CN115716833A - Preparation method of antiviral nucleoside analogue - Google Patents

Preparation method of antiviral nucleoside analogue Download PDF

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CN115716833A
CN115716833A CN202110988001.1A CN202110988001A CN115716833A CN 115716833 A CN115716833 A CN 115716833A CN 202110988001 A CN202110988001 A CN 202110988001A CN 115716833 A CN115716833 A CN 115716833A
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formula
compound
reagent
acid
reacting
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田广辉
李建
谢元超
徐万斌
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Suzhou Vigonvita Life Sciences Co ltd
Shanghai Institute of Materia Medica of CAS
Wuhan Institute of Virology of CAS
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Suzhou Vigonvita Life Sciences Co ltd
Shanghai Institute of Materia Medica of CAS
Wuhan Institute of Virology of CAS
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Abstract

The invention belongs to the field of medicines, and particularly relates to a preparation method of an antiviral nucleoside analogue, which comprises the following steps: reacting the compound shown in the formula (VIII) with a reagent A to generate a compound shown in the formula (VII); reacting the compound shown in the formula (VII) with a reagent B under the action of a metal reagent M to generate a compound shown in a formula (VI); reacting the compound shown in the formula (VI) with a reagent C to generate a compound shown in the formula (V); reacting the compound shown in the formula (V) with a reagent D to generate a compound shown in the formula (IV); reacting the compound shown in the formula (IV) with a reagent E to generate a compound shown in a formula (III); reacting the compound shown in the formula (III) with a reagent F to generate a compound shown in the formula (II); reacting the compound of formula (II) with a reagent G to produce the compound of formula (I). The reaction condition is mild, the process is easy to control, the operation is simple, and the method is suitable for industrial large-scale production.

Description

Preparation method of antiviral nucleoside analogue
Technical Field
The invention relates to the field of medicines, in particular to a preparation method of an antiviral nucleoside analogue.
Background
The novel coronavirus pneumonia (COVID-19) is an acute respiratory infectious disease caused by 2019 novel coronavirus (SARS-CoV-2) infection. The vaccine is the most effective method for preventing virus infection, and SARS-CoV-2 vaccine is inoculated in various countries in the world at present. Therefore, the development of low-toxicity and high-efficiency antiviral drugs has important significance for preventing and treating COVID-19.
SARS-CoV-2 is a positive-stranded RNA virus whose replication is mediated by a multimeric replication/transcription complex of the viral nonstructural protein (nsp), the core component of which is an RNA-dependent RNA polymerase (RdRp, also known as nsp 12). The active center of RNA-dependent RNA polymerase has high conservation, is an important target for developing anti-SARS-CoV-2 drugs, and the approved and under-developed nucleoside analogue drugs may have the potential for resisting SARS-CoV-2 infection.
VV116 is an orally available nucleoside anti-SARS-CoV-2 candidate:
Figure BDA0003231447290000011
after entering into the body, the nucleotide is converted into an active form of nucleoside triphosphate through hydrolysis and stepwise phosphorylation under the action of enzyme, and the triphosphate can be inserted into an RNA chain of a virus which is being extended, so that the extension of the triphosphate is stopped to inhibit the proliferation of the virus. VV116 has stronger anti-SARS-CoV-2 activity and lower cytotoxicity on Vero E6 cells, and is superior to the control drug Reidesvir; on an adenovirus transduction mouse model expressing a new coronavirus receptor human ACE2, the oral administration can be carried out once a day, and the virus load of the lung of a mouse can be reduced in a dose-dependent manner. Moreover, the candidate drug also has inhibitory activity against other viruses (such as respiratory syncytial virus, dengue virus, hepatitis C virus, zika virus, etc.), and has broad-spectrum antiviral characteristics.
VV116 is a COVID-19 therapeutic drug with great development prospect, so that the search for an efficient, economical and practical preparation method can help the further development of the candidate drug and has important significance for preventing and/or treating COVID-19.
Disclosure of Invention
Problems to be solved by the invention
The invention provides a preparation method of an antiviral nucleoside analogue VV116, which has the advantages of mild reaction conditions, easily controlled process and simple operation and is suitable for industrial large-scale production.
Means for solving the problems
The invention provides a process for the preparation of a compound of formula (I) which comprises the steps of:
1) Reacting a compound of formula (VIII) with a reagent A under the action of an acid to obtain a compound of formula (VII):
Figure BDA0003231447290000021
wherein X is halogen;
2) Reacting a compound of formula (VII) with a reagent B under the action of a metal reagent M to obtain a compound of formula (VI):
Figure BDA0003231447290000022
3) Reacting a compound of formula (VI) with reagent C to give a compound of formula (V):
Figure BDA0003231447290000023
4) Reacting a compound of formula (V) with a reagent D to give a compound of formula (IV):
Figure BDA0003231447290000024
5) Reacting a compound of formula (IV) with a reagent E under the action of an organic base to obtain a compound of formula (III):
Figure BDA0003231447290000025
6) Reacting a compound of formula (III) with a reagent F to give a compound of formula (II):
Figure BDA0003231447290000031
7) Reacting a compound of formula (II) with a reagent G to give a compound of formula (I):
Figure BDA0003231447290000032
preferably, the process for the preparation of the compounds of formula (I) according to the invention, step 1),
x is I, br or Cl, and the reagent A is N-iodosuccinimide or I 2 、Br 2 One of N-bromosuccinimide, dibromohydantoin or N-chlorosuccinimide; preferably, X is I or Br, and the reagent A is N-iodosuccinimide, I 2 、Br 2 One of N-bromosuccinimide or dibromohydantoin; more preferably, X is I and the reagent a is N-iodosuccinimide;
the acid is an organic acid, preferably one of trifluoroacetic acid, trichloroacetic acid or acetic acid, and more preferably trifluoroacetic acid;
the reaction solvent is one of N, N-dimethylformamide, tetrahydrofuran or acetonitrile, and preferably acetonitrile;
the reaction temperature is 0-50 ℃, preferably 20-30 ℃, and more preferably 25 ℃;
wherein the molar ratio of the compound of the formula (VIII), the reagent A and the acid is 1 (1-1.5) to (0.1-0.5), preferably 1.
Preferably, in the preparation method of the compound of formula (i), step 2), the reagent B is one of deuterium gas, a deuterated acidic reagent or deuterium oxide.
Further preferably, according to the preparation method of the compound of formula (i), step 2), the compound of formula (vii) is reacted with the deuterium gas under the action of the metal reagent M and an organic base;
the metal reagent M is a palladium catalyst, preferably palladium carbon; the organic base is one of triethylamine, N-diisopropylethylamine, trimethylamine, ammonia gas, ammonia water, DBU or pyridine, and preferably triethylamine; the reaction solvent is one of tetrahydrofuran, methanol, ethanol, isopropanol or ethyl acetate, and is preferably tetrahydrofuran; the reaction pressure is 0.1-2 MPa, preferably 1.0MPa; the reaction temperature is 25-65 ℃, preferably 55-65 ℃;
wherein the mass ratio of the compound of the formula (VII) to the palladium carbon dry basis is 1 (0.01-0.2), and the molar ratio of the compound of the formula (VII) to the organic base is 1 (1-3).
Further preferably, according to the process for the preparation of the compound of formula (i) of the present invention, in step 2), said compound of formula (vii) is reacted with said deuterated acidic reagent under the action of said metal reagent M;
the deuterated acidic reagent is one of deuterated hydrochloric acid, deuterated sulfuric acid, deuterated acetic acid, deuterated trifluoroacetic acid or deuterated ammonium chloride; the metal reagent M is zinc and/or iron; the reaction solvent is ultra-dry tetrahydrofuran; the reaction temperature is 0-50 ℃, and preferably 20-30 ℃;
wherein the molar ratio of the compound shown in the formula (VII), the deuterated acidic reagent and the metal reagent M is 1 (4.0-4.5) to (4.0-6.0).
Further preferably, according to the process for the preparation of the compound of formula (i) of the present invention, in step 2), the compound of formula (vii) is reacted with the heavy water under the action of the metal reagent M and the reagent B';
the metal reagent M is zinc and/or iron; the reagent B' is one of phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, boron trichloride or aluminum trichloride; the reaction solvent is ultra-dry tetrahydrofuran; the reaction temperature is 0-50 ℃, and room temperature is preferred;
wherein the molar ratio of the compound of the formula (VII), the heavy water, the metal reagent M and the reagent B' is 1 (15-25) to (2-4) to (1-2).
Preferably, according to the preparation method of the compound of formula (i), in step 3), the reagent C is boron trichloride and/or boron tribromide, the reaction solvent is dichloromethane, and the reaction temperature is-35 to-25 ℃;
wherein the molar ratio of the compound shown in the formula (VI) to the reagent C is 1 (3-6).
Preferably, according to the process for the preparation of the compound of formula (i) according to the present invention, in step 4), the reagent D is N, N-dimethylformamide dimethyl acetal or N, N-dimethylformamide diethyl acetal, preferably N, N-dimethylformamide dimethyl acetal; the reaction solvent is tetrahydrofuran; the reaction temperature is 20-55 ℃, preferably 45-55 ℃;
wherein the molar ratio of the compound of the formula (V) to the reagent D is 1 (2-4).
Preferably, according to the preparation method of the compound of formula (i), in step 5), the reagent E is one of isobutyryl chloride, isobutyric anhydride or isobutyric acid;
when the reagent E is isobutyryl chloride or isobutyric anhydride, reacting the compound of the formula (IV) with the reagent E under the action of an organic base and a catalyst, wherein the organic base is triethylamine and/or N, N-diisopropylethylamine, and preferably triethylamine; the catalyst is 4-dimethylaminopyridine; the reaction solvent is dichloromethane; the reaction temperature is 5-30 ℃, preferably 5-15 ℃;
wherein the molar ratio of the compound shown in the formula (IV), the reagent E, the organic base and the catalyst is 1 (3-5) to (4-6) to (0.01-0.1);
when the reagent E is isobutyric acid, reacting the compound shown in the formula (IV) with the reagent E under the action of an organic base and a condensing agent, wherein the organic base is triethylamine and/or N, N-diisopropylethylamine; the condensing agent is one of dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or 1-hydroxybenzotriazole; the reaction solvent is dichloromethane; the reaction temperature is 5-30 ℃ and 5-15 ℃.
Preferably, according to the preparation method of the compound of formula (i), in step 6), the reagent F is one of acetic acid, trifluoroacetic acid, hydrochloric acid or hydrazine hydrate, preferably acetic acid; the reaction solvent is one of ethanol, isopropanol, tetrahydrofuran or acetonitrile, preferably ethanol; the reaction temperature is 0-55 ℃, preferably 45-55 ℃; wherein the molar ratio of the compound (III) to the reagent F is 1 (15-25);
in the step 7), the reagent G is hydrobromic acid, and the reaction temperature is 15-25 ℃; wherein the molar ratio of the compound shown in the formula (II) to the reagent G is 1 (1-1.2).
ADVANTAGEOUS EFFECTS OF INVENTION
The preparation method of the antiviral nucleoside analogue VV116 provided by the invention has the advantages of mild reaction conditions, easily-controlled process and simple operation, is beneficial to further development of the candidate drug, is suitable for industrial large-scale production, is efficient, economic and practical, and has important significance for preventing and/or treating COVID-19.
Detailed Description
Various exemplary embodiments, features and aspects of the present invention will be described in detail below. The word "exemplary" is used exclusively herein to mean "serving as an example, embodiment, or illustration. Any embodiment described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments.
Furthermore, in the following detailed description, numerous specific details are set forth in order to provide a better understanding of the present invention. It will be understood by those skilled in the art that the present invention may be practiced without some of these specific details. In other instances, methods, means, devices and steps which are well known to those skilled in the art have not been described in detail so as not to obscure the invention.
Unless otherwise stated, in the present specification, the case where no specific condition is specified is performed according to the conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
In the specification, all units used are international standard units, and numerical values and numerical ranges appearing in the invention are all understood to include systematic errors inevitable in industrial production.
In the present specification, the meaning of "may" includes both the meaning of performing a certain process and the meaning of not performing a certain process.
Reference in the specification to "some specific/preferred embodiments," "other specific/preferred embodiments," "embodiments," and so forth, means that a particular element (e.g., feature, structure, property, and/or characteristic) described in connection with the embodiment is included in at least one embodiment described herein, and may or may not be present in other embodiments. In addition, it is to be understood that the described elements may be combined in any suitable manner in the various embodiments.
The invention provides a process for the preparation of a compound of formula (I),
Figure BDA0003231447290000051
the method comprises the following steps:
1) Reacting a compound of formula (VIII) with a reagent A under the action of an acid to obtain a compound of formula (VII):
Figure BDA0003231447290000052
wherein X is halogen;
2) Reacting a compound of formula (VII) with a reagent B under the action of a metal reagent M to obtain a compound of formula (VI):
Figure BDA0003231447290000053
3) Reacting a compound of formula (VI) with a reagent C to give a compound of formula (V):
Figure BDA0003231447290000054
4) Reacting a compound of formula (V) with a reagent D to give a compound of formula (IV):
Figure BDA0003231447290000061
5) Reacting a compound of formula (IV) with a reagent E under the action of an organic base to obtain a compound of formula (III):
Figure BDA0003231447290000062
6) Reacting a compound of formula (III) with a reagent F to give a compound of formula (II):
Figure BDA0003231447290000063
7) Reacting a compound of formula (II) with a reagent G to give a compound of formula (I):
Figure BDA0003231447290000064
in the above embodiment:
step 1)
In some embodiments of the invention, X is I, br or Cl and reagent A is N-iodosuccinimide (NIS), I 2 、Br 2 N-bromosuccinimide (NBS), dibromohydantoin or N-chlorosuccinimide (NCS).
In some preferred embodiments of the invention, X is I orBr, reagent A is N-iodosuccinimide, I 2 、Br 2 One of N-bromosuccinimide and dibromohydantoin.
In some more preferred embodiments of the invention, X is I and reagent A is N-iodosuccinimide.
In some embodiments of the invention, the acid is an organic acid. In some preferred embodiments of the invention, the organic acid is one of trifluoroacetic acid, trichloroacetic acid or acetic acid, more preferably trifluoroacetic acid.
In some specific embodiments of the invention, the reaction solvent is one of N, N-dimethylformamide, tetrahydrofuran or acetonitrile, preferably acetonitrile.
In some embodiments of the invention, the reaction temperature is from 0 to 50 deg.C, preferably from 20 to 30 deg.C, and more preferably 25 deg.C. Illustratively, the reaction temperature may be 0 ℃,10 ℃,20 ℃, 25 ℃,30 ℃, 40 ℃, 50 ℃ or the like.
In some embodiments of the invention, the reaction time is 3 to 5 hours, preferably 4 hours.
Wherein, the molar ratio of the compound of formula (VIII), the reagent A and the acid is 1 (1-1.5) to (0.1-0.5), and exemplarily, the molar ratio of the compound of formula (VIII), the reagent A and the acid can be 1. In some preferred embodiments of the invention, the molar ratio of compound of formula (viii), reagent a and acid is 1.3.
Step 2)
In the step, the reagent B is one of deuterium gas, a deuterated acidic reagent or heavy water, and can obtain higher deuteration rate.
In some embodiments of the invention, the selected reagent B is deuterium, and the compound of formula (VII) is reacted with deuterium in the presence of a metal reagent M and an organic base to give the deuterated product (VI).
The metal reagent M is a palladium catalyst, preferably palladium carbon; the organic base is one of triethylamine, N-diisopropylethylamine, trimethylamine, ammonia gas, ammonia water, DBU or pyridine, and triethylamine is preferred; the reaction solvent is one of tetrahydrofuran, methanol, ethanol, isopropanol or ethyl acetate, and is preferably tetrahydrofuran; the reaction pressure is 0.1-2 MPa, preferably 1.0MPa; the reaction temperature is 25 to 65 ℃, preferably 55 to 65 ℃, and exemplarily, the reaction temperature can be 25 ℃, 35 ℃, 45 ℃, 50 ℃,55 ℃, 60 ℃, 65 ℃ and the like; the reaction time is 0.5 to 2.0 hours, preferably 1 to 1.5 hours.
Wherein, the mass ratio of the compound of formula (vii) to the palladium on carbon is 1 (0.01-0.2), and the mass ratio may be 1.01, 1. The palladium carbon is conventional wet palladium carbon sold in the market, contains about 55 percent of water and 5 to 10 percent of palladium.
The molar ratio of the compound of formula (VII) to the organic base is 1 (1-3), preferably 1.
In some embodiments of the invention, the reagent B used is a deuterated acidic reagent, and the compound of formula (VII) is reacted with a deuterated acidic reagent in the presence of a metal reagent M to give the deuterated product (VI).
The deuterated acidic reagent is one of deuterated hydrochloric acid, deuterated sulfuric acid, deuterated acetic acid, deuterated trifluoroacetic acid or deuterated ammonium chloride, preferably deuterated hydrochloric acid; the metal reagent M is zinc and/or iron, preferably zinc; the reaction solvent is ultra-dry tetrahydrofuran; the reaction temperature is 0 to 50 ℃, preferably 20 to 30 ℃, exemplarily 0 ℃,10 ℃,20 ℃, 25 ℃,30 ℃, 40 ℃, 50 ℃ and the like; the reaction time is 0.1 to 10 hours, preferably 0.2 to 4.0 hours.
Wherein, the molar ratio of the compound of formula (VII), the deuterated acidic reagent and the metal reagent M is 1 (4.0-4.5) to (4.0-6.0), and the molar ratio can be 1.
In some embodiments of the invention, reagent B is used as deuterium oxide, and the compound of formula (VII) is reacted with deuterium oxide under the action of metal reagent M and reagent B' to give deuterated product (VI).
The metal reagent M is zinc and/or iron, preferably zinc; the reagent B' is selected from substances which can generate acid by reacting with heavy water, and comprises one of phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, boron trichloride and aluminum trichloride, and preferably the phosphorus oxychloride; the reaction solvent is ultra-dry tetrahydrofuran; the reaction temperature is 0-50 ℃, and the room temperature is preferred; the reaction time is 0.1 to 10 hours, preferably 0.2 to 4.0 hours.
Wherein, the molar ratio of the compound of formula (VII), the heavy water, the metal reagent M and the reagent B' is 1 (15-25) to (2-4) to (1-2), and the molar ratio can be 1.
Step 3)
In the step, a reagent C is boron trichloride or boron tribromide, and preferably boron trichloride; the reaction solvent is dichloromethane; the reaction temperature is-35 to-25 ℃, preferably-30 to-25 ℃, and illustratively, the reaction temperature may be-35 ℃,30 ℃, 25 ℃ or the like; the reaction time is 0.1 to 3 hours, preferably 0.2 to 1 hour.
The molar ratio of the compound of formula (vi) to the reagent C is 1 (3 to 6), and may be, for example, 1.
After the reaction is completed, adding methanol to quench the reaction, heating to 10-20 ℃, stirring for several hours, dropwise adding n-heptane to separate out solids, filtering, suspending the filter cake in water, then adjusting the pH value to 8-9 by using 10wt% sodium carbonate solution, filtering to obtain a crude product, and heating and pulping by using acetonitrile to obtain a pure compound of the formula (V).
Wherein, the ratio of the weight part of the compound of the formula (VI) to the volume part of the methanol is 1 (5-15), and can be 1; the ratio of parts by weight of the compound of formula (VI) to parts by volume of n-heptane is 1 (5-15), and illustratively, may be 1; the ratio of parts by weight of the compound of formula (VI) to parts by volume of acetonitrile is 1 (1 to 10), and illustratively may be 1. Wherein, the corresponding relation between the parts by weight and the parts by volume is g/mL.
Step 4)
In this step, the reagent D is N, N-dimethylformamide dimethyl acetal or N, N-dimethylformamide diethyl acetal, preferably N, N-dimethylformamide dimethyl acetal; the reaction solvent is tetrahydrofuran; the reaction temperature is 20 to 55 ℃, preferably 45 to 55 ℃, and exemplarily, the reaction temperature may be 45 ℃, 50 ℃,55 ℃ or the like; the reaction time is 3 to 8 hours, and illustratively, the reaction time is 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, etc., preferably 5 hours.
Wherein, the molar ratio of the compound of formula (V) to the reagent D is 1 (2-4), preferably 1 (3-4), and illustratively, the molar ratio is 1.
And after the reaction is completed, adding methanol to quench the reaction, concentrating, adding a mixed solvent of ethyl acetate and n-heptane, pulping at 15-25 ℃, stirring for 1-2 hours, filtering, and leaching a filter cake with n-heptane to obtain the compound shown in the formula (IV).
Wherein the volume ratio of the ethyl acetate to the n-heptane in the mixed solvent is 1 (2-10).
Step 5)
In this step, reagent E is one of isobutyryl chloride, isobutyric anhydride, or isobutyric acid.
In some embodiments of the invention, reagent E is isobutyryl chloride or isobutyric anhydride, and the compound of formula (IV) is reacted with isobutyryl chloride or isobutyric anhydride in the presence of an organic base and a catalyst, preferably isobutyric anhydride.
The organic base is triethylamine and/or N, N-diisopropylethylamine, preferably triethylamine; the catalyst is 4-dimethylaminopyridine; the reaction solvent is dichloromethane; the reaction temperature is 5 to 30 ℃, preferably 5 to 15 ℃, illustratively 5 ℃,10 ℃,15 ℃ and the like; the reaction time is 1 to 2 hours.
Wherein, the molar ratio of the compound of formula (IV), isobutyric anhydride, triethylamine and 4-lutidine is 1 (3-5) to (4-6) to (0.01-0.1), and the molar ratio can be, for example, 1.
In some embodiments of the invention, reagent E is isobutyric acid and the compound of formula (IV) is reacted with isobutyric acid under the action of an organic base and a condensing agent.
The organic base is triethylamine and/or N, N-diisopropylethylamine, preferably triethylamine; the condensing agent is one of dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or 1-hydroxybenzotriazole; the reaction temperature is 5 to 30 ℃, preferably 5 to 15 ℃, and illustratively, the reaction temperature may be 5 ℃,10 ℃,15 ℃ or the like; the reaction time is 1 to 2 hours.
Step 6)
In the step, the reagent F is one of acetic acid, trifluoroacetic acid, hydrochloric acid or hydrazine hydrate, preferably acetic acid; the reaction solvent is one of ethanol, isopropanol, tetrahydrofuran or acetonitrile, preferably ethanol; the reaction temperature is 0-55 ℃, preferably 45-55 ℃; the reaction time is 8 to 10 hours.
The molar ratio of the compound (iii) to the reagent F is 1 (15 to 25), and may be, for example, 1.
Step 7)
In this step, reagent G is hydrobromic acid, preferably 48% aqueous hydrogen bromide; the reaction solvent is acetonitrile; the reaction temperature is 15-25 ℃, and the reaction time is 0.5-1.5 hours.
Wherein the molar ratio of the compound shown in the formula (II) to the hydrobromic acid is 1 (1-1.2).
And after the reaction is finished, pulping and purifying, wherein the solvent is one of methyl tert-butyl ether, acetone, ethyl acetate or isopropanol, and preferably methyl tert-butyl ether.
Wherein, the ratio of the weight portion of the compound shown in the formula (II) to the volume portion of the methyl tert-butyl ether is 1 (1-10), and the corresponding relation of the weight portion and the volume portion is g/mL.
In other preferred embodiments, the present invention provides a process for the preparation of a compound of formula (i), comprising the steps of:
1) Adding the compound of the formula (VIII) into a reaction solvent, controlling the temperature at 25 ℃ under the protection of nitrogen, adding the reagent A in batches, and then adding acid to react to obtain the compound of the formula (VII).
2) Adding the compound shown in the formula (VII) into a reaction solvent, then sequentially adding triethylamine and palladium-carbon, replacing with nitrogen, introducing deuterium gas, pressurizing to about 1.0MPa, heating to 55-65 ℃, and reacting to obtain the compound shown in the formula (VI).
3) Dissolving the compound shown in the formula (VI) in dichloromethane, reducing the temperature to-35-25 ℃ under the protection of nitrogen, and dropwise adding a dichloromethane solution of boron trichloride; and (3) after the reaction is completed, adding methanol to quench the reaction, heating to 10-20 ℃, stirring for several hours, dropwise adding n-heptane, precipitating solids after the dropwise adding is completed, filtering, suspending the filter cake in water, adjusting the pH to 8-9 by using 10wt% of sodium carbonate solution, filtering to obtain a crude product of the compound of the formula (V), heating and pulping the crude product by using acetonitrile to obtain a pure product of the compound of the formula (V).
4) Adding a compound shown in the formula (V) and a reagent D into tetrahydrofuran, heating to 45-55 ℃ under the protection of nitrogen, concentrating a reaction solution when the compound shown in the formula (V) is completely converted, adding methanol for pulping, concentrating the reaction solution, adding a mixed solvent of ethyl acetate and n-heptane for pulping, and obtaining the compound shown in the formula (IV).
5) Adding the compound of the formula (IV) into dichloromethane, and then sequentially adding triethylamine, 4-dimethylaminopyridine and isobutyric anhydride to react to obtain the compound of the formula (III).
6) Adding a compound shown in the formula (III) into a solvent, then adding a reagent F, and heating to 45-55 ℃ for reaction to obtain a compound shown in the formula (II).
7) Adding the compound of the formula (II) into a solvent, then adding activated carbon and anhydrous sodium sulfate, filtering, cooling the filtrate to below 15 ℃, dropwise adding hydrobromic acid, then stirring for 1 hour at the temperature of 15-25 ℃, concentrating to a small volume, refluxing and pulping by using methyl tert-butyl ether, then cooling and filtering to obtain the compound of the formula (I).
In other preferred embodiments, step 2) may be replaced by adding the compound of formula (VII) to tetrahydrofuran, followed by the sequential addition of deuterium oxide, zinc powder and phosphorus oxychloride to obtain the compound of formula (VI).
In other preferred embodiments, step 2) may be replaced by adding the compound of formula (vii) to tetrahydrofuran, followed by the sequential addition of deuterated hydrochloric acid and zinc powder to give the compound of formula (vi).
For the above-mentioned steps 1) to 7),
in some more preferred embodiments of the invention, in step 1), the reaction solvent is acetonitrile.
In some more preferred embodiments of the invention, in step 1), X is I and reagent A is N-iodosuccinimide.
In some more preferred embodiments of the invention, in step 1), the acid is trifluoroacetic acid.
In some more preferred embodiments of the invention, in step 1), the molar ratio of the compound of formula (viii), reagent a, acid is 1.
In some more preferred embodiments of the present invention, in step 2), the reaction solvent is tetrahydrofuran.
In some more preferred embodiments of the invention, in step 2), the molar ratio of the compound of formula (vii) and triethylamine is 1.
In some more preferred embodiments of the invention, in step 2), the weight ratio of the compound of formula (vii) to the palladium on carbon, calculated on the dry mass of the palladium on carbon, is 1.03 (on the dry mass basis).
In some more preferred embodiments of the invention, in step 3), the molar ratio of the compound of formula (vi) to boron trichloride is 1.
In some more preferred embodiments of the invention, in step 3), the ratio of parts by weight of the compound of formula (VI) to parts by volume of methanol is 1 (5 to 15), which may be, illustratively, 1; wherein, the corresponding relation between the weight parts and the volume parts is g/mL.
In some more preferred embodiments of the invention, in step 3), the ratio of parts by weight of the compound of formula (vi) to parts by volume of n-heptane is 1 (5 to 15), and may be, illustratively, 1; wherein, the corresponding relation between the weight parts and the volume parts is g/mL.
In some more preferred embodiments of the invention, in step 3), the ratio of parts by weight of the compound of formula (vi) to parts by volume of acetonitrile is 1 (1 to 10), which may be, illustratively, 1; wherein, the corresponding relation between the parts by weight and the parts by volume is g/mL.
In some more preferred embodiments of the invention, in step 4), reagent D is N, N-dimethylformamide dimethyl acetal.
In some more preferred embodiments of the present invention, the volume ratio of ethyl acetate to n-heptane used for beating in step 4) is 1 (2-10).
In some more preferred embodiments of the present invention, in step 5), the molar ratio of the compound of formula (IV), isobutyric anhydride, triethylamine and 4-dimethylaminopyridine is 1 (3-5) to (4-6) to (0.01-0.1).
In some more preferred embodiments of the invention, in step 6), the solvent is ethanol and the reagent F is acetic acid.
In some more preferred embodiments of the present invention, in step 7), the ratio of parts by weight of the compound of formula (II) to parts by volume of methyl t-butyl ether is 1 (1 to 10), the relationship between parts by weight and parts by volume being g/mL.
Example 1
1) Preparation of a compound of formula (VII):
Figure BDA0003231447290000101
A30L reactor was charged with the compound of formula (VIII) (4.5kg, 1eq), acetonitrile (22.5L, 5V), while maintaining a temperature of 25 ℃ under nitrogen, NIS (2.34kg, 1.3eq) was added in portions, after completion of addition, trifluoroacetic acid (183.9g, 0.2eq) was added dropwise with continued temperature control, after completion of addition, reaction was carried out at 25 ℃ for 4h, and TLC showed that the starting material had reacted to completion. Concentrating acetonitrile, adding DCM (31.5L, 7V), stirring for dissolving, preparing a mixed solution (22.5L, 5V) of sodium bicarbonate (1.35kg, 2eq) and sodium sulfite (1kg, 1eq), dropwise adding the mixed solution into the reaction solution at the temperature of 25 ℃, stirring for liquid separation, washing an organic phase with an aqueous solution (22.5L) of sodium bicarbonate (1.35kg, 2eq), liquid separation and concentration; then slurried with toluene (25L) for 1h, filtered, and the filter cake washed with toluene (2.5L) to give the compound of formula (VII) as an off-white solid (5.35 kg, yield: 97.2%).
2) Preparation of a compound of formula (VI):
Figure BDA0003231447290000102
dissolving a compound (600g, 1eq) of the formula (VII) in THF (9L, 15V), placing the solution in a 20L autoclave, adding triethylamine (176.4 g, 2eq) and palladium-carbon (40.5 g (55.6% of water) of a wet product, 3% of the wet product based on the mass of a dry base), replacing the solution with nitrogen twice, pressurizing deuterium gas to normal pressure, heating the kettle to 60 ℃, pressurizing the deuterium gas to about 1.0MPa, keeping the pressure of the deuterium-supplemented gas to 1.0MPa and keeping the pressure of the deuterium-supplemented gas constant for about 0.5h, continuously stirring the solution at a controlled temperature for 1h, cooling the solution to 20 ℃, replacing the nitrogen once, TLC indicating that the reaction is finished, adding 500mL of water, stirring for 5min, discharging the reaction solution, washing with 400mL of THF, filtering, rinsing a filter cake with THF and water, concentrating the filtrate, adding DCM (4.2L) and water (3L), separating the solution, washing an organic layer with water (3L), filtering, concentrating the organic phase, pulping the toluene (3.6L), filtering to obtain a white solid compound of the formula (VI), wherein the yield is more than 451g and the substituted solid product (99 percent).
3) Preparation of a Compound of formula (V):
Figure BDA0003231447290000103
adding a compound (451g, 1eq) of the formula (VI) into DCM (4.51L, 10V), reducing the internal temperature to-30 ℃ under the protection of nitrogen, dropwise adding a dichloromethane solution (3.56L, 4.4eq, 1N) of boron trichloride, controlling the temperature in the process to be below-25 ℃, keeping the temperature and stirring for 0.5h after the dropwise adding is finished, and then, TLC shows that the reaction is complete. Controlling the temperature to be below 30 ℃ below zero, dropwise adding methanol for quenching reaction, after the dropwise adding reaction, raising the internal temperature to 15 ℃, keeping the temperature and stirring for 2h, dropwise adding n-heptane, after the dropwise adding reaction is kept at the temperature and stirring for 1h, filtering under the protection of nitrogen, leaching a filter cake by using a mixed solvent of dichloromethane and n-heptane, suspending the filter cake in water (2.7L), slowly dropwise adding 10wt% of sodium carbonate aqueous solution to adjust the pH value to 8-9, stirring the mixture for 1h, filtering, leaching the filter cake by using water, collecting a wet filter cake, adding acetonitrile (1.8L), heating to reflux, performing reflux pulping for 1-2 h, cooling to 5 ℃, stirring for 1-2 h, and filtering to obtain a compound of the formula (V) and a red powdery solid (128.7 g, yield: 55.0%).
4) Preparation of a compound of formula (IV):
Figure BDA0003231447290000111
the compound of formula (V) (0.914kg, 1eq) was added to tetrahydrofuran (8.1kg, 10V), and the mixture was stirred and heated to make the solid substantially insoluble, and when the internal temperature of the reaction solution rose to 55 ℃, N-dimethylformamide dimethyl acetal (1.304kg, 3.5eq) was added, and the temperature was controlled at 50 ℃ to react for 5 hours. TLC shows that the raw materials are completely reacted, heating is stopped, the temperature is reduced to 20 ℃ by stirring, the reaction solution is concentrated, methanol (9.14L, 10V) is added for pulping for 1 hour, the reaction solution is concentrated to be semisolid, a mixed solvent of ethyl acetate and n-heptane is added for pulping, the mixture is stirred for 1 to 2 hours at the temperature of 20 +/-5 ℃ and then filtered, and a filter cake is leached by n-heptane to obtain the compound of the formula (IV) and red powdery solid (1.059 kg, the yield: 97.2%).
5) Preparation of a compound of formula (III):
Figure BDA0003231447290000112
adding a compound (1.057 kg) of a formula (IV) into dichloromethane (6.34L, 6V), cooling a reaction liquid to below 15 ℃, adding triethylamine (1.539kg, 5eq) and 4-dimethylaminopyridine (0.0186kg, 0.05eq), then dropwise adding isobutyric anhydride (1.925 kg, 4 eq), controlling the temperature of the reaction liquid to be not more than 15 ℃ in the dropwise adding process, and after the dropwise adding is finished, controlling the reaction temperature to be 10 ℃ and reacting for 1.5h. TLC shows that the reaction is complete, dichloromethane (4.2L, 4V) is added into the reaction liquid, 0.1N dilute hydrochloric acid aqueous solution (10.57L, 10V) is added into the reaction liquid, after stirring for 10min, the mixture is kept stand for layering, an organic phase is collected, then saturated sodium bicarbonate aqueous solution (10.57L, 10V) is added into the organic phase, after stirring for 30min, the mixture is kept stand for layering, the organic phase is collected, then the mixture is washed by water (10.57L, 10V), the mixture is kept stand for layering, anhydrous sodium sulfate is dried, filtered, filtrate is concentrated, and the compound shown in the formula (III) and a reddish brown oily substance VV116-5 are obtained and are directly used for the next reaction.
6) Preparation of a Compound of formula (II):
Figure BDA0003231447290000113
the compound of formula (III) (1.7kg, 1eq) obtained in the above step was added to ethanol (13.6L, 8V), acetic acid (3.658 kg, 20 eq) was added, and the reaction solution was heated to 50 ℃ and reacted at 55 ℃ for 9 hours with controlled temperature. TLC showed the starting material reaction was complete. Concentrating the reaction liquid until no drop is dripped, adding ethyl acetate (13.6L, 8V) for dilution, then adding saturated sodium bicarbonate solution for neutralizing acetic acid, stirring for 1h, taking the water phase, detecting the pH value to be about 7-8, standing for layering, collecting an organic phase, then washing with saturated sodium chloride solution (10.2L, 6V), standing for layering, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate to obtain a compound shown in a formula (II) and a reddish brown oily VV116-6.
7) Preparation of a Compound of formula (I):
Figure BDA0003231447290000121
adding the compound of formula (II) (1.256kg, 1eq) to acetonitrile (8.79L, 7V), cooling to below 15 deg.C, adding 48% hydrobromic acid (0.421kg, 1eq) dropwise, stirring at 20 deg.C for 1h after the addition is complete, and concentrating. Concentrating the reaction solution to small volume, adding methyl tert-butyl ether (8.79L, 7V), heating to reflux, stirring for 2 hr, naturally cooling to 20 + -5 deg.C, and stirring for 12 hr. The reaction mixture was filtered to obtain the compound of formula (I) as a white powdery solid (1.05 kg, yield: 72.2%).
Example 2
This example provides a process for the preparation of a compound of formula (I) as in example 1 except for step 2).
2) Preparation of a compound of formula (VI):
Figure BDA0003231447290000122
the compound of formula (VII) (3.44g, 1eq) was dissolved in ultra-dry THF (20 mL, available from Annaiji), followed by addition of deuterium oxide (1.8mL, 20eq), concentration to dryness at 50 ℃ and subsequent addition of ultra-dry THF (20 mL), zinc powder (9811mg, 3eq) and deuterium oxide (1.8mL, 20eq), and phosphorus oxychloride (1.15g, 1.5eq) was added dropwise under ice-cooling. After addition, the ice bath was removed and stirred at room temperature, after 30 minutes TLC showed the starting material was completely reacted. Filtering, washing filter residue with ethyl acetate, adding ethyl acetate (100 mL) into the filtrate, washing with saturated sodium bicarbonate and saturated salt water, drying with anhydrous sodium sulfate, concentrating the solvent to dryness, pulping the residue with toluene (25 mL), and filtering to obtain the compound of formula (VI), wherein the compound is off-white solid (2.2 g, yield: 78%), and the deuteration rate of the product is more than 98%.
Example 3
This example provides a process for the preparation of a compound of formula (I) as in example 1 except for step 2).
2) Preparation of a compound of formula (VI):
Figure BDA0003231447290000123
dissolving a compound (2g, 2.90mmol) of a formula (VII) in ultra-dry tetrahydrofuran (30 mL), adding heavy water (3 mL) for concentration, repeating the operation for 1 time, dissolving the treated compound (VII) in tetrahydrofuran (30 mL), adding zinc powder (943 mg, 14.50mmol), slowly and dropwise adding a heavy aqueous solution (2.0mL, 12.00mmol) of 6N deuterated hydrochloric acid at 0-5 ℃ under the protection of nitrogen, keeping the temperature and stirring for 30 minutes, then TLC displaying that the raw material disappears, filtering the reaction solution, adding water and ethyl acetate, standing for layering, extracting the aqueous phase with ethyl acetate for 1 time, combining the organic phase, washing with saturated sodium bicarbonate and saturated common salt in sequence, drying with anhydrous sodium sulfate, filtering, concentrating, and pulping with methyl tert-butyl ether to obtain the compound (VI), wherein the compound is a white-like solid (1.1 g, the yield is 68 percent, and the product deuteration rate is more than 98 percent.
Industrial applicability
The preparation method of the antiviral nucleoside analogue VV116 provided by the invention can be applied in industry.
Having described embodiments of the present disclosure, the foregoing description is intended to be exemplary, not exhaustive, and not limited to the disclosed embodiments. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is chosen in order to best explain the principles of the embodiments, the practical application, or improvements made to the technology in the marketplace, or to enable others of ordinary skill in the art to understand the embodiments disclosed herein.

Claims (10)

1. A process for the preparation of a compound of formula (i) which comprises the steps of:
1) Reacting a compound of formula (VIII) with a reagent A under the action of an acid to obtain a compound of formula (VII):
Figure FDA0003231447280000011
wherein X is halogen;
2) Reacting a compound of formula (VII) with a reagent B under the action of a metal reagent M to obtain a compound of formula (VI):
Figure FDA0003231447280000012
3) Reacting a compound of formula (VI) with a reagent C to give a compound of formula (V):
Figure FDA0003231447280000013
4) Reacting a compound of formula (V) with a reagent D to give a compound of formula (IV):
Figure FDA0003231447280000014
5) Reacting a compound of formula (IV) with a reagent E under the action of an organic base to obtain a compound of formula (III):
Figure FDA0003231447280000015
6) Reacting a compound of formula (III) with a reagent F to give a compound of formula (II):
Figure FDA0003231447280000021
7) Reacting a compound of formula (II) with a reagent G to give a compound of formula (I):
Figure FDA0003231447280000022
2. the process for the preparation of the compound of formula (I) according to claim 1, wherein, in step 1),
x is I, br or Cl, and the reagent A is N-iodosuccinimide or I 2 、Br 2 One of N-bromosuccinimide, dibromohydantoin or N-chlorosuccinimide; preferably, X is I or Br, and the reagent A is N-iodosuccinimide, I 2 、Br 2 One of N-bromosuccinimide or dibromohydantoin; more preferably, X is I and the reagent a is N-iodosuccinimide;
the acid is an organic acid, preferably one of trifluoroacetic acid, trichloroacetic acid or acetic acid, and more preferably trifluoroacetic acid;
the reaction solvent is one of N, N-dimethylformamide, tetrahydrofuran or acetonitrile, and preferably acetonitrile;
the reaction temperature is 0-50 ℃, preferably 20-30 ℃, and more preferably 25 ℃;
wherein the molar ratio of the compound of formula (VIII), the reagent A and the acid is 1 (1-1.5) to (0.1-0.5), preferably 1.
3. The process for the preparation of the compound of formula (i) according to claim 1 or 2, wherein in step 2), the agent B is one of deuterium gas, a deuterated acidic agent or deuterium oxide.
4. The process for the preparation of the compound of formula (i) according to claim 3, wherein in step 2), the compound of formula (vii) is reacted with deuterium gas under the action of the metal reagent M and an organic base;
the metal reagent M is a palladium catalyst, preferably palladium carbon; the organic base is one of triethylamine, N-diisopropylethylamine, trimethylamine, ammonia gas, ammonia water, DBU or pyridine, and preferably triethylamine; the reaction solvent is one of tetrahydrofuran, methanol, ethanol, isopropanol or ethyl acetate, and is preferably tetrahydrofuran; the reaction pressure is 0.1-2 MPa, preferably 1.0MPa; the reaction temperature is 25-65 ℃, preferably 55-65 ℃;
wherein the mass ratio of the compound of the formula (VII) to the palladium carbon dry basis is 1 (0.01-0.2), and the molar ratio of the compound of the formula (VII) to the organic base is 1 (1-3).
5. The process for the preparation of the compound of formula (i) according to claim 3, characterized in that, in step 2), the compound of formula (vii) is reacted with the deuterated acidic reagent under the action of the metal reagent M;
the deuterated acidic reagent is one of deuterated hydrochloric acid, deuterated sulfuric acid, deuterated acetic acid, deuterated trifluoroacetic acid or deuterated ammonium chloride; the metal reagent M is zinc and/or iron; the reaction solvent is ultra-dry tetrahydrofuran; the reaction temperature is 0-50 ℃, and preferably 20-30 ℃;
wherein the molar ratio of the compound shown in the formula (VII), the deuterated acidic reagent and the metal reagent M is 1 (4.0-4.5) to (4.0-6.0).
6. The process for the preparation of the compound of formula (i) according to claim 3, wherein in step 2), the compound of formula (vii) is reacted with the heavy water under the action of the metal reagent M and the reagent B';
the metal reagent M is zinc and/or iron; the reagent B' is one of phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, boron trichloride or aluminum trichloride; the reaction solvent is ultra-dry tetrahydrofuran; the reaction temperature is 0-50 ℃, and room temperature is preferred;
wherein the molar ratio of the compound of the formula (VII), the heavy water, the metal reagent M and the reagent B' is 1 (15-25) to (2-4) to (1-2).
7. The process for the preparation of the compound of formula (i) according to any one of claims 1 to 6, wherein in step 3), the reagent C is boron trichloride or boron tribromide, the reaction solvent is dichloromethane, and the reaction temperature is from-35 ℃ to-25 ℃;
wherein the molar ratio of the compound shown in the formula (VI) to the reagent C is 1 (3-6).
8. The process for the preparation of the compound of formula (i) according to any one of claims 1 to 7, wherein in step 4) the reagent D is N, N-dimethylformamide dimethyl acetal or N, N-dimethylformamide diethyl acetal, preferably N, N-dimethylformamide dimethyl acetal; the reaction solvent is tetrahydrofuran; the reaction temperature is 20-55 ℃, preferably 45-55 ℃;
wherein the molar ratio of the compound shown in the formula (V) to the reagent D is 1 (2-4).
9. The process for preparing a compound of formula (i) according to any one of claims 1 to 8, wherein in step 5), the reagent E is one of isobutyryl chloride, isobutyric anhydride or isobutyric acid;
when the reagent E is isobutyryl chloride or isobutyric anhydride, reacting the compound shown in the formula (IV) with the reagent E under the action of an organic base and a catalyst, wherein the organic base is triethylamine and/or N, N-diisopropylethylamine, preferably triethylamine; the catalyst is 4-dimethylaminopyridine; the reaction solvent is dichloromethane; the reaction temperature is 5-30 ℃, preferably 5-15 ℃;
wherein the molar ratio of the compound shown in the formula (IV), the reagent E, the organic base and the catalyst is 1 (3-5) to (4-6) to (0.01-0.1);
when the reagent E is isobutyric acid, reacting the compound shown in the formula (IV) with the reagent E under the action of an organic base and a condensing agent, wherein the organic base is triethylamine and/or N, N-diisopropylethylamine; the condensing agent is one of dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or 1-hydroxybenzotriazole; the reaction solvent is dichloromethane; the reaction temperature is 5 to 30 ℃, preferably 5 to 15 ℃.
10. The process for the preparation of the compound of formula (i) according to any one of claims 1 to 9, wherein in step 6), the reagent F is one of acetic acid, trifluoroacetic acid, hydrochloric acid or hydrazine hydrate, preferably acetic acid; the reaction solvent is one of ethanol, isopropanol, tetrahydrofuran or acetonitrile, preferably ethanol; the reaction temperature is 0-55 ℃, preferably 45-55 ℃; wherein the molar ratio of the compound (III) to the reagent F is 1 (15-25);
in the step 7), the reagent G is hydrobromic acid, and the reaction temperature is 15-25 ℃; wherein the molar ratio of the compound shown in the formula (II) to the reagent G is 1 (1-1.2).
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023143630A1 (en) * 2022-01-26 2023-08-03 苏州旺山旺水生物医药有限公司 Preparation method for nucleoside analogue vv116
US11963967B2 (en) 2020-10-16 2024-04-23 Gilead Sciences, Inc. Phospholipid compounds and uses thereof
US12030904B2 (en) 2023-04-14 2024-07-09 Gilead Sciences, Inc. Phospholipid compounds and uses thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11963967B2 (en) 2020-10-16 2024-04-23 Gilead Sciences, Inc. Phospholipid compounds and uses thereof
WO2023143630A1 (en) * 2022-01-26 2023-08-03 苏州旺山旺水生物医药有限公司 Preparation method for nucleoside analogue vv116
US12030904B2 (en) 2023-04-14 2024-07-09 Gilead Sciences, Inc. Phospholipid compounds and uses thereof

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