CN110776512A - Preparation method of nucleoside analogue - Google Patents
Preparation method of nucleoside analogue Download PDFInfo
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- CN110776512A CN110776512A CN201911193110.3A CN201911193110A CN110776512A CN 110776512 A CN110776512 A CN 110776512A CN 201911193110 A CN201911193110 A CN 201911193110A CN 110776512 A CN110776512 A CN 110776512A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D487/04—Ortho-condensed systems
Abstract
The invention belongs to the technical field of chemical synthesis, and particularly relates to a novel preparation method of (2R, 3R, 4S, 5R) -2- (4-aminopyrrolo [1,2-f ] [1,2,4] triazine-7-yl) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile, which comprises the following steps: 1) synthesizing an intermediate I by using 2, 3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone and 4-amino-7-bromopyrrolo [2,1-f ] [1,2,4] triazine as raw materials; 2) preparing an intermediate II from the intermediate I; 3) directly dissolving the prepared intermediate II in dichloromethane, cooling to below-15 ℃, dropwise adding boron trichloride, after the reaction is finished, quenching by using methanol, concentrating under reduced pressure, adding a mixed solution of methanol and water, adjusting the pH value to 7, stirring overnight, and separating out a solid compound to obtain the compound. The preparation method has high yield and less byproducts, and can efficiently produce (2R, 3R, 4S, 5R) -2- (4-aminopyrrolo [1,2-f ] [1,2,4] triazine-7-yl) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile in large scale.
Description
Technical Field
The invention relates to the technical field of chemical synthetic drugs, in particular to a preparation method of a nucleoside analogue.
Background
The virus infectious diseases are the diseases with the highest morbidity in the world at present, more than 60 percent of infectious diseases are caused by viruses, and new viruses are continuously discovered, have the characteristics of high infectivity and high lethality rate, and cause serious harm to human health. Antiviral therapy is the fundamental treatment of viral infectious diseases. For acute infections, it helps to relieve symptoms and shorten the course of treatment; for chronic persistent infection, such as AIDS, hepatitis B, hepatitis C, etc., antivirus is the root of the treatment. Different viral infections cause different conditions and require different antiviral medications. Although the development of genetically engineered and chemically synthesized antiviral drugs has provided more choices and opportunities for clinical use of drugs for controlling viral infection over the years, the antiviral drugs which have been proved to have clinical value at present have more index-yielding numbers and limited indications. Especially, it is difficult to cure some chronic viral infections. Since viruses are obligate intracellular parasites, whose proliferation is dependent on the biosynthesis of the host cell, the nucleic acids of some viruses are directly integrated into the genes of the host cell. Therefore, antiviral drugs must be selected according to the characteristics of the viruses, and antiviral treatment guidelines must be established. The antiviral agent should selectively destroy or inhibit the virus inside and outside the cell without causing lethal damage to the cell, at least to uninfected cells. Therefore, it is difficult to inhibit intracellular viruses and achieve clinical antiviral effects without adversely affecting host cell metabolism. In addition, the antiviral drug has good curative effect on protecting uninfected cells and generating no obvious pathological changes in the early stage of infection, but the symptoms of common virus infectious diseases lack specificity and are difficult to diagnose early, and when the virus infection has clinical symptoms, the virus proliferation in the organism reaches a certain degree. For example, in the clinical onset of influenza and encephalitis B, a large amount of virus is proliferated and released in infected cells, and the body is in the viremia stage or the later viremia stage, so that tissue damage is caused. Viral-induced syndromes are somewhat common and relatively benign or self-limiting, and therefore only drugs with very high therapeutic indices (ratio of therapeutic efficacy to toxicity) are acceptable. Therefore, the vigorous development and development of antiviral drugs with safety, effectiveness, strong selectivity and convenient use is still a very difficult task.
Nucleoside antiviral drugs are artificially synthesized nucleotide analogs, have simple chemical structures, are convenient to modify and synthesize, are the fastest-developing antiviral drugs, and are a series of new efficient low-toxicity nucleoside analog antiviral drugs developed successively. The compound (2R, 3R, 4S, 5R) -2- (4-aminopyrrolo [1,2-f ] [1,2,4] triazine-7-yl) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile, as a C-nucleoside analogue, shows antibacterial, antiviral and antitumor properties, has biological medicinal value, can be used as an active ingredient of an antiviral medicament, and has potential application prospects in developing new antiviral nucleoside medicaments. In the existing synthesis method of the compound (2R, 3R, 4S, 5R) -2- (4-aminopyrrolo [1,2-f ] [1,2,4] triazine-7-yl) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile, as a final product may have chiral molecules, the generated chiral molecules are directly screened in the previous step of synthesizing the final product, and then molecules with required configuration are screened out to finally synthesize the final product molecules with single configuration, so that although the purity of the final product molecules can be improved, the waste of raw materials is serious, the yield is extremely low, labor and time are wasted, the production efficiency of the final product is greatly reduced, the problems that the production efficiency of the compound (2R, 3R, 4S, 5R) -2- (4-aminopyrrolo [1, industrial application and development of 2-f ] [1,2,4] triazin-7-yl) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile.
Disclosure of Invention
The invention aims to provide a preparation method of nucleoside analogue, which has high yield and less by-products and can be efficiently produced in large scale.
The invention provides a preparation method of a nucleoside analogue, which comprises the following specific synthetic route and preparation process:
(1) 2, 3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone and 4-amino-7-bromopyrrolo [2,1-f ] [1,2,4] triazine are used as raw materials to synthesize an intermediate I, and the synthetic route is as follows:
(2) under the protection of inert gas, dissolving the intermediate I in a solvent, cooling to 20-minus 20 ℃, and slowly dropwise adding trimethylsilyl cyanide and trimethylsilyl trifluoromethanesulfonate in sequence to obtain an intermediate II, wherein the intermediate II has two chiral molecular configurations, and the synthetic route is as follows:
(3) directly dissolving an intermediate II containing two chiral molecular configurations in dichloromethane, cooling to below-15 ℃, dropwise adding boron trichloride, quenching by using methanol after the reaction is finished, concentrating under reduced pressure, adding a mixed solution of methanol and water, adjusting the pH of the solution to 7, stirring overnight, and obtaining a precipitated solid compound which is a required final product, wherein the synthetic route is as follows:
the intermediate II is prepared by screening the intermediate II (β configuration) directly in the process of preparing the intermediate II, and then preparing a final product by using the screened intermediate II (β configuration).
The technical scheme directly uses the intermediate II with two configurations to directly prepare the final product, and finally can realize chiral conversion in the reaction process through a special preparation method and specific reaction conditions to obtain the final product with the required configuration.
In addition, the synthesis process of the intermediate II is the existing synthesis process, namely the selection of raw materials and the preparation process of the intermediate I have the existing mature technology, and as the final product is also a chiral molecule with two configurations, but only one configuration of the final product is used as a medicine, the key technical point is that the intermediate II with two configurations is directly used for preparing the final product with the required configuration.
Compared with the prior art, the invention has the following advantages and beneficial effects:
the invention provides a novel synthesis method of (2R, 3R, 4S, 5R) -2- (4-aminopyrrolo [1,2-f ] [1,2,4] triazine-7-yl) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile, the method is different from the traditional preparation method, directly uses the intermediate II with two configurations to directly prepare the final product, through a special preparation method and specific reaction conditions, chiral conversion can be finally realized in the reaction process, a final product with a required configuration is obtained, the steps are simplified, the yield of the final product and the utilization rate of raw materials are improved, the waste of the raw materials is greatly reduced, the synthesis cost of the final product is reduced, the industrial high-efficiency large-scale production is realized, and the development of research on nucleoside analogues is promoted. .
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto, and various substitutions and alterations can be made without departing from the technical idea of the present invention as described above, according to the common technical knowledge and the conventional means in the field.
The present invention will be described in further detail with reference to the following examples for the purpose of making clear the objects, process conditions and advantages of the present invention, which are given by way of illustration only and are not intended to be limiting of the present invention.
Example 1:
in the embodiment, 2, 3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone and 4-amino-7-bromopyrrolo [2,1-f ] [1,2,4] triazine are used as raw materials to synthesize an intermediate I.
The specific synthetic route is as follows:
the specific synthesis method comprises the following steps:
weighing 300 g of 4-amino-7-bromopyrrolo [2,1-f ] [1,2,4] triazine (1.4mol), dissolving in a solvent a, adding 375ml (2.95mol) of trimethylchlorosilane under the protection of inert gas, cooling to-70 ℃, dropwise adding 2250ml (3.6mol) of n-butyllithium, after the n-butyllithium is added, weighing 620 g (1.5mol) of 2, 3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone, dissolving in the solvent a, adding into a reaction solution, monitoring the reaction progress by TLC, quenching with acetic acid after the reaction is finished, concentrating and washing under reduced pressure, and separating by using column chromatography to obtain an intermediate I (about 225 g).
The yield of this intermediate I was 29.2%.
It is composed of
1The H NMR data are as follows:
1the H NMR data are as follows:
1HNMR(400MHz，CDCl
3):δ7.88～7.92(s，2H)，7.13～7.32(m，15H)，6.81～6.85(m，1H)，6.68～6.72(m，1H)，6.25～6.29(bs，2H)，5.63～5.66(t，J＝3.9Hz，1H)，5.18～5.20(brs，1H)，4.92～4.97(brs，1H)，4.33～4.78(m，4H)，4.05～4.11(m，2H)，3.92～3.97(m，2H).
wherein, the eluent for column chromatography separation is a mixed solution of petroleum ether and ethyl acetate according to the volume ratio of 3: 1; the solvent a is one of tetrahydrofuran or anhydrous ether, in this embodiment, tetrahydrofuran is preferably used as the solvent, and the other solvents can be selected; the inert gas used is argon, and other inert gases which do not influence the reaction can be selected and have the protection function.
Example 2:
this example prepares intermediate II from intermediate I prepared in the above example.
The specific synthetic route is as follows:
the specific synthesis method comprises the following steps:
under the protection of inert gas, 300 g (0.54mol) of intermediate I is weighed and dissolved in a solvent b, the temperature is reduced to-5 ℃, 268ml (2.01mol) of trimethylsilyl cyanide is added dropwise, 450ml (2.49mol) of trimethylsilyl trifluoromethanesulfonate is added dropwise, the progress of the reaction is monitored by TLC, the carbon after the reaction is quenched and washed by sodium bicarbonate aqueous solution, and about 262g of intermediate II is obtained by column chromatography separation.
The yield of this intermediate II was 85.3%.
It is composed of
1The H NMR data are as follows:
1H NMR(400MHz，CDCl
3):δ7.92～7.94(s，2H)，7.16～7.29(m，15H)，6.82～6.85(m，1H)，6.68～6.72(m，1H)，6.25～6.29(bs，2H)，5.21～5.23(brs，1H)，4.96～4.99(brs，1H)，4.36～4.76(m，4H)，4.08～4.14(m，2H)，3.94～3.99(m，2H).
wherein, the eluent for column chromatography separation is a mixed solution of petroleum ether and ethyl acetate according to the volume ratio of 2: 1; the solvent b is one of tetrahydrofuran, dichloromethane and chloroform, dichloromethane is preferably used as the solvent in the embodiment, and the other solvents can be selected; the inert gas used for protection is preferably argon, and other inert gases which do not influence the reaction and have the protection function can also be selected.
Example 3:
this example prepared the intermediate II (including two chiral molecules in configuration) prepared in the above example to give the final product ((2R, 3R, 4S, 5R) -2- (4-aminopyrrolo [1,2-f ] [1,2,4] triazin-7-yl) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile).
The specific reaction route is as follows:
the preparation process comprises the following steps: weighing 200 g (0.355mol) of intermediate II (containing two configuration chiral molecules) and dissolving in Dichloromethane (DCM), cooling to-15 ℃, dropwise adding 1400ml (1.4mol) of boron trichloride, monitoring the reaction progress by TLC, after the reaction is finished, quenching methanol, concentrating under reduced pressure, adding a mixed solution formed by mixing methanol and water according to the volume ratio of 1:1, adjusting the pH to 7 by using potassium carbonate aqueous solution, stirring overnight, and precipitating about 95 g of a solid final product.
The yield of the final product was 55.6%.
It is composed of
1The H NMR data are as follows:
1H NMR(400MHz,DMSO):δ7.92(s，3H)，6.88～6.91(m，2H)，6.10～6.12(d，J＝6.0Hz，1H)，5.20～5.21(brs，1H)，4.92～4.95(brs，1H)，4.63～4.66(t，J＝3.9Hz，1H)，4.05～4.08(m，1H)，3.94～3.98(brs，1H)，3.63～3.67(m，2H).
while embodiments of the invention have been shown and described, it will be understood by those of ordinary skill in the art that: various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.
Claims (10)
1. A process for preparing a nucleoside analog, wherein the nucleoside analog is (2R, 3R, 4S, 5R) -2- (4-aminopyrrolo [1,2-f ] [1,2,4] triazin-7-yl) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile, which comprises the steps of:
(1) synthesizing an intermediate I by using 2, 3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone and 4-amino-7-bromopyrrolo [2,1-f ] [1,2,4] triazine as raw materials;
(2) dissolving the intermediate I in a solvent under the protection of inert gas, cooling to 20 to-20 ℃, and then slowly dropwise adding trimethylsilyl cyanide and trimethylsilyl trifluoromethanesulfonate to prepare an intermediate II, wherein the intermediate II has two chiral molecular configurations;
(3) directly dissolving an intermediate II containing two chiral molecular configurations in dichloromethane, cooling to below 0 to-50 ℃, dropwise adding boron trichloride, quenching with methanol after the reaction is finished, concentrating under reduced pressure, adding a mixed solution of methanol and water, adjusting the pH of the solution to 7, stirring overnight, and precipitating a solid compound which is the required final product.
2. A process for preparing a nucleoside analogue according to claim 1, wherein the intermediate I in step (1) is prepared by the following steps:
(1.1) respectively dissolving 4-amino-7-bromopyrrolo [2,1-f ] [1,2,4] triazine and 2, 3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone in two parts of the same solvent a, and separately placing for later use;
(1.2) dissolving the solution of 4-amino-7-bromopyrrolo [2,1-f ] [1,2,4] triazine, adding trimethylchlorosilane under the protection of inert gas, cooling to-38 to-70 ℃, and dropwise adding n-butyllithium;
(1.3) adding a solvent in which the 2, 3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone is dissolved into the solution prepared in the step (1.2), after the reaction is finished, quenching the solution with acetic acid, concentrating and washing the solution under reduced pressure, and separating an intermediate I through column chromatography to obtain the intermediate I.
3. The method of claim 2, wherein the solvent a used in step (1.1) is one of tetrahydrofuran and dehydrated ether.
4. A process for preparing a nucleoside analogue according to claim 3, wherein the inert gas used in step (1.2) is argon.
5. A process for preparing a nucleoside analogue according to any one of claims 2 to 4, wherein the eluent used in the step (1.3) for separating intermediate I by column chromatography is a mixture of petroleum ether and ethyl acetate in a volume ratio of 3: 1.
6. The method for preparing a nucleoside analogue according to claim 1, wherein the intermediate II in the step (2) is prepared by a specific process comprising:
(2.1) under the protection of inert gas, dissolving the intermediate I prepared in the step (1) in a solvent b to prepare a mixed solution for later use;
(2.2) cooling the mixed solution prepared in the step (2.1) to below 5 ℃, dropwise adding trimethylsilyl cyanide and trimethylsilyl trifluoromethanesulfonate in sequence, after the reaction is finished, quenching and washing the mixed solution by using an aqueous sodium bicarbonate solution, and separating an intermediate II by column chromatography to obtain the intermediate II, wherein the intermediate II comprises chiral molecules with α and β configurations.
7. A process for preparing a nucleoside analogue according to claim 6, wherein the inert gas used in step (2.1) is argon, and the solvent b used is one of tetrahydrofuran, dichloromethane and chloroform.
8. The method according to claim 6 or 7, wherein the eluent for separating intermediate II by column chromatography in step (2.2) is a mixture of petroleum ether and ethyl acetate at a volume ratio of 2: 1.
9. A process for producing a nucleoside analogue according to claim 1, wherein the mixed solution of methanol and water added in the step (3) is a mixed solution of methanol and water in a volume ratio of 1: 1.
10. A process according to claim 1, wherein the intermediate I, intermediate II and final product are prepared by TLC to determine the completion of the reaction.
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| CN111484537A (en) * | 2020-05-19 | 2020-08-04 | 南京工业大学 | Method for preparing Rudesiwei key intermediate by using microchannel reaction device |
| CN113387954A (en) * | 2020-03-11 | 2021-09-14 | 上海特化医药科技有限公司 | Preparation method of Reidesciclovir intermediate |
| WO2022029704A1 (en) | 2020-08-06 | 2022-02-10 | Richter Gedeon Nyrt. | Remdesivir intermediates |
| CN115028672A (en) * | 2022-06-14 | 2022-09-09 | 南京正济医药研究有限公司 | Ruideciclovir intermediate crystal and preparation method thereof |
| US11697666B2 (en) | 2021-04-16 | 2023-07-11 | Gilead Sciences, Inc. | Methods of preparing carbanucleosides using amides |
| US11701372B2 (en) | 2020-04-06 | 2023-07-18 | Gilead Sciences, Inc. | Inhalation formulations of 1'-cyano substituted carba-nucleoside analogs |
| US11767337B2 (en) | 2020-02-18 | 2023-09-26 | Gilead Sciences, Inc. | Antiviral compounds |
| US11780844B2 (en) | 2022-03-02 | 2023-10-10 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
| US11814406B2 (en) | 2020-08-27 | 2023-11-14 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
| US11903953B2 (en) | 2020-05-29 | 2024-02-20 | Gilead Sciences, Inc. | Remdesivir treatment methods |
| US11939347B2 (en) | 2020-06-24 | 2024-03-26 | Gilead Sciences, Inc. | 1′-cyano nucleoside analogs and uses thereof |
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| CN113387954A (en) * | 2020-03-11 | 2021-09-14 | 上海特化医药科技有限公司 | Preparation method of Reidesciclovir intermediate |
| CN113387954B (en) * | 2020-03-11 | 2024-03-19 | 上海特化医药科技有限公司 | Preparation method of adefovir intermediate |
| US11701372B2 (en) | 2020-04-06 | 2023-07-18 | Gilead Sciences, Inc. | Inhalation formulations of 1'-cyano substituted carba-nucleoside analogs |
| CN111484537B (en) * | 2020-05-19 | 2021-10-01 | 南京工业大学 | Method for preparing Rudesiwei key intermediate by using microchannel reaction device |
| CN111484537A (en) * | 2020-05-19 | 2020-08-04 | 南京工业大学 | Method for preparing Rudesiwei key intermediate by using microchannel reaction device |
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| US11939347B2 (en) | 2020-06-24 | 2024-03-26 | Gilead Sciences, Inc. | 1′-cyano nucleoside analogs and uses thereof |
| WO2022029704A1 (en) | 2020-08-06 | 2022-02-10 | Richter Gedeon Nyrt. | Remdesivir intermediates |
| US11814406B2 (en) | 2020-08-27 | 2023-11-14 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
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| US11697666B2 (en) | 2021-04-16 | 2023-07-11 | Gilead Sciences, Inc. | Methods of preparing carbanucleosides using amides |
| US11780844B2 (en) | 2022-03-02 | 2023-10-10 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
| US11851438B2 (en) | 2022-03-02 | 2023-12-26 | Gilead Sciences, Inc. | 1′-cyano nucleoside analogs and methods for treatment of viral infections |
| US11845755B2 (en) | 2022-03-02 | 2023-12-19 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
| CN115028672A (en) * | 2022-06-14 | 2022-09-09 | 南京正济医药研究有限公司 | Ruideciclovir intermediate crystal and preparation method thereof |
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Application publication date: 20200211 |