CN118184599A - Preparation method of amoenavir intermediate - Google Patents

Abstract

The invention provides a protonic acid-catalyzed synthesis method of an amonetvir intermediate 3-(4-nitrobenzene)-1,2,4-oxadiazole, the method comprising the step of adding a protonic acid to a triethyl orthoformate solution of 4-nitrobenzylamide oxime. The method has mild reaction conditions, simple operation, good product purity and high yield.

Description

A preparation method of an amoenavir intermediate

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and specifically relates to a method for preparing an amonetir intermediate 3-(4-nitrobenzene)-1,2,4-oxadiazole.

Background technique

Amenamevir is a small molecule drug developed by Astellas Pharma Inc. of Japan. It has the function of inhibiting the activity of the helicase and primase complexes, which are enzymes necessary for the DNA replication of herpes virus, and inhibiting the cleavage of double-stranded DNA and the synthesis of RNA primers. It is mainly used in the treatment of herpes zoster. The drug was approved for marketing by the Japanese PMDA in July 2017. Its structural formula is as follows:

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3-(4-nitrobenzene)-1,2,4-oxadiazole is a key intermediate in the preparation of amounevir. Its quality and process seriously affect the application and promotion of amounevir.

There are two main methods for preparing 3-(4-nitrobenzene)-1,2,4-oxadiazole disclosed so far.

Patent WO2020038812A1/US2009239848A1 discloses a method for preparing 3-(4-nitrobenzene)-1,2,4-oxadiazole: adding a boron trifluoride ether solution to a triethyl orthoformate solution of 4-nitrobenzylamine oxime, removing the solvent after the reaction is completed, and obtaining the target product. This method has the following defects. First, the yield of this method is low, only 55%; second, the boron trifluoride ether solution used is expensive and the amount used is large; third, this method requires distillation to remove the high-boiling triethyl orthoformate, which is complicated to operate.

Patent WO2012009678A1 discloses another method for preparing 3-(4-nitrobenzene)-1,2,4-oxadiazole: a solution of triethyl orthoformate of 4-nitrobenzylamine oxime is heated to reflux, and after the reaction is completed, the solvent is removed under reduced pressure to obtain the target product. This method has a high yield (92%), but the reaction temperature is relatively high (about 140-150°C), and the high-boiling triethyl orthoformate needs to be removed by distillation. In addition, when we reproduced the process, we found that a large amount of impurity p-nitrobenzonitrile would be generated under this condition, which would be further derived and carried to the finished product of amonetavir and was difficult to remove; in addition, the reaction was not thorough, and a large amount of intermediates existed in the reaction solution.

Patent JP2005336101A discloses that isopropanol, methanol or ethanol are added to a mixed solution of 4-nitrobenzylamine oxime and triethyl orthoformate, and then 98% sulfuric acid is added dropwise at 20-30°C. After the reaction is carried out under the corresponding temperature conditions, the target product is obtained by cooling, crystallizing and filtering. This method requires the use of concentrated sulfuric acid, and has high corrosion resistance requirements for production equipment.

Therefore, it is necessary to develop a mild, economical and easy-to-operate method for preparing 3-(4-nitrobenzene)-1,2,4-oxadiazole.

Summary of the invention

The present invention provides a method for preparing an amonetir intermediate 3-(4-nitrobenzene)-1,2,4-oxadiazole, which comprises the following steps:

(1) Add protonic acid to a solution of 4-nitrobenzylamine oxime in triethyl orthoformate and heat to react;

(2) After the reaction is completed, a solvent is added to crystallize, and the solid is separated to obtain 3-(4-nitrobenzene)-1,2,4-oxadiazole.

Preferably, in step (1), the protonic acid is selected from one or more of formic acid, acetic acid, propionic acid, butyric acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid and oxalic acid, preferably formic acid.

Preferably, in step (1), the molar ratio of protonic acid to 4-nitrobenzylamine oxime is 0.3-0.7.

Preferably, in step (1), the temperature during the temperature-raising reaction is 45-105 ^° C.

Preferably, in step (2), the solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol, preferably ethanol and tert-butanol.

The method of the invention adopts cheap protonic acid as a catalyst, does not need to distill high-boiling-point triethyl orthoformate, does not use strong acid, has mild reaction conditions, is simple to operate, has high purity and high yield of the obtained product, and is suitable for large-scale production.

Detailed ways

The following examples are representative and are used to further understand and illustrate the essence of the present invention, but are not intended to limit the scope of the present invention in any way.

Example 1

Add 28.27 g of 4-nitrobenzylamine oxime, 100.64 g of triethyl orthoformate, and 5.09 g of formic acid into the reaction bottle, heat to 70±5°C and react for 3 h. After the reaction is completed, add ethanol dropwise for crystallization, filter, and dry the filter cake under reduced pressure to obtain 27.80 g of 3-(4-nitrobenzene)-1,2,4-oxadiazole with a yield of 93.19% and a purity of 100%.

Example 2

Add 15.00 g 4-nitrobenzylamine oxime, 53.37 g triethyl orthoformate, and 1.16 g formic acid into the reaction bottle, heat to 70±5°C and react for 6 h. After the reaction is completed, add ethanol dropwise for crystallization, filter, and dry the filter cake under reduced pressure to obtain 14.49 g of 3-(4-nitrobenzene)-1,2,4-oxadiazole with a yield of 91.55% and a purity of 99.8%.

Example 3

Add 1.04 kg 4-nitrobenzylamine oxime, 3.70 kg triethyl orthoformate, and 0.19 kg formic acid into the reaction bottle, heat to 100±5°C and react for 3 h. After the reaction is completed, add ethanol dropwise for crystallization, filter, and dry the filter cake under reduced pressure to obtain 0.99 kg of 3-(4-nitrobenzene)-1,2,4-oxadiazole, with a yield of 90.21% and a purity of 99.1%.

Example 4

Add 20.00 g 4-nitrobenzylamine oxime, 71.20 g triethyl orthoformate, and 3.60 g formic acid into the reaction bottle, heat to 50±5°C and react for 8 h. After the reaction is completed, add ethanol dropwise for crystallization, filter, and dry the filter cake under reduced pressure to obtain 19.41 g of 3-(4-nitrobenzene)-1,2,4-oxadiazole with a yield of 91.9% and a purity of 98.8%.

Example 5

Add 30.00 g 4-nitrobenzylamine oxime, 160.20 g triethyl orthoformate, and 5.40 g formic acid into the reaction bottle, heat to 70±5°C and react for 4 hours. After the reaction is completed, add ethanol dropwise for crystallization, centrifuge and dry under reduced pressure to obtain 28.59 g of 3-(4-nitrobenzene)-1,2,4-oxadiazole, with a yield of 90.31% and a purity of 99.5%.

Example 6

Add 18.00 g of 4-nitrobenzylamine oxime, 64.08 g of triethyl orthoformate, and 4.17 g of acetic acid to the reaction bottle, heat to 70±5°C and react for 5 hours. After the reaction is completed, add ethanol dropwise for crystallization, filter, and dry the filter cake under reduced pressure to obtain 15.60 g of 3-(4-nitrobenzene)-1,2,4-oxadiazole, with a yield of 82.15% and a purity of 99.8%.

Example 7

Add 10.00 g of 4-nitrobenzylamine oxime, 64.08 g of triethyl orthoformate, and 3.48 g of oxalic acid to the reaction bottle, heat to 70±5°C and react for 3 h. After the reaction is completed, add ethanol dropwise for crystallization, filter, and dry the filter cake under reduced pressure to obtain 8.30 g of 3-(4-nitrobenzene)-1,2,4-oxadiazole with a yield of 78.66% and a purity of 97.6%.

Example 8

Add 13.00 g of 4-nitrobenzylamine oxime, 70.00 g of triethyl orthoformate, and 9.56 g of p-toluenesulfonic acid monohydrate to the reaction bottle, heat to 70±5°C for 2 h, add ethanol dropwise for crystallization after the reaction is completed, filter, and slurry the filter cake with sodium bicarbonate aqueous solution and purified water, and dry under reduced pressure to obtain 10.08 g of 3-(4-nitrobenzene)-1,2,4-oxadiazole, with a yield of 73.48% and a purity of 93.8%.

Example 9

Add 5.00 g 4-nitrobenzylamine oxime, 18.00 g triethyl orthoformate, and 0.64 g formic acid into the reaction bottle, heat to 70±5°C and react for 6 h. After the reaction is completed, add ethanol dropwise for crystallization, filter, and dry the filter cake under reduced pressure to obtain 4.88 g of 3-(4-nitrobenzene)-1,2,4-oxadiazole with a yield of 92.49% and a purity of 99.7%.

Example 10

Add 17.00 g of 4-nitrobenzylamine oxime, 60.50 g of triethyl orthoformate, and 3.06 g of formic acid into the reaction bottle, heat to 70±5°C and react for 3 h. After the reaction is completed, add tert-butanol dropwise to crystallize, filter, and dry the filter cake under reduced pressure to obtain 16.68 g of 3-(4-nitrobenzene)-1,2,4-oxadiazole with a yield of 92.98% and a purity of 99.8%.

Embodiment 11

Add 5.00 g of 4-nitrobenzylamine oxime, 18.00 g of triethyl orthoformate, and 0.25 g of formic acid into the reaction bottle, heat to 100±5°C for 3 h, and send the reaction solution for inspection. The remaining 4-nitrobenzylamine oxime raw material is 17.67%, which cannot be completely converted.

Claims (6)

1. A method for preparing an amonetir intermediate 3-(4-nitrobenzene)-1,2,4-oxadiazole, comprising the following steps: (1) Add protonic acid to a solution of 4-nitrobenzylamine oxime in triethyl orthoformate and heat to react; (2) After the reaction is completed, a solvent is added to crystallize, and the solid is separated to obtain 3-(4-nitrobenzene)-1,2,4-oxadiazole; In the step (1), the protonic acid is selected from one or more of formic acid, acetic acid, propionic acid, butyric acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid and oxalic acid. 2. The preparation method according to claim 1, wherein in step (1), the molar ratio of protonic acid to 4-nitrobenzylamine oxime is 0.3-0.7. 3. The preparation method according to claim 2, wherein in step (1), the protonic acid is formic acid. 4. The preparation method according to claim 1, wherein in step (1), the temperature during the temperature-raising reaction is 45-105 ^° C. 5. The preparation method according to claim 1, wherein in step (2), the solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol. 6. The preparation method according to claim 5, wherein in step (2), the solvent is ethanol or tert-butanol.