CN116891474A - Preparation method of monoisobutyryl nucleoside analogue - Google Patents

Preparation method of monoisobutyryl nucleoside analogue Download PDF

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CN116891474A
CN116891474A CN202310329413.3A CN202310329413A CN116891474A CN 116891474 A CN116891474 A CN 116891474A CN 202310329413 A CN202310329413 A CN 202310329413A CN 116891474 A CN116891474 A CN 116891474A
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acid
compound
formula
reaction
solvent
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朱富强
胡天文
谢元超
沈敬山
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Wangshan Wangshui Lianyungang Pharmaceutical Co ltd
Suzhou Vigonvita Life Sciences Co ltd
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Wangshan Wangshui Lianyungang Pharmaceutical Co ltd
Suzhou Vigonvita Life Sciences Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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Abstract

The application relates to a preparation method of a monoisobutyryl nucleoside analogue, which comprises the following steps: condensation reaction, acylation reaction and deprotection reaction to obtain the monoisobutyryl nucleoside analogue or the salt thereof. The preparation method has the advantages of high yield, few byproducts, easy control of the process, simple operation, safety and environmental protection, and is suitable for industrial mass production.

Description

Preparation method of monoisobutyryl nucleoside analogue
The present application claims priority to chinese application number 202210333362.7 filed on month 2022, 03 and 31, the entire contents and disclosure of which are incorporated herein by reference.
Technical Field
The application belongs to the technical field of pharmacy, and particularly relates to a preparation method of a monoisobutyryl nucleoside analogue.
Background
The monoisobutyrate prodrug form of nucleoside and its analogues can improve physicochemical and metabolic properties of the parent nucleoside, and improve oral bioavailability, for example, compound GS-441524 has good in vitro antiviral activity, but has low oral bioavailability, and compound a after introduction of an isobutyryl group at its 5' position has significantly improved oral bioavailability (Bioor.Med.Chem, 2021,46,116364;J.Med.Chem.2022,65,4,2785). The 5' -isobutyrate prodrug compound A of the nucleoside analogue has wide application prospect in the field of antiviral treatment, and has important significance in researching a simple and efficient synthesis method of the prodrug.
The prior art reports the preparation of 5' -isobutyric acid esters using a method for simultaneously protecting hydroxyl and amine groups using N, N-dimethylformamide dimethyl acetal (DMF-DMA), wherein the by-product of deprotection is N, N-Dimethylformamide (DMF), which is unfavorable for three-waste treatment in the mass production stage and increases the risk of containing genotoxic impurity dimethyl nitrosamine in the crude drug.
The prior patent application CN 113735862A,CN 113754665A reports a strategy for protecting dihydroxyl by acetonide, but uses the condensing agent Dicyclohexylcarbodiimide (DCC) and column chromatography for purification, and the final deprotection yield is lower (49% -66%).
The existing synthesis method of the 5 '-isobutyrate prodrug compound A of the compound GS-441524 is not beneficial to large-scale production, so that the development steps are simple and convenient, and the novel synthesis method of the green sustainable 5' -isobutyrate prodrug is suitable for large-scale production and has important significance.
Disclosure of Invention
The invention aims to solve the technical problems of overcoming the defects in the prior art and providing the preparation method of the monoisobutyryl nucleoside analogue, which has the advantages of high yield, easily controlled process, simple operation and suitability for industrial mass production.
In order to solve the technical problems, the invention adopts the following technical scheme:
A method for preparing a monoisobutyryl nucleoside analog, comprising the steps of:
step a: carrying out condensation reaction on the compound of the formula (II) to obtain a compound of the formula (III);
step b: acylating the compound of formula (III) to obtain a compound of formula (IV);
step c: deprotecting the compound of formula (IV) to give a monoisobutyryl nucleoside analogue of formula (I) or a salt thereof;
wherein X is selected from H or D;
R 3 selected from H or isobutyryl;
y is selected from
R 1 Selected from methyl, ethyl, n-propyl or n-butyl,
R 2 selected from H, C1-C10 alkyl, aryl,
z is selected from oxygen or a direct bond,
R 4 selected from H, C1-C20 alkyl, aryl.
Preferably, the compound of formula (II) is condensed with an orthoformate reagent to give a compound of formula (V),
preferably, the orthoformate reagent is selected from one of trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate and trimethyl orthobutyrate;
preferably, the condensation reaction is carried out in a solvent selected from one or more of C4-C20 orthoformate, C5-C20 hydrocarbon, C6-C20 aromatic hydrocarbon, C1-C20 halogenated hydrocarbon, C2-C20 ester, C2-C20 ether, C1-C20 alcohol, polar aprotic solvent and acetonitrile;
preferably, the solvent is selected from one or more of trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate, trimethyl orthobutyrate, N-hexane, N-heptane, toluene, chlorobenzene, dichloromethane, ethyl acetate, isopropyl acetate, butyl acetate, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methanol, ethanol, isopropanol, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane and acetonitrile;
Preferably, the condensation reaction is carried out with or without the addition of an acid selected from one or more of an organic acid, an inorganic acid and a lewis acid;
more preferably, the organic acid is selected from one or more of formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, isobutyric acid, pivalic acid, benzoic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid;
the inorganic acid is selected from one or more of sulfuric acid, hydrochloric acid, phosphoric acid and perchloric acid;
the Lewis acid is one or more selected from aluminum trichloride, boron trifluoride tetrahydrofuran solution, magnesium chloride, magnesium bromide, stannic chloride, titanium tetrachloride and zinc chloride;
preferably, the ratio of the weight of the compound of formula (II) to the volume of the reaction solvent is 1 (1-30);
preferably, the reaction temperature is-20 to 80 ℃;
preferably, the molar ratio of the compound of formula (II) to the orthoformate agent is 1: (1.0 to 100);
preferably, the molar ratio of the compound of formula (II) to the acid is 1: (0.01-3.0).
Preferably, the compound of formula (II) and boric acid or boric acid ester reagent are subjected to condensation reaction to obtain the compound of formula (VI),
preferably, the boric acid or borate reagent is selected from one of butyl boric acid, phenyl boric acid, trimethyl borate and triisopropyl borate;
Preferably, the condensation reaction is carried out with or without the addition of a dehydrating agent selected from one or more of sodium sulfate, potassium sulfate, magnesium sulfate, calcium sulfate, potassium chloride, magnesium chloride and calcium chloride;
preferably, the condensation reaction is carried out in a solvent selected from one or more of C5-C20 hydrocarbons, C6-C20 aromatic hydrocarbons, C1-C20 halogenated hydrocarbons, C2-C20 esters, C2-C20 ethers, pyridines, polar aprotic solvents and acetonitrile;
preferably, the ratio of the weight of the compound of formula (II) to the volume of the reaction solvent is 1 (1-30);
preferably, the reaction temperature is 10-150 ℃;
preferably, the molar ratio of the compound of formula (II) to the boric acid or borate reagent is 1: (1.0 to 10.0);
preferably, the molar ratio of the compound of formula (II) to the dehydrating agent is 1: (1.0-10.0).
Preferably, the compound of formula (V) is reacted with an isobutyrylating agent to provide a compound of formula (VII),
preferably, the isobutyrylating agent is selected from isobutyryl chloride or isobutyric anhydride;
preferably, the acylation reaction is carried out under the action of a base selected from organic and/or inorganic bases;
more preferably, the organic base is selected from one or more of pyridine, 4-dimethylaminopyridine, 2,4, 6-trimethylpyridine, 2, 6-trimethylpyridine, 3-methylpyridine, triethylamine, N-methylimidazole, N, N-diisopropylethylamine and N, N-dimethylaniline;
The inorganic base is selected from one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium acetate, potassium acetate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate and dipotassium hydrogen phosphate;
preferably, the acylation reaction is carried out in a solvent selected from one or more of C5-C20 hydrocarbons, C6-C20 aromatic hydrocarbons, C1-C20 halogenated hydrocarbons, C2-C20 esters, C2-C20 ethers, polar aprotic solvents and acetonitrile;
preferably, the ratio of the weight of the compound of formula (V) to the volume of the reaction solvent is 1 (1-30);
preferably, the reaction temperature is-20 to 80 ℃;
preferably, the molar ratio of the compound of formula (V) to isobutyrylating agent is 1: (1.0 to 5.0);
preferably, the molar ratio of the compound of formula (V) to the base is 1: (0.01-5.0);
preferably, the molar ratio of the compound of formula (V) to isobutyrylating agent to base is 1: (1.0-2.5): (0.01-5.0).
Preferably, the compound of formula (VI) is reacted with an isobutyrylating agent to provide the compound of formula (VIII),
preferably, the isobutyrylating agent is selected from isobutyryl chloride or isobutyric anhydride;
preferably, the acylation reaction is carried out under the action of a base selected from organic and/or inorganic bases;
more preferably, the organic base is selected from one or more of pyridine, 4-dimethylaminopyridine, 2,4, 6-trimethylpyridine, 2, 6-trimethylpyridine, 3-methylpyridine, triethylamine, N-methylimidazole, N, N-diisopropylethylamine and N, N-dimethylaniline;
The inorganic base is selected from one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium acetate, potassium acetate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate and dipotassium hydrogen phosphate;
preferably, the acylation reaction is carried out in a solvent selected from one or more of C5-C20 hydrocarbons, C6-C20 aromatic hydrocarbons, C1-C20 halogenated hydrocarbons, C2-C20 esters, C2-C20 ethers, polar aprotic solvents and acetonitrile;
preferably, the ratio of the weight of the compound of formula (V) to the volume of the reaction solvent is 1 (1-30);
preferably, the reaction temperature is-20 to 80 ℃;
preferably, the molar ratio of the compound of formula (V) to isobutyrylating agent is 1: (1.0 to 5.0);
preferably, the molar ratio of the compound of formula (V) to the base is 1: (0.01-5.0);
preferably, the molar ratio of the compound of formula (V) to isobutyrylating agent to base is 1: (1.0-2.5): (0.01-5.0).
Preferably, the compound of formula (VII) is deprotected under acidic conditions to give a compound of formula (I) or a salt thereof,
wherein the salt of the compound of formula (I) is selected from the group consisting of hydrochloride, hydrobromide, sulfate, hemisulfate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, phosphate, maleate, fumarate, tartrate, oxalate, malonate or citrate;
Preferably, the acid is selected from one or more of organic acids, inorganic acids and lewis acids;
more preferably, the organic acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, butyric acid, oxalic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, isobutyric acid, pivalic acid, benzoic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid;
the inorganic acid is selected from one or more of sulfuric acid, hydrochloric acid, phosphoric acid and perchloric acid;
the Lewis acid is selected from one or more of aluminum trichloride, magnesium chloride, magnesium bromide, tin tetrachloride, titanium tetrachloride and zinc chloride;
preferably, the deprotection reaction is carried out in a solvent selected from one or more of C5-C20 hydrocarbons, C6-C20 aromatic hydrocarbons, C1-C20 halogenated hydrocarbons, C2-C20 esters, C1-C20 alcohols, C2-C20 ethers, polar aprotic solvents, acetonitrile and water;
preferably, the ratio of the weight of the compound of formula (VII) to the volume of the reaction solvent is 1 (2-30);
preferably, the reaction temperature is 30 to 100 ℃, preferably 40 to 80 ℃, more preferably 50 to 70 ℃;
preferably, the molar ratio of the compound of formula (VII) to the acid is 1: (0.05-5.0).
Preferably, the compound of formula (VIII) is deprotected under acidic conditions to give a compound of formula (I) or a salt thereof,
Wherein the salt of the compound of formula (I) is selected from the group consisting of hydrochloride, hydrobromide, sulfate, hemisulfate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, phosphate, maleate, fumarate, tartrate, oxalate, malonate or citrate;
preferably, the acid is selected from one or more of organic acids, inorganic acids and lewis acids;
more preferably, the organic acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, butyric acid, oxalic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, isobutyric acid, pivalic acid, benzoic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid;
the inorganic acid is selected from one or more of sulfuric acid, hydrochloric acid, phosphoric acid and perchloric acid;
the Lewis acid is selected from one or more of aluminum trichloride, magnesium chloride, magnesium bromide, tin tetrachloride, titanium tetrachloride and zinc chloride;
preferably, the deprotection reaction is carried out in a solvent selected from one or more of C5-C20 hydrocarbons, C6-C20 aromatic hydrocarbons, C1-C20 halogenated hydrocarbons, C2-C20 esters, C1-C20 alcohols, C2-C20 ethers, polar aprotic solvents, acetonitrile and water;
Preferably, the ratio of the weight of the compound of formula (VII) to the volume of the reaction solvent is 1 (2-30);
preferably, the reaction temperature is 30 to 100 ℃, preferably 40 to 80 ℃, more preferably 50 to 70 ℃;
preferably, the molar ratio of the compound of formula (VII) to the acid is 1: (0.05-5.0).
Preferably, when R 3 When selected from H, deprotecting the compound of formula (VIII) in the presence of water to give a compound of formula (I) or a salt thereof,
when R is 3 When selected from isobutyryl, deprotecting the compound of formula (VIII) in the presence of water to give a compound of formula (IX), further deprotecting the compound of formula (IX) under acidic conditions to give a compound of formula (I) or a salt thereof,
wherein the salt of the compound of formula (I) is selected from the group consisting of hydrochloride, hydrobromide, sulfate, hemisulfate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, phosphate, maleate, fumarate, tartrate, oxalate, malonate or citrate;
preferably, the water is pure water or an aqueous solution containing a solute;
preferably, the acid is selected from one or more of organic acids, inorganic acids and lewis acids;
more preferably, the organic acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, butyric acid, oxalic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, isobutyric acid, pivalic acid, benzoic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid;
The inorganic acid is selected from one or more of sulfuric acid, hydrochloric acid, phosphoric acid and perchloric acid;
the Lewis acid is selected from one or more of aluminum trichloride, magnesium chloride, magnesium bromide, tin tetrachloride, titanium tetrachloride and zinc chloride.
Preferably, R 1 Selected from methyl, ethyl, n-propyl or n-butyl, R 2 Selected from H, methyl, ethyl, propyl or butyl.
Preferably, Z is selected from direct bonds.
Further preferably, R 4 Selected from phenyl groups.
Due to the adoption of the technical scheme, compared with the prior art, the invention has the following advantages:
the preparation method of the monoisobutyryl nucleoside analogue has the advantages of high yield, few byproducts, easy control of the process, simple operation, safety and environmental protection, and is suitable for industrial mass production.
Detailed Description
In order to make the technical scheme and the beneficial effects of the invention more obvious and understandable, the following detailed description is given by way of example. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention.
The experimental procedure, in which specific conditions are not noted in the examples below, generally follows conventional experimental conditions. The reagents and materials used in the present invention are commercially available unless otherwise specified.
The weight to volume ratio described in the present invention was g/ml unless otherwise specified.
The invention discloses a preparation method of a monoisobutyryl nucleoside analogue, which comprises the following steps:
step a: the compound of the formula II undergoes condensation reaction to protect 2',3' -dihydroxyl of ribose fragment to obtain a compound of the formula III;
step b: the compound of the formula III and an acylating reagent undergo an acylation reaction to obtain a compound of the formula IV;
step c: deprotecting the compound of formula IV to obtain a monoisobutyryl nucleoside analog of formula I or a salt thereof;
wherein X is selected from H or D;
R 3 selected from H or isobutyryl;
y is selected from
R 1 Selected from methyl, ethyl, n-propyl or n-butyl,
R 2 selected from H, C1-C10 alkyl, aryl, in some specific embodiments, R 2 Selected from H, methyl, ethyl, propyl or butyl, more preferably H;
z is selected from oxygen or a direct bond, in some specific embodiments Z is selected from a direct bond;
R 4 selected from H, C1-C20 alkyl, aryl, in some specific embodiments, R 4 Selected from methyl, butyl or phenyl, more preferably phenyl.
In a specific embodiment, step a is specifically: the compound of the formula II and an orthoformate reagent undergo condensation reaction to obtain a compound of the formula V,
The structure of the orthoformate reagent is shown as a formula IX:
R 4 selected from methyl, ethyl, n-propyl or n-butyl, in some specific embodiments R 4 Selected from methyl or ethyl, more preferably methyl; r is R 5 Selected from H, C1-C10 alkyl, aryl, in some specific embodiments, R 5 Selected from H, methyl, ethyl, propyl or butyl, more preferably H.
In some specific embodiments, the orthoformate agent is selected from one of trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate, and trimethyl orthobutyrate, more preferably trimethyl orthoformate.
In some specific embodiments, the condensation reaction is carried out in a solvent with or without the addition of an acid, specifically, the compound of formula II, the acid and the orthoformate reagent are added to the solvent to react, after the reaction is finished, the mixture is concentrated with or without the addition of a base, and then water and the solvent are added to extract and purify the compound of formula V.
In some specific embodiments, the solvent is selected from one or more of C4-C20 orthoformate, C5-C20 hydrocarbon, C6-C20 aromatic hydrocarbon, C1-C20 halogenated hydrocarbon, C2-C20 ester, C2-C20 ether, C1-C20 alcohol, polar aprotic solvent, and acetonitrile.
In some specific embodiments, the solvent is selected from one or more of trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate, trimethyl orthobutyrate, N-hexane, N-heptane, toluene, chlorobenzene, dichloromethane, ethyl acetate, isopropyl acetate, butyl acetate, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methanol, ethanol, isopropanol, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, and acetonitrile; more preferably one or more of trimethyl orthoformate, dichloromethane and N-methylpyrrolidone, and still more preferably trimethyl orthoformate.
In some specific embodiments, the acid is selected from one or more of an organic acid, an inorganic acid, and a lewis acid.
In some specific embodiments, the organic acid is selected from one or more of formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, isobutyric acid, pivalic acid, benzoic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid;
the inorganic acid is selected from one or more of sulfuric acid, hydrochloric acid, phosphoric acid and perchloric acid;
The Lewis acid is selected from one or more of aluminum trichloride, boron trifluoride tetrahydrofuran solution, magnesium chloride, magnesium bromide, tin tetrachloride, titanium tetrachloride and zinc chloride.
More preferably, the acid is selected from one or more of p-toluenesulfonic acid, boron trifluoride tetrahydrofuran solution and phosphoric acid, more preferably p-toluenesulfonic acid monohydrate.
In some specific embodiments, the ratio of the weight of the compound of formula II to the volume of the reaction solvent is 1: (1 to 30), preferably 1: (3-20), more preferably 1: (5-10), more specifically 1:8, 8;
the reaction temperature is-20 to 80 ℃, preferably 0 to 60 ℃, more preferably 15 to 50 ℃, more preferably 15 to 45 ℃;
the molar ratio of the compound of formula II to the orthoformate reagent is 1: (1.0 to 100);
the molar ratio of the compound of formula II to the acid is 1: (0.01 to 3.0), preferably 1: (0.05 to 2.0), more preferably 1: (0.10 to 0.50), more specifically 1:0.20.
in a specific embodiment, step a is specifically: the compound of the formula II and boric acid or boric acid ester reagent are subjected to condensation reaction to obtain a compound of the formula VI,
in some specific embodiments, the boric acid or borate reagent is selected from boric acid, a C1-C20 organoboric acid, or a C1-C20 borate, preferably one of butylboric acid, phenylboric acid, trimethyl borate, and triisopropyl borate, more preferably phenylboric acid.
In some specific embodiments, the condensation reaction is performed with or without the addition of a dehydrating agent.
The dehydrating agent is selected from one or more of sodium sulfate, potassium sulfate, magnesium sulfate, calcium sulfate, potassium chloride, magnesium chloride and calcium chloride, preferably sodium sulfate.
In some specific embodiments, the condensation reaction is performed in a solvent, specifically, a compound of formula II, boric acid or boric acid ester reagent, with or without a dehydrating agent, is added to the solvent, and after the reaction is finished, the mixture is concentrated with or without alkali, then water and the solvent are added, and the mixture is extracted and purified to obtain the compound of formula VI.
In some specific embodiments, the solvent is selected from one or more of C5-C20 hydrocarbons, C6-C20 aromatic hydrocarbons, C1-C20 halogenated hydrocarbons, C2-C20 esters, C2-C20 ethers, pyridines, polar aprotic solvents, and acetonitrile, preferably one or more of toluene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, and pyridine, more preferably one or more of 2-methyltetrahydrofuran, acetonitrile, and pyridine, and more preferably acetonitrile.
In some specific embodiments, the ratio of the weight of the compound of formula II to the volume of the reaction solvent is 1: (1 to 30), preferably 1: (3-20), more preferably 1: (5-10), more specifically 1:8, 8;
the reaction temperature is 10 to 150 ℃, preferably 50 to 120 ℃, more preferably 60 to 100 ℃, more preferably 70 to 80 ℃;
the molar ratio of the compound of the formula II to the boric acid or boric acid ester reagent is 1: (1.0 to 10.0), preferably 1: (1.0 to 5.0), more preferably 1: (1.0 to 3.0), more specifically 1:2;
the molar ratio of the compound of formula II to the dehydrating agent is 1: (1.0 to 10.0), preferably 1: (1.0 to 5.0), more preferably 1: (1.0 to 3.0), more specifically 1:2.
in a specific embodiment, step b is specifically: reacting the compound of formula V with an isobutyrylating agent to obtain a compound of formula VII,
in some specific embodiments, the compound of formula V is reacted with an isobutyrylating agent and a base to provide a compound of formula VII, specifically, the compound of formula V, the base and the isobutyrylating agent are added to a solvent to react, and after the reaction is completed, water is added, extracted, concentrated, and purified to provide the compound of formula VII.
In some specific embodiments, the isobutyrylating agent is selected from isobutyryl chloride or isobutyric anhydride, preferably isobutyryl chloride.
In some specific embodiments, the base is selected from organic bases and/or inorganic bases;
the organic base is preferably one or more of pyridine, 4-dimethylaminopyridine, 2,4, 6-trimethylpyridine, 2, 6-trimethylpyridine, 3-methylpyridine, triethylamine, N-methylimidazole, N, N-diisopropylethylamine and N, N-dimethylaniline, more preferably 4-dimethylaminopyridine and/or triethylamine, still more preferably triethylamine and 4-dimethylaminopyridine;
the inorganic base is preferably one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium acetate, potassium acetate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate and dipotassium hydrogen phosphate, more preferably sodium carbonate and/or potassium carbonate.
In some specific embodiments, the solvent is selected from one or more of C5-C20 hydrocarbons, C6-C20 aromatic hydrocarbons, C1-C20 halogenated hydrocarbons, C2-C20 esters, C2-C20 ethers, polar aprotic solvents and acetonitrile, preferably one or more of N-hexane, N-heptane, toluene, chlorobenzene, dichloromethane, ethyl acetate, isopropyl acetate, butyl acetate, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane and acetonitrile, more preferably one or more of toluene, dichloromethane and N-methylpyrrolidone, more preferably dichloromethane.
In some specific embodiments, the ratio of the weight of the compound of formula V to the volume of the reaction solvent is 1: (1 to 30), preferably 1: (2-20); more preferably 1: (5 to 10), more preferably 1: 8-10;
the reaction temperature is-20 to 80 ℃, preferably 20 to 70 ℃, more preferably 30 to 60 ℃, more preferably 15 to 35 ℃;
the molar ratio of the compound of formula V to isobutyrylating agent is 1: (1.0 to 5.0), preferably 1: (1.0 to 4.0), more preferably 1: (1.0 to 3.0);
the molar ratio of the compound of formula V to the base is 1: (0.01-5.0);
the molar ratio of the compound of formula V to isobutyrylating agent to base is 1: (1.0-2.5): (0.01-5.0).
In a specific embodiment, step b is specifically: reacting the compound of formula VI with an isobutyrylating agent to obtain a compound of formula VIII,
in some specific embodiments, the compound of formula VI is reacted with an isobutyrylating agent and a base to obtain the compound of formula VIII, specifically, the compound of formula VI, the base and the isobutyrylating agent are added to a solvent to react, and after the reaction is completed, water is added, extracted, concentrated, and purified to obtain the compound of formula VIII.
In some specific embodiments, the isobutyrylating agent is selected from isobutyryl chloride or isobutyric anhydride, preferably isobutyryl chloride;
In some specific embodiments, the base is selected from organic bases and/or inorganic bases;
the organic base is preferably one or more of pyridine, 4-dimethylaminopyridine, 2,4, 6-trimethylpyridine, 2, 6-trimethylpyridine, 3-methylpyridine, triethylamine, N-methylimidazole, N, N-diisopropylethylamine and N, N-dimethylaniline, more preferably 4-dimethylaminopyridine and/or triethylamine, still more preferably triethylamine and 4-dimethylaminopyridine;
the inorganic base is preferably one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium acetate, potassium acetate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate and dipotassium hydrogen phosphate, more preferably sodium carbonate and/or potassium carbonate.
In some specific embodiments, the acylation reaction is carried out in a solvent selected from one or more of C5-C20 hydrocarbons, C6-C20 aromatic hydrocarbons, C1-C20 halogenated hydrocarbons, C2-C20 esters, C2-C20 ethers, polar aprotic solvents and acetonitrile, preferably one or more of N-hexane, N-heptane, toluene, chlorobenzene, dichloromethane, ethyl acetate, isopropyl acetate, butyl acetate, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane and acetonitrile, more preferably one or more of toluene, dichloromethane and N-methylpyrrolidone, more preferably dichloromethane.
In some specific embodiments, the ratio of the weight of the compound of formula V to the volume of the reaction solvent is 1: (1 to 30), preferably 1: (2-20); more preferably 1: (5 to 10), more preferably 1: 8-10;
the reaction temperature is-20 to 80 ℃, preferably 20 to 70 ℃, more preferably 30 to 60 ℃, more preferably 15 to 35 ℃;
the molar ratio of the compound of formula V to isobutyrylating agent is 1: (1.0 to 5.0), preferably 1: (1.0 to 4.0), more preferably 1: (1.0 to 3.0);
the molar ratio of the compound of formula V to the base is 1: (0.01-5.0);
the molar ratio of the compound of formula V to isobutyrylating agent to base is 1: (1.0-2.5): (0.01-5.0).
In a specific embodiment, step c is specifically: deprotecting a compound of formula VII under acidic conditions to obtain a compound of formula I or a salt thereof,
wherein the salt of the compound of formula I is selected from the group consisting of hydrochloride, hydrobromide, sulfate, hemisulfate, mesylate, besylate, p-toluenesulfonate, triflate, phosphate, maleate, fumarate, tartrate, oxalate, malonate or citrate.
In some specific embodiments, the compound of formula VII is obtained by removing the protecting group in the presence of an acid, or removing the protecting group and the N-isobutyryl group simultaneously, and specifically, the compound of formula VII is added into a solvent, then an acid is added to react, after the reaction is finished, the concentration is performed under reduced pressure, water and the solvent are added, extraction and concentration are performed, and the compound of formula I is obtained by purification.
In some specific embodiments, the acid is selected from one or more of an organic acid, an inorganic acid, and a lewis acid;
the organic acid is preferably one or more of formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, butyric acid, oxalic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, isobutyric acid, pivalic acid, benzoic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid;
the mineral acid is preferably one or more of sulfuric acid, hydrochloric acid, phosphoric acid and perchloric acid;
the lewis acid is preferably one or more of aluminum trichloride, magnesium chloride, magnesium bromide, tin tetrachloride, titanium tetrachloride and zinc chloride.
In some specific embodiments, the acid is preferably one or more of formic acid, acetic acid, hydrobromic acid, and phosphoric acid.
In some specific embodiments, the solvent is selected from one or more of C5-C20 hydrocarbons, C6-C20 aromatic hydrocarbons, C1-C20 halogenated hydrocarbons, C2-C20 esters, C1-C20 alcohols, C2-C20 ethers, polar aprotic solvents, acetonitrile and water, preferably one or more of N-heptane, toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, methanol, ethanol, isopropanol, tetrahydrofuran, methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, acetonitrile and water, more preferably one or more of ethyl acetate, ethanol and acetonitrile.
In some specific embodiments, the ratio of the weight of the compound of formula VII to the volume of the reaction solvent is 1: (2 to 30), preferably 1: (3-20), more preferably 1: (5 to 10), more preferably 1: 8-10;
the reaction temperature is 30-100 ℃, preferably 40-80 ℃, more preferably 50-70 ℃;
the molar ratio of the compound of formula VII to acid is 1: (0.05 to 5.0), preferably 1: (0.2 to 2.5), more preferably 1: (1.0-2.0).
In a specific embodiment, step c is specifically: deprotecting the compound of formula VIII under acidic conditions to obtain a compound of formula I or a salt thereof,
wherein the salt of the compound of formula I is selected from the group consisting of hydrochloride, hydrobromide, sulfate, hemisulfate, mesylate, besylate, p-toluenesulfonate, triflate, phosphate, maleate, fumarate, tartrate, oxalate, malonate or citrate.
In some specific embodiments, the compound of formula VIII is deprotected in the presence of an acid, or the protecting group and the N-isobutyryl group are simultaneously deprotected to give a compound of formula I, specifically, the compound of formula VIII is added to a solvent, followed by the addition of an acid, the reaction is completed, and after the reaction is completed, the concentration under reduced pressure, the addition of water and solvent, the extraction, concentration, and purification are performed to give a compound of formula I.
In some specific embodiments, the acid is selected from one or more of an organic acid, an inorganic acid, and a lewis acid;
the organic acid is preferably one or more of formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, butyric acid, oxalic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, isobutyric acid, pivalic acid, benzoic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid;
the mineral acid is preferably one or more of sulfuric acid, hydrochloric acid, phosphoric acid and perchloric acid;
the lewis acid is preferably one or more of aluminum trichloride, magnesium chloride, magnesium bromide, tin tetrachloride, titanium tetrachloride and zinc chloride.
In some specific embodiments, the acid is preferably one or more of formic acid, acetic acid, hydrobromic acid, and phosphoric acid.
In some specific embodiments, the solvent is selected from one or more of C5-C20 hydrocarbons, C6-C20 aromatic hydrocarbons, C1-C20 halogenated hydrocarbons, C2-C20 esters, C1-C20 alcohols, C2-C20 ethers, polar aprotic solvents, acetonitrile and water, preferably one or more of N-heptane, toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, methanol, ethanol, isopropanol, tetrahydrofuran, methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, acetonitrile and water, more preferably one or more of ethyl acetate, ethanol and acetonitrile.
In some specific embodiments, the ratio of the weight of the compound of formula VII to the volume of the reaction solvent is 1: (2 to 30), preferably 1: (3-20), more preferably 1: (5 to 10), more preferably 1: 8-10;
the reaction temperature is 30-100 ℃, preferably 40-80 ℃, more preferably 50-70 ℃;
the molar ratio of the compound of formula VII to acid is 1: (0.05 to 5.0), preferably 1: (0.2 to 2.5), more preferably 1: (1.0-2.0).
In some specific embodiments, when R 3 When selected from H, deprotecting the compound of formula (VIII) in the presence of water to give a compound of formula (I) or a salt thereof,
when R is 3 Selected from isobutyryl groupsDeprotecting a compound of formula (VIII) in the presence of water to give a compound of formula (IX), further deprotecting the compound of formula (IX) under acidic conditions to give a compound of formula (I) or a salt thereof,
wherein the salt form of the compound of formula (I) is selected from the group consisting of hydrochloride, hydrobromide, sulfate, hemisulfate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, phosphate, maleate, fumarate, tartrate, oxalate, malonate or citrate.
In some specific embodiments, the water is pure water or an aqueous solution containing a solute, which may be a sodium chloride solution.
In some specific embodiments, the acid is selected from one or more of an organic acid, an inorganic acid, and a lewis acid.
In some specific embodiments, the organic acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, butyric acid, oxalic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, isobutyric acid, pivalic acid, benzoic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
In some specific embodiments, the mineral acid is selected from one or more of sulfuric acid, hydrochloric acid, phosphoric acid, and perchloric acid.
In some specific embodiments, the lewis acid is selected from one or more of aluminum trichloride, magnesium chloride, magnesium bromide, tin tetrachloride, titanium tetrachloride, and zinc chloride.
In some embodiments, the reaction conditions and interrelationships of the reactants may be referred to above for deprotection of a compound of formula VIII under acidic conditions to provide a related procedure for the compound of formula I or a salt thereof.
EXAMPLE 1 preparation of Compound 1
Compound GS-441524 (5.0 g,17.2 mmol) was added to N-methylpyrrolidone (25 mL), then trimethyl orthoformate (5.5 g,51.6 mmol) and p-toluenesulfonic acid monohydrate (0.65 g,3.4 mmol) were added, reacted at 15-25℃for 16 hours, sodium methoxide (0.19 g,3.4 mmol) was added, concentrated under reduced pressure, ethyl acetate (100 mL) and water (70 mL) were added to the concentrated residue, the layers were separated by extraction, the organic phase was washed twice with water, dried over anhydrous sodium sulfate, filtered, concentrated to give compound 1 (5.3 g, yield 93%, two isomer compounds showing a ratio of both of about 6:4).
1H NMR(400MHz,DMSO)δppm 7.96(brs,3H),6.96–6.86(m,2H),6.28(s,0.6H),6.12(s,0.4H),5.59(d,0.6H),5.34(d,0.4H),5.05–5.02(m,1H),4.95–4.88(m,1H),4.43(d,0.4H),4.31(d,0.6H),3.57–3.48(m,2H),3.43(s,1.2H),3.28(s,1.8H).MS m/z＝334.0[M+l] + 。
EXAMPLE 2 preparation of Compound 1
Compound GS-441524 (5.0 g,17.2 mmol) was added to trimethyl orthoformate (25 mL), p-toluenesulfonic acid monohydrate (0.65 g,3.4 mmol) was added, reacted at 15-25℃for 20 hours, concentrated under reduced pressure, added to water and methyl tert-butyl ether, separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, added n-heptane, stirred, filtered, and dried to give compound 1 (5.2 g, yield 91%). The nuclear magnetic hydrogen spectrum is identical to that of example 1.
EXAMPLE 3 preparation of Compound 3
Compound 2 (10.0 g,34.2 mmol) was added to trimethyl orthoformate (60 mL), p-toluenesulfonic acid monohydrate (0.65 g,3.4 mmol) was added, reacted at 10-20℃for 20 hours, concentrated under reduced pressure, added to water and methyl tert-butyl ether, separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, added n-heptane, stirred, filtered, and dried to give compound 3 (10.3 g, yield 88%).
1H NMR(400MHz,DMSO)δppm7.96(brs,3H),6.92(d,0.6H),6.82(d,0.4H),6.28(s,0.6H),6.10(s,0.4H),5.59(d,0.6H),5.34(d,0.4H),5.05–5.02(m,1H),4.93–4.85(m,1H),4.43(d,0.4H),4.31(d,0.6H),3.57–3.48(m,2H),3.43(s,1.2H),3.26(s,1.8H).MS m/z＝335.0[M+l] + 。
EXAMPLE 4 preparation of Compound 4
Compound 1 (15.0 g,45 mmol) and 4-dimethylaminopyridine (0.55 g,4.5 mmol) were added to N-methylpyrrolidone (60 mL), cooled to 0℃and isobutyric anhydride (7.8 g,49.5 mmol) was added dropwise, after reacting for 4 hours, the reaction solution was poured into a mixed solution of ice water (250 mL) and methyl tert-butyl ether (100 mL), then washed successively with saturated sodium hydrogencarbonate solution (80 mL), 5% hydrobromic acid solution (50 mL) and water (80 mL), the organic phase was concentrated, then N-heptane was added, solid was precipitated, filtered and dried to give compound 4 (16.7 g, yield 92%).
1H NMR(400MHz,DMSO)δppm7.96(brs,3H),6.93–6.83(m,1.6H),6.81(s,0.4H),6.30(s,0.6H),6.15(s,0.4H),5.62(d,0.6H),5.54(d,0.4H),5.05–5.02(m,1H),4.59–4.58(m,1H),4.24–4.10(m,2H),3.44(s,1.2H),3.29(s,1.8H),2.50–2.43(m,1H),1.07–2.99(m,6H).MS m/z＝404.0[M+l] + 。
EXAMPLE 5 preparation of Compound 5
Compound 1 (7.5 g,22.5 mmol) was added to dichloromethane (75 mL), triethylamine (5.7 g,56.2 mmol) and 4-dimethylaminopyridine (0.55 g,4.5 mmol) were further added, the temperature was lowered to 0℃and isobutyryl chloride (6.0 g,56.2 mmol) was added dropwise, then the temperature was raised to 35-40℃to react, after the reaction was completed, the reaction solution was poured into ice water (100 mL), the layers were separated, the separated organic phase was washed with water (100 mL) and saturated sodium bicarbonate solution (200 mL) in this order, the organic phase was concentrated, n-heptane was then added, solid was precipitated, cooled, filtered, and dried to obtain Compound 5 (10.0 g, yield 94%).
1 H NMR(400MHz,DMSO)δ12.02,10.93(d,1H),8.45(d,J＝1.9Hz,1H),7.26–7.03(m,2H),6.32,6.17(d,1H),5.62-5.43(dd,1H),5.04-4.97(m,1H),4.71-4.64(m,1H),4.23–4.11(m,2H),3.44.3.30(d,3H),3.13-3.10(m,1H),2.49–2.37(m,1H),1.14–0.92(m,12H).
ESI-MS：m/z＝474.1[M+H] + 。
EXAMPLE 6 preparation of Compound 6
Compound 3 (8.0 g,23.9 mmol) and 4-dimethylaminopyridine (0.29 g,2.4 mmol) were added to N-methylpyrrolidone (40 mL), cooled to 0℃and isobutyric anhydride (4.2 g,26.3 mmol) was added dropwise, after reacting for 4 hours, the reaction solution was poured into a mixed solution of ice water (200 mL) and methyl tert-butyl ether (80 mL), then washed successively with saturated sodium hydrogencarbonate solution (60 mL), 5% hydrobromic acid solution (50 mL) and water (80 mL), the organic phase was concentrated, then N-heptane was added, solid was precipitated, filtered, and dried to give compound 6 (8.6 g, yield 89%).
1 H NMR(400MHz,DMSO)δ7.99(d,3H),6.89,6.80(d,1H),6.30,6.14(d,1H),6.62-6.40(dd,1H),5.04–5.01(m,1H),4.67–4.57(m,1H),4.26–4.10(m,2H),3.43,3.29(s,3H),3.29(s,2H),2.46–2.42(m,1H),1.08–0.89(m,6H).
ESI-MS：m/z＝405.1[M+H] + 。
EXAMPLE 7 preparation of Compound 7
Compound 3 (12 g,35.9 mmol) was added to dichloromethane (120 mL), triethylamine (9.1 g,89.8 mmol) and 4-dimethylaminopyridine (0.44 g,3.6 mmol) were further added, the temperature was lowered to 0℃and isobutyryl chloride (9.6 g,89.8 mmol) was added dropwise, then the temperature was raised to 25-35℃to react, after the reaction was completed, the reaction solution was poured into ice water (120 mL), and the separated organic phase was separated by layering, then washed with water (100 mL) and saturated sodium hydrogencarbonate solution (200 mL) in this order, the organic phase was concentrated, then n-heptane was added, solid was precipitated, cooled, filtered and dried to obtain Compound 7 (15.5 g, yield 91%).
1 H NMR(400MHz,DMSO)δ12.02,10.93(d,1H),8.45(d,J＝1.9Hz,1H),7.13,7.04(d,1H),6.32,6.17(d,1H),5.62-5.43(dd,1H),5.04-4.97(m,1H),4.71-4.64(m,1H),4.23–4.11(m,2H),3.44.3.30(d,3H),3.13-3.10(m,1H),2.49–2.37(m,1H),1.14–0.92(m,12H).
ESI-MS：m/z＝475.2[M+H] + 。
EXAMPLE 8 preparation of Compound A hydrobromide
Compound 4 (106 mg,0.263 mmol) was added to ethanol (2 mL), 48% aqueous HBr (46 mg,0.276 mmol), and the reaction stirred at room temperature overnight, concentrated, and EA (2 mL) was slurried to give compound 8 as a white solid, compound A hydrobromide (80 mg, 69% yield).
1 H NMR(400MHz,DMSO)δ9.44(bs,1H),8.88(bs,1H),8.19(s,1H),7.28(s,1H),6.96(s,1H),5.55(bs,3H),4.63(d,J＝4.9Hz,1H),4.33–4.24(m,2H),4.24–4.12(m,1H),3.94(dd,J＝6.5,4.9Hz,1H),2.52(m,1H),1.13–0.88(m,6H).
ESI-MS：m/z＝362.2[M+H] + 。
Example 9 preparation of deuterated Compound A hydrobromide
Compound 6 (106 mg,0.263 mmol) was added to ethanol (2 mL), 48% aqueous HBr (46 mg,0.276 mmol), stirred at room temperature overnight, concentrated, and EA (2 mL) slurried to afford compound 9 as a white solid, deuterated compound A hydrobromide (85 mg, 73% yield).
1 H NMR(400MHz,DMSO)δ9.44(bs,1H),8.88(bs,1H),8.19(s,1H),6.96(s,1H),5.55(bs,3H),4.63(d,J＝4.9Hz,1H),4.33–4.24(m,2H),4.24–4.12(m,1H),3.94(dd,J＝6.5,4.9Hz,1H),2.52(m,1H),1.13–0.88(m,6H).
ESI-MS：m/z＝363.2[M+H] + 。
EXAMPLE 10 preparation of Compound A
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Compound 5 (150 mg,0.317 mmol) was added to ethanol (4 mL), followed by addition of phosphoric acid (85%, 11mg,0.095 mmol), heating to reflux, concentrating under reduced pressure after completion of the reaction, adding methyltetrahydrofuran (10 mL) and saturated sodium bicarbonate (5 mL), stirring, standing, discarding the aqueous layer, then washing the organic layer with water (5 mL) and saturated sodium bicarbonate solution (5 mL) in sequence, concentrating the organic phase, then adding n-heptane, precipitating solid, cooling, filtering, and drying to give Compound 10, namely Compound A (80 mg, yield 70%).
1 H NMR(400MHz,DMSO-d6)δ7.92(s,3H),6.91(d,J＝4.5Hz,1H),6.81(d,J＝4.5Hz,1H),6.31(d,J＝5.9Hz,1H),4.69(t,J＝5.3Hz,1H),4.34–4.13(m,3H),4.02(dq,J＝54.1,5.5Hz,2H),2.54(d,J＝7.0Hz,1H),1.05(dd,J＝7.0,2.0Hz,6H).
ESI-MS：m/z＝362.2[M+H] + 。
Example 11 preparation of deuterated Compound A
Compound 7 (150 mg,0.317 mmol) was added to ethanol (4 mL), followed by addition of phosphoric acid (85%, 11mg,0.095 mmol), heating to reflux, concentrating under reduced pressure after completion of the reaction, adding methyltetrahydrofuran (10 mL) and saturated sodium bicarbonate (5 mL), stirring, standing, discarding the aqueous layer, then washing the organic layer with water (5 mL), saturated sodium bicarbonate solution (5 mL) in sequence, concentrating the organic phase, then adding n-heptane, precipitating solid, cooling, filtering, drying to give compound 11, deuterated compound A (85 mg, yield 74.5%).
1 H NMR(400MHz,DMSO-d6)δ7.92(s,3H),6.9(s,1H),6.31(d,J＝5.9Hz,1H),4.69(t,J＝5.3Hz,1H),4.34–4.13(m,3H),4.02(dq,J＝54.1,5.5Hz,2H),2.54(d,J＝7.0Hz,1H),1.05(dd,J＝7.0,2.0Hz,6H).
ESI-MS：m/z＝363.2[M+H] + 。
EXAMPLE 12 preparation of Compound 12
Compound GS-441524 (300 mg,1.03 mmol) and phenylboronic acid (131.86 mg,1.08 mmol) were added to pyridine (5 mL), nitrogen was purged, and the mixture was heated to reflux, reacted for 6 hours, and concentrated under reduced pressure. To the concentrated residue was added 1, 4-dioxane (5 mL), and the mixture was dissolved by stirring, methyl t-butyl ether (25 mL) was slowly added dropwise, and crystallization was carried out at 10.+ -. 5 ℃ for 18 hours. Filtration, rinsing of the filter cake with methyl tert-butyl ether (3 mL) and vacuum drying of the filter cake afforded compound 12 as an off-white solid (381 mg, 98% yield).
1 H NMR(400MHz,DMSO-d6)δ8.00(d,J＝21.5Hz,3H),7.78–7.71(m,2H),7.57–7.48(m,1H),7.46–7.42(m,2H),7.04(d,J＝4.6Hz,1H),6.97(d,J＝4.6Hz,1H),5.79(d,J＝7.5Hz,1H),5.16–5.04(m,2H),4.30(q,J＝4.7Hz,1H),3.67(t,J＝5.3Hz,2H).
EXAMPLE 13 preparation of Compound 13
Compound 2 (300 mg,1.03 mmol) and phenylboronic acid (132.05 mg,1.08 mmol) were added to pyridine (5 mL), nitrogen blanketed, warmed to reflux, reacted for 6 hours, and concentrated under reduced pressure. To the concentrated residue was added 1, 4-dioxane (5 mL), and the mixture was dissolved by stirring, methyl t-butyl ether (25 mL) was slowly added dropwise, and crystallization was carried out at 10.+ -. 5 ℃ for 18 hours. Filtration, rinsing of the filter cake with methyl tert-butyl ether (3 mL) and vacuum drying of the filter cake afforded compound 13 as an off-white solid (392 mg, 99% yield).
1 H NMR(400MHz,DMSO-d6)δ8.02–7.91(m,3H),7.78–7.73(m,2H),7.53(t,J＝7.4Hz,1H),7.44(d,J＝8.3Hz,2H),7.04(s,1H),5.79(d,J＝7.5Hz,1H),5.10(t,J＝6.0Hz,2H),4.30(d,J＝4.7Hz,1H),3.67(t,J＝5.2Hz,2H).
EXAMPLE 14 preparation of Compound A
Compound 12 (100 mg,0.27 mmol), 4-dimethylaminopyridine (2.6 mg,0.02 mmol) was added to N-methylpyrrolidone (3 mL), nitrogen was used to protect, the ice salt bath was cooled to about 0deg.C, isobutyric anhydride (46.07 mg,0.29 mmol) was slowly added dropwise, and the reaction was continued for 2 hours. The reaction was washed with 15% sodium chloride solution, extracted with ethyl acetate, and dried and concentrated on a column (MeOH: dcm=1:10) to give compound a (58 mg, yield 62%).
1 H NMR(400MHz,DMSO-d6)δ7.92(s,3H),6.91(d,J＝4.5Hz,1H),6.81(d,J＝4.5Hz,1H),6.31(d,J＝5.9Hz,1H),4.69(t,J＝5.3Hz,1H),4.34–4.13(m,3H),4.02(dq,J＝54.1,5.5Hz,2H),2.54(d,J＝7.0Hz,1H),1.05(dd,J＝7.0,2.0Hz,6H).
ESI-MS：m/z＝362.2[M+H] + 。
Example 15 preparation of deuterated Compound A
Compound 13 (300 mg,0.79 mmol), 4-dimethylaminopyridine (7.7 mg,0.06 mmol) was added to N-methylpyrrolidone (5 mL), nitrogen was purged, the ice salt bath was cooled to about 0deg.C, isobutyric anhydride (137.87 mg,0.87 mmol) was slowly added dropwise, and the reaction was continued for 2 hours. The reaction was washed with 15% sodium chloride solution, extracted with ethyl acetate, and dried and concentrated on a column (MeOH: dcm=1:10) to give deuterated compound a (186 mg, yield 65%).
1 H NMR(400MHz,DMSO-d6)δ7.92(s,3H),6.9(s,1H),6.31(d,J＝5.9Hz,1H),4.69(t,J＝5.3Hz,1H),4.34–4.13(m,3H),4.02(dq,J＝54.1,5.5Hz,2H),2.54(d,J＝7.0Hz,1H),1.05(dd,J＝7.0,2.0Hz,6H).
ESI-MS：m/z＝363.2[M+H] + 。
EXAMPLE 16 preparation of Compound 16
Compound 12 (100 mg,0.27 mmol) was added to methylene chloride (2 mL), triethylamine (6.8 mg,0.68 mmol) and 4-dimethylaminopyridine (0.0036 g,0.03 mmol) were further added, the temperature was lowered to 0℃and isobutyryl chloride (72 mg,0.68 mmol) was added dropwise, the temperature was raised to 25-35℃after the addition was completed, the reaction mixture was poured into ice water (10 mL), the layers were separated, the separated organic phase was washed with water (10 mL) and saturated sodium hydrogencarbonate solution (20 mL) in this order, the organic phase was concentrated, n-heptane was added, a solid was precipitated, filtered, and dried to give Compound 16 (102 mg, yield 90%).
EXAMPLE 17 preparation of Compound 17
Compound 13 (100 mg,0.27 mmol) was added to methylene chloride (2 mL), triethylamine (6.8 mg,0.68 mmol) and 4-dimethylaminopyridine (0.0036 g,0.03 mmol) were further added, the temperature was lowered to 0℃and isobutyryl chloride (72 mg,0.68 mmol) was added dropwise, the temperature was raised to 25-35℃after the addition was completed, the reaction mixture was poured into ice water (10 mL), the layers were separated, the separated organic phase was washed with water (10 mL) and saturated sodium hydrogencarbonate solution (20 mL) in this order, the organic phase was concentrated, n-heptane was added, solid was precipitated, filtered, and dried to give compound 17 (0.1 g, yield 89%).
EXAMPLE 18 preparation of Compound A
Compound 16 (102 mg,0.236 mmol) was added to ethanol (3 mL) and dissolved with stirring, phosphoric acid (85%, 10mg,0.095 mmol) was added, the mixture was warmed to reflux, after the reaction was completed, concentrated under reduced pressure, methyl tetrahydrofuran (10 mL) and saturated sodium bicarbonate (5 mL) were added, stirred, left standing, the aqueous layer was discarded, then the organic layer was washed with water (5 mL) and saturated sodium bicarbonate solution (5 mL) successively, the organic phase was concentrated, n-heptane was then added, solids were precipitated, cooled, filtered, and dried to give Compound 10, compound A (59.8 mg, yield 70%).
1 H NMR(400MHz,DMSO-d6)δ7.92(s,3H),6.91(d,J＝4.5Hz,1H),6.81(d,J＝4.5Hz,1H),6.31(d,J＝5.9Hz,1H),4.69(t,J＝5.3Hz,1H),4.34–4.13(m,3H),4.02(dq,J＝54.1,5.5Hz,2H),2.54(d,J＝7.0Hz,1H),1.05(dd,J＝7.0,2.0Hz,6H).
ESI-MS：m/z＝362.2[M+H] + 。
Example 19 preparation of deuterated Compound A
Compound 17 (98 mg,0.227 mmol) was dissolved in ethanol (2.5 mL) with stirring, phosphoric acid (85%, 11mg,0.095 mmol) was added, the mixture was warmed to reflux, concentrated under reduced pressure after the completion of the reaction, methyltetrahydrofuran (10 mL) and saturated sodium bicarbonate (5 mL) were added, stirred, left to stand, the aqueous layer was discarded, then the organic layer was washed with water (5 mL) and saturated sodium bicarbonate solution (5 mL) in sequence, the organic phase was concentrated, n-heptane was then added, solids were precipitated, cooled, filtered, and dried to give Compound 10, deuterated Compound A (58 mg, yield 71%).
1 H NMR(400MHz,DMSO-d6)δ7.92(s,3H),6.9(s,1H),6.31(d,J＝5.9Hz,1H),4.69(t,J＝5.3Hz,1H),4.34–4.13(m,3H),4.02(dq,J＝54.1,5.5Hz,2H),2.54(d,J＝7.0Hz,1H),1.05(dd,J＝7.0,2.0Hz,6H).
ESI-MS：m/z＝363.2[M+H] + 。
EXAMPLE 20 preparation of Compound A
Compound 12 (98 mg,0.26 mmol), 4-dimethylaminopyridine (2.5 mg,0.02 mmol) was added to N-methylpyrrolidone (2.5 mL), nitrogen was used to protect, the ice salt bath was cooled to about 0deg.C, isobutyric anhydride (45.18 mg,0.29 mmol) was slowly added dropwise, and the reaction was continued for 2 hours. Ethanol (4 mL) and phosphoric acid (85%, 11mg,0.095 mmol) were added to the reaction mixture, stirred for 30 minutes, washed with 15% sodium chloride solution, extracted with ethyl acetate, and dried and concentrated over column (MeOH: dcm=1:10) to give compound a (55 mg, yield 59%).
1 H NMR(400MHz,DMSO-d6)δ7.92(s,3H),6.91(d,J＝4.5Hz,1H),6.81(d,J＝4.5Hz,1H),6.31(d,J＝5.9Hz,1H),4.69(t,J＝5.3Hz,1H),4.34–4.13(m,3H),4.02(dq,J＝54.1,5.5Hz,2H),2.54(d,J＝7.0Hz,1H),1.05(dd,J＝7.0,2.0Hz,6H).
ESI-MS：m/z＝362.2[M+H] + 。
Example 21 preparation of deuterated Compound A
Compound 13 (303 mg,0.80 mmol), 4-dimethylaminopyridine (8.1 mg,0.07 mmol) was added to N-methylpyrrolidone (5 mL), nitrogen was purged, the ice salt bath was cooled to about 0deg.C, isobutyric anhydride (138.56 mg,0.88 mmol) was slowly added dropwise, and the reaction was continued for 2 hours. To the reaction was added ethanol (8 mL), phosphoric acid (85%, 22mg,0.19 mmol) and stirred for 30 min, washed with 15% sodium chloride solution, extracted with ethyl acetate, and dried and concentrated over column (MeOH: dcm=1:10) to give deuterated compound a (189 mg, yield 65%).
1 H NMR(400MHz,DMSO-d6)δ7.92(s,3H),6.9(s,1H),6.31(d,J＝5.9Hz,1H),4.69(t,J＝5.3Hz,1H),4.34–4.13(m,3H),4.02(dq,J＝54.1,5.5Hz,2H),2.54(d,J＝7.0Hz,1H),1.05(dd,J＝7.0,2.0Hz,6H).
ESI-MS：m/z＝363.2[M+H] + 。
EXAMPLE 22 preparation of Compound A
Compound 4 (10 g,24.8 mmol) was added to ethanol (100 mL), formic acid (88%, 1.56g,29.8 mmol) was added, the reaction was warmed to 75-80℃and after the completion of the reaction, concentrated under reduced pressure, water and sodium hydrogencarbonate (4.6 g,54.6 mmol) were added to the concentrate, stirred, filtered and dried to give Compound A (8.2 g, yield 91%).
1 H NMR(400MHz,DMSO)δppm8.00-7.80(m,3H),6.92(d,1H),6.82(d,1H),6.33(d,1H),5.39(d,1H),4.70(t,1H),4.32(dd,1H),4.27 -4.21(m,1H),4.18(dd,1H),(m,1H),3.99-3.94(m,1H),2.57-2.52(m,1H),1.07(d,3H),1.06(d,3H),MS m/z＝362.0[M+l] + 。
EXAMPLE 23 preparation of Compound A
Compound GS-441524 (10 g,34.4 mmol) was added to acetonitrile (100 mL), phenylboronic acid (6.3 g,51.6 mmol) and anhydrous sodium sulfate (12.2 g,86 mmol) were then added, reacted at 75-80℃for 16 hours, concentrated under reduced pressure, ethyl acetate (100 mL) and water (70 mL) were added to the concentrated residue, the layers were separated by extraction, the organic phase was washed twice with aqueous sodium hydrogencarbonate, washed twice with water, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 12.
All of the compound 12 obtained in the previous step was added to N-methylpyrrolidone (50 mL) and 4-dimethylaminopyridine (0.42 g,3.44 mmol), cooled to 0℃and isobutyric anhydride (5.4 g,34.4 mmol) was added dropwise thereto, after reacting for 4 hours, the reaction solution was poured into a mixed solution of ice water (250 mL) and methyl tert-butyl ether (100 mL), and the layers were separated, and then the organic layer was washed with saturated sodium hydrogencarbonate solution and water in this order, and concentrated to obtain the compound 14.
All of the compound 14 obtained in the previous step was added to ethanol (100 mL), followed by addition of phosphoric acid (85%, 6.7g,68.8 mmol), the mixture was warmed to 75-80℃and reacted, after the completion of the reaction, concentrated under reduced pressure, methyl tert-butyl ether, water and aqueous sodium hydrogencarbonate solution were added to the concentrate, the mixture was stirred and layered, the organic layer was dried over anhydrous sodium sulfate, stirred, filtered, concentrated under reduced pressure, n-heptane was added, stirred, filtered and dried to give compound A (9.3 g, yield 75%).
It should be understood that the above examples are illustrative and are not intended to encompass all possible implementations encompassed by the claims. Various modifications and changes may be made in the above embodiments without departing from the scope of the disclosure. Likewise, the individual features of the above embodiments can also be combined arbitrarily to form further embodiments of the invention which may not be explicitly described. Therefore, the above examples merely represent several embodiments of the present invention and do not limit the scope of protection of the patent of the present invention.

Claims (10)

1. A method for preparing a monoisobutyryl nucleoside analogue, which is characterized by comprising the following steps: the method comprises the following steps:
step a: carrying out condensation reaction on the compound of the formula (II) to obtain a compound of the formula (III);
step b: acylating the compound of formula (III) to obtain a compound of formula (IV);
step c: deprotecting the compound of formula (IV) to give a monoisobutyryl nucleoside analogue of formula (I) or a salt thereof;
wherein X is selected from H or D;
R 3 selected from H or isobutyryl;
y is selected from
R 1 Selected from methyl, ethyl, n-propylA base group or a n-butyl group,
R 2 selected from H, C1-C10 alkyl, aryl,
z is selected from oxygen or a direct bond,
R 4 selected from H, C1-C20 alkyl, aryl.
2. The method for preparing Shan Yiding acyl nucleoside analog according to claim 1, wherein:
the compound of the formula (II) and an orthoformate reagent undergo condensation reaction to obtain a compound of the formula (V),
preferably, the orthoformate reagent is selected from one of trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate and trimethyl orthobutyrate;
preferably, the condensation reaction is carried out in a solvent selected from one or more of C4-C20 orthoformate, C5-C20 hydrocarbon, C6-C20 aromatic hydrocarbon, C1-C20 halogenated hydrocarbon, C2-C20 ester, C2-C20 ether, C1-C20 alcohol, polar aprotic solvent and acetonitrile;
preferably, the solvent is selected from one or more of trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate, trimethyl orthobutyrate, N-hexane, N-heptane, toluene, chlorobenzene, dichloromethane, ethyl acetate, isopropyl acetate, butyl acetate, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methanol, ethanol, isopropanol, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane and acetonitrile;
Preferably, the condensation reaction is carried out with or without the addition of an acid selected from one or more of an organic acid, a mineral acid and a lewis acid;
more preferably, the organic acid is selected from one or more of formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, isobutyric acid, pivalic acid, benzoic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid;
the inorganic acid is selected from one or more of sulfuric acid, hydrochloric acid, phosphoric acid and perchloric acid;
the Lewis acid is selected from one or more of aluminum trichloride, boron trifluoride tetrahydrofuran solution, magnesium chloride, magnesium bromide, tin tetrachloride, titanium tetrachloride and zinc chloride;
preferably, the ratio of the weight of the compound of formula (II) to the volume of the reaction solvent is 1 (1-30);
preferably, the reaction temperature is-20 to 80 ℃;
preferably, the molar ratio of the compound of formula (II) to the orthoformate agent is 1: (1.0 to 100);
preferably, the molar ratio of the compound of formula (II) to the acid is 1: (0.01-3.0).
3. The method for preparing Shan Yiding acyl nucleoside analog according to claim 1, wherein:
The compound of the formula (II) and boric acid or boric acid ester reagent are subjected to condensation reaction to obtain the compound of the formula (VI),
preferably, the boric acid or borate reagent is selected from one of butyl boric acid, phenyl boric acid, trimethyl borate and triisopropyl borate;
preferably, the condensation reaction is carried out with or without the addition of a dehydrating agent selected from one or more of sodium sulfate, potassium sulfate, magnesium sulfate, calcium sulfate, potassium chloride, magnesium chloride and calcium chloride;
preferably, the condensation reaction is carried out in a solvent selected from one or more of C5-C20 hydrocarbons, C6-C20 aromatic hydrocarbons, C1-C20 halogenated hydrocarbons, C2-C20 esters, C2-C20 ethers, pyridines, polar aprotic solvents and acetonitrile;
preferably, the ratio of the weight of the compound of formula (II) to the volume of the reaction solvent is 1 (1-30);
preferably, the reaction temperature is 10-150 ℃;
preferably, the molar ratio of the compound of formula (II) to the boric acid or borate reagent is 1: (1.0 to 10.0);
preferably, the molar ratio of the compound of formula (II) to the dehydrating agent is 1: (1.0-10.0).
4. The method for preparing Shan Yiding acyl nucleoside analog according to claim 2, wherein:
Reacting the compound of formula (V) with an isobutyrylating agent to obtain a compound of formula (VII),
preferably, the isobutyrylating agent is selected from isobutyryl chloride or isobutyric anhydride;
preferably, the acylation reaction is carried out under the action of a base selected from organic and/or inorganic bases;
more preferably, the organic base is selected from one or more of pyridine, 4-dimethylaminopyridine, 2,4, 6-trimethylpyridine, 2, 6-trimethylpyridine, 3-methylpyridine, triethylamine, N-methylimidazole, N, N-diisopropylethylamine and N, N-dimethylaniline;
preferably, the inorganic base is selected from one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium acetate, potassium acetate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate and dipotassium hydrogen phosphate;
preferably, the acylation reaction is carried out in a solvent selected from one or more of C5-C20 hydrocarbons, C6-C20 aromatic hydrocarbons, C1-C20 halogenated hydrocarbons, C2-C20 esters, C2-C20 ethers, polar aprotic solvents and acetonitrile;
preferably, the ratio of the weight of the compound of formula (V) to the volume of the reaction solvent is 1 (1-30);
preferably, the reaction temperature is-20 to 80 ℃;
preferably, the molar ratio of the compound of formula (V) to isobutyrylating agent is 1: (1.0 to 5.0);
Preferably, the molar ratio of the compound of formula (V) to the base is 1: (0.01-5.0);
preferably, the molar ratio of the compound of formula (V) to isobutyrylating agent to base is 1: (1.0-2.5): (0.01-5.0).
5. A process for the preparation of Shan Yiding acyl nucleoside analogues according to claim 3, wherein:
reacting the compound of formula (VI) with an isobutyrylating agent to obtain a compound of formula (VIII),
preferably, the isobutyrylating agent is selected from isobutyryl chloride or isobutyric anhydride;
preferably, the acylation reaction is carried out under the action of a base selected from organic and/or inorganic bases;
more preferably, the organic base is selected from one or more of pyridine, 4-dimethylaminopyridine, 2,4, 6-trimethylpyridine, 2, 6-trimethylpyridine, 3-methylpyridine, triethylamine, N-methylimidazole, N, N-diisopropylethylamine and N, N-dimethylaniline;
preferably, the inorganic base is selected from one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium acetate, potassium acetate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate and dipotassium hydrogen phosphate;
preferably, the acylation reaction is carried out in a solvent selected from one or more of C5-C20 hydrocarbons, C6-C20 aromatic hydrocarbons, C1-C20 halogenated hydrocarbons, C2-C20 esters, C2-C20 ethers, polar aprotic solvents and acetonitrile;
Preferably, the ratio of the weight of the compound of formula (V) to the volume of the reaction solvent is 1 (1-30);
preferably, the reaction temperature is-20 to 80 ℃;
preferably, the molar ratio of the compound of formula (V) to isobutyrylating agent is 1: (1.0 to 5.0);
preferably, the molar ratio of the compound of formula (V) to the base is 1: (0.01-5.0);
preferably, the molar ratio of the compound of formula (V) to isobutyrylating agent to base is 1: (1.0-2.5): (0.01-5.0).
6. The method for preparing Shan Yiding acyl nucleoside analog according to claim 4, wherein:
deprotecting a compound of formula (VII) under acidic conditions to give a compound of formula (I) or a salt thereof,
wherein the salt of the compound of formula (I) is selected from the group consisting of hydrochloride, hydrobromide, sulfate, hemisulfate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, phosphate, maleate, fumarate, tartrate, oxalate, malonate or citrate;
preferably, the acid is selected from one or more of an organic acid, an inorganic acid and a lewis acid;
more preferably, the organic acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, butyric acid, oxalic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, isobutyric acid, pivalic acid, benzoic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid;
The inorganic acid is selected from one or more of sulfuric acid, hydrochloric acid, phosphoric acid and perchloric acid;
the Lewis acid is selected from one or more of aluminum trichloride, magnesium chloride, magnesium bromide, tin tetrachloride, titanium tetrachloride and zinc chloride;
preferably, the deprotection reaction is carried out in a solvent selected from one or more of C5-C20 hydrocarbons, C6-C20 aromatic hydrocarbons, C1-C20 halogenated hydrocarbons, C2-C20 esters, C1-C20 alcohols, C2-C20 ethers, polar aprotic solvents, acetonitrile and water;
preferably, the ratio of the weight of the compound of formula (VII) to the volume of the reaction solvent is 1 (2-30);
preferably, the reaction temperature is 30 to 100 ℃, preferably 40 to 80 ℃, more preferably 50 to 70 ℃;
preferably, the molar ratio of the compound of formula (VII) to the acid is 1: (0.05-5.0).
7. The method for preparing Shan Yiding acyl nucleoside analog according to claim 5, wherein:
deprotecting a compound of formula (VIII) under acidic conditions to give a compound of formula (I) or a salt thereof,
wherein the salt of the compound of formula (I) is selected from the group consisting of hydrochloride, hydrobromide, sulfate, hemisulfate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, phosphate, maleate, fumarate, tartrate, oxalate, malonate or citrate;
Preferably, the acid is selected from one or more of an organic acid, an inorganic acid and a lewis acid;
more preferably, the organic acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, butyric acid, oxalic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, isobutyric acid, pivalic acid, benzoic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid;
the inorganic acid is selected from one or more of sulfuric acid, hydrochloric acid, phosphoric acid and perchloric acid;
the Lewis acid is selected from one or more of aluminum trichloride, magnesium chloride, magnesium bromide, tin tetrachloride, titanium tetrachloride and zinc chloride;
preferably, the deprotection reaction is carried out in a solvent selected from one or more of C5-C20 hydrocarbons, C6-C20 aromatic hydrocarbons, C1-C20 halogenated hydrocarbons, C2-C20 esters, C1-C20 alcohols, C2-C20 ethers, polar aprotic solvents, acetonitrile and water;
preferably, the ratio of the weight of the compound of formula (VII) to the volume of the reaction solvent is 1 (2-30);
preferably, the reaction temperature is 30 to 100 ℃, preferably 40 to 80 ℃, more preferably 50 to 70 ℃;
preferably, the molar ratio of the compound of formula (VII) to the acid is 1: (0.05-5.0).
8. The method for preparing Shan Yiding acyl nucleoside analog according to claim 5, wherein:
when R is 3 When selected from H, deprotecting the compound of formula (VIII) in the presence of water to give a compound of formula (I) or a salt thereof,
when R is 3 When selected from isobutyryl, deprotecting the compound of formula (VIII) in the presence of water to give a compound of formula (IX), further deprotecting the compound of formula (IX) under acidic conditions to give a compound of formula (I) or a salt thereof,
wherein the salt of the compound of formula (I) is selected from the group consisting of hydrochloride, hydrobromide, sulfate, hemisulfate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, phosphate, maleate, fumarate, tartrate, oxalate, malonate or citrate;
preferably, the water is pure water or an aqueous solution containing a solute;
preferably, the acid is selected from one or more of an organic acid, an inorganic acid and a lewis acid;
more preferably, the organic acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, butyric acid, oxalic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, isobutyric acid, pivalic acid, benzoic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid;
The inorganic acid is selected from one or more of sulfuric acid, hydrochloric acid, phosphoric acid and perchloric acid;
the Lewis acid is selected from one or more of aluminum trichloride, magnesium chloride, magnesium bromide, tin tetrachloride, titanium tetrachloride and zinc chloride.
9. The method for preparing a Shan Yiding acyl nucleoside analogue according to any one of claims 1, 2, 4 or 6, which is characterized in that: the R is 1 Selected from methyl, ethyl, n-propyl or n-butyl, said R 2 Selected from H, methyl, ethyl, propyl or butyl.
10. The method for preparing a Shan Yiding acyl nucleoside analogue according to any one of claims 1, 3, 5, 7 or 8, which is characterized in that: the Z is selected from a direct bond;
preferably, said R 4 Selected from phenyl groups.
CN202310329413.3A 2022-03-31 2023-03-30 Preparation method of monoisobutyryl nucleoside analogue Pending CN116891474A (en)

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