WO2024143276A1 - オリゴヌクレオチドの製造方法 - Google Patents

オリゴヌクレオチドの製造方法 Download PDF

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Publication number
WO2024143276A1
WO2024143276A1 PCT/JP2023/046424 JP2023046424W WO2024143276A1 WO 2024143276 A1 WO2024143276 A1 WO 2024143276A1 JP 2023046424 W JP2023046424 W JP 2023046424W WO 2024143276 A1 WO2024143276 A1 WO 2024143276A1
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Prior art keywords
oligonucleotide
group
mer
flp
less
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PCT/JP2023/046424
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French (fr)
Japanese (ja)
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雄樹 田中
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Sumitomo Chemical Co Ltd
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Sumitomo Chemical Co Ltd
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Priority to JP2024567802A priority Critical patent/JPWO2024143276A1/ja
Priority to CN202380086686.8A priority patent/CN120418262A/zh
Priority to KR1020257019981A priority patent/KR20250128304A/ko
Priority to EP23912055.3A priority patent/EP4644404A1/en
Publication of WO2024143276A1 publication Critical patent/WO2024143276A1/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
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • 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
    • C07H21/02—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical

Definitions

  • a method for decomposing the branch bodies is known in which, for example, triethylamine trihydrofluoride is mixed with the branch bodies to decompose the branch bodies (see Non-Patent Document 2).
  • a method for decomposing phosphoramidate bonds using 80% aqueous acetic acid is also known (see Non-Patent Document 3).
  • these methods require harsh reaction conditions, and the target oligonucleotide is also decomposed. Therefore, a method for selectively decomposing the branch bodies under milder conditions is required.
  • aqueous solutions having a pH of 1 to less than 6.8 include aqueous solutions of acetic acid or acetate salts.
  • aqueous solutions having a pH of 6.8 or more and 8 or less include Tris-HCl buffer.
  • the reaction conditions in the "step of reacting an n-mer oligonucleotide (n is any integer of 2 or more) with water or an aqueous solution having a pH of 1 to 8 to degrade the branched body" require mixing an n-mer oligonucleotide (n is any integer of 2 or more) with water or an aqueous solution having a pH of 1 to 8 and reacting for a certain period of time or more.
  • the reaction time may vary depending on the oligonucleotide reactant used, the water or aqueous solution having a pH of 1 to 8, the reaction temperature, etc., and is not particularly limited as long as the conditions are such that decomposition of the branched body can be sufficiently achieved, but for example, 10 minutes or more is preferable.
  • the reaction time may be from several tens of minutes to several weeks, and examples of the reaction time include 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, 24 hours, 48 hours (2 days), 72 hours (3 days), 1 week, several weeks, 1 month, and several months.
  • the reaction time is preferably shorter, for example, at least 10 minutes, 30 minutes, or 60 minutes, while it is at least 1 week, 72 hours, 24 hours, or 12 hours.
  • Specific reaction times include, for example, 30 minutes to 1 week, 2 hours to 72 hours, and 6 hours to 24 hours, and more preferably 30 minutes to 24 hours.
  • the reaction temperature may vary depending on the oligonucleotide reactant used, the water or aqueous solution with a pH of 1 to 8, the reaction time, etc., and is not particularly limited as long as the conditions are such that sufficient decomposition of the branched body can be achieved.
  • a lower reaction temperature is preferable. Specific examples include 0°C or higher, room temperature or higher (e.g., 25°C or higher), 40°C or higher, and 50°C or higher, while examples include 60°C or lower, 50°C or lower, and 40°C or lower.
  • Specific reaction temperatures include, for example, 0°C to 60°C, 10 to 60°C, 20 to 60°C, 20 to 50°C, and 20 to 40°C.
  • the reaction conditions for the decomposition reaction of the branch body include, but are not limited to, conditions in which the pH of the aqueous solution is 1-2 and the reaction temperature is 0-30°C, conditions in which the pH of the aqueous solution is 3-4 and the reaction temperature is 0-50°C, and conditions in which the pH of the aqueous solution is 5-8 and the reaction temperature is 20-60°C.
  • Reaction conditions for the decomposition reaction of the branched body include, but are not limited to, for example, a condition in which the pH of the aqueous solution is 1-2, the reaction temperature is 0-30°C, and the reaction time is 10 minutes to 12 hours (e.g., 30 minutes to 2 hours), a condition in which the pH of the aqueous solution is 3-4, the reaction temperature is 0-50°C, and the reaction time is 6 hours to 48 hours (e.g., 12 hours to 24 hours), and a condition in which the pH of the aqueous solution is 5-8, the reaction temperature is 20-60°C, and the reaction time is 48 hours to several weeks (e.g., 24 hours to 1 week).
  • R 1 in the above formula (A) includes, but is not limited to, a hydrogen atom, an alkyl group (e.g., a methyl group, an ethyl group), and the like.
  • the crude oligonucleotide subjected to the decomposition reaction of the branched body may be a generally known crude oligonucleotide after liquid phase synthesis before purification, for example, a crude oligonucleotide with protected nucleobases, or a crude oligonucleotide with deprotected nucleobases before purification.
  • it may be a crude oligonucleotide after solid phase synthesis before purification, for example, a crude oligonucleotide with protected nucleobases, or a crude oligonucleotide with deprotected nucleobases before purification. It is preferable that it is a crude oligonucleotide after solid phase synthesis.
  • the protecting group may be any that can be used in the amidite method, for example, 2'-tert-butyldimethylsilyl (TBDMS) group, 2'-bis (2-acetoxyethoxy) methyl (ACE) group, 2'- (triisopropylsilyloxy) methyl (TOM) group, 2'- (2-cyanoethoxy) ethyl (CEE) group, 2'- (2-cyanoethoxy) methyl (CEM) group, 2'-para-tolylsulfonylethoxymethyl (TEM) group, 2'-EMM group (WO 2006/022323), as well as those described in WO 2013/027843 and WO 2019/208571.
  • TDMS 2'-tert-butyldimethylsilyl
  • ACE ACE
  • TOM triisopropylsilyloxy) methyl
  • CEE 2'- (2-cyanoethoxy) ethyl
  • CEM 2'-para
  • the uridine derivatives described in the following examples and comparative examples refer to compounds represented by the following structural formula.
  • the circle illustrated in the following structural formula is a schematic representation of CPG.
  • Example 3 3 mg of the crude product obtained in Reference Example 1 was placed in a 2 mL glass vial (manufactured by Agilent) and dissolved in 1 mL of 0.5% aqueous acetic acid solution. The vial containing the mixed solution was placed in an incubator (manufactured by Kenis) whose temperature was adjusted to 25° C., and allowed to stand for 24 hours. After standing, the vial was removed from the incubator, and the ratio of branch body and FLP was calculated by the method described in the measurement method 1 above. The results are shown in Table 2.
  • Example 5 3 mg of the crude product obtained in Reference Example 1 was placed in a 2 mL glass vial (manufactured by Agilent) and dissolved in 1 mL of UF water. The vial containing the mixed solution was placed in an incubator (manufactured by Kenis) whose temperature was adjusted to 25° C., and allowed to stand for one week. After standing, the vial was removed from the incubator, and the ratio of branch body and FLP was calculated by the method described in the measurement method 1 above. The results are shown in Table 2.
  • Example 6 3 mg of the crude product obtained in Reference Example 1 was placed in a 2 mL glass vial (manufactured by Agilent) and dissolved in 1 mL of UF water. The vial containing the mixed solution was placed in an incubator (manufactured by Kenis) whose temperature was adjusted to 40° C., and allowed to stand for 72 hours. After standing, the vial was taken out of the incubator and cooled to room temperature, and the ratio of branch body and FLP was calculated by the method described in the measurement method 1 above. The results are shown in Table 2.
  • Example 7 3 mg of the crude product obtained in Reference Example 1 was placed in a 2 mL glass vial (manufactured by Agilent) and dissolved in 1 mL of UF water. The vial containing the mixed solution was placed in an incubator (manufactured by Kenis) whose temperature was adjusted to 50° C., and allowed to stand for 24 hours. After standing, the vial was taken out of the incubator and cooled to room temperature, and the ratio of branch body and FLP was calculated by the method described in the measurement method 1 above. The results are shown in Table 2.
  • Example 8 3 mg of the crude product obtained in Reference Example 1 was placed in a 2 mL glass vial (manufactured by Agilent) and dissolved in 1 mL of UF water. The vial containing the mixed solution was placed in an incubator (manufactured by Kenis) whose temperature was adjusted to 60° C., and allowed to stand for 6 hours. After standing, the vial was taken out of the incubator and cooled to room temperature, and the ratio of branch body and FLP was calculated by the method described in the measurement method 1 above. The results are shown in Table 2.
  • Comparative Example 2 (Initial value: before reaction) 3 mg of the crude product obtained in Reference Example 1 was dissolved in 1 mL of UF water, and the ratio of branch body to FLP was calculated by the method described in the above-mentioned Measurement Method 1. The results are shown in Table 2.
  • Comparative Example 3 (Reaction conditions described in Non-Patent Document 2) According to the method described in Non-Patent Document 2 (Oligonucleotides 2006, 16, 181-185), the crude oligonucleotide after synthesis was treated with triethylamine trihydrofluoride. Specifically, 3 mg of the crude product obtained in Reference Example 1 was placed in a 2 mL glass vial (manufactured by Agilent) and triethylamine trihydrofluoride was added. The vial containing the mixture was placed in an incubator (manufactured by Kenis) whose temperature was adjusted to 65° C. and allowed to stand for 1.5 hours. After standing, the vial was taken out of the incubator and cooled to room temperature, and the ratio of branch body and FLP was calculated by the method described in the measurement method 1. The results are shown in Table 2.
  • the branch body proportion means the proportion (area percentage) of the branch body in the oligonucleotide, determined by analyzing the oligonucleotide using the above-mentioned Measurement Method 1.
  • the FLP proportion means the proportion (area percentage) of FLP in the oligonucleotide, determined by analyzing the oligonucleotide using the above-mentioned Measurement Method 1.
  • the manufacturing method of the present invention makes it possible to selectively decompose the branch bodies produced during the production of oligonucleotides, which is expected to improve the yield and purity of oligonucleotides.
  • Sequence numbers 1 to 10 in the sequence table represent the base sequences of oligonucleotides produced according to the method for producing oligonucleotides of the present invention.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Saccharide Compounds (AREA)
PCT/JP2023/046424 2022-12-26 2023-12-25 オリゴヌクレオチドの製造方法 Ceased WO2024143276A1 (ja)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2024567802A JPWO2024143276A1 (https=) 2022-12-26 2023-12-25
CN202380086686.8A CN120418262A (zh) 2022-12-26 2023-12-25 寡核苷酸的制造方法
KR1020257019981A KR20250128304A (ko) 2022-12-26 2023-12-25 올리고뉴클레오티드의 제조 방법
EP23912055.3A EP4644404A1 (en) 2022-12-26 2023-12-25 Oligonucleotide production method

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JP2022-208672 2022-12-26

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Citations (11)

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WO2001053528A1 (en) 2000-01-18 2001-07-26 Isis Pharmaceuticals, Inc. Antisense inhibition of ptp1b expression
JP3745226B2 (ja) 1998-09-29 2006-02-15 アイシス・ファーマシューティカルス・インコーポレーテッド サービビン発現のアンチセンス・モジュレーション
WO2006022323A1 (ja) 2004-08-26 2006-03-02 Nippon Shinyaku Co., Ltd. ホスホロアミダイト化合物及びオリゴｒｎａの製法
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JP4705716B2 (ja) 1999-02-05 2011-06-22 ジーイー・ヘルスケア・バイオサイエンス・コーポレイション オリゴヌクレオチドの脱保護法
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CN120418262A (zh) 2025-08-01
EP4644404A1 (en) 2025-11-05
JPWO2024143276A1 (https=) 2024-07-04

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