CN114573590B - Preparation method and application of tetraisobutyryl nucleoside analogue - Google Patents

Preparation method and application of tetraisobutyryl nucleoside analogue Download PDF

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CN114573590B
CN114573590B CN202210271113.XA CN202210271113A CN114573590B CN 114573590 B CN114573590 B CN 114573590B CN 202210271113 A CN202210271113 A CN 202210271113A CN 114573590 B CN114573590 B CN 114573590B
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acid
potassium
sodium
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formula
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CN114573590A (en
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朱富强
谢元超
胡天文
沈敬山
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Suzhou Wangshan Wangshui Biopharmaceutical Co ltd
Wangshan Wangshui Lianyungang Pharmaceutical 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a preparation method and application of a tetraisobutyryl nucleoside analogue. The preparation method has the advantages of mild reaction conditions, few byproducts, high yield, easy control of the process and simple operation, and is suitable for industrial mass production.

Description

Preparation method and application of tetraisobutyryl nucleoside analogue
Technical Field
The invention belongs to the technical field of pharmacy, and particularly relates to a preparation method and application of a tetraisobutyryl nucleoside analogue.
Background
VV116 and A131 are novel orally taken anti-novel coronavirus nucleoside compounds, and have good inhibitory activity on other viruses, such as respiratory syncytial virus, dengue virus, hepatitis C virus, zika virus and the like, and the structure is shown as follows. The triisobutyrate prodrug forms in the molecular structures of the VV116 and the A131 greatly improve the physicochemical property and in-vivo metabolic property of parent nucleosides, and the application of the VV116 and the A131 as oral medicines has wide application prospect in the field of antiviral treatment, and has important significance in researching simple and efficient synthesis methods of the prodrugs.
The preparation of triisobutyrate reported in the prior literature (Cell Research,2021,31,1212-1214) uses a protecting group strategy, adding a reaction step.
Another document (J.Med. Chem.,2021,64,5001-5017) reports the use of the condensation reaction of a parent nucleoside compound 5 with isobutyric acid to give triisobutyrate compound 6 directly, but the use of the condensing agent diisopropylcarbodiimide and the polar aprotic solvent N, N-Dimethylformamide (DMF) with an increase in by-products.
Patent (CN 113735862) reports that the reaction of parent nucleoside compound 5 with isobutyric anhydride produced prodrug compound 6 in only 35% yield.
Existing methods for synthesizing triisobutyrate prodrugs of VV116 and the like are not conducive to mass production. Therefore, the development steps are simple and convenient, the method is suitable for large-scale production, and the novel green sustainable method for synthesizing the triisobutyrate prodrug has important significance.
Disclosure of Invention
The preparation method has the advantages of mild reaction conditions, few byproducts, high yield, easily controlled process and simple operation, and is suitable for industrial mass production.
In order to solve the technical problems, the invention adopts the following technical scheme:
a tetraisobutyryl nucleoside analog has a structure shown in formula (I),
wherein X is selected from one of D, cl, br and I.
In order to solve the technical problems, the invention adopts the following technical scheme:
a method for preparing a tetraisobutyryl nucleoside analog as described above, comprising the steps of:
reacting a compound with a structure shown in a formula (II) or a salt thereof with an acylating agent under the action of alkali to obtain a tetraisobutyryl nucleoside analogue with a structure shown in a formula (I);
wherein X is selected from one of H, D, cl, br or I.
Specifically, a compound with a structure shown in a formula II or a salt thereof, alkali and an acylating reagent are added into a solvent for reaction, water is added after the reaction is finished, extraction, concentration and purification are carried out, and the tetraisobutyryl nucleoside analogue with the structure shown in the formula (I) is obtained.
Preferably, the salt of the compound of formula (II) is selected from the hydrochloride or hydrobromide salts;
preferably, the acylating reagent is selected from isobutyryl chloride or isobutyric anhydride;
preferably, the 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, N.N-dimethylaniline, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium acetate, potassium acetate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate;
more preferably, the base is selected from one or both of triethylamine or 4-dimethylaminopyridine.
Preferably, the reaction is carried out in a solvent selected from one or more of N, N-dimethylacetamide, N-dimethylformamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, toluene, methyl tert-butyl ether, isopropyl acetate;
more preferably, the solvent is methylene chloride.
Preferably, the ratio of parts by weight of the compound of formula (II) to parts by volume of the reaction solvent is 1 (1-20);
more preferably, the ratio of parts by weight of the compound of formula (II) to parts by volume of the reaction solvent is 1: (2-10);
more preferably, the ratio of parts by weight of the compound of formula (II) to parts by volume of the reaction solvent is 1: (3-5);
more preferably, the volume ratio of parts by weight of the compound of formula (II) to the reaction solvent is 1: (5-8).
Preferably, the reaction temperature is from-20 to 80 ℃, more preferably the reaction temperature is from 20 to 70 ℃, more preferably the reaction temperature is from 30 to 60 ℃, more preferably the reaction temperature is from 35 to 45 ℃.
Preferably, the molar ratio of the compound of formula (II) to the acylating agent is 1: (4.0 to 7.0), more preferably, the molar ratio of the compound of formula (II) to the acylating agent is 1: (4.2 to 6.0), more preferably, the molar ratio of the compound of formula (II) to the acylating agent is 1: (4.5-5.0).
Preferably, the molar ratio of the compound of formula (II) to the base is 1: (4.0 to 7.0), more preferably, the molar ratio of the compound of formula (II) to the base is 1: (4.2 to 6.0), more preferably, the molar ratio of the compound of formula (II) to the base is 1: (4.5-5.0).
Preferably, the compound of formula (II): acylation: the molar ratio of the alkali is 1: (4.5-5.0): (4.5-5.0).
In order to solve the technical problems, the invention adopts the following technical scheme:
the use of a tetraisobutyryl nucleoside analog as described above for preparing a triisobutyrate compound having a structure represented by the formula (III) or a salt thereof,
wherein y=d.
In order to solve the technical problems, the invention adopts the following technical scheme:
a triisobutyrate has a structure shown in a formula (III),
wherein y=d.
In order to solve the technical problems, the invention adopts the following technical scheme:
a process for the preparation of triisobutyrate as described above, comprising the steps of:
the tetraisobutyryl nucleoside analog having the structure shown in formula (I) as described above is subjected to N-isobutyryl removal under the action of acid or alkali to obtain triisobutyrate compound having the structure shown in formula (III) or a salt thereof,
wherein x=y=d.
Specifically, adding a compound of formula I into a solvent, then adding acid or alkali for reaction, concentrating under reduced pressure after the reaction is finished, adding water and the solvent, extracting, concentrating, and purifying to obtain a compound of formula III.
Preferably, the salt of the triisobutyrate compound of the structure represented by formula (III) is one selected from the group consisting of hydrochloride, hydrobromide, sulfate, hemisulfate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, phosphate, maleate, fumarate, tartrate, oxalate, malonate, citrate;
preferably, the acid is selected from one or more of organic acid, inorganic acid or lewis acid;
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, p-toluenesulfonic acid;
preferably, the inorganic acid is selected from one or more of sulfuric acid, hydrochloric acid, phosphoric acid and perchloric acid;
preferably, the lewis acid is selected from one or more of aluminum trichloride, magnesium chloride, magnesium bromide, tin tetrachloride, titanium tetrachloride, zinc chloride;
more preferably, the acid is selected from one or more of acetic acid, isobutyric acid, phosphoric acid.
Preferably, the alkali is selected from one or more of non-metal organic alkali, inorganic alkali and metal organic alkali;
preferably, the nonmetallic organic base is selected from one or more of ammonia water, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine and 2, 6-tetramethylpiperidine;
more preferably, the non-metal organic base is selected from triethylamine;
preferably, the inorganic base is selected from one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium phosphate monobasic, potassium phosphate monobasic, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide or magnesium oxide;
more preferably, the inorganic base is selected from sodium carbonate;
preferably, the metal organic base is selected from one or more of lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide or magnesium tert-butoxide;
more preferably, the metal organic base is selected from sodium acetate.
Preferably, the reaction is carried out in a solvent selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, isobutanol, isoamyl alcohol, toluene, xylene, chlorobenzene, isopropyl acetate, n-butyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl t-butyl ether, anisole, acetonitrile, dichloromethane;
more preferably, the solvent is selected from methanol, ethanol, isopropanol, acetonitrile;
still more preferably, the solvent is selected from ethanol, isopropanol.
Preferably, the ratio of parts by weight of the compound of formula (I) to parts by volume of the reaction solvent is 1 (1-20), preferably the ratio of parts by weight of the compound of formula (I) to parts by volume of the reaction solvent is 1: (2-10); more preferably, the ratio of parts by weight of the compound of formula (I) to parts by volume of the reaction solvent is 1: (3-5).
Preferably, the reaction temperature is 30 to 100 ℃, preferably, the reaction temperature is 40 to 80 ℃, more preferably, the reaction temperature is 50 to 70 ℃.
Preferably, the molar ratio of the compound of formula (I) to the acid or base is 1: (0.05 to 1.0), preferably the molar ratio of the compound of formula (I) to the acid or base is 1: (0.2-0.5).
In order to solve the technical problems, the invention adopts the following technical scheme:
a process for the preparation of triisobutyrate as described above, comprising the steps of:
step a, the tetraisobutyryl nucleoside analogue with the structure shown in the formula (I) is subjected to dehalogenation reaction with hydrogen or deuterium in a solvent under the action of a catalyst and alkali to obtain a compound with the structure shown in the formula (IV);
specifically, adding a compound of the formula I into a solvent, adding a catalyst and alkali, replacing air in a reaction system with nitrogen, introducing hydrogen or nitrogen for reaction, cooling to room temperature after the reaction is finished, replacing hydrogen or deuterium in the reaction system with nitrogen, concentrating under reduced pressure, adding water and the solvent, extracting, concentrating, and purifying to obtain a compound of the formula IV;
step b, removing N-isobutyryl from the compound with the structure shown in the formula (IV) under the action of acid or alkali to obtain a triisobutyrate compound with the structure shown in the formula (III) or a salt thereof;
specifically, adding a compound of formula IV into a solvent, then adding acid or alkali for reaction, concentrating under reduced pressure after the reaction is finished, adding water and the solvent, extracting, concentrating, and purifying to obtain a compound of formula III;
wherein X is selected from one of Cl, br and I; y is selected from one of H and D.
Preferably, the salt of the triisobutyrate compound of the structure represented by formula (III) is one selected from the group consisting of hydrochloride, hydrobromide, sulfate, hemisulfate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, phosphate, maleate, fumarate, tartrate, oxalate, malonate, citrate;
preferably, the catalyst in step a is selected from one or more of palladium on carbon, platinum on carbon or raney nickel;
more preferably, the catalyst is selected from palladium on carbon;
preferably, the dry basis content of palladium carbon is 5 to 10%, and the mass ratio of the compound of formula (IV) to palladium carbon is 1 (0.01 to 0.2) based on the mass of the dry basis of palladium carbon.
Preferably, the base in step a is selected from one or more of ammonia, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-N-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, N-dimethylaniline, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine;
more preferably, the base is selected from one or both of triethylamine or diisopropylethylamine;
preferably, step a is carried out in a solvent selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, isobutanol, isoamyl alcohol, toluene, xylene, isopropyl acetate, n-butyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl t-butyl ether, anisole, acetonitrile, dichloromethane;
more preferably, the solvent is selected from one or more of toluene, ethyl acetate, acetonitrile, tetrahydrofuran, methyl tert-butyl ether;
still preferably, the solvent is selected from one or two of tetrahydrofuran and methyl tert-butyl ether;
preferably, the reaction pressure in step a is 0.1 to 3.0Mpa;
more preferably, the reaction pressure is 1.0 to 2.0Mpa;
preferably, the reaction temperature of step a is 25 to 100 ℃;
more preferably, the reaction temperature is 55 to 75 ℃;
preferably, the ratio of parts by weight of the compound of formula (IV) to parts by volume of the solvent is 1 (1-30);
more preferably, the ratio of parts by weight of the compound of formula (IV) to parts by volume of the solvent is 1 (3-10);
preferably, the molar ratio of the compound of formula (VI) to the base is 1 (1-3);
more preferably, the molar ratio of the compound of formula (VI) to the base is 1 (1.5-2.5);
preferably, the weight ratio of the compound of formula (VI) to the catalyst is 1 (0.01 to 0.5);
more preferably, the weight ratio of the compound of formula (VI) to the catalyst is 1 (0.02-0.2);
more preferably, the weight ratio of the compound of formula (VI) to the catalyst is 1 (0.05 to 0.15);
preferably, the acid in step b is selected from one or more of an organic acid, an inorganic acid or a lewis acid;
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, p-toluenesulfonic acid;
preferably, the mineral acid is selected from one or more of sulfuric acid, hydrochloric acid, phosphoric acid, perchloric acid;
preferably, the lewis acid is selected from one or more of aluminum trichloride, magnesium chloride, magnesium bromide, tin tetrachloride, titanium tetrachloride, zinc chloride;
more preferably, the acid is preferably selected from one or more of acetic acid, isobutyric acid, phosphoric acid;
preferably, the base in step b is selected from one or more of a non-metal organic base, an inorganic base, a metal organic base;
preferably, the nonmetallic organic base is selected from one or more of ammonia, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine;
more preferably, the non-metal organic base is selected from triethylamine;
preferably, the inorganic base is selected from one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium phosphate monobasic, potassium phosphate monobasic, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide or magnesium oxide;
more preferably, the inorganic base is selected from sodium carbonate;
preferably, the metal organic base is selected from one or more of lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide or magnesium tert-butoxide;
more preferably, the metal organic base is selected from sodium acetate;
preferably, the solvent in step b is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, isobutanol, isoamyl alcohol, toluene, xylene, chlorobenzene, isopropyl acetate, n-butyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl t-butyl ether, anisole, acetonitrile, dichloromethane;
more preferably, the solvent is selected from methanol, ethanol, isopropanol, acetonitrile;
more preferably, the solvent is selected from ethanol, isopropanol.
Preferably, the ratio of parts by weight of the compound of formula (VI) to parts by volume of the reaction solvent in step b is 1 (1-20), preferably the ratio of parts by weight of the compound of formula (VI) to parts by volume of the reaction solvent is 1: (2-10); more preferably, the ratio of parts by weight of (VI) compound to parts by volume of reaction solvent is 1: (3-5);
preferably, the reaction temperature is 30 to 100 ℃, preferably, the reaction temperature is 40 to 80 ℃, more preferably, the reaction temperature is 50 to 70 ℃;
preferably, the molar ratio of (VI) compound to acid or base is 1: (0.05 to 1.0), preferably the molar ratio of (VI) compound to acid or base is 1: (0.2-0.5).
Due to the adoption of the technical scheme, compared with the prior art, the invention has the following advantages:
the preparation method has the advantages of mild reaction conditions, few byproducts, high yield, easy control of the process and simple operation, 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.
EXAMPLE 1 preparation of Compound 7
Compound 5 (10.0 g,34.3 mmol) was added to dichloromethane (100 mL), triethylamine (15.6 g,154.3 mmol) and 4-dimethylaminopyridine (0.84 g,6.86 mmol) were further added, the temperature was lowered to 0 ℃, isobutyryl chloride (16.4 g,154.3 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 (250 mL), then washed with water (100 mL) saturated sodium bicarbonate solution (50 mL) in sequence, the organic phase was concentrated, then n-heptane was added, solid was precipitated, cooled, filtered, and dried to obtain compound 7 (16.9 g, yield 86%).
1 H NMR(400MHz,DMSO)δppm 10.92(s,1H),8.41(s,1H),7.28(d,J＝4.8Hz,1H),7.00(d,J＝4.8Hz,1H),6.05(t,J＝5.9Hz,1H),5.47(dd,J＝5.6,3.6Hz,1H),4.69(q,J＝3.5Hz,1H),4.32(m,2H),3.11(m,1H),2.63(m,2H),2.45(m,1H),1.15–1.39(m,24H)。ESI-MS：m/z＝572.5[M+H] + 。
EXAMPLE 2 preparation of Compound 8
Compound 5 (5.0 g,17.1 mmol) was added to dichloromethane (50 mL), triethylamine (7.8 g,76.9 mmol) and 4-dimethylaminopyridine (0.63 g,5.1 mmol) were further added, the temperature was lowered to 0℃and isobutyric anhydride (11.6 g,73.5 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 (200 mL), then washed with water (100 mL) saturated sodium bicarbonate solution (200 mL) in sequence, the organic phase was concentrated, then n-heptane was added, solid was precipitated, cooled, filtered, and dried to obtain Compound 8 (8.6 g, yield 88%).
1H NMR(400MHz,DMSO)δppm 10.92(s,1H),8.41(s,1H),7.01(s,1H),6.06(t,J＝5.9Hz,1H),5.47(dd,J＝5.6,3.6Hz,1H),4.69(q,J＝3.5Hz,1H),4.32(m,2H),3.11(hept,J＝6.77Hz,1H),2.64(m,1H),2.45(m,1H),1.15–1.39(m,24H)。ESI-MS：m/z＝573.3[M+H]+。
EXAMPLE 3 preparation of Compound 8
Compound 9 (6.5 g,19.8 mmol) was added to dichloromethane (80 mL), pyridine (7.2 g,91.1 mmol) and 4-dimethylaminopyridine (0.37 g,3.0 mmol) were added, the temperature was lowered to 0 ℃, isobutyryl chloride (9.5 g,89.1 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 (120 mL), then washed with water (100 mL) saturated sodium bicarbonate solution (70 mL) in sequence, the organic phase was concentrated, then n-heptane was added, solid was precipitated, cooled, filtered, and dried to obtain compound 8 (9.2 g, yield 81%). The nuclear magnetic hydrogen spectrum is consistent with the results of example 2.
EXAMPLE 4 preparation of Compound 11
Compound 10 (10.0 g,27.0 mmol) was added to methylene chloride (150 mL), triethylamine (12.3 g,121.5 mmol) and 4-dimethylaminopyridine (0.66 g,5.4 mmol) were further added, the temperature was lowered to 0℃and isobutyric anhydride (18.4 g,116.1 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 (200 mL), then washed with water (100 mL) saturated sodium bicarbonate solution (200 mL) in sequence, the organic phase was concentrated, then n-heptane was added, and solids were precipitated, cooled, filtered and dried to give compound 11 (16.0 g, yield 91%).
1 H NMR(400MHz,DMSO)δppm 10.35(s,1H),8.52(s,1H),7.22(s,1H),5.94(t,J＝12.4Hz,1H),5.46(dt,J＝13.1,6.5Hz,1H),4.77–4.65(m,1H),4.32(m,2H),2.90(hept,J＝6.9Hz,1H),2.75–2.56(m,2H),2.50–2.41(m,1H),1.28–0.97(m,24H)。ESI-MS：m/z＝650.3[M+H] + 。
EXAMPLE 5 preparation of Compound 6
Compound 7 (3.5 g,6.1 mmol) was added to ethanol (35 mL), triethylamine (0.19 g,1.83 mmol) was further added, the mixture was warmed to reflux, after the reaction was completed, the mixture was concentrated under reduced pressure, n-heptane was then added, and a solid was separated out, cooled, filtered and dried to give Compound 6 (2.9 g, yield 95%).
1H NMR(400MHz,DMSO)δppm8.06(brs,1H),7.99(brs,1H),7.94(s,1H),6.95(d,J＝4.6Hz,1H),6.77(d,J＝4.6Hz,1H),6.09(d,J＝5.7Hz,1H),5.45(dd,J＝5.7,3.7Hz,1H),4.64(q,J＝3.6Hz,1H),4.32(qd,J＝12.4,3.7Hz,2H),2.63(ddq,J＝21.0,14.0,7.0Hz,2H),2.52–2.45(m,1H),1.17(dd,J＝13.0,7.0Hz,6H),1.13–1.09(m,6H),1.04(dd,J＝16.2,7.0Hz,6H)。ESI-MS：m/z＝500.3[M-H]+。
EXAMPLE 6 preparation of Compound 4
Compound 8 (15 g,26.2 mmol) was added to ethanol (262 mL), phosphoric acid (85%, 0.91g,7.86 mmol) was further added, the mixture was warmed to reflux, concentrated under reduced pressure after the reaction was completed, methyl tert-butyl ether (100 mL) and water (50 mL) were added, stirred, left stand, the aqueous layer was discarded, then the organic layer was washed successively with water (100 mL) saturated sodium bicarbonate solution (200 mL), the organic phase was concentrated, n-heptane was then added, solids were precipitated, cooled, filtered, and dried to give compound 4 (12.2 g, yield 93%).
1H NMR(400MHz,DMSO)δppmδppm 8.00(brs,2H),7.92(s,1H),6.75(s,1H),6.07(d,J＝5.7Hz,1H),5.43(dd,J＝5.7,3.7Hz,1H),4.62(q,J＝3.7Hz,1H),4.30(qd,J＝12.4,3.7Hz,2H),2.68–2.55(m,2H),2.49–2.43(m,1H),1.15(dd,J＝9.7,7.0Hz,6H),1.10(d,J＝7.0Hz,6H),1.03(dd,J＝12.6,7.0Hz,6H)。ESI-MS：m/z＝503.1[M+H]+。
EXAMPLE 7 preparation of Compound VV116
Compound 8 (10 g,17.5 mmol) was added to ethanol (100 mL), hydrobromic acid (48%, 3.1g,18.4 mmol) was added, the mixture was warmed to reflux, after the reaction was completed, concentrated under reduced pressure, methyl tert-butyl ether and n-heptane were added, and the mixture was stirred, cooled, filtered and dried to give Compound VV116 (8.9 g, yield 87%).
1H NMR(400MHz,DMSO)δppm 13.05(s,1H),9.73(s,1H),9.46(s,1H),8.00(s,1H),7.04(s,1H),6.02(d,J＝5.8Hz,1H),5.41(5dd,J＝5.8,4.0Hz,1H),4.65(q,J＝4.0Hz,1H),4.40–4.33(m,2H),2.71–2.60(m,2H),2.58–2.52(m,1H),1.26–1.22(m,6H),1.21–1.18(m,6H),1.17–1.13(m,6H)。ESI-MS：m/z＝503.1[M+H]+。
EXAMPLE 8 preparation of Compound 4
Compound 11 (5.0 g,7.7 mmol) and tetrahydrofuran (80 mL) were charged into a 250mL autoclave, and then triethylamine (1.56 g,15.4 mmol) and palladium on carbon (1.25 g, water content 60%, dry basis content 5%) were added, and after three nitrogen substitutions, deuterium gas was charged to 1.5MPa and the temperature was raised to 60℃for reaction for 5 hours. Then cooled to room temperature, after three times of nitrogen substitution, the reaction solution was filtered and dried, the filtrate was concentrated under reduced pressure, methyl tert-butyl ether (100 mL) and water (50 mL) were added to stir, left stand, the aqueous layer was discarded, then the organic layer was washed with water (100 mL) saturated sodium bicarbonate solution (50 mL) in sequence, the organic phase was concentrated, then n-heptane was added, and the mixture was cooled, filtered and dried to give compound 8 (4.2 g, yield 96%).
Compound 8 (2.5 g,4.4 mmol) was added to ethanol (20 mL), acetic acid (0.78 g,13.1 mmol) was added thereto, the mixture was warmed to reflux, concentrated under reduced pressure after the completion of the reaction, methyl tert-butyl ether (50 mL) and water (20 mL) were added thereto, stirred, left standing, the aqueous layer was discarded, then the organic layer was washed successively with water (20 mL) saturated sodium hydrogencarbonate solution (10 mL), the organic phase was concentrated, then methyl tert-butyl ether and n-heptane were added thereto, solid was precipitated, cooled, filtered, and dried to obtain compound 4 (1.93 g, yield 88%). The nuclear magnetic hydrogen spectrum is consistent with the results of example 6.
EXAMPLE 9 preparation of Compound VV116
Compound 11 (10.0 g,15.4 mmol) and methyl tert-butyl ether (100 mL) were charged into a 250mL autoclave, and then triethylamine (3.12 g,30.8 mmol) and palladium on carbon (2.5 g, water content 60%, dry basis content 5%) were added, and after three nitrogen substitutions, deuterium gas was charged to 1.2MPa and the temperature was raised to 60℃for reaction for 8 hours. Then cooled to room temperature, after three times of nitrogen substitution, the reaction solution was filtered and dried, the filtrate was concentrated under reduced pressure, methyl tert-butyl ether (100 mL) and water (50 mL) were added to stir, left stand, the aqueous layer was discarded, then the organic layer was washed with water (100 mL) saturated sodium bicarbonate solution (50 mL) in sequence, the organic phase was concentrated, then n-heptane was added, cooled, filtered, and dried to give compound 8 (8.1 g, yield 93%).
Compound 8 (3.0 g,5.2 mmol) was added to ethanol (20 mL), hydrobromic acid (48%, 0.93g,5.5 mmol) was added, the mixture was warmed to reflux, after the reaction was completed, concentrated under reduced pressure, methyl tert-butyl ether (100 mL) was added, further concentrated under reduced pressure, n-heptane was added, cooled, filtered, and dried to give Compound VV116 (2.6 g, yield 86%). The nuclear magnetic hydrogen spectrum is consistent with the results of example 7.
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 (12)

1. Use of a tetraisobutyryl nucleoside analog, characterized in that: the tetraisobutyryl nucleoside analogue has a structure shown in a formula (I),
wherein X is selected from one of H, D, cl, br and I
The tetraisobutyryl nucleoside analogue is used for preparing a triisobutyrate compound with a structure shown in a formula (III) or a salt thereof,
wherein y=d or H.
2. A method for preparing triisobutyrate, which is characterized by comprising the following steps: the method comprises the following steps:
the tetraisobutyryl nucleoside analog having the structure of formula (I) according to claim 1, wherein the N-isobutyryl group is removed under the action of acid or alkali to obtain triisobutyrate compound having the structure of formula (III) or a salt thereof,
wherein x=y=d;
the acid is selected from one or more of organic acid, inorganic acid or Lewis acid;
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, magnesium chloride, magnesium bromide, tin tetrachloride, titanium tetrachloride and zinc chloride;
the alkali is one or more selected from non-metal organic alkali, inorganic alkali and metal organic alkali;
the nonmetallic organic base is selected from one or more of ammonia water, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine and 2, 6-tetramethylpiperidine;
the inorganic base is selected from one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium phosphate monobasic, potassium phosphate monobasic, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide or magnesium oxide;
the metal organic base is selected from one or more of lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide or magnesium tert-butoxide.
3. A process for the preparation of triisobutyrate as defined in claim 2, wherein: the salt of the triisobutyrate compound with the structure shown in the formula (III) is one of hydrochloride, hydrobromide, sulfate, hemisulfate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, phosphate, maleate, fumarate, tartrate, oxalate, malonate and citrate.
4. A process for the preparation of triisobutyrate as defined in claim 2, wherein: the reaction is carried out in a solvent selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, isoamyl alcohol, toluene, xylene, chlorobenzene, isopropyl acetate, n-butyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, anisole, acetonitrile and dichloromethane.
5. A method for preparing triisobutyrate, which is characterized by comprising the following steps: the method comprises the following steps:
step a, the tetraisobutyryl nucleoside analogue with the structure shown in the formula (I) in the claim 1 is subjected to dehalogenation reaction with hydrogen or deuterium in a solvent under the action of a catalyst and alkali to obtain a compound with the structure shown in the formula (IV);
step b, removing N-isobutyryl from the compound with the structure shown in the formula (IV) under the action of acid or alkali to obtain a triisobutyrate compound with the structure shown in the formula (III) or a salt thereof;
wherein X is selected from one of Cl, br and I; y is selected from one of H and D;
the catalyst in the step a is selected from one or more of palladium carbon, platinum carbon or Raney nickel;
the alkali in the step a is selected from one or more of ammonia water, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-N-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, N-dimethylaniline, tetrahydropyrrole, morpholine, piperidine and 2, 6-tetramethylpiperidine;
the acid in the step b is selected from one or more of organic acid, inorganic acid or Lewis acid;
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, magnesium chloride, magnesium bromide, tin tetrachloride, titanium tetrachloride and zinc chloride;
the alkali in the step b is selected from one or more of non-metal organic alkali, inorganic alkali and metal organic alkali;
the nonmetallic organic base is selected from one or more of ammonia water, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine and 2, 6-tetramethylpiperidine;
the inorganic base is selected from one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium phosphate monobasic, potassium phosphate monobasic, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide or magnesium oxide;
the metal organic base is selected from one or more of lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide or magnesium tert-butoxide.
6. A process for preparing triisobutyrate according to claim 5, wherein the process comprises the steps of: the salt of the triisobutyrate compound with the structure shown in the formula (III) is one of hydrochloride, hydrobromide, sulfate, hemisulfate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, phosphate, maleate, fumarate, tartrate, oxalate, malonate and citrate.
7. A process for preparing triisobutyrate according to claim 6, wherein the process comprises the steps of: the step a is carried out in a solvent, wherein the solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tertiary butanol, isobutanol, isoamyl alcohol, toluene, xylene, isopropyl acetate, n-butyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tertiary butyl ether, anisole, acetonitrile and dichloromethane.
8. A process for preparing triisobutyrate according to claim 7, wherein the process comprises the steps of: the reaction pressure of the step a is 0.1-3.0 Mpa.
9. A process for preparing triisobutyrate according to claim 8, wherein the process comprises the steps of: the reaction temperature of the step a is 25-100 ℃.
10. A process for the preparation of triisobutyrate as defined in claim 9, wherein: the ratio of the parts by weight of the compound of formula (IV) to the parts by volume of the solvent is 1 (1-30).
11. A process for preparing triisobutyrate as defined in claim 10, wherein: the molar ratio of the compound of formula (VI) to the base is 1 (1-3).
12. A process for preparing triisobutyrate as defined in claim 11, wherein: the weight ratio of the compound of formula (VI) to the catalyst is 1 (0.01-0.5).
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