Preparation method of R-configuration ribofuranose derivative

Abstract

The invention provides a method for converting a 4-C-hydroxymethyl-1, 2-O-isopropylidene-alpha-D-ribofuranose derivative from an S configuration to an R configuration isomer through a silicon-based migration reaction, and the method can be applied to further reaction in preparation of locked nucleic acid derivatives. The method has the advantages of high yield, high purity, simplicity in operation, stable process, easiness in industrial production and the like, and has a very good application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of nucleic acid intermediate synthesis, and particularly relates to a preparation method of an R configuration furanose derivative. BACKGROUND

[0002] Locked nucleic acid (LNA) is an oligonucleotide derivative. Since the end of last century, LNA has been rapidly applied in the fields of biology, chemistry, medicine and the like. Specifically, the main applications include antisense drugs, SNP typing detection, gene mutation detection, LNA modified aptamer, tumor treatment monitoring and the like. The 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-furanose intermediate with substituents at positions 3 and 5 is an important basic intermediate raw material for synthesis of LNA, and has an irreplaceable role. In the scientific research field and pharmaceutical industry production, the 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-furanose intermediate has a broad market demand and great application prospect.

[0003] In the synthesis method of the R configuration 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-furanose derivative disclosed at present, R and S configurations are generated at the same time. Due to the existence of a high content of S type isomer, it is extremely difficult to separate the R configuration product, and therefore the price of the R configuration 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-furanose derivative is high, which seriously hinders the research and production of LNA drugs. In order to improve the yield of the R configuration 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-furanose derivative, the method of the prior art focuses on reducing the proportion of the byproduct S isomer, and mainly improves the R / S ratio by screening alkali, prolonging the reaction time and replacing different protecting groups, that is, the isomer ratio is improved by means of the proton abstraction ability of alkali and the steric hindrance of the protecting group, and then the R configuration 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-furanose derivative is obtained by chiral separation, so as to improve the yield of the R configuration 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-furanose derivative. However, due to the large amount of S configuration, it is a great challenge to separate the two isomers, and in the separation process, the product is greatly lost, the reagent consumption is large, the operation is complex, and a large amount of financial and material resources is consumed. Therefore, it is still a difficult problem to effectively prepare the R configuration 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-furanose derivative with high yield and high purity. SUMMARY

[0004] The present application aims at overcoming the problems of low yield, low selectivity and low purity in preparing R configuration 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranose derivative in the prior art, and provides an R configuration 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranose derivative with simple steps, stable process and easy industrial production.

[0005] Specifically, the present application first provides a method for synthesizing R configuration 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranose derivative, and the specific technical solution is as follows: the S configuration 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranose derivative shown in formula I is dissolved in a solvent, and is converted into the R configuration 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranose derivative shown in formula II through silicon-based migration reaction under the action of a base.

[0006]

[0007] In the formula, R1 and R2 are hydroxyl protecting groups.

[0008] Further, the above-mentioned synthesis method further comprises a recrystallization step.

[0009] On the other hand, the present application also provides a preparation method of R configuration 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranose derivative, which comprises the following steps:

[0010] Step one), the compound of formula III is subjected to hydroxyl protection reaction with a hydroxyl protection reagent R2X under the action of a base to obtain a mixture of formula I and formula II;

[0011] Step two), the mixture obtained in step one) is reacted under the action of a base to prepare formula II, and the synthesis route is as follows:

[0012]

[0013] In the formula, R1 and R2 are hydroxyl protecting groups.

[0014] Further, the above-mentioned synthesis method further comprises a recrystallization step.

[0015] Compared with the prior art, the present application has the following beneficial effects:

[0016] (1) The S configuration by-product obtained by using the method of the prior art is directly converted into the R configuration 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranose derivative, which has great economic value.

[0017] (2) The preparation method of the present application can directly convert the reaction into the R configuration of 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranose derivative without the need to separate the mixture of R / S configuration.

[0018] (3) The preparation method of the present application can directly prepare the R configuration of 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranose derivative with higher purity, and can also prepare the R configuration of 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranose derivative with higher purity through recrystallization, the post-treatment process is more green and environmentally friendly, and is conducive to scale-up production. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 High performance liquid chromatogram of the reaction liquid of Example 1

[0020] Figure 2 High performance liquid chromatogram of the reaction liquid of Comparative Example 1

[0021] Figure 3 High performance liquid chromatogram of the reaction liquid of Comparative Example 2

[0022] Figure 4 High performance liquid chromatogram of the reaction liquid of Comparative Example 9

[0023] Figure 5 High performance liquid chromatogram of the reaction liquid of Example 1 after recrystallization purification

[0024] Figure 6 Nuclear magnetic resonance hydrogen spectrum of the product (R)-3-O-(2-naphthylmethyl)-4-C-hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O-isopropylidene-α-D-ribofuranose of Example 1 DETAILED DESCRIPTION

[0025] The specific embodiments of the present application will be further described in detail below with reference to the examples and drawings. In order to make the purpose, technical scheme and advantages of the embodiments of the present application more clear, the technical scheme in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application. Unless otherwise explicitly indicated, in the entire specification and claims, the term "comprise" or its variants such as "include" or "comprise" and the like will be understood to include the stated component or step, and not exclude other material components or steps.

[0026] In the present application, the halogen is fluorine, chlorine, bromine and iodine.

[0027] Room temperature in the present application refers to 20℃±5℃.

[0028] In addition, for a better illustration of the present application, numerous specific details are given in the following specific embodiments. Those skilled in the art should understand that the present application can also be implemented without certain specific details. In some embodiments, the raw materials, methods, means and the like which are well known to those skilled in the art are not described in detail, in order to highlight the main idea of the present application.

[0029] Specifically, the present application first provides a method for synthesizing R configuration 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranose derivative, and the specific technical solutions are as follows: the S configuration 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranose derivative shown by formula I is converted into the R configuration 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranose derivative shown by formula II under the action of a base.

[0030]

[0031] In the formula, R1 and R2 are hydroxyl protecting groups.

[0032] R1 is preferably one of acetyl, tert-butyl, tert-butyloxymethyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl, diphenylmethyl, p-methoxybenzyl, p-nitrobenzyl, di(2-acetoxyethoxy)methyl, 2-trimethylsilylethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tritylsilyl, [(triisopropylsilyl)oxy]methyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, diphenylacetyl, pivaloyl, benzoyl, p-phenylbenzoyl, benzoylformate, 9-fluorenylmethyl carbonate, mesylate, p-toluenesulfonate, trityl, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl, 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, 9-phenylxanthine-9-yl, 9-(p-methoxyphenyl)xanthine-9-yl and 2-naphthylmethyl.

[0033] R2 is preferably one of trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and tritylsilyl, and is particularly preferably tert-butyldiphenylsilyl.

[0034] In the above synthesis method, the base is an organic base or an inorganic base; the inorganic base is preferably one of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, potassium acetate, sodium acetate, and sodium hydride; the organic base is preferably one of N,N-diisopropylethylamine, triethylamine, imidazole, triethylenediamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and diisobutylaluminum hydride; and sodium hydride is particularly preferred.

[0035] In the above synthesis method, the molar ratio of the base to formula I is 0.5-5:1, preferably 1.1-4:1.

[0036] In the above synthesis method, the reaction time is 8-22 hours, preferably 16-22 hours; and the reaction temperature is -20-35℃, preferably -10- room temperature, and more preferably -10-10℃.

[0037] In the above synthesis method, the reaction is preferably carried out under the protection of an inert gas, preferably nitrogen or argon; and the reaction is preferably carried out with formula I dissolved in a solvent, which includes water and an organic solvent, preferably an organic solvent, and the organic solvent is preferably one of dichloromethane, ethyl acetate, tetrahydrofuran, acetonitrile, dioxane, methanol, ethanol, toluene, sec-butanol, and N,N-dimethylformamide, and N,N-dimethylformamide is particularly preferred.

[0038] Further, the above synthesis method further includes a recrystallization step.

[0039] The recrystallization step includes the steps of adding the crude product of R-configuration 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranose derivative to an organic solvent, heating and dissolving, cooling, and filtering.

[0040] In the above recrystallization step, the organic solvent is preferably one or more of n-hexane, n-heptane, acetone, ethyl acetate, chloroform, and dioxane, and n-heptane is more preferred.

[0041] In the above recrystallization step, the heating and dissolving process is preferably carried out under stirring, and after cooling, incubation is preferably carried out at -10-25℃. The incubation time is 0.5-10h, and stirring is preferably carried out during the incubation.

[0042] Further, the present application also provides a synthesis method of an R-configuration compound shown as formula II, which prepares the compound shown as formula II from a compound shown as formula III, and specifically includes the following steps:

[0043] Step one), the compound shown as formula III is subjected to a hydroxyl protection reaction with a hydroxyl protection reagent R2X under the action of a base to obtain a mixture of formula I and formula II;

[0044] Step two), the mixture obtained in step one) is reacted in the presence of a base to produce Formula II, the synthetic route is as follows:

[0045]

[0046] wherein R1, R2 are hydroxyl protecting groups, and X is a leaving group.

[0047] R1 is preferably acetyl, tert-butyl, tert-butoxymethyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl, diphenylmethyl, p-methoxybenzyl, p-nitrobenzyl, di(2-acetoxyethoxy)methyl, 2-trimethylsilylethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triphenylsilyl, [(triisopropylsilyl)oxy]methyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, diphenylacetyl, pivaloyl, benzoyl, p-phenylbenzoyl, benzoylformate, 9-fluorenylmethyl carbonate, mesylate, p-toluenesulfonate, trityl, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl, 1-(2-fluorophenyl)-4-methoxy-piperidin-4-yl, 9-phenylxanthin-9-yl, 9-(p-methoxyphenyl)xanthin-9-yl, or 2-naphthylmethyl.

[0048] R2 is preferably one of trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and particularly preferably tert-butyldiphenylsilyl.

[0049] X is preferably halogen.

[0050] The above-mentioned step one) is preferably carried out in an organic solvent, which can be one of N,N-dimethylformamide, dichloromethane, ethyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, acetonitrile, dioxane, and preferably N,N-dimethylformamide.

[0051] The above-mentioned base in step one) is an organic base or an inorganic base; the inorganic base includes sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, potassium acetate, sodium acetate, sodium hydride; the organic base includes N,N-diisopropylethylamine, triethylamine, imidazole, triethylenediamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, diisobutylaluminum hydride, pyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine; preferably triethylamine;

[0052] The hydroxyl-protecting reagent R2X in step 1) is one of trimethylsilyl chloride, triethylsilyl chloride, tert-butyldimethylsilyl chloride, tert-butyldiphenylsilyl chloride, triphenylsilyl chloride, preferably tert-butyldiphenylsilyl chloride.

[0053] Preferably, step 1) is carried out under the protection of an inert gas, preferably nitrogen or argon.

[0054] The reaction time of step 1) is 16-48 hours, preferably 22-40 hours; the reaction temperature is -5-35℃, preferably 25-35℃.

[0055] In step 1), the molar ratio of the compound of formula III, the hydroxyl-protecting reagent R2X and the base is 1:1.20-1.40:1.55-1.65.

[0056] In step 2), the base is an organic base or an inorganic base; the inorganic base is preferably one of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, potassium acetate, sodium acetate, sodium hydride; the organic base is preferably one of N,N-diisopropylethylamine, triethylamine, imidazole, triethylenediamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, diisobutylaluminum hydride; particularly preferably, the base is sodium hydride.

[0057] In step 2), the molar ratio of the base to the compound of formula III is 0.25-2.5:1, preferably 0.5-2:1.

[0058] In step 2), the reaction time is 8-22 hours, preferably 16-22 hours; the reaction temperature is -20-35℃, preferably -10- room temperature, more preferably -10-10℃.

[0059] In step 2), the reaction is preferably carried out in a solvent, which includes water and an organic solvent, preferably an organic solvent, and the organic solvent is preferably one of ethanol, toluene, sec-butanol and N,N-dimethylformamide, particularly preferably N,N-dimethylformamide. Preferably, the reaction is carried out under the protection of an inert gas, preferably nitrogen or argon.

[0060] Preferably, the preparation method further comprises a recrystallization step, which comprises the steps of adding the crude product of R configuration 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranose derivative into an organic solvent, heating to dissolve, cooling, and filtering.

[0061] In the recrystallization step, the organic solvent is preferably one or more of n-hexane, n-heptane, acetone, ethyl acetate, chloroform and dioxane, more preferably n-heptane.

[0062] The heating and dissolving process in the recrystallization step is preferably carried out under stirring, and after cooling, the temperature is preferably maintained at -10-25°C. The temperature maintaining time is 0.5-10h, and preferably, stirring is carried out during the temperature maintaining process.

[0063] In the following examples, the experimental methods not specified in the specific conditions are preferably referred to the guidelines given in the present application, and can also be carried out according to the experimental manuals or conventional conditions in the art, or according to other experimental methods known in the art, or according to the conditions suggested by the manufacturers. In the following specific examples, the measurement parameters of the raw material components, such as the amount, can have slight deviations within the weighing accuracy range if not otherwise specified. The temperature and time parameters allow acceptable deviations caused by the instrument testing accuracy or operation accuracy. The experimental methods used in the following examples are conventional methods if not otherwise specified. The reagents, materials, etc. used in the following examples can be obtained from commercial channels if not otherwise specified.

[0064] Example 1: Synthesis of (R)-3-O-(2-naphthylmethyl)-4-C-hydroxymethyl-5-O-tert- butyldiphenylsilyl-1,2-O-isopropylidene-α-D-ribofuranose

[0065]

[0066] Under nitrogen protection, 5.00L of DMF was added to a reaction kettle, and (S)-3-O-(2-naphthylmethyl)-4-C-hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O- isopropylidene-α-D-ribofuranose (1.00kg, 1.67mol) was added and stirred to dissolve. The temperature was lowered to -10-0°C, and sodium hydride (44.08g, 1.84mol) was slowly added in multiple batches, and the temperature was kept below 0°C during the process. After the addition was completed, the temperature was kept for 16 hours, and the reaction was stopped. HPLC showed that the ratio of R configuration and S configuration was 98:2. 10.00L of water was slowly added dropwise, and the temperature was kept below 0°C during the process. After the dropwise addition was completed, the stirring was continued for 30 minutes, and ethyl acetate was added to extract the reaction solution. The organic phase was washed with 2.00L of saturated ammonium chloride solution, water, and sodium chloride solution, respectively, each for one time. After the organic phase was concentrated under reduced pressure, it was recrystallized with n-heptane, filtered and centrifuged, and dried to obtain 0.95kg of (R)-3-O-(2-naphthylmethyl)-4-C-hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O-isopropylidene-α-D-ribofuranose in the form of white powder solid, with a HPLC purity of 99.71% and a yield of 94.81%. 1H NMR (300 MHz, Chloroform-d) δ 7.85 - 7.78 (m, 4H), 7.62 - 7.46 (m, 7H), 7.41 - 7.27 (m, 6H), 5.81 (d, J = 3.7 Hz, 1H), 4.97 (d, J = 12.0 Hz, 1H), 4.74 - 4.64 (m, 2H), 4.48 (d, J = 5.2 Hz, 1H), 3.94 - 3.80 (m, 2H), 3.80 - 3.65 (m, 2H), 1.99 (br, 1H), 1.67 (s, 3H), 1.38 (s, 3H), 0.92 (s, 9H).

[0067] Example 2: Synthesis of (R)-3-O-(2-naphthylmethyl)-4-C-hydroxymethyl-5-O-tert- butyldiphenylsilyl-1,2-O-isopropylidene-a-D-ribofuranose

[0068]

[0069] Into a reaction kettle, 27.50 L of dichloromethane was added, 3-O-(2- naphthylmethyl)-4-C-hydroxymethyl-1,2-O-isopropylidene-a-D-ribofuranose (5.5 kg, 15.26 mol) was added, heated to 30 °C and stirred for 30 min until the solution was clear. The temperature was lowered to -5 °C, and TBDPSCl (5.03 kg, 18.31 mol) was added dropwise, and stirring was continued for 30 min. Triethylamine (2.47 kg, 24.42 mol) was added slowly in portions, and the temperature was maintained below 0 °C during the addition. After the addition was completed, the temperature was maintained and stirring was continued for 30 min. The temperature was raised to 30 °C and stirring was continued for 32 h. HPLC monitoring showed that the remaining raw material was <2%, the reaction was stopped, and the ratio of R configuration and S configuration was 76:24. The temperature was lowered to -5 °C. 19.25 L of 1 N HC1 was added slowly dropwise, and the temperature was maintained below 0 °C during the addition. After the addition was completed, stirring was continued for 30 min, and the mixture was allowed to stand for 1 h, and then it was separated into layers. The organic phase was washed with 9% NaHC03 aqueous solution, saturated sodium chloride solution, and water, respectively, each once. The organic phase was concentrated under reduced pressure and introduced into the reaction kettle.

[0070] Into the reactor, 27.50 L of DMF was added and stirred to dissolve. The temperature was lowered to -10-0 °C, and sodium hydride (219.73 g, 9.16 mol) was slowly added in portions, keeping the temperature below 0 °C. After the addition was completed, the temperature was maintained for 16 hours. The reaction was stopped, and HPLC showed that the ratio of R configuration and S configuration was 98:2. 110.00 L of water was slowly added dropwise, keeping the temperature below 0 °C during the dropwise addition. After the dropwise addition was completed, the mixture was stirred for 30 minutes. Ethyl acetate was added to extract the reaction solution. The organic phase was washed with 11.00 L of saturated ammonium chloride solution, water, and sodium chloride solution, respectively, once each. The organic phase was concentrated under reduced pressure, and then recrystallized with n-heptane. After filtration, centrifugation, and drying, 7.43 kg of (R)-3-O-(2-naphthylmethyl)-4-C-hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O- isopropylidene-α-D-ribofuranose was obtained as a white powder solid, with a HPLC purity of 96.71%, and a two-step yield of 81.31%.

[0071] Example 3: Synthesis of (R)-3-O-benzyl-4-C-hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O- isopropylidene-α-D-ribofuranose

[0072]

[0073] Into the reactor, 27.50 L of DMF was added and stirred to dissolve. The temperature was lowered to -10-0 °C, and sodium hydride (219.73 g, 9.16 mol) was slowly added in portions, keeping the temperature below 0 °C. After the addition was completed, the temperature was maintained for 16 hours. The reaction was stopped, and HPLC showed that the ratio of R configuration and S configuration was 98:2. 110.00 L of water was slowly added dropwise, keeping the temperature below 0 °C during the dropwise addition. After the dropwise addition was completed, the mixture was stirred for 30 minutes. Ethyl acetate was added to extract the reaction solution. The organic phase was washed with 11.00 L of saturated ammonium chloride solution, water, and sodium chloride solution, respectively, once each. The organic phase was concentrated under reduced pressure, and then recrystallized with n-heptane. After filtration, centrifugation, and drying, 7.43 kg of (R)-3-O-(2-naphthylmethyl)-4-C-hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O- isopropylidene-α-D-ribofuranose was obtained as a white powder solid, with a HPLC purity of 96.71%, and a two-step yield of 81.31%.

[0074] Into the reactor, 5.00 L of DMF was added and stirred to dissolve. The temperature was lowered to -10-0°C, and sodium hydride (46.40 g, 1.93 mol) was slowly added in portions, and the temperature was kept below 0°C during the process. After the addition was completed, the temperature was kept for 16 hours. HPLC showed that the ratio of R configuration and S configuration was 96:4. 10.00 L of water was slowly added dropwise, and the temperature was kept below 0°C during the process. After the dropwise addition was completed, the mixture was stirred for 30 minutes. Ethyl acetate was added to extract the reaction solution. The organic phase was washed with 2.00 L of saturated ammonium chloride solution, water, and sodium chloride solution, respectively. The organic phase was concentrated under reduced pressure, and then recrystallized with n-heptane. After filtration, centrifugation, and drying, 1.47 kg of (R)-3-O-benzyl-4-C-hydroxymethyl-5-O-tert-butyldimethylsilyl-1,2-O- isopropylidene-α-D-ribofuranose was obtained as a white powder solid, with a purity of 94.70% by HPLC, and a yield of 83.14% for two steps.

[0075] Example 4: Synthesis of (R)-3-O-(2-naphthylmethyl)-4-C-hydroxymethyl-5-O-tert- butyldimethylsilyl-1,2-O-isopropylidene-α-D-ribofuranose

[0076]

[0077] Into the reactor, 5.00 L of DMF was added and stirred to dissolve. The temperature was lowered to -10-0°C, and sodium hydride (46.40 g, 1.93 mol) was slowly added in portions, and the temperature was kept below 0°C during the process. After the addition was completed, the temperature was kept for 16 hours. HPLC showed that the ratio of R configuration and S configuration was 96:4. 10.00 L of water was slowly added dropwise, and the temperature was kept below 0°C during the process. After the dropwise addition was completed, the mixture was stirred for 30 minutes. Ethyl acetate was added to extract the reaction solution. The organic phase was washed with 2.00 L of saturated ammonium chloride solution, water, and sodium chloride solution, respectively. The organic phase was concentrated under reduced pressure, and then recrystallized with n-heptane. After filtration, centrifugation, and drying, 1.47 kg of (R)-3-O-benzyl-4-C-hydroxymethyl-5-O-tert-butyldimethylsilyl-1,2-O- isopropylidene-α-D-ribofuranose was obtained as a white powder solid, with a purity of 94.70% by HPLC, and a yield of 83.14% for two steps.

[0078] Into the above reactor, 5.00 L of DMF was added and stirred to dissolve. The temperature was lowered to -10-0 °C, and sodium hydride (39.95 g, 1.66 mol) was slowly added in multiple batches, keeping the temperature below 0 °C. After the addition was completed, the temperature was maintained for 16 hours. HPLC showed that the ratio of R configuration to S configuration was 90:10. 10.00 L of water was slowly added, keeping the temperature below 0 °C during the addition. After the addition was completed, the mixture was stirred for 30 minutes, and ethyl acetate was added to extract the reaction solution. The organic phase was washed with 2.00 L of saturated ammonium chloride solution, water, and sodium chloride solution, respectively. The organic phase was concentrated under reduced pressure, and then recrystallized with n-heptane. After filtration, centrifugation, and drying, 0.84 kg of (R)-3-O-(2-naphthylmethyl)-4-C-hydroxymethyl-5-O-tert-butyldimethylsilyl-1,2-O- isopropylidene-α-D-ribofuranose was obtained as a white powder solid, with a HPLC purity of 91.24% and a yield of 63.78%.

[0079] Example 1: Synthesis of (R)-3-O-(2-naphthylmethyl)-4-C-hydroxymethyl-5-O-tert- butyldiphenylsilyl-1,2-O-isopropylidene-α-D-ribofuranose

[0080] The difference between Comparative Example 1 and Example 1 is only that the base is potassium tert-butoxide.

[0081] HPLC results showed that R:S = 61:39.

[0082] Example 1: Synthesis of (R)-3-O-(2-naphthylmethyl)-4-C-hydroxymethyl-5-O-tert- butyldiphenylsilyl-1,2-O-isopropylidene-α-D-ribofuranose

[0083] The difference between Comparative Example 2 and Example 1 is only that the base is triethylamine.

[0084] HPLC results showed that R:S = 2:98.

[0085] Example 1: Synthesis of (R)-3-O-(2-naphthylmethyl)-4-C-hydroxymethyl-5-O-tert- butyldiphenylsilyl-1,2-O-isopropylidene-α-D-ribofuranose

[0086] The difference between Comparative Example 3 and Example 1 is only that the base is 1,8- diazabicyclo[5.4.0]undec-7-ene.

[0087] HPLC results showed that R:S = 62:38.

[0088] Example 1: Synthesis of (R)-3-O-(2-naphthylmethyl)-4-C-hydroxymethyl-5-O-tert- butyldiphenylsilyl-1,2-O-isopropylidene-α-D-ribofuranose

[0089] Comparative Example 4 differs from Example 1 only in that the base is potassium carbonate.

[0090] The HPLC results show R:S = 11 :89.

[0091] Comparative Example 5: Synthesis of (R)-3-O-(2-naphthylmethyl)-4-C- hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O-isopropylidene-α-D- ribofuranose

[0092] Comparative Example 5 differs from Example 1 only in that the molar amount of the base is 0.5 times the molar amount of the starting material (S)-3-O-(2- naphthylmethyl)-4-C-hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O- isopropylidene-α-D-ribofuranose.

[0093] The HPLC results show R:S = 44:56.

[0094] Comparative Example 6: Synthesis of (R)-3-O-(2-naphthylmethyl)-4-C- hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O-isopropylidene-α-D- ribofuranose

[0095] Comparative Example 6 differs from Example 1 only in that the molar amount of the base is 0.8 times the molar amount of the starting material (S)-3-O-(2- naphthylmethyl)-4-C-hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O- isopropylidene-α-D-ribofuranose.

[0096] The HPLC results show R:S = 84:16.

[0097] Comparative Example 7: Synthesis of (R)-3-O-(2-naphthylmethyl)-4-C- hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O-isopropylidene-α-D- ribofuranose

[0098] Comparative Example 7 differs from Example 1 only in that the molar amount of the base is 1.2 times the molar amount of the starting material (S)-3-O-(2- naphthylmethyl)-4-C-hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O- isopropylidene-α-D-ribofuranose.

[0099] The HPLC results show R:S = 98:2.

[0100] Comparative Example 8: Synthesis of (R)-3-O-(2-naphthylmethyl)-4-C- hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O-isopropylidene-α-D- ribofuranose

[0101] Comparative Example 8 differs from Example 1 only in that the molar amount of the base is 2.0 times the molar amount of the starting material (S)-3-O-(2-naphthylmethyl)-4-C-hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O- isopropylidene-α-D-ribofuranose.

[0102] The HPLC results show that the R:S = 98:2.

[0103] Comparative Example 9: Synthesis of (R)-3-O-(2-naphthylmethyl)-4-C- hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O-isopropylidene-α-D-ribofuranose

[0104] Comparative Example 9 differs from Example 1 only in that the reaction temperature is room temperature.

[0105] The HPLC results show that the product in the R configuration is only 54.36% and there is no peak of the product in the S configuration.

[0106] Comparative Example 10: Synthesis of (R)-3-O-(2-naphthylmethyl)-4-C- hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O-isopropylidene-α-D-ribofuranose

[0107] Comparative Example 10 differs from Example 1 only in that the reaction time is 6 hours.

[0108] The HPLC results show that the R:S = 37:63.

[0109] Comparative Example 11: Synthesis of (R)-3-O-(2-naphthylmethyl)-4-C- hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O-isopropylidene-α-D-ribofuranose,

[0110] Comparative Example 11 differs from Example 1 only in that the reaction time is 12 hours.

[0111] The HPLC results show that the R:S = 52:48.

[0112] Comparative Example 12: Synthesis of (R)-3-O-(2-naphthylmethyl)-4-C- hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O-isopropylidene-α-D-ribofuranose

[0113] Comparative Example 12 differs from Example 1 only in that the reaction time is 22 hours.

[0114] The HPLC results show that the R:S = 98:2.

[0115] Comparative Example 13: Synthesis of (R)-3-O-(2-naphthylmethyl)-4-C- hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O-isopropylidene-α-D-ribofuranose

[0116] Comparative Example 13 differs from Example 1 only in that the reaction solvent is dichloromethane.

[0117] The HPLC result shows that R:S = 75:25.

[0118] Comparative Example 14: Synthesis of (R)-3-O-(2-naphthylmethyl)-4-C- hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O-isopropylidene-α-D-ribofuranose

[0119] Comparative Example 14 differs from Example 1 only in that the reaction solvent is toluene.

[0120] The HPLC result shows that R:S = 66:34.

[0121] Comparative Example 15: Synthesis of (R)-3-O-(2-naphthylmethyl)-4-C- hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O-isopropylidene-α-D-ribofuranose

[0122] Comparative Example 15 differs from Example 1 only in that the recrystallization solvent is n-hexane.

[0123] The HPLC result shows that the purity of the obtained product is 94.61%, and the yield is 87.04%.

[0124] Comparative Example 16: Synthesis of (R)-3-O-(2-naphthylmethyl)-4-C- hydroxymethyl-5-O-tert-butyldiphenylsilyl-1,2-O-isopropylidene-α-D-ribofuranose

[0125] Comparative Example 16 differs from Example 1 only in that the recrystallization solvent is ethyl acetate.

[0126] The HPLC result shows that the purity of the obtained product is 85.29%, and the yield is 64.38%.

[0127] The process of the present application is illustrated by the above examples, but the present application is not limited to the above process steps, i.e. it does not mean that the present application must rely on the above process steps to be implemented. It should be understood by those skilled in the art that any improvement of the present application, equivalent replacement of the raw materials selected by the present application, addition of auxiliary ingredients, selection of specific modes, etc. fall within the protection scope and disclosure scope of the present application.

Claims

1. A method for synthesizing a compound of formula II, characterized in that, It includes the following steps: the compound of formula I undergoes a silicon-based migration reaction under the action of a base to transform into the compound of formula II. R1 and R2 are hydroxyl protecting groups.

2. The synthesis method according to claim 1, characterized in that, R1 is selected from acetyl, tert-butyl, tert-butoxymethyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl, diphenylmethyl, p-methoxybenzyl, p-nitrobenzyl, di(2-acetoxyethoxy)methyl, 2-trimethylsilylethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triphenylmethylsilyl, [( One of the following: triisopropylsilyl)oxy]methyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, diphenylacetyl, p-valeryl, benzoyl, p-phenylbenzoyl, benzoylcarboxylate, 9-fluorenylmethyl carbonate, methanesulfonate, p-toluenesulfonate, triphenylmethyl, monomethoxytriphenylmethyl, dimethoxytriphenylmethyl, trimethoxytriphenylmethyl, 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, 9-phenylxanthine-9-yl, 9-(p-methoxyphenyl)xanthine-9-yl or 2-naphthylmethyl; R2 is selected from one of trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and triphenylmethylsilyl, with tert-butyldiphenylsilyl being particularly preferred.

3. The synthesis method according to claim 1, characterized in that, The alkali is an organic or inorganic alkali; the inorganic alkali is preferably one of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, potassium acetate, sodium acetate, and sodium hydride; the organic alkali is preferably one of N,N-diisopropylethylamine, triethylamine, imidazole, triethylenediamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and diisobutylaluminum hydride; sodium hydride is particularly preferred; preferably, the molar ratio of the alkali to Formula I is 0.5-5:1, more preferably 1.1-4:

1.

4. The synthesis method according to claim 1, characterized in that, The compound of Formula I is dissolved in a solvent to carry out the reaction, said solvent including water and organic solvents, preferably organic solvents, and the organic solvent is preferably one of dichloromethane, ethyl acetate, tetrahydrofuran, acetonitrile, dioxane, methanol, ethanol, toluene, sec-butanol and N,N-dimethylformamide, particularly preferably N,N-dimethylformamide.

5. The synthesis method according to any one of claims 1-4, characterized in that, It also includes a recrystallization step, which includes: adding the crude product containing the R-configuration 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranoside derivative to an organic solvent, heating to dissolve, cooling, and filtering.

6. A method for preparing Formula II, characterized in that, Includes the following steps: Step 1) Compound III reacts with hydroxyl protecting agent R2X under the action of a base to obtain a mixture of Formula I and Formula II; The mixture obtained in steps two and one is reacted under the action of alkali to prepare formula II. The synthetic route is as follows: In this context, R1 and R2 are hydroxyl protecting groups, and X is a leaving group.

7. The method according to claim 6, characterized in that, R1 is selected from acetyl, tert-butyl, tert-butoxymethyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl, diphenylmethyl, p-methoxybenzyl, p-nitrobenzyl, di(2-acetoxyethoxy)methyl, 2-trimethylsilylethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triphenylmethylsilyl, [( One of the following: triisopropylsilyl)oxy]methyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, diphenylacetyl, p-valeryl, benzoyl, p-phenylbenzoyl, benzoylcarboxylate, 9-fluorenylmethyl carbonate, methanesulfonate, p-toluenesulfonate, triphenylmethyl, monomethoxytriphenylmethyl, dimethoxytriphenylmethyl, trimethoxytriphenylmethyl, 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, 9-phenylxanthine-9-yl, 9-(p-methoxyphenyl)xanthine-9-yl or 2-naphthylmethyl; R2 is selected from one of trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and triphenylmethylsilyl, with tert-butyldiphenylsilyl being particularly preferred; X is preferably a halogen.

8. The method according to claim 6, characterized in that, Step 1) Preferably, the reaction is carried out in an organic solvent, which may be one of N,N-dimethylformamide, dichloromethane, ethyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, acetonitrile, and dioxane, with N,N-dimethylformamide being preferred.

9. The method according to claim 6, characterized in that, The base mentioned in step one) is an organic or inorganic base; the inorganic base includes: sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, potassium acetate, sodium acetate, and sodium hydride; the organic base includes N,N-diisopropylethylamine, triethylamine, imidazole, triethylenediamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, diisobutylaluminum hydride, pyridine, 2,6-dimethylpyridine, and 4-dimethylaminopyridine; preferably triethylamine; the hydroxyl protecting agent R2X is one of trimethylchlorosilyl, triethylchlorosilane, tert-butyldimethylchlorosilane, tert-butyldiphenylchlorosilane, and triphenylmethylchlorosilane, preferably tert-butyldiphenylchlorosilane.

10. The method according to any one of claims 6-9, characterized in that, The preparation method also includes a recrystallization step, which includes: adding the crude product containing the R-configuration 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-furanose derivative to an organic solvent, heating to dissolve, cooling, and filtering.

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