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CN114805402A - Large-scale preparation method of oral anti-coronavirus infection medicine - Google Patents

Large-scale preparation method of oral anti-coronavirus infection medicine Download PDF

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CN114805402A
CN114805402A CN202210520184.9A CN202210520184A CN114805402A CN 114805402 A CN114805402 A CN 114805402A CN 202210520184 A CN202210520184 A CN 202210520184A CN 114805402 A CN114805402 A CN 114805402A
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李硕
李官官
刘新军
李迎君
周启璠
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Shenzhen Antai Weishengwu Pharmaceutical Co ltd
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Shenzhen Antai Weishengwu Pharmaceutical Co ltd
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    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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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 discloses a large-scale preparation method of an oral anti-coronavirus infection medicine, belonging to the field of pharmaceutical chemicals; the oral anti-coronavirus infection medicine is a novel cyclohexyl formate oral antiviral medicine, and the structure of the oral anti-coronavirus infection medicine is a compound shown in a formula I and a preparation method of pharmaceutically acceptable salt of the oral anti-coronavirus infection medicine.

Description

Large-scale preparation method of oral anti-coronavirus infection medicine
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a large-scale preparation method of an oral anti-coronavirus infection medicine.
Background
The RNA-dependent RNA polymerase (RdRp) inhibitor Reddesivir (Remdesivir) can inhibit the synthesis of viral nucleic acid and is the first marketed drug for SARS-CoV-2 infection (NCT 04257656). However, clinical efficacy has been questioned due to its administration of liver-targeted Protide prodrug forms. And the complex prodrug form makes the molecular synthesis steps long, expensive and requires intravenous injection, and its application and accessibility are limited.
The research team changes the prodrug form of original drug GS-441524 of the Reidesciclovir and develops a novel nucleoside micromolecule with effective oral administration, and the code is ATV014(CN 113735862A). Against SARS-CoV-2 mutant, ATV014 showed antiviral activity about 95 times better than both Redcisvir and GS-4415248. In the delta variant infected K18 mouse model, ATV014 reduced viral RNA copies and infectious viral titers in the lungs in a dose-dependent manner, and the antiviral effect was superior to that of another marketed oral anti-neocoronary drug EIDD-2801(Medicinal Chemistry research.2022,31, 232-. The PK results indicate that ATV014 has high oral bioavailability, reaching 72% in rats. Therefore, in order to meet the requirements of subsequent clinical research and market supply, the research on the scale preparation process of the ATV014 has important meaning.
He Zhong Gui et al (Molecular pharmaceuticals, 2009,6(1), 315-Bu 325) firstly selectively protected the amino group at the 4-position of cytarabine with benzyl chloroformate (Cbz-Cl), then directly condensed with amino acid, finally Pd catalyzed hydrogenation deprotection to obtain the 5' -position esterification product. Because the hydroxyl on ribose is not protected, 2 'position and 3' position substitution byproducts are generated, and the method is not suitable for industrial production. Liu et al (Tetrahedron,2015,71(9),1409-1412.) in the preparation of 5 '-amino acid ester prodrug, occupy the 5' -position of the sugar ring with a triarylmethylating agent, then use allyloxycarbonylation reagent to acidify and protect the remaining hydroxyl and amino groups, etc., then selectively remove triarylmethyl protecting group under acidic condition, then condense with carboxylic acid, finally palladium acetate removes allyloxycarbonyl protecting group. 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.
Both of the above methods involve palladium-catalyzed deprotection, which not only increases the cost, but also may cause problems such as heavy metal residue in industrial production. When Shanghai drug institute patent (CN 112778310A) prepares nucleoside 5' -hydroxyl ester type prodrug, sugar ring hydroxyl is protected, and simultaneously, N-dimethylformamide dimethyl acetal is used for protecting 4-amino of basic group, and hydrazine hydrate is removed, the route relates to protection and removal reaction on two protecting groups, the route is longer, and loss is easily caused in production.
Research shows that (Bioorg Med Chem,2021,46,116364) ribose 5' ester is easy to hydrolyze under acidic and alkaline conditions, and how to selectively remove acetone protecting group under acidic conditions to obtain high yield is also one of the difficulties. In the earlier stage of the subject group, a preparation method (CN113754665A) of nucleoside compounds is disclosed, and 5' esterified nucleoside compounds are obtained by taking nucleoside as a raw material and carrying out three steps of reactions of ketal protection, esterification and deprotection. In the first step of the process, ketal protection is carried out, concentrated sulfuric acid is used as acid for catalysis, and the reaction is too fast and uncontrollable; DCC is used in the second step of the route, so that the feeding is not easy in the amplification production, and the generated cyclohexylurea is not easy to completely remove; the reaction in the third step of the route is catalyzed by 6N HCl serving as acid, and partial products are decomposed in the process, so that the step of purifying the products cannot avoid column chromatography. Aiming at the problems, the route is comprehensively optimized, and a preparation method which is better suitable for large-scale production is obtained.
Disclosure of Invention
The invention aims to provide a large-scale preparation method of an oral nucleoside compound shown in formula (I), which is simple to operate, high in product yield and qualified in product purity, and effectively avoids the generation of acylation products at positions except for a 5' hydroxyl group in the synthesis process.
In order to solve the problems, the technical scheme of the invention is as follows:
in one aspect, a method for preparing a compound of formula (II),
Figure BDA0003643009290000021
it includes: selectively protecting hydroxyl by using the compound (GS-441524) and a hydroxyl protecting group under the catalysis of acid to obtain a compound shown in a formula II;
Figure BDA0003643009290000022
the hydroxyl protecting group and acid are 2, 2-dimethoxypropane in combination with p-toluenesulfonic acid.
In a second aspect, there is provided a process for the preparation of a compound of formula (III),
Figure BDA0003643009290000031
it includes: the compound shown in the formula II and cyclohexyl formic acid are subjected to condensation reaction,
Figure BDA0003643009290000032
the condensing agent is selected from DCC or DIC or a combination thereof, and the reaction solvent of the condensation reaction is selected from a nitrile solvent or a halogenated hydrocarbon solvent.
In some embodiments, the condensation reaction is carried out at a temperature of-5 to 20 ℃, preferably 5 to 10 ℃. In order to maintain the reaction temperature, it is preferable to add a condensing agent dropwise to the reaction system to reduce the generation of the main by-product (IV).
In a third aspect, a preparation method of an oral nucleoside compound is provided, which comprises the following steps:
1) selectively protecting hydroxyl of a compound (GS-441524) in the presence of 2, 2-dimethoxypropane, organic acid, inorganic acid or macroporous resin to obtain a compound shown in a formula II;
Figure BDA0003643009290000033
2) condensing the compound shown in the formula II with cyclohexyl formic acid to form ester (formula III);
Figure BDA0003643009290000041
3) removing ketal protection from the compound shown in the formula III under acidic condition or under the catalysis of macroporous resin to obtain nucleoside compound (formula I).
Figure BDA0003643009290000042
In some embodiments, the step 1) reaction solvent may be selected from dichloromethane, dichloroethane, chloroform, acetone, acetonitrile, or different combinations of the foregoing solvents; a small amount of other solvents such as ether solvents, hydrocarbon solvents, etc. may be added to the above solvent; preferably, methylene chloride.
In some embodiments, the organic acid of step 1) is selected from p-toluenesulfonic acid, glacial acetic acid, trifluoroacetic acid, p-toluenesulfonic acid monohydrate or methanesulfonic acid, or a combination thereof, and the inorganic acid is selected from concentrated sulfuric acid, tetrafluoroboric acid, concentrated hydrochloric acid, or a combination thereof, and comprises a macroporous resin Amberlyst 15, and in some embodiments p-toluenesulfonic acid is used as the acid catalyst, such that the reaction proceeds in a controlled manner and at room temperature, enabling large scale production, and thus p-toluenesulfonic acid is preferred.
In some embodiments, step 1) compound GS-441524: 2, 2-Dimethoxypropane (DMP): the organic acid molar ratio is 1 (5-10) to (1.0-2.0), and the compound GS-441524 is preferably selected: 2, 2-Dimethoxypropane (DMP): the organic acid molar ratio is 1:6.2: 1.1.
In some embodiments, step 1) is carried out at-20 ℃ to reflux, preferably 25 ± 5 ℃, more preferably 25 ℃.
In some embodiments, the post-treatment of step 1) is carried out by diluting the reaction solution with a poor solvent, stirring at room temperature for crystallization, wherein the poor solvent is petroleum ether, n-hexane, cyclohexane, n-heptane, preferably n-heptane; then the mixed solution is stirred and crystallized at room temperature, washed by alkaline water after being directly filtered, and directly obtained after being dried without any other purification process; the alkaline water is 20% sodium carbonate aqueous solution, saturated sodium carbonate solution, saturated potassium carbonate solution, saturated sodium bicarbonate solution, and ammonia water, preferably 20% sodium carbonate aqueous solution.
In some embodiments, in step 2), the condensing agent used in the condensation reaction may be selected from N, N '-Dicyclohexylcarbodiimide (DCC), N' -Diisopropylcarbodiimide (DIC), N '-tetramethyl-O- (7-azabenzotriazol-1-yl) urea Hexafluorophosphate (HATU), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), N' -Carbonyldiimidazole (CDI), 1-Hydroxybenzotriazole (HOBT), 1-hydroxy-7-azobenzotriazol (HOAT), or the like. The condensing agent is selected from DCC or DIC or the combination thereof. DIC or DCC were found to be better able to catalyze the OH esterification selectively in the reaction under suitable condensation conditions, while producing less bis-acylated by-product (IV). In addition, DIU (1, 3-diisopropylurea) as a by-product is easier to remove by ethanol beating than DCU (ethyl N, N-dichlorocarbamate). DIC is therefore further preferred.
Figure BDA0003643009290000051
In some embodiments, a small amount of catalyst may be added to the condensation reaction in step 2), which may be selected from 4-dimethylaminopyridine, pyridine, triethylamine or diisopropylethylamine or a combination thereof, preferably 4-dimethylaminopyridine.
In some embodiments, in step 2), the solvent selected is dichloromethane, dichloroethane, chloroform, diethyl ether, 1, 2-dimethoxyethane, benzene, toluene, xylene, chlorobenzene, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, acetonitrile, N-dimethylformamide, or different combinations of the above solvents; acetonitrile is preferred as the solvent because it is found by orthogonal design that the reaction is complete and that the acylation side product (IV) is low.
In some embodiments, the condensation reaction of step 2) is carried out at a temperature controlled within a range of-5 to 20 ℃, preferably within a range of 5 to 10 ℃. In order to maintain the reaction temperature, we drop the condensing agent DIC into the reaction system, reducing the generation of the main by-product (IV).
In some embodiments, the synthesis method, step 2) HPLC, after complete consumption of the starting material is monitored, DIU produced during the reaction is removed by filtration. Adding 5V EA and acid into the filtrate, stirring for 1h to remove DMAP in the system, separating an organic layer, extracting a water layer with EA, respectively washing the combined organic layer with alkali, water and saturated sodium chloride, drying with anhydrous sodium sulfate, and performing suction filtration and evaporation to obtain a product which 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
In some embodiments, the acid used for deprotection in step 3) comprises concentrated hydrochloric acid, 6N hydrochloric acid, 3N hydrochloric acid, 50% -80% formic acid solution, TFA, hydrochloric acid deprotection needs to be performed at low temperature of-10 ℃, and partial ester hydrolysis occurs with time to generate the raw material of step 1), therefore, 67% formic acid is preferred,
in some embodiments, the deprotection of step 3) is reacted at-10 ℃ to 50 ℃, preferably 35 ± 5 ℃.
In some embodiments, the synthesis method comprises, after the reaction is completed in step 3) HPLC monitoring, adding EA (2V), adjusting pH to 7-8 with 50% sodium carbonate aqueous solution at 0 ± 5 ℃, filtering, washing the filter cake with water, adding ethanol, heating to 50 ± 5 ℃, stirring, and filtering to obtain the target compound. The residual DIU and other byproducts in the step 2) can be removed by the ethanol, the purity of the product is effectively improved, the treatment after the reaction is simple, and the large-scale production is convenient.
The invention provides a reaction route of nucleoside compounds, and the process has the advantages of short technical route, little environmental pollution and simple process operation.
For the purposes of the present invention, the invention first considers the use of the compound (GS-441524) as starting material, which, according to the technical scheme of the invention, requires only 3 reaction steps to obtain the end product (formula I). The selection of the compound (GS-441524) as starting material requires the following technical problems to be solved: the technical personnel in the field know that the compound (GS-441524) has three hydroxyl active groups at 2 ', 3 ', 5 ' positions and an amino active group at 6 positions, the 2 ', 3 ' hydroxyl is selectively protected by selecting proper reaction conditions in the first step, and through continuous attempts, the 2 ', 3 ' hydroxyl can be selectively protected at high degree under the catalysis of 2, 2-dimethoxypropane and p-toluenesulfonic acid, while the product is decomposed into unknown impurities or the ketal protection reaction cannot be catalyzed efficiently along with the reaction time when other catalysts such as concentrated sulfuric acid and the like are adopted, the raw materials are remained, the reaction process is easy to be uncontrollable anyway, and the industrial production is not suitable; step 2) condensing the organic carboxylic acid selectively at the 5' -hydroxyl to form ester (formula III); the amino basically does not generate condensation reaction, and through continuous trial, DIC/DMAP or DCC/DMAP is finally found to be used as a condensing agent, the reaction feeding sequence is controlled, and the condensing agent is dropwise added into a reaction system at low temperature to selectively condense 5' -hydroxyl into ester; satisfactory selectivity was not achieved with other condensing agents, and the proportion of diacylated by-products reached 12%. When EDCI is used as a condensing agent for acylation, the product is poor in selectivity, the aminoacylation proportion accounts for 14.9%, and a diacyl byproduct IV has solubility similar to that of a target compound III and is difficult to remove by a filtration or pulping method, so that other methods adopting EDCI and other condensing agents are not suitable for industrial production.
And 3) screening various acids, and finally screening formic acid aqueous solution for catalytic deprotection to selectively remove the 2 ', 3' -acetonylidene protection without influencing ester.
The final product ATV014 was poorly soluble in ethanol, while the second byproduct DIU was well soluble in ethanol, and DIU was smoothly removed to trace amounts by ethanol pulping.
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 a fussy protecting group, and has high atom economy. The technical route provided by the invention not only shortens the reaction steps, can be prepared in kilogram level, but also improves the yield and purity by screening acid-base catalysts, controlling the reaction temperature and changing the feeding sequence, and the total yield of the three steps is more than 70% and the HPLC purity is more than 99%.
2) The technical scheme provided by the invention adopts a route without using a reagent or a solvent seriously polluted, 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. And the treatment after the reaction is relatively simple, and most of products with HPLC purity higher than 90%, preferably more than 92%, and more preferably more than 95% can be obtained by filtration.
Drawings
FIG. 1 shows an HPLC chromatogram of ATV014 (formula I) prepared according to the example of the invention.
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.
In describing the details of the experiments, certain abbreviations and acronyms were used. Although most of them are understood by those skilled in the art, the following table contains a list of these abbreviations and acronyms.
Abbreviations Means of
ACN Acetonitrile
DCC Dicyclohexylcarbodiimide
DCM Methylene dichloride
DMAP 4-dimethylaminopyridine
DMP 2, 2-dimethoxypropane
EA Ethyl acetate
DIC N, N' -diisopropylcarbodiimide
DIU 1, 3-diisopropylurea
EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
EtOH Ethanol
PE Petroleum ether
rt At room temperature
TEA Triethylamine
THF Tetrahydrofuran (THF)
TLC Thin layer chromatography
HPLC High performance liquid chromatography
Detailed Description
The claims of the present invention are described in further detail below with reference to specific embodiments.
EXAMPLE 1 optimized preparation of Compounds of formula II
Figure BDA0003643009290000081
Dichloromethane (5V,20.0L) was charged to the reactor at 25. + -. 5 ℃ and the compounds GS-441524(1.0eq,4.0 kg) and DMP (6.2eq,8.9kg) were added followed by the addition of TsOH (1.1eq,2.9kg) in portions and stirred at 25. + -. 5 ℃ for 3 hours to monitor the reaction, which was deemed to be complete when the area of the peak of GS-441524 was < 0.5%. After the reaction was complete, n-heptane (5V,20.0L) was added, and after stirring at 25. + -. 5 ℃ for 2 hours, the mixture was centrifuged and washed with 20% Na 2 CO 3 Pulping (5V,20L), centrifuging, washing with purified water (3V × 2, 12.0L × 2), centrifuging, and drying at 45 + -5 deg.C to obtain 93.3% yield and 99.9% HPLC purity.
Example 2 optimized preparation of Compounds of formula III
Figure BDA0003643009290000082
II (1.0eq,6.5kg), DMAP (0.5eq,1.2kg), cyclohexanecarboxylic acid (1.2eq,3.0kg) and CH were mixed at 25. + -. 5 ℃ 3 CN (5V,32.5L) was charged into the reactor, and DIC (1.25eq,3.1kg) was added as CH 3 CN(2V13L) solution was added dropwise to the above mixture, stirred at 5. + -. 5 ℃ for 48 hours, centrifuged after completion of the reaction, EA (5V,32.5L) and 20% citric acid (5V,32.5L) were added, liquid was separated, the aqueous phase was extracted with EA (3V,19.5L), the organic phases were combined, 20% Na was added 2 CO 3 (5V,32.5L), separated and concentrated to give 11.8kg of a pale yellow oil, which was used directly in the next reaction.
Example 3 optimized preparation of Compounds of formula I
Figure BDA0003643009290000083
Adding formula III (1.0eq,11.8kg) into a reactor at 35 +/-5 ℃, adding 66.7% formic acid (60L,5V), stirring for 48h, monitoring the complete consumption of raw materials by HPLC, stopping the reaction, recovering the redundant formic acid by reduced pressure distillation, adding EA (23.6L,2V) into the residue, adjusting the pH to 7-8 by saturated sodium carbonate, controlling the temperature to be 5-10 ℃, continuously stirring for 2h for full solidification, performing suction filtration, washing a filter cake by a large amount of water to obtain 14kg of wet crude product with the purity of 92.9%, pulping the crude product by ethanol (56L,4V), stirring for 5h at 50 +/-5 ℃, performing suction filtration, and performing vacuum drying on the filter cake at 50 ℃ to obtain 10.7kg of white solid with the yield of 73% and the purity of 99%. 1 H NMR(600MHz,DMSO-d 6 )δ(ppm):7.92(s,1H),7.86(br,1H), 6.92(d,J＝4.5Hz,1H),6.81(d,J＝4.5Hz,1H),6.33(d,J＝5.9Hz,1H),5.38(d,J＝5.9Hz,1H),4.70 (t,J＝5.3Hz,1H),4.32-4.29(dd,J＝12.2Hz,2.6Hz,1H),4.24-4.21(m,1H),4.16-4.13(dd,J＝12.3 Hz,4.8Hz,1H),3.98-3.95(q,J＝5.9Hz,1H),2.26-2.22(m,1H),1.75-1.72(m,2H),1.64-1.56(m, 3H),1.30-1.12(m,5H). 13 C NMR(150MHz,DMSO-d 6 )δ(ppm):175.34,156.06,148.4,124.0, 117.4,117.0,110.7,101.2,81.7,79.4,74.5,70.6,63.0,42.6,29.0,28.9,25.7,25.2, 25.1.ESI-HRMS:m/z[M+H] + calcd for C 19 H 24 N 5 O 5 :402.1772；found:402.1765.
Example 4 catalytic preparation of concentrated sulfuric acid as a compound of formula II
Adding GS-441524(1g,1.0eq) into a reaction flask, adding dried acetone (5mL), adding 2, 2-dimethoxypropane (1.7g,4.8eq), dropwise adding concentrated sulfuric acid (0.47g,1.4eq) into the system at room temperature, starting to dissolve a solid, reacting at room temperature, monitoring the reaction by HPLC, basically completely reacting after 0.5h, adjusting the pH to 7-8 by using a saturated sodium bicarbonate solution, distilling under reduced pressure to remove the solvent, adding ethyl acetate (5mL) into the residue, washing an organic layer by using water and saturated saline respectively, drying by anhydrous sodium sulfate, and evaporating to obtain 1.1g of the compound of the formula II, wherein the yield is 95.1%.
Example 5 preparation of Compound of formula II Using acetone as solvent
In a reaction flask, GS-441524(1g,1.0eq) was added, acetone dried over magnesium sulfate (5mL) was added, 2-dimethoxypropane (1.7g,4.8eq) was added, p-toluenesulfonic acid (0.58g,1.0eq) was added to the system at room temperature to react at room temperature, HPLC monitoring the reaction after 24h to completion of the reaction, saturated sodium carbonate (5mL) was added, after stirring was sufficient, acetone was removed by distillation under reduced pressure, ethyl acetate (5mL) was added to the residue, the organic layer was washed with water and saturated saline, respectively, dried over anhydrous sodium sulfate and evaporated to dryness to give 1.08g of the compound of formula II with a yield of 95.8%.
EXAMPLE 6 preparation of Compound of formula II
To a reaction flask, GS-441524(1g,1.0eq) was added, dried DCM (5mL) was added, 2-dimethoxypropane (3.5g,10eq) was added, p-toluenesulfonic acid (1.17g,2.0eq) was added to the system at room temperature, the solid began to dissolve, the reaction was carried out at room temperature, the reaction was monitored by HPLC, after 2h the reaction was substantially complete, saturated sodium carbonate (10mL) was added, after stirring was sufficient, acetone was removed by distillation under reduced pressure, ethyl acetate (10mL) was added to the residue, the organic layer was washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate and evaporated to dryness to give 1.11g of the compound of formula II with a yield of 98.2%.
EXAMPLE 7 preparation of Compound of formula III
II (1g,1.0eq), cyclohexanecarboxylic acid (0.46g,1.2eq), DMAP (0.18mg,0.5 eq) and DCM (10mL,10V) were charged into a reaction flask, and the flask was stirred in a cold well at 5-10 ℃ to add DIC (0.5g,1.33eq) dropwise while maintaining the temperature at 5-10 ℃. And (3) continuing keeping the temperature for reaction for 5 hours, monitoring the reaction by HPLC, completely reacting the raw materials, filtering to remove insoluble matters, washing the filtrate by using 20% citric acid, saturated sodium carbonate and saturated sodium chloride solutions respectively, drying by using sodium sulfate, and evaporating to dryness to obtain 1.2g of the compound shown in the formula III, wherein the yield is 93%.
EXAMPLE 8 preparation of Compound of formula III
II (1g,1.0eq), cyclohexanecarboxylic acid (0.46g,1.2eq), DMAP (0.18mg,0.5 eq) and DCM (10mL,10V) were added to the reaction flask, the reaction flask was placed in a cold well at 5-10 ℃ and stirred, and a solution of DCC (0.77g,1.33eq) in DCM (5mL) was added dropwise while maintaining the temperature at 5-10 ℃. And (3) continuing the heat preservation reaction for 8 hours, monitoring the reaction by HPLC, completely reacting the raw materials, filtering to remove insoluble substances, washing the filtrate by using 20% citric acid, saturated sodium carbonate and saturated sodium chloride solutions respectively, drying sodium sulfate, and evaporating to dryness to obtain 1.25g of the compound shown in the formula III, wherein the yield is 95%.
EXAMPLE 9 preparation of Compound of formula IV
In a reaction flask, III (1g,1.0eq), formic acid (5mL,5V) and water (5mL,5V) were added and stirred at 35 ℃, after 24h of reaction, HPLC monitored that the reaction was essentially complete, leaving a small amount of starting material, evaporated to dryness, EA (10mL), saturated sodium carbonate solution (5mL) were added to the residue, after stirring well, a white solid precipitated, suction filtered, the filter cake washed with water and dried at 50 ℃ to give 0.62g of compound of formula IV in 68% yield.
EXAMPLE 10 preparation of Compound of formula IV
In a reaction flask, III (1g,1.0eq), formic acid (5mL,5V) and water (5mL,5V) were added and stirred at 50 ℃, after 24h of reaction, HPLC monitored that the reaction was essentially complete, leaving a small amount of starting material, evaporated to dryness, EA (10mL), saturated sodium carbonate solution (5mL) were added to the residue, after stirring well, a white solid precipitated, suction filtered, the filter cake washed with water and dried at 50 ℃ to give 0.62g of compound of formula IV in 68% yield.
EXAMPLE 11 preparation of Compound of formula IV
In a reaction flask, III (1g,1.0eq), formic acid (5mL,5V), water (1.3mL,1.3V) were added, stirred at 35 ℃, after 24h of reaction, HPLC monitored for substantial completion of the reaction, a small amount of starting material, evaporated to dryness, EA (10mL), saturated sodium carbonate solution (5mL) were added to the residue, after stirring well, a white solid precipitated, suction filtered, the filter cake washed with water, dried at 50 ℃ to give 0.52g of compound of formula IV in 65% yield.
EXAMPLE 12 preparation of Compound of formula IV
Adding III (1g,1.0eq), 3N hydrochloric acid (0.67mL,12.0eq) and THF (1mL) into a reaction bottle, stirring at-10 ℃, after 8 hours of reaction, monitoring by HPLC that the reaction is almost complete, adding saturated sodium carbonate into the reaction system to adjust the pH to 7-8, adding EA, stirring, precipitating a white solid, performing suction filtration, washing the filter cake with EA and water respectively, and drying at 50 ℃ to obtain 0.54g of the compound shown in the formula IV, wherein the yield is 67%.
TABLE 1 ATV014 (formula I) HPLC method
Figure BDA0003643009290000111

Claims (10)

1.A preparation method of a compound shown as a formula (II),
Figure RE-FDA0003695746650000011
it includes: selectively protecting hydroxyl by using the compound (GS-441524) and a hydroxyl protecting group under the catalysis of acid to obtain a compound shown in a formula II;
Figure RE-FDA0003695746650000012
the hydroxyl protecting group and acid are 2, 2-dimethoxypropane in combination with p-toluenesulfonic acid.
2. A process for the preparation of a compound of formula (III),
Figure RE-FDA0003695746650000013
it includes: the compound shown in the formula II and cyclohexyl formic acid are subjected to condensation reaction,
Figure RE-FDA0003695746650000014
the condensing agent is selected from DCC or DIC or a combination thereof, and the reaction solvent of the condensation reaction is selected from a nitrile solvent or a halogenated hydrocarbon solvent.
3. A process for preparing the oral medicine of ATV014 (formula I) for treating coronavirus infection,
Figure RE-FDA0003695746650000021
the method is characterized by comprising the following steps:
1) selectively protecting hydroxyl of a compound (GS-441524) in the presence of 2, 2-dimethoxypropane and organic acid, inorganic acid or macroporous resin to obtain a compound shown in a formula II;
Figure RE-FDA0003695746650000022
2) condensing the compound shown in the formula II with cyclohexyl formic acid to form ester (formula III);
Figure RE-FDA0003695746650000023
3) removing ketal protection from the compound shown in the formula III under acidic conditions to obtain the nucleoside compound (formula I).
4. The process of claim 3, wherein the reaction solvent of step 1) is dichloromethane, chloroform, tetrahydrofuran, acetone, acetonitrile or various combinations thereof; the organic acid in the step 1) is p-toluenesulfonic acid, glacial acetic acid, p-toluenesulfonic acid monohydrate or methanesulfonic acid, the inorganic acid is concentrated sulfuric acid, tetrafluoroboric acid or concentrated hydrochloric acid, and the macroporous resin is Amberlyst 15.
5. The process for the preparation of formula I according to claim 3, wherein step 1) compound GS-441524: 2, 2-dimethoxypropane: the molar ratio of the organic acid or the inorganic acid is 1 (5-10) to 1.0-2.0.
6. The process for preparing formula I according to claim 3, wherein the condensing agent used in the condensation reaction in step 2) is N, N '-dicyclohexylcarbodiimide, N' -diisopropylcarbodiimide, N '-tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N' -carbonyldiimidazole, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazol; and adding a catalyst in the condensation reaction, wherein the catalyst is 4-dimethylaminopyridine, pyridine, triethylamine or diisopropylethylamine.
7. The process of claim 3, wherein the catalyst of step 2) is 4-dimethylaminopyridine.
8. A process according to claim 3, wherein the solvent used in step 2) is dichloromethane, dichloroethane, chloroform, diethyl ether, 1, 2-dimethoxyethane, benzene, toluene, xylene, chlorobenzene, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, acetonitrile, N-dimethylformamide, or different combinations of the above solvents.
9. The synthesis method according to any one of claims 1 to 3, wherein the condensation reaction is carried out at a temperature of 5 to 10 ℃, and a condensing agent is slowly added dropwise into the reaction system, so that the hydroxyl group can be selectively esterified.
10. The process of claim 3, wherein the acid used for deprotection in step 3) comprises concentrated hydrochloric acid, 6N hydrochloric acid, 3N hydrochloric acid, 2N hydrochloric acid, 50% to 80% formic acid solution, TFA; step 3) the deprotection is carried out at-10 ℃ to 50 ℃.
CN202210520184.9A 2022-05-13 2022-05-13 Large-scale preparation method of oral anti-coronavirus infection medicine Pending CN114805402A (en)

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Publication number Priority date Publication date Assignee Title
CN117815242A (en) * 2023-01-05 2024-04-05 深圳安泰维生物医药有限公司 Use of compound ATV014 in resisting new coronavirus infection

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WO2022047065A2 (en) * 2020-08-27 2022-03-03 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections

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WO2022047065A2 (en) * 2020-08-27 2022-03-03 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections

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