CN115716833A - Preparation method of antiviral nucleoside analogue - Google Patents

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

A kind of preparation method of antiviral nucleoside analog

technical field

The invention relates to the field of medicine, in particular to a preparation method of an antiviral nucleoside analogue.

Background technique

Novel coronavirus pneumonia (COVID-19) is an acute respiratory infectious disease caused by 2019 novel coronavirus (SARS-CoV-2) infection. Vaccines are the most effective way to prevent viral infections, and countries around the world have gradually begun to vaccinate against SARS-CoV-2. Therefore, the development of antiviral drugs with low toxicity and high efficiency will be of great significance to the prevention and treatment of COVID-19.

SARS-CoV-2 is a positive-strand RNA virus whose replication is mediated by a multi-subunit replication/transcription complex of the viral nonstructural protein (nsp), a core component of which is the RNA-dependent RNA Polymerase (RdRp, also known as nsp12). The active center of RNA-dependent RNA polymerase is highly conserved and is an important target for the development of anti-SARS-CoV-2 drugs. Nucleoside analogue drugs that have been approved and under research may have anti-SARS-CoV-2 infection potential.

VV116 is an orally available nucleoside anti-SARS-CoV-2 drug candidate:

After entering the body, it undergoes hydrolysis and gradual phosphorylation under the action of enzymes and converts it into an active form of nucleoside triphosphates. The triphosphates can be inserted into the RNA chain of the virus being extended to terminate its extension to inhibit virus proliferation. VV116 has strong anti-SARS-CoV-2 activity and low cytotoxicity on VeroE6 cells, which is superior to the control drug remdesivir; on an adenovirus-transduced mouse model expressing the new coronavirus receptor human ACE2 , which can be administered orally once a day, can dose-dependently reduce the viral load in the lungs of mice. 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 highly promising COVID-19 therapeutic drug, therefore, finding an efficient, economical and practical preparation method will contribute to the further development of this candidate drug, which has the potential to prevent and/or treat COVID-19. Significance.

Contents of the invention

The problem to be solved by the invention

The invention provides a preparation method of antiviral nucleoside analog VV116, the method has mild reaction conditions, easy process control, simple operation and is suitable for large-scale industrial production.

solutions to problems

The present invention provides a preparation method of a compound of formula (I), which comprises the following steps:

1) The compound of formula (Ⅷ) reacts with reagent A under the action of acid to obtain the compound of formula (Ⅶ):

Wherein, X is a halogen;

2) The compound of formula (VII) reacts with reagent B under the action of metal reagent M to obtain the compound of formula (VI):

3) The compound of formula (Ⅵ) reacts with reagent C to obtain the compound of formula (Ⅴ):

4) The compound of formula (Ⅴ) reacts with reagent D to obtain the compound of formula (Ⅳ):

5) The compound of formula (Ⅳ) reacts with reagent E under the action of an organic base to obtain the compound of formula (Ⅲ):

6) The compound of formula (Ⅲ) reacts with reagent F to obtain the compound of formula (Ⅱ):

7) The compound of formula (II) reacts with reagent G to obtain the compound of formula (I):

Preferably, in the preparation method of the compound of formula (I) according to the present invention, in step 1),

X is I, Br or Cl, and the reagent A is N-iodosuccinimide, I ₂ , Br ₂ , N-bromosuccinimide, dibromohydantoin or N-chlorobutanedi One of imides; preferably, X is I or Br, and the reagent A is N-iodosuccinimide, I ₂ , Br ₂ , N-bromosuccinimide or dibromo One of hydantoin; 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, more preferably trifluoroacetic acid;

The reaction solvent is one of N,N-dimethylformamide, tetrahydrofuran or acetonitrile, preferably acetonitrile;

The reaction temperature is 0-50°C, preferably 20-30°C, more preferably 25°C;

Wherein, the molar ratio of the compound of formula (VIII), the reagent A and the acid is 1:(1-1.5):(0.1-0.5), preferably 1:1.3:0.2.

Preferably, in the preparation method of the compound of formula (I) according to the present invention, in step 2), the reagent B is one of deuterium gas, deuterated acidic reagent or heavy water.

Further preferably, according to the preparation method of the compound of formula (I) according to the present invention, in step 2), the compound of formula (VII) reacts 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,N-diisopropylethylamine, trimethylamine, ammonia gas, ammonia water, DBU or pyridine , preferably triethylamine; the reaction solvent is one of tetrahydrofuran, methanol, ethanol, isopropanol or ethyl acetate, preferably tetrahydrofuran; the reaction pressure is 0.1-2MPa, preferably 1.0MPa; the reaction temperature is 25-65 °C, preferably 55-65 °C;

Wherein, the mass ratio of the compound of the formula (VII) to the dry base of the palladium carbon 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 preparation method of the compound of formula (I) according to the present invention, in step 2), the compound of formula (VII) reacts with the deuterated acidic reagent under the action of the metal reagent M;

The deuterated acid 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°C, preferably 20-30°C;

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):(4.0-6.0).

Further preferably, according to the preparation method of the compound of formula (I) according to the present invention, in step 2), the compound of formula (VII) reacts with the heavy water under the action of the metal reagent M and 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°C, preferably room temperature;

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):(2-4):(1-2).

Preferably, according to the preparation method of the compound of formula (I) according to the present invention, in step 3), the reagent C is boron trichloride and/or boron tribromide, the reaction solvent is dichloromethane, and the reaction temperature is -35～-25℃;

Wherein, the molar ratio of the compound of formula (VI) to the reagent C is 1:(3-6).

Preferably, in the preparation method 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-dimethyl Formamide diethyl acetal, preferably N,N-dimethylformamide dimethyl acetal; the reaction solvent is tetrahydrofuran; the reaction temperature is 20-55°C, preferably 45-55°C;

Wherein, the molar ratio of the compound of formula (V) to the reagent D is 1:(2-4).

Preferably, according to the preparation method of the compound of formula (I) according to the present invention, 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, the compound of formula (IV) reacts with the reagent E under the action of an organic base and a catalyst, and 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°C, preferably 5-15°C;

Wherein, the molar ratio of the compound of formula (IV), the reagent E, the organic base and the catalyst is 1:(3-5):(4-6):(0.01-0.1);

When the reagent E is isobutyric acid, the compound of formula (IV) reacts with the reagent E under the action of an organic base and a condensing agent, and the organic base is triethylamine and/or N,N-diisopropyl Ethylamine; the condensing agent is dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or 1-hydroxybenzotriazole One; the reaction solvent is dichloromethane; the reaction temperature is 5-30°C, and the reaction temperature is 5-15°C.

Preferably, in the preparation method of the compound of formula (I) according to the present invention, 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 to 55°C, preferably 45 to 55°C; wherein, the molar ratio of the compound (Ⅲ) to the reagent F is 1: (15～25);

In step 7), the reagent G is hydrobromic acid, and the reaction temperature is 15-25°C; wherein, the molar ratio of the compound of formula (II) to the reagent G is 1:(1-1.2).

The effect of the invention

The preparation method of the antiviral nucleoside analog VV116 provided by the present invention has mild reaction conditions, easy control of the process, and simple operation, which will help the further development of the candidate drug and is suitable for large-scale industrial production. It is efficient, economical, and practical. It is of great significance for the prevention and/or treatment of COVID-19.

Detailed ways

Various exemplary embodiments, features, and aspects of the invention are described in detail below. The word "exemplary" as used herein means "serving as an example, embodiment, or illustration." Any embodiment described herein as "exemplary" is not necessarily to be construed as superior or better than other embodiments.

In addition, in order to better illustrate the present invention, numerous specific details are given in the specific embodiments below. It will be understood by those skilled in the art that the present invention may be practiced without certain of the specific details. In other instances, methods, means, devices and steps well known to those skilled in the art are not described in detail in order to highlight the gist of the present invention.

If there is no special statement, in this manual, if no specific conditions are indicated, follow the general conditions or the conditions suggested by the manufacturer. The reagents or instruments used were not indicated by the manufacturer, and they were all commercially available conventional products.

In this specification, the units used are all international standard units, and the numerical values and numerical ranges appearing in the present invention should be understood as including inevitable systematic errors in industrial production.

In this specification, the meaning expressed by "may" includes the meaning of performing certain processing and not performing certain processing.

In this specification, references to "some specific/preferred embodiments", "other specific/preferred embodiments", "embodiments" and the like refer to specific elements described in relation to the embodiments (for example, A feature, structure, property and/or characteristic) 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 present invention provides the present invention provides a preparation method of the compound of formula (I),

Include the following steps:

1) The compound of formula (Ⅷ) reacts with reagent A under the action of acid to obtain the compound of formula (Ⅶ):

Wherein, X is a halogen;

2) The compound of formula (VII) reacts with reagent B under the action of metal reagent M to obtain the compound of formula (VI):

3) The compound of formula (Ⅵ) reacts with reagent C to obtain the compound of formula (Ⅴ):

4) The compound of formula (Ⅴ) reacts with reagent D to obtain the compound of formula (Ⅳ):

5) The compound of formula (Ⅳ) reacts with reagent E under the action of an organic base to obtain the compound of formula (Ⅲ):

6) The compound of formula (Ⅲ) reacts with reagent F to obtain the compound of formula (Ⅱ):

7) The compound of formula (II) reacts with reagent G to obtain the compound of formula (I):

In the above embodiment:

step 1)

In some specific embodiments of the present invention, X is I, Br or Cl, reagent A is N-iodosuccinimide (NIS), I ₂ , Br ₂ , N-bromosuccinimide ( NBS), dibromohydantoin or N-chlorosuccinimide (NCS).

In some preferred embodiments of the present invention, X is I or Br, and reagent A is N-iodosuccinimide, I ₂ , Br ₂ , N-bromosuccinimide or dibromohydantoin kind of.

In some more preferred embodiments of the invention, X is I and reagent A is N-iodosuccinimide.

In some specific embodiments of the invention, the acid is an organic acid. In some preferred embodiments of the present invention, the organic acid is one of trifluoroacetic acid, trichloroacetic acid or acetic acid, more preferably trifluoroacetic acid.

In some specific embodiments of the present invention, the reaction solvent is one of N,N-dimethylformamide, tetrahydrofuran or acetonitrile, preferably acetonitrile.

In some specific embodiments of the present invention, the reaction temperature is 0-50°C, preferably 20-30°C, more preferably 25°C. Exemplarily, the reaction temperature may be 0°C, 10°C, 20°C, 25°C, 30°C, 40°C, 50°C, etc.

In some specific embodiments of the present invention, the reaction time is 3-5 hours, preferably 4 hours.

Wherein, the molar ratio of formula (Ⅷ) compound, reagent A and acid is 1:(1～1.5):(0.1～0.5), illustratively, the molar ratio of formula (Ⅷ) compound, reagent A and acid can be 1 :1:0.1, 1:1.25:0.2, 1:1.3:0.2, 1:1.35:0.2, 1:1.5:0.5, etc. In some preferred embodiments of the present invention, the molar ratio of the compound of formula (VIII), reagent A and acid is 1:1.3:0.2.

Step 2)

In this step, reagent B is one of deuterium gas, deuterated acidic reagent or heavy water, all of which can obtain higher deuterated rate.

In some specific embodiments of the present invention, the selected reagent B is deuterium gas, and the compound of formula (VII) reacts with deuterium gas under the action of the metal reagent M and an organic base to obtain the deuterated product (VI).

The above metal reagent M is a palladium catalyst, preferably palladium carbon; the organic base is one of triethylamine, N,N-diisopropylethylamine, trimethylamine, ammonia gas, ammonia water, DBU or pyridine, preferably Triethylamine; the reaction solvent is one of tetrahydrofuran, methanol, ethanol, isopropanol or ethyl acetate, preferably tetrahydrofuran; the reaction pressure is 0.1-2MPa, preferably 1.0MPa; the reaction temperature is 25-65°C, preferably 55-65°C. Exemplarily, the reaction temperature can be 25°C, 35°C, 45°C, 50°C, 55°C, 60°C, 65°C, etc.; the reaction time is 0.5-2.0 hours, preferably 1-1.5 hours .

Wherein, the mass ratio of the compound of formula (VII) to palladium carbon dry base is 1:(0.01～0.2), for example, the mass ratio can be 1:0.01, 1:0.03, 1:0.05, 1:0.08, 1 :0.1, 1:0.12, 1:0.15, 1:0.2, etc., preferably 1:0.03. The palladium carbon is conventional commercially available wet palladium carbon, containing about 55% water, and the palladium content is 5-10%.

The molar ratio of the compound of formula (VII) to the organic base is 1:(1-3), preferably 1:2.

In some specific embodiments of the present invention, the reagent B used is a deuterated acidic reagent, and the compound of formula (VII) reacts with the deuterated acidic reagent under the action of the metal reagent M to obtain the deuterated product (VI).

The above-mentioned 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; metal reagent M is zinc and/or iron, preferably Zinc; the reaction solvent is ultra-dry tetrahydrofuran; the reaction temperature is 0-50°C, preferably 20-30°C, for example, the reaction temperature is 0°C, 10°C, 20°C, 25°C, 30°C, 40°C, 50°C, etc.; 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):(4.0～6.0), illustratively, the molar ratio can be 1:4.0:4.0,1 :4.14:5.0, 1:4.5:6.0, etc., preferably 1:4.14:5.0.

In some specific embodiments of the present invention, the reagent B used is heavy water, and the compound of formula (VII) reacts with heavy water under the action of the metal reagent M and reagent B' to obtain the deuterated product (VI).

Above-mentioned metal reagent M is zinc and/or iron, preferably zinc; Reagent B' is selected from the material that can generate acid with heavy water reaction, comprises phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, boron trichloride and trichloride One of aluminum chloride, preferably phosphorus oxychloride; the reaction solvent is ultra-dry tetrahydrofuran; the reaction temperature is 0-50°C, preferably room temperature; the reaction time is 0.1-10 hours, preferably 0.2-4.0 hours.

Wherein, the molar ratio of formula (VII) compound, heavy water, metal reagent M and reagent B' is 1:(15～25):(2～4):(1～2), illustratively, its molar ratio can be 1:15:2:1, 1:20:3:1.5, 1:25:4:2, etc., preferably 1:20:3:1.5.

step 3)

In this step, the reagent C is boron trichloride or boron tribromide, preferably boron trichloride; the reaction solvent is dichloromethane; the reaction temperature is -35～-25°C, preferably -30～-25°C, for example Typically, the reaction temperature can be -35°C, -30°C, -25°C, etc.; the reaction time is 0.1-3 hours, preferably 0.2-1 hour.

Wherein, the molar ratio of the compound of formula (VI) to reagent C is 1:(3-6), for example, the molar ratio can be 1:3, 1:4, 1:4.4, 1:5, etc., preferably 1:4, 1:4.4.

After the reaction is complete, add methanol to quench the reaction, raise the temperature to 10-20°C, stir for several hours, add n-heptane dropwise and solids will precipitate out, filter, suspend the filter cake in water, and then use 10wt% sodium carbonate solution to adjust the pH The value was adjusted to 8-9, and the crude product was obtained by filtration, and heated and beaten with acetonitrile to obtain the pure product of the compound of formula (Ⅴ).

Wherein, the ratio of the weight part of the compound of formula (VI) to the volume part of methanol is 1: (5-15), for example, it can be 1:5, 1:10, 1:15, etc.; the weight part of the compound of formula (VI) The ratio of the volume parts of n-heptane is 1: (5-15), for example, it can be 1:5, 1:10, 1:15, etc.; the ratio of the weight parts of the compound of formula (VI) to the volume parts of acetonitrile is 1:(1-10), for example, may be 1:5, 1:4, 1:7.5, 1:10, etc. Wherein, the corresponding relationship between parts by weight and 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 base acetal; the reaction solvent is tetrahydrofuran; the reaction temperature is 20-55°C, preferably 45-55°C, for example, the reaction temperature can be 45°C, 50°C, 55°C, etc.; the reaction time is 3-8 hours, Exemplarily, 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 reagent D is 1:(2-4), preferably 1:(3-4), for example, the molar ratio is 1:3, 1:3.5, 1: 4 etc., preferably 1:3.5.

After the reaction is complete, add methanol to quench the reaction, add a mixed solvent of ethyl acetate and n-heptane after concentration, beat at 15-25°C, stir for 1-2 hours, filter, and rinse the filter cake with n-heptane to obtain Compounds of formula (IV).

Wherein, in the mixed solvent, the volume ratio of ethyl acetate and n-heptane is 1:(2～10).

Step 5)

In this step, the reagent E is one of isobutyryl chloride, isobutyric anhydride or isobutyric acid.

In some specific embodiments of the present invention, the reagent E used is isobutyryl chloride or isobutyric anhydride, and the compound of formula (IV) reacts with isobutyryl chloride or isobutyric anhydride under the action of an organic base and a catalyst, preferably isobutyryl anhydride.

The above-mentioned 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 °C, preferably 5-15 °C, for example, the reaction temperature is 5 °C, 10 °C, 15 °C, etc.; the reaction time is 1-2 hours.

Wherein, the molar ratio of the compound of formula (IV), isobutyric anhydride, triethylamine and 4-lutidine is 1:(3～5):(4～6):(0.01～0.1), exemplarily, Its molar ratio can be 1:3:4:0.01, 1:4:5:0.05, 1:5:6:0.1, etc., preferably 1:4:5:0.05.

In some specific embodiments of the present invention, the reagent E used is isobutyric acid, and the compound of formula (IV) reacts with isobutyric acid under the action of an organic base and a condensing agent.

The above-mentioned organic base is triethylamine and/or N,N-diisopropylethylamine, preferably triethylamine; the condensing agent is dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)- One of 3-ethylcarbodiimide hydrochloride or 1-hydroxybenzotriazole; the reaction temperature is 5-30°C, preferably 5-15°C. Exemplarily, the reaction temperature can be 5°C, 10 °C, 15 °C, etc.; the reaction time is 1 to 2 hours.

Step 6)

In this 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°C, preferably 45-55°C; the reaction time is 8-10 hours.

Wherein, the molar ratio of compound (III) to reagent F is 1:(15-25), for example, the molar ratio can be 1:15, 1:20, 1:25, etc., preferably 1:20.

Step 7)

In this step, the reagent G is hydrobromic acid, preferably 48% aqueous hydrogen bromide; the reaction solvent is acetonitrile; the reaction temperature is 15-25° C., and the reaction time is 0.5-1.5 hours.

Wherein, the molar ratio of the compound of formula (II) to hydrobromic acid is 1:(1-1.2).

After the reaction is finished, beating and purifying, the solvent used is one of methyl tert-butyl ether, acetone, ethyl acetate or Virahol, preferably methyl tert-butyl ether.

Wherein, the ratio of the weight part of the compound of formula (II) to the volume part of methyl tert-butyl ether is 1: (1-10), and the corresponding relationship between the weight part and the volume part is g/mL.

In other preferred embodiments, the preparation method of the compound of formula (I) provided by the present invention comprises the following steps:

1) The compound of formula (Ⅷ) is added to the reaction solvent, under nitrogen protection, the temperature is controlled at 25°C, the reagent A is added in batches, and then the acid is added to react to obtain the compound of formula (VII).

2) Add the compound of formula (VII) to the reaction solvent, then add triethylamine and palladium carbon in sequence, replace with nitrogen, pass in deuterium gas, pressurize to about 1.0MPa, heat up to 55-65°C, and react to obtain the formula ( VI) Compounds.

3) Dissolve the compound of formula (Ⅵ) in dichloromethane, under nitrogen protection, cool down to -35～-25°C, add a solution of boron trichloride in dichloromethane dropwise; when the reaction is complete, add methanol to quench the reaction, Then heat up to 10-20°C, stir for several hours, add n-heptane dropwise, solids precipitate out at the end of the dropwise addition, filter, suspend the filter cake in water, then adjust the pH to 8-9 with 10wt% sodium carbonate solution, filter , to obtain a crude product of the compound of formula (Ⅴ), which was heated and beaten with acetonitrile to obtain a pure product of the compound of formula (Ⅴ).

4) Add the compound of formula (Ⅴ) and reagent D into tetrahydrofuran, protect it with nitrogen, and raise the temperature to 45-55°C. After the compound of formula (Ⅴ) is completely converted, concentrate the reaction solution, then add methanol for beating, and concentrate the reaction solution. Add a mixed solvent of ethyl acetate and n-heptane to make a slurry to obtain the compound of formula (IV).

5) Add the compound of formula (IV) into dichloromethane, then add triethylamine, 4-dimethylaminopyridine and isobutyric anhydride in sequence, and react to obtain the compound of formula (III).

6) Add the compound of formula (III) to the solvent, then add reagent F, heat up to 45-55°C for reaction, and obtain the compound of formula (II).

7) Add the compound of formula (II) to the solvent, then add activated carbon and anhydrous sodium sulfate, filter, cool the filtrate to below 15°C, add hydrobromic acid dropwise, then stir at 15-25°C for 1 hour, concentrate to a small volume, and refluxed with methyl tert-butyl ether to make a slurry, then cooled and filtered to obtain the compound of formula (I).

In other preferred embodiments, step 2) can be replaced by adding the compound of formula (VII) to tetrahydrofuran, and then adding heavy water, zinc powder and phosphorus oxychloride in sequence to react to obtain the compound of formula (VI).

In other preferred embodiments, step 2) can be replaced by adding the compound of formula (VII) to tetrahydrofuran, and then adding deuterated hydrochloric acid and zinc powder in sequence to react to obtain the compound of formula (VI).

For the above steps 1) to 7),

In some more preferred embodiments of the present invention, in step 1), the reaction solvent is acetonitrile.

In some more preferred embodiments of the present invention, in step 1), X is I, and reagent A is N-iodosuccinimide.

In some more preferred embodiments of the present invention, in step 1), the acid is trifluoroacetic acid.

In some more preferred embodiments of the present invention, in step 1), the molar ratio of the compound of formula (VIII), reagent A, and acid is 1:1.3:0.2.

In some more preferred embodiments of the present invention, in step 2), the reaction solvent is tetrahydrofuran.

In some more preferred embodiments of the present invention, in step 2), the molar ratio of the compound of formula (VII) to triethylamine is 1:2.

In some more preferred embodiments of the present invention, in step 2), the weight ratio of the compound of formula (VII) to palladium on carbon is 1:0.03 (on a dry basis) based on the dry basis of palladium on carbon.

In some more preferred embodiments of the present invention, in step 3), the molar ratio of the compound of formula (VI) to boron trichloride is 1:4.

In some more preferred embodiments of the present invention, in step 3), the ratio of the weight part of the compound of formula (VI) to the volume part of methanol is 1: (5-15), for example, it can be 1:5, 1: 10, 1:15, etc.; wherein, the corresponding relationship between parts by weight and parts by volume is g/mL.

In some more preferred embodiments of the present invention, in step 3), the ratio of the weight part of the compound of formula (VI) to the volume part of n-heptane is 1: (5-15), for example, it can be 1:5, 1:10, 1:15, etc.; wherein, the corresponding relationship between parts by weight and parts by volume is g/mL.

In some more preferred embodiments of the present invention, in step 3), the ratio of the weight part of the compound of formula (VI) to the volume part of acetonitrile is 1: (1-10), for example, it can be 1:5, 1: 7.5, 1:10, etc.; wherein, the corresponding relationship between parts by weight and parts by volume is g/mL.

In some more preferred embodiments of the present invention, in step 4), the reagent D is N,N-dimethylformamide dimethyl acetal.

In some more preferred embodiments of the present invention, in step 4), the volume ratio of ethyl acetate and n-heptane used for beating 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):(4 ~6): (0.01~0.1).

In some more preferred embodiments of the present 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 the weight part of the compound of formula (II) to the volume part of methyl tert-butyl ether is 1: (1-10), and the corresponding ratio of the weight part to the volume part The relationship is g/mL.

Example 1

1) Preparation of formula (Ⅶ) compound:

Add the compound of formula (Ⅷ) (4.5kg, 1eq) and acetonitrile (22.5L, 5V) into the 30L reactor. Under the protection of nitrogen, the temperature is controlled at 25°C, NIS (2.34kg, 1.3eq) is added in batches, and the addition is completed. Continue to add trifluoroacetic acid (183.9 g, 0.2 eq) dropwise under temperature control. After the drop is complete, react at 25° C. for 4 h. TLC shows that the raw material has been completely reacted. Concentrate acetonitrile, add DCM (31.5L, 7V) and stir to dissolve, prepare a mixed solution (22.5L, 5V) of sodium bicarbonate (1.35kg, 2eq) and sodium sulfite (1kg, 1eq), add dropwise to the reaction at 25°C liquid, stirred and separated, the organic phase was washed with an aqueous solution (22.5L) of sodium bicarbonate (1.35kg, 2eq), separated and concentrated; then it was beaten with toluene (25L) for 1h, filtered, and the filter cake was washed with toluene (2.5L ), the compound of formula (VII) was obtained as an off-white solid (5.35 kg, yield: 97.2%).

2) preparation of formula (Ⅵ) compound:

The compound of formula (VII) (600g, 1eq) was dissolved in THF (9L, 15V), placed in a 20L autoclave, triethylamine (176.4 g, 2eq), palladium carbon (wet product 40.5g (water content 55.6%) , 3% by mass on a dry basis), after nitrogen replacement twice, deuterium is pressurized to normal pressure, after the temperature in the kettle is raised to 60°C, deuterium is pressurized to about 1.0MPa, and deuterium is added during the period to maintain the pressure to 1.0MPa , the pressure remained basically unchanged for about 0.5h. After continuing to control the temperature and stir for 1h, lower the temperature to 20°C and replace with nitrogen once. TLC showed that the reaction was complete. Add 500mL of water, stir for 5min, release the reaction solution, wash with 400mL THF, filter, Rinse with THF and water, concentrate the filtrate, add DCM (4.2L) and water (3L), separate the layers, wash the organic layer with water (3L), filter, concentrate the organic phase, beat toluene (3.6L), and filter to obtain the formula (Ⅵ) compound, off-white solid (451 g, yield: 92%), the deuteration rate of the product is greater than 99%.

3) preparation of formula (Ⅴ) compound:

The compound of formula (Ⅵ) (451g, 1eq) was added to DCM (4.51L, 10V), under the protection of nitrogen, the internal temperature was lowered to -30°C, and a dichloromethane solution of boron trichloride (3.56L, 4.4eq , 1N), during this process, the temperature was controlled below -25°C, and after dropping and stirring for 0.5h, TLC showed that the reaction was complete. At -30°C, add methanol dropwise to quench the reaction. After dropping, raise the inner temperature to 15°C and keep stirring for 2 hours. Then add n-heptane dropwise. After adding, keep stirring for 1 hour and filter under nitrogen protection. Rinse with a mixed solvent of dichloromethane and n-heptane, suspend the filter cake in water (2.7L), slowly add 10wt% sodium carbonate aqueous solution dropwise to adjust the pH to 8-9, stir the mixture for 1 hour and filter, then rinse the filter cake with water Wash, collect the wet filter cake, add acetonitrile (1.8 L), heat up to reflux, reflux beating for 1 to 2 hours, cool to 5°C, stir for 1 to 2 hours, and filter to obtain the compound of formula (Ⅴ), a red powdery solid (128.7 g, yield: 55.0%).

4) Preparation of the compound of formula (Ⅳ):

Add the compound of formula (Ⅴ) (0.914kg, 1eq) into tetrahydrofuran (8.1kg, 10V), stir and heat, the solid is basically insoluble, when the internal temperature of the reaction solution rises to 55°C, add N,N-dimethylformamide Dimethyl acetal (1.304kg, 3.5eq) was reacted at a temperature of 50°C for 5h. After TLC showed that the reaction of the raw materials was complete, stop heating, stir and cool down to 20°C, concentrate the reaction solution, add methanol (9.14L, 10V) for beating for 1h, concentrate the reaction solution to a semi-solid state, add a mixed solvent of ethyl acetate and n-heptane After beating, stirring at 20±5°C for 1-2 hours, filtering, and washing the filter cake with n-heptane, the compound of formula (IV) was obtained as a red powdery solid (1.059kg, yield: 97.2%).

5) Preparation of the compound of formula (Ⅲ):

Add the compound of formula (IV) (1.057kg) into dichloromethane (6.34L, 6V), cool the reaction solution below 15°C, add triethylamine (1.539kg, 5eq) and 4-dimethylaminopyridine ( 0.0186kg, 0.05eq), and then add isobutyric anhydride (1.925kg, 4eq) dropwise. During the dropwise addition, control the temperature of the reaction solution not to exceed 15°C. After the dropwise addition, control the reaction temperature at 10°C for 1.5h. TLC shows that the reaction is complete, and dichloromethane (4.2L, 4V) is added to the reaction solution, and 0.1N dilute hydrochloric acid aqueous solution (10.57L, 10V) is added, after stirring for 10min, the layers are left to stand, the organic phase is collected, and then Add saturated aqueous sodium bicarbonate solution (10.57L, 10V) to the organic phase, stir for 30min, then let stand to separate layers, collect the organic phase, then wash with water (10.57L, 10V), stand to separate and dry over anhydrous sodium sulfate, After filtration, the filtrate was concentrated to obtain the compound of formula (Ⅲ), a reddish-brown oil VV116-5, which was directly used in the next reaction.

6) Preparation of the compound of formula (II):

The compound of formula (III) obtained in the previous step (1.7kg, 1eq) was added to ethanol (13.6L, 8V), and acetic acid (3.658kg, 20eq) was added, and the reaction solution was heated to 50°C, and the temperature was controlled at 55°C for 9h. TLC showed the starting material was completely reacted. Concentrate the reaction solution until there is no liquid drop, add ethyl acetate (13.6L, 8V) to dilute, then add saturated sodium bicarbonate solution to neutralize the acetic acid, stir for 1 hour, take the water phase to measure the pH value of about 7-8, Stand to separate layers, collect the organic phase, then wash with saturated sodium chloride solution (10.2L, 6V), stand to separate layers, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain the compound of formula (II) as a reddish-brown oil Object VV116-6.

7) Preparation of the compound of formula (I):

The compound of formula (II) (1.256kg, 1eq) was added to acetonitrile (8.79L, 7V), cooled to below 15°C, and 48% hydrobromic acid (0.421kg, 1eq) was added dropwise. Stir for 1h and concentrate. After the reaction solution was concentrated to a small volume, methyl tert-butyl ether (8.79L, 7V) was added, heated to reflux, stirred at reflux for 2h, cooled naturally to 20±5°C, and stirred for 12h. The reaction solution was filtered to obtain the compound of formula (I) as an off-white powdery solid (1.05kg, yield: 72.2%).

Example 2

This embodiment provides a preparation method of the compound of formula (I), which is the same as that of Embodiment 1 except step 2).

2) preparation of formula (Ⅵ) compound:

The compound of formula (VII) (3.44g, 1eq) was dissolved in ultra-dry THF (20mL, purchased from Anaiji), added heavy water (1.8mL, 20eq), concentrated to dryness at 50°C, and then added ultra-dry THF (20mL) , zinc powder (981mg, 3eq) and heavy water (1.8mL, 20eq), under ice-cooling, drop phosphorus oxychloride (1.15g, 1.5eq). After the addition, the ice bath was removed and stirred at room temperature. After 30 minutes, TLC showed that the reaction of the raw materials was complete. Filter, wash the filter residue with ethyl acetate, add ethyl acetate (100 mL) to the filtrate, wash with saturated sodium bicarbonate and saturated brine, dry over anhydrous sodium sulfate, concentrate the solvent to dryness, and use toluene (25 mL) to make a slurry for the residue. After filtration, the compound of formula (VI) was obtained as an off-white solid (2.2 g, yield: 78%), and the deuteration rate of the product was greater than 98%.

Example 3

This embodiment provides a preparation method of the compound of formula (I), which is the same as that of Embodiment 1 except step 2).

2) preparation of formula (Ⅵ) compound:

Dissolve the compound of formula (VII) (2g, 2.90mmol) in ultra-dry tetrahydrofuran (30mL), then add heavy water (3mL) and concentrate to dryness. The above operation is repeated once, and the treated compound of formula (VII) is dissolved in tetrahydrofuran ( 30mL), then add zinc powder (943 mg, 14.50mmol), under the protection of nitrogen, slowly add 6N heavy aqueous solution of deuterated hydrochloric acid (2.0mL, 12.00mmol) dropwise at 0-5°C, keep stirring for 30 minutes, TLC If the raw material disappeared, the reaction solution was filtered, then water and ethyl acetate were added, and the layers were separated. The aqueous phase was extracted once with ethyl acetate, and the organic phases were combined, washed successively with saturated sodium bicarbonate and saturated brine, and anhydrous Dry over sodium sulfate, filter, concentrate, and beat with methyl tert-butyl ether to obtain the compound of formula (VI) as an off-white solid (1.1 g, yield: 68%), and the deuteration rate of the product is greater than 98%.

Industrial availability

The preparation method of the antiviral nucleoside analog VV116 provided by the present invention can be applied in industry.

Having described various embodiments of the present disclosure above, the foregoing description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and alterations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The choice of terminology used herein is intended to best explain the principle of each embodiment, practical application or improvement to the technology in the market, or to enable other persons of ordinary skill in the art to understand each embodiment disclosed herein.

Claims (10)

1. A preparation method of a compound of formula (I), comprising the following steps: 1) The compound of formula (Ⅷ) reacts with reagent A under the action of acid to obtain the compound of formula (Ⅶ):

Wherein, X is a halogen; 2) The compound of formula (VII) reacts with reagent B under the action of metal reagent M to obtain the compound of formula (VI):

3) The compound of formula (Ⅵ) reacts with reagent C to obtain the compound of formula (Ⅴ):

4) The compound of formula (Ⅴ) reacts with reagent D to obtain the compound of formula (Ⅳ):

5) The compound of formula (Ⅳ) reacts with reagent E under the action of an organic base to obtain the compound of formula (Ⅲ):

6) The compound of formula (Ⅲ) reacts with reagent F to obtain the compound of formula (Ⅱ):

7) The compound of formula (II) reacts with reagent G to obtain the compound of formula (I):

2. The preparation method of the compound of formula (I) according to claim 1, characterized in that, in step 1), X is I, Br or Cl, and the reagent A is N-iodosuccinimide, I ₂ , Br ₂ , N-bromosuccinimide, dibromohydantoin or N-chlorobutanedi One of imides; preferably, X is I or Br, and the reagent A is N-iodosuccinimide, I ₂ , Br ₂ , N-bromosuccinimide or dibromo One of hydantoin; 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, more preferably trifluoroacetic acid; The reaction solvent is one of N,N-dimethylformamide, tetrahydrofuran or acetonitrile, preferably acetonitrile; The reaction temperature is 0-50°C, preferably 20-30°C, more preferably 25°C; Wherein, the molar ratio of the compound of formula (VIII), the reagent A and the acid is 1:(1-1.5):(0.1-0.5), preferably 1:1.3:0.2. 3. The preparation method of the compound of formula (I) according to claim 1 or 2, characterized in that, in step 2), the reagent B is one of deuterium gas, deuterated acidic reagent or heavy water. 4. the preparation method of formula (I) compound according to claim 3, is characterized in that, in step 2), described formula (VII) compound and described deuterium gas are under the action of described metal reagent M and organic base reaction; The metal reagent M is a palladium catalyst, preferably palladium carbon; the organic base is one of triethylamine, N,N-diisopropylethylamine, trimethylamine, ammonia gas, ammonia water, DBU or pyridine , preferably triethylamine; the reaction solvent is one of tetrahydrofuran, methanol, ethanol, isopropanol or ethyl acetate, preferably tetrahydrofuran; the reaction pressure is 0.1-2MPa, preferably 1.0MPa; the reaction temperature is 25-65 °C, preferably 55-65 °C; Wherein, the mass ratio of the compound of the formula (VII) to the dry base of the palladium carbon 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 preparation method of formula (I) compound according to claim 3 is characterized in that, in step 2), described formula (VII) compound reacts with described deuterated acidic reagent under the action of described metal reagent M ; The deuterated acid 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°C, preferably 20-30°C; 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):(4.0-6.0). 6. The preparation method of the compound of formula (I) according to claim 3, characterized in that, in step 2), the compound of formula (VII) and the heavy water are under the action of the metal reagent M and reagent B' reaction; 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°C, preferably room temperature; 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):(2-4):(1-2). 7. according to the preparation method of the compound of formula (I) described in any one of claim 1-6, it is characterized in that, in step 3), described reagent C is boron trichloride or boron tribromide, and reaction solvent is Dichloromethane, the reaction temperature is -35～-25°C; Wherein, the molar ratio of the compound of formula (VI) to the reagent C is 1:(3-6). 8. The preparation method of the compound of formula (I) according to any one of claims 1-7, characterized in that, in step 4), the reagent D is N,N-dimethylformamide dimethyl acetal Aldehyde 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°C; Wherein, the molar ratio of the compound of formula (V) to the reagent D is 1:(2-4). 9. according to the preparation method of the compound of formula (I) described in any one of claim 1-8, it is characterized in that, in step 5), described reagent E is in isobutyryl chloride, isobutyric anhydride or isobutyric acid A sort of; When the reagent E is isobutyryl chloride or isobutyric anhydride, the compound of formula (IV) reacts with the reagent E under the action of an organic base and a catalyst, and 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°C, preferably 5-15°C; Wherein, the molar ratio of the compound of formula (IV), the reagent E, the organic base and the catalyst is 1:(3-5):(4-6):(0.01-0.1); When the reagent E is isobutyric acid, the compound of formula (IV) reacts with the reagent E under the action of an organic base and a condensing agent, and the organic base is triethylamine and/or N,N-diisopropyl Ethylamine; the condensing agent is dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or 1-hydroxybenzotriazole One; the reaction solvent is dichloromethane; the reaction temperature is 5-30°C, preferably 5-15°C. 10. The preparation method of the compound of formula (I) according to any one of claims 1-9, characterized in that, in step 6), the reagent F is one of acetic acid, trifluoroacetic acid, hydrochloric acid or hydrazine hydrate species, preferably acetic acid; the reaction solvent is one of ethanol, isopropanol, tetrahydrofuran or acetonitrile, preferably ethanol; the reaction temperature is 0 to 55°C, preferably 45 to 55°C; wherein, the (Ⅲ) compound The molar ratio with the reagent F is 1:(15～25); In step 7), the reagent G is hydrobromic acid, and the reaction temperature is 15-25°C; wherein, the molar ratio of the compound of formula (II) to the reagent G is 1:(1-1.2).