CN112552288A

CN112552288A - Preparation method of 4-oxime-5' - (2-methylpropionyl) uridine

Info

Publication number: CN112552288A
Application number: CN202110188342.0A
Authority: CN
Inventors: 陈剑; 余长泉; 陈晨
Original assignee: Nanjing Huaguan Biotechnology Co ltd
Current assignee: Nanjing Huaguan Biotechnology Co ltd
Priority date: 2021-02-19
Filing date: 2021-02-19
Publication date: 2021-03-26

Abstract

The invention discloses a preparation method of 4-oxime-5' - (2-methylpropionyl) uridine, which comprises the following steps: s1: reacting compound 1 and 2, 2-dimethoxypropane in an organic solvent in the presence of an acid to obtain compound 2; s2: reacting the compound 2 in an organic solvent in the presence of a base to obtain a compound 3; s3: reacting a compound 3 in an organic solvent in the presence of an aqueous hydroxylamine solution to obtain a compound 4; s4: compound 4 is reacted in an organic solvent in the presence of an acid to give compound I. The solid with good crystallinity prepared by the invention has simple preparation conditions and good conversion rate and atom economy.

Description

Preparation method of 4-oxime-5' - (2-methylpropionyl) uridine

Technical Field

The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of 4-oxime-5' - (2-methylpropionyl) uridine.

Background

Molnupiarvir (structure I) (EIDD-2801, MK-4482) is an orally bioactive prodrug of the ribonucleoside analog β -d-N4-Hydroxycytidine (NHC; EIDD-1931) with broad-spectrum antiviral activity against the pathogens SARS-CoV-2, MERS-CoV, SARS-CoV and COVID-19. Molnupiravir may prove to be an effective antiviral drug in a variety of settings. Because of the convenient use of the oral medicine, the oral medicine can be used as a preventive medicine and is also suitable for outpatients and inpatients

。

The main synthetic route of Molnupiravir is patent WO2019113463, and the synthetic route of the compound reported in WO2019173602 is as follows:

the method comprises the following steps:

；

step two:

；

step three:

；

step four:

；

step five:

。

in the compound report route, the multi-step intermediate is oily and needs column chromatography purification, thereby leading to difficult purification and lower yield and higher cost.

Disclosure of Invention

The present invention is directed to a method for producing 4-oxime-5' - (2-methylpropionyl) uridine, which solves the problems of the background art.

A method for synthesizing 4-oxime-5' - (2-methylpropionyl) uridine comprises the following steps:

S1：

；

S2：

；

S3：

；

S4：

。

in order to achieve the purpose, the invention provides the following technical scheme: a process for the preparation of 4-oxime-5' - (2-methylpropionyl) uridine, comprising the following steps in sequence:

s1: reacting compound 1 and 2, 2-dimethoxypropane in an organic solvent in the presence of an acid to obtain compound 2;

s2: reacting the compound 2 in an organic solvent in the presence of a base to obtain a compound 3;

s3: reacting a compound 3 in an organic solvent in the presence of an aqueous hydroxylamine solution to obtain a compound 4;

s4: reacting compound 4 in an organic solvent in the presence of an acid to obtain compound I;

the structural formula of the compound 1 is

(ii) a The structural formula of the compound 2 is

(ii) a The structural formula of the compound 3 is

(ii) a The structural formula of the compound 4 is

(ii) a The structural formula of the compound I is

。

Preferably, in step S1, the acid is sulfuric acid, and the solvent is one of acetone, acetonitrile, and tetrahydrofuran.

In any of the above schemes, preferably, in step S2, the base is one of DBU, TEA, and DIPEA, and the organic solvent is one of acetonitrile, tetrahydrofuran, ethyl acetate, and dichloromethane.

In any of the above embodiments, in step S3, the organic solvent is preferably one of isopropyl alcohol, methanol, ethanol, and water.

In any of the above schemes, preferably, in step S4, the acid is one of formic acid, acetic acid, trifluoroacetic acid and HCl.

The invention has the technical effects and advantages that: the solid with good crystallinity, simple preparation condition, and good conversion rate and atom economy is prepared by the preparation method of the 4-oxime-5' - (2-methylpropionyl) uridine.

Detailed Description

The following will clearly and completely describe the technical solutions in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1:

in a 500 mL three-necked reaction flask, 118.8 g of the compound, 40.7 g of 2, 2-dimethoxypropane and 188.0 mL of acetone are sequentially added and stirred at room temperature, then 8.0 g of sulfuric acid is dropwise added, the system is stirred at room temperature for 2 hours, after TLC (thin layer chromatography) shows that the conversion of the raw materials is complete, filtration is carried out, and a filter cake is rinsed with 100.0 mL of acetone to obtain 28.1 g of the product 2 ', 3' -O-isopropylidene cytidine sulfate (compound 2), yield: 95.25% of white solid.

Example 2:

in a 500 mL reaction flask, 250.0 g of the compound was charged, followed by sequentially adding 150 mL of anhydrous acetonitrile, 3.3 g of DMAP and 41.0mL of DBU, stirring at room temperature, then dropwise adding 54.0 mL of isobutyric anhydride, stirring at 60 ℃ for reaction for 3 hours, after TLC showed complete conversion of the starting materials, then cooling, distilling under reduced pressure to remove acetonitrile, adding 300.0 mL of dichloromethane and 200.0 mL of saturated sodium bicarbonate to the oil, separating the layers, extracting the dichloromethane layer twice with 200.0 mL of dilute hydrochloric acid (1M), collecting the dichloromethane phase, drying, and concentrating to obtain 49.9 g of the product 2 ', 3 ' -O- (1-methyl-1-oxopropyl) -N- (2-methyl-1-oxopropyl) -5 ' - (2-methylpropionyl) uridine (compound 3), yield: 89.88%, white solid.

Example 3:

adding 350.0 g of compound into a 500 mL reaction bottle, sequentially adding 200.0 mL of isopropanol, 100.0 mL of water and 50% of 7.3mL of hydroxylamine aqueous solution, stirring and reacting at 80 ℃ for 20 hours, reducing the temperature after TLC shows that the raw material conversion is complete, distilling under reduced pressure to remove the isopropanol, adding 200.0 mL of ethyl acetate and 200.0 mL of saturated sodium chloride aqueous solution into oil, separating layers, extracting an ethyl acetate layer twice with 200.0 mL of water, collecting an ethyl acetate phase, drying and concentrating to obtain a yellow crude product, and pulping with 60mL of methyl tert-butyl ether and 60mL of petroleum ether to obtain a product 2, 3 '-O- (1-methyl-1-oxopropyl) -4-oxime-5' - (2-methylpropionyl) uridine (compound 4), 37.5 g and yield: 85.91% and white solid.

Example 4:

adding 410.0 g of compound and 80.0 ml of formic acid into a 250 ml reaction flask, stirring at room temperature, reacting for 20 hours, after TLC shows that the raw materials are completely converted, distilling under reduced pressure to remove formic acid, carrying out rotary evaporation on formic acid by using 100.0 ml of ethanol, and recrystallizing the oily matter by using 60.0 ml of methyl tert-butyl ether and 6.0ml of isopropanol to obtain a product, namely compound I, 5.8 g, yield: 64.8% and white solid.

Although the present invention has been described with reference to a preferred embodiment, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

1. A process for the preparation of 4-oxime-5' - (2-methylpropionyl) uridine, characterized in that: the method comprises the following steps in sequence:

s3: reacting the compound 3 in an organic solvent in the presence of an aqueous hydroxylamine solution to obtain a compound 4;

the structural formula of the compound 1 is

(ii) a The structural formula of the compound 2 is

(ii) a The structural formula of the compound 3 is shown as follows; the structural formula of the compound 4 is

(ii) a The structural formula of the compound I is

。

2. The process for the preparation of 4-oxime-5' - (2-methylpropionoyl) uridine according to claim 1, wherein: in step S1, the acid is sulfuric acid, and the organic solvent is one of acetone, acetonitrile, and tetrahydrofuran.

3. The process for the preparation of 4-oxime-5' - (2-methylpropionoyl) uridine according to claim 1, wherein: in step S2, the base is one of DBU, TEA, DIPEA, and the organic solvent is one of acetonitrile, tetrahydrofuran, ethyl acetate, and dichloromethane.

4. The process for the preparation of 4-oxime-5' - (2-methylpropionoyl) uridine according to claim 1, wherein: in step S3, the organic solvent is one of isopropyl alcohol, methanol, ethanol, and water.

5. The process for the preparation of 4-oxime-5' - (2-methylpropionoyl) uridine according to claim 1, wherein: in step S4, the acid is one of formic acid, acetic acid, trifluoroacetic acid, and HCl.