WO2021022690A1

WO2021022690A1 - Nucleoside salt and preparation method therefor

Info

Publication number: WO2021022690A1
Application number: PCT/CN2019/115540
Authority: WO
Inventors: 胡虹艳; 张淑芳
Original assignee: 木天(济南)生物科技有限公司
Priority date: 2019-08-08
Filing date: 2019-11-05
Publication date: 2021-02-11
Also published as: CN110330540A

Abstract

The present invention relates to the field of chemical synthesis, in relates particular to a nucleoside salt represented by formula (III) or formula (IV), and a preparation method therefor. The method provided by the present invention is simple in operation, has a simple route, and a high yield. The reagents used are all commonly used reagents. The preparation of 10-100 grams may be easily achieved in laboratories and the method is suitable for large-scale preparation.

Description

Nucleoside salt and preparation method thereof

Technical field

The invention relates to the field of chemical synthesis, in particular to a nucleoside salt and a preparation method thereof.

Background technique

Since Ebola virus disease (EVD) first broke out in Zaire (now the Democratic Republic of the Congo) and Sudan in 1976, there have been many intermittent outbreaks, which have aroused special international public health concerns. Ebola virus disease (EVD) is a severe infectious disease caused by Ebola virus that produces Ebola hemorrhagic fever in humans and primates. Ebola virus (ebov) has been listed by the World Health Organization as one of the most harmful viruses due to its extremely high fatality rate. Among survivors, Ebola virus (ebov) can persist in body fluids for months after the onset of an acute infection, which may cause sequelae and viral recurrence associated with Ebola virus disease (EVD). Although the current epidemic is over, the future will also have a devastating epidemic and the possibility of persistent viruses observed in survivors. During the Ebola virus disease (EVD) outbreak, interfering RNA, monoclonal antibodies (ZMAPP) and small molecule nucleoside (TEAD) antiviral drugs such as favipiravir and brincidofovir have been used as anti-Ebola drugs. It was evaluated in early clinical trials. In addition, a nucleoside analogue Galidesivir has also entered the clinical development stage. But so far, these potential therapies lack programs that can treat acute infections or viral persistence and sequelae. Therefore, it is of great significance to develop safe and effective drugs for the treatment of Ebola virus disease (EVD).

In recent years, research on nucleoside antiviral drugs has been extremely active. Up to now, many patents and documents have been reported (see WO 2015/069939A1; WO 2017/184668A1; ES 2 465 265 T3; CN 102015714 A). In particular, from the antiviral library composed of thousands of different nucleosides and nucleoside phosphonic acid analogues, GS-5734 (shown in formula II) composed of the precursor compound Nucleoside (Nuc, shown in formula I) is preferred. As a monophosphate amide prodrug of adenosine analogue, it has anti-Ebola virus (ebov) activity (Nature 2016,531,381-385; J.Med.Chem.2017,60,1648-1661; Veterinary Microbiology 2018 , 219, 226-233). Due to the fact that Nucleoside is difficult to dissolve in neutral water and most organic solvents (dissolves only in dimethyl sulfoxide, N,N-dimethylformamide) and other reasons, almost all literature data are concentrated in the front In drug research, many prodrugs containing phosphate fragments have application prospects as new types of anti-Ebola virus (ebov) compounds. However, due to the poor solubility of Nucleoside (Nuc) compounds, the pharmacological bases of these compounds have not been reported in the literature. From the perspective of medicinal chemistry research, it is possible that Nucleoside (Nuc) salt that meets pharmaceutical research may replace its prodrugs. Therefore, research on stable and high-purity Nucleoside (Nuc) salt is particularly important. Nucleoside (Nuc) molecule itself contains multiple hydroxyl groups, which is difficult to synthesize and purify. At present, for the synthesis of Nucleoside (Nuc), most of the hydroxyl groups are protected by multi-benzyl groups. The final debenzylation and nitrile group removal must be at low temperature -78. It reacts under harsher conditions such as temperature. Therefore, it is of great significance to establish a kind of Nucleoside (Nuc) hydrochloride and sulfate with mild conditions, high efficiency, low cost, and high optical activity.

Summary of the invention

In view of this, the present invention provides a nucleoside salt and a preparation method thereof. The method provided by the present invention is simple in operation, simple in route, and high in yield. The reagents used are all commonly used reagents, which can be easily implemented in the laboratory. The preparation of ~100 grams is suitable for large-scale preparation.

The present invention provides a nucleoside salt represented by formula (III) or formula (IV):

The nucleoside salt provided by the present invention is the hydrochloride (formula (III)) or sulfate (formula (IV)) of the antiviral active nucleoside Nucleoside. The hydrochloride or sulfate provided by the present invention has good water solubility and shows good application prospects.

The present invention also provides a preparation method of nucleoside salt, including the following steps:

Step 1: D-ribose is converted into compound 2;

Step 2: Convert compound 2 to compound 3;

Step 3: Convert compound 3 to compound 4;

Step 4: Convert compound 4 to compound 5;

Step 5: Convert compound 5 to compound 6;

Step 6: Convert compound 6 into compound 7;

Step 7: Compound 7 is converted into a nucleoside salt represented by formula (III) or formula (IV);

The present invention uses D-Ribose as a raw material. Firstly, tert-butyl dimethylsiloxy (TBSO) is used to protect one of the hydroxyl groups, and the other hydroxyl group is oxidized with trimethylsilyl ether (OTMS). The protected 7-iodopyrrolo[2,1-F][1,2,4]triazine-4-amine is reacted, and one of them is protected with trimethylsiloxy trifluoromethanesulfonate (TMSO) after deprotection The hydroxyl group and the other hydroxyl group react with trimethylsilyl cyanide, and then react with hydrochloric acid, sulfuric acid or oxalyl chloride to obtain the nucleoside salt represented by formula (III) or formula (IV).

The synthesis process of the nucleoside salt is as follows:

First, convert D-ribose into compound 2. The specific steps include:

D-ribose is reacted with concentrated sulfuric acid in acetone, and the pH value is adjusted with alkali to obtain compound 2.

Dissolve D-Ribose in dry acetone, add concentrated sulfuric acid, and react at room temperature for 2-12 hours. Then, alkali was added to adjust the pH to 7, filtered, and concentrated to obtain compound 2 as a light yellow viscous oil. Wherein, the base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate or potassium bicarbonate, especially selected from sodium bicarbonate or calcium hydroxide.

After obtaining compound 2, protect one of the hydroxyl groups to obtain compound 3. The specific steps are as follows:

Compound 2 is reacted with tert-butyldimethylchlorosilane or tert-butyldimethylsilyl trifluoromethanesulfonate in an organic solvent in the presence of an organic base to obtain compound 3.

The specific operation process is as follows:

Dissolve compound 2 in an organic solvent, add organic base and stir well, add tert-butyldimethylchlorosilane or tert-butyldimethylsilyl trifluoromethanesulfonate, stir overnight, add water to quench, ethyl acetate Extraction, washing with brine, drying with anhydrous sodium sulfate, and column chromatography to obtain compound 3.

Wherein, the organic solvent is selected from dichloromethane, tetrahydrofuran, acetonitrile or N,N-dimethylformamide. The organic base is selected from imidazole, triethylamine or 2,6-lutidine.

After obtaining compound 3, oxidizing the hydroxyl group therein to obtain compound 4, which specifically includes the following steps:

Compound 3 is reacted with oxidant in dichloromethane to obtain compound 4.

The specific operation process is as follows:

Compound 3 was reacted with oxidant in dichloromethane for 0.5-12 hours, quenched with water, then extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography to obtain compound 4 as a white solid.

Wherein, the oxidant is selected from pyridinium chlorochromate (PCC), Dess-Martin oxidant (DMP), dimethyl sulfoxide/acetic anhydride or pyridine dichromate (PDC), preferably selected from Dess-Martin oxidant ( DMP) or dimethyl sulfoxide/acetic anhydride.

After obtaining compound 4, react it with 7-iodopyrrolo[2,1-F][1,2,4]triazine-4-amine protected by trimethylchlorosiloxy to obtain compound 5, which specifically includes :

7-Iodopyrrolo[2,1-F][1,2,4]triazine-4-amine and trimethylchlorosilane react with compound 4 in tetrahydrofuran under the action of phenylmagnesium chloride and isopropylmagnesium chloride , Compound 5.

The specific operations are as follows:

Dissolve 7-iodopyrrolo[2,1-F][1,2,4]triazine-4-amine in dry tetrahydrofuran, add trimethylchlorosilane, stir at room temperature for 10 minutes, and cool in an ice bath Then, phenyl magnesium chloride was added, after stirring for 20 minutes, isopropyl magnesium chloride was added dropwise, stirred for 15 minutes, and then the temperature was lowered to -15°C, the tetrahydrofuran solution of compound 4 was added dropwise, and then reacted at -15°C for 5 hours. It was quenched by adding ammonium chloride aqueous solution, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography to obtain compound 5 as a pale yellow foam solid.

After obtaining compound 5, deprotect it to obtain compound 6, which specifically includes:

Dissolve compound 5 in tetrahydrofuran. After cooling in an ice bath, add deprotection reagent, react at room temperature for 1-12 hours, dilute with ethyl acetate, wash with water and brine, dry with anhydrous sodium sulfate, concentrate, and column chromatography , Compound 6.

Wherein, the deprotection reagent is selected from hydrofluoric acid, tetrabutylammonium fluoride, tetramethylammonium fluoride or tetraethylammonium fluoride, preferably selected from tetrabutylammonium fluoride or tetramethylammonium fluoride .

After obtaining compound 6, transform it into compound 7, which specifically includes:

Compound 6 is reacted with trimethylsilyl trifluoromethanesulfonate under alkaline conditions, and then reacted with trimethylsilyl cyanide to obtain compound 7.

The specific operations are as follows:

Compound 6 was dissolved in dry dichloromethane, alkali was added, and trimethylsilyl trifluoromethanesulfonate was slowly added dropwise. After the addition, after 5 minutes of reaction, trimethylsilyl cyanide was added and reacted at room temperature for 2 hours. It was quenched with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography to obtain compound 7 as a white solid.

Wherein, the base is selected from N,N-dimethylaniline, N,N-diethylaniline, tetramethylethylenediamine, triethylamine or N-methylmorpholine, preferably selected from N,N- Dimethylaniline or triethylamine.

After obtaining compound 7, react it with acid to obtain the nucleoside salt represented by formula (III) or formula (IV), which specifically includes:

Compound 7 reacts with hydrochloric acid, sulfuric acid or oxalyl chloride to obtain the nucleoside salt represented by formula (III) or formula (IV).

The specific operation process is as follows:

Add hydrochloric acid/dioxane, hydrochloric acid/methanol, oxalyl chloride/methanol or sulfuric acid/methanol to compound 7, and after reacting for 2-12 hours, concentrate to obtain a white solid compound, which is represented by formula (III) or formula (IV)的nucleoside salt.

The present invention uses D-Ribose as a raw material. Firstly, tert-butyl dimethylsiloxy (TBSO) is used to protect one of the hydroxyl groups, and the other hydroxyl group is oxidized with trimethylsilyl ether (OTMS). The protected 7-iodopyrrolo[2,1-F][1,2,4]triazine-4-amine is reacted, and one of them is protected with trimethylsiloxy trifluoromethanesulfonate (TMSO) after deprotection The hydroxyl group and the other hydroxyl group react with trimethylsilyl cyanide, and then react with hydrochloric acid, sulfuric acid or oxalyl chloride to obtain the nucleoside salt represented by formula (III) or formula (IV). The method provided by the invention is simple in operation, simple in route, and high in yield. The reagents used are all commonly used reagents. The preparation of 10-100 grams can be conveniently realized in the laboratory, and it is suitable for large-scale preparation.

Description of the drawings

Figure 1 is a crystal structure diagram of the hydrochloride represented by formula (III) provided in Example 1 of the present invention.

detailed description

Example 1

Synthesis of (3aR,6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl and hydrofuran[3,4-d][1,3 ]Dioxolane-4(3aH)-one (Compound 4)

D-ribose (20.0 g, 133.2 mmol) was dissolved in 200 mL dry acetone, 0.5 mL concentrated sulfuric acid was added, and the reaction was carried out at room temperature for 5 hours. Add sodium bicarbonate to adjust the pH to 7, filter and concentrate to obtain compound 2 (25g, 99%) as a pale yellow viscous oil. Dissolve compound 2 in 50mL of dry N,N-dimethylformamide, add imidazole (25g, 368.4mmol) and stir well, then add tert-butyldimethylchlorosilane (21.8g, 144.7mmol) and stir overnight , Quenched with water, extracted with ethyl acetate, washed with brine, dried with anhydrous sodium sulfate, and column chromatography to obtain compound 3 (26.0 g, 65%). Then compound 3 was dissolved in 400 mL of dry dimethyl sulfoxide, 92 mL of acetic anhydride was added, and the reaction was carried out at room temperature for 12 hours. It was quenched by adding 300 mL of water, then extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography gave a white solid compound 4 (22.7 g, 88%). ¹ H NMR (400MHz, CDCl ₃ ) δ4.75-4.69 (m, 2H), 4.62-4.59 (m, 1H), 3.92-3.87 (m, 1H), 3.83-3.78 (m, 1H), 1.48 (s ,3H),1.39(s,3H),0.88(s,9H),0.07(s,3H),0.06(s,3H)ppm.

7-((3aR,6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-4-((trimethylsilyl)oxy )Tetrahydrofuran[3,4-d][1,3]dioxolane-4-)pyrrole[2,1-f][1,2,4]triazine-4-amine (Compound 5)

Dissolve 7-iodopyrrolo[2,1-F][1,2,4]triazine-4-amine (2.34g, 9.0mmol) in 45mL dry tetrahydrofuran, add trimethylchlorosilane (2.3mL , 18.0mmol), stirred at room temperature for 10 minutes, after cooling in an ice bath, slowly added phenyl magnesium chloride (9.0mL, 18.0mmol, 2M in THF), stirred for 20 minutes, dripped isopropyl magnesium chloride (4.5mL, 9.0mmol , 2M in THF), after the addition, stir for 15 minutes, then lower the temperature to -15°C, add dropwise compound 4 (2.72g, 9.0mmol) in tetrahydrofuran solution, and then react at -15°C for 5 hours. It was quenched by adding ammonium chloride aqueous solution, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography to obtain a pale yellow foam solid compound 5 (2.0 g, 44%). ¹ H NMR(400MHz,DMSO-D ₆ )δ7.87(s,1H),7.74(s,2H), 6.85(d,J=4.0Hz,1H), 6.64(d,J=4.0Hz,1H) , 4.97-4.93 (m, 1H), 4.72-4.67 (m, 1H), 4.30-4.24 (m, 1H), 3.86-3.76 (m, 2H), 1.57 (s, 3H), 1.31 (s, 3H) ,0.84(s,9H),0.02(s,15H)ppm.

(3aR,4R,6R,6aR)-4-(4-Aminopyrrole[2,1-f][1,2,4]triazine-7-)-2,2-dimethyl-6-(( (Trimethylsilyl)oxy)methyl)tetrahydrofuran[3,4-d][1,3]dioxolane-4-carbonitrile (Compound 7)

Compound 5 (600mg, 1.18mmol) was dissolved in 12mL of tetrahydrofuran, after cooling under an ice bath, tetrabutylammonium fluoride (2.4mL, 2.4mmol, 1M in THF) was added, and reacted at room temperature for 1 hour, with 50mL ethyl acetate The ester was diluted, washed with water and brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography to obtain compound 6 (322 mg, 85%). Compound 6 was dissolved in 5mL of dry dichloromethane, stirred to completely dissolve, then added triethylamine (0.42mL, 3.0mmol), slowly added dropwise trimethylsilyl trifluoromethanesulfonate (0.9mL, 5.0 mmol), after the addition, after 5 minutes of reaction, add trimethylnitrile silane (0.5 mL, 4.0 mmol), and react at room temperature for 2 hours. It was quenched with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography to obtain compound 7 (202 mg, 50%) as a white solid. ¹ H NMR(400MHz,DMSO-D ₆ )δ7.90(s,1H),7.81(s,2H),6.86(d,J=4.4Hz,1H),6.66(d,J=4.4Hz,1H) ,5.43-5.39(m,1H),4.97-4.93(m,1H),4.55-4.50(m,1H),3.86-3.76(m,2H),1.14(s,3H),0.78(s,3H) ,0.14(s,9H)ppm.

(2R,3R,4S,5R)-2-(4-Aminopyrrole[2,1-f][1,2,4]triazine-7-)-3,4-dihydroxy-5-(hydroxymethyl Base) tetrahydrofuran-2-carbonitrile hydrochloride (compound represented by formula (III))

Compound 7 (5.0 g, 12.4 mmol) was added with 20 mL of hydrochloric acid/dioxane (6M), reacted at room temperature for 3 hours, and concentrated to obtain the compound represented by formula (III) (4.06 g, 100%). ¹ H NMR(400MHz,DMSO-D ₆ )δ10.22(s,1H), 9.35(s,1H), 8.21(s,1H), 7.47(d,J=4.8Hz,1H), 7.02(d, J = 4.4Hz, 1H), 4.45 (d, J = 4.8 Hz, 1H), 4.00-3.95 (m, 1H), 3.86 (dd, J = 5.2, 4.4 Hz, 1H), 3.54 (dd, J = 12.4 ,3.2Hz,1H),3.41(dd,J=12.4,4.0Hz,1H)ppm; ¹³ C{ ¹ H}NMR(CDCl ₃ ,100MHz)δ150.5,139.2,129.1,117.3,114.8,112.7,108.3,85.8 , 78.2, 75.6, 70.3, 60.9ppm.

Its crystal structure is shown in Figure 1.

Example 2

The preparation of compounds 2, 5, 6, 7 and the compound represented by formula (III) is the same as in Example 1.

D-ribose (20.0 g, 133.2 mmol) was dissolved in 200 mL dry acetone, 0.5 mL concentrated sulfuric acid was added, and the reaction was carried out at room temperature for 5 hours. Add calcium hydroxide to adjust the pH to 7, filter and concentrate to obtain compound 2 (22.7g, 90%) in the form of a light yellow viscous oil. Dissolve compound 2 in 50mL of dry dichloromethane, add 2,6-lutidine (19.2g, 179.0mmol) and stir evenly, then add tert-butyl dimethylsilyl triflate (31.5g , 119.3 mmol), stirred overnight, quenched with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and column chromatography to obtain compound 3 (30.9 g, 85%). Then compound 3 was dissolved in 500 mL of dry dichloromethane, and then Dess-Martin oxidant (51.6 g, 101.5 mmol) was added, and the reaction was carried out at room temperature for 12 hours. It was quenched with sodium bicarbonate and sodium thiosulfate, then extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography to obtain white solid compound 4 (28.2 g, 92%).

Example 3

The preparation of compounds 2, 3, 4 and 5 is the same as in Example 1.

Compound 5 (30.0g, 59.0mmol) was dissolved in 250mL of tetrahydrofuran. After cooling in an ice bath, tetramethylammonium fluoride (8.3g, 88.0mmol) was added. The reaction was carried out at room temperature for 2 hours, and then diluted with ethyl acetate. Wash with water and brine, dry with anhydrous sodium sulfate, concentrate, and column chromatography to obtain compound 6 (17 g, 87%). Dissolve compound 6 in 200 mL of dry dichloromethane, stir to dissolve completely, then add N,N-dimethylaniline (19g, 158.0mmol), slowly add trimethylsilyl trifluoromethanesulfonate ( 48mL, 264mmol). After the addition was completed, after 5 minutes of reaction, trimethylsilyl cyanide (26mL, 211mmol) was added and reacted at room temperature for 2 hours. It was quenched with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography to obtain a white solid compound 7 (13 g, 60%).

Compound 7 (50.0g, 124mmol) was dissolved in 400mL methanol, after cooling in an ice bath, oxalyl chloride (16mL, 186mmol) was added, reacted at room temperature for 6 hours, and concentrated to obtain the compound represented by formula (III) (40.6g, 100 %).

Example 4

The preparation of compounds 2, 3, 4, 5, 6 and 7 is the same as in Example 1.

(2R,3R,4S,5R)-2-(4-Aminopyrrole[2,1-f][1,2,4]triazine-7-)-3,4-dihydroxy-5-(hydroxymethyl Base) Tetrahydrofuran-2-nitrile sulfate (compound represented by formula (IV))

Compound 7 (50.0g, 124mmol) was dissolved in 400mL methanol, after cooling in an ice bath, 6N sulfuric acid (50mL) was added dropwise, reacted at room temperature for 10 hours, and concentrated to obtain the compound represented by formula (IV) (31g, 74%) ).

The above are only the preferred embodiments of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications are also It should be regarded as the protection scope of the present invention.

Claims

Nucleoside salt represented by formula (III) or formula (IV):
A preparation method of nucleoside salt, characterized in that it comprises:

Step 1: D-ribose is converted into compound 2;

Step 2: Convert compound 2 to compound 3;

Step 3: Convert compound 3 to compound 4;

Step 4: Convert compound 4 to compound 5;

Step 5: Convert compound 5 to compound 6;

Step 6: Convert compound 6 into compound 7;

Step 7: Compound 7 is converted into a nucleoside salt represented by formula (III) or formula (IV);
The preparation method according to claim 2, wherein step 1 specifically includes:

D-ribose reacts with concentrated sulfuric acid in acetone, and adjusts the pH with alkali to obtain compound 2;

The base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate or potassium bicarbonate.
The preparation method according to claim 3, wherein step 2 specifically includes:

Compound 2 is reacted with tert-butyldimethylchlorosilane or tert-butyldimethylsilyl trifluoromethanesulfonate in an organic solvent in the presence of an organic base to obtain compound 3;

The organic solvent is selected from dichloromethane, tetrahydrofuran, acetonitrile or N,N-dimethylformamide, and the organic base is selected from imidazole, triethylamine or 2,6-lutidine.
The preparation method according to claim 2, wherein said step 3 specifically comprises:

Compound 3 is reacted with oxidant in dichloromethane to obtain compound 4.
The preparation method according to claim 5, wherein in the step 3, the oxidant is selected from pyridinium chlorochromate, Dess-Martin oxidant, dimethyl sulfoxide/acetic anhydride or pyridine dichromate.
The preparation method according to claim 2, wherein step 4 specifically includes:

7-Iodopyrrolo[2,1-F][1,2,4]triazine-4-amine and trimethylchlorosilane react with compound 4 in tetrahydrofuran under the action of phenylmagnesium chloride and isopropylmagnesium chloride , Compound 5.
The preparation method according to claim 2, wherein step 5 specifically includes:

Deprotection of compound 5 to obtain compound 6;

The deprotection reagent is selected from hydrofluoric acid, tetrabutylammonium fluoride, tetramethylammonium fluoride or tetraethylammonium fluoride.
The preparation method according to claim 2, wherein step 6 specifically includes:

Compound 6 is reacted with trimethylsilyl trifluoromethanesulfonate under alkaline conditions, and then reacted with trimethylsilyl cyanide to obtain compound 7;

The base is selected from N,N-dimethylaniline, N,N-diethylaniline, tetramethylethylenediamine, triethylamine or N-methylmorpholine.
The preparation method according to claim 2, wherein step 7 specifically comprises: reacting compound 7 with hydrochloric acid, sulfuric acid or oxalyl chloride to obtain the nucleoside salt represented by formula (III) or formula (IV).