CN-121736022-B - Preparation method of locked nucleic acid intermediate

Abstract

The invention discloses a method for synthesizing a locked nucleic acid intermediate, the intermediate disclosed by the invention has a specific formula I structure, I, wherein the definition of the substitution is defined in the specification. The invention adopts a step-by-step synthesis method, overcomes the defects of more byproducts and high production cost in the prior art, has milder reaction conditions and higher reaction yield, and is more suitable for batch production.

Inventors

• TANG JIYAO
• PANG YONG
• SUN XIANGXIANG
• LIU XUDONG

Assignees

• 北京瑞博奥医药科技有限公司

Dates

Publication Date

20260512

Application Date

20260228

Claims (2)

1. 1. A process for the preparation of a compound of formula I comprising the steps of: Step one), performing ring closure reaction on a compound II in the presence of alkali to obtain a compound III; Step two), the compound III reacts in the presence of iodide and alkyl halogenated silane to prepare a compound of a formula I; the synthetic route is as follows: , Wherein, the R 1 is tert-butyldiphenyl silicon group, R 2 is naphthylmethyl, R 3 is H, R 4 is Ms, R 5 is acetoxy; step one), the reaction is carried out in a solvent, wherein the solvent is methanol; The iodide is potassium iodide or sodium iodide; the alkyl halogenated silane is trimethyl chlorosilane, trimethyl bromosilane or replaced by trimethylsilyl trifluoro methane sulfonate or trimethylsilyl cyanide.
2. 2. The method according to claim 1, wherein the base is one or more selected from the group consisting of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.

Description

Preparation method of locked nucleic acid intermediate Technical Field The invention relates to the technical field of synthesis of pharmaceutical chemistry and fine chemical intermediates, in particular to a synthesis method of an oxygen heterocyclic compound. More particularly, to a method for efficiently preparing a locked nucleic acid intermediate by a stepwise, mild alkali-promoted ring closure and a silicon reagent-mediated demethylation reaction. Background The core of the efficacy of antisense oligonucleotides (e.g., ASOs) is their specific, high affinity hybridization to target RNA sequences. First and second generation chemical modifications (e.g., PS backbone, 2' -O-MOE) improve pharmacokinetics, but have limited affinity enhancement. The discovery of Locked Nucleic Acids (LNA) and their derivatives (LNA/cEt) is a breakthrough development, which is characterized in that the 2'-O and 4' -C of ribofuranose are immobilized via a bridging structure to form a rigid N-type conformation, thus pre-organizing the oligonucleotide backbone such that it does not require entropy compensation when complementary to RNA, achieving a dramatic increase in binding affinity (Tm value). However, this generic affinity boosting is not equal in the context of different base sequences. It was found that guanine residues play a particularly critical and complex role in LNA/cEt modified oligonucleotides, affecting far beyond other bases (A, C, U/T), directly related to potency, specificity and safety of the drug. The deep understanding and optimization of the G-containing LNA/cEt unit is a key technical step in the development of efficient and safe nucleic acid pharmaceuticals. The compounds of formula I are key intermediates for the synthesis of LNA/cEt, I , Wherein R 1,R2 represents a protecting group for a hydroxyl group, and R 3 represents H, CN, C 1-C6 alkyl or substituted C 1-C6 alkyl. A typical process of the existing synthesis method of the general formula I is a one-pot method, and the specific reaction process comprises the steps of adding sodium hydride into tetrahydrofuran under anhydrous and anaerobic conditions, adding 3-hydroxy propionitrile under ice bath, stirring at room temperature for 1 hour, heating to room temperature, and continuing stirring for 16 hours. The process utilizes the extremely strong alkalinity of sodium hydride to simultaneously complete two key conversions (i) the deprotonation of the hydroxypropionitrile to form oxygen anions, and further nucleophilic attack is carried out on the electrophilic site in the molecule to realize ring closure, and (ii) the substitution of chlorine atom oxygen anions on guanine is carried out, and then the target product is obtained through one step of beta-elimination under the action of strong alkali. The existing technical route has the following defects: 1. Sodium hydride (NaH) is a dangerous product that reacts vigorously with water and releases hydrogen, with a risk of combustion and explosion. During large-scale production, great potential safety hazards exist in the links of feeding, reaction, quenching and post-treatment, and the requirements on equipment, operation rules and fire fighting in factories are extremely high. 2. The reaction must be carried out under strict anhydrous and inert gas (such as argon or nitrogen) protection, the dryness requirements on raw materials, solvents and equipment are extremely strict, any trace moisture can lead to reagent failure and risk initiation, and the process complexity and cost are increased. 3. Poor chemoselectivity the strong basicity and high reactivity of NaH often lead to the formation of by-product 1. These side reactions reduce the yield and selectivity of the main reaction, resulting in reduced product purity and difficulty in subsequent purification. 4. The limited functional group tolerance is that the strong base system has poor compatibility with a plurality of common functional groups (such as ester groups, amide groups, certain halogens, active hydrogen and the like), so that the generation of byproducts 2 is caused, the application of the strong base system in the synthesis of complex molecules or substrates with sensitive groups is severely limited, and the method has insufficient universality. The structures of byproducts 1 and 2 are as follows: 。 5. The process control and optimization are difficult, and the reaction progress and the intermediate quality of each step are difficult to be independently monitored and optimized because the ring closure and the demethylation continuously occur in one pot. Once a problem arises, the entire batch of material may be scrapped and the process robustness is poor. Therefore, there is an urgent need in the art to develop a new method that is safer to operate, milder in conditions, more selective, and more suitable for industrial production. Disclosure of Invention In view of various drawbacks of the prior art, the present invention provides a method