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Optically active fragment for synthesizing stereocontrolled oligonucleotide, method for producing same, and method for synthesizing stereocontrolled oligonucleotide using same

An oligonucleotide and optically active technology, which is applied in the field of synthesis of phosphorus atom-modified oligonucleotides, can solve problems such as excessive dosage and side effects, and achieve the effect of reducing the number of procedures and purification load

Pending Publication Date: 2022-04-01
株式会社纳蒂亚斯
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] On the other hand, direct administration in the case of mixing diastereomers may cause side effects, or in order to ensure the amount of phosphorothioate having a stereostructure that exerts the desired effect, it may be necessary to make the diastereomers Enantiomer mixture administered to the body in excess

Method used

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  • Optically active fragment for synthesizing stereocontrolled oligonucleotide, method for producing same, and method for synthesizing stereocontrolled oligonucleotide using same
  • Optically active fragment for synthesizing stereocontrolled oligonucleotide, method for producing same, and method for synthesizing stereocontrolled oligonucleotide using same
  • Optically active fragment for synthesizing stereocontrolled oligonucleotide, method for producing same, and method for synthesizing stereocontrolled oligonucleotide using same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] (Step 1: Synthesis of Optically Active Phosphorylating Agents)

[0084] [chemical 9]

[0085]

[0086] Phosphorus trichloride (3.5 mL, 5.5 g, 40 mmol) was dissolved in toluene (50 mL) at -78°C. Separately, L-prolinol (3.9 mL, 4.0 g, 40 mmol) and triethylamine (12 mL, 8.9 g, 88 mmol) were dissolved in toluene (50 mL), and added dropwise to phosphorus trichloride over 1 hour. After directly stirring for 12 hours, return to 0° C. and stir for another 1 hour. After the reaction, a precipitate formed as a by-product was filtered off with celite, and the solvent was distilled off under reduced pressure to obtain a crude product. This was distilled under reduced pressure (65° C., 1.0 mmHg) to obtain the target phosphorous oxychloride 1 (3.2 g, 19 mmol, yield 48%).

[0087] (Step 2: Synthesis of Optically Active Phosphoramidite 2)

[0088] [chemical 10]

[0089]

[0090] 5'-DMTr-protected thymidine (11 g, 21 mmol, manufactured by Shanghai Zhaowei Technology Developme...

Embodiment 2

[0117] (Step 9: Synthesis of Optically Active Dinucleotides (N-Acetyl Termination))

[0118] [chemical 17]

[0119]

[0120] Optically active phosphoramidite 2 (2.7 g, 4.0 mmol) and 5'-hydroxyl unprotected nucleoside 3 (1.0 g, 3.1 mmol) were dissolved in acetonitrile (20 mL), to which was added benzimidazolium triflate Salt (1.2 g, 4.6 mmol). After 30 minutes, N-methylimidazole (0.49 mL, 510 mg, 6.2 mmol) was added, followed by acetic anhydride (0.73 mL, 790 mg, 7.7 mmol), followed by stirring for 30 minutes. Finally, phenylacetyl disulfide (1.9 g, 6.2 mmol) was added and stirred for 30 minutes. The reaction mixture was partitioned between dichloromethane (100 mL) and saturated aqueous sodium bicarbonate (100 mL), and the organic layer was recovered. The organic layer was washed with saturated brine (50 mL), and dried over sodium sulfate to obtain a crude product. This was purified by column chromatography using hexane-ethyl acetate-methanol as an eluting solvent to obt...

Embodiment 3

[0147] (oligonucleotide synthesis)

[0148] The optically active phosphoramidite obtained in this embodiment was used in the oligonucleotide solid-phase synthesis apparatus to synthesize stereocontrolled oligonucleotides. After carrying out condensation reaction, end-capping reaction, and oxidation or sulfuration reaction according to the standard experimental protocol of the device, the solid phase carrier is taken out, the obtained oligonucleotide is cut out from the solid phase carrier, and deprotected with concentrated ammonia water.

[0149] Based on the above results, the optically active fragment for synthesizing a stereocontrolled oligonucleotide according to this embodiment uses L- or D-prolinol derivatives as one of the raw materials as a chiral source, and can have multiple Stereo-controlled phosphorothioate groups, not limited to one. Therefore, the number of steps required for synthesizing a stereocontrol oligonucleotide of the same length can be reduced compared...

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Abstract

Provided are: an optically active fragment for synthesizing a stereocontrolled oligonucleotide represented by formula (I); a method for producing the optically active fragment; and a method for synthesizing a stereocontrolled oligonucleotide using the optically active fragment. In the formula, B is a protected / unprotected nucleoside base, R1 is a substituted / unsubstituted aliphatic group, R2 and R3 are DMTr groups or-P (R11) (NR12) 2, R11 is OCH2CH2CN, SCH2CH2CN and the like, and R12 is a substituted / unsubstituted aliphatic group or aromatic group; x is H, an alkyl group, an O-alkyl group or the like, Y is H, NHR13, a halogen or the like, or an acyl group, an ether group, a silyl group protected hydroxyl group or forms an X-Y bond with X, and n is an integer from 0 to 4 (inclusive).

Description

technical field [0001] The present invention relates to a synthetic optically active fragment for sterically controlled phosphorus atom-modified oligonucleotides, a method for producing the same, and a method for synthesizing stereocontrolled phosphorus atom-modified oligonucleotides using the optically active fragment. Background technique [0002] In recent years, there has been increasing attention to nucleic acid drugs based on natural or non-natural oligonucleotides. In order to obtain nucleic acid drugs designed to achieve targeted effects, chemical synthesis methods are widely used. [0003] Phosphorothioate oligonucleotides, which are widely used as nucleic acid drugs, in the presence of phosphorothioate in the phosphodiester bond, due to the substituted sulfur atom of one of the non-crosslinking oxygen atoms of the phosphodiester bond There is a chiral center on the phosphorus atom forming the phosphodiester bond. [0004] In the widely used method for synthesizin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H1/00C07H1/02C07H21/04
CPCC07H21/04C07H1/00C07H1/02Y02P20/55C07B2200/07C07H21/00
Inventor 片冈正典兵藤守
Owner 株式会社纳蒂亚斯
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