Preparation method of Mariobavir

Abstract

The invention relates to Mariobavir, in particular to a novel method for preparing Mariobavir. The method comprises the following steps: 1) reacting a compound I (the chemical name is 4, 5-dichloro-1, 2-phenylenediamine) with (2S, 3R, 4R, 5R)-5-(acetoxymethyl) tetrahydrofuran-2, 3, 4-triacetic acid triester II to obtain an intermediate III; 2) performing ring closing on the intermediate III and isopropylamine under the action of triethyl orthoformate to obtain an intermediate IV; and (3) removing an acetyl protecting group from the intermediate IV under the action of sodium hydroxide to generate Maribavir. The process route provided by the invention has the advantages that the route is short, the total yield is high, the atom economy is improved, and the production cost is remarkably reduced. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a method for synthesizing maribavir, and in particular to a new method for preparing maribavir. Background Art

[0002] Human cytomegalovirus (CMV) is a double-stranded linear DNA virus belonging to human herpesvirus. Human CMV infection is extremely common and is usually latent infection, but when the human immune system is low (such as immunodeficiency, organ transplantation, tumor patients, pregnancy and newborns), CMV is transformed from a latent state into a primary or secondary infection, causing serious clinical symptoms or even death. Ganciclovir, a DNA polymerase inhibitor, is the most commonly used first-line drug for the treatment of CMV infection, but its toxic side effects are large, and in recent years, drug-resistant CMV infections have increased, bringing difficulties to clinical treatment. Therefore, finding drugs for the treatment of CMV infection with new mechanisms of action is a hot topic in this field.

[0003] Maribavir is a new benzimidazole riboside drug, which belongs to the pUL97 protein kinase inhibitor and has a unique mechanism of action against CMV. Maribavir has a high oral absorption rate and few adverse reactions, and has good clinical safety. Maribavir was originally developed by the University of Michigan and then licensed to GlaxoSmithKline Pharmaceuticals. Currently, maribavir is being tested in Phase III clinical trials in many countries and regions around the world by GlaxoSmithKline Pharmaceuticals, Shire Pharmaceuticals and Takeda Pharmaceuticals. Takeda Pharmaceuticals announced on February 12, 2021 that its Phase III clinical trial was successful. Previously, maribavir was granted orphan drug status by the U.S. Food and Drug Administration and the European Commission for the treatment of severe cytomegalovirus viremia in high-risk patient groups and the treatment of CMV infection in immunocompromised patients. Maribavir has also been granted breakthrough drug status in the United States for the treatment of CMV infection in transplant recipients. In China, maribavir obtained clinical trial approval in April 2020 and was included in the breakthrough therapy category, with indications for the treatment of CMV infection or disease. The structural formula of maribavir is shown below:

[0004]

[0005] The currently reported synthetic routes of maribavir are as follows:

[0006] 1. U.S. Patent No. 6077832 reports a synthetic route of maribavir with a total yield of 27%, wherein the yield of the first step reaction is extremely low, less than 6%, as shown below:

[0007]

[0008] 2. Patent WO2001077083 reports another synthetic route of maribavir, with a total yield of nearly 20%. However, the highly toxic phosphorus oxybromide is used in the reaction process, and the reaction conditions are harsh, which is not conducive to environmental protection and industrial production needs, and the atom economy is poor, as shown below:

[0009]

[0010] 3. Patent 6617315 reports a synthetic route for maribavir with a total yield of nearly 49%. The reaction also uses regulated hazardous chemicals such as isopropyl isothiocyanate and pyridine as reaction solvents with strong odor, which is not conducive to environmental protection requirements, as shown below:

[0011]

[0012] In summary, the current synthesis technology of maribavir has defects such as cumbersome operation, poor atom economy, and high safety risks, which seriously affect the production scale and popularization of maribavir. Therefore, developing a new preparation method to reduce the production cost of maribavir and improve efficiency and safety is a technical problem that needs to be solved urgently. Summary of the invention

[0013] In order to overcome the defects of the above-mentioned technical route, such as high manufacturing and separation costs, the use of highly toxic and hazardous chemicals, and being unfavorable to environmental protection and industrial production, the present invention provides a new method for synthesizing maribavir, which adopts the following technical route:

[0014]

[0015] The steps are as follows:

[0016] S1: Synthesis of Compound III

[0017] Dissolve compound I and compound II in acetonitrile, add DABCO, and react under nitrogen protection to obtain compound III;

[0018] S2: Synthesis of Compound IV

[0019] Dissolve compound III in 1,4-dioxane solution, add isopropylamine and triethyl orthoformate, and heat to react to obtain compound IV;

[0020] S3: Synthesis of Maribavir

[0021] The compound IV is dissolved in an ethanol reaction system, and sodium hydroxide is added to obtain maribavir.

[0022] Wherein, in step S1, the reaction temperature is 80-90°C, and the molar ratio of compound I:compound II is 1:1.1;

[0023] In step S2, the molar ratio of compound III: isopropylamine: triethyl orthoformate is 1:1.5:2, and the reaction temperature is 80-90°C;

[0024] The reaction temperature in step S3 is 20-30°C.

[0025] Beneficial Effects

[0026] 1. Compared with the prior art, the reaction route of the present invention is short, the atom economy is improved, the production cost is significantly reduced, and unexpected technical effects are produced, which is very suitable for industrial production.

[0027] 2. The present invention provides a new method for preparing maribavir, which avoids the defects of supervising highly toxic hazardous chemicals, harsh reaction conditions, and expensive starting materials, and greatly reduces the harm to humans and the environment.

[0028] 3. The raw materials of the method of the present invention are cheap and readily available, the reaction conditions are mild, and the atom economy is good. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is the hydrogen spectrum detection spectrum of maribavir. DETAILED DESCRIPTION

[0030] In order to make the purpose, technical scheme and advantages of the present invention clearer, the following specific examples further describe the present invention in detail. The experimental methods in the present invention are conventional methods unless otherwise specified. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0031] The reaction progress of the present invention can be monitored by conventional monitoring methods in the art (such as TLC, LCMS or NMR), and the reaction endpoint is generally when the raw material disappears. DABCO is 1,4-diazabicyclo[2.2.2]octane; the chemical reagents and raw materials of the present invention are purchased from Sane Chemical Technology (Shanghai) Co., Ltd.

[0032] Example 1: The present invention provides a method for preparing an intermediate III, and its synthetic route is as follows:

[0033]

[0034] The specific preparation method is as follows:

[0035] Compound I (10 g, 56.49 mmol) was dissolved in acetonitrile (100 mL), and compound II (19.78 g, 62.14 mmol) and DABCO (9.50 g, 84.73 mmol) were added and replaced with nitrogen three times. The temperature was controlled at 80-90°C and the reaction was stirred for 10 h. TLC was performed until compound I disappeared. The reaction solution was removed, ethyl acetate (0.1 L*3) and water (0.1 L) were added, and the liquids were separated and extracted. The organic phase was removed to obtain 22 g of compound III with a yield of 89.48%. ESI-MS (m / z): 435.1.

[0036] Example 2: The present invention provides a method for preparing an intermediate IV, and its synthetic route is as follows:

[0037]

[0038] The specific preparation method is as follows:

[0039] Compound III (10 g, 22.98 mmol) was dissolved in anhydrous 1,4-dioxane (0.1 L), and isopropylamine (2.04 g, 34.46 mmol) and triethyl orthoformate (6.81 g, 45.95 mmol) were added, followed by reaction at 80-90°C for 10 h. Compound III disappeared after TLC detection. The solvent was removed under reduced pressure, and 1 M dilute hydrochloric acid was added to precipitate a large amount of white solid. The solid was washed with ethanol (20 mL*2) to obtain 11 g of compound IV with a yield of 95.31%. ESI-MS (m / z): 502.1.

[0040] Example 3: The present invention provides a method for preparing maribavir:

[0041]

[0042] Compound IV (5 g, 9.95 mmol) and sodium hydroxide (1.19 g, 29.86 mmol) were dissolved in ethanol (0.1 L), and the reaction was stirred at 20-30 ° C for 6 h. TLC was detected until compound IV disappeared. The solvent was removed under reduced pressure, and the solid was slurried with isopropanol / water = 10 / 1 to obtain 3.5 g of maribavir with a yield of 93.46%. ESI-MS (m / z): 376.1.

[0043] 1HNMR (400MHz, DMSO), δ7.61(s,1H),7.37(s,1H),6.92(d,J=7.6Hz,1H),5.75(d,J=7.6Hz,1H),5.65-5.60(m,1H) ,5.28-5.24(m,2H),4.40-4.25(m,1H),4.20-4.00(m,2H),3.98(s,1H),3.80-3.60(m,2H),1.20(d,J=6.4Hz,6H)

[0044] The specific implementation of the present invention described above does not constitute a limitation on the protection scope of the present invention. Any other corresponding changes and modifications made based on the technical concept of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A method for synthesizing maribavir, characterized in that: Follow these steps to achieve this: S1: Synthesis of Compound III: Dissolve compound I and compound II in acetonitrile, add DABCO, and react under nitrogen protection to obtain compound III; S2: Synthesis of compound IV: Dissolve compound III in 1,4-dioxane solution, add isopropylamine and triethyl orthoformate, and heat to react to obtain compound IV; S3: Synthesis of Maribavir: The compound IV is dissolved in an ethanol reaction system, and sodium hydroxide is added to obtain maribavir.

2. The method according to claim 1, characterized in that In step S1, the reaction temperature is 80-90° C., and the molar ratio of compound I:compound II is 1:1.

1.

3. The method according to claim 1, characterized in that In step S2, the molar ratio of compound III: isopropylamine: triethyl orthoformate is 1:1.5:2, and the reaction temperature is 80-90°C.

4. The method according to claim 1, characterized in that: The reaction temperature in step S3 is 20-30°C.

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