WO2025256544A1 - 一种1-氨烷基修饰的呋喃核糖衍生物的制备方法 - Google Patents

一种1-氨烷基修饰的呋喃核糖衍生物的制备方法

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Publication number
WO2025256544A1
WO2025256544A1 PCT/CN2025/100366 CN2025100366W WO2025256544A1 WO 2025256544 A1 WO2025256544 A1 WO 2025256544A1 CN 2025100366 W CN2025100366 W CN 2025100366W WO 2025256544 A1 WO2025256544 A1 WO 2025256544A1
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Prior art keywords
compound
formula
preparing
iii
reacting
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English (en)
French (fr)
Inventor
黄庆港
吴明昌
郭昌山
黄文华
王新新
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Fujian Shengdi Pharmaceutical Co Ltd
Jiangsu Hengrui Pharmaceutical Co Ltd
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Fujian Shengdi Pharmaceutical Co Ltd
Jiangsu Hengrui Pharmaceutical Co Ltd
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Publication of WO2025256544A1 publication Critical patent/WO2025256544A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives

Definitions

  • This disclosure relates to a method for preparing a 1-aminoalkyl-modified furanose derivative, which belongs to the field of chemistry.
  • RNA RNA
  • One method to achieve specific targeting is to conjugate a target moiety to nucleic acids (e.g., oligonucleotides).
  • the target moiety helps guide the nucleic acid to the site of interest. Delivery can be improved through receptor-mediated endocytosis, a process initiated by the activation of cell surface or membrane receptors after a specific ligand binds to the receptor.
  • ASGP-R asialyl glycoprotein receptor
  • GalNAc N-acetyl-D-galactosamine
  • 1-aminoalkyl-modified furanose derivatives have been used as novel junctions for nucleic acid delivery. Developing processes suitable for industrial production of 1-aminoalkyl-modified furanose derivatives is of great significance for the production of nucleic acid drugs.
  • This disclosure provides a method for preparing the compound shown in formula (III), comprising the step of reacting the compound shown in formula (I) with the compound shown in formula (II).
  • R1 is selected from hydrogen, halogen, hydroxyl, alkoxy, and haloalkoxy.
  • PG 1 is a hydroxyl protecting group
  • X is a halogen
  • R2 , R3 , R4 , R5 , R6 , R7 , R8 , R9 , R10 , and R11 are each independently selected from hydrogen, halogen, alkyl, or haloalkyl;
  • m is selected from 0, 1, 2 or 3.
  • the method for preparing the compound represented by formula (III) provided in this disclosure wherein PG 1 is selected from Bn or PMB, and X is I.
  • the method for preparing the compound represented by formula (III) provided in this disclosure includes the step of reacting the compound represented by formula (I-1) with the compound represented by formula (II) to obtain the compound represented by formula (III-1).
  • PG1 , X, R10 , R11 , and m are defined in the compounds shown in formula (I).
  • the method for preparing the compound shown in formula (III) provided in this disclosure includes the step of reacting the compound shown in formula (I-1) with the compound shown in formula (II) to obtain the compound shown in formula (III-1), wherein R10 and R11 are hydrogen, and m is selected from 0 or 1;
  • the method for preparing the compound represented by formula (III) provided in this disclosure includes the step of reacting the compound represented by formula (I-2) with the compound represented by formula (II) to obtain the compound represented by formula (III-2).
  • PG1 , X, R10 , R11 , and m are defined in the compounds shown in formula (I).
  • the method for preparing the compound shown in formula (III) provided in this disclosure includes the step of reacting the compound shown in formula (I-2) with the compound shown in formula (II) to obtain the compound shown in formula (III-2), wherein R10 and R11 are hydrogen, and m is selected from 0 or 1.
  • the method for preparing the compound represented by formula (III) provided in this disclosure is as follows: compound B-A4 reacts with the compound represented by formula (II) to obtain compound B-A5.
  • the method for preparing the compound represented by formula (III) provided in this disclosure uses a nonpolar solvent (e.g., DMF, THF, DMSO, NMP) as the reaction solvent.
  • a nonpolar solvent e.g., DMF, THF, DMSO, NMP
  • the reaction occurs under the protection of an inert gas (e.g., N2 ).
  • an inert gas e.g., N2
  • the reaction temperature can be selected from 50-120°C, for example 60-110°C, for example 75-100°C, specifically from 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, or any temperature between two points.
  • the reaction further includes an acid treatment step (e.g., hydrochloric acid, citric acid, oxalic acid, phosphoric acid, etc.), which mainly converts the unreacted compound shown in formula (II) into phthalamide for easier post-processing.
  • an acid treatment step e.g., hydrochloric acid, citric acid, oxalic acid, phosphoric acid, etc.
  • This disclosure also provides a method for preparing the compound of formula (VI), comprising the steps of hydrolysis or hydrazinolysis of the compound of formula (V).
  • R1 , R2 , R3 , R4 , R5 , R6 , R7 , R8 , R9 , R10 , R11 , and m are defined in the compounds shown in formula (I).
  • the method for preparing the compound represented by formula (VI) provided in this disclosure includes the steps of hydrolysis or hydrazinolysis of the compound represented by formula (V-1).
  • R10 , R11 , and m are defined in the compounds shown in formula (I).
  • the method for preparing the compound shown in formula (VI) provided in this disclosure includes the steps of hydrolysis or hydrazine hydrolysis of the compound shown in formula (V-1), wherein R10 and R11 are hydrogen, and m is selected from 0 or 1.
  • the method for preparing the compound represented by formula (VI) provided in this disclosure includes the steps of hydrolysis or hydrazinolysis of the compound represented by formula (V-2).
  • R10 , R11 , and m are defined in the compounds shown in formula (I).
  • the method for preparing the compound shown in formula (VI) provided in this disclosure includes the steps of hydrolysis or hydrazine hydrolysis of the compound shown in formula (V-2), wherein R10 and R11 are hydrogen, and m is selected from 0 or 1.
  • the method for preparing the compound shown in formula (VI) provided in this disclosure includes the steps of hydrolyzing or hydrazinolyzing compound B-A7 to obtain compound NAG0052B.
  • An optional method for preparing the compound of formula (VI) provided in this disclosure involves reacting under any of the following conditions:
  • the reaction occurs under the protection of an inert gas (e.g., N2 ).
  • an inert gas e.g., N2
  • the reaction temperature is selected from 20-80°C, for example 40-70°C, for example 50-65°C, specifically 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C or 80°C, or any temperature between two points.
  • the method for preparing the compound of formula (VI) provided in this disclosure further includes the step of removing the protecting group PG1 from the compound of formula (III) to obtain the compound of formula (IV), and then reacting the compound of formula (IV) with DMTrCl to obtain the compound of formula (V).
  • R1 , PG1 , R2 , R3 , R4 , R5 , R6 , R7 , R8 , R9 , R10 , R11 , and m are defined in the compounds shown in formula (I).
  • the method for preparing the compound of formula (VI) provided in this disclosure includes the steps of removing the protecting group PG1 from the compound of formula (III-1) to obtain the compound of formula (IV-1), and then reacting the compound of formula (IV-1) with DMTrCl to obtain the compound of formula (V-1).
  • PG1 , R10 , R11 , and m are defined in the compounds shown in formula (I).
  • the method for preparing the compound of formula (VI) provided in this disclosure includes the steps of removing the protecting group PG1 from the compound of formula (III-1) to obtain the compound of formula (IV-1), and then reacting the compound of formula (IV-1) with DMTrCl to obtain the compound of formula (V-1), wherein R10 and R11 are hydrogen, and m is selected from 0 or 1.
  • the method for preparing the compound of formula (VI) provided in this disclosure includes the steps of removing the protecting group PG1 from the compound of formula (III-2) to obtain the compound of formula (IV-2), and then reacting the compound of formula (IV-2) with DMTrCl to obtain the compound of formula (V-2).
  • PG1 , R10 , R11 , and m are defined in the compounds shown in formula (I).
  • the method for preparing the compound shown in formula (VI) provided in this disclosure includes the steps of removing the protecting group PG1 from the compound shown in formula (III-2) to obtain the compound shown in formula (IV-2), and then reacting the compound shown in formula (IV-2) with DMTrCl to obtain the compound shown in formula (V-2), wherein R10 and R11 are hydrogen, and m is selected from 0 or 1.
  • the method for preparing the compound shown in formula (VI) provided in this disclosure includes the steps of deprotecting compound B-A5 to obtain compound B-A6, and then reacting compound B-A6 with DMTrCl to obtain compound B-A7.
  • the step of removing the protecting group PG1 from the compound shown in formula (III-1) to obtain the compound shown in formula (IV-1) is carried out at low temperature under the catalysis of a catalyst (e.g., boron trichloride, palladium catalyst, trimethyliodosilane).
  • a catalyst e.g., boron trichloride, palladium catalyst, trimethyliodosilane.
  • the reaction temperature can be selected from -20°C to -80°C, for example, from -30°C to -50°C, or any point value within the range.
  • the molar ratio of the compound shown in formula (III-1) to the catalyst is selected from 1:1 to 1:10, for example 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, or any point value within the range.
  • reaction solvent is acetonitrile, methanol, ethanol, dichloromethane, or dichloroethane, etc.
  • the step of reacting the compound shown in formula (IV) with DMTrCl to obtain the compound shown in formula (V) occurs under alkaline conditions (e.g., pyridine, 4-dimethylaminopyridine, triethylamine, or N,N-diisopropylethylamine, etc.).
  • alkaline conditions e.g., pyridine, 4-dimethylaminopyridine, triethylamine, or N,N-diisopropylethylamine, etc.
  • the reaction occurs under the protection of an inert gas (e.g., N2 ) and/or anhydrous conditions (which typically require the addition of a desiccant such as a molecular sieve for the purpose of dehydration).
  • an inert gas e.g., N2
  • anhydrous conditions which typically require the addition of a desiccant such as a molecular sieve for the purpose of dehydration.
  • the reaction occurs at room temperature, specifically at any temperature between 0 and 40°C.
  • the molar ratio of the compound shown in reaction formula (IV) to DMTrCl can be selected from 1:3 to 3:1, for example from 1:2 to 2:1, and can be any point value within this range.
  • the method for preparing the compound of formula (VI) provided in this disclosure further includes the preparation steps of the compound of formula (III) described above.
  • the method for preparing 1-aminoalkyl-modified furanose derivatives disclosed herein facilitates the post-processing of subsequent reaction products by reacting the starting materials with the compound shown in formula (II).
  • alkyl refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms are also included. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and their various branched isomers.
  • alkoxy refers to -O- (alkyl), where alkyl is defined as described above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy.
  • hydroxyl group refers to the -OH group
  • hydroxyl protecting group is a group known in the art that can be used to protect hydroxyl groups, see the hydroxyl protecting group in the literature (Protective Groups in Organic Synthesis, 5th Ed. TW Greene & P. GMWuts).
  • the hydroxyl protecting group can be a (C 1-10 alkyl or aryl) 3 -silyl, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc.; can be a C 1-10 alkyl or substituted alkyl, such as: methyl, tert-butyl, allyl, benzyl, methoxymethyl, ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; can be a (C 1-10 alkyl or aromatic) acyl, such as: formyl, acetyl, benzoyl, etc.; can be a (C 1-6 alkyl or C 6-10 aryl) sulfonyl; or can be a (C 1-6 alkoxy or C 6-10 aryloxy) carbony
  • Post-processing The reaction vessel was brought to room temperature, the solution was filtered, and the filtrate was collected. The filtrate was transferred to the vessel, and a saturated sodium thiosulfate aqueous solution was added to quench the reaction. The solution was then concentrated under reduced pressure at 35-40°C to remove most of the acetonitrile. The solution was then transferred to the vessel, and extracted twice with DCM. The organic phases were combined and washed three times with 0.6M dilute hydrochloric acid aqueous solution. The organic phase was collected and concentrated under reduced pressure at 35-40°C to obtain a pale yellow oily substance with a yield of 96%. This was used directly in the next reaction.
  • Post-processing Quench the reaction by adding isopropanol dropwise, control the temperature to ⁇ -35°C, allow it to heat naturally, transfer it to a rotary evaporator, concentrate it under reduced pressure at 35-40°C, and obtain a black solid.
  • NMP N-methylpyrrolidone
  • Post-processing Filtration, washing of the filter cake with DCM, quenching of the filtrate with saturated sodium thiosulfate aqueous solution, extraction with DCM, drying with anhydrous sodium sulfate, and concentration of the organic phase under reduced pressure to obtain a brown oily substance, which was directly used in the next reaction.
  • NMP and potassium phthalimide salt to the reactor and maintain a nitrogen atmosphere; start heating and control the internal temperature at 85-95°C; dissolve B-A4 in NMP and add it dropwise to the reactor over 40-50 minutes; after the addition is complete, keep the temperature and stir for 1-2 hours.
  • Post-processing Filter, wash the filter cake with methanol, concentrate the filtrate under reduced pressure to obtain a brownish-black crude product, add n-heptane to the reactor, dissolve the crude product in dichloromethane, methanol and isopropanol, add dropwise to the reactor, stir overnight, filter, collect the filter cake, transfer to a vacuum drying oven, dry under vacuum at 40°C for 16-18h, collect the material to obtain a black solid, yield: 70%.

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Abstract

本公开提供了一种1-氨烷基修饰的呋喃核糖衍生物的制备方法。具体而言，本公开提供了一种式(III)所示化合物的制备方法。该方法收率高，后处理简单，适应于工业化大规模生产。

Description

一种1-氨烷基修饰的呋喃核糖衍生物的制备方法 技术领域
本公开涉及一种1-氨烷基修饰的呋喃核糖衍生物的制备方法，属于化学领域。
背景技术
将RNA等遗传物质有效递送至体内细胞需要特定的靶向和保护,以免受细胞外环境(尤其是血清蛋白)的影响，实现特异性靶向的一种方法是将靶向部分缀合至核酸(例如寡核苷酸)。靶向部分有助于将核酸引导至感兴趣的位点，靶向部分可以通过受体介导的内吞作用来改善递送，该过程是通过特定配体与受体结合后细胞表面或膜受体的激活来启动的。许多受体介导的内吞系统是已知的，包括识别糖(例如半乳糖、甘露糖、6-磷酸甘露糖)、肽和蛋白质(例如转铁蛋白、脱唾液酸糖蛋白、维生素B12、胰岛素和表皮生长因子(EGF))的系统。脱唾液酸糖蛋白受体(ASGP-R)是一种高容量受体，在肝细胞上含量很高。ASGP-R对N-乙酰基-D-半乳糖胺(GalNAc)的亲和力高于D-Gal。
最新的研究中(例如WO2023014938A、WO2023274395A)，1-氨烷基修饰的呋喃核糖衍生物被用做核酸递送的新型结头，开发适合于工业化生产的1-氨烷基修饰的呋喃核糖衍生物的工艺，对于核酸类药物的生产具有重要意义。
发明内容
本公开提供一种式(III)所示化合物的制备方法，包括式(I)所示化合物与式(II)所示化合物反应的步骤，
其中，R1选自氢、卤素、羟基、烷氧基、卤代烷氧基；
PG1为羟基保护基；
X为卤素；
R2、R3、R4、R5、R6、R7、R8、R9、R10、R11各自独立地选自氢、卤素、烷基或卤代烷基；
所述m选自0、1、2或3。
可选的实施方案中，本公开提供的式(III)所示化合物的制备方法，所述PG1选自Bn或PMB，所述X为I。
可选的实施方案中，本公开提供的式(III)所示化合物的制备方法，所述PG1为Bn，所述X为I。
可选的实施方案中，本公开提供的式(III)所示化合物的制备方法，包括式(I-1)与式(II)所示化合物反应得到式(III-1)所示化合物的步骤，
所述PG1、X、R10、R11、m分别如式(I)所示化合物中定义。
可选的实施方案中，本公开提供的式(III)所示化合物的制备方法，包括式(I-1)与式(II)所示化合物反应得到式(III-1)所示化合物的步骤，所述R10、R11为氢，所述m选自0或1；
可选的实施方案中，本公开提供的式(III)所示化合物的制备方法，包括式(I-2)与式(II)所示化合物反应得到式(III-2)所示化合物的步骤，
所述PG1、X、R10、R11、m分别如式(I)所示化合物中定义。
可选的实施方案中，本公开提供的式(III)所示化合物的制备方法，包括式(I-2)与式(II)所示化合物反应得到式(III-2)所示化合物的步骤，所述R10、R11为氢，所述m选自0或1。
可选的实施方案中，本公开提供的式(III)所示化合物的制备方法，其为：化合物B-A4与式(II)所示化合物反应得到化合物B-A5，
一些实施方案中，本公开中提供的式(III)所示化合物的制备方法，反应溶剂为非极性溶剂(例如DMF、THF、DMSO、NMP)。
可选的实施方案中，该反应在惰性气体(例如N2)保护下发生。
可选的实施方案中，该反应的温度可选自50-120℃，例如60-110℃，例如75-100℃，具体的可选自50℃、55℃、60℃、65℃、70℃、75℃、80℃、85℃、90℃、95℃、100℃、105℃、110℃、115℃、120℃，或者任意两点之间的温度。
可选的实施方案中，该反应进一步包括酸(例如盐酸、柠檬酸、草酸、磷酸等)处理的步骤，该步骤主要是让未完全参与反应的式(II)所示化合物转化成邻苯二甲酰胺，方便后处理。
本公开另一方面提供一种式(VI)所示化合物的制备方法，包含式(V)所示化合物水解或或肼解的步骤，
所述R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、m如式(I)所示化合物中定义。
可选的实施方案中，本公开提供的式(VI)所示化合物的制备方法，包含式(V-1)所示化合物水解或肼解的步骤，
所述R10、R11、m分别如式(I)所示化合物中定义。
可选的实施方案中，本公开提供的式(VI)所示化合物的制备方法，包含式(V-1)所示化合物水解或肼解的步骤，所述R10、R11为氢，所述m选自0或1。
可选的实施方案中，本公开提供的式(VI)所示化合物的制备方法，包含式(V-2)所示化合物水解或肼解的步骤，
所述R10、R11、m分别如式(I)所示化合物中定义。
可选的实施方案中，本公开提供的式(VI)所示化合物的制备方法，包含式(V-2)所示化合物水解或肼解的步骤，所述R10、R11为氢，所述m选自0或1。
可选的实施方案中，本公开提供的式(VI)所示化合物的制备方法，包括化合物B-A7水解或肼解为化合物NAG0052B的步骤，
本公开提供的式(VI)所示化合物的制备方法，其中，式(V)所示化合物水解或肼解的步骤为盖布瑞尔合成(Gabriel Synthesis)反应中的一步，反应条件可以是酸性或者强碱条件，或者是肼的水溶液或乙醇溶液(Ing-Manske法)。
可选的本公开提供的式(VI)所示化合物的制备方法，在以下任选一个条件下发生反应：
a)甲胺乙醇溶液；
b)氢氧化钠水溶液与乙醇组合；
c)水合肼与甲醇/甲苯组合；
d)乙醇胺与三乙胺和甲苯组合。
可选的实施方案中，该反应在惰性气体(例如N2)保护下发生。
可选的实施方案中，该反应的反应温度选自20-80℃，例如40-70℃，例如50-65℃，具体可选20℃、25℃、30℃、35℃、40℃、45℃、50℃、55℃、60℃、65℃、70℃、75℃或80℃，或者任意两点之间的温度。
一些实施方案中，本公开提供的式(VI)所示化合物的制备方法，进一步包括式(III)所示化合物脱除保护基PG1得到式(IV)所示化合物，后式(IV)所示化合物与DMTrCl反应得到式(V)所示化合物的步骤，
其中，R1、PG1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、m分别如式(I)所示化合物中定义。
可选的实施方案中，本公开提供的式(VI)所示化合物的制备方法，包括式(III-1)所示化合物脱除保护基PG1得到式(IV-1)所示化合物，后式(IV-1)所示化合物与DMTrCl反应得到式(V-1)所示化合物的步骤，
所述PG1、R10、R11、m分别如式(I)所示化合物中定义。
可选的实施方案中，本公开提供的式(VI)所示化合物的制备方法，包括式(III-1)所示化合物脱除保护基PG1得到式(IV-1)所示化合物，后式(IV-1)所示化合物与DMTrCl反应得到式(V-1)所示化合物的步骤，所述R10、R11为氢，所述m选自0或1。
可选的实施方案中，本公开提供的式(VI)所示化合物的制备方法，包括式(III-2)所示化合物脱除保护基PG1得到式(IV-2)所示化合物，后式(IV-2)所示化合物与DMTrCl反应得到式(V-2)所示化合物的步骤，
所述PG1、R10、R11、m分别如式(I)所示化合物中定义。
可选的实施方案中，本公开提供的式(VI)所示化合物的制备方法，包括式(III-2)所示化合物脱除保护基PG1得到式(IV-2)所示化合物，后式(IV-2)所示化合物与DMTrCl反应得到式(V-2)所示化合物的步骤，所述R10、R11为氢，所述m选自0或1。
可选的实施方案中，本公开提供的式(VI)所示化合物的制备方法，包括化合物B-A5脱保护基得到化合物B-A6，后化合物B-A6与DMTrCl反应得到化合物B-A7的步骤，
可选的实施方案中，本公开提供的制备方法中，前述式(III-1)所示化合物脱除保护基PG1得到式(IV-1)所示化合物的步骤，反应在催化剂(例如三氯化硼、钯催化剂、三甲基碘硅烷)的催化、低温下发生，具体地，反应温度可选-20℃至-80℃，例如，-30℃至-50℃，或者区间范围内的任意点值。
可选的实施方案中，式(III-1)所示化合物与催化剂的摩尔比选自1:1至1:10，例如1:1、1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9、1:10，或者区间范围内的任意点值。
可选的实施方案中，所述反应溶剂为乙腈、甲醇、乙醇、二氯甲烷或二氯乙烷等。
可选的实施方案中，本公开提供的制备方法中，前述式(IV)所示化合物与DMTrCl反应得到式(V)所示化合物的步骤在碱性(例如吡啶、4-二甲氨基吡啶、三乙胺或N,N-二异丙基乙胺等)条件下发生。
可选的实施方案中，该反应在惰性气体(例如N2)保护和/或无水条件(通常需要加干燥剂例如分子筛得到除水的目的)下发生。
可选的实施方案中，该反应在室温发生，具体温度可选0-40℃之间的任意温度值。
可选的实施方案中，该反应式(IV)所示化合物与DMTrCl的摩尔比可选1:3至3:1，例如1:2至2:1，具体可以是该区间范围内的任意点值。
一些实施方案中，本公开提供的式(VI)所示化合物的制备方法，进一步包括前述的式(III)所示化合物的制备步骤。
本公开进一步提供如下化合物：
本公开提供的1-氨烷基修饰的呋喃核糖衍生物的制备方法避免了现有技术中异构体的拆分。
本公开提供的1-氨烷基修饰的呋喃核糖衍生物的制备方法，起始原料通过与式(II)所示化合物反应，方便了后续反应产物的后处理。
术语解释
术语“烷基”指饱和的脂族烃基团，包括1至20个碳原子的直链和支链基团。含有1至6个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基及其各种支链异构体等；
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基；
术语“羟基”指-OH基团；
术语“卤素”指氟、氯、溴或碘；
本公开“羟基保护基”是本领域已知的、能用于保护羟基的基团，参见文献(《Protective Groups in Organic Synthesis》，5Th Ed.T.W.Greene&P.G.M.Wuts)中的羟基保护基团。作为示例，包括但不限于作为示例，优选地，所述的羟基保护基可以是(C1-10烷基或芳基)3硅烷基，例如：三乙基硅基、三异丙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基等；可以是C1-10烷基或取代烷基，例如：甲基、叔丁基、烯丙基、苄基、甲氧基甲基、乙氧基乙基、2-四氢吡喃基(THP)等；可以是(C1-10烷基或芳香基)酰基，例如：甲酰基、乙酰基、苯甲酰基等；可以是(C1-6烷基或C6-10芳基)磺酰基；也可以是(C1-6烷氧基或C6-10芳基氧基)羰基，可以是乙酰基(Ac)、2-甲氧基乙氧甲基醚(MEM)、甲氧甲基醚(MOM)、对甲氧基苄基醚(PMB)、甲硫甲基醚(MTM)。
本公开中使用的缩写解释如下：
具体实施方式
本公开提供下面的实施例以说明但不限制所要求保护的发明。
实施例1.化合物NAG0052B的制备

步骤1：B-A4的合成
向反应釜中加入水，加入AgClO4，搅拌至溶清，滴加2,4,6-三甲基吡啶，搅拌12-16h，控温20-25℃；过滤，收集固体，30℃真空干燥12-16h，固体为：Ag(sym-coll)2ClO4。(水分约为6-20％)
向反应釜中加入乙腈，加入Ag(sym-coll)2ClO4，搅拌溶清，保持氮气氛；加入碘；降温至内温≤-25℃，加入B-A3，搅拌12-16h，取样送HPLC检测：控制B-A3的量应不得过10.0％。
后处理：将反应釜回温至室温，溶液过滤，收集滤液；将滤液转移至釜中，加入饱和硫代硫酸钠水溶液淬灭反应；将溶液控制再35-40℃减压浓缩，将大部分的乙腈除去后，转移至釜中，加入DCM萃取*2次，合并有机相，用0.6M的稀盐酸水溶液洗涤*3次，收集有机相，35-40℃减压浓缩得淡黄色油状物，收率96％。直接用于下一步反应。
步骤2：B-A5的合成
反应釜中加入DMF，加入邻苯二甲酰亚胺钾盐，保持氮气氛；开始升温，控制内温85-95℃；将B-A4用DMF溶解，滴加至反应釜中，滴加40-50min；滴加完毕，保温搅拌1-2h；
取样HPLC检测:滴加至0.6N稀盐酸中，加入乙酸乙酯，取上层送样，B-A4的量不得过5％，开始降温。
后处理：降温至室温，用稀盐酸淬灭反应，加入乙酸乙酯萃取，收集有机相，加入饱和食盐水洗涤有机相。有机相减压浓缩得棕色化合物，收率：70％。
1H NMR(400MHz,DMSO)δ＝7.92–7.80(m,4H),7.38–7.30(m,5H),4.76(t,J＝5.7,1H),4.58–4.50(m,1H),4.47–4.40(m,1H),4.32(dt,J＝11.7,3.7,1H),4.06–4.02(m,2H),3.94(dd,J＝13.8,8.2,1H),3.60(dd,J＝13.8,4.7,1H),3.27(dt,J＝11.4,5.8,1H),2.25–2.16(m,1H),1.94(d,J＝13.6,1H).
MS(ESI)m/z:[M+H]+368.1492。
步骤3：B-A6的合成
反应釜中加入二氯甲烷，加入B-A5，搅拌溶清，保持氮气氛，降温至-35～-45℃；搅拌下滴加三氯化硼的二氯甲烷溶液，控温≤-35℃，加毕，反应液在-35～-45℃搅拌1h。
取样HPLC检测：异丙醇淬灭后送样，B-A5的量应不得过5.0％。
后处理：滴加异丙醇淬灭反应，控温≤-35℃，自然升温，转移至旋蒸中，35-40℃减压浓缩，得到黑色固体。
一次析晶：釜中加入的正庚烷，同时固体用异丙醇和乙酸乙酯溶解，滴加至釜中，有明显黑色固体析出，搅拌过夜，过滤，收集滤饼。
二次析晶：釜中加入正庚烷，滤饼用二氯甲烷、甲醇、异丙醇溶解，滴加至釜中，搅拌过夜，过滤，收集滤饼。
三次析晶：釜中加入甲苯，加入滤饼，搅拌过夜，过滤，收集固体，转移至真空干燥箱中，40℃真空干燥16-18h，收料，得到黑色固体,收率：72％。
1H NMR(400MHz,DMSO)δ＝7.93–7.81(m,4H),4.24(ddd,J＝12.4,8.1,4.8,1H),4.09(dt,J＝6.9,4.1,1H),3.94(dd,J＝13.8,8.3,1H),3.73(dd,J＝8.7,4.5,1H),3.55(dd,J＝13.8,4.5,1H),3.31(dd,J＝4.7,2.1,2H),2.19(dt,J＝13.1,7.2,1H),1.65(dt,J＝12.9,4.6,1H).
MS(ESI)m/z:[M+H]+278.1023。
步骤4：B-A7的合成
将原料用吡啶溶解，保持氮气氛；加入DMCTrCl，保持室温搅拌4h；
后处理：反应过滤，收集滤液，35～40℃减压浓缩，粗品柱层析纯化(乙酸乙酯/正庚烷＝1：1)，得淡黄色固体，收率86％。
1H NMR(400MHz,DMSO)δ＝7.92(dt,J＝7.0,3.6,2H),7.89–7.82(m,2H),7.34(d,J＝7.5,2H),7.28–7.14(m,7H),6.81(dd,J＝8.9,2.3,4H),4.39–4.26(m,1H),4.07(dd,J＝10.8,5.9,1H),3.98–3.85(m,2H),3.72(t,J＝7.3,5H),3.65(dd,J＝13.9,4.3,1H),2.95(dd,J＝9.8,3.4,1H),2.86(dd,J＝9.8,5.5,1H),2.31–2.19(m,1H),1.71–1.56(m,1H).
MS(ESI)m/z:[M+Na]+602.2149。
步骤5：NAG0052B的合成
将原料用甲苯溶解，加入乙醇胺，加入三乙胺，保持氮气氛，升温至90℃，搅拌16-20h；
后处理：分液，收集甲苯相，下层用甲苯萃取，合并甲苯相，45～50℃减压浓缩，粗品柱层析纯化(甲醇/二氯甲烷＝1：10)，得到黄色麦芽糖状半固体，收率90％，HPLC纯度97％。
实施例2.化合物B-A6的制备
步骤1：B-C4的合成
反应釜中加入N-甲基吡咯烷酮(NMP)，加入NaHCO3以及I2搅拌；降温，将内温控制在-20℃；将B-C3溶于NMP中，缓慢加入到反应釜中，在-20℃下反应12-16h。用TLC板监测反应。
后处理：过滤，用DCM洗涤滤饼，滤液用饱和硫代硫酸钠水溶液淬灭，用DCM萃取，无水硫酸钠干燥，有机相减压浓缩得褐色油状物，直接用于下一步反应。
1H NMR(500MHz,DMSO)δ＝7.35–7.19(m,2H),6.95–6.86(m,2H),4.40(s,2H),4.22–4.12(m,1H),4.09–3.98(m,2H),3.75(s,3H),3.41–3.36(m,2H),3.36–3.29(m,2H),2.30–2.21(m,1H),1.90(ddd,J＝13.3,4.8,3.5Hz,1H).
MS(ESI)m/z:[M+NH4]+396.0657。
步骤2：B-C5的合成
反应釜中加入NMP，加入邻苯二甲酰亚胺钾盐，保持氮气氛；开始升温，控制内温85-95℃；将B-A4用NMP溶解，滴加至反应釜中，滴加40-50min；滴加完毕，保温搅拌1-2h；
取样HPLC检测:滴加至0.6N稀盐酸中，加入乙酸乙酯，取上层送样，B-A4的量不得过5％，开始降温。
后处理：降温至室温，用稀盐酸淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥。减压浓缩得棕色化合物。用柱层析纯化(DCM/MeOH＝30/1)，冲出产品溶液，收集并浓缩有机相，收率72％。
1H NMR(500MHz,DMSO)δ＝7.92–7.79(m,4H),7.34–7.20(m,2H),6.99–6.84(m,2H),4.72(t,J＝5.7Hz,1H),4.51–4.34(m,2H),4.31(tdd,J＝8.1,4.8,3.5Hz,1H),4.06–3.97(m,2H),3.92(dd,J＝13.8,8.1Hz,1H),3.75(s,3H),3.59(dd,J＝13.8,4.8Hz,1H),3.27(dt,J＝11.4,5.8Hz,1H),2.18(ddd,J＝14.0,7.8,6.5Hz,1H),1.91(ddd,J＝13.5,3.6,2.4Hz,1H).
MS(ESI)m/z:[M+Na]+398.1588。
步骤3：B-A6的合成
反应釜中加入甲醇，加入化合物B-C5，加入钯碳，保持氢气氛；35-40℃搅拌12-16h；
取样HPLC检测：直接过滤，甲醇稀释送样，B-C5的量应不得过5.0％。
后处理：过滤，滤饼用甲醇淋洗，滤液减压浓缩得棕黑色粗品，釜中加入正庚烷，粗品用二氯甲烷、甲醇、异丙醇溶解，滴加至釜中，搅拌过夜，过滤，收集滤饼，转移至真空干燥箱中，40℃真空干燥16-18h，收料，得到黑色固体,收率：70％。
1H NMR(400MHz,DMSO)δ＝7.93–7.81(m,4H),4.24(ddd,J＝12.4,8.1,4.8,1H),4.09(dt,J＝6.9,4.1,1H),3.94(dd,J＝13.8,8.3,1H),3.73(dd,J＝8.7,4.5,1H),3.55(dd,J＝13.8,4.5,1H),3.31(dd,J＝4.7,2.1,2H),2.19(dt,J＝13.1,7.2,1H),1.65(dt,J＝12.9,4.6,1H).
MS(ESI)m/z:[M+H]+278.1023。

Claims (12)

  1. 一种式(III)所示化合物的制备方法，包括式(I)所示化合物与式(II)所示化合物反应的步骤，
    其中，R1选自氢、卤素、羟基、烷氧基、卤代烷氧基；
    PG1为羟基保护基；
    X为卤素；
    R2、R3、R4、R5、R6、R7、R8、R9、R10、R11各自独立地选自氢、卤素、烷基或卤代烷基；
    所述m选自0、1、2或3；
    优选地，所述PG1选自Bn或PMB，所述X为I；
    最优选地，所述PG1为Bn，所述X为I；
  2. 根据权利要求1所述的式(III)所示化合物的制备方法，反应溶剂选自非极性溶剂，优选DMF。
  3. 根据权利要求1至2任一项所述的式(III)所示化合物的制备方法，包括式(I-1)与式(II)所示化合物反应得到式(III-1)所示化合物的步骤，
    所述PG1、X、R10、R11、m分别如权利要求1中定义；
    进一步地，所述R10、R11为氢，所述m选自0或1；
    优选地，包含式(I-2)与式(II)所示化合物反应得到式(III-2)所示化合物的步骤，
    所述PG1、X、R10、R11、m分别如权利要求1中定义；
    进一步地，所述R10、R11为氢，所述m选自0或1。
  4. 根据权利要求1至3任一项所述的式(III)所示化合物的制备方法，其为：化合物B-A4与式(II)所示化合物反应得到化合物B-A5，
  5. 一种式(VI)所示化合物的制备方法，包含式(V)所示化合物水解或肼解的步骤，
    所述R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、m分别如权利要求1中定义。
  6. 根据权利要求5所述的式(VI)所示化合物的制备方法，包含式(V-1)所示化合物水解或肼解的步骤，
    所述R10、R11、m分别如权利要求1中定义；进一步地，所述R10、R11为氢，所述m选自0或1；
    优选地，包含式(V-2)所示化合物水解或肼解的步骤，
    所述R10、R11、m分别如权利要求1中定义；
    进一步地，所述R10、R11为氢，所述m选自0或1。
  7. 根据权利要求5至6任一项所述的式(VI)所示化合物的制备方法，包括化合物B-A7水解或肼解为化合物NAG0052B的步骤，
  8. 根据权利要求5至7任一项所述的式(VI)所示化合物的制备方法，进一步包括式(III)所示化合物脱除保护基PG1得到式(IV)所示化合物，式(IV)所示化合物与DMTrCl反应得到式(V)所示化合物的步骤，
    其中，R1、PG1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、m如权利要求1定义。
  9. 根据权利要求8所述的式(VI)所示化合物的制备方法，包括式(III-1)所示化合物脱除保护基PG1得到式(IV-1)所示化合物，式(IV-1)所示化合物与DMTrCl反应得到式(V-1)所示化合物的步骤，
    所述PG1、R10、R11、m分别如权利要求1中定义；进一步地，所述R10、R11为氢，所述m选自0或1；
    优选地，包括式(III-2)所示化合物脱除保护基PG1得到式(IV-2)所示化合物，式(IV-2)所示化合物与DMTrCl反应得到式(V-2)所示化合物的步骤，
    所述PG1、R10、R11、m分别如权利要求1中定义；进一步地，所述R10、R11为氢，所述m选自0或1。
  10. 根据权利要求8或9所述的式(VI)所示化合物的制备方法，包括化合物B-A5脱保护基得到化合物B-A6，后化合物B-A6与DMTrCl反应得到化合物B-A7的步骤，
  11. 根据权利要求5至10任一项所述的式(VI)所示化合物的制备方法，进一步包括权利要求1至4任一项所述的式(III)所示化合物的制备步骤。
  12. 一种如下化合物：
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