CN114456169B - 3' -deoxy-3 ',4' -didehydroribonucleoside analogues and preparation method thereof - Google Patents
3' -deoxy-3 ',4' -didehydroribonucleoside analogues and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a novel 3 '-deoxy-3' -didehydroribonucleoside analogue, in particular to a 3 '-deoxy-4' -didehydroribonucleoside analogue, a preparation method and application thereof, belonging to the field of nucleoside chemistry and pharmaceutical chemistry. It has a structure shown in formula 1:
Description
Technical Field
The invention belongs to the field of nucleotide chemistry and pharmaceutical chemistry, and particularly relates to a novel 3' -deoxy-3 ',4' -didehydroribonucleoside analogue and a preparation method thereof.
Background
Viral infectious diseases have become a major medical problem facing humans, with millions of people dying from viral infectious diseases each year. Antiviral drug therapy is a common method for clinical antiviral treatment, and about half of antiviral drugs are nucleoside drugs. Nucleoside drugs act mainly by the following two ways: (1) As inhibitors of viral replicase (primarily reverse transcriptase, DNA or RNA polymerase), inhibiting enzymatic activity, thereby blocking viral RNA synthesis; (2) As a substrate for viral polymerase, competes with the natural nucleotides for incorporation into the viral RNA strand, thereby terminating further amplification of the viral RNA strand. Nucleoside drugs are mainly obtained by modifying the base and sugar ring sites of natural nucleosides.
The Viperin protein is an antiviral protein, known as an antiviral immune factor, and is widely present in humans and other mammals. The protein has the function of resisting DNA and RNA viruses in a broad spectrum, and has antiviral effect on a plurality of viruses including West Nile virus, zika virus, hepatitis C virus, rabies virus, HIV and the like. Recent studies (Nature, 2018,558, 610-614) found that Viperin proteins catalyze the conversion of Cytidine Triphosphate (CTP) to 3' -deoxy-3 ',4' -didehydrocytidine triphosphate (ddhCTP). The ddhCTP molecule is a virus RNA chain terminator, can be recognized by virus polymerase to be incorporated into a virus RNA chain, stops the growth of the chain and plays an antiviral role. Researches also find that bacterial prokaryotic Viperin protein can not only produce ddhCTP, but also produce antiviral ddhGTP and ddhUTP, and show that 3' -deoxy-3 ',4' -didehydroribonucleoside is a compound with important development value. Kellan et al (j.med. Chem.2021,64, 15429-15439) synthesized ddhC and its ProTide prodrug (structure below), and found that ddhC had no antiviral activity and that after conversion to the ProTide prodrug, antiviral activity was greatly enhanced. ddhC-ProTide reduced West Nile Virus (WNV) levels in Huh7 cells by 4 titers compared to ddhC, and the prodrug was not cytotoxic. However, the activity of the compound is not enough to prepare medicaments at present, and further research space is provided. Based on the above, the invention synthesizes a series of 3' -deoxy-3 ',4' -didehydroribonucleoside analogues, and through further screening of prodrugs in different forms, better and stronger antiviral agents are expected to be found.
Disclosure of Invention
The invention aims to provide a novel 3' -deoxy-3 ',4' -didehydroribonucleoside analogue with antiviral activity or serving as an antiviral precursor; another object is to provide a process for the preparation thereof.
In order to achieve the purpose of the invention, the commercially available 2,3,4-tri-O-benzoyl-1-O-acetyl ribose is subjected to glycosylation reaction and deprotection to obtain the ribonucleoside analogue containing a natural base and a non-natural base. Protecting 2',3' -hydroxyl of the ribonucleoside analogue, converting 5 '-hydroxymethyl into functional group containing carbonyl, removing protective group by alkali treatment, and reducing to obtain the novel 3' -deoxy-3 ',4' -didehydroribonucleoside analogue.
The novel 3' -deoxy-3 ',4' -didehydroribonucleoside analogues are represented by general formula 1:
wherein B represents the following bases:
the compound represented by formula 1 was synthesized by the following method:
the preparation method is detailed as follows:
(1) And reacting the compound I with silanized basic group under the catalysis of Lewis acid through Vorburgen to obtain a nucleoside derivative intermediate II.
The silanized basic group can be obtained by treating basic group with hexamethyl disilazane in the presence of catalytic amount of ammonium sulfate; or directly treating the base with N, O-bis (trimethylsilyl) acetamide (BSA) in the reaction system.
The Lewis acid is trimethylsilyl trifluoromethanesulfonate (TMSOTf) or tin tetrachloride.
(2) And removing benzoyl from the intermediate II by using an alkaline reagent, and performing column chromatography to obtain an intermediate III.
The alkaline reagent may be methanolic ammonia solution, ammonia water, sodium methoxide or potassium carbonate.
(3) Suspending the intermediate III in acetone, adding 2, 2-dimethoxypropane, adding acid at room temperature or under heating for catalysis, and separating by column chromatography to obtain compound IV.
Commonly used acids are perchloric acid, p-toluenesulfonic acid or sulfuric acid.
(4) And dissolving the intermediate IV in a solution of acetonitrile and water, adding an oxidant, and after the reaction is finished, performing column chromatography separation to obtain a compound V.
Common oxidants are iodophenylenediacetic acid/2, 6-tetramethylpiperidine oxide, potassium permanganate or pyridine dichromate. The preferred oxidizing agent is iodophenylenediacetic acid/2, 6-tetramethylpiperidine oxide.
(5) And under the protection of nitrogen, dissolving the intermediate V in dry isopropanol, and adding thionyl chloride for esterification to obtain a compound VI.
(6) Dissolving the intermediate VI in anhydrous isopropanol, adding an alkaline reagent to remove the propylidene, simultaneously performing elimination reaction to form a double bond, and performing column chromatography separation to obtain an intermediate VII.
The basic agent is usually selected from sodium isopropoxide/isopropanol, potassium tert-butoxide/tert-butanol, potassium carbonate/DMF or triethylamine, preferably sodium isopropoxide/isopropanol.
(7) And dissolving the intermediate VII in a solvent, adding a reducing agent for reduction, adding a terminating agent for treatment after the reaction is finished, and performing column chromatography separation to obtain the target compound 1.
A commonly used reducing agent is lithium aluminum hydride or sodium borohydride.
The terminating agent is: one or two of Ethylene Diamine Tetraacetic Acid (EDTA), N, N, N ', N' -Tetramethylethylenediamine (TMEDA), triethylenediamine (TEDA), citric acid, acetic acid and tartaric acid. Tartaric acid or N, N' -Tetramethylethylenediamine (TMEDA) is preferred.
The invention has the advantages that:
1. the invention provides a method for synthesizing a novel 3' -deoxy-3 ',4' -didehydroribonucleoside analogue, which has the advantages of cheap and easily obtained raw materials, simple operation and no need of protecting basic groups.
2. The compound has potential antiviral activity and good development prospect, and opens up a new way for the synthesis of abundant unsaturated nucleosides and the discovery of new bioactive substances.
3. The target compound 3' -deoxy-3 ',4' -didehydroribonucleoside analogue provided by the invention is a high-activity endogenous metabolite of an immune factor Viperin, and can be further used for researching the termination activity of the analogue on a virus polymerase chain and the selectivity of the analogue on cell polymerase. The compound is used as an active ingredient for preparing antiviral drugs or a precursor for preparing the antiviral drugs.
Detailed Description
The present invention is described in detail with reference to the following examples, but is not limited to the following.
Example 1: synthesis of 1'- (5-fluorouracil) -3' -deoxy-3 ',4' -didehydroribonucleoside (compound 1a, B = 5-fluorouracil in formula 1)
After dehydrating the basic group 5-fluoro-uracil (2.01g, 15.46mmol) by azeotropic distillation with toluene, anhydrous toluene (150 mL) was added, the mixture was placed in an oil bath at 120 ℃ and hexamethyldisilazane (57mL, 273.5 mmol) and ammonium sulfate (200 mg) were added, the mixture was stirred under reflux until the system was clear, and the mixture was slightly cooled and concentrated under reduced pressure.
Then taking compound I (6 g,11.9 mmol) and toluene for azeotropic dehydration, dissolving and transferring the compound I into the system containing the basic group by acetonitrile (250 mL), placing the system in an ice bath for stirring for 10min, adding anhydrous tin tetrachloride (8.9 mL,77.3 mmol), reacting for 1h, completely reacting the raw materials, adding saturated NaHCO 3 The solution was quenched, transferred to a separatory funnel, extracted three times with ethyl acetate, the ethyl acetate layers were combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give compound II (6.57g, 96.3%).
Compound II (6.57g, 11.4 mmol) was added to a saturated methanolic ammonia solution (250 mL), and the mixture was stirred at room temperature for 12 hours, after completion of the reaction of the starting material, concentrated under reduced pressure, purified by silica gel column chromatography (dichloromethane: methanol volume ratio = 15), and concentrated to obtain compound III (2.81g, 93.7%).
After compound III (2.79g, 10.64mmol) was dissolved in acetone (75 mL), p-toluenesulfonic acid (500mg, 3.19mmol) and 2, 2-dimethoxypropane (4ml, 32mmol) were added to the solution in an ice bath, and after 10min of reaction, the solution was transferred to an oil bath at 60 ℃ and heated under reflux, and after completion of the reaction, the solution was cooled to room temperature, quenched with ammonia, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane: methanol volume ratio = 40), whereby compound IV (2.7g, 83.9%) was obtained.
Compound IV (2.63g, 8.7 mmol) was poured into a round-bottomed flask, and 2, 6-tetramethylpiperidine oxide (543mg, 3.48mmol) and iodobenzene diacetic acid (9.8g, 30.4 mmol) were weighed, water and acetonitrile (volume ratio 1, 100mL) were added, and the reaction was stirred at room temperature. After 10 hours of reaction, the starting material was completely reacted, separated and purified by silica gel column chromatography (dichloromethane: methanol volume ratio =5: 1), and concentrated to obtain compound V (2g, 72.7%).
Compound V (947mg, 3mmol) was taken and subjected to azeotropic dehydration with toluene, anhydrous isopropanol (20 mL) was added, thionyl chloride (1.41mL, 19.46mmol) was added under ice bath, and after stirring for a while under ice, the mixture was allowed to stand at room temperature for reaction overnight (under nitrogen). When the raw materials are completely reacted, saturated NaHCO is added 3 The solution was made neutral, extracted three times with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. Filtering, and concentrating under reduced pressure to obtain compound VI (837mg, 78%).
Taking a compound VI (837mg, 2.34mmol), carrying out azeotropic dehydration on toluene, adding anhydrous isopropanol and a sodium isopropoxide solution, stirring at room temperature for reaction, adding acetic acid until the reaction is neutral, concentrating, and carrying out silica gel column chromatography separation and purification (dichloromethane: methanol volume ratio = 30).
After taking compound VII (220mg, 0.732mmol), ethanol and water (10 mL, ethanol: water =7 3) were added, and sodium borohydride (83mg, 2.2mmol) was added under ice bath, the reaction was terminated by adding acetic acid, and the reaction was purified by silica gel column chromatography (dichloromethane: methanol volume ratio =20, 1), and concentrated under reduced pressure to obtain compound 1a (98mg, 55%). 1 H NMR(400MHz,DMSO-d 6 )δ12.03(s,1H),7.52(d,J＝6.7Hz,1H),6.08(t,J＝1.9Hz,1H),5.65(s,1H),5.32(s,1H),5.19-5.10(m,1H),4.81(s,1H),4.04(s,2H).
Example 2: synthesis of 1'- (5-chlorouracil) -3' -deoxy-3 ',4' -didehydroribonucleoside (compound 1B, B = 5-chlorouracil in formula 1)
In the same manner as in example 1, tartaric acid was added to terminate the reaction, and a white solid 1b was obtained by treatment. 1 H NMR(400MHz,DMSO-d 6 )δ12.01(s,1H),7.57(s,1H),6.07(d,J＝2.2Hz,1H),5.64(d,J＝6.0Hz,1H),5.35(s,1H),5.29–5.11(m,1H),4.84(s,1H),4.05(s,2H).
Example 3: synthesis of 1 '-uracil-3' -deoxy-3 ',4' -didehydroribonucleosides (compound 1c, B = uracil in formula 1)
The reaction was terminated by adding citric acid in the same manner as in example 2 to obtainTo a white solid 1c. 1 H NMR(400MHz,DMSO-d 6 )δ11.46(s,1H),7.26(d,J＝8.1Hz,1H),6.12(d,J＝2.2Hz,1H),5.65(d,J＝8.0Hz,2H),5.29(s,1H),5.19–5.07(m,1H),4.79(s,1H),4.03(s,2H).
Example 4: synthesis of 1'- (5-methylcytosine) -3' -deoxy-3 ',4' -didehydroribonucleosides (compound 1d, B = 5-methylcytosine in formula 1)
In the same manner as in example 1, acetic acid and triethylenediamine were added in this order to obtain a white solid 1d. 1 H NMR(400MHz,DMSO-d 6 )δ7.42(s,1H),7.02(s,1H),6.91(s,1H),6.22(s,1H),5.54(d,J＝6.1Hz,1H),5.27(t,J＝5.8Hz,1H),5.10(s,1H),4.79–4.59(m,1H),4.03(d,J＝5.6Hz,2H),1.82(s,3H).
Example 5: synthesis of 1'- (adenine) -3' -deoxy-3 ',4' -didehydroribonucleosides (compound 1e, B = adenine in formula 1)
In the same manner as in example 2, a white solid 1e was obtained. 1 H NMR(400MHz,D MSO-d 6 )δ8.17(d,J＝9.7Hz,2H),7.36(s,2H),6.27(s,1H),5.78(s,1H),5.33(s,1H),5.24(d,J＝3.4Hz,2H),4.02(s,2H).
Example 6: synthesis of 1'- (2-chloroadenine) -3' -deoxy-3 ',4' -didehydroribonucleoside (compound 1f, B = 2-chloroadenine in formula 1)
In the same manner as in example 4, acetic acid and N, N, N ', N' -tetramethylethylenediamine were added in this order to obtain a white solid 1f. 1 H NMR(400MHz,DMSO-d 6 )δ8.15(s,1H),7.90(s,2H),6.19(d,J＝2.3Hz,1H),5.77(d,J＝5.8Hz,1H),5.29(t,J＝5.8Hz,1H),5.27–5.23(m,1H),5.16(s,1H),4.04(d,J＝5.3Hz,2H).
Example 7: synthesis of 1'- (2-fluoroadenine) -3' -deoxy-3 ',4' -didehydroribonucleosides (Compound 1g, B = 2-fluoroadenine in formula 1)
In the same manner as in example 3, 1g of a white solid was obtained. 1 H NMR(400MHz,DMSO-d 6 )δ8.13(s,1H),7.92(s,2H),6.16(d,J＝2.4Hz,1H),5.75(d,J＝5.9Hz,1H),5.28(t,J＝5.9Hz,1H),5.24(s,1H),5.20–5.11(m,1H),4.03(d,J＝5.8Hz,2H).
Example 8: synthesis of 1 '-guanine-3' -deoxy-3 ',4' -didehydroribonucleosides (compound 1h, B = guanine in formula 1)
In the same manner as in example 1, a white solid was obtained for 1 hour. 1 H NMR(400MHz,D MSO-d 6 )δ10.69(s,1H),7.64(d,J＝3.1Hz,1H),6.56(s,2H),6.04(s,1H),5.71(dd,J＝5.9,3.1Hz,1H),5.36–5.15(m,2H),5.07(s,1H),4.01(s,2H).
Example 9: synthesis of 1 '-cytosine-3' -deoxy-3 ',4' -didehydroribonucleosides (compound 1i, B = cytosine in formula 1)
In the same manner as in example 6, a white solid 1i was obtained.
1 H NMR(400MHz,DMSO-d 6 )δ7.29(s,1H),7.22(d,J＝7.4Hz,2H),6.21(d,J＝2.2Hz,1H),5.73(d,J＝7.4Hz,1H),5.56(d,J＝6.1Hz,1H),5.27(t,J＝5.9Hz,1H),5.10(d,J＝2.4Hz,1H),4.71–4.57(m,1H),4.03(d,J＝5.8Hz,2H).
Example 10: synthesis of 1'- (5-fluoro-cytosine) -3' -deoxy-3 ',4' -didehydroribonucleosides (Compound 1j, B = 5-fluorocytosine in formula 1)
The reaction was quenched using N, N, N ', N' -tetramethylethylenediamine in the same manner as in example 9 to obtain 1j as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ7.87(s,1H),7.62(s,1H),7.41(d,J＝6.8Hz,1H),6.13(s,1H),5.55(d,J＝6.1Hz,1H),5.27(t,J＝5.8Hz,1H),5.11(d,J＝1.7Hz,1H),4.69(d,J＝6.0Hz,1H),4.04(d,J＝5.8Hz,2H).。
Claims (2)
- A process for the preparation of a 3' -deoxy-3 ',4' -didehydroribonucleoside analogue, characterised in that it is carried out by:
b represents one of the following bases:
- 2. a process for the preparation of a 3' -deoxy-3 ',4' -didehydroribonucleoside analogue according to claim 1, which is carried out by:(1) Reacting the compound I with a silanized base under the catalysis of Lewis acid through Vorburggen to obtain a nucleoside derivative intermediate II;the silanized basic group is obtained by treating the basic group with hexamethyldisilazane in the presence of a catalytic amount of ammonium sulfate; or treating the base directly with N, O-bis (trimethylsilyl) acetamide (BSA) in the reaction system;the Lewis acid uses trimethylsilyl trifluoromethanesulfonate (TMSOTf) or stannic chloride;(2) Removing benzoyl from the intermediate II by using an alkaline reagent, and performing column chromatography to obtain an intermediate III;the alkaline reagent is methanol ammonia solution, ammonia water, sodium methoxide or potassium carbonate;(3) Suspending the intermediate III in acetone, adding 2, 2-dimethoxypropane, adding acid at room temperature or under heating for catalysis, and separating by column chromatography to obtain compound IV after reaction;the acid is perchloric acid, p-toluenesulfonic acid or sulfuric acid;(4) Dissolving the intermediate IV in a solution of acetonitrile and water, adding an oxidant, and after the reaction is finished, performing column chromatography separation to obtain a compound V;the oxidant is iodobenzene diacetic acid/2, 6-tetramethyl piperidine oxide, potassium permanganate or pyridine dichromate;(5) Under the protection of nitrogen, dissolving the intermediate V in dry isopropanol, and adding thionyl chloride for esterification to obtain a compound VI;(6) Dissolving the intermediate VI in anhydrous isopropanol, adding an alkaline reagent to remove propylidene, simultaneously performing elimination reaction to form a double bond, and performing column chromatography separation to obtain an intermediate VII;the alkaline reagent is selected from sodium isopropoxide/isopropanol, potassium tert-butoxide/tert-butanol, potassium carbonate/DMF or triethylamine;(7) Dissolving the intermediate VII in a solvent, adding a reducing agent for reduction, adding a terminating agent for treatment after the reaction is finished, and performing column chromatography separation to obtain a target compound 1;the reducing agent is lithium aluminum hydride and/or sodium borohydride;the terminating agent is: one or two of Ethylene Diamine Tetraacetic Acid (EDTA), N, N, N ', N' -Tetramethylethylenediamine (TMEDA), triethylenediamine (TEDA), citric acid, acetic acid and tartaric acid.
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