CN114573590B - Preparation method and use of tetraisobutyryl nucleoside analog - Google Patents

Abstract

The invention relates to a preparation method and use of a tetraisobutyryl nucleoside analogue. The preparation method has mild reaction conditions, less by-products, high yield, easy process control, simple operation, and is suitable for industrial large-scale production.

Description

Preparation method and use of tetraisobutyryl nucleoside analog

Technical field

The invention belongs to the field of pharmaceutical technology, and specifically relates to a preparation method and use of a tetraisobutyryl nucleoside analog.

Background technique

VV116 and A131 are a new class of oral anti-COVID-19 nucleoside compounds that also have good inhibitory activity against other viruses, such as respiratory syncytial virus, dengue virus, hepatitis C virus, Zika virus, etc. Their structure is as follows Show. The triisobutyrate prodrug form in the molecular structure of VV116 and A131 greatly improves the physical and chemical properties and in vivo metabolic properties of the parent nucleoside. As oral drugs, VV116 and A131 have broad application prospects in the field of antiviral treatment. Research on this Simple and efficient synthesis methods of prodrugs are of great significance.

The preparation method of triisobutyrate reported in the existing literature (Cell Research, 2021, 31, 1212-1214) uses a protecting group strategy and adds reaction steps.

Another document (J. Med. Chem., 2021, 64, 5001–5017) reported the use of the parent nucleoside compound 5 to undergo a condensation reaction with isobutyric acid to directly obtain triisobutyrate compound 6, but the condensation reaction was used. The mixture of diisopropylcarbodiimide and polar aprotic solvent N,N-dimethylformamide (DMF) increases by-products.

The patent (CN113735862) reports the reaction of parent nucleoside compound 5 with isobutyric anhydride to prepare prodrug compound 6, with a yield of only 35%.

The existing synthesis methods of triisobutyrate prodrugs of VV116 and analogs are not conducive to large-scale production. Therefore, the development steps are simple, suitable for scale-up production, and a green and sustainable new synthesis method of triisobutyrate prodrug is of great significance.

Contents of the invention

The technical problem to be solved by the present invention is to overcome the deficiencies in the prior art and provide a preparation method and use of tetraisobutyryl nucleoside analogues. The preparation method has mild reaction conditions, few by-products, high yield and easy process. control, simple operation, suitable for industrial large-scale production.

In order to solve the above technical problems, the technical solutions adopted by the present invention are:

A tetraisobutyryl nucleoside analog having a structure shown in formula (I),

Wherein, X is selected from one of D, Cl, Br and I.

In order to solve the above technical problems, another technical solution adopted by the present invention is:

A method for preparing the tetraisobutyryl nucleoside analog as described above, including the following steps:

The compound with the structure represented by formula (II) or its salt reacts with an acylating reagent under the action of a base to obtain a tetraisobutyryl nucleoside analog with the structure represented by formula (I);

Wherein, X is selected from one of H, D, Cl, Br or I.

Specifically, the compound with the structure shown in formula II or its salt, a base and an acylating reagent are added to the solvent to carry out the reaction. After the reaction is completed, water is added, extracted, concentrated and purified to obtain the tetraisoisopropyl compound with the structure shown in formula (I). Butyryl nucleoside analogues.

Preferably, the salt of the compound having the structure shown in formula (II) is selected from hydrochloride or hydrobromide;

Preferably, the acylating reagent is selected from isobutyryl chloride or isobutyric anhydride;

Preferably, the base is selected from pyridine, 4-dimethylaminopyridine, 2,4,6-trimethylpyridine, 2,6-trimethylpyridine, 3-methylpyridine, triethylamine, N-methyl Imidazole, 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 , one or more of 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, and the solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dichloro One or more of methane, toluene, methyl tert-butyl ether, and isopropyl acetate;

More preferably, the solvent is methylene chloride.

Preferably, the ratio of the weight parts of the compound of formula (II) to the volume parts of the reaction solvent is 1:(1~20);

More preferably, the ratio of the weight parts of the compound of formula (II) to the volume parts of the reaction solvent is 1: (2-10);

More preferably, the ratio of the weight part of the compound of formula (II) to the volume part of the reaction solvent is 1: (3～5);

More preferably, the volume ratio of the weight part of the compound of formula (II) to the reaction solvent is 1: (5-8).

Preferably, the reaction temperature is -20~80°C, more preferably, the reaction temperature is 20~70°C, more preferably, the reaction temperature is 30~60°C, and more preferably, the reaction temperature is 35~45°C.

Preferably, the molar ratio of the compound of formula (II) to the acylating reagent is 1: (4.0～7.0), more preferably, the molar ratio of the compound of formula (II) to the acylating reagent is 1: (4.2～6.0), more preferably Preferably, the molar ratio of the compound of formula (II) to the acylating reagent is 1: (4.5-5.0).

Preferably, the molar ratio of the compound of formula (II) to the base is 1: (4.0～7.0). More preferably, the molar ratio of the compound of formula (II) to the base is 1: (4.2～6.0). More preferably, the molar ratio of the compound of formula (II) to the base is 1: (4.2～6.0). More preferably, the molar ratio of the compound of formula (II) to the base is 1: (4.2～6.0). (II) The molar ratio of compound to base is 1: (4.5～5.0).

Preferably, the molar ratio of compound of formula (II): acylation: base is 1: (4.5～5.0): (4.5～5.0).

In order to solve the above technical problems, another technical solution adopted by the present invention is:

The use of a tetraisobutyryl nucleoside analog as described above for preparing a triisobutyrate compound or a salt thereof with a structure shown in formula (III),

Among them, Y=D.

In order to solve the above technical problems, another technical solution adopted by the present invention is:

A triisobutyrate having a structure shown in formula (III),

Among them, Y=D.

In order to solve the above technical problems, another technical solution adopted by the present invention is:

A method for preparing triisobutyrate as described above, including the following steps:

The above-mentioned tetraisobutyryl nucleoside analog having the structure shown in formula (I) removes the N-isobutyryl group under the action of acid or alkali to obtain the triisobutyrate compound having the structure shown in formula (III). or its salt,

Among them, X=Y=D.

Specifically, the compound of formula I is added to the solvent, and then an acid or a base is added to react. After the reaction is completed, the mixture is concentrated under reduced pressure, water and solvent are added, extracted, concentrated, and purified to obtain the compound of formula III.

Preferably, the salt of the triisobutyrate compound having the structure shown in formula (III) is selected from the group consisting of hydrochloride, hydrobromide, sulfate, hemisulfate, methanesulfonate, benzenesulfonate, and p-toluenesulfonate. Acid, triflate, phosphate, maleate, fumarate, tartrate, oxalate, malonate, citrate;

Preferably, the acid is selected from one or more of organic acids, inorganic acids or Lewis acids;

Preferably, the organic acid is selected from the group consisting 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, One or more of benzenesulfonic acid and p-toluenesulfonic acid;

Preferably, the inorganic acid is selected from one or more types 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, and zinc chloride;

More preferably, the acid is selected from one or more of acetic acid, isobutyric acid, and phosphoric acid.

Preferably, the base is selected from one or more of non-metal organic bases, inorganic bases, and metal organic bases;

Preferably, the non-metallic organic base is selected from ammonia, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, One or more of 6-lutidine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, and 2,2,6,6-tetramethylpiperidine;

More preferably, the non-metal organic base is selected from triethylamine;

Preferably, the inorganic base is selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide , one or more of 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 the group consisting of lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, and tert-butyl alcohol. One or more of lithium, 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, and the solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, isoamyl alcohol, toluene, xylene, chlorobenzene, isoacetate. One or more of propyl ester, n-butyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, anisole, acetonitrile, and dichloromethane;

More preferably, the solvent is selected from methanol, ethanol, isopropyl alcohol, and acetonitrile;

Preferably, the solvent is selected from ethanol and isopropyl alcohol.

Preferably, the ratio of the weight part of the compound of formula (I) to the volume part of the reaction solvent is 1:(1~20). Preferably, the ratio of the weight part of the compound of formula (I) to the volume part of the reaction solvent is 1:(2) -10); More preferably, the ratio of the weight part of the compound of formula (I) to the volume part of the reaction solvent is 1: (3-5).

Preferably, the reaction temperature is 30-100°C, preferably, the reaction temperature is 40-80°C, and more preferably, the reaction temperature is 50-70°C.

Preferably, the molar ratio of the compound of formula (I) to acid or alkali is 1: (0.05-1.0). Preferably, the molar ratio of the compound of formula (I) to acid or alkali is 1: (0.2-0.5).

In order to solve the above technical problems, another technical solution adopted by the present invention is:

A method for preparing triisobutyrate as described above, including the following steps:

Step a. The tetraisobutyryl nucleoside analogue having the structure represented by formula (I) as described above undergoes a dehalogenation reaction with hydrogen or deuterium gas in a solvent under the action of a catalyst and a base to obtain the structure represented by formula (IV). compound of;

Specifically, the compound of formula I is added to the solvent, then a catalyst and a base are added, the air in the reaction system is replaced with nitrogen, and hydrogen or nitrogen is introduced to react. After the reaction is completed, the reaction is reduced to room temperature, and nitrogen is used to replace the hydrogen in the reaction system. Or deuterium gas, concentrate under reduced pressure, add water and solvent, extract, concentrate and purify to obtain the compound of formula IV;

Step b. The compound with the structure represented by formula (IV) removes the N-isobutyryl group under the action of acid or alkali to obtain the triisobutyrate compound with the structure represented by formula (III) or a salt thereof;

Specifically, the compound of formula IV is added to the solvent, and then an acid or alkali is added to react. After the reaction is completed, the compound of formula III is obtained by concentrating under reduced pressure, adding water and solvent, extracting, concentrating, and purifying;

Among them, 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 having the structure shown in formula (III) is selected from the group consisting of hydrochloride, hydrobromide, sulfate, hemisulfate, methanesulfonate, benzenesulfonate, and p-toluenesulfonate. Acid, triflate, phosphate, maleate, fumarate, tartrate, oxalate, malonate, citrate;

Preferably, the catalyst in step a is selected from one or more of palladium carbon, platinum 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%. Calculated based on the mass of dry matrix palladium carbon, the mass ratio of the compound of formula (IV) to palladium carbon is 1:(0.01~0.2).

Preferably, the base in step a is selected from ammonia, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2 , one of 6-dimethylpyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, tetrahydropyrrole, morpholine, piperidine, and 2,2,6,6-tetramethylpiperidine species or species;

More preferably, the base is selected from one or both of triethylamine or diisopropylethylamine;

Preferably, step a is carried out in a solvent, and the solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, isoamyl alcohol, toluene, xylene, and isopropyl acetate. , one or more of n-butyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, anisole, acetonitrile, and dichloromethane;

More preferably, the solvent is selected from one or more of toluene, ethyl acetate, acetonitrile, tetrahydrofuran, and methyl tert-butyl ether;

Preferably, the solvent is selected from one or both of tetrahydrofuran and methyl tert-butyl ether;

Preferably, the reaction pressure in step a is 0.1~3.0Mpa;

More preferably, the reaction pressure is 1.0~2.0Mpa;

Preferably, the reaction temperature in step a is 25-100°C;

More preferably, the reaction temperature is 55~75°C;

Preferably, the ratio of the weight parts of the compound of formula (IV) to the volume parts of the solvent is 1: (1-30);

More preferably, the ratio of the weight part of the compound of formula (IV) to the volume part 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:(0.01~0.5);

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: (0.05~0.15);

Preferably, the acid in step b is selected from one or more organic acids, inorganic acids or Lewis acids;

Preferably, the organic acid is selected from the group consisting 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, One or more of benzenesulfonic acid and 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, and zinc chloride;

More preferably, the acid is one or more selected from acetic acid, isobutyric acid, and phosphoric acid;

Preferably, the base in step b is selected from one or more of non-metal organic bases, inorganic bases, and metal organic bases;

Preferably, the non-metallic organic base is selected from ammonia, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, One or more of 6-lutidine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, and 2,2,6,6-tetramethylpiperidine;

More preferably, the non-metal organic base is selected from triethylamine;

Preferably, the inorganic base is selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide , one or more of 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 the group consisting of lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, and tert-butyl alcohol. One or more of lithium, 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 the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, isoamyl alcohol, toluene, xylene, chlorobenzene, and isopropyl acetate. , one or more of n-butyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, anisole, acetonitrile, and dichloromethane;

More preferably, the solvent is selected from methanol, ethanol, isopropyl alcohol, and acetonitrile;

More preferably, the solvent is selected from ethanol and isopropyl alcohol.

Preferably, the ratio of the weight part of the compound of formula (VI) to the volume part of the reaction solvent in step b is 1:(1-20). Preferably, the ratio of the weight part of the compound (VI) to the volume part of the reaction solvent is 1:( 2-10); More preferably, the ratio of the weight part of the compound (VI) to the volume part of the reaction solvent is 1: (3-5);

Preferably, the reaction temperature is 30-100°C, preferably, the reaction temperature is 40-80°C, and more preferably, the reaction temperature is 50-70°C;

Preferably, the molar ratio of compound (VI) to acid or alkali is 1: (0.05-1.0). Preferably, the molar ratio of compound (VI) to acid or alkali is 1: (0.2-0.5).

Due to the adoption of the above technical solutions, the present invention has the following advantages compared with the prior art:

The preparation method of the invention has mild reaction conditions, less by-products, high yield, easy process control, simple operation, and is suitable for industrial large-scale production.

Detailed ways

In order to make the technical solutions and beneficial effects of the present invention more obvious and understandable, detailed descriptions are given below by enumerating specific embodiments. It should be understood that these examples are only used to illustrate the invention and are not intended to limit the scope of the invention. Experimental methods that do not indicate specific conditions in the following examples usually follow conventional experimental conditions. The reagents and raw materials used in the present invention are all commercially available unless otherwise specified.

Example 1 Preparation of Compound 7

Add compound 5 (10.0g, 34.3mmol) to dichloromethane (100mL), then add triethylamine (15.6g, 154.3mmol) and 4-dimethylaminopyridine (0.84g, 6.86mmol), and cool to 0 ℃, add isobutyryl chloride (16.4g, 154.3mmol) dropwise, and then raise the temperature to 35-40℃ for reaction. After the reaction is completed, pour the reaction solution into ice water (250mL), and then saturated sodium bicarbonate with water (100mL). The solution (50 mL) was washed, the organic phase was concentrated, and then n-heptane was added. A solid precipitated. The solution was 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

Add compound 5 (5.0g, 17.1mmol) to dichloromethane (50mL), then add triethylamine (7.8g, 76.9mmol) and 4-dimethylaminopyridine (0.63g, 5.1mmol), and cool to 0 ℃, add isobutyric anhydride (11.6g, 73.5mmol) dropwise, and then raise the temperature to 35-40℃ for reaction. After the reaction is completed, pour the reaction solution into ice water (200mL), and then saturated sodium bicarbonate with water (100mL). The solution (200 mL) was washed, the organic phase was concentrated, and then n-heptane was added. A solid precipitated. The solution was 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, 3.6 Hz,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

Add compound 9 (6.5g, 19.8mmol) to dichloromethane (80mL), then add pyridine (7.2g, 91.1mmol) and 4-dimethylaminopyridine (0.37g, 3.0mmol), and cool to 0°C. Isobutyryl chloride (9.5g, 89.1mmol) was added dropwise, and then the temperature was raised to 35-40°C for reaction. After the reaction was completed, the reaction solution was poured into ice water (120mL), and then followed by water (100mL) and saturated sodium bicarbonate solution ( 70 mL), the organic phase was concentrated, then n-heptane was added, solid precipitated, cooled, filtered, and dried to obtain compound 8 (9.2 g, yield 81%). The proton nuclear magnetic spectrum was consistent with the results of Example 2.

Example 4 Preparation of Compound 11

Add compound 10 (10.0g, 27.0mmol) to dichloromethane (150mL), then add triethylamine (12.3g, 121.5mmol) and 4-dimethylaminopyridine (0.66g, 5.4mmol), and cool to 0 ℃, add isobutyric anhydride (18.4g, 116.1mmol) dropwise, and then raise the temperature to 35-40℃ for reaction. After the reaction is completed, pour the reaction solution into ice water (200mL), and then saturated sodium bicarbonate with water (100mL). The solution (200 mL) was washed, the organic phase was concentrated, and then n-heptane was added. A solid precipitated. The solution was cooled, filtered, and dried to obtain 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

Add compound 7 (3.5g, 6.1mmol) to ethanol (35mL), then add triethylamine (0.19g, 1.83mmol), heat to reflux reaction, after the reaction is completed, concentrate under reduced pressure, then add n-heptane, A solid precipitated, cooled, filtered, and dried to obtain 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

Add compound 8 (15g, 26.2mmol) to ethanol (262mL), then add phosphoric acid (85%, 0.91g, 7.86mmol), heat to reflux reaction, after the reaction is completed, concentrate under reduced pressure, and add methyl tert-butyl Stir ether (100 mL) and water (50 mL), let it stand, discard the aqueous layer, then wash the organic layer with water (100 mL) and saturated sodium bicarbonate solution (200 mL) in sequence, concentrate the organic phase, then add n-heptane, and a solid will precipitate. , cooled, filtered and dried to obtain compound 4 (12.2g, yield 93%).

1H NMR (400MHz, DMSO) δppm δppm 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, 3.7 Hz,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, 7.0 Hz, 6H), 1.10 ( d, J = 7.0 Hz, 6H), 1.03 ( dd, J = 12.6, 7.0 Hz, 6H). ESI-MS: m/z=503.1[M+H]+.

Example 7 Preparation of Compound VV116

Add compound 8 (10g, 17.5mmol) to ethanol (100mL), then add hydrobromic acid (48%, 3.1g, 18.4mmol), heat to reflux reaction, after the reaction is completed, concentrate under reduced pressure, add methyl tert. Butyl ether and n-heptane, stirred, cooled, filtered and dried to obtain compound VV116 (8.9g, 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＝5.8 Hz,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

Add compound 11 (5.0g, 7.7mmol) and tetrahydrofuran (80mL) into a 250mL autoclave, then add triethylamine (1.56g, 15.4mmol) and palladium on carbon (1.25g, water content 60%, dry basis content 5%) , after nitrogen replacement three times, deuterium gas was filled to 1.5Mpa, and the temperature was raised to 60°C for 5 hours. Then it was cooled to room temperature and replaced with nitrogen three times. 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, stirred, let it stand, discarded the aqueous layer, and then used water ( Wash the organic layer with 100 mL) saturated sodium bicarbonate solution (50 mL), concentrate the organic phase, add n-heptane, cool, filter and dry to obtain compound 8 (4.2 g, yield 96%).

Add compound 8 (2.5g, 4.4mmol) to ethanol (20mL), then add acetic acid (0.78g, 13.1mmol), heat to reflux reaction, after the reaction is completed, concentrate under reduced pressure, add methyl tert-butyl ether ( 50 mL) and water (20 mL) were stirred and allowed to stand. The aqueous layer was discarded, and then the organic layer was washed with water (20 mL) and saturated sodium bicarbonate solution (10 mL). The organic phase was concentrated, and then methyl tert-butyl ether and n-heptane were added. , a solid precipitated, cooled, filtered, and dried to obtain compound 4 (1.93g, yield 88%). The proton nuclear magnetic spectrum was consistent with the results of Example 6.

Example 9 Preparation of Compound VV116

Add compound 11 (10.0g, 15.4mmol) and methyl tert-butyl ether (100mL) into a 250mL autoclave, then add triethylamine (3.12g, 30.8mmol) and palladium on carbon (2.5g, 60% water, dry base content 5%), after nitrogen replacement three times, deuterium gas was filled to 1.2Mpa, and the temperature was raised to 60°C for 8 hours. Then it was cooled to room temperature and replaced with nitrogen three times. 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, stirred, let it stand, discarded the aqueous layer, and then used water ( Wash the organic layer with 100 mL) saturated sodium bicarbonate solution (50 mL), concentrate the organic phase, then add n-heptane, cool, filter, and dry to obtain compound 8 (8.1 g, yield 93%).

Add compound 8 (3.0g, 5.2mmol) to ethanol (20mL), then add hydrobromic acid (48%, 0.93g, 5.5mmol), heat to reflux reaction, after the reaction is completed, concentrate under reduced pressure, and add methyl Tert-butyl ether (100 mL) was continued to be concentrated under reduced pressure, n-heptane was added, cooled, filtered, and dried to obtain compound VV116 (2.6 g, yield 86%). The proton nuclear magnetic spectrum was consistent with the results of Example 7.

It should be understood that the above embodiments are exemplary and are not intended to include all possible implementations included in the claims. Various modifications and changes can also be made on the basis of the above embodiments without departing from the scope of the present disclosure. Similarly, various technical features of the above embodiments may also be combined arbitrarily to form additional embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only express several implementation modes 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).