentioned. When these acids are used, they may be used in combination with a base (for example, triethylamine) to adjust the acidity.
  • a base for example, triethylamine
  • the amount of the acid that can be used in this elimination reaction for example, the amount in the range of 1 to 500 times the molar ratio is appropriate with respect to 1 mol of the compound [C-1], and the amount is 2 times.
  • the amount is preferably in the range of about 200 times.
  • the acid that can be used in this elimination reaction is appropriately diluted with a suitable solvent to a concentration in the range of, for example, 5% to 80%, and is in the range of 5% to 50%. It is preferable to dilute to the concentration of.
  • the solvent for dissolving the acid that can be used in this desorption reaction is not particularly limited, and is, for example, chloroform, dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,2-trichloroethane, 1 , 2-Dichloroethylene, 2,2,2-trifluoroethanol or a mixed solvent thereof.
  • a scavenger may be used if necessary. Examples of "scavengers” that can be used in this elimination reaction include ethanol, triisopropylsilane, 1-hydroxybenzotriazole, pyrrole, indole, 2,2,2-trifluoroethanol, methanol, anisole, mercaptoethanol, and thio.
  • anisole can be mentioned.
  • the amount of the scavenger that can be used in this elimination reaction for example, the amount in the range of 1 to 100 times the molar ratio is appropriate with respect to 1 mol of the compound [C-1], and the amount is 1 time. The amount is preferably in the range of about 50 times.
  • G is substituted with (1) silicon substituent, (2) long chain alkyl-carbonyl, (3) 1-5 long chain alkyloxy and / or long chain alkenyloxy. If it is a benzoyl or (4) substituent [7] (except when Z is a solid phase carrier), for example, (1) compound [C-1] is placed in a suitable reaction vessel. [C-1] and the acid are stirred in an appropriate reaction solvent, or (2) the solution containing the compound [C-1] and the solution containing the acid are independently distributed through the supply channel. This desorption reaction can be carried out by supplying the solution to the reactor or the reaction flow path and mixing the solutions in the flow reactor or the like.
  • the solvent that can be used in this elimination reaction is not particularly limited, but for example, a mixed solvent of a polar solvent and a halogen-based solvent can be used.
  • the lower limit of the ratio of the polar solvent in the mixed solvent of the polar solvent and the halogen-based solvent is 1.0% by weight, preferably 2.0% by weight, more preferably 3.0% by weight, still more preferably 5.0. % By weight.
  • the upper limit thereof is 90% by weight, preferably 75% by weight, more preferably 50% by weight, still more preferably 40% by weight, and particularly preferably 30% by weight.
  • the upper limit and the lower limit thereof can be used in combination as appropriate, and the ratio of the polar solvent in the mixed solvent of the polar solvent and the halogen-based solvent is suitable, for example, in the range of 1% to 50%.
  • the range of 1% to 40% is preferable, and the range of 1% to 30% is particularly preferable.
  • Examples of the "acid" that can be used in this elimination reaction include the same as described above. When these acids are used, they may be used in combination with a base (for example, triethylamine) to adjust the acidity.
  • a base for example, triethylamine
  • the amount of the acid that can be used in this elimination reaction for example, the amount in the range of 1 to 500 times the molar ratio is appropriate with respect to 1 mol of the compound [C-1], and the amount is 2 times.
  • the amount is preferably in the range of about 200 times.
  • the acid that can be used in this elimination reaction is appropriately diluted with a suitable solvent to a concentration in the range of, for example, 5% to 80%, and is in the range of 5% to 50%. It is preferable to dilute to the concentration of.
  • the solvent for dissolving the acid that can be used in this desorption reaction is not particularly limited, and is, for example, chloroform, dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,2-trichloroethane, 1 , 2-Dichloroethylene, 2,2,2-trifluoroethanol or a mixed solvent thereof. Further, in this step, a scavenger may be used if necessary.
  • Examples of the "scavenger” that can be used in this elimination reaction include the same as described above.
  • the amount of the scavenger that can be used in this elimination reaction for example, the amount in the range of 1 to 100 times the molar ratio is appropriate with respect to 1 mol of the compound [C-1], and the amount is 1 time. The amount is preferably in the range of about 50 times.
  • a pump for supplying a liquid usually used in this field specifically, for example, a syringe pump, a plunger pump, a diaphragm pump, etc.
  • Gear pumps can be mentioned.
  • Examples of the flow reactor that can be used in this elimination reaction include in-line mixers such as a microreactor and a static mixer. As a means for guiding from the supply flow path to the reaction flow path that can be used in this elimination reaction, for example, a multi-stage collision type micromixer can be mentioned.
  • Examples of the materials of the supply channel and the reaction channel that can be used in this desorption reaction include fluororesins such as perfluoroalkoxy alkane (PFA), vinyl chloride resins, polyamide resins, and aromatic polyetherketones.
  • Examples include synthetic resin tubes selected from the group consisting of resins, or metal tubes selected from the group consisting of stainless steel, copper and its alloys and titanium and its alloys.
  • the inner diameters of the supply flow path and the reaction flow path that can be used in this elimination reaction may be appropriately selected from, for example, a size within the range of 0.1 mm to 1.0 mm, and for example, 0.2 mm to 1 It is preferable to select from a size within the range of 0.0 mm.
  • the compound [A-1] and the compound [B-1] are condensed by using a reaction accelerator in the method for producing the compound [E-1].
  • a reaction accelerator in the method for producing the compound [E-1]
  • the compound was carried out elimination reaction for Q 1 of [A-1-1]
  • compounds [A It can be carried out as this continuous reaction, which comprises subjecting -1] and compound [B-1] to a condensation reaction to form compound [C-1].
  • the solvent that can be used in this continuous reaction is not particularly limited as long as it is a solvent usually used in the art, and the solvent may be used alone, or two or more solvents may be mixed and used. You may. Examples thereof include aromatic solvents such as benzene, toluene, xylene and mesitylene; ester solvents such as ethyl acetate and isopropyl acetate; aliphatic solvents such as hexane, pentane, heptane, octane, nonane and cyclohexane. Two or more kinds of these solvents may be mixed and used. Examples of the solvent that can be used in this continuous reaction include polar solvents and halogen-based solvents.
  • the solvent that can be used in this continuous reaction is not particularly limited, but for example, a mixed solvent of a polar solvent and a halogen-based solvent can be used.
  • the lower limit of the ratio of the polar solvent in the mixed solvent of the polar solvent and the halogen-based solvent is 1.0% by weight, preferably 2.0% by weight, more preferably 3.0% by weight, still more preferably 5.0. % By weight.
  • the upper limit thereof is 90% by weight, preferably 75% by weight, more preferably 50% by weight, still more preferably 40% by weight, and particularly preferably 30% by weight.
  • the upper limit and the lower limit thereof can be used in combination as appropriate, and the ratio of the polar solvent in the mixed solvent of the polar solvent and the halogen-based solvent is suitable, for example, in the range of 1% to 50%.
  • the range of 1% to 40% is preferable, and the range of 1% to 30% is particularly preferable.
  • Equation [A-1-1] [During the ceremony, BP is a nucleobase that may be protected; Q 1 represents a leaving group capable under acidic conditions; W is an oxygen atom or a sulfur atom; X is a di (C1-6 alkyl) amino or general formulas [2-1] to [2-8]: [In the formula, * represents the connection position with P] Selected from the substituents represented by, preferably di (C1-6 alkyl) amino, more preferably dimethylamino; G is the general formula [7]: (During the ceremony, * Represents the connection position with T; Z is a general formula [8A] to [8D], [8E], [8G], [8H], [8J], [8K], [8N]: (During the ceremony, * Represents the connection position with L; k represents an integer from 0 to 5; R 8a represents a hydrogen atom or C 1-6 alkyl; R 8b represents a long
  • R 8d is the same or different, each of which is a hydrogen atom, a halogen, a long-chain alkyl optionally substituted with 1 to 13 halogens, or a long-chain alkyl optionally substituted with 1 to 13 halogens.
  • R 8e is (1) Long chain alkyl, Represents (2) long-chain alkyl-carbonyl or (3) benzoyl substituted with 1-5 long-chain alkyloxy and / or long-chain alkenyloxy; and
  • R 8f (1) Long chain alkyl, Represents (2) long-chain alkyl-carbonyl or (3) long-chain alkenyl-carbonyl.
  • L is the general formula [10]: (During the ceremony, * Represents the connection position with Z; ** represents the position of bond with the oxygen atom; and L 1 represents the optionally substituted C 2-10 alkylene or the optionally substituted C 6-10 arylene. ) It is a substituent represented by. ) It is a substituent represented by; T is a single bond or the following general formula [11]: (During the ceremony, X and W are synonymous with the above; * Represents the connection position with O; ** represents the position of connection with G; and q represents an integer from 0 to 10. ) It is a substituent represented by n is 1 to 25.
  • Equation [A-1] [In the formula, BP , W, X, G, T, and n are synonymous with the above. ]
  • Equation [B-1] [In the formula, BP , Q 1 , W, X, G, and T are synonymous with the above; D is a halogen, p is an integer from 1 to 10]
  • Equation [C-1] [In the formula, n, p, BP , Q 1 , W, X, G, and T are synonymous with the above. ] Examples thereof include a method for preparing the compound of.
  • Equation [A-1-1] For example, in the presence of a reaction accelerator, Equation [A-1-1]: [During the ceremony, Q 1 is trityl, monomethoxytrityl, or dimethoxytrityl, and n, BP , W, X, G, and T are synonymous with the above. ] From the compound of In the presence of trifluoroacetic acid and 2,2,2-trifluoroethanol, optionally triisopropylsilane or ethanol, It can include removing Q1. This continuous reaction can be carried out in a distribution reactor.
  • a solution containing the compound of the general formula [A-1-1] and a solution containing an acid were supplied to the flow reactor to remove Q1 to obtain a compound of the formula [A-1], and then A solution containing the compound of the general formula [A-1] and a solution containing the compound of the general formula [B-1] are supplied to the next flow reactor, and the compound of the general formula [C-1] is supplied.
  • There is a method of preparing In some cases, a distribution reactor that supplies a solution containing a compound of formula [A-1] and a solution containing a scavenger, or a surplus compound of formula [B-1] and a compound of formula [C-1] are contained.
  • a flow reactor can be used that supplies the solution to be used and a solution containing at least one selected from the group consisting of morpholine, 1-methylpiperazine, and N-ethylmorpholine.
  • n, p, BP , G, Q 1 , R 4a , T, W and X are synonymous with the above.
  • Step 1 In the production compound [C-2] of the compound [D-2] , when G is a substituent [7] and Z is a solid phase carrier, the oxidation reaction of the phosphorus atom is carried out by a method known per se. It can be carried out according to (Curent Protocols in Nuclic Acid Chemistry).
  • Examples of the oxidizing agent that can be used in this step include a commercially available oxidizing solution for nucleic acid synthesis [oxidizing solution-2, 0.1 mol / L iodine / 78% tetrahydrofuran / 20% pyridine / 2% water, Fujifilm Wako Jun.
  • oxidizing agent examples include commercially available sulfide reagents for nucleic acid synthesis [3- ⁇ (N, N-dimethylaminomethylidene) amino ⁇ ) -3H-1,2,4-dithiazole-5. -Thion (DDTT), manufactured by Glen Research Co., Ltd .; 5-phenyl-3H-1,2,4-dithiazole-3-one for nucleic acid synthesis, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.].
  • DDTT sulfide reagents for nucleic acid synthesis
  • DDTT DDTT
  • 5-phenyl-3H-1,2,4-dithiazole-3-one for nucleic acid synthesis, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.
  • G is substituted with (1) silicon substituent, (2) long chain alkyl-carbonyl, (3) 1-5 long chain alkyloxy and / or long chain alkenyloxy.
  • substituent [7] except when Z is a solid phase carrier, the oxidation reaction of the phosphorus atom can be carried out according to a method known per se (excluding the case where Z is a solid phase carrier). See, for example, Nucleic Acids Research, Vol. 21, No. 5, 1231-1217 (1993)).
  • Examples of the oxidizing agent that can be used in this step include (+)-camforylsulfonyl oxaziridine (CSO) (+)-(8,8-dichlorocamphorylsulfonyl) -oxadylidine (DCSO) and methyl ethyl ketone peroxide. Oxides such as tert-butyl hydroperoxide (TBHP) can be mentioned.
  • Step 2 Production of compound [E-2] By reacting compound [D-2] with an acid, it is replaced with the oxygen atom at the 5'position of the nucleoside unit on the 5'terminal side of compound [D-2]. Q 1 can be detached.
  • Compounds from [D-2] produced by desorbing a to Q 1 in the molecule, the compound represented by the general formula [E-2] (hereinafter. Referred to as "Compound [E-2]" can do.
  • G is a substituent [7] and Z is a solid phase carrier in compound [D-2]
  • compound [D-2] is packed in an appropriate column to elute a solution containing an acid.
  • it can be carried out by shaking or stirring a solution containing compound [D-2] and an acid in a reaction vessel with a filter.
  • Elimination reaction for Q 1 in the molecule of the compound [D-2] can be carried out according to methods known per se (see, for example, Current Protocols in Nucleic Acid Chemistry.) .
  • Examples of the acid that can be used in this step include a commercially available deblocking solution for nucleic acid synthesis [for example, deblocking solution-1,3 w / v% trichloroacetic acid / dichloromethane solution (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.). Deblocking Mix 3% dichloroacetic acid / dichloromethane solution (manufactured by Glen Research Co., Ltd.)] can be mentioned.
  • deblocking solution-1,3 w / v% trichloroacetic acid / dichloromethane solution manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.
  • Deblocking Mix 3% dichloroacetic acid / dichloromethane solution manufactured by Glen Research Co., Ltd.
  • G is substituted with (1) silicon substituent, (2) long chain alkyl-carbonyl, (3) 1-5 long chain alkyloxy and / or long chain alkenyloxy. If it is a benzoyl or (4) substituent [7] (except when Z is a solid phase carrier), for example, (1) compound [D-2] is placed in a suitable reaction vessel. [D-2] and the acid are stirred in an appropriate reaction solvent, or (2) the solution containing the compound [D-2] and the solution containing the acid are independently distributed through the supply flow path. It can be carried out by supplying the solution to the reactor or the reaction channel and mixing the solutions in the flow reactor or the like.
  • Elimination reaction for Q 1 in the molecule of the compound [D-2] can be carried out according to methods known per se (e.g., Nucleic Acids Research, Vol.21, No.5,1213-1217 (1993 ).).
  • Examples of the acid that can be used in this step include dichloroacetic acid and trichloroacetic acid.
  • the "compound, [C-1] the desorption process for Q 1 in the molecule of” the same as the “acid” described in desorption for Q 1 in the molecule of the “compound [C-2]
  • the compound [C-1] can be prepared by treating it with the same "acid” as described in "Step 2 Production of the compound [E-2]" of "Method” or by treating with a solution obtained by diluting hydrochloric acid or acetic acid with an appropriate solvent.
  • a group that can be eliminated under acidic conditions which is substituted with a protective group for the amino group at the 3'position of the nucleoside on the 3'end side and a hydroxyl group at the 5'position of the nucleoside on the 5'end side of the compound [D-2]. Can be removed.
  • the group that can be eliminated under acidic conditions which is substituted with the hydroxyl group at the 5'position of the nucleoside on the 5'terminal side of compound [D-2] after removing the protective group of the nucleic acid base portion.
  • a mixed solution of, for example, 20 mM triethylamine / acetate buffer and acetonitrile can be used as the elution solvent.
  • a mixed solution of 1 M saline solution and 10 mM sodium hydroxide aqueous solution or 0.3 M saline solution of 50 mM phosphate buffer is used. Can be used.
  • the compound [D-2] or the compound from which all the protective groups contained in the compound [E-2] have been removed can be obtained from the above reaction mixture by conventional separation and purification means, for example, extraction, concentration, neutralization, filtration, centrifugation, Recrystallization, C 8 to C 18 reverse phase column chromatography, C 8 to C 18 reverse phase cartridge column, cation exchange column chromatography, anion exchange column chromatography, gel filtration column chromatography, high speed liquid chromatography, It can be isolated and purified by using means such as dialysis and marginal filtration alone or in combination.
  • separation and purification means for example, extraction, concentration, neutralization, filtration, centrifugation, Recrystallization, C 8 to C 18 reverse phase column chromatography, C 8 to C 18 reverse phase cartridge column, cation exchange column chromatography, anion exchange column chromatography, gel filtration column chromatography, high speed liquid chromatography, It can be isolated and purified by using means such as dialysis and marginal filtration alone or in combination.
  • the “eluting solvent” examples include a single solvent of acetonitrile, methanol, ethanol, isopropyl alcohol or water, or a mixed solvent of any ratio of these solvents.
  • sodium phosphate, potassium phosphate, sodium chloride, potassium chloride, ammonium acetate, triethylammonium acetate, sodium acetate, potassium acetate, tris-hydrochloric acid or ethylenediamine tetraacetic acid are added as additives at a concentration of 1 mM to 2 M.
  • the pH of the solution can also be adjusted in the range of 1-9.
  • Step 1 Production of a compound represented by the above general formula [A-1a-Q1] (hereinafter, referred to as “compound [A-1a-Q1]”)
  • a compound represented by the above general formula [21] hereinafter, ""
  • a compound represented by the above general formula [20A] hereinafter referred to as “Compound [20A]”
  • a silicon substituent is attached to the hydroxyl group at the 5'end of the compound [21].
  • This silicon substituent introduction reaction can be carried out according to a method known per se.
  • Step 2 Production of Compound [A-1a]
  • Compound [A-1a] can be produced by treating compound [A-1a-Q1] with an acid.
  • the "acid” that can be used in this step include the same "acid” described in the above-mentioned “Method for desorbing Q 1 in the molecule of compound [C-1]".
  • the amount of the acid that can be used in this step for example, the amount in the range of 1 to 500 times the molar ratio is appropriate with respect to 1 mol of the compound [A-1a-Q1], and the amount is 2 times. The amount is preferably in the range of about 200 times.
  • the acid that can be used in this step may be diluted with an appropriate solvent and is not particularly limited.
  • chloroform for example, chloroform, dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,2-trichloroethane, 1 , 2-Dichloroethylene, 2,2,2-trifluoroethanol or a mixed solvent thereof.
  • a scavenger may be used if necessary.
  • “Scavenger” which can be used in this step may include the same as the “scavenger", as described in the "compound desorption method for Q 1 in the molecule [C-1]".
  • the amount of the scavenger that can be used in this step for example, the amount in the range of 1 to 100 times the molar ratio is appropriate with respect to 1 mol of the compound [A-1a-Q1], and the amount is 1 time. The amount is preferably in the range of about 50 times.
  • the compound represented by the general formula [A-1b] (hereinafter, referred to as “compound [A-1b]”) has a G of (1) long-chain alkyl-carbonyl and (2) 1 to 5 G.
  • Compound [A-1] which is a benzoyl or (3) substituent [7] substituted with a long-chain alkyloxy and / or a long-chain alkenyloxy, and T is a single bond.
  • An example of a method for producing the compound [A-1b] will be described below.
  • Step 1 Production of a compound represented by the above general formula [A-1b-Q1] (hereinafter, referred to as "compound [A-1b-Q1]”)
  • the compound [21] is represented by the above general formula [20B].
  • the compound [A-1b-Q1] can be produced by condensing with a compound (hereinafter, referred to as "compound [20B]”).
  • the condensation reaction can be carried out according to a method known per se.
  • the compound [20B] in which Y is a hydroxyl group is used in this step, it can be carried out in the range of ⁇ 20 ° C. to 100 ° C. using a condensing agent in the presence or absence of a base.
  • the compound [20B] in which Y is halogen when used in this step, it can be carried out in the range of ⁇ 20 ° C. to 100 ° C. in the presence of a base.
  • the condensing agent that can be used in this step include 1,1'-oxalyldiimidazole, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, diethyl cyanophosphonate, and O- (benzotriazole).
  • bases that can be used in this step include organic bases of triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, pyridine, and 1,8-diazabicyclo [5,4,0] -7-undecene.
  • the solvent that can be used in this step is not particularly limited, but is, for example, ethers such as THF, 1,4-dioxane and diethyl ether, amides such as dimethylformamide and dimethylacetamide, and nitriles such as acetonitrile and propionitrile.
  • Examples include hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chloroform and methylene chloride, and mixed solvents thereof.
  • an additive can be used if necessary.
  • Examples of the additive that can be used in this step include 4-dimethylaminopyridine, 1-hydroxybenzotriazole, and 1-hydroxy-7-azabenzotriazole.
  • the reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually in the range of 10 minutes to 24 hours.
  • the appropriate amount of the compound [21] and the condensing agent to be used is, for example, in the range of 1 to 1.5 times the mole with respect to 1 mol of the compound [20B].
  • the amount of the base used is, for example, in the range of 1 equivalent to 10 equivalents, preferably in the range of 1 equivalent to 4 equivalents, relative to compound [20B].
  • Step 2 Production of Compound [A-1b]
  • Compound [A-1b] can be produced by treating compound [A-1b-Q1] with an acid.
  • Examples of the “acid” that can be used in this step include the same “acid” described in the above-mentioned “Method for desorbing Q 1 in the molecule of compound [C-1]".
  • the amount of the acid that can be used in this step for example, the amount in the range of 1 to 500 times the molar ratio is appropriate with respect to 1 mol of the compound [A-1b-Q1], and the amount is 2 times. The amount is preferably in the range of about 200 times.
  • the acid that can be used in this step may be diluted with an appropriate solvent and is not particularly limited.
  • chloroform for example, chloroform, dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,2-trichloroethane, 1 , 2-Dichloroethylene, 2,2,2-trifluoroethanol or a mixed solvent thereof.
  • a scavenger may be used if necessary.
  • “Scavenger” which can be used in this step may include the same as the “scavenger", as described in the "compound desorption method for Q 1 in the molecule [C-1]".
  • the amount of the scavenger that can be used in this step for example, the amount in the range of 1 to 100 times the molar ratio is appropriate with respect to 1 mol of the compound [A-1b-Q1], and the amount is 1 time. The amount is preferably in the range of about 50 times.
  • the compound represented by the above general formula [A-1c] (hereinafter, referred to as “compound [A-1c]”) has a G of (1) long-chain alkyl-carbonyl and (2) 1 to 5 G.
  • Compound [A-1] which is a benzoyl or (3) substituent [7] substituted with a long-chain alkyloxy and / or a long-chain alkenyloxy, wherein T is a substituent [11].
  • An example of a method for producing the compound [A-1c] will be described below.
  • Step 1 Production of a compound represented by the above general formula [23] (hereinafter, referred to as “Compound [23]”)
  • a compound represented by the above general formula [20C] (hereinafter, referred to as “Compound [20C]”).
  • the compound [23] can be produced by condensing the compound represented by the above general formula [22] (hereinafter, referred to as “compound [22]”).
  • compound [20C] is a carboxylic acid compound
  • a reactive derivative thereof can also be used in this step.
  • Examples of the reactive derivative of the compound [20C] include those usually used in an ester condensation formation reaction such as an acid halide (for example, acid chloride and acid bromide).
  • Compound [22] can be produced according to a known method (see, for example, US Patent Application Publication No. 2014/0330006A1). Also, according to a known method (see, for example, International Publication No. 2014/077292A1), a benzoyl in which G is substituted with 1 to 5 long-chain alkyloxy and / or long-chain alkenyloxy. A compound [20C] can be produced.
  • Step 2 Production of compound represented by the above general formula [24] (hereinafter referred to as “compound [24]”)
  • Compound [24] is prepared by removing the trityl group in the molecule with an acid. Can be manufactured.
  • Step 3 Production of a compound represented by the above general formula [A-1c-Q1] (hereinafter, referred to as "compound [A-1c-Q1]”) Represented by the compound [24] and the above general formula [25].
  • Compound [A-1c-Q1] can be produced by condensing a compound (hereinafter referred to as “compound [25]”). The condensation reaction and deprotection reaction can be carried out according to a method known per se.
  • Step 4 Production of Compound [A-1c]
  • Compound [A-1c] can be produced by treating compound [A-1c-Q1] with an acid.
  • the "acid” that can be used in this step include the same "acid” described in the above-mentioned “Method for desorbing Q 1 in the molecule of compound [C-1]".
  • the amount of the acid that can be used in this step for example, the amount in the range of 1 to 500 times the molar ratio is appropriate with respect to 1 mol of the compound [A-1c-Q1], and the amount is 2 times. The amount is preferably in the range of about 200 times.
  • the acid that can be used in this step may be diluted with an appropriate solvent and is not particularly limited.
  • chloroform for example, chloroform, dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,2-trichloroethane, 1 , 2-Dichloroethylene, 2,2,2-trifluoroethanol or a mixed solvent thereof.
  • a scavenger may be used if necessary.
  • “Scavenger” which can be used in this step may include the same as the “scavenger", as described in the "compound desorption method for Q 1 in the molecule [C-1]".
  • the amount of the scavenger that can be used in this step for example, the amount in the range of 1 to 100 times the molar ratio is appropriate with respect to 1 mol of the compound [A-1c-Q1], and the amount is 1 time. The amount is preferably in the range of about 50 times.
  • compound [A-1d] The compound represented by the general formula [A-1d] (hereinafter, referred to as “compound [A-1d]”) has a compound [A] in which G is a substituent [7] and T is a single bond. -1].
  • An example of a method for producing the compound [A-1d] will be described below.
  • Step 1 Production of a compound represented by the above general formula [A-1d-Q1] (hereinafter, referred to as "Compound [A-1d-Q1]”)
  • a compound represented by the above general formula [20D] (hereinafter, "" Compound [20D] ”) is referred to as a compound represented by the above general formula [21] (hereinafter, compound [21]).
  • the compound [A-1d-Q1] can be produced.
  • the condensation reaction can be carried out according to a method known per se.
  • compound [20D] is a carboxylic acid compound, a reactive derivative thereof can also be used in this step.
  • Examples of the reactive derivative of the compound [20D] include those usually used in an ester condensation formation reaction such as an acid halide (for example, acid chloride and acid bromide).
  • an acid halide for example, acid chloride and acid bromide
  • the reaction can be carried out in the range of ⁇ 20 ° C. to 100 ° C. using a condensing agent in the presence or absence of a base.
  • the condensing agent that can be used in this step include 1,1'-oxalyldiimidazole, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, diethyl cyanophosphonate, and O- (benzotriazole).
  • bases that can be used in this step include organic bases such as triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, pyridine, and 1,8-diazabicyclo [5,4,0] -7-undecene.
  • the solvent that can be used in this step is not particularly limited, but is, for example, ethers such as THF, 1,4-dioxane and diethyl ether, amides such as dimethylformamide and dimethylacetamide, and nitriles such as acetonitrile and propionitrile.
  • additives can be used if necessary. Examples of the additive that can be used in this step include 4-dimethylaminopyridine, 1-hydroxybenzotriazole, and 1-hydroxy-7-azabenzotriazole.
  • the reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually in the range of 10 minutes to 24 hours.
  • the appropriate amount of the compound [21] and the condensing agent to be used is, for example, in the range of 1-fold to 1.5-fold mol with respect to 1 mol of the compound [20D].
  • the amount of the base used is, for example, in the range of 1 equivalent to 10 equivalents, preferably in the range of 1 equivalent to 4 equivalents, relative to compound [20D].
  • Step 2 Production of compound [A-1d]
  • Compound [A-1d] can be produced by acid-treating compound [A-1d-Q1].
  • Examples of the "acid” that can be used in this step include the same “acid” described in the above-mentioned “Method for desorbing Q 1 in the molecule of compound [C-1]".
  • the amount of the acid that can be used in this step for example, the amount in the range of 1 to 500 times the molar ratio is appropriate with respect to 1 mol of the compound [A-1d-Q1], and the amount is 2 times.
  • the amount is preferably in the range of about 200 times.
  • the acid that can be used in this step may be diluted with an appropriate solvent and is not particularly limited.
  • scavenger which can be used in this step may include the same as the “scavenger”, as described in the "compound desorption method for Q 1 in the molecule [C-1]".
  • the amount of the scavenger that can be used in this step for example, the amount in the range of 1 to 100 times the molar ratio is appropriate with respect to 1 mol of the compound [A-1d-Q1], and the amount is 1 time.
  • the amount is preferably in the range of about 50 times.
  • compound [20D] can be produced according to the production method described below. [During the ceremony, L 1 and Z are defined as above; R represents C 1-6 alkyl. ]
  • Step 1 Production of a compound represented by the above general formula [28] (hereinafter, referred to as “Compound [28]”)
  • a compound represented by the above general formula [26] (hereinafter, referred to as “Compound [26]”).
  • Compound [27] can be produced by condensing compound [28] with a compound represented by the above general formula [27] (hereinafter, referred to as “compound [27]”).
  • the condensation reaction can be carried out according to a method known per se.
  • the same reagents as in the above-mentioned "Production of compound [A-1b-Q1]" can be used.
  • Step 2 Production of compound [20D]
  • Compound [20D] can be produced by ester-hydrolyzing compound [28].
  • the ester hydrolysis reaction can be carried out according to a method known per se.
  • the solvent that can be used in this step is not particularly limited, but is, for example, water, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, 1,4-dioxane and diethyl ether, and nitriles such as acetonitrile and propionitrile.
  • Hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chloroform and methylene chloride, or a mixed solvent thereof. This step is carried out in the range of 20 ° C.
  • reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually in the range of 10 minutes to 24 hours.
  • compound [26] can be produced, for example, according to the methods described in (a) to (j) below.
  • A For example, by using a commercially available primary amine compound or by amifying a commercially available alkyl halide, Z is a substituent [8A] and R 8a.
  • Compound [26] can be prepared in which is a hydrogen atom and R 8b is a long-chain alkyl.
  • B For example, by alkylating a commercially available primary amine compound, Z is a substituent [8A] or a substituent [8B] and R 8a is a C 1-6 alkyl.
  • Compound [26] can be prepared in which R 8b is the same or different, respectively, and is a long-chain alkyl.
  • the alkylation reaction can be carried out according to a method known per se.
  • Z is a substituent according to a known method (see, for example, Cancer Res., 2008 Nov 1; 68 (21): 8843-8851, Chem. Sci., 2016, 7, 2308-2321).
  • Compound [26], which is [8C] can be produced.
  • D For example, a compound in which methyl phthalate is condensed with 1- (tert-butoxycarbonyl) piperazine, then the ester moiety is hydrolyzed with an alkali such as sodium hydroxide, and Z is a substituent [8A].
  • the compound [26] in which Z is a substituent [8D] can be produced by removing the tert-butoxycarbonyl group with an acid such as trifluoroacetic acid.
  • the condensation reaction, the hydrolysis reaction using an alkali, and the deprotection reaction of the tert-butoxycarbonyl group using an acid can be carried out according to a method known per se.
  • E For example, by alkylating one hydroxyl group of ethane-1,2-diol with an alkyl halide, Z is a substituent [8E] and R 8e is a long-chain alkyl group. Certain compounds [26] can be produced.
  • compound [26] in which one hydroxyl group of ethane-1,2-diol is long-chain alkyl-carbonylated so that Z is a substituent [8E] and R 8e is a long-chain alkyl-carbonyl. ] can be manufactured.
  • the compound used for long-chain alkyl-carbonylation for example, the corresponding carboxylic acid compound or a reactive derivative thereof can be used.
  • the reactive derivative include those usually used in an ester condensation formation reaction, such as an acid halide (for example, acid chloride and acid bromide).
  • Z is a substituent [8E] and R 8e is 1 to 5 long-chain alkyl.
  • Compound [26] which is a benzoyl group substituted with oxy and / or long chain alkenyloxy, can be prepared.
  • F For example, 2-amino-ethanol is used instead of ethane-1,2-diol, and Z is substituted according to the same method as that for producing the compound (18) in which Z is a substituent [8E].
  • the compound [26] which is a group [8F] can be produced.
  • (G) For example, 9-fluorenylmethyloxycarbonyl-phenylalanine is condensed with compound [26] in which Z is a substituent [8A], and then the 9-fluorenylmethyloxycarbonyl group is eliminated with piperidine. Thereby, the compound [26] in which Z is a substituent [8G] can be produced.
  • the condensation reaction and the deprotection reaction of the 9-fluorenylmethyloxycarbonyl group can be carried out according to a method known per se.
  • (H) For example, using 1- (tert-butoxycarbonyl) piperazine instead of ethane-1,2-diol, according to the same method as the method for producing the compound [26] in which Z is the substituent [8E].
  • a compound [21] can be produced.
  • n, BP , D, Q 1 , X and W are synonymous with the above.
  • Ac represents acetyl.
  • Step 1 In the presence of a production base for the compound represented by the general formula [30] (hereinafter referred to as “compound [30]”), the compound represented by the general formula [29] (for example, International Publication No. 2). 91/09033A1) can be acetylated with acetic anhydride to produce compound [30].
  • the acetylation reaction can be carried out according to a method known per se.
  • Step 2 Production of the compound represented by the general formula [31] (hereinafter, referred to as “compound [31]”)
  • the compound [31] can be produced by acid-treating the compound [30]. Elimination reaction of Q 1 is can be performed according to methods known per se.
  • Step 3 The production compound [31] of the compound represented by the general formula [33] (hereinafter, referred to as “compound [33]”) is replaced with the compound represented by the general formula [32] (hereinafter, “Compound [32]”). ] ”),
  • the compound [33] can be produced.
  • the condensation reaction can be carried out according to a method known per se (see, for example, International Publication No. 91/09033A1).
  • Compound [32] can be produced, for example, according to a known method (see, for example, International Publication No. 91/09033A1).
  • Step 4 Production of Compound [21]
  • Compound [21] can be produced by selectively removing the acetyl group of compound [33] using, for example, an alkali metal alkoxide such as sodium methoxide. ..
  • the elimination reaction of acetyl can be carried out according to a method known per se (see, for example, Tetrahedron Letters, Vol. 50, 1751-1753 (2009)).
  • Step 1 Production of a compound represented by the above general formula [A-2a-Q1] (hereinafter referred to as “compound [A-2a-Q1]”)
  • a compound represented by the above general formula [34] (hereinafter referred to as “”
  • Compound [34] ” is referred to as compound [20A]
  • a silicon substituent is introduced into the hydroxyl group at the 3'position of the nucleoside unit on the 3'-terminal side of compound [34] to introduce compound [A-2a].
  • -Q1] can be manufactured.
  • This silicon substituent introduction reaction can be carried out according to a method known per se.
  • Step 2 Production of compound [A-2a]
  • Compound [A-2a] can be produced by acid-treating compound [A-2a-Q1].
  • “Acid” which can be used in this step may include the same as the “acid” described in the "elimination reaction for Q 1 in the molecule of the compound [D-2]".
  • the amount of the acid that can be used in this step for example, the amount in the range of 1 to 500 times the molar ratio is appropriate with respect to 1 mol of the compound [A-2a-Q1], and the amount is 2 times. The amount is preferably in the range of about 200 times.
  • the acid that can be used in this step may be diluted with an appropriate solvent and is not particularly limited.
  • chloroform for example, chloroform, dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,2-trichloroethane, 1 , 2-Dichloroethylene, 2,2,2-trifluoroethanol or a mixed solvent thereof.
  • a scavenger may be used if necessary.
  • "Scavenger” which can be used in this step may include the same as the “scavenger", as described in the "elimination reaction for Q 1 in the molecule of the compound [D-2]".
  • the amount of the scavenger that can be used in this step for example, the amount in the range of 1 to 100 times the molar ratio is appropriate with respect to 1 mol of the compound [A-2a-Q1], and the amount is 1 time. The amount is preferably in the range of about 50 times.
  • the compound represented by the general formula [A-2b] (hereinafter, referred to as “compound [A-2b]”) has a G of (1) long-chain alkyl-carbonyl and (2) 1 to 5 G.
  • Step 1 Production of a compound represented by the above general formula [A-2b-Q1] (hereinafter, referred to as “Compound [A-2b-Q1]”) By condensing the compound [20B] with the compound [34].
  • Compound [A-2b-Q1] can be produced.
  • the condensation reaction can be carried out according to a method known per se.
  • the compound [20B] in which Y is a hydroxyl group it can be carried out in the range of ⁇ 20 ° C. to 100 ° C. using a condensing agent in the presence or absence of a base.
  • the compound [20B] in which Y is halogen is used in this step, it can be carried out in the range of ⁇ 20 ° C.
  • condensing agent examples include 1,1'-oxalyldiimidazole, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, diethyl cyanophosphonate, and O- (benzotriazole).
  • bases that can be used in this step include organic bases of triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, pyridine, and 1,8-diazabicyclo [5,4,0] -7-undecene.
  • the solvent that can be used in this step is not particularly limited, but is, for example, ethers such as THF, 1,4-dioxane and diethyl ether, amides such as dimethylformamide and dimethylacetamide, and nitriles such as acetonitrile and propionitrile.
  • Examples include hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chloroform and methylene chloride, and mixed solvents thereof. Further, when the compound [20B] in which Y is a hydroxyl group is used in this step, an additive can be used if necessary. Examples of additives that can be used include 4-dimethylaminopyridine, 1-hydroxybenzotriazole, and 1-hydroxy-7-azabenzotriazole.
  • the reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually in the range of 10 minutes to 24 hours.
  • the appropriate amount of the compound [20B] and the condensing agent to be used is, for example, in the range of 1-fold to 1.5-fold mol with respect to 1 mol of the compound [34].
  • the amount of the base used is, for example, in the range of 1 equivalent to 10 equivalents, preferably in the range of 1 equivalent to 4 equivalents, relative to compound [34].
  • Step 2 Production of compound [A-2b]
  • Compound [A-2b] can be produced by acid-treating compound [A-2b-Q1].
  • “Acid” which can be used in this step may include the same as the “acid” described in the "elimination reaction for Q 1 in the molecule of the compound [D-2]".
  • the amount of the acid that can be used in this step for example, the amount in the range of 1 to 500 times the molar ratio is appropriate with respect to 1 mol of the compound [A-2b-Q1], and the amount is 2 times. The amount is preferably in the range of about 200 times.
  • the acid that can be used in this step may be diluted with an appropriate solvent and is not particularly limited.
  • chloroform for example, chloroform, dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,2-trichloroethane, 1 , 2-Dichloroethylene, 2,2,2-trifluoroethanol or a mixed solvent thereof.
  • a scavenger may be used if necessary.
  • "Scavenger” which can be used in this step may include the same as the “scavenger", as described in the "elimination reaction for Q 1 in the molecule of the compound [D-2]".
  • the amount of the scavenger that can be used in this step for example, the amount in the range of 1 to 100 times the molar ratio is appropriate with respect to 1 mol of the compound [A-2b-Q1], and the amount is 1 time. The amount is preferably in the range of about 50 times.
  • the compound represented by the general formula [A-2c] (hereinafter, referred to as “compound [A-2c]”) has a G of (1) long-chain alkyl-carbonyl and (2) 1 to 5 G.
  • Compound [A-2] which is a benzoyl or (3) substituent [7] substituted with a long-chain alkyloxy and / or a long-chain alkenyloxy, and T is a substituent [11].
  • Step 1 Production of the compound represented by the general formula [36] (hereinafter, referred to as “compound [36]”)
  • the compound [36] can be produced.
  • the condensation reaction and deprotection reaction can be carried out according to a method known per se.
  • Step 2 Production of a compound represented by the above general formula [A-2c-Q1] (hereinafter referred to as "compound [A-2c-Q1]”)
  • compound [A-2c-Q1] By allowing an oxidizing agent to act on the compound [36], the compound [ A-2c-Q1] can be produced.
  • the oxidation reaction can be carried out according to a method known per se.
  • the "oxidizing agent” include iodine and tert-butyl hydroperoxide.
  • the oxidizing agent that can be used in this step can be diluted with an appropriate solvent so as to have a concentration of 0.05 to 2M.
  • the solvent is not particularly limited, and examples thereof include pyridine, tetrahydrofuran, water, and a mixed solvent thereof.
  • iodine / water / pyridine-tetrahydrofuran, iodine / pyridine-acetic acid, or a peroxide agent can be used.
  • the reaction temperature is preferably 20 ° C to 50 ° C.
  • the reaction time varies depending on the type of oxidizing agent used and the reaction temperature, but is usually 1 to 30 minutes.
  • the amount of the oxidizing agent used is preferably 1 to 100 times the molar amount, more preferably 10 to 50 times the molar amount of the compound [36].
  • Step 3 Production of compound [A-2c]
  • Compound [A-2c] can be produced by acid-treating compound [A-2c-Q1].
  • “Acid” which can be used in this step may include the same as the “acid” described in the "elimination reaction for Q 1 in the molecule of the compound [D-2]".
  • the amount of the acid that can be used in this step for example, the amount in the range of 1 to 500 times the molar ratio is appropriate with respect to 1 mol of the compound [A-2c-Q1], and the amount is 2 times. The amount is preferably in the range of about 200 times.
  • the acid that can be used in this step may be diluted with an appropriate solvent and is not particularly limited.
  • scavenger which can be used in this step may include the same as the “scavenger", as described in the "elimination reaction for Q 1 in the molecule of the compound [D-2]".
  • the amount of the scavenger that can be used in this step for example, the amount in the range of 1 to 100 times the molar ratio is appropriate with respect to 1 mol of the compound [A-2c-Q1], and the amount is 1 time.
  • the amount is preferably in the range of about 50 times.
  • condensing agent in the presence or absence of a base.
  • condensing agent examples include 1,1'-oxalyldiimidazole, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, diethyl cyanophosphonate, and O- (benzotriazole).
  • bases that can be used in this step include organic bases of triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, pyridine, and 1,8-diazabicyclo [5,4,0] -7-undecene.
  • the solvent that can be used in this step is not particularly limited, but is, for example, ethers such as THF, 1,4-dioxane and diethyl ether, amides such as dimethylformamide and dimethylacetamide, and nitriles such as acetonitrile and propionitrile.
  • additives can be used if necessary. Examples of the additive that can be used in this step include 4-dimethylaminopyridine, 1-hydroxybenzotriazole, and 1-hydroxy-7-azabenzotriazole.
  • the reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually in the range of 10 minutes to 24 hours.
  • the appropriate amount of the compound [20D] and the condensing agent to be used is, for example, in the range of 1-fold to 1.5-fold mol with respect to 1 mol of the compound [34].
  • the amount of the base used is, for example, in the range of 1 equivalent to 10 equivalents, preferably in the range of 1 equivalent to 4 equivalents, relative to compound [34].
  • Step 2 The compound [A-2d] can be produced by treating the compound [A-2d-Q1] with an acid.
  • “Acid” which can be used in this step may include the same as the “acid” described in the "elimination reaction for Q 1 in the molecule of the compound [D-2]".
  • the amount of the acid that can be used in this step for example, the amount in the range of 1 to 500 times the molar ratio is appropriate with respect to 1 mol of the compound [A-2d-Q1], and the amount is 2 times. The amount is preferably in the range of about 200 times.
  • the acid that can be used in this step may be diluted with an appropriate solvent and is not particularly limited.
  • scavenger which can be used in this step may include the same as the “scavenger", as described in the "elimination reaction for Q 1 in the molecule of the compound [D-2]".
  • the amount of the scavenger that can be used in this step for example, the amount in the range of 1 to 100 times the molar ratio is appropriate with respect to 1 mol of the compound [A-2d-Q1], and the amount is 1 time.
  • the amount is preferably in the range of about 50 times.
  • Compound “A-2” is a compound in which each nucleoside unit constituting the compound is a nucleoside unit [4a], but all or part of the nucleoside unit [4a] is a nucleoside unit [4b] or a nucleoside unit [4c]. ] Can also be produced by using the same method as described above.
  • Step 1 Production of a compound represented by the above general formula [39] (hereinafter referred to as “Compound [39]”)
  • a compound represented by the above general formula [37] (hereinafter referred to as “Compound [37]”).
  • Compound [38] Can be produced by condensing compound [39] with a compound represented by the above general formula [38] (hereinafter, referred to as “compound [38]”).
  • the condensation reaction can be carried out according to a method known per se (see, for example, US Patent Application Publication No. 2014/0330006A1, International Publication No. 2012/0437330A1, International Publication No. 2013/082548A1).
  • Step 2 Production of Compound [B-1]
  • Compound [B-1] is produced by condensing a compound represented by the above general formula [40] (hereinafter referred to as “Compound [40]”) with Compound [39].
  • the condensation reaction is carried out by a method known per se (see, for example, US Patent Application Publication No. 2014/0330006A1, International Publication No. 2012/0437330A1, International Publication No. 2013/082548A1, International Publication No. 91/09033A1). It can be carried out according to the above.
  • the compound [40] can be produced by using the same method as the method for producing the compound [21].
  • Step 1 Production of the compound [37] produced by the compound represented by the general formula [42] (hereinafter, referred to as “compound [42]”)
  • the compound [37] represented by the general formula [41] (hereinafter, “Compound [41]”). ] ”)
  • the compound [42] can be produced.
  • the reaction is carried out by a method known per se (eg, Helvetica Chemica Acta, Vol. 70, 175-186 (1987), WO 2003/106468A1, Acta Nature, 6,116-118 (2014), Russian Journal of General. It can be carried out according to Chemistry, Vol. 67, No. 1, 62-64 (1997)).
  • Step 2 Production of compound [B-2]
  • compound [42] is allowed to act on a compound represented by the above general formula [43] (hereinafter, referred to as “compound [43]”) at the 3'end.
  • Compound “B-2] can be carried out by introducing a substituent containing a phosphorus atom into the hydroxyl group at the 3'position of the nucleoside unit on the side. If necessary, an activator can also be used in this step.
  • the solvent used in this step is not particularly limited, and examples thereof include acetonitrile and tetrahydrofuran.
  • the amount of the compound [42] to be used is appropriately 1 to 20 times the molar amount, preferably 1 to 10 times the molar amount with respect to the compound [43].
  • the "activator” include 1H-tetrazole, 5-ethylthiotetrazole, 4,5-dichloroimidazole, 4,5-dicyanoimidazole, benzotriazole triflate, imidazole triflate, pyridinium triflate, N, N-diisopropylethylamine. , 2,4,6-colysine / N-methylimidazole.
  • the amount of the "activator" to be used is appropriately 1 to 20 times the molar amount, preferably 1 to 10 times the molar amount with respect to the compound [43].
  • the appropriate reaction temperature is 0 ° C to 120 ° C.
  • the reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually 30 minutes to 24 hours.
  • Compound [B-2] is a compound in which each nucleoside unit constituting the compound is a nucleoside unit [4e], but all or part of the nucleoside unit [4e] is a nucleoside unit [4f] or a nucleoside unit [4g]. ] Can also be produced according to the same method as described above.
  • the “conversion yield (%)” means the rate at which the raw material is converted to the target product, and the peak corresponding to the target product detected by " ⁇ high performance liquid chromatography (hereinafter referred to as” HPLC ”)". Area (%) ⁇ ⁇ ⁇ Peak area (%) corresponding to the raw material detected by HPLC + Peak area (%) ⁇ ⁇ 100 corresponding to the target product detected by HPLC.
  • HPLC conditions 0.5 mg of the product is dissolved in acetonitrile or 80% aqueous acetonitrile solution, and HPLC analysis is performed under the following conditions.
  • Example 1 4- (octadecylamino) -4-oxobutanoic acid [(2S, 6R) -6- (5-methyl-2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) morpholine- 2-Il] Methyl (hereinafter referred to as "G1-suc-morT-OFF”) Step 1 Production of 4- (octadecylamino) -4-oxobutanoic acid (hereinafter referred to as "G1-suc") Succinic anhydride (8) in a solution of octadecane-1-amine (21.94 g) in dichloromethane (500 mL).
  • Step 2 4- (Octadecylamino) -4-oxobutanoic acid [(2S, 6R) -6- (5-methyl-2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) morpholine-2 -Il] Methyl (hereinafter referred to as "G1-suc-morT-OFF”) production G1-suc (14.4 g) in tetrahydrofuran (150 mL) solution with 1-ethyl-3- (3-dimethylaminopropyl) Carbodiimide hydrochloride (8.56 g, 1.2 eq.) was added and stirred at room temperature.
  • G1-suc-morT-OFF Methyl
  • Step 2 Succinic acid ⁇ [(2S, 6R) -6- (5-methyl-2,4-dioxo-3,4-dihydropyrimidine-1-yl) -4-trityl-morpholine-2-yl] methyl ⁇ ⁇ 2-Octadecanoyloxy-1-[(octadecanoyloxymethyl) ethyl] ⁇ (hereinafter referred to as "G2-suc-morT-ON”) production G2-suc (900 mg, 1.24 mmol) and 1- Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 277 mg (1.45 mmol) was added with dichloromethane (5.2 mL), followed by morT-OH 500 mg (1.03 mmol), 4- (N, N-dimethylamino).
  • Step 3 Production of G2-suc-morT-OFF Dichloromethane (4.2 mL) was added to G2-suc-morT-ON, and the mixture was stirred at 0 ° C. Then, 127 ⁇ L (0.62 mmol) of triisopropylsilane and 64 ⁇ L (0.82 mmol) of trifluoroacetic acid were added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the mixture was extracted with dichloromethane, dried over sodium sulfate, and the solvent was distilled off.
  • Step 2 Manufacture of G3-suc-morT-OFF
  • Example 2 Manufactured in the same manner as in Step 3.
  • Step 2 4-oxo-4- (4-stearoylpiperazin-1-yl) butanoic acid ⁇ (2S, 6R) -6- (5-methyl-2,4-dioxo-3,4-dihydropyrimidine-1 (2H) ) -Il) -4-tritylmorpholine-2-yl ⁇ methyl (hereinafter referred to as "G4-suc-morT-ON”) production G4-suc (982 mg, 2.17 mmol) and 1-ethyl-3- () Tetrahydrofuran (10 mL) was added to 555 mg (2.90 mmol) of 3-dimethylaminopropyl) carbodiimide hydrochloride, and the mixture was stirred at 70 ° C.
  • Step 3 Manufacture of G4-suc-morT-OFF Manufactured in the same manner as in Step 3 of Example 2.
  • Example 5 4- (octadecylcarbamoyl) benzoic acid [(2S, 6R) -6- (5-methyl-2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) morpholin-2-yl) ] Methyl (hereinafter referred to as "G5-tpa-morT-OFF")
  • Step 1 4- (Octadecylcarbamoyl) benzoic acid [(2S, 6R) -6- (5-methyl-2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) -4-tritylmorpholine- 2-Il] Methyl (hereinafter referred to as "G5-tpa-morT-ON”) was produced using 4- (octadecylcarbamoyl) benzoic acid in the same manner as in Step 2 of Example 2.
  • Step 2 Manufacture of G5-tpa-morT-OFF Manufactured in the same manner as in Step 3 of Example 2.
  • Example 6 4- (4- (4- (octadecylcarbamoyl) benzoyl) piperazine-1-yl) -4-oxobutanoic acid ⁇ (2S, 6R) -6- (5-methyl-2,4-dioxo-3) , 4-Dihydropyrimidine-1 (2H) -yl) morpholine-2-yl ⁇ methyl (hereinafter referred to as "G6-suc-morT-OFF”)
  • Step 1 4- (4- (4- (Octadecylcarbamoyl) benzoyl) piperazine-1-yl) -4-oxobutanoic acid (hereinafter referred to as "G6-suc”) production 4- (octadecylcarbamoyl) instead of stearic acid ) Using benzoic acid, it was produced in the same manner as in Step 1 of Example 4.
  • Step 2 4- [4- ⁇ 4- (Okudadecylcarbamoyl) benzoyl ⁇ piperazine-1-yl] -4-oxobutanoic acid ⁇ (2S, 6R) -6- (5-methyl-2,4-dioxo-3, 4-Dihydropyrimidine-1 (2H) -yl) -4-tritylmorpholine-2-yl ⁇ methyl (hereinafter referred to as "G6-suc-morT-ON”) production The same method as in step 2 of Example 2. Manufactured in.
  • Step 3 Production of G6-suc-morT-OFF 4.6 mL of dichloromethane and 0.4 mL of 2,2,2-trifluoroethanol were added to 493 mg (0.47 mmol) of G6-suc-morT-ON, and the mixture was stirred at 0 ° C. Then, 145 ⁇ L (0.70 mmol) of triisopropylsilane and 53 ⁇ L (0.70 mmol) of trifluoroacetic acid were added at 0 ° C., and the mixture was stirred at room temperature for 1 hour.
  • Example 7 3,4,5-tris (octadecyloxy) benzoic acid ⁇ (2S, 6R) -6- (5-methyl-2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) Morpholine-2-yl ⁇ methyl (hereinafter referred to as "G7-morT-OFF”)
  • Step 1 3,4,5-tris (octadecyloxy) benzoic acid ⁇ (2S, 6R) -6- (5-methyl-2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl)- Production of 4-Trityl-Morpholine-2-yl ⁇ Methyl (hereinafter referred to as "G7-morT-ON”) Using 3,4,5-trioctadecoxybenzoic acid, the same as in Step 2 of Example 2.
  • Step 2 Manufacture of G7-morT-OFF Manufactured in the same manner as in Step 3 of Example 2.
  • 1 1 H-NMR (CDCl 3 ): ⁇ 7.98 (1H, bs); 7.22 (3H, m); 5.69 to 5.72 (1H, m); 4.32 to 4.36 (2H, m). m); 4.08 to 4.12 (1H, m); 3.94 to 4.01 (6H, m); 3.11 to 3.14 (1H, m); 3.02 to 3.05 ( 1H, m); 2.64 to 2.72 (2H, m); 1.90 (3H, m); 1.23 to 1.45 (96H, m) 0.86 (9H, t, J 7) .2Hz)
  • Step 2 Succinate ⁇ (2S, 6R) -6- (5-methyl-2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) -4-tritylmorpholine-2-yl ⁇ methyl ( 2- [ ⁇ 3,4,5-tris (octadecyloxy) benzoyloxy ⁇ oxy] ethyl) (hereinafter referred to as "G8-suc-morT-ON”) by the same method as in step 1 of Production Example 2.
  • G8-suc 4-Oxo-4- (2-[ ⁇ 3,4,5-tris (octadecyloxy) benzoyl ⁇ oxy] ethoxy) succinic acid (hereinafter referred to as "G8-suc"), and then Example 2.
  • G8-suc-morT-ON was obtained in the same manner as in Step 2.
  • Step 3 Manufacture of G8-suc-morT-OFF G8-suc-morT-OFF G8-suc-morT-OFF was obtained in the same manner as in Step 3 of Example 2.
  • 1 1 H-NMR (CDCl 3 ): ⁇ 7.96 (1H, bs); 7,23 (3H, m); 5.67 to 5.69 (1H, m); 4.40 to 4.47 (5H, 5H,) m); 3.94 to 4.11 (8H, m); 3.09 to 3.12 (1H, m); 2.89 to 2.92 (1H, m); 2.53 to 2.65 ( 6H, m) 1.90 (3H, s); 1.23 to 1.45 (96H, m); 0.86 (9H, t, J 6.8Hz)
  • Example 9 4- (dioctadecylamino) -4-oxobutanoic acid ⁇ (2S, 6R) -6- (5-methyl-2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) morpholine -2-Il ⁇ methyl (hereinafter referred to as "G9-suc-morT-OFF")
  • Step 1 4- (Dioctadecylamino) -4-oxobutanoic acid ⁇ (2S, 6R) -6- (5-methyl-2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) -4 Production of -tritylmorpholine-2-yl ⁇ methyl (hereinafter referred to as "G9-suc-morT-ON”) Using N-octadecyloctadecan-1-amine as a raw material, 4 in the same manner as in step 1
  • G9-suc -(Dioctadecylamino) -4-oxobutanoic acid
  • Step 2 Manufacture of G9-suc-morT-OFF Manufactured in the same manner as in Step 3 of Example 2.
  • 1 1 H-NMR (CDCl 3 ): ⁇ 8.14 (1H, bs); 7.27 (1H, s); 5.68 to 5.72 (1H, m): 4.12 to 4.20 (2H, 2H,) m); 3.98 to 4.01 (1H, m); 3.10 to 3.29 (5H, m); 2.94 to 2.97 (1H, m); 2.60 to 2.70 ( 6H, m); 1.95 (3H, s); 1.25 to 1.49 (64H, m); 0.88 (6H, t, J 7.2Hz)
  • Example 10 4-[ ⁇ 1- (octadecylamino) -1-oxo-3-phenylpropan-2-yl ⁇ amino] -4-oxobutanoic acid ⁇ (2S, 6R) -6- (5-methyl-2, 4-Dioxo-3,4-dihydropyrimidine-1 (2H) -yl) morpholine-2-yl ⁇ methyl (hereinafter referred to as "G10-suc-morT-OFF”)
  • Step 1 4-[ ⁇ 1- (octadecylamino) -1-oxo-3-phenylpropane-2-yl ⁇ amino] -4-oxobutanoic acid ⁇ (2S, 6R) -6- (5-methyl-2,4) -Dioxo-3,4-dihydropyrimidine-1 (2H) -yl) -4-tritylmorpholine-2-yl ⁇ methyl (hereinafter referred to as "G10-su
  • Step 2 Production of G10-suc-morT-OFF
  • the target product was obtained in the same manner as in Step 3 of Example 2.
  • 1 1 H-NMR (CDCl 3 ): ⁇ 8.33 (1H, bs); 7.16 to 7.32 (6H, m); 6.38 to 6.40 (1H, m); 5.67 to 5. 71 (2H, m); 4.54 to 4.58 (1H, m); 4.08 to 4.16 (3H, m); 3.94 to 4.01 (1H, m); 2.91 to 3.17 (5H, m); 2.46 to 2.79 (5H, m); 1.94 (3H, s); 1.13 to 1.36 (32H, m); 0.88 (3H, m) t, J 7.6Hz)
  • Example 11 G1-suc-PMO [A Bz -A Bz] Production of -ON (using tetrabutylammonium chloride as a reaction accelerator, the reaction time (30 min)) 14.1 mg (0.02 mmol) of G1-suc-morA-OFF, 7.6 ⁇ L (0.06 mmol) of N-ethylmorpholine and 16.7 mg (0.06 mmol) of tetrabutylammonium chloride were dissolved in 200 ⁇ L of dichloromethane. To this, 200 ⁇ L of dichloromethane in which 21.7 mg (0.03 mmol) of mora was dissolved was added, and the mixture was shaken at 40 ° C. for 30 minutes.
  • G1-suc-morA-OFF ((2S, 6R) -6- (6-benzamide-9H-purine-9-yl) morpholine-2-yl) methyl 4- (octadecylamino) -4-oxobutanoate
  • G1-suc-morA-OFF was replaced with "N-(9-((2R, 6S) -6- (hydroxymethyl-4-trityl)" in step 2 of Example 1 instead of "morT-OH”. It was synthesized using "morpholine-2-yl) -9H-purine-6-yl) benzamide (morA-OH).
  • Example 12 Production of G1-suc-PMO [ ABz- T] -ON (using 1-butyl-1-methylpyrrolidinium chloride as a reaction accelerator, reaction time (60 minutes))
  • Example 13 G1-suc-PMO [A Bz -G CE, Pac -T-T-T-C Bz -T-T] ( used as reaction accelerator 1-butyl-1-methyl-pyrrolidinium chloride) production of -OFF
  • the solution a shown below was sent at 0.05 mL / min and the solution b was sent at 0.2 mL / min, respectively, and after mixing the two solutions, the reaction was carried out at 40 ° C. for 120 minutes in a 30 mL tube reactor. After the reaction, the mixture was mixed with the liquid c shown below, which was sent at 0.6 mL / min, and the reaction was carried out at 40 ° C. for 5.9 minutes in a 5 mL tube reactor.
  • Solution a 3.17 g (5.2 mmol) of morT was dissolved in 5 mL of dichloromethane.
  • Solution c 3.33 mL (30 mmol) of 1-methylpiperazine was dissolved in 96.7 mL of dichloromethane.
  • Liquid d Aqueous solution of sodium dihydrogen phosphate (1M) and saturated brine were mixed at a ratio of 1: 1 and ethanol of 5% by volume was added.
  • Solution e 4 mL of trifluoroacetic acid, 1 mL of ethanol, 1 mL of triethylamine, 30 mL of trifluoroethanol, and 64 mL of dichloromethane were mixed.
  • Liquid f Saturated saline and water were mixed 1: 1.
  • Liquid g 1% aqueous trifluoroacetic acid solution and saturated brine were mixed at a ratio of 1: 1 and ethanol at a volume ratio of 5% was added.
  • Example 14 G1-suc-PMO [TGCE, Pac] using a reaction accelerator (1-butyl-1-methylpyrrolidinium chloride: BMPC) and a solvent (1,3-dimethyl-2-imidazolidinone / dichloromethane) -G CE, 1-butyl Pac -G CE, Pac -A Bz -T -C Bz -C Bz -A Bz -G CE, as prepared (reaction accelerator of Pac -T-a Bz] -ON -1- Methylpyrrolidinium chloride is used, 1,3-dimethyl-2-imidazolidinone / dichloromethane is used as a solvent, reaction time (120 minutes)) G1-suc-PMO [T- G CE, Pac -G CE, Pac -G CE, Pac -A Bz -T-C Bz -C Bz -A Bz -G CE, Pac -T] -OFF 1.26g ( 0.213
  • G1-suc-PMO [T- G CE, Pac -G CE, Pac -G CE, Pac -A Bz -T-C Bz -C Bz -A Bz -G CE, Pac -T-A Bz -T] - Production of ON (1-butyl-1-methylpyrrolidinium chloride as a reaction accelerator, 1,3-dimethyl-2-imidazolidinone / dichloromethane as a solvent, reaction time (120 minutes)) G1-suc-PMO [T- G CE, Pac -G CE, Pac -G CE, Pac -A Bz -T-C Bz -C Bz -A Bz -G CE, Pac -T-A Bz] -OFF 1 .17 g (0.209 mmol), morT 191 mg (0.314 mmol), N-ethylmorpholine 79 ⁇ L (0.628 mmol) and 1-butyl-1-methylpyrrolidinium chloride
  • G1-suc-PMO [T- G CE, Pac -G CE, Pac -G CE, Pac -A Bz -T-C Bz -C Bz -A Bz -G CE, Pac -T-A Bz -T-A Bz ] -ON production (1-butyl-1-methylpyrrolidinium chloride as a reaction accelerator, 1,3-dimethyl-2-imidazolidinone / dichloromethane as a solvent, reaction time (120 minutes))
  • G1-suc-PMO [T- G CE, Pac -G CE, Pac -G CE, Pac -A Bz -T-C Bz -C Bz -A Bz -G CE, Pac -T-A Bz -T] - OFF 1.08 g (0.182 mmol), mora 198 mg (0.274 mmol), N-ethylmorpholine 69 ⁇ L (0.547 mmol) and 1-butyl-1-
  • Example 15 G1-suc-PMO [TG CE, Pac- G CE, Pac- G CE, Pac- A using a reaction accelerator (1-butyl-1-methylpyrrolidinium chloride: BMPC) and a solvent (dichloromethane) Bz -T-C Bz -C Bz -A Bz -G CE, Pac -T-a Bz] using 1-butyl-1-methyl-pyrrolidinium chloride as the manufacture of -ON (reaction accelerator, dichloromethane as solvent Use, reaction time (120 minutes))
  • G1-suc-PMO [T- G CE, Pac -G CE, Pac -G CE, Pac -A Bz -T-C Bz -C Bz -A Bz -G CE, Pac -T] -OFF 2.14g ( 0.361 mmol), morA 391 mg (0.542 mmol), N-ethylmorpholine 137 ⁇ L (1.08 mmol) and 1-but
  • G1-suc-PMO [T- G CE, Pac -G CE, Pac -G CE, Pac -A Bz -T-C Bz -C Bz -A Bz -G CE, Pac -T-A Bz -T] - Production of ON (1-butyl-1-methylpyrrolidinium chloride as a reaction accelerator, dichloromethane as a solvent, reaction time (120 minutes))
  • G1-suc-PMO [T- G CE, Pac -G CE, Pac -G CE, Pac -A Bz -T-C Bz -C Bz -A Bz -G CE, Pac -T-A Bz] -OFF 2 9.0 g (0.357 mmol), morT 326 mg (0.536 mmol), N-ethylmorpholine 136 ⁇ L (1.07 mmol) and 1-butyl-1-methylpyrrolidinium chloride 318 mg (1.79 mmol) to 11.9 m
  • G1-suc-PMO [T- G CE, Pac -G CE, Pac -G CE, Pac -A Bz -T-C Bz -C Bz -A Bz -G CE, Pac -T-A Bz -T-A Bz ] -ON production (1-butyl-1-methylpyrrolidinium chloride used as reaction accelerator, dichloromethane used as solvent, reaction time (120 minutes))
  • G1-suc-PMO [T- G CE, Pac -G CE, Pac -G CE, Pac -A Bz -T-C Bz -C Bz -A Bz -G CE, Pac -T-A Bz -T] - OFF 1.90 g (0.321 mmol), mora 348 mg (0.481 mmol), N-ethylmorpholine 122 ⁇ L (0.962 mmol) and 1-butyl-1-methylpyrrolidinium chloride 285 mg (1.60 mmol)

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