CN112661802B - Synthetic method of 3' -methoxyguanosine - Google Patents
Synthetic method of 3' -methoxyguanosine Download PDFInfo
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- CN112661802B CN112661802B CN202110093399.2A CN202110093399A CN112661802B CN 112661802 B CN112661802 B CN 112661802B CN 202110093399 A CN202110093399 A CN 202110093399A CN 112661802 B CN112661802 B CN 112661802B
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Abstract
The invention discloses a synthetic method of 3' -methoxyguanosine, and relates to the technical field of medicines. The method uses 1,2-OThe preparation method comprises the following steps of taking-isopropylidene-alpha-D-xylofuranose I as an initial raw material, selectively protecting primary alcohol, turning the configuration of the other secondary alcohol in a molecule through oxidation and reduction processes, methylating hydroxyl to obtain an intermediate V, removing an acetal protecting group from the intermediate V, carrying out a double acetylation reaction by a one-pot method to obtain a product VI, and reacting the product VI with the intermediate VNCoupling 2-acetyl guanine to obtain a product VII, and finally removing two acyl protecting groups and a silicon-based protecting group to obtain the target product. The method has the advantages of simple operation, mild reaction conditions, convenient purification, high yield and suitability for large-scale production.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a synthetic method of 3' -methoxyguanosine.
Background
In eukaryotic cells, the 5' end of most messenger rnas (mrnas) is blocked, or "capped," which facilitates their normal function in the cell. In vitro synthesis of capped RNA molecules is of great interest for research applications and commercial production of polypeptides. 3' -methoxyguanosine is widely used for synthesizing chain-terminating dinucleotide mRNA Cap analogs, and has also been reported to be used as an Anti-reverse Cap Analog (ARCA) effective for promoting translation of transcripts into proteins.
Currently, very few synthetic methods have been reported for 3' -methoxyguanosine, and the following synthetic methods have been reported by the s.e. bernier group:
the method starts from guanosine, firstly converts guanosine into 2-amino adenosine, then carries out methylation by diazomethane to respectively obtain 2-position and 3-position hydroxyl methylated products, and finally converts amino into acyl by adenosine deaminase to respectively obtain corresponding products. The method has the following defects: 1, diazomethane is extremely toxic and explosive, and has huge potential threats in preparation and reaction; 2, 2-position and 3-position methylation products are very polar and close and are difficult to separate; 3, adenosine deaminase is expensive and not economical. Therefore, this method is not suitable for mass production.
Disclosure of Invention
The invention aims to overcome the defects in the synthesis of 3 '-methoxyguanosine in the prior art and provides a method which has simple route and mild conditions and is suitable for large-scale synthesis of 3' -methoxyguanosine.
In order to achieve the purpose, the invention provides the following technical scheme:
the specific route is as follows:
the invention aims to be realized by the following technical scheme and steps:
(1) reacting the compound I with tert-butyldiphenylchlorosilane, and selectively protecting primary alcohol to obtain a compound II;
(2) the compound II is oxidized to ketone III;
(3) reducing the compound III into alcohol IV, and inverting the configuration of secondary alcohol;
(4) methylating the compound IV to obtain an intermediate V;
(5) carrying out one-pot deprotection on the compound V, and acetylating to obtain an intermediate VI;
(6) compound VI andN-2-acetyl guanine is coupled to obtain an intermediate VII;
(7) removing two acetyl groups from the compound VII to obtain a compound VIII;
(8) and removing the silicon-based protecting group from the compound VIII to obtain a final product IX.
The first step of reaction process is as follows:
the alkali used in the step is one of imidazole, pyridine, 4-dimethylamino pyridine, triethylamine and diisopropylethylamine. The molar ratio of the compound I, tert-butyldiphenylchlorosilane and alkali is 1: (1.1-1.5) and (2-3). The organic solvent is anhydrousN,N-one of dimethylformamide, anhydrous dichloromethane, anhydrous tetrahydrofuran.
The second step of reaction process is:
the solvent used in the step is anhydrous dichloromethane, the reaction temperature is-60 ℃ to room temperature, and the oxidant used can also be chromium trioxide, dessimutan oxidant and the like.
The third step of reaction process is:
the molar ratio of the compound III to the sodium borohydride in the step is 1: (6-8), wherein the volume ratio of the mixed solvent ethanol to the water is 3: 1.
The fourth reaction process comprises the following steps:
the methylating agent used in the step is one of methyl iodide, dimethyl sulfate and trimethyl oxonium tetrafluoroborate, and the solvent used is anhydrousN,N-dimethylformamide.
The fifth step is as follows:
the reagent for removing acetal in the step can be one of 75% acetic acid and 50% trifluoroacetic acid, and the acetylation reagent can be one of acetic anhydride and acetyl chloride.
The sixth reaction process comprises the following steps:
the reagent for coupling with the compound VI in the step isN-2-acetylguanine, compound VI,N-a 2-acetyl-guanine in the presence of a ligand,N,Obis-trisilylacetamide and trifluromethylThe mol ratio of the sulfonic acid trifluoromethyl silicone grease is 1:1:6:3, the used solvent is anhydrous 1, 2-dichloroethane, and the reaction temperature is 100 ℃.
The seventh step comprises the following reaction processes:
in the step, the solvent is a mixture of ethanol and 40% methylamine water solution, and the volume ratio of the solvent is 2: 1.
The eighth step comprises the following reaction processes:
the method for removing the silicon-based protecting group in this step may be any one of a tetrabutylammonium fluoride/tetrahydrofuran system, a 3% hydrochloric acid/methanol system, a hydropyridine fluoride/tetrahydrofuran system, or a hydrofluoric acid/acetonitrile system.
Compared with the prior art, the method has the advantages of simple operation, mild reaction conditions, convenient purification, high yield and suitability for large-scale production.
Detailed Description
The embodiments are merely preferred versions of the invention, which are not intended to be limiting in any way, and other variations and modifications may be made without departing from the spirit and scope of the invention as defined by the claims.
The first step is as follows:
adding 1,2-O-isopropylidene-alpha-D-xylofuranose (5.70 g, 29.99 mmol), imidazole (5.76 g, 84.65 mmol) and 30mL of ultra dryN,N-dimethylformamide. The reaction flask was placed in an ice bath at 0 ℃ and t-butyldiphenylchlorosilane (10mL, 38.46 mmol) was then added dropwise, the reaction was stirred at room temperature for 4 h, water (100 mL) and ethyl acetate (50 mL) were added, extraction was performed with ethyl acetate (50 mL. times.2), the combined organic phases were washed with saturated brine (50 mL. times.2), anhydrous Na was added2SO4Drying, filtering, and separating by column chromatography (PE: EA = 30:1 to6:1) to obtain colorless liquid which is actually the target product through nuclear magnetic identification.
The hydrogen spectrum of compound ii obtained is as follows:
1H NMR (400 MHz, CDCl3) δ 1.05 (9H, s), 1.33 (3H, s), 1.47 (3H, s), 4.10-4.14 (4H, m), 4.38 (1H, d, J = 2.1 Hz), 4.55 (1H, d, J = 3.6 Hz), 6.01 (1H, d, J = 3.7 Hz), 7.38-7.45 (6H, m), 7.68 (2H, dt, J = 6.7, 1.5 Hz), 7.72 (2H, dt, J = 6.7, 1.5 Hz).
the second step is that:
adding oxalyl chloride (2.8mL, 30.09 mmol) and anhydrous dichloromethane (40 mL) into a 150mL two-neck flask, placing the reaction flask into a low-temperature tank at-60 ℃, slowly adding anhydrous dimethyl sulfoxide (4.7mL, 66.17 mmol), dissolving a product II in dichloromethane (20 mL), slowly adding the mixture into the reaction system through a syringe, continuing stirring for 30min after dropwise addition is completed, then adding triethylamine (13.8mL, 99.28 mmol), stirring for 1 h at-60 ℃, stirring for 2h at room temperature, adding water to quench the reaction, extracting with dichloromethane (50 mL x 2), combining organic phases, washing with saturated common salt (50 mL x 1), adding anhydrous Na2SO4Drying, filtering and spin-drying to obtain the product which is directly put into the next step.
The third step:
dissolving the product III obtained in the previous step in ethanol (90 mL) and water (30 mL), placing the reaction flask in an ice bath at 0 ℃, adding sodium borohydride (7.44g, 196.67 mmol) in portions, then stirring at room temperature for 12 h, after TLC shows that the reaction is completed, adding 100mL of water, extracting with ethyl acetate (100 mL. times.3), combining the organic phases, washing with saturated saline (100 mL. times.2), adding anhydrous Na2SO4Drying, filtering, rotary evaporation to remove solvent, and column chromatography (PE: EA = 30:1 to 6:1) to obtain 11.1g of colorless liquid, wherein nuclear magnetism indicates that the product is indeed the target product and the total yield of three steps is 86%.
The hydrogen spectrum of compound IV obtained is as follows:
1H NMR (400 MHz, CDCl3) δ 1.05 (9H, s), 1.39 (3H, s), 1.56 (3H, s), 2.32 (1H, d, J = 10.0 Hz), 3.83-3.88 (2H, m), 3.94-3.99 (1H, m), 4.10-4.18 (1H, m), 4.60 (1H, dd, J = 5.1, 3.8 Hz), 5.85 (1H, d, J = 3.6 Hz), 7.35-7.44 (6H, m), 7.68-7.71 (4H, m).
the fourth step:
the alcohol IV obtained in the previous step (6.23g, 20.45 mmol) was dissolved in dry ethanolN,N-dimethylformamide (50 mL), the reaction flask was placed in an ice bath at 0 ℃, 60% sodium hydride (2.13g, 53.33 mmol) was added in portions, stirred at this temperature for 30min, iodomethane (3.2mL,51.40 mmol) was added dropwise, then stirred at room temperature for 2h, after TLC showed that the reaction had been completed, 50mL of saturated aqueous ammonium chloride was added, extracted with ethyl acetate (50 mL × 3), the combined organic phases were washed with saturated brine (50 mL × 2), and anhydrous Na was added2SO4Drying, filtration, rotary evaporation to remove solvent, column chromatography (PE: EA = 30:1 to 1:1) gave 10.00 g of colorless liquid, nuclear magnetic resonance indicated indeed the target product, yield 87%.
The hydrogen spectrum of compound v obtained is as follows:
1H NMR (400 MHz, CDCl3) δ 1.08 (9H, s), 1.39 (3H, s), 1.60 (3H, s), 3.52 (3H, s), 3.84 (1H, dd, J = 11.8, 2.9 Hz), 3.93 (1H, dd, J = 8.8, 4.3 Hz), 4.03 (1H, dd, J = 11.8, 1.9 Hz), 4.08 (1H, dt, J = 8.8, 2.4 Hz), 4.72 (1H, dd, J = 3.9, 4.0 Hz), 5.82 (1H, d, J = 3.6 Hz), 7.36-7.44 (6H, m), 7.70-7.72 (4H, m).
the fifth step:
dissolving the product V (1.38 g, 3.11 mmol) obtained in the previous step in 75% glacial acetic acid water solution, stirring at 80 deg.C for 9 h until the raw material disappears completely, removing acetic acid by rotary evaporation, dissolving the obtained product in 20mL pyridine, dropwise adding acetic anhydride (3.5mL, 37.03 mmol), stirring at room temperature for 5 h, and slowly adding saturated NaHCO3The reaction was quenched, extracted with dichloromethane (60 mL. times.2), the combined organic phases washed with saturated brine, and anhydrous Na was added2SO4Drying, filtering, rotary evaporation to remove solvent, and column chromatography (PE: EA = 15:1) to isolate product VI 0.58g, 39% yield.
The hydrogen spectrum of compound vi obtained is as follows:
1H NMR (400 MHz, CDCl3) δ 1.07 (9H, s), 1.92 (3H, s), 2.16 (3H, s), 3.40 (3H, s), 3.74 (1H, dd, J = 11.6, 3.4 Hz), 3.91 (1H, dd, J = 11.6, 2.9 Hz), 4.10 (1H, dt, J = 11.6, 3.74 Hz), 4.25 (1H, dd, J = 7.6, 4.6 Hz), 5.34 (1H, d, J = 4.4 Hz), 6.15 (1H, s), 7.37-7.44 (6H, m), 7.67-7.70 (4H, m).
and a sixth step:
in a 150mL two-necked flask, product VI (0.93 g,1.90 mmol) andN2-acetylguanine (0.37 g, 1.92 mmol), 20mL of ultra-dry 1, 2-dichloroethane are added, followed byN,OBis-trimethylsilyl acetamide (2.8mL, 11.45 mmol), refluxing at 100 deg.C for 30min, adding trifluoromethyl silyl trifluoromethanesulfonate (1.05 mL,5.80 mmol), refluxing for 1 h, cooling to room temperature, and slowly adding saturated NaHCO3The reaction was quenched, extracted with dichloromethane (30 mL. times.2), the combined organic phases washed with saturated brine, and anhydrous Na was added2SO4Drying, filtration, solvent removal by rotary evaporation and column chromatography (PE: EA = 1:2 to 1:3) gave 640 mg of a yellow solid as product VII by nuclear magnetic resonance in 54% yield.
The hydrogen spectrum of the obtained compound VII is as follows:
1H NMR (400 MHz, CDCl3) δ 1.06 (9H, s), 2.08 (3H, s), 2.24 (3H, s), 3.35 (3H, s), 3.81 (1H, dd, J = 11.7, 3.3 Hz), 4.00 (1H, dd, J = 11.7, 3.0 Hz), 4.14-4.17 (1H, m), 4.27 (1H, dd, J = 5.1, 5.1 Hz), 5.58 (1H, dd, J = 4.8, 4.8 Hz), 6.01 (1H, d, J = 4.6 Hz), 7.33-7.43 (6H, m), 7.64-7.66 (4H, m), 8.00 (1H, s), 10.25 (1H, s br), 12.25 (1H, s br).
the seventh step:
dissolving the product VII (252.1 mg, 0.41 mmol) in 6 mL of ethanol and 3mL of 40% methylamine aqueous solution, stirring for 20 h at room temperature, removing the solvent by rotary evaporation, adding diethyl ether (15 mL) and dichloromethane (5 mL) for pulping to generate a large amount of white solid, and filtering to obtain 148 mg of white powdery solid which is exactly the target product determined by nuclear magnetism, wherein the yield is 69%.
The hydrogen spectrum of compound VIII obtained is as follows:
1H NMR (400 MHz, DMSO-d 6) δ 1.00 (9H, s), 3.40 (3H, s), 3.74 (1H, m), 3.84 (1H, m), 3.96 (1H, m), 4.03 (1H, m), 4.59 (1H, s br), 5.56 (1H, s), 5.73 (1H, m), 6.50 (2H, s br), 7.41-7.45 (6H, m), 7.61-7.62 (4H, m), 7.84 (1H, s), 10.48 (1H, s br).
eighth step:
suspending the product VIII (54.3 mg, 0.10 mmol) in 3mL tetrahydrofuran, adding tetrabutylammonium fluoride in tetrahydrofuran (1M, 0.2 mL), allowing the reaction solution to quickly become clear, stirring at room temperature for 2h, removing the solvent by rotary evaporation, extracting with dichloromethane and water, transferring the product into the water phase, removing water by rotary evaporation, and recrystallizing (MeOH: Et)2O) to give a white solid which was confirmed by nuclear magnetism to be the desired product in 99.9% yield.
The hydrogen spectrum of compound IX obtained is as follows:
1H NMR (400 MHz, DMSO-d 6) δ 3.40 (3H, s), 3.51-3.53 (1H, m), 3.60-3.62 (1H, m), 3.79-3.81 (1H, m), 3.94-3.96 (1H, m), 4.56 (1H, s br), 5.20 (1H, s br), 5.45 (1H, s), 5.68 (1H, d, J = 6.1 Hz), 6.01 (2H, s br), 7.90 (1H, s), 11.03 (1H, s br).
finally, it should be noted that: the foregoing is illustrative of the preferred embodiments of the present invention, and is not to be construed as limiting thereof,
although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. A method for synthesizing 3' -methoxyguanosine has the following structure:
the specific technical scheme is realized by the following steps:
the method is characterized in that: the preparation method comprises the following steps:
(1) reacting the compound I with tert-butyldiphenylchlorosilane, and selectively protecting primary alcohol to obtain a compound II;
(2) the compound II is oxidized to ketone III;
(3) reducing the compound III into alcohol IV, and inverting the configuration of secondary alcohol;
(4) methylating the compound IV to obtain an intermediate V;
(5) carrying out one-pot deprotection on the compound V, and carrying out acetylation to obtain an intermediate VI;
(6) compound VI andN-2-acetyl guanine is coupled to obtain an intermediate VII;
(7) removing two acetyl groups from the compound VII to obtain a compound VIII;
(8) and removing the silicon-based protecting group from the compound VIII to obtain a final product IX.
2. The method of synthesizing 3' -methoxyguanosine according to claim 1, wherein: the alkali used in the step (1) is one of imidazole, pyridine, 4-dimethylaminopyridine, triethylamine and diisopropylethylamine, the compound I is tert-butyldiphenylchlorosilane, and the molar ratio of the alkali is 1: (1.1-1.5) and (2-3) in the presence of an anhydrous organic solventN,N-one of dimethylformamide, anhydrous dichloromethane, anhydrous tetrahydrofuran.
3. The method of synthesizing 3' -methoxyguanosine according to claim 1, wherein: the solvent used in the step (2) is anhydrous dichloromethane, the reaction temperature is-60 ℃ to room temperature, and the used oxidant can also be chromium trioxide, a dessimutan oxidant and the like.
4. The method of synthesizing 3' -methoxyguanosine according to claim 1, wherein: the molar ratio of the compound III to the sodium borohydride in the step (3) is 1: (6-8), wherein the volume ratio of the mixed solvent ethanol to the water is 3: 1.
5. The method of synthesizing 3' -methoxyguanosine according to claim 1, wherein: the methylating agent used in the step (4) is one of methyl iodide, dimethyl sulfate and trimethyl oxonium tetrafluoroborate, and the used solvent is anhydrousN,N-dimethylformamide.
6. The method of synthesizing 3' -methoxyguanosine according to claim 1, wherein: the de-acetalization reagent in the step (5) can be one of 75% acetic acid and 50% trifluoroacetic acid, and the acetylation reagent can be one of acetic anhydride and acetyl chloride.
7. The method of synthesizing 3' -methoxyguanosine according to claim 1, wherein: the reagent for coupling with the compound VI in the step (6) isN-2-acetylguanine, compound VI,N-a 2-acetyl-guanine in the presence of a ligand,N,Othe molar ratio of bis (trimethylsilyl) acetamide to trifluoromethanesulfonic acid trifluoromethyl silicone grease is 1:1:6:3, the solvent used is anhydrous 1, 2-dichloroethane, and the reaction temperature is 100 ℃.
8. The method of synthesizing 3' -methoxyguanosine according to claim 1, wherein: in the step (7), the solvent is a mixture of ethanol and 40% methylamine water solution, and the volume ratio of the solvent is 2: 1.
9. The method of synthesizing 3' -methoxyguanosine according to claim 1, wherein: the method for removing the silicon-based protecting group in step (8) may be any one of a tetrabutylammonium fluoride/tetrahydrofuran system, a 3% hydrochloric acid/methanol system, a hydrogen fluoride pyridine/tetrahydrofuran system, or a hydrofluoric acid/acetonitrile system.
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| WO2015038596A1 (en) * | 2013-09-11 | 2015-03-19 | Emory University | Nucleotide and nucleoside compositions and uses related thereto |
| WO2016145142A1 (en) * | 2015-03-10 | 2016-09-15 | Emory University | Nucleotide and nucleoside therapeutics compositions and uses related thereto |
| WO2020092127A1 (en) * | 2018-10-29 | 2020-05-07 | Venenum Biodesign, LLC | Novel sting agonists |
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| WO2015038596A1 (en) * | 2013-09-11 | 2015-03-19 | Emory University | Nucleotide and nucleoside compositions and uses related thereto |
| WO2016145142A1 (en) * | 2015-03-10 | 2016-09-15 | Emory University | Nucleotide and nucleoside therapeutics compositions and uses related thereto |
| WO2020092127A1 (en) * | 2018-10-29 | 2020-05-07 | Venenum Biodesign, LLC | Novel sting agonists |
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