CN105732618A - Method for synthesizing 4-(2-oxo-piperidine-1-yl)aryl-carboxylic ethyl ester compound - Google Patents

Abstract

The invention discloses a new method for synthesizing 4(2-oxopiperidinyl)aryl carboxylate ethyl esters. The raw materials, tetrahydrofuran and dichloromethane are used as a mixed solvent, and a lactamization reaction occurs under the action of a strong alkali sodium hydride to obtain the product 4 (2-oxopiperidinyl) aryl carboxylate ethyl esters. This type of ethyl 4(2-oxopiperidinyl)arylcarboxylate compound contains the parent structure for synthesizing oral anticoagulants for preventing thrombosis, and has a good market prospect. The ethyl 4(2-oxopiperidinyl)arylcarboxylate compound prepared by the method has the advantages of high yield, high purity, relatively economical materials, wide application value, etc., and is a better synthetic method.

Description

A method for synthesizing 4-(2-oxopiperidin-1-yl) aryl carboxylate ethyl esters

technical field

The invention relates to the technical field of lactamization reaction in organic synthesis, in particular to a new method for synthesizing ethyl 4-(2-oxopiperidin-1-yl) aryl carboxylates.

Background technique

The 4-(2-oxopiperidin-1-yl) aryl carboxylate ethyl ester compound synthesized by the invention can be used as an intermediate for synthesizing an oral selective activation factor X inhibitor. The drug is used to prevent blood clots, and is the third new generation of oral anticoagulant on the market. It has the "best in class" clinical trial results, and the effect of reducing the risk of major bleeding is very significant, and its safety and efficacy are superior to similar drugs . Therefore, the ethyl 4-(2-oxopiperidin-1-yl)aryl carboxylate compound has broad market prospects and great application value. There are also many ways to synthesize such compounds before. For example, the reaction system mentioned in the document WO2007001385A is trifluoroacetic acid/triethyl orthoformate, NMP, and NaOEt in EtOH. There are many kinds of reagents used in this reaction, and the system is relatively complicated. In particular, the water removal system trifluoroacetic acid/triethyl orthoformate is used.

Contents of the invention

The object of the present invention is to provide a new method for synthesizing 4-(2-oxopiperidin-1-yl) aryl carboxylate ethyl esters. In the invention, under the condition of strong alkali sodium hydride, nitrogen negative ions attack the carbon atom substituted by chlorine, and lactamization and ring closure occur to obtain the product.

The method for synthesizing 4-(2-oxopiperidin-1-yl) aryl carboxylate ethyl esters described in the present invention is based on 4-(5-chloropenteramido) aryl carboxylate ethyl esters The compound (formula A) is the reaction raw material, tetrahydrofuran and dichloromethane are used as the mixed solvent, and the lactamization reaction occurs under the action of strong alkali sodium hydride to obtain the product 4-(2-oxopiperidin-1-yl)aryl carboxylic acid Ethyl esters (Formula B). The reaction formula is as follows:

The structure of Ar can be benzene ring, single-substituted benzene ring, multi-substituted benzene ring; the structure of Het can be various heterocycles, for example: pyrrole ring, pyridine ring, piperidine ring, etc.

In the method of the present invention, because the reaction raw materials contain ester groups, they are easily hydrolyzed in the presence of water, so the reaction requires strict water control to avoid yield loss caused by excessive hydrolysis. The sodium hydride used in the reaction is used both as an alkali and as a water removal agent. Sodium hydride should be washed 4-6 times with petroleum ether under the protection of nitrogen or argon, and then pumped dry for later use.

In the present invention, the selected solvent is a mixed solvent of tetrahydrofuran and dichloromethane, and the moisture content of the solvent is required to be controlled below 0.1%.

In the method of the present invention, it is preferable to feed under nitrogen protection.

Since the product is foamy after concentration, it is difficult to obtain a solid product by concentrating under reduced pressure, so this step reaction is selected to add a solvent to make a slurry, and then filter to obtain a better solid.

A specific step is: Dissolve the washed NaH in THF under the protection of N ₂ , add dropwise DCM with the starting material at low temperature, after the addition is completed, heat up and stir, and monitor the reaction by TLC until the starting material is normalized If the area is less than 1.0%, add cold water to quench the reaction, extract, beat, filter, wash and dry.

The amount of DCM (v/w) is equivalent to 8-12 times the amount of the starting material, the amount of THF (v/w) is equivalent to 5-9 times the amount of the starting material, and the molar amount used by NaH is 3-3 times the molar amount of the reaction raw material. 4 times the amount, the dropping temperature is below 20°C, the reaction temperature is 20-30°C, and the amount of cold water (w/v) for quenching the reaction is equivalent to 9-15 times the amount of the starting material, the purity and yield of the product Rates are high.

Compared with the prior art, the method of the invention has the advantages of economy, simple operation, high purity and high yield.

detailed description

When implementing the present invention, feed under nitrogen protection. During a reaction, a variety of factors can affect the progress and thereby alter the outcome. Therefore, it is necessary to explore various factors to find an optimal condition level.

The reaction raw materials used in the present invention contain ester groups, which are easily hydrolyzed in the presence of water, so the reaction requires strict water control to avoid yield loss caused by excessive hydrolysis. In the reaction, sodium hydride is used as both alkali and water-removing agent, so the control of the amount of sodium hydride is particularly important when exploring the optimal condition level.

The amount of solvent also has a great influence on the reaction result. In order to dissolve all the reaction raw materials and facilitate the complete lactamization reaction, it is necessary to explore the amount of solvent used.

In addition, the reaction time is also an important factor; as well as the control of the reaction temperature, it is necessary to complete the reaction of the raw materials within the reaction time, and to prevent the generation of hydrolyzed impurities due to hydrolysis due to high temperature.

Example 1

Weigh 0.53g starting material 1-(4-methoxyphenyl)-7-oxo-6-[4-(5-chloropenterylamino)phenyl]-4,5,6,7-tetra Hydrogen-1H-pyrazolo[3,4,c]pyridine-3-carboxylic acid ethyl ester in a one-necked flask, add 5.3ml DCM (v/w=10), stir to dissolve, and take another dry three-necked flask , N ₂ protection, weighed in 0.048g (2eq) of NaH, added 5.3ml THF (v/w=10), stirred and dissolved below 20°C. The dichloromethane solution of the starting material was added dropwise, and the temperature was controlled below 20°C. After the dropwise addition was completed, the temperature was raised to 30°C and stirred for 24 hours, and the reaction was monitored by TLC. Add 5ml of cold water to quench the reaction, extract, beat, filter, wash, and dry to obtain the white powder product 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidine -1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester, yield 80%, purity 55 %.

Example 2

The difference from Example 1 is: adding NaH 0.072g (3eq), and other operations are basically the same, the yield of the white powder product is 95%, and the purity is 81%.

Example 3

The difference with Example 1 is: adding NaH 0.1g (4eq), and other operations are basically the same, the yield of the white powder product is 94%, and the purity is 80%.

Example 4

The difference from Example 1 is that: 0.084g (3.5eq) of NaH was added, and other operations were basically the same, the yield of the white powder product was 95.2%, and the purity was 86.3%.

Example 5

Weigh 1.05 g of starting material 1-(4-methoxyphenyl)-7-oxo-6-[4-(5-chloropentanylamino)phenyl]-4,5,6,7-tetra Hydrogen-1H-pyrazolo[3,4,c]pyridine-3-carboxylic acid ethyl ester in a one-necked flask, add 8ml DCM (v/w=8), stir to dissolve, and take another dry three-necked flask, N ₂ protected, weighed in 0.17g (3.5eq) of NaH, added 5ml of THF (v/w=5), stirred and dissolved below 20°C. The dichloromethane solution of the starting material was added dropwise, and the temperature was controlled below 20°C. After the dropwise addition was completed, the temperature was raised to 30°C and stirred for 24 hours, and the reaction was monitored by TLC. Add 10ml of cold water to quench the reaction, extract, beat, filter, wash, and dry to obtain the white powder product 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidine -1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester, yield 92%, purity 85.7 %.

Example 6

The difference with Example 5 is: add 8ml DCM (v/w=12), add 5ml THF (v/w=9), under the situation that other operations are basically the same, the yield that obtains white powder product is 95%, purity was 86.1%.

Example 7

Weigh 2.1 g of starting material 1-(4-methoxyphenyl)-7-oxo-6-[4-(5-chlorovalerylamino)phenyl]-4,5,6,7-tetra Hydrogen-1H-pyrazolo[3,4,c]pyridine-3-carboxylic acid ethyl ester in a one-necked flask, add 25.2ml DCM (v/w=12), stir to dissolve, and take another dry three-necked flask , under N ₂ protection, weighed in 0.34g (3.5eq) of NaH, added 19ml of THF (v/w=9), stirred and dissolved below 20°C. The dichloromethane solution of the starting material was added dropwise, and the temperature was controlled below 20°C. After the dropwise addition was completed, the temperature was raised to 30°C and stirred, and the reaction was monitored by TLC. Add 20ml of cold water to quench the reaction, extract, beat, filter, wash, and dry to obtain the white powder product 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidine -1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester, yield 94%, purity 84 %.

Example 8

The difference with Example 7 is that: after the dropwise addition, the reaction was stirred at 15°C, and the other operations were basically the same, and the reaction was monitored by TLC. When the normalized area of the starting material was less than 1.0%, the reaction time was extended to 36h, and the obtained The yield of the white powder product was 93%, and the purity was 80.3%.

Example 9

The difference with Example 7 is that: after the dropwise addition, the reaction was stirred at 25°C, and the other operations were basically the same, and the reaction was monitored by TLC. When the normalized area of the starting material was less than 1.0%, the reaction time was 22h, and a white The yield of the powder product was 95.2%, and the purity was 88.6%.

Example 10

Weigh 2.1 g of starting material 1-(4-methoxyphenyl)-7-oxo-6-[4-(5-chlorovalerylamino)phenyl]-4,5,6,7-tetra Hydrogen-1H-pyrazolo[3,4,c]pyridine-3-carboxylic acid ethyl ester in a one-necked flask, add 25.2ml DCM (v/w=12), stir to dissolve, and take another dry three-necked flask , under N ₂ protection, weighed in 0.34g (3.5eq) of NaH, added 19ml of THF (v/w=9), stirred and dissolved below 20°C. Add the dichloromethane solution of the starting material dropwise. The temperature is controlled below 20°C. After the dropwise addition is completed, the temperature is raised to 25°C and stirred. Sampling and tracking are taken at different times. The reaction time is set to 12h, 20h, 22h, 24h, and 30h respectively. The reaction solution was monitored by HPLC. As the reaction progressed, the reaction degree of the starting materials was different at different times. At 12 hours, the remaining raw materials were 30.83%, and the normalized area of the main peak was 67.95%. At 22 hours, the normalized area of the raw materials was less than 1.0%, and the main peak The normalized area was 97.8%, and the normalized area of the main peak was 80.46% at 30 h, resulting in larger unknown impurities and larger hydrolyzed impurities.

Claims (5)

1. the method for synthesis 4-(2-oxo-piperidine-1-base) aryl carboxylic acid ethyl ester compound, it is characterised in that with 4-(5-chlorine penta Amide groups) aryl carboxylic acid ethyl ester compound is that reaction raw materials, oxolane and dichloromethane make mixed solvent, at highly basic sodium hydride Effect is lower occurs lactamization reaction to obtain product 4-(2-oxo-piperidine-1-base) aryl carboxylic acid ethyl ester compound.

The synthetic method of 4-the most according to claim 1 (2-oxo-piperidine-1-base) aryl carboxylic acid ethyl ester compound, its feature exists In: the sodium hydride that reaction uses will under nitrogen or argon, and petroleum ether is washed 4-6 time, and then oil pump is drained standby.

The synthetic method of 4-the most according to claim 1 (2-oxo-piperidine-1-base) aryl carboxylic acid ethyl ester compound, its feature exists In: selected solvent is the mixed solvent of oxolane and dichloromethane, controls the moisture requirement of solvent below 0.1%.

The synthetic method of 4-the most according to claim 1 (2-oxo-piperidine-1-base) aryl carboxylic acid ethyl ester compound, its feature exists In: the mole of the sodium hydride used is 3-4 times of reaction raw materials mole, and solvent DCM volumetric usage is equivalent to react former 8-12 times of material quality, THF volumetric usage is equivalent to 5-9 times of initiation material quality, and reaction temperature controls at 20-30 DEG C.

The synthetic method of 4-the most according to claim 1 (2-oxo-piperidine-1-base) aryl carboxylic acid ethyl ester compound, its feature exists In: feed under nitrogen protection.