CN110330540A - Nucleosides salt and preparation method thereof - Google Patents
Nucleosides salt and preparation method thereof Download PDFInfo
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- CN110330540A CN110330540A CN201910728181.2A CN201910728181A CN110330540A CN 110330540 A CN110330540 A CN 110330540A CN 201910728181 A CN201910728181 A CN 201910728181A CN 110330540 A CN110330540 A CN 110330540A
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Abstract
The present invention relates to nucleosides salt shown in the field of chemical synthesis more particularly to formula (III) or formula (IV) and preparation method thereof.Method provided by the invention is easy to operate, and route is succinct, and yield is higher, and reagent used is common agents, can facilitate the preparation for realizing 10-100 gram-grade in the lab, can be suitble to large scale preparation.
Description
Technical field
The present invention relates to the field of chemical synthesis more particularly to a kind of nucleosides salt and preparation method thereof.
Background technique
Ebola disease viral disease (EVD) from 1976 for the first time Zaire (existing Democratic Republic of the Congo) and the Sudan break out with
Come, has occurred that a lot of intermittent epidemic situations, caused international sanitarian special attention.Ebola disease viral disease (EVD) is
The mankind as caused by Ebola virus and primate generate the deadly infectious disease of Ebola hemorrhagic fever.Ebola virus
(ebov) one of the virus that the mankind are endangered with most serious is classified as by the World Health Organization due to its high lethality.In survivor
In, Ebola virus (ebov) acute infection breaking-out after can in body fluid periods of months, may cause and ebola disease viral disease
(EVD) relevant sequelae and virus recurrence.It is following that equally there is destructive epidemic situation although current epidemic situation is over
And survivor with it observe persistent virus a possibility that.During ebola disease viral disease (EVD) outburst, interference
RNA, monoclonal antibody (ZMAPP) and small molecule nucleosides (TEAD) antiviral drugs such as favipiravir and brincidofovir
All it is used as anti-Ebola's drug, is assessed in early studies in man.In addition, a kind of nucleoside analog
Galidesivir has also entered clinical development.But urgency can be treated by so far, lacking in these potential treatment methods
Scheme in terms of sexuality dye or viral persistence and sequelae.Therefore, safe and effective treatment ebola disease viral disease is developed
(EVD) drug is significant.
In recent years, extremely active about the antiviral class drug research of ucleosides, so far, have numerous patents and document
It is reported (see 2015/069939 A1 of WO；WO 2017/184668 A1；ES 2 465 265T 3；CN 102015714
A).In particular, preferably going out precursor chemical combination from the antiviral library that thousands of different nucleosides objects similar with nucleoside phosphonate forms
A kind of single phosphorus of the GS-5734 (shown in Formula II) of object nucleosides Nucleoside (Nuc, shown in Formulas I) composition as neplanocin
Sour amide prodrug, the activity (Nature 2016,531,381-385 with anti-Ebola virus (ebov)；
J.Med.Chem.2017,60,1648-1661；Veterinary Microbiology 2018,219,226-233).Due to
Nucleoside in neutral water and most organic solvent all indissoluble solutions (only in dimethyl sulfoxide, n,N-Dimethylformamide
Middle dissolution) etc. reasons, concentrate on almost all of documents and materials all in the research of its prodrug, make its many phosphorous acid fragment
Prodrug has the application prospect as novel anti-Ebola virus (ebov) compound.However, because Nucleoside (Nuc) changes
The slightly solubility for closing object causes the pharmaceutically alkali of such compound to there is no Research Literature document announcement.From pharmaceutical chemistry research angle
For, Nucleoside (Nuc) salt for solving to meet study of pharmacy is possible to that its prodrug, therefore stable high-purity can be substituted
The research of Nucleoside (Nuc) salt is particularly important.Nucleoside (Nuc) molecule itself contains multiple hydroxyls, and synthesis, purifying are difficult
Spend larger, at present for the synthesis of Nucleoside (Nuc), take more benzyl protection hydroxyls mostly, last debenzylation and
Upper itrile group is both needed to react under the more exacting terms such as degree of low temperature -78.Therefore, establish a kind of mild condition, it is efficient, low at
This, can amplify and prepare Nucleoside (Nuc) hydrochloride, sulfate and its preparation of high optical activity and be of great significance.
Summary of the invention
In view of this, method provided by the invention is easy to operate the present invention provides a kind of nucleosides salt and preparation method thereof,
Route is succinct, and yield is higher, and reagent used is common agents, can facilitate the system of 10~100 gram-grade of realization in the lab
It is standby, large scale preparation can be suitble to.
The present invention provides nucleosides salt shown in formula (III) or formula (IV):
The hydrochloride (shown in formula (III)) or sulphur that nucleosides salt provided by the invention is antiviral activity nucleosides Nucleoside
Hydrochlorate (shown in formula (IV)).Hydrochloride or sulfate provided by the invention have good water solubility, show good answer
Use prospect.
The present invention also provides a kind of preparation methods of nucleosides salt, comprising the following steps:
Step 1:D- ribose is converted into compound 2；
Step 2: compound 2 is converted into compound 3；
Step 3: compound 3 is converted into compound 4；
Step 4: compound 4 is converted into compound 5；
Step 5: compound 5 is converted into compound 6；
Step 6: compound 6 is converted into compound 7；
Step 7: compound 7 is converted into nucleosides salt shown in formula (III) or formula (IV)；
The present invention for raw material, uses tertiary butyl dimethyl Si base (TBSO) will wherein first with D-ribose (D-Ribose)
One hydroxyl protection, by another hydroxyl oxidation after with trimethyl silicane ether (OTMS) protection 7- iodol simultaneously [2,1-F] [1,
2,4] triazine -4- amine reacts, and protects one of hydroxyl with trifluoromethanesulfonic acid trimethylsiloxy group (TMSO) after deprotection, another
A hydroxyl is reacted with trimethylsilyl cyanide, then is reacted with hydrochloric acid or sulfuric acid or oxalyl chloride, is obtained shown in formula (III) or formula (IV)
Nucleosides salt.
The synthesis process of the nucleosides salt is as follows:
Compound 2 is converted by D-ribose first, specific steps include:
D-ribose with strong sulfuric acid response, obtains compound 2 after adjusting pH value with alkali in acetone.
D-ribose (D-Ribose) is dissolved in dry acetone, the concentrated sulfuric acid is added, is reacted 2~12 hours at room temperature.So
Adjusting PH with base value is added afterwards to 7, filters, concentration obtains thick pale yellow oily compound 2.Wherein, the alkali be selected from sodium hydroxide,
Potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate or saleratus, are especially selected from sodium bicarbonate
Or calcium hydroxide.
After obtaining compound 2, one of hydroxyl is protected, obtains compound 3, the specific steps are as follows:
Under the conditions of compound 2 is existing for the organic base with tert-butyl chloro-silicane or tert-butyl dimethyl silyl fluoroform
Sulphonic acid ester reacts in organic solvent, obtains compound 3.
Specific operation process is as follows:
Compound 2 is dissolved in organic solvent, be added organic base after mixing evenly, be added tert-butyl chloro-silicane or
Tert-butyl dimethyl silyl triflate, is stirred overnight, water quenching is added to go out, ethyl acetate extraction, brine It, anhydrous slufuric acid
Sodium is dry, and column chromatographs to obtain compound 3.
Wherein, the organic solvent is selected from methylene chloride, tetrahydrofuran, acetonitrile or n,N-Dimethylformamide.It is described to have
Machine alkali is selected from imidazoles, triethylamine or 2,6- lutidines.
After obtaining compound 3, hydroxyl therein is aoxidized, obtains compound 4, specifically includes the following steps:
Compound 3 reacts in methylene chloride with oxidant, obtains compound 4.
Specific operation process is as follows:
Compound 3 is reacted 0.5~12 hour in methylene chloride with oxidant, water quenching is added to go out, then uses ethyl acetate
Extraction, brine It, anhydrous sodium sulfate is dry, and concentration, column chromatographs to obtain compound as white solid 4.
Wherein, the oxidant is selected from pyridinium chloro-chromate (PCC), Dai Si-Martin's oxidant (DMP), dimethyl sulfoxide/second
Acid anhydrides or Pyridinium dichromate (PDC) are preferably selected from Dai Si-Martin's oxidant (DMP) or dimethyl sulfoxide/acetic anhydride.
After obtaining compound 4, by the 7- iodol of its protection with trimethylchloro-silicane oxygroup simultaneously [2,1-F] [1,2,4] triazine-
The reaction of 4- amine, obtains compound 5, specifically includes:
7- iodol simultaneously [2,1-F] [1,2,4] triazine -4- amine and trim,ethylchlorosilane in phenyl-magnesium-chloride and isopropyl chloride
It is reacted in tetrahydrofuran with compound 4 under the action of change magnesium, obtains compound 5.
Concrete operations are as follows:
By 7- iodol, simultaneously [2,1-F] [1,2,4] triazine -4- amine is dissolved in dry tetrahydrofuran, and trimethyl chlorine is added
Silane stirs 10 minutes at room temperature, after cooling under ice bath, phenyl-magnesium-chloride is added, stirring after twenty minutes, instills isopropyl chlorination
Magnesium stirs 15 minutes, then cools to -15 DEG C, instills the tetrahydrofuran solution of compound 4, and then reaction 5 is small at -15 DEG C
When.Aqueous ammonium chloride solution is added to be quenched, ethyl acetate is extracted twice, and anhydrous sodium sulfate dries, filters, and concentration, column chromatographs shallowly
Yellow foamy solid compound 5.
It after obtaining compound 5, is deprotected, obtains compound 6, specifically include:
Compound 5 is dissolved in tetrahydrofuran, after cooling under ice bath, deprotecting regent is added, it is small to react 1~12 at room temperature
When, it is diluted with ethyl acetate, uses water and brine It respectively, anhydrous sodium sulfate is dry, concentration, and column chromatography obtains compound 6.
Wherein, the deprotecting regent is selected from hydrofluoric acid, tetrabutyl ammonium fluoride, Methanaminium, N,N,N-trimethyl-, fluoride or tetraethyl fluorination
Ammonium is preferably selected from tetrabutyl ammonium fluoride or Methanaminium, N,N,N-trimethyl-, fluoride.
After obtaining compound 6, it is translated into compound 7, is specifically included:
Compound 6 is reacted with Trimethylsilyl trifluoromethanesulfonate under alkaline condition, then after reacting with trimethylsilyl cyanide
Obtain compound 7.
Concrete operations are as follows:
Compound 6 is dissolved in dry methylene chloride, alkali is added, Trimethylsilyl trifluoromethanesulfonate is slowly added dropwise, adds
Finish, after five minutes, trimethylsilyl cyanide is added in reaction, reacts 2 hours at room temperature.Water quenching is added to go out, ethyl acetate extraction, saline solution
Washing, anhydrous sodium sulfate is dry, and concentration, column chromatographs to obtain compound as white solid 7.
Wherein, the alkali is selected from n,N-Dimethylaniline, N, N- diethylaniline, tetramethylethylenediamine, triethylamine or N-
Methyl morpholine is preferably selected from n,N-Dimethylaniline or triethylamine.
After obtaining compound 7, it is reacted with acid, nucleosides salt shown in formula (III) or formula (IV) is obtained, specifically includes:
Compound 7 is reacted with hydrochloric acid, sulfuric acid or oxalyl chloride, obtains nucleosides salt shown in formula (III) or formula (IV).
Specific operation process is as follows:
Hydrochloric acid/dioxane, hydrochloric acid/methanol, oxalyl chloride/methanol or sulfuric acid/methanol, reaction 2~12 are added in compound 7
After hour, it is concentrated to give compound as white solid, as nucleosides salt shown in formula (III) or formula (IV).
The present invention for raw material, uses tertiary butyl dimethyl Si base (TBSO) will wherein first with D-ribose (D-Ribose)
One hydroxyl protection, by another hydroxyl oxidation after with trimethyl silicane ether (OTMS) protection 7- iodol simultaneously [2,1-F] [1,
2,4] triazine -4- amine reacts, and protects one of hydroxyl with trifluoromethanesulfonic acid trimethylsiloxy group (TMSO) after deprotection, another
A hydroxyl is reacted with trimethylsilyl cyanide, then is reacted with hydrochloric acid or sulfuric acid or oxalyl chloride, is obtained shown in formula (III) or formula (IV)
Nucleosides salt.Method provided by the invention is easy to operate, and route is succinct, and yield is higher, and reagent used is common agents, in reality
The preparation for realizing 10-100 gram-grade can be facilitated by testing in room, can be suitble to large scale preparation.
Detailed description of the invention
The crystal structure figure of hydrochloride shown in the formula (III) that Fig. 1 provides for the embodiment of the present invention 1.
Specific embodiment
Embodiment 1
Synthesize (3aR, 6R, 6aR) -6- (((t-Butyldimethylsilyl) oxygen) methyl) -2,2- dimethyl and hydrogen furans [3,
4-d] [1,3] dioxolanes -4 (3aH) -one (compound 4)
D-ribose (20.0g, 133.2mmol) is dissolved in the dry acetone of 200mL, the 0.5mL concentrated sulfuric acid is added, at room temperature
Reaction 5 hours.Add sodium bicarbonate tune pH to 7, filter, concentration obtains thick pale yellow oily compound 2 (25g, 99%).It will change
It closes object 2 to be dissolved in the dry n,N-Dimethylformamide of 50mL, imidazoles (25g, 368.4mmol) is added after mixing evenly, is added
Tert-butyl chloro-silicane (21.8g, 144.7mmol), is stirred overnight, water quenching is added to go out, ethyl acetate extraction, salt washing
It washs, anhydrous sodium sulfate is dry, and column chromatographs to obtain compound 3 (26.0g, 65%).Then compound 3 is dissolved in dry two of 400mL
In first sulfoxide, 92mL acetic anhydride is then added, reacts 12 hours at room temperature.Add 300mL water quenching to go out, is then extracted with ethyl acetate
It takes, brine It, anhydrous sodium sulfate is dry, and concentration, column chromatographs to obtain compound as white solid 4 (22.7g, 88%).1H NMR
(400MHz, CDCl3) δ 4.75-4.69 (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- (((t-Butyldimethylsilyl) oxygen) methyl) -2,2- dimethyl -4- ((trimethyl
Silicon substrate) oxygen) tetrahydrofuran [3,4-d] [1,3] dioxolanes -4-) pyrroles [2,1-f] [1,2,4] triazine -4- amine (compound 5)
By 7- iodol, simultaneously [2,1-F] [1,2,4] triazine -4- amine (2.34g, 9.0mmol) is dissolved in the dry tetrahydro of 45mL
It in furans, is added trim,ethylchlorosilane (2.3mL, 18.0mmol), stirs 10 minutes at room temperature, after cooling under ice bath, slowly add
Enter phenyl-magnesium-chloride (9.0mL, 18.0mmol, 2 M in THF), stirs 20 minutes, instillation isopropylmagnesium chloride (4.5mL,
9.0mmol, 2M in THF), stirring 15 minutes is finished, then cools to -15 DEG C, is added dropwise compound 4 (2.72g, 9.0mmol)
Tetrahydrofuran solution, then reacted 5 hours at -15 DEG C.Aqueous ammonium chloride solution is added to be quenched, ethyl acetate is extracted twice,
Anhydrous sodium sulfate dries, filters, and concentration, column chromatographs to obtain light yellow foam solid chemical compound 5 (2.0g, 44%).1H NMR
(400MHz, DMSO-D6) δ 7.87 (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- amino-pyrroles [2,1-f] [1,2,4] triazine -7-) -2,2- dimethyl -6-
(((trimethyl silicon substrate) oxygen) methyl) tetrahydrofuran [3,4-d] [1,3] dioxolanes -4- nitrile (compound 7)
Compound 5 (600mg, 1.18mmol) is dissolved in 12mL tetrahydrofuran, after cooling under ice bath, tetrabutyl fluorine is added
Change ammonium (2.4mL, 2.4mmol, 1M in THF), react 1 hour at room temperature, diluted with 50mL ethyl acetate, uses water and food respectively
Salt water washing, anhydrous sodium sulfate is dry, concentration, and column chromatography obtains compound 6 (322mg, 85%).Compound 6 is dissolved in 5mL to do
In dry methylene chloride, stirring is made it completely dissolved, and triethylamine (0.42mL, 3.0mmol) then is added, fluoroform is slowly added dropwise
Sulfonic acid trimethylsilyl group (0.9mL, 5.0mmol), finishes, and reacts after five minutes, addition trimethyl nitrile silane (0.5mL,
4.0mmol), it reacts 2 hours at room temperature.Water quenching is added to go out, ethyl acetate extraction, brine It, anhydrous sodium sulfate is dry, dense
Contracting, column chromatograph to obtain compound as white solid 7 (202mg, 50%).1H NMR (400 MHz, DMSO-D6) δ 7.90 (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- amino-pyrroles [2,1-f] [1,2,4] triazine -7-) -3,4- dihydroxy -5- (hydroxyl first
Base) tetrahydrofuran -2- nitrile hydrochloride (compound shown in formula (III))
20mL hydrochloric acid/dioxane (6M) is added in compound 7 (5.0g, 12.4mmol), reacts 3 hours at room temperature, it is dense
Contract to obtain compound (4.06g, 100%) shown in formula (III).1H NMR (400MHz, DMSO-D6) δ 10.22 (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=4.8Hz, 1H),
4.00-3.95 (m, 1H), 3.86 (dd, J=5.2,4.4Hz, 1H), 3.54 (dd, J=12.4,3.2Hz, 1H), 3.41 (dd, J
=12.4,4.0Hz, 1H) ppm；13C{1H}NMR(CDCl3, 100MHz) and δ 150.5,139.2,129.1,117.3,114.8,
112.7,108.3,85.8,78.2,75.6,70.3,60.9ppm.
Its crystal structure is as shown in Figure 1.
Embodiment 2
Preparing for compound shown in compound 2,5,6,7 and formula (III) is same as Example 1.
Synthesize (3aR, 6R, 6aR) -6- (((t-Butyldimethylsilyl) oxygen) methyl) -2,2- dimethyl and hydrogen furans [3,
4-d] [1,3] dioxolanes -4 (3aH) -one (compound 4)
D-ribose (20.0g, 133.2mmol) is dissolved in the dry acetone of 200mL, the 0.5mL concentrated sulfuric acid is added, at room temperature
Reaction 5 hours.Add calcium hydroxide tune pH to 7, filter, concentration obtains thick pale yellow oily compound 2 (22.7g, 90%).It will
Compound 2 is dissolved in the dry methylene chloride of 50mL, and 2,6- lutidines (19.2g, 179.0mmol) is added and stirs evenly
Afterwards, tert-butyl dimethyl silyl triflate (31.5g, 119.3mmol) is added, is stirred overnight, water quenching is added to go out, ethyl acetate
Extraction, brine It, anhydrous sodium sulfate is dry, and column chromatographs to obtain compound 3 (30.9g, 85%).Then compound 3 is dissolved in
In 500mL dry methylene chloride, Dai Si-Martin's oxidant (51.6g, 101.5mmol) is then added, it is small to react 12 at room temperature
When.Add sodium bicarbonate and sodium thiosulfate to be quenched, be then extracted with dichloromethane, brine It, anhydrous sodium sulfate is dry, dense
Contracting, column chromatograph to obtain compound as white solid 4 (28.2g, 92%).
Embodiment 3
Preparing for compound 2,3,4 and 5 is same as Example 1.
(3aR, 4R, 6R, 6aR) -4- (4- amino-pyrroles [2,1-f] [1,2,4] triazine -7-) -2,2- dimethyl -6-
(((trimethyl silicon substrate) oxygen) methyl) tetrahydrofuran [3,4-d] [1,3] dioxolanes -4- nitrile (compound 7)
Compound 5 (30.0g, 59.0mmol) is dissolved in 250mL tetrahydrofuran, after cooling under ice bath, tetramethyl is added
Ammonium fluoride (8.3g, 88.0mmol) is reacted 2 hours at room temperature, is diluted with ethyl acetate, uses water and brine It, nothing respectively
Aqueous sodium persulfate is dry, concentration, and column chromatography obtains compound 6 (17g, 87%).Compound 6 is dissolved in the dry methylene chloride of 200mL
In, stirring makes it completely dissolved, and n,N-Dimethylaniline (19g, 158.0mmol) then is added, trifluoromethanesulfonic acid is slowly added dropwise
Trimethylsilyl group (48mL, 264mmol), finishes, and reaction after five minutes, is added trimethylsilyl cyanide (26mL, 211mmol), room temperature
Lower reaction 2 hours.Water quenching is added to go out, ethyl acetate extraction, brine It, anhydrous sodium sulfate is dry, and concentration, column chromatographs white
Solid chemical compound 7 (13g, 60%).
(2R, 3R, 4S, 5R) -2- (4- amino-pyrroles [2,1-f] [1,2,4] triazine -7-) -3,4- dihydroxy -5- (hydroxyl first
Base) tetrahydrofuran -2- nitrile hydrochloride (compound shown in formula (III))
Compound 7 (50.0g, 124mmol) is dissolved in 400mL methanol, after cooling under ice bath, addition oxalyl chloride (16mL,
186mmol), it reacts 6 hours at room temperature, is concentrated to give compound shown in formula (III) (40.6g, 100%).
Embodiment 4
Preparing for compound 2,3,4,5,6 and 7 is same as Example 1.
(2R, 3R, 4S, 5R) -2- (4- amino-pyrroles [2,1-f] [1,2,4] triazine -7-) -3,4- dihydroxy -5- (hydroxyl first
Base) tetrahydrofuran -2- nitrile sulfate (compound shown in formula (IV))
Compound 7 (50.0g, 124mmol) is dissolved in 400mL methanol, after cooling under ice bath, the sulfuric acid of 6N is added dropwise
(50mL) reacts 10 hours at room temperature, is concentrated to give compound shown in formula (IV) (31g, 74%).
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. nucleosides salt shown in formula (III) or formula (IV):
2. a kind of preparation method of nucleosides salt characterized by comprising
Step 1:D- ribose is converted into compound 2；
Step 2: compound 2 is converted into compound 3；
Step 3: compound 3 is converted into compound 4；
Step 4: compound 4 is converted into compound 5；
Step 5: compound 5 is converted into compound 6；
Step 6: compound 6 is converted into compound 7；
Step 7: compound 7 is converted into nucleosides salt shown in formula (III) or formula (IV)；
3. preparation method according to claim 2, which is characterized in that step 1 specifically includes:
D-ribose with strong sulfuric acid response, obtains compound 2 after adjusting pH value with alkali in acetone；
The alkali is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate or carbon
Potassium hydrogen phthalate.
4. preparation method according to claim 3, which is characterized in that step 2 specifically includes:
Under the conditions of compound 2 is existing for the organic base with tert-butyl chloro-silicane or tert-butyl dimethyl silyl trifluoromethanesulfonic acid
Ester reacts in organic solvent, obtains compound 3；
The organic solvent is selected from methylene chloride, tetrahydrofuran, acetonitrile or n,N-Dimethylformamide, and the organic base is selected from miaow
Azoles, triethylamine or 2,6- lutidines.
5. preparation method according to claim 2, which is characterized in that the step 3 specifically includes:
Compound 3 reacts in methylene chloride with oxidant, obtains compound 4.
6. preparation method according to claim 5, which is characterized in that in the step 3, the oxidant is selected from chloro-chromic acid
Pyridiniujm, Dai Si-Martin's oxidant, dimethyl sulfoxide/acetic anhydride or Pyridinium dichromate.
7. preparation method according to claim 2, which is characterized in that step 4 specifically includes:
7- iodol simultaneously [2,1-F] [1,2,4] triazine -4- amine and trim,ethylchlorosilane in phenyl-magnesium-chloride and isopropylmagnesium chloride
Under the action of reacted in tetrahydrofuran with compound 4, obtain compound 5.
8. preparation method according to claim 2, which is characterized in that step 5 specifically includes:
Compound 5 is deprotected, and obtains compound 6；
The deprotecting regent is selected from hydrofluoric acid, tetrabutyl ammonium fluoride, Methanaminium, N,N,N-trimethyl-, fluoride or tetraethyl ammonium fluoride.
9. preparation method according to claim 2, which is characterized in that step 6 specifically includes:
Compound 6 is reacted with Trimethylsilyl trifluoromethanesulfonate under alkaline condition, then is obtained after reacting with trimethylsilyl cyanide
Compound 7；
The alkali is selected from n,N-Dimethylaniline, N, N- diethylaniline, tetramethylethylenediamine, triethylamine or N-methylmorpholine.
10. preparation method according to claim 2, which is characterized in that step 7 specifically includes: compound 7 and hydrochloric acid, sulphur
Acid or oxalyl chloride reaction, obtain nucleosides salt shown in formula (III) or formula (IV).
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| PCT/CN2019/115540 WO2021022690A1 (en) | 2019-08-08 | 2019-11-05 | Nucleoside salt and preparation method therefor |
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Cited By (22)
| Publication number | Priority date | Publication date | Assignee | Title |
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