A method for preparing a compound

Abstract

The present disclosure relates to a method for preparing a compound, which comprises contacting a mixture with an organic base under conditions where a silyl migration reaction can occur, wherein the mixture contains a compound of formula (II) and an organic solvent, and the organic solvent is a solvent in which the compound of formula (I) is slightly soluble at room temperature. In the compound of formula (I) and the compound of formula (II), R1 is a silyl protecting group; R2 is a non-silyl protecting group; R3, R4, R5 and R6 are each independently one of hydrogen and C1-C4 alkyl; B is a group having a molecular weight between 50-420 and not participating in the silyl migration reaction. The method of the present invention has few operating steps, and most of the by-products are converted into products, the total yield is improved, and it is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for preparing a compound. Background Art

[0002] Phosphoramidite nucleoside monomers are key starting materials for the synthesis of small nucleic acid drugs. The nucleoside intermediates with protected 5' and 2' hydroxyl groups on the ribose ring and unprotected 3' hydroxyl group used in the preparation process are key intermediates for the preparation of phosphoramidite nucleoside monomers. Among them, the hydroxyl protecting group of the 2' hydroxyl group is generally a silane protecting group.

[0003] Non-patent literature (Damha MJ, Ogilvie KK (1993), Oligonucleotide synthesis: thsilyl-phosphoramidite method. In: Protocols for Oligonucleotides and Analogs: Synthesis and Properties, Methods in Molecular Biology (Agrawal S, ed.) Vol. 20. Totowa, NJ: The Humana Press Inc. pp. 81-114) discloses that nucleic acid base monomers protected by tert-butyldimethylsilyl (TBDMS) or triisopropylsilyl (TIPS) are easily generated during preparation as isomer mixtures in which the 2'- and 3'-hydroxyls have silane protecting groups. The 3'-silyl isomer can be isomerized to an equilibrium mixture of 2'- and 3'-silyl isomers in an approximately 1:1 ratio in an alkaline solution such as 9:1 pyridine: water (TBDMS protection) or 1% ammonia: ethanol (TIPS / N-Bz combination), thereby increasing the recovery rate of the 3'-silyl isomer. However, the aqueous phase solution used in this method is not suitable for the anhydrous and oxygen-free system required by the nucleoside phosphoramidite process currently widely used in the field of small nucleic acid drug synthesis, and requires additional product purification steps such as water removal; at the same time, this method can only obtain an equilibrium mixture of 2'- and 3'-silyl isomers, but cannot be completely converted. Therefore, the isomer mixture also requires additional separation steps to obtain the desired 2'-silyl isomer. Summary of the invention

[0004] The present disclosure provides a method for preparing a compound, which comprises contacting a mixture with an organic base under conditions capable of causing a silyl migration reaction, wherein the mixture contains a compound of formula (II) and an organic solvent, and the organic solvent is a solvent in which the compound of formula (I) is slightly soluble at room temperature:

[0005] Formula (I) Formula (II);

[0006] R1 is a silyl protecting group;

[0007] R2 is a non-silane hydroxyl protecting group;

[0008] R3, R4, R5 and R6 are each independently one of hydrogen and C1-C4 alkyl;

[0009] B is a group having a molecular weight of 50-420 and not participating in the silyl group migration reaction.

[0010] Beneficial Effects

[0011] Compared with the traditional nucleoside monomer preparation process, which requires more operation steps to convert the 3'-isomer byproduct into the 2'-isomer and the total yield of the product is not high, the method of the present invention has fewer operation steps, and most of the byproducts are converted into products, the total yield is improved, and it is suitable for industrial production.

[0012] For example, it is difficult to obtain a high-purity 2'-silyl isomer with high efficiency and high yield only by column chromatography separation method, and a large amount of 2'-, 3'-silyl isomer mixture is difficult to further separate. In contrast, using the method disclosed in the present invention, various compounds of formula (II) in a mixture containing different compounds of formula (II) and organic solvents can be efficiently converted into compounds of formula (I), and the compounds of formula (I) can be obtained by solid-liquid separation, with a yield of at least 73.8%, and a purity of at least 95.5% in the product of the compound of formula (I). Further, within the range of moderate organic base dosage, the method disclosed in the present invention can obtain a higher conversion rate and a higher product purity, with a yield of up to 89.3%; a purity of at least 97.5wt%, or even 98.2wt%; the content of by-products and impurities in the final product is low, and the content of the compound of formula (II) can be controlled below 0.5wt%, or even as low as 0.1wt%.

[0013] Incorporated by Reference

[0014] All publications, patents, and patent applications mentioned in this specification are incorporated by reference into the present disclosure to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference into the present disclosure. DETAILED DESCRIPTION

[0015] The specific embodiments of the present disclosure are described in detail below. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present disclosure, and are not used to limit the present disclosure.

[0016] It will be understood by those skilled in the art that for any group comprising one or more substituents, these groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically unfeasible, and / or inherently unstable.

[0017] Unless otherwise described, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. If a term is defined in multiple ways herein, the definition in that section shall prevail unless otherwise indicated. The singular forms "a", "an", and "the" used in this specification and the appended claims include plural indicators unless the context clearly dictates otherwise. Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are used. In addition, the use of the term "includes" and other forms, such as "comprises", "contains", and "includes" is not restrictive.

[0018] Although the present disclosure has been described and illustrated in detail in the foregoing description, these descriptions should be considered illustrative or exemplary rather than restrictive. The present disclosure is not limited to the disclosed embodiments. By studying the present disclosure and the appended claims, those skilled in the art can understand and implement changes in the disclosed embodiments in practicing the disclosure claimed for protection.

[0019] Unless otherwise defined, all terms (including technical and scientific terms) shall be given their ordinary and customary meanings to those of ordinary skill in the art and shall not be limited to special or customary meanings unless expressly defined herein. It should be noted that the use of a particular term when describing certain features or aspects of the present disclosure should not be understood as indicating that the term is hereby redefined to be limited to including any particular feature of the feature or aspect of the present disclosure associated with the term.

[0020] Where a range of values ​​is provided, it is understood that the upper and lower limits and every intervening value between the upper and lower limits of that range is encompassed within the embodiments.

[0021] As used herein, "nucleoside" is similar in structure to nucleotide, but lacks a phosphate moiety. An example of a nucleoside analog is a nucleoside analog in which a label is attached to a base and a phosphate group is not attached to the sugar molecule. The term "nucleoside" is used herein with its common meaning as understood by those skilled in the art. Examples include, but are not limited to, ribonucleosides comprising a ribose moiety and deoxyribonucleosides comprising a deoxyribose moiety. The modified pentose moiety is a pentose moiety in which an oxygen atom has been replaced by a carbon and / or a carbon has been replaced by a sulfur or oxygen atom. "Nucleoside" is a monomer that can have a substituted and / or sugar moiety. In addition, nucleosides can be incorporated into larger DNA and / or RNA polymers and oligomers.

[0022] As used herein, the terms "protecting group" and "protecting groups" refer to any atom or group of atoms added to a molecule to prevent an existing group in the molecule from undergoing an undesirable chemical reaction. Examples of protecting group moieties are described in TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd ed. John Wiley & Sons, 1999, and described in JFW McOmie, Protective Groups in Organic Chemistry, Plenum Press, 1973, which are limited to the purpose of disclosing suitable protecting groups, and are incorporated herein by reference. The selection of protecting groups can make them stable to certain reaction conditions and can be removed at a convenient stage using methods known in the art. A non-limiting list of protecting groups includes benzyl (Bn); substituted benzyl; alkylcarbonyl (e.g., tert-butyloxycarbonyl (BOC), acetyl (i.e., -C(=O)CH3 or Ac) or isobutyryl (iBu); arylalkylcarbonyl (e.g., benzyloxycarbonyl or benzoyl); silyl (e.g., trimethylsilyl (TMS), triethylsilyl, triisopropylsilyl), tert-butyldimethylsilyl (TBDMS), triisopropylsilyloxymethyl (TOM) or tert-butyldiphenylsilyl); and triarylmethyl groups (e.g., trityl; monomethoxytrityl (MMTr); 4,4''-dimethoxytrityl (DMTr); or 4,4'',4"-trimethoxytrityl (TMTr)).

[0023] As used herein, "derivatives" or "analogs" refer to synthetic nucleosides or nucleotide derivatives having modified base moieties and / or modified sugar moieties. Such derivatives and analogs are discussed, for example, in Scheit, Nucleotide Analogs (John Wiley & Sons, 1980) and Uhlman et al., Chemical Reviews 90: 543-584, 1990. As used herein, "derivatives" and "analogs" are used interchangeably and are covered by the term "nucleoside" as defined herein.

[0024] The present disclosure provides a method for preparing a compound, which comprises contacting a mixture with an organic base under conditions capable of causing a silyl migration reaction, wherein the mixture contains a compound of formula (II) and an organic solvent, and the organic solvent is a solvent in which the compound of formula (I) is slightly soluble at room temperature:

[0025] Formula (I) Formula (II);

[0026] R1 is a silyl protecting group;

[0027] R2 is a non-silane hydroxyl protecting group;

[0028] R3, R4, R5 and R6 are each independently one of hydrogen and C1-C4 alkyl;

[0029] B is a group having a molecular weight of 50-420 and not participating in the silyl group migration reaction.

[0030] Without being limited by theory, it is known in the art that under conditions where a silyl migration reaction can occur, the 2'hydroxyl group and the 3'hydroxyl group are unprotected and the other isomers of the nucleoside intermediate protected by a silyl protecting group are isomerized in the solution, and there is a dynamic equilibrium of mutual conversion between different isomers. The inventors of the present disclosure unexpectedly found that due to the different solubility of 2'- and 3'-silyl isomers in the same solvent, in a specific type of organic solvent, the 2'-silyl isomer can be separated from the solvent by crystallization, so that in order to maintain the above dynamic equilibrium in the solution, the 3'-silyl isomer is continuously converted to the 2'-silyl isomer until almost all of them are converted to the 2'-silyl isomer and crystallized, thereby completing the present disclosure. In order to achieve the above purpose, the organic solvent is a solvent in which the compound of formula (I) is slightly soluble at room temperature. In some embodiments, "slightly soluble" includes a solubility of 0.01g-1g / L at 20°C and 1 atmosphere. In some embodiments, the organic solvent is selected from one or more of alcohols, esters, ethers, acids, ketones, nitrogen-containing heterocyclic compounds and halogenated alkanes. In some embodiments, the organic solvent is selected from one or more of methanol, ethanol, acetone, pyridine, acetic acid, isopropyl ester, ethyl acetate, methyl tert-butyl ether and / or dichloromethane. In some embodiments, the organic solvent is selected from one or more of methanol, ethanol, acetone, pyridine, acetic acid and isopropyl ester. In order to achieve the complete degree of the above-mentioned conversion and the cost balance of the amount of solvent used, in some embodiments, the weight-to-volume ratio of the compound of formula (II) to the organic solvent is 1: 1-20kg / L. In some embodiments, the weight-to-volume ratio of the compound of formula (II) to the organic solvent is 1: 2-6kg / L.

[0031] Those skilled in the art are aware of various reaction conditions for the migration of silicon-based protective groups. As long as the reaction conditions are such that the migration of silicon-based protective groups occurs after the mixture containing the compound of formula (II) and the organic solvent is contacted with the organic base, the reaction conditions can be used in the present disclosure. In some embodiments, the conditions for the silyl migration reaction to occur include one or more of the following conditions:

[0032] The reaction temperature is -10-35°C;

[0033] The reaction time is 4-36 hours;

[0034] The weight volume ratio of the compound of formula (II) to the organic base is 1:0.1-1.2 kg / L.

[0035] In some embodiments, the conditions under which the silane migration reaction can occur include one or more of the following conditions:

[0036] The reaction temperature is -5°C-30°C;

[0037] The reaction time is 10-14 hours;

[0038] The weight volume ratio of the compound of formula (II) to the organic base is 1:0.4-0.6 kg / L.

[0039] In some embodiments, the conditions under which the silyl group migration reaction can occur further include carrying out the reaction under a suitable pressure and atmosphere, such as carrying out the reaction under normal pressure and air atmosphere.

[0040] The role of the organic base is to provide alkaline reaction conditions, promote the breaking of the chemical bond between the silicon atom in the silane protecting group and the oxygen atom in the silane protecting group, thereby facilitating the occurrence of the silane migration reaction. In some embodiments, the organic base is selected from one or more of C3-C12 organic amine compounds and nitrogen-containing heterocyclic compounds. In some embodiments, the amine compound is at least one of trimethylamine, triethylamine, tripropylamine, diisopropylamine, N,N-diisopropylethylamine or diisopropylamine; in some embodiments, the nitrogen-containing heterocyclic compound is selected from imidazole or pyridine. In some embodiments, the organic base is selected from one or more of diisopropylamine, pyridine, propylenediamine or triethylamine.

[0041] In some embodiments, B is a nucleic acid base or a universal base group in which any amino group (if any) is protected; in some embodiments, B is selected from one of U, T, protected A, protected C, protected 5-methyl C, and protected G. "Universal base" refers to a base analog that can replace a nucleic acid base and pair with all four standard bases. In some embodiments, the universal base is one of hypoxanthine bromouracil, 3-nitropyrrole, 5-nitroindole, or 7-azaindole.

[0042] In some embodiments, B is one of the following groups:

[0043]

[0044] Among them, R Nis an amino protecting group. N is one of acetyl, propionyl, isobutyryl, benzoyl, Fmoc protecting group or Boc protecting group. N is one of acetyl, isobutyryl or benzoyl. In some embodiments, B is one of A (Bz), G (iBu), C (Ac) and U:

[0045] (A(Bz))、 (G(iBu))、 (C(Ac)), (U).

[0046] The silyl protecting group is a silyl protecting group commonly used in the field of nucleic acid pharmaceuticals in the art. In some embodiments, the silyl protecting group is a substituted silyl group. In some embodiments, the silyl protecting group is a trialkyl substituted silyl group. In some embodiments, the silyl protecting group is (R a )3Si- or (R a )2SiR b - shown group, where each R a , R b Each is independently hydrogen, a C1-C6 straight or branched alkyl, a phenyl or a substituted phenyl, but not simultaneously hydrogen. In some embodiments, the silyl protecting group is selected from one of tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), trimethylsilyl (TMS), triethylsilyl (TES) and methyldiisopropylsilyl (MDIPS).

[0047] The non-silane hydroxyl protecting group is a ribose 5' hydroxyl protecting group commonly used in the field of nucleic acid pharmaceuticals. In some embodiments, the non-silane hydroxyl protecting group is (R c )3C- shown as a triarylmethyl group, each R cIn some embodiments, the non-silane hydroxyl protecting group is 4,4'-dimethoxytrityl, trityl or 4-methoxytriphenyl, acetyl, tert-butyl, tert-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, bis(2-acetoxyethoxy)methyl (ACE), benzoylformate, chloroacetyl, tris(2-acetoxyethoxy)methyl, ... Chloroacetyl, trifluoroacetyl, pivaloyl, benzoyl, p-phenylbenzoyl, 9-fluorenylmethyl carbonate, mesylate, tosylate, triphenylmethyl (trityl), monomethoxytrityl, dimethoxytrityl (DMT), trimethoxytrityl, 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl (FPMP), 9-phenylxanthine-9-yl (Pixyl) and 9-(p-methoxyphenyl)xanthine-9-yl (MOX) are one of them. In some embodiments, the non-silane hydroxyl protecting group is 4,4'-dimethoxytrityl or trityl or 4-methoxytriphenyl.

[0048] R3, R4, R5 and R6 are each independently one of hydrogen and C1-C4 alkyl. Considering the balance between cost and synthesis efficiency, in some embodiments, R3, R4, R5 and R6 are each independently hydrogen, methyl or ethyl. In some embodiments, R3, R4, R5 and R6 are all hydrogen.

[0049] In some embodiments, the compound of formula (II) is

[0050] ,

[0051] or .

[0052] In some embodiments, the mixture further contains a compound represented by formula (I):

[0053] Formula (I)

[0054] Wherein, the definition and selection range of R1-R6 and B are the same as above. In some embodiments, R1-R6 and B in the compound represented by formula (I) contained in the mixture are the same as R1-R6 and B in the compound represented by formula (II), and the only difference is that the connection position of the silyl protecting group represented by R1 is different.

[0055] In some embodiments, the weight ratio of the compound of formula (I) to the compound of formula (II) in the mixture is 1:1.2-2.0. In some embodiments, based on the total weight of the compound of formula (I) and the compound of formula (II), the content of the compound of formula (I) is 15-40wt.%; the content of the compound of formula (II) is 55%-85wt.%. In some embodiments, the content of the compound of formula (I) is 20-35wt.%; the content of the compound of formula (II) is 60%-80wt.%. In some embodiments, the compound of formula (I) and the compound of formula (II) in the mixture are obtained by silylation reaction of the compound represented by formula (III):

[0056] Formula (III)

[0057] The definitions and selection ranges of R2-R6 and B are the same as above.

[0058] In some embodiments, the compound of formula (I) is , or .

[0059] In some embodiments, the method further includes the step of performing solid-liquid separation. In some embodiments, the solid-liquid separation may include the following steps in sequence: filtering the reaction mixture to separate the solid; rinsing the obtained solid with an organic solvent; and collecting the solid after drying and removing the solvent. In some embodiments, the organic solvent used for rinsing is the same as the organic solvent in the mixture in which the silane migration reaction occurs. In some embodiments, the organic solvent used for rinsing is selected from one or more of methyl tert-butyl ether, methanol, ethanol, n-butanol, dichloromethane and ethyl acetate. Various suitable filtering methods can be used in the present disclosure. In some embodiments, examples include but are not limited to vacuum filtration and centrifugal filtration. In some embodiments, the solid-liquid separation is carried out at a temperature of -5°C-35°C. In some embodiments, the rinsing is carried out at a temperature of -5°C-5°C.

[0060] Example

[0061] The present disclosure and its beneficial effects are described in detail below in conjunction with specific embodiments.

[0062] The sources of the reagents and instruments used in the following examples are shown in Table 1 below:

[0063] Table 1 Sources of reagents and instruments

[0064]

[0065] Example 1

[0066] 200g of 5'-DMT-isobutyrylguanosine (mixture of 2'- and 3'-tert-butyldimethylsilane protecting group isomers) (HPLC detection showed that the purity of 2'-silyl isomer was 23wt%, the purity of 3'-silyl isomer was 72wt%, and the rest were impurities) was added to a reaction bottle containing 800mL of acetone and ethanol mixed solvent (the volume ratio of acetone to ethanol was 1:1). At this time, the system was a yellow turbid liquid. 6 0mL propylenediamine was stirred at room temperature (25℃-30℃) for 12hrs to precipitate a white solid. The whole system changed from yellow to off-white. The turbid liquid was vacuum filtered and the filter cake was washed three times with a mixed solvent of acetone and ethanol at 0℃ (volume ratio of 1:1), 50ml each time, filtered and dried to obtain 153g of solid with a yield of 73.8wt%. HPLC analysis showed that it contained 96.5wt% of 2'-silyl isomers and only 0.5wt% of 3'-silyl isomers.

[0067] Example 2

[0068] 200g of a mixture of 5'-DMT-uridine (a mixture of 2'- and 3'-tert-butyldimethylsilane protecting group isomers) (HPLC detection showed that the purity of the 2'-silyl isomer was 33wt%, the purity of the 3'-silyl isomer was 63wt%, and the rest were impurities) was added to a reaction bottle containing 800mL of methanol. At this time, the system was dissolved and clarified. 80mL of triethylamine was added under stirring at room temperature (25℃-30℃). After stirring at room temperature (25℃-30℃) for 12hrs, a white solid was precipitated. The mixture was vacuum filtered, and the filter cake was rinsed three times with 0℃ methanol solution, 50ml each time, filtered, and dried to obtain 166g of solid with a yield of 80.9wt%. HPLC detection showed that the 2'-silyl isomer was 97.5wt%, and the 3'-silyl isomer content was only 0.4wt%.

[0069] Example 3

[0070] 200g of 5'-DMT-N6-Bz-adenosine (mixture of 2'- and 3'-tert-butyldimethylsilane protecting group isomers) (HPLC detection showed that the purity of 2'-silyl isomer was 27wt%, the purity of 3'-silyl isomer was 65wt%, and the rest were impurities) was added to a reaction bottle containing 800mL of pyridine, and the system was dissolved at room temperature (25℃-30℃) until it was clear. After stirring at room temperature (25℃-30℃) for 18hrs, a white solid was precipitated, and vacuum filtered. The filter cake was rinsed with 0℃ pyridine three times, 50ml each time, filtered, and dried to obtain 170g of solid with a yield of 81.1%. The content of 2'-silyl isomer was 95.5wt%, and the content of 3'-silyl isomer was only 0.4wt%.

[0071] Example 4

[0072] 200g of 5'-DMT-acetylcytidine (mixture of 2'- and 3'-tert-butyldimethylsilane protecting group isomers) (HPLC detection showed that the purity of 2'-silyl isomer was 22wt%, the purity of 3'-silyl isomer was 75wt%, and the rest were impurities) was added into a reaction bottle containing 800ml of a mixed solvent of acetic acid and isopropyl ester (the volume ratio of acetic acid to isopropyl ester was 1:1). The mixture dissolved and the system became clear. Stir at room temperature (25℃-30℃) for 3 hours. After stirring, 80 mL of diisopropylamine was added. After stirring at room temperature (25°C-30°C) for 12 hrs, a white solid was precipitated and the whole system changed from yellow to off-white. The turbid liquid was vacuum filtered and the filter cake was rinsed three times with the aforementioned acetic acid and isopropyl ester mixed solvent at 0°C, 50 ml each time, filtered, dried, and scraped off the filter cake to obtain 182 g of filter cake with a yield of 89.3%, containing 98.2 wt% of 2'-silyl isomers and only 0.1 wt% of 3'-silyl isomers.

[0073] The results of the above examples show that the method of the present invention can efficiently convert various compounds of formula (II) in a mixture containing different compounds of formula (II) and organic solvents into compounds of formula (I), and obtain compounds of formula (I) by solid-liquid separation, with a yield of at least 73.8%, and a purity of at least 95.5% for the compound of formula (I) in the product. Furthermore, within a moderate range of organic base dosage, the method of the present invention can achieve a higher conversion rate and a higher product purity, with a yield of up to 89.3%; a purity of at least 97.5wt%, or even 98.2wt%; and a low content of by-products and impurities in the final product, and the content of the by-product compound of formula (II) can be controlled below 0.5wt%, or even as low as 0.1wt%.

[0074] Comparative Example 1

[0075] Column chromatography was used to separate 200 g of 5'-DMT-isobutyrylguanosine (a mixture of 2'- and 3'-tert-butyldimethylsilane protecting group isomers) (HPLC detection showed that the purity of the 2'-silyl isomer was 44 wt%, the purity of the 3'-silyl isomer was 52 wt%, and the rest were impurities) in 200 mL of dichloromethane. The column chromatography used 1 kg of 100-200 mesh silica gel as the stationary phase, and the column was neutralized with 5 L of n-hexane containing 3‰ (v / v) triethylamine, and the sample was loaded by wet method. The eluent was first eluted with pure dichloromethane until the 2'-tert-butyldimethylsilane protecting group isomer was obtained, and then a mixed solvent of ethyl acetate: dichloromethane = 4:1 (v / v) was used. The isomer composition in the eluent was monitored by TLC monitoring plate, and the eluents containing 2'-tert-butyldimethylsilane protecting group isomer, 2'-, 3'-tert-butyldimethylsilane protecting group isomer mixture and 3'-tert-butyldimethylsilane protecting group isomer were collected respectively. The eluents containing different isomers were evaporated to dryness and weighed to obtain 40g of 2'-silyl isomer with a purity of 95%, 110g of 2'-, 3'-silyl isomer mixture, and 45g of 3'-silyl isomer with a purity of 95%. The yield of 2'-silyl isomer was only 20%.

[0076] It can be seen from the above results that it is difficult to obtain high-purity 2'-silyl isomers with high efficiency and high yield only by column chromatography separation method, and a large amount of 2'- and 3'-silyl isomer mixtures are difficult to further separate. In contrast, the method of the present invention can effectively obtain 2'-silyl isomers with high yield and purity, low content of impurities (such as 3'-silyl isomers), and is suitable for industrial production.

Claims

1. A method for preparing a compound of formula (I), comprising contacting a mixture with an organic base under conditions capable of causing a silyl migration reaction, wherein: The mixture contains a compound of formula (II) and an organic solvent, Formula (I) Formula (II), wherein The compound of formula (II) is specifically: , , or , The weight volume ratio of the compound of formula (II) to the organic solvent is 1:2-6 kg / L; the organic solvent is selected from one or more of methanol, ethanol, acetone, pyridine, acetic acid or isopropyl ester; The weight volume ratio of the compound of formula (II) to the organic base is 1:0.4-0.6 kg / L, and the organic base is one or more of trimethylamine, triethylamine, tripropylamine, diisopropylamine, N,N-diisopropylethylamine, propylenediamine, imidazole or pyridine; The conditions under which the silane migration reaction can occur are: The reaction temperature is -10-35°C; The reaction time is 4-36 hours.

2. The method according to claim 1, wherein: The conditions under which the silane migration reaction can occur are: The reaction temperature is -5°C-35°C; The reaction time is 10-14 hours.

3. The method according to claim 1 or 2, wherein: The organic base is selected from one or more of diisopropylamine, pyridine, propylenediamine or triethylamine.

4. The method according to claim 1 or 2, wherein: The mixture also contains a compound represented by formula (I); Alternatively, the weight ratio of the compound of formula (I) to the compound of formula (II) in the mixture is 1:1.2-2.

0.

5. The method according to claim 4, wherein: The compound of formula (I) is , or .

6. The method according to claim 1, further comprising the step of performing solid-liquid separation.

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