CN113278040A - Preparation method of 5' -isobutyryl-N4-hydroxycytidine - Google Patents
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Abstract
The invention discloses a preparation method of 5' -isobutyryl-N4-hydroxycytidine with the function of preventing and treating various virus infections including new corona (COVID-19), which comprises the following steps: the compound 5' -isobutyryl-N4-hydroxycytidine of the formula I is prepared by taking D-ribose and cytosine as starting raw materials and performing protection, acylation and hydroxylamination reactions of mesityl oxide and the obtained compound through condensation and hydrolysis reactions. The preparation method has the advantages of easily available raw materials, simple process, economy and environmental protection, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of organic synthesis route design and preparation of raw material medicines and intermediates thereof, and particularly relates to a preparation method of 5' -isobutyryl-N4-hydroxycytidine with the effect of preventing and treating various virus infections including new corona (COVID-19).
Background
Ribonucleosides and analogues thereof, which are common reverse transcriptase inhibitors, have been widely used clinically for the prevention and treatment of HIV, MCV and MBV. Further research shows that the N4-hydroxyl ribonucleoside and the derivative thereof can inhibit the replication of various RNA viruses and have strong inhibition capability on respiratory syncytial virus, influenza virus, chikungunya fever virus, Ebola virus, Venezuela equine encephalitis virus, eastern equine encephalitis virus and the like. Meanwhile, the compounds also show inhibitory activity against coronaviruses including SARS, MERS and SARS-CoV-2. "SCIENCE ADVANCES [ Science advances (2020),6(27) ]" and "NATURE [ Nature (2021),591(7850),451 + 457 ]" report the preventive and therapeutic effects of the derivatives "EIDD-2801" and "EIDD-1931" having the N4-hydroxycytidine structure against the novel coronavirus (COVID-19).
The compound of formula I, EIDD-2801, has the chemical generic name: (((2R,3S,4R,5R) -3, 4-dihydroxy-5 β -4- (hydroxyimino) -2-oxo-3, 4-dihydropyrimidin-1 (2H) -yl) tetrahydrofuran-2-yl) isobutyric acid methyl ester; they may also be named 5 '-isobutyryl-N4-hydroxycytidine or 5' -isobutyryl-4-oxime uridine, respectively, according to their nucleoside structures. This application is named after 5' -isobutyryl-N4-hydroxycytidine. The structural formula is as follows:
french patent FR2199460A1 (1972, 21) and British patent GB1386334A (1972, 9, 22) disclose compounds of the formulaWherein R is1Is isobutyryl, and Y is hydroxyl, the compound of formula I is the target structure of the present invention.
The inhibition mechanisms of the compounds of formula I against E.coli, Escherichia coli and Salmonella typhimurium are reported in the documents "Mol Gen Genet (1982)186, 411-418" and "Proc. int. Symp. biomol. Structure. interactions, suppl. J. biosci. (1985),8(3&4), 657-668". International patents WO2019113462 and WO2019173602, as well as the literature "Journal of Physical Chemistry Letters (2020),11(21), 9408-9414.", "Frontiers in pharmacy (2020),11,1196.", "Journal of Medical Virology (2021),93(1), 300-310.", "Journal of Chemical Information and Modeling (2021),61(3), 1402-1411.", and "Nature Microbiology (2021),6(1), 11-18." etc. report on the prevention and treatment studies of influenza virus, SARS-CoV-2 and COVID-19 infections with N-hydroxycytosine and its analogs as one of the hotspots of the field of research.
The synthesis of compounds of formula I is reported in International patent Nos. WO2016106050, WO2019173602, WO2019113462, WO2002032920, WO2002018404 and Chinese patent application CN112608357A, and in the literature "Journal of Organic Chemistry, (2004),69(23)," 8148-.
The existing synthesis reports are comprehensively analyzed, and although various differences exist in functional group protection and deprotection modes, catalyst selection (including enzyme catalyst) and dosage thereof, unit reaction selection and reaction sequence, reaction condition setting, equipment selection and microchannel application and the like, the synthetic routes are basically consistent, namely cytidine or uridine is used as starting materials, and the isobutylation of 5' -hydroxyl and the hydroxylamination of N-4 amino are realized through the protection and the deprotection of different functional groups.
Comparing and comparing the preparation methods in the prior documents, it is found that due to the existence of a plurality of hydroxyl groups and amino groups in the raw materials, multiple competing side reactions are generated when the above reactions and deprotection occur, so that the whole preparation process appears to be extremely complicated, and the total yield is generally low. Meanwhile, the physicochemical property difference of the raw materials and the products is small, so that the separation and purification difficulty is increased, column chromatography or liquid phase preparation is mostly adopted for separation and purification in the post-treatment, and the requirements of industrial production cannot be met obviously.
Therefore, the preparation method of the compound shown in the formula I, which is simple, rapid, economic and environment-friendly and convenient to industrialize, is designed and developed, and has very important practical significance for the application of the compound in the field of antivirus, especially for the prevention and treatment of new coronavirus infection at present.
Disclosure of Invention
The invention aims to provide a preparation method of N4-hydroxycytidine shown in the formula I, which has simple process, is economic and environment-friendly and is suitable for industrial production.
In order to achieve the purpose, the invention adopts the following main technical scheme: a process for the preparation of a compound of formula I useful in the treatment of viral infections, in particular the prevention and treatment of influenza and various coronavirus infections,
the preparation method comprises the following steps: the D-ribose and acetone are subjected to acetone forking protection to prepare 2,3-O- (1-methylethylidene) -D-ribose (II); 2,3-O- (1-methylethylidene) -D-ribose (II) and isobutyric anhydride or isobutyryl chloride are subjected to acylation reaction to prepare 1, 5-diisobutyryl-2, 3- (1-methylethylidene) -D-ribose (III); carrying out a hydroxylamination reaction on cytosine and hydroxylamine under a certain pH value condition to obtain N4-hydroxylamine cytosine (IV); n4-hydroxylamine cytosine (IV) is subjected to silanization protection and then undergoes condensation reaction with 1, 5-diisobutyryl-2, 3- (1-methylethylidene) -D-ribose (III) under the action of Lewis acid to prepare 5 ' -isobutyryl-2 ', 3 ' - (1-methylethylidene) -N4-hydroxycytidine (V); and hydrolyzing the 5 '-isobutyryl-2', 3 '- (1-methylethylidene) -N4-hydroxycytidine (V) to obtain the 5' -isobutyryl-N4-hydroxycytidine (I).
In addition, the invention also provides the following auxiliary technical scheme:
the solvent of the acetone forking protection reaction is acetone, and the catalyst is sulfuric acid.
The acylating agent for the acylation reaction is isobutyric anhydride or isobutyryl chloride, wherein the feeding molar ratio of the raw material 2,3-O- (1-methylethylidene) -D-ribose (II) to the acylating agent is 1: 2.0-4.0, preferably 1: 2.0-3.0.
The acid-binding agent for the acylation reaction is sodium hydroxide, potassium carbonate, cesium carbonate, triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, 4-dimethylaminopyridine, triethylenediamine, 1, 8-diazabicycloundecen-7-ene or tetramethylethylenediamine, preferably triethylamine or 1, 8-diazabicycloundecen-7-ene.
The solvent for the acylation reaction is dioxane, toluene, xylene, tetrahydrofuran, acetonitrile, dichloromethane or chloroform, preferably dichloromethane or acetonitrile.
The temperature of the acylation reaction is 0-50 ℃, preferably 5-25 ℃.
The hydroxylamine in the hydroxylamination reaction is hydroxylamine hydrochloride, hydroxylamine sulfate or hydroxylamine acetate, preferably hydroxylamine hydrochloride.
The feeding molar ratio of raw materials cytosine to hydroxylamine in the hydroxylamination reaction is 1: 1.0-6.0, preferably 1: 1.5-2.5.
The pH value of the hydroxylamine amination reaction is 3-7, and the preferable pH value is 5-7.
The temperature of the hydroxylamination reaction is 25-80 ℃, and preferably 55-65 ℃.
The solvent of the hydroxylamination reaction is water or an organic solvent such as methanol, ethanol, isopropanol, N-butanol, tetrahydrofuran, dioxane or N, N-dimethylformamide, or a mixed solvent of water and the organic solvent; the volume ratio of water to the organic solvent in the mixed solvent is 1: 0.1-0.9. Preferably water or a mixed solvent of water and ethanol (volume ratio is 1: 0.2-0.5).
The silanization reagent for silanization protection is hexamethyldisilazane and trimethylchlorosilane.
The reaction temperature of the silanization protection is 50-150 ℃, and preferably 90-110 ℃.
The solvent of the silanization protection reaction is toluene, dioxane, tetrahydrofuran, acetonitrile, dimethyl sulfoxide or N, N-dimethylformamide, and toluene is preferred.
The feeding molar ratio of the raw materials of the condensation reaction, namely N4-hydroxycytosine (IV), 1, 5-diisobutyryl-2, 3- (1-methylethylidene) -D-ribose (III) and Lewis acid is 1: 0.8-1.2: 1.0-2.0, and 1:1.0:1.2 is preferred.
The Lewis acid of the condensation reaction is zinc chloride, zinc iodide, aluminum trichloride, ferric trichloride, boron trifluoride, stannic chloride and niobium pentachloride, and stannic chloride is preferred.
The solvent for the condensation reaction is toluene, dioxane, tetrahydrofuran, acetonitrile, dichloromethane or chloroform, preferably dichloromethane.
The condensation reaction is carried out at a temperature of-25 to 50 ℃, preferably 0 to 25 ℃.
The hydrolysis reaction is preferably acidic hydrolysis, and the acid used is hydrochloric acid, sulfuric acid, hydrobromic acid, formic acid, acetic acid, trifluoroacetic acid or trifluoromethanesulfonic acid, preferably hydrochloric acid or formic acid.
The solvent for hydrolysis reaction is methanol, formic acid, ethanol, acetic acid, isopropanol, acetonitrile, tetrahydrofuran or 2-methyltetrahydrofuran, preferably methanol or formic acid
The temperature of the hydrolysis reaction is 0-50 ℃, and preferably 20-30 ℃.
Compared with the prior art, the preparation method of the compound 5' -isobutyryl-N4-hydroxycytidine (I) in the formula I has the characteristics of simple process, environmental protection, economy, easy separation and purification and the like, is favorable for industrial production of the compound, and promotes the development of economic technology of the compound.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of a compound of formula I in accordance with a preferred embodiment of the present invention;
FIG. 2 is a mass spectrum of a compound of formula I according to a preferred embodiment of the present invention;
FIG. 3 is a nuclear magnetic hydrogen spectrum of a compound of formula IV in accordance with a preferred embodiment of the present invention;
FIG. 4 is a mass spectrum of a compound of formula IV according to a preferred embodiment of the present invention.
Detailed Description
The following non-limiting detailed description of the present invention is provided in connection with the preferred embodiments and accompanying drawings. In the description of the present invention, it is to be understood that the terms "center", "longitudinal", "lateral", "length", "width", "thickness", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", "clockwise", "counterclockwise", "axial", "radial", "circumferential", etc., indicate orientations or positional relationships based on the orientation or positional relationships shown in the drawings. Furthermore, the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one such feature. In the description of the present invention, "a plurality" means at least two, e.g., two, three, etc., unless specifically limited otherwise. The embodiments described below with reference to the drawings are illustrative and intended to be illustrative of the invention and are not to be construed as limiting the invention.
The first embodiment is as follows:
d-ribose (30.0g, 0.2mol) and acetone (300mL) were added to a reaction flask, sulfuric acid (98%, 1.0mL) was added with stirring, and the reaction was carried out at 20 to 25 ℃ for 4 to 5 hours. Adding sodium bicarbonate until no carbon dioxide is discharged in the system, and continuously stirring for 1 hour at room temperature until the reaction is finished. Filtering, washing filter cakes with acetone, combining filtrates, and concentrating under reduced pressure to obtain light yellow oily matter 2,3-O- (1-methylethylidene) -D-ribose (II) (which can be directly used for the next reaction) 35.2g, and the yield is 92.9%.
Example two:
2,3-O- (1-methylethylidene) -D-ribose (II) (19.0g, 0.1mol), 1, 8-diazabicycloundecen-7-ene (38.1g,0.25mol) and acetonitrile (200mL) were charged into a reaction flask, and isobutyric anhydride (39.6g,0.25mol) was added dropwise at room temperature with stirring, and the reaction was continued for 10 to 12 hours. Concentration, dichloromethane dissolution, washing twice with water, drying over anhydrous sodium sulfate, concentration and vacuum drying to obtain oil 1, 5-diisobutyryl-2, 3- (1-methylethylidene) -D-ribose (III)29.8g, yield 90.3%. EI-MS (M/z):331[ M + H]+。
Example three:
2,3-O- (1-methylethylidene) -D-ribose (II) (19.0g, 0.1mol), isobutyryl chloride (25.6g,0.24mol) and dichloromethane (300mL) were added to a reaction flask, the temperature was reduced to 5-15 ℃, triethylamine (24.3g,0.24mol) was added in portions with stirring, and the reaction was maintained at the temperature for 3-5 hours. Adding water to quench the reaction, washing with water, separating an organic phase, and drying with anhydrous sodium sulfate. Concentration and vacuum drying to obtain oil 1, 5-diisobutyryl-2, 3- (1-methylethylidene) -D-ribose (III)31.4g with yield 95.4%. EI-MS (M/z):331[ M + H]+。
Example four:
adding 11.1g of cytosine (0.1 mol), 13.9g of hydroxylamine hydrochloride (0.2 mol) and 200mL of water into a reaction bottle in sequence, adding sodium acetate to adjust the pH value to 5-7 under stirring, gradually raising the temperature to 55-65 ℃, keeping the temperature within the temperature range for reaction for 3-5 hours, slowly cooling to room temperature to separate out a precipitate, continuously cooling to 0 ℃, fully crystallizing for 4 hours, filtering, washing a filter cake with cold methanol to obtain 11.6g of white-like solid N4-hydroxycytosine (IV), wherein the yield is 91.3%. EI-MS (M/z) 128[ M + H ].
Example five:
in the reverse directionAdding 11.1g of cytosine (0.1 mol), 26.2g of hydroxylamine sulfate (0.2 mol), 200mL of water and 50mL of ethanol (the volume ratio of the water to the ethanol is 1:0.25) into a bottle in sequence, adding sodium acetate to adjust the pH value to 5-7 while stirring, gradually heating to 55-65 ℃, keeping the temperature range for reaction for 3-5 hours, slowly cooling to room temperature to precipitate, continuously cooling to 0 ℃, fully crystallizing for 4 hours, filtering, washing a filter cake with cold methanol to obtain 11.9g of white-like solid N4-hydroxycytosine (IV), wherein the yield is 93.7%.1H NMR(DMSO-d6) δ 9.82(d, J ═ 13.2Hz,1H),9.62(s,1H),9.10(s,1H),6.62(q, J ═ 7.6,5.2Hz,1H),5.36(d, J ═ 8.0Hz, 1H); the nuclear magnetic hydrogen spectrum diagram is shown in the attached figure 3 in the specification in detail. EI-MS (M/z) 128[ M + H]+(ii) a The mass spectrum is shown in figure 4 in the specification.
Example six:
under the protection of nitrogen, adding N4-hydroxycytosine (IV) (12.7g, 0.1mol), hexamethyldisilazane (16.1g, 0.1mol), trimethylchlorosilane (2.2g, 0.02mol) and toluene (100mL) into a three-opening reaction bottle, slowly heating to 95-105 ℃, reacting for 1-2 hours under heat preservation, cooling to 50-75 ℃, and concentrating under reduced pressure to obtain intermediate state silanized N4-hydroxycytosine. Dichloromethane (200mL) was added to the concentrate at room temperature, the temperature was reduced to 0 to 5 ℃,1, 5-diisobutyryl-2, 3- (1-methylethylidene) -D-ribose (III) (33.0g, 0.1mol) was added thereto, and the mixture was stirred for 15 to 30 minutes. Tin tetrachloride (31.2g, 0.12mol) was added and stirring was continued for 15 minutes after the addition. Raising the temperature to room temperature and continuing the reaction for 2-4 hours. Adding water to quench the reaction, standing for layering, separating an organic phase, and extracting a water phase twice by using dichloromethane. The organic phases were combined, washed successively with aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was recrystallized from ethanol to give 29.0g of 5 ' -isobutyryl-2 ', 3 ' - (1-methylethylidene) -N4-hydroxycytidine (V), which is an off-white solid product, in 78.6% yield. EI-MS (M/z) 370[ M + H]+。
Example seven:
at room temperature, 5 ' -isobutyryl-2 ', 3 ' - (1-methylethylidene) -N4-hydroxycytidine (V) (18.5g,0.05mol), diluted hydrochloric acid (1.0M, 100mL) and 100mL of methanol are added into a reaction bottle, stirred and reacted for 1-2 hours, and the TLC detection reaction is completed. Reduced pressureConcentrating to dryness, adding a proper amount of water, adjusting the pH value to 6-7 by using sodium bicarbonate, cooling to 0-5 ℃, and crystallizing for 2-3 hours. Filtering, recrystallizing the filter cake with ethanol, and vacuum drying to obtain 12.2g of white solid 5' -isobutyryl-N4-hydroxycytidine (I), with yield of 74.2%; EI-MS M/z 330[ M + H ]]+。
Example eight:
at room temperature, 5 ' -isobutyryl-2 ', 3 ' - (1-methylethylidene) -N4-hydroxycytidine (V) (18.5g,0.05mol) and formic acid (200mL) are added into a reaction bottle, and the mixture is stirred at room temperature for reaction for 5-6 hours, and the TLC detection reaction is finished. Concentrating under reduced pressure, recrystallizing the residue with isopropanol, and vacuum drying to obtain white solid 5' -isobutyryl-N4-hydroxycytidine (I)13.2g with yield 80.2%;1H NMR(D2o) δ 6.88(d, J ═ 8.0Hz,1H),5.78(d, J ═ 4.4Hz,1H),5.68(d, J ═ 8.0Hz,1H),4.69(brs,3H),4.26(m,3H),4.17(m,2H),2.60(p, J ═ 6.4Hz,1H),1.08(d, J ═ 6.8Hz, 6H); the nuclear magnetic hydrogen spectrum diagram is shown in the attached figure 1 in the specification in detail. EI-MS M/z 330[ M + H ]]+(ii) a The mass spectrum is shown in figure 2 in the specification.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. A preparation method of 5' -isobutyryl-N4-hydroxycytidine with the efficacy of preventing and treating virus infection as shown in formula I,
the preparation method comprises the following steps: the D-ribose and acetone are subjected to acetone forking protection to prepare 2,3-O- (1-methylethylidene) -D-ribose; acylation reaction of 2,3-O- (1-methylethylidene) -D-ribose with isobutyric anhydride or isobutyryl chloride to obtain 1, 5-diisobutyryl-2, 3- (1-methylethylidene) -D-ribose; carrying out a hydroxylamination reaction on cytosine and hydroxylamine under a certain pH value condition to obtain N4-hydroxylamine cytosine; carrying out silanization protection on N4-hydroxylamine cytosine, and carrying out condensation reaction with 1, 5-diisobutyryl-2, 3- (1-methylethylidene) -D-ribose under the action of Lewis acid to prepare 5 ' -isobutyryl-2 ', 3 ' - (1-methylethylidene) -N4-hydroxycytidine; 5 '-isobutyryl-2', 3 '- (1-methylethylidene) -N4-hydroxycytidine is hydrolyzed to prepare the compound 5' -isobutyryl-N4-hydroxycytidine of the formula I.
2. A process for the preparation of a compound of formula I according to claim 1, characterized in that: the acylating agent for the acylation reaction is isobutyric anhydride or isobutyryl chloride, wherein the feeding molar ratio of the raw material 2,3-O- (1-methylethylidene) -D-ribose to the acylating agent is 1: 2.0-4.0.
3. A process for the preparation of a compound of formula I according to claim 1, characterized in that: hydroxylamine in the hydroxylamination reaction is hydroxylamine hydrochloride, hydroxylamine sulfate or hydroxylamine acetate; wherein the feeding molar ratio of the raw materials of cytosine to hydroxylamine is 1: 1.0-6.0.
4. A process for the preparation of a compound of formula I according to claim 1, characterized in that: the pH value of the hydroxylamine amination reaction is 3-7; the temperature of the hydroxylamination reaction is 25-80 ℃.
5. A process for the preparation of a compound of formula I according to claim 1, characterized in that: the solvent of the hydroxylamination reaction is water or an organic solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, dioxane or N, N-dimethylformamide, or a mixed solvent of water and any one of the organic solvents; the volume ratio of water to the organic solvent in the mixed solvent is 1: 0.1-0.9.
6. A process for the preparation of a compound of formula I according to claim 1, characterized in that: the feeding molar ratio of the raw materials N4-hydroxycytosine, 1, 5-diisobutyryl-2, 3- (1-methylethylidene) -D-ribose and Lewis acid in the condensation reaction is 1: 0.8-1.2: 1.0-2.0.
7. A process for the preparation of a compound of formula I according to claim 1, characterized in that: the Lewis acid of the condensation reaction is zinc chloride, zinc iodide, aluminum trichloride, ferric trichloride, boron trifluoride, stannic chloride and niobium pentachloride.
8. A process for the preparation of a compound of formula I according to claim 1, characterized in that: the solvent of the condensation reaction is toluene, dioxane, tetrahydrofuran, acetonitrile, dichloromethane or trichloromethane; the condensation reaction is carried out at a temperature of-25 to 50 ℃.
9. A process for the preparation of a compound of formula I according to claim 1, characterized in that: the acid used in the hydrolysis reaction is hydrochloric acid, sulfuric acid, hydrobromic acid, formic acid, acetic acid, trifluoroacetic acid or trifluoromethanesulfonic acid.
10. A process for the preparation of a compound of formula I according to claim 1, characterized in that: the solvent of the hydrolysis reaction is methanol, formic acid, ethanol, acetic acid, isopropanol, acetonitrile, tetrahydrofuran or 2-methyltetrahydrofuran; the temperature of the hydrolysis reaction is 0-55 ℃.
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| CN113735928A (en) * | 2021-10-21 | 2021-12-03 | 药康众拓(江苏)医药科技有限公司 | N4-hydroxycytidine derivative and preparation method and application thereof |
| CN113880902A (en) * | 2021-10-26 | 2022-01-04 | 江苏睿实生物科技有限公司 | Molnupiravir drug intermediate and preparation method thereof |
| CN113956312A (en) * | 2021-10-29 | 2022-01-21 | 山东诚创蓝海医药科技有限公司 | Preparation method of mopilavir |
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| CN115873055B (en) * | 2022-11-30 | 2023-11-03 | 山东诚汇双达药业有限公司 | Method for safely producing mopiravir intermediate |
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