CN113754665B - Preparation method of nucleoside compound - Google Patents
Preparation method of nucleoside compound Download PDFInfo
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- CN113754665B CN113754665B CN202110621245.6A CN202110621245A CN113754665B CN 113754665 B CN113754665 B CN 113754665B CN 202110621245 A CN202110621245 A CN 202110621245A CN 113754665 B CN113754665 B CN 113754665B
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention belongs to the technical field of organic synthesis, and discloses a method for synthesizing nucleoside compounds, which are compounds shown in formula I and pharmaceutically acceptable salts thereofA method is provided.
Wherein R is 1 is-C (═ O) CHR 2 R 3 ；R 2 Is selected from C 1 ‑C 10 Alkyl, aralkyl; r 3 Selected from H, amino, C 1 ‑C 10 An alkyl group; or R 2 R 3 Form C 3 ‑C 10 A carbocyclic group; the synthesis steps are as follows: 1) protecting hydroxyl in a nucleoside drug sugar structure part; 2) condensing with organic acid and 5' -hydroxyl to obtain ester; 3) the ketal protection is removed under acidic conditions. The method has the advantages of short reaction route, small environmental pollution and simple process operation, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of nucleoside compounds.
Background
Reddesivir (Remdesivir) belongs to nucleoside analogs, is an RNA-dependent RNA polymerase (RdRp) inhibitor, can be used for resisting virus by inhibiting viral nucleic acid synthesis, and is the only drug for SARS-CoV-2 infection on the market at present. While Reidesciclovir has been FDA approved for use in the treatment of a novel coronavirus infection (SARS-CoV-2, its efficacy is questionable because Reidesciclovir has a long molecular synthesis step, is expensive, and requires forced intravenous injection, its application and accessibility are limited.
Therefore, the rapid development of an effective anti-new coronavirus drug or vaccine is an important task in the current drug development.
The research team found that the metabolite GS-441524 of Reideciclovir effectively inhibits SARS-CoV-2 infection in a mouse model. Compared with the Rudexilexir, the GS-441524 has the advantages of simple structure, short synthesis steps and low cost, and is suitable for rapid mass production as an epidemic situation emergency medicine. Clinical pharmacokinetic studies of Reidesciclovir indicate that the metabolite GS-441524 has a half-life of about 27h in humans and has good pharmacokinetic properties. The safety and efficacy of GS-441524 against COVID-19 and other coronavirus infections highlight the necessity to develop clinical trials for the treatment of COVID-19. In order to overcome the problems of high polarity, poor membrane permeability and the like of GS-441524, the subject group develops an esterified derivative of a candidate drug GS-441524 as an oral anti-neocoronin drug, which has high oral bioavailability, and the research is successfully disclosed in Chinese patent application CN2020116139433, which is named as a nucleoside compound for treating coronavirus infection and a prodrug thereof, so the research has important significance on the synthesis process research of the esterified derivative of GS-441524 and provides crude drugs for drug substitution tests and the like.
Liu et al (Tetrahedron,71(9), 1409-1412; 2015) in the preparation of 5 ' -amino acid ester prodrug, firstly, nucleoside drugs and triaryl methylating agent are selectively subjected to 5 ' -primary alcohol ether formation protection, then, the nucleoside drugs and allyloxycarbonylating agent are used for protecting active functional groups such as residual hydroxyl and amino, then, triaryl methyl protecting groups are selectively removed under acidic conditions, then, the nucleoside drugs and allyloxycarbonylating agent are condensed, finally, palladium acetate is used for removing allyloxycarbonyl protecting groups, and regioselective esterification at 5 ' -position is realized. However, the route is long, the number of deprotection steps is large, and the atom economy is not high. And some reactions such as the allyloxycarbonyl removal process need low temperature condition of 50 ℃ below zero, the equipment requirement is high, and the industrial production is not facilitated.
Regional selective esterification method for nucleoside compound 5' -position reported by Scheme 1 Liu et al
He Zhou Zhong Gui et al (Molecular pharmaceuticals, 2009,6(1), 315-325) selectively protects cytosine arabinoside 4-amino by benzyl chloroformate (Cbz-Cl), then directly condenses with amino acid, and finally Pd catalyzed hydrogenation deprotection obtains 5' -position esterification product. However, the hydroxyl on ribose is not protected by the route, so that the reaction is complex, and a 2 '-position substitution product and a 3' -position substitution product are generated, so that the yield of the target product is low, and the method is not suitable for industrial production.
The synthesis routes combining the reported representative nucleoside compounds with 5' -hydroxyl esterification all have certain disadvantages. Therefore, it is necessary to design a route suitable for industrial production.
Disclosure of Invention
The invention aims to provide a reaction route of nucleoside compounds, and the process has the advantages of short technical route, little environmental pollution and simple process operation.
Therefore, the technical scheme provided by the invention is as follows:
a method for synthesizing nucleoside compounds (formula I),
wherein R is 1 is-C (═ O) CHR 2 R 3 ；R 2 Is selected from C 1 -C 10 Alkyl, aralkyl; r 3 Selected from H, amino, C 1 -C 10 An alkyl group; or R 2 R 3 Form C 3 -C 10 A carbocyclic group;
the method comprises the following steps:
1) selectively protecting hydroxyl of a compound (GS-441524) in the presence of 2, 2-dimethoxypropane and a dehydrating agent to obtain a compound shown as a formula II;
2) condensing the compound shown in the formula II and organic carboxylic acid selectively with 5' -hydroxyl to synthesize ester (formula III);
3) removing ketal protection from the compound shown in the formula III to obtain the nucleoside compound (formula I).
In some embodiments, the dehydrating agent of step 1 is p-toluenesulfonic acid, methanesulfonic acid, or concentrated sulfuric acid. In some embodiments, the dehydrating agent is concentrated sulfuric acid and the selectively protecting the hydroxyl group is performed at about 35 degrees celsius to reflux, preferably about 40 degrees celsius to about 50 degrees celsius, more preferably 45 degrees celsius. In some embodiments, the dehydrating agent of step 1 is p-toluenesulfonic acid, methanesulfonic acid, and the selectively protecting hydroxyl groups is performed in refluxing toluene.
In some embodiments, the post-treatment of step 1 is first dissolved with a small amount of ethyl acetate, and the solution is then poured into a poor solvent, such as petroleum ether, n-hexane, n-heptane, etc., and stirred.
In some embodiments, the organic acid of step 2 is R is HO-C (═ O) CHR 2 R 3 ；R 2 Is selected from C 1 -C 10 Alkyl, aralkyl; r is 3 Selected from H, amino, C 1 -C 10 An alkyl group; or R 2 R 3 Form C 3 -C 10 A carbocyclic group.
In some embodiments, the condensation reaction of step 2 is carried out in the presence of DCC/DMAP or EDCI/HOBt, preferably a DCC/DMAP system.
In some embodiments, the condensation reaction of step 2 is carried out at a temperature of 5-10 ℃ and DCC is added dropwise to the reaction system.
In some embodiments, the R is 2 Is selected from C 1 -C 8 Alkyl, arylmethyl; r is 3 Selected from H, amino, C 1 -C 6 An alkyl group; or R 2 R 3 Form C 3 -C 7 A carbocyclic group.
In some embodiments, the R is 2 Is selected from C 1 -C 8 Alkyl radical, R 3 Is selected from H。
In some embodiments, the C 1 -C 8 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or the like.
In some embodiments, the method of claim 1, the acid used for deprotection in step 3 comprises concentrated hydrochloric acid, 6N hydrochloric acid, 3N hydrochloric acid, formic acid, 98% formic acid, 80% formic acid, acetic acid, 90% acetic acid, TFA, 95% TFA, PPTS, methanesulfonic acid, p-toluenesulfonic acid monohydrate, and the like, preferably 6N hydrochloric acid.
In some embodiments, the method of claim 1, step 3 reacting at a temperature of-10 degrees celsius to room temperature.
In some embodiments, the nucleoside compound (formula I) is the following compound:
for ease of illustration, the structural numbering of intermediates and products is as follows, in the case of the synthesis of isobutyrate prodrugs:
in some examples, after 3-8h of reaction in step 1), the pH of the work-up is adjusted to 7-8 with sodium bicarbonate, acetone is recovered by distillation under reduced pressure, ethyl acetate is added to the residue, the residue is washed with ethyl acetate water, dried and evaporated to dryness by suction filtration.
In some embodiments, in the above method for synthesizing a nucleoside compound, after reacting for 3 to 8 hours in step 1), the method further comprises the steps of evaporating the residue after removing the ethyl acetate, slowly adding the residue into a poor solvent of the product, rapidly stirring, slowly precipitating a solid, performing suction filtration, leaching a filter cake with the poor solvent, and drying to obtain a white solid intermediate II.
In some embodiments, in the synthesis method, after the reaction raw materials are completely consumed in step 2) HPLC monitoring, acid is added under an ice bath to convert DCC which is not completely reacted into DCU, the DCC is directly filtered after stirring for 10 minutes, the filtrate is layered, an organic layer is separated, the organic layer is respectively washed by acid, alkali, water and saturated sodium chloride, anhydrous sodium sulfate is dried, and the product obtained by filtering and evaporating is directly used for the next reaction; the acid is one of 20% citric acid, ammonium chloride and 1N hydrochloric acid, and the alkali is one or more of saturated sodium bicarbonate solution, saturated sodium carbonate solution and ammonia water. Further detecting the content of each substance in the reaction process to determine the specific reaction time, wherein the result is as follows:
as is clear from the results in the table, after 3.5 hours of the reaction, the starting material was substantially consumed, and a small amount of IMP01, which is a by-product of diacylation, began to be produced. Therefore, the reaction time is preferably 3.5 to 4 hours.
In some embodiments, the step 3) of removing ketal protection is performed in the presence of an acid selected from concentrated hydrochloric acid, 6N hydrochloric acid, 3N hydrochloric acid, formic acid, 98% formic acid, 80% formic acid, acetic acid, 90% acetic acid, TFA, 95% TFA, PPTS, methanesulfonic acid, p-toluenesulfonic acid monohydrate, preferably 6N hydrochloric acid, taking into consideration material cost and post-treatment factors, the reaction using a solvent selected from the group consisting of a 1-6 carbon alcohol solvent selected from methanol, ethanol, N-propanol, isopropanol, N-butanol, isobutanol, t-butanol, or various combinations thereof; the ethereal solvent is selected from diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 2-dimethoxyethane, 1, 4-dioxane or different combinations of these solvents, preferably tetrahydrofuran. The reaction temperature is-20 to 25 ℃, and 0 ℃ is preferred.
In some embodiments, the synthesis method comprises, after the reaction is monitored by HPLC in step 3), adjusting pH to 7-8 with sodium bicarbonate, adding ethyl acetate for extraction, washing the ethyl acetate layer with water and saturated saline, drying with magnesium sulfate, performing suction filtration and evaporation to recover the solvent to obtain a crude product. Further detecting the content of each substance in the reaction process to determine the specific reaction time, wherein the result is as follows:
as can be seen from the table, the optimum reaction time for 6N HCl deprotection was about 9 h.
In some embodiments, the synthesis method, wherein step 3) adopts column chromatography, and uses dichloromethane and methanol as eluents, to obtain a relatively pure compound of formula (I), which has an HPLC purity of 90% or more, preferably 95% or more, and more preferably 97% or more.
The invention provides a reaction route of nucleoside compounds, and the process has the advantages of short technical route, small environmental pollution and simple process operation.
In order to realize the purpose of the invention, the invention firstly considers that the compound GS-441524 is used as a starting material, only 3 steps of reaction are needed to obtain a final product through the technical scheme of the invention,
Through continuous attempts, DCC/DMAP as a condensing agent is finally found to be capable of selectively condensing the hydroxyl at the 5' -position to form ester, and when the condensation is carried out by EDCI/HOBt or anhydride/triethylamine system, a considerable proportion of diacylation byproducts are easily generated.
In summary, compared with the prior art, the technical scheme provided by the invention has the following advantages:
1) the technical scheme provided by the invention can obtain the final product only by 3 steps of reaction, has short reaction route, does not use fussy protecting groups, and has high atom economy. In the condensation reaction process, the generation of the double acylation byproducts is controlled by a method of slowly dripping a condensing agent at low temperature.
2) The technical scheme provided by the invention adopts a route without using a reagent or a solvent which causes serious pollution, and belongs to an environment-friendly process.
3) The technical scheme provided by the invention mainly adopts a route between 0 and 50 ℃, and has low equipment cost and less energy consumption.
Description of terms:
"ambient temperature" in the present invention refers to ambient temperature, and the temperature is from about 10 ℃ to about 40 ℃. In some embodiments, "room temperature" refers to a temperature of from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" refers to a temperature of from about 25 ℃ to about 30 ℃; in still other embodiments, "room temperature" refers to 10 ℃,15 ℃,20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, etc.
An "alkyl" group is a hydrocarbon containing a primary, secondary, tertiary, or ring carbon atom. For example, the alkyl group can have 1 to 10 carbon atoms (i.e., C) 1 -C 10 Alkyl), 1 to 8 carbon atoms (i.e., C) 1 -C 8 Alkyl) or 1 to 6 carbon atoms (i.e., C) 1 -C 6 Alkyl groups). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH) 3 ) Ethyl (Et-CH) 2 CH 3 ) 1-propyl (i-Pr, i-propyl, -CH) 2 CH 2 CH 3 ) 2-propyl (i-Pr, i-propyl, -CH (CH) 3 ) 2 ) 1-butyl (n-Bu, n-butyl, -CH) 2 CH 2 CH 2 CH 3 ) 2-methyl-1-propyl (i-Bu, i-butyl, -CH) 2 CH(CH 3 ) 2 ) 2-butyl (s-Bu, s-butyl, -CH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH) 3 ) 3 ) 1-pentyl (n-pentyl, -CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) 1-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH)) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 And octyl (- (CH) 2 ) 7 CH 3 )。
Aryl "means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, the aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, groups derived from benzene (e.g., phenyl), substituted benzenes, naphthalenes, anthracenes, biphenyls, and the like.
"arylalkyl" refers to a radical in which the carbon atom to which it is bonded (usually terminally)Or sp 3 Carbon atom) is replaced with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenyleth-1-yl, naphthylmethyl, 2-naphthyleth-1-yl, naphthobenzyl, 2-naphthophenyleth-1-yl, and the like. Arylalkyl groups can include 7 to 20 carbon atoms, for example, the alkyl portion is I to 6 carbon atoms and the aryl portion is 6 to 14 carbon atoms.
Detailed Description
The claims of the present invention are described in further detail below with reference to specific embodiments.
EXAMPLE 1 preparation of Compound represented by formula (Ia)
1) In a 500mL reactor, a stirrer, a thermometer, a constant pressure dropping funnel were installed, GS-441524(10g,0.03mol) was added, acetone dried over magnesium sulfate (300mL) was added, 2-dimethoxypropane (17g,0.16mol) was added, concentrated sulfuric acid (2.4mL,0.04mol) was added dropwise to the system at room temperature, after 5 min, the dropwise addition was completed, the solid began to dissolve, the temperature was raised to 45 ℃ to continue the reaction for 4h, and the reaction was monitored by HPLC for completion (OD-3 column, mobile phase: n-hexane/isopropanol 80:20, flow rate: 0.8mL/min, sample introduction amount of 1. mu.L), stop the reaction, add NaHCO into the reaction solution after cooling in ice bath 3 The solid (10g), water (30mL), pH7-8 with further sodium bicarbonate, solvent removed by distillation under reduced pressure, the residue diluted with ethyl acetate (300mL), the ethyl acetate layer washed with water (80mL), saturated brine (80mL) respectively, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation of the filtrate to residual solvent of about 100mL, slow pouring of the residue into ice-bath cooled petroleum ether, vigorous stirring, washing out a large amount of white solid, suction filtration to obtain 10.5g of white solid, yield 91%.
2) In a 500mL reactor equipped with a stirrer, thermometer, and dropping funnel at constant pressure, the ketal-protected product of the previous step (10g,0.03mol), isobutyric acid (3.2g/0.036mol), DMAP (1.8g, 0.015mol), and purified DCM (150mL) were charged, and the reaction flask was charged toAfter stirring in a cold well at 5-10 deg.C, a solution of DCC (8g,0.04mol) in DCM (50mL) was added to the addition funnel. Slowly adding DCC solution dropwise, controlling the temperature to be about 10 ℃, after 1h, finishing the dropwise addition, continuously keeping the temperature for 5h, detecting the reaction by HPLC to be complete and basically not generating double acylation products, adding 20% citric acid solution (50mL) into the reaction system at 5-10 ℃, stirring for 10min, adding DCM (100mL) for dilution, standing and layering. The organic layer was separated, washed with 20% citric acid (100mL), saturated sodium carbonate (80mL), water (80mL), saturated brine (80mL), and dried over anhydrous sodium sulfate. The mixture was filtered and evaporated to dryness to give 13.1g of a white solid in a yield of 109% (containing some of the byproduct dicyclohexylurea DCU), the product was dissolved in 100mL of DCM, cooled in a-20 ℃ freezer, filtered to remove insoluble material, and the filtrate was evaporated to dryness to give 10.8g of an oil in a yield of 90%. 1 H NMR (400MHz,CDCl 3 )δ(ppm):7.99(s,1H),6.99(d,J＝4.6Hz,1H),6.62(d,J＝4.6Hz, 1H),5.72(br,2H),5.49(d,J＝6.8Hz,1H),4.93-4.90(dd,J＝6.8Hz,4.3Hz,1H), 4.61-4.58(q,J＝4.4Hz,1H),4.44-4.26(m,2H),2.61-2.50(m,1H),1.77(s,3H),1.42 (s,3H),1.17-1.14(q,J＝3.8Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ(ppm):176.7, 155.2,147.3,123.5,117.2,116.7,115.6,112.6,100.0,83.8,83.0,82.0,81.4,63.1, 33.8,26.4,25.6,18.9.
3) In a 250mL reactor, a stirrer, a thermometer and a constant pressure dropping funnel are installed, the condensation product (10.8g,0.027mol) in the step 2 is added, THF (90mL) is used for dissolution, a reaction bottle is placed in a cold well at 0 ℃ for stirring, 6N HCl (90mL,0.54mol) is slowly dropped, the reaction is kept for 7 hours after the addition is finished, HPLC monitors that the raw materials are completely consumed, the reaction is stopped, NaHCO is used for stopping the reaction 3 The pH of the solid was adjusted to 7-8, THF was removed by distillation under reduced pressure, a solid precipitated, the ethyl acetate layers were extracted with ethyl acetate (150 mL. times.2), and the ethyl acetate layers were combined, washed with water (100mL), washed with saturated brine (100mL), and dried over magnesium sulfate. Suction filtration and evaporation to dryness to obtain 8g of crude product, column chromatography (1.2 times of silica gel mixed sample, 5 times of silica gel loaded column, eluent: dichloromethane/methanol 40:1) to obtain 6.5g of pure product, recovering GS-4415241 g, yield 66.3%, purity: 98.82% (chromatographic conditions: column: OD-3, mobile phase: n-hexane: isopropanol: 80:20, flow rate: 0.8mL/min, sample size: 1. mu.L). 1 H NMR(600MHz, DMSO-d 6 )δ(ppm):7.93(s,1H),7.89(br,2H),6.92(d,J＝4.3Hz,1H),6.81(d,J＝4.3 Hz,1H),6.32(d,J＝5.9Hz,1H),5.38(d,J＝5.7Hz,1H),4.7(t,J＝5.2Hz,1H), 4.32-4.30(m,1H),4.25-4.22(m,1H),4.19-4.16(m,1H),3.98-3.95(q,J＝5.6 Hz,1H), 2.55-2.50(m,1H),1.06-1.05(dd,J＝6.8Hz,1.8Hz,6H). 13 C NMR(150MHz, DMSO-d 6 )δ(ppm):176.4,156.1,148.4,124.0,117.4,117.0,110.7,101.3,81.7,79.5, 74.5,70.6,63.4,33.6,19.2,19.1.
EXAMPLE 2 preparation of Compound of formula (Ia)
1) In a 1000mL reactor, a stirrer, a thermometer and a constant pressure dropping funnel are installed, GS-441524(30g,0.10mol) is added, toluene (600mL) is added, 2-dimethoxypropane (51g, 0.48mol) is added, p-toluenesulfonic acid (0.13mol) is added into a system at room temperature, after 10min of dropwise addition, the temperature is raised to reflux for continuous reaction for 2h, HPLC (high performance liquid chromatography) monitors that the reaction is complete, the reaction is stopped, NaHCO is added into a reaction solution after ice bath cooling 3 Solid (30g), water (15mL), pH of the reaction mixture was further adjusted to 7-8 with sodium hydrogencarbonate, the solvent was distilled off under reduced pressure, ethyl acetate (500mL) and water (100mL) were added to the residue, the mixture was stirred to separate an organic layer, and the organic layer was washed with water (100mL) and saturated brine (100mL) and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation of the filtrate to residual solvent of about 100mL, slow pouring of the residue into ice-bath cooled petroleum ether, vigorous stirring, washing out a large amount of white solid, suction filtration to obtain 10.5g of white solid, yield 91%.
2) In a 1000mL reactor, a stirrer, a thermometer, and a constant pressure dropping funnel were installed, the ketal-protected product of the previous step (30g,0.09mol), isobutyric acid (9.6g/0.108mol), DMAP (5.4g, 0.045mol), and DCM 300mL were added, the reaction flask was stirred in a cold well at 5-10 ℃ and a solution of DCC (24g,0.12mol) in DCM (150mL) was added to the dropping funnel. Slowly dripping DCC solution, controlling the temperature to be about 10 ℃, after 1h, finishing dripping, continuously keeping the temperature for reaction for 5h, detecting the reaction completion by HPLC, adding 20% citric acid solution (50mL) into the reaction system at 5-10 ℃, stirring for 10min, removing DCU by suction filtration, and standing and layering the filtrate. The organic layer was separated, washed with 20% citric acid (100 mL. times.2), saturated sodium carbonate solution (100 mL. times.1), water (100 mL. times.1), saturated brine (100 mL. times.1), and dried over anhydrous sodium sulfate. The reaction mixture was filtered and evaporated to dryness to give 36g of a white solid in 99.7% yield, which was used in the next reaction without further purification.
3) In a 1000mL reactor, a stirrer, a thermometer and a constant pressure dropping funnel are installed, the condensation product (36g,0.09mol) in the step 2 is added, THF (300mL) is used for dissolving, a reaction bottle is placed in a cold well at 0 ℃ for stirring, 6N HCl (300mL,1.8mol) is slowly added dropwise, the reaction is kept for 7 hours after the addition is finished, HPLC monitors the complete consumption of raw materials, the reaction is stopped, NaHCO is used for stopping the reaction 3 The pH of the solid was adjusted to 7-8, THF was removed by distillation under the reduced pressure, the ethyl acetate layer was extracted with ethyl acetate (300 mL. times.2), and the ethyl acetate layers were combined, washed with water (150mL), washed with saturated brine (150mL), and dried over magnesium sulfate. Vacuum-filtering and evaporating to obtain 30g of crude product, performing column chromatography (1.2 times of silica gel for sample mixing, 5 times of silica gel for column packing, eluent: dichloromethane/methanol 40:1) to obtain 20g of pure product, recovering GS-4415240.8 g, and combining the yield with the step 2 to obtain 61.5% of purity: 100 percent.
Example 3 preparation of Compound of formula (Ia)
1) In a 1000mL reactor, a stirrer, a thermometer and a constant pressure dropping funnel are installed, GS-441524(50g,0.17mol) is added, acetone dried with magnesium sulfate (800mL) is added, 2-dimethoxypropane (86g,0.82mol) is added, concentrated sulfuric acid (12mL,0.22mol) is added dropwise to the system at room temperature, dropwise addition is carried out at 45 ℃, dropwise addition is completed after 10min, the reaction is continued for 4h, HPLC (high performance liquid chromatography) monitors the reaction to be complete, the reaction is stopped, NaHCO is added to the reaction liquid after ice bath cooling 3 Solid (50g), water (50mL), adjusting pH to 7-8 with sodium bicarbonate, distilling off the solvent under reduced pressure, adding ethyl acetate (1000mL), water (150mL) to the residue, stirring to separate the organic layer, and separating the organic layerWashed with water (200mL) and saturated brine (200mL) and dried over anhydrous sodium sulfate. Suction filtration is carried out, the filtrate is decompressed and distilled until about 200mL of solvent is remained, the residue is slowly poured into petroleum ether cooled by an ice bath and is stirred vigorously, a large amount of white solid is washed out, and the yield is 93 g of white solid obtained by suction filtration.
2) In a 1000mL reactor, a stirrer, a thermometer, and a constant pressure dropping funnel were installed, the ketal-protected product of the previous step (40g,0.12mol), isobutyric acid (12.8g,0.14mol), DMAP (7.2g, 0.06mol), and DCM 600mL were added, the reaction flask was placed in a 5-10 ℃ cold well and stirred, and a solution of DCC (32g,0.16mol) in DCM (250mL) was added to the dropping funnel. Slowly dripping DCC solution, controlling the temperature to be about 10 ℃, finishing dripping after 1.5h, continuously carrying out heat preservation reaction for 5h, detecting the reaction completion by HPLC, adding 20% citric acid solution (100mL) into the reaction system at 5-10 ℃, stirring, carrying out suction filtration to remove DCU, and standing and layering the filtrate. The organic layer was separated, washed with 20% citric acid (100 mL. times.2), saturated sodium carbonate solution (200 mL. times.1), water (100 mL. times.1), saturated brine (100 mL. times.1), and dried over anhydrous sodium sulfate. The reaction mixture was evaporated to dryness by suction filtration to give 50g of a white solid which was used in the next reaction without further purification.
3) In a 1000mL reactor, a stirrer, a thermometer and a constant pressure dropping funnel are installed, the condensation product (36g,0.09mol) in the step 2 is added, THF (300mL) is used for dissolving, a reaction bottle is placed in a cold well at 0 ℃ for stirring, 6N HCl (300mL,1.8mol) is slowly added dropwise, the reaction is kept for 7 hours after the addition is finished, HPLC monitors the complete consumption of raw materials, the reaction is stopped, NaHCO is used for stopping the reaction 3 The solid was adjusted to pH7 to 8, THF was removed by distillation under reduced pressure, the mixture was extracted with ethyl acetate (300 mL. times.2), the ethyl acetate layers were combined, washed with water (150mL), washed with saturated brine (150mL), and dried over magnesium sulfate. Vacuum-filtering and evaporating to obtain 40g of crude product, performing column chromatography (1.2 times of silica gel mixed sample, 5 times of silica gel loaded column, eluent: dichloromethane/methanol 40:1) to obtain 26g of pure product, recovering GS-4415242.2 g, and combining the yield with the step 2 to obtain the product with the purity of 60 percent: 99.2 percent.
EXAMPLE 4 preparation of methyl ((2R,3S,4R,5R) -5- (4-Aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) acetate
The isobutyric acid in step 2 of example 1 was replaced with acetic acid in a crude yield of 98%. Compound Ib was prepared by following the remaining steps in example 1 to give 5.6g of a white solid with a purity of 98.7% and a total yield in three steps of 56%. 1 H NMR(600MHz,CD 3 OD)δ(ppm):7.86(s,1H),6.89(t,J＝5.0Hz, 2H),4.87(s,1H),4.43-4.41(dd,J＝12Hz,2.8Hz,1H),4.37-4.34(m,1H),4.30-4.27 (m,1H),4.13(t,J＝5.7Hz,1H),2.03(s,3H). 13 C NMR(150MHz,CD 3 OD)δ(ppm): 171.0,155.8,146.9,124.2,116.6,116.2,110.7,101.1,81.9,80.2,74.1,70.7,63.1, 19.3.
EXAMPLE 5 preparation of methyl ((2R,3S,4R,5R) -5- (4-Aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) propionate
Propionic acid was substituted for isobutyric acid in step 2 of example 1, resulting in a crude yield of 106%. Compound Ic was prepared by following the remaining steps of the reaction in example 1 to give 5.0g of a white solid with 98% purity and 48% three-step overall yield. 1 H NMR(600MHz,CD 3 OD)δ(ppm):7.86(s,1H),6.90-6.88(q,J＝4.5Hz, 2H),4.87-4.86(m,1H),4.46-4.43(dd,J＝12Hz,2.8Hz,1H),4.37-4.36(m,1H), 4.31-4.28(m,1H),4.15(t,J＝5.8Hz,1H),2.38-2.28(m,2H),1.08(t,J＝7.5Hz, 3H). 13 C NMR(150MHz,CD 3 OD)δ(ppm):174.3,155.8,146.9,124.2,116.5,116.2, 110.7,101.1,82.0,80.1,74.2,70.7,62.9,26.7,7.9.
EXAMPLE 6 preparation of methyl ((2R,3S,4R,5R) -5- (4-Aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) butanoate
Isobutyric acid in step 2 of example 1 was replaced with n-butyric acid and the crude yield was 106%. Compound Id was prepared by following the remaining steps of example 1 to give 6.0g of a white solid with 97% purity and 56% three-step overall yield. 1 H NMR(600MHz,CD 3 OD)δ(ppm):7.86(s,1H),6.90-6.88(q,J＝4.5 Hz,2H),4.87-4.86(m,1H),4.44-4.42(dd,J＝12Hz,2.8Hz,1H),4.37-4.35(m,1H), 4.31-4.28(m,1H),4.14(t,J＝5.8Hz,1H),2.32-2.23(m,2H),1.62-1.56(m,2H),0.91 (t,J＝7.4Hz,3H). 13 C NMR(150MHz,CD 3 OD)δ(ppm):174.3,155.9,146.9,124.3, 116.5,116.2,110.7,101.1,82.0,80.1,74.2,70.7,62.8,35.4,17.9,12.5.
EXAMPLE 7 preparation of methyl ((2R,3S,4R,5R) -5- (4-Aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) nonanoate
Substituting isobutyric acid in step 2 of example 1 with nonanoic acid gave a crude yield of 101%. Compound Ie was prepared by reaction of the remaining steps in example 1 to give 5.2g of a white solid with 98% purity and 40.3% overall yield over three steps. 1 H NMR(600MHz,CD 3 OD)δ(ppm):7.86(s,1H),6.90-6.88(q,J＝4.5 Hz,2H),4.87-4.86(m,1H),4.43-4.41(dd,J＝12Hz,2.8Hz,1H),4.37-4.35(m,1H), 4.32-4.29(m,1H),4.14(t,J＝5.8Hz,1H),2.38-2.23(m,2H),1.56-1.53(m,2H), 1.29-1.27(m,10H),0.87(t,J＝7.0Hz,3H). 13 C NMR(150MHz,CD 3 OD)δ(ppm): 173.7,155.9,146.9,124.3,116.5,116.2,110.7,101.1,82.0,74.2,70.7,62.8,33.5, 31.5,28.8,28.7,24.6,22.3.
EXAMPLE 8 preparation of methyl ((2R,3S,4R,5R) -5- (4-Aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-2-ethylbutanoate
The isobutyric acid in step 2 of example 1 was replaced with 2-ethylbutyric acid, and the crude yield was 102%. Compound If was prepared by reacting the remaining steps in example 1 to give 6.0g of a white solid with a purity of 98.3% and a total yield in three steps of 51.3%. 1 H NMR(600MHz,CD 3 OD)δ(ppm):7.86(s,1H),6.89(s,2H), 4.87-4.86(m,1H),4.39-4.43(dd,J＝12Hz,2.8Hz,1H),4.37-4.35(m,1H),4.14(t, J＝5.8Hz,1H),2.38-2.22(m,1H),1.60-1.45(m,4H),0.86-0.82(m,6H). 13 C NMR (150MHz,CD 3 OD)δ(ppm):176.1,155.9,146.9,124.3,116.6,116.2,110.7,101.1, 81.9,79.9,74.2,70.7,62.8,48.9,24.7,24.6.10.7,10.6.
EXAMPLE 9 preparation of methyl ((2R,3S,4R,5R) -5- (4-Aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-cyclopropanecarboxylate
The isobutyric acid in step 2 of example 1 was replaced with cyclopropanecarboxylic acid, resulting in a crude yield of 107%. Compound Ig was prepared by following the remaining steps of example 1 to yield 6.7g of a white solid with 97% purity and 62% overall yield over three steps. 1 H NMR(600MHz,CD 3 OD)δ(ppm):7.86(s,1H),6.89(t,J＝4.5Hz, 2H),4.87-4.86(m,1H),4.46-4.44(dd,J＝12Hz,2.8Hz,1H),4.36-4.34(m,1H), 4.29-4.26(m,1H),4.15(t,J＝5.8Hz,1H),1.64-1.60(m,1H),0.92-0.87(m,4H). 13 C NMR(150MHz,CD 3 OD)δ(ppm):174.9,155.9,146.9,124.2,116.6,116.2,110.7, 101.1,80.2,80.1,74.2,70.6,63.0,12.1,7.5,7.4.
EXAMPLE 10 preparation of ((2R,3S,4R,5R) -5- (4-Aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-L-valine ester
The isobutyric acid in step 2 of example 1 was replaced with Boc protected L-valine with a column chromatography yield of 86%.Step 3, the charging ratio of 6N hydrochloric acid was changed to 50 times, and the compound Ih was prepared according to the preparation method in example 1 in the remaining steps to obtain a near-white solid 2.6g, purity 97%, and total yield in three steps was 22.2%. 1 H NMR (400MHz,DMSO-d 6 )δ(ppm):8.04(br,1H),7.92(s,1H),7.88(br,1H),6.98(d, J＝4.6Hz,1H),6.85(d,J＝4.5Hz,1H),6.38(br,1H),4.73(d,J＝4.8Hz,1H), 4.34-4.25(m,3H),3.97(t,J＝5.2Hz,1H),3.28(d,J＝5.1Hz,1H),1.89-1.82(m,1H), 0.85-0.80(m,6H).
EXAMPLE 11((2R,3S,4R,5R) -5- (4-Aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-D-valine ester preparation
Compound Ii was prepared in a three-step reaction using Boc protected D-valine instead of isobutyric acid in example 10 to give a nearly white solid 2.5g, 98% pure, 21.4% three-step overall yield. 1 H NMR(400 MHz,DMSO-d 6 )δ(ppm):7.92(s,1H),7.88(br,2H),6.92(d,J＝4.2Hz,1H),6.83(d, J＝4.2Hz,1H),6.34(d,J＝5.6Hz,1H),5.39(s,1H),4.71(s,1H),4.33-4.17(m,3H), 3.97(s,1H),3.10(d,J＝5.0Hz,1H),1.80-1.74(m,1H),0.84-0.74(m,6H). 13 C NMR (100MHz,DMSO-d 6 )δ(ppm):175.0,155.5,147.8,123.4,116.8,116.5,110.2,100.7, 81.1,78.9,73.9,70.2,63.1,59.3,31.6,19.1,17.0.
Comparative example 1
Isobutyric acid (0.29g,3.3mmol), EDCI (0.86g,4.5 mmol), HOBt (0.6g,4.5mmol), triethylamine (1.5g,15mmol) and DCM 20mL were added to a 100mL three-necked flask, and the reaction flask was stirred in a cold well at 5-10 ℃ and after stirring for 20 minutes, a solution of the ketal protected product of the previous step (1g,3mmol) in DCM (10mL) was added dropwise to the reaction system. After 16h of reaction, HPLC showed the remaining starting material and a 40% content of diacylated product, the reaction was diluted with 50mL of DCM, and the organic solution was washed with 1N hydrochloric acid, saturated sodium carbonate, saturated brine, and dried over anhydrous sodium sulfate. Suction filtering and evaporating to dryness, and performing column chromatography to obtain 0.6g of condensation product in the step 2, wherein the yield is 50%.
Comparative example 2
Adding the ketal protected product (0.5g,1.5mmol), triethylamine (0.76g,7.5 mmol), DMAP (0.01g,0.08mmol) into a 100mL three-necked bottle, dissolving with 10mL dichloromethane, placing the reaction system in an ice bath for cooling, dropwise adding isobutyric anhydride (0.24g,1.6mmol), slowly raising the temperature to room temperature after dropwise adding, continuing to react for 7h, monitoring by HPLC that most of the conversion is complete, and a large amount of double acylation byproducts are generated without selectivity, separating and purifying by column chromatography to obtain 0.26g of the 5' -position esterification product, wherein the yield is 43%.
Comparative example 3
General procedure for deprotection of acid Condition screening Process
And (2) adding the ketal protected product (0.2g,0.5mmol) obtained in the step (2) into a 100mL reactor, dissolving with 4mL THF, slowly adding corresponding acid (12.5mmol) under an ice bath condition, raising the temperature to room temperature after the addition, continuing to react for 7h, monitoring the reaction by HPLC, treating the reaction solution, adjusting the pH to 7-8 by using sodium bicarbonate, adding 10mL ethyl acetate for dilution, separating an organic layer, washing the organic layer with saturated common salt water, evaporating to obtain a crude product, and separating and purifying by column chromatography.
ND:Not determined； a The product is completely converted into GS-441524; b the product is very complex and is not separated; c the reaction is carried out in a dichloromethane medium.
Comparative example 4
In a 250mL reactor, equipped with stirrer, thermometer, isobaric dropping funnel, add the ketal protected product of step 2 (13.49g,0.034mol), dissolve with 100mL DCM, place the reaction flask in an ice bath, and add trifluoroacetic acid (68mL,0.918mol) dropwise. And after ten minutes, after the dropwise addition, raising the temperature to room temperature, continuing to react for 48 hours, treating, distilling under reduced pressure to remove the solvent and redundant trifluoroacetic acid, adding water to the residue, slowly dropwise adding a 5% sodium hydroxide solution under an ice bath condition to adjust the pH to 7-8, extracting with ethyl acetate for three times, combining organic layers, washing the organic layers with water, washing with saturated salt water, and drying with sodium sulfate. Suction filtration and evaporation to dryness, and crude product column chromatography to obtain 7g of white solid, yield of 58%, purity: 98.2 percent.
The above examples are only intended to further illustrate the preparation of (((2R,3S,4R,5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-isobutyric acid methyl ester) according to the present invention, but the present invention is not limited to the examples, and any simple modifications, equivalent changes and modifications made to the above examples according to the technical spirit of the present invention fall within the scope of the technical solution of the present invention.
Claims (8)
1. A method for synthesizing nucleoside compounds shown as a formula I,
wherein R is 1 is-C (═ O) CHR 2 R 3 ；R 2 Is selected from C 1 -C 10 Alkyl, aralkyl; r 3 Selected from H, C 1 -C 10 An alkyl group; the method comprises the following steps:
1) selectively protecting hydroxyl by using a compound GS-441524 in the presence of 2, 2-dimethoxypropane and a dehydrating agent to obtain a compound shown as a formula II;
2) condensing the compound shown in the formula II and organic acid selectively with 5' -hydroxyl to synthesize ester shown in the formula III;
3) removing ketal protection from the compound shown in the formula III to obtain a nucleoside compound shown in the formula I;
the condensation reaction in the step 2 is carried out in the presence of DCC/DMAP;
the dehydrating agent in the step 1 is concentrated sulfuric acid, and the selective protection of the hydroxyl is carried out under the condition of 35 ℃ to reflux; or the dehydrating agent in the step 1 is p-toluenesulfonic acid and methanesulfonic acid, and the selective protection of the hydroxyl is carried out in refluxing toluene.
2. The method of claim 1, wherein the post-treatment in step 1 is carried out by dissolving with a small amount of ethyl acetate, pouring the solution into a poor solvent comprising petroleum ether, n-hexane, and n-heptane, and stirring.
3. The method of claim 1, wherein in step 2 the organic acid is HO-C (═ O) CHR 2 R 3 (ii) a Wherein R is 2 Is selected from C 1 -C 10 Alkyl, aralkyl; r 3 Selected from H, C 1 -C 10 An alkyl group.
4. The synthesis method according to claim 1, wherein the condensation reaction in step 2 is carried out at a temperature of 5-10 ℃ and DCC is added dropwise to the reaction system.
5. The synthetic method of claim 3, wherein R 2 Is selected from C 1 -C 8 Alkyl, arylmethyl; r 3 Selected from H, C 1 -C 6 An alkyl group; or R 2 R 3 Form C 3 -C 7 A carbocyclic group.
6. The method of claim 1, wherein the deprotecting acid of step 3 comprises 6N HCl, 3N HCl, 98% formic acid, 80% formic acid, 90% acetic acid, 95% trifluoroacetic acid, pyridine p-toluenesulfonate, methanesulfonic acid, p-toluenesulfonic acid monohydrate.
7. The method of claim 1, wherein step 3 is performed at a temperature of between-10 ℃ and room temperature.
8. The method of claim 1, wherein the nucleoside compound of formula I is the following:
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