AU2018101137A4

AU2018101137A4 - P-aminobenzaldehyde drug intermediates synthesis method

Info

Publication number: AU2018101137A4
Application number: AU2018101137A
Authority: AU
Inventors: Yida Yan
Original assignee: Chengdu Ao Ka Te Technology Co Ltd
Current assignee: Chengdu Ao Ka Te Technology Co Ltd
Priority date: 2017-09-17
Filing date: 2018-08-12
Publication date: 2018-09-13
Anticipated expiration: 2026-08-12
Also published as: CN108238961A; GB201715108D0; IE20180290U1

Abstract

P-aminobenzaldehyde drug intermediates synthesis method Abstract 5 The present invention discloses p-aminobenzaldehyde drug intermediates synthesis method, comprises the following steps: nitrobenzene methanol and potassium sulfate solution are added to the reaction vessel, controls the temperature of the solution, lead dioxide is added, controls the stirring speed, continues to react; then cyclohexane solution is added, nickel chloride powder is added in batches, raises the 10 temperature of the solution, react, reduces the temperature, set static, washed with sodium chloride solution, washed with diethylene glycol ethyl ether solution, washed with butyl ether solution, recrystallized in the cyclooctane solution, dehydrated with dehydration, got the finished product p-aminobenzaldehyde.

Description

The present invention discloses p-aminobenzaldehyde drug intermediates synthesis method, comprises the following steps: nitrobenzene methanol and potassium sulfate solution are added to the reaction vessel, controls the temperature of the solution, lead dioxide is added, controls the stirring speed, continues to react; then cyclohexane solution is added, nickel chloride powder is added in batches, raises the temperature of the solution, react, reduces the temperature, set static, washed with sodium chloride solution, washed with diethylene glycol ethyl ether solution, washed with butyl ether solution, recrystallized in the cyclooctane solution, dehydrated with dehydration, got the finished product p-aminobenzaldehyde.

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2018101137 12Aug2018

P-aminobenzaldehyde drug intermediates synthesis method

FIELD OF THE INVENTION

The present invention relates to a method for preparing a pharmaceutical 5 intermediate which belongs to the field of organic synthesis, more particularly, relates to p-aminobenzaldehyde drug intermediates synthesis method.

GENERAL BACKGROUND

P-aminobenzaldehyde is used for the synthesis of sulfonamides antibacterial synergist trimethoprim (TMP); and used for anisic aldehyde, vanillin intermediates in fragrance industry; used for chlorobenzaldehyde raw materials in pesticide industry, but also available to the manufacture of photoresistor and synthesis of mechanical metal protective film. Most of the existing synthesis methods are obtained by oxidation and reduction of p-nitrotoluene, dissolving sodium sulfide and sodium hydroxide in water, filtering, heating the filtrate, adding sulfur powder, adding ethanol and p-nitrotoluene, recovering ethanol after reaction, steam distillation, removing the by-product p-aminotoluene, extracts the reaction solution with benzene, water steam distillation, cooling, filtration, drying to get products. This synthesis method requires the use of sodium sulfide, sodium hydroxide, sulfur powder as the reaction material, the sodium sulfide comes up to deliquescence in the air, while oxidation happens gradually; it can be explosive when meets impact and high fever, releasing toxic hydrogen sulfide gas in case of acid, it’s flammable, letting out toxic sulfur oxide smoke when heated. These factors will increase the risk of the reaction process and compromise the health of synthesis operators. Raw materials sodium hydroxide has strong stimulation and corrosivity, dust or smoke will stimulate the eyes and respiratory tract, erodes the nasal septum, the health of the production operators get greater harm; and strong corrosion of sodium hydroxide will increase the corrosion resistance requirements of the reaction device, resulting in the reaction equipment manufacturing costs increasing, which is not conducive to reducing the cost of the reaction. The reaction of raw materials, sulfur powder is flammable and explosive products, it’s easy to produce explosion or combustion when mixed with air, sulfur

2018101137 12Aug2018 burns to steam and the sulfur dioxide is highly toxic to human body, it will come up to a violent reaction after contact with halogen, metal powder, sulfur is a bad conductor, will produce static charge in the storage and transportation process, it can also lead to dust, dust and air or oxidant’s mixture will form an explosive mixture, these factors will increase the risk of synthesis reaction process coefficient that is not conducive to safe production. Comprehensive analysis shows that, factors above will lead to many shortcomings about this synthesis method, therefore, it is necessary to propose a new synthesis method.

SUMMARY

Based on the technical problems of the background technology, the purpose of the present invention is to provide p-aminobenzaldehyde drug intermediates synthesis method, comprises the following steps:

A: nitrobenzene methanol and potassium sulfate solution are added to the reaction vessel, controls the temperature of the solution at 30-37°C, lead dioxide is added, controls the stirring speed at 310-330 rpm, continues to react for 70-90 min;

B: then cyclohexane solution is added, nickel chloride powder is added in batches in 30-50 min, raises the temperature of the solution to 50-56 °C, react for 3-4 h, reduces the temperature to 5-9 °C, set static for 30-50 min, washed with sodium chloride solution for 30-60 min, washed with diethylene glycol ethyl ether solution for 40-50 min, washed with butyl ether solution for 60-80 min, recrystallized in the cyclooctane solution, dehydrated with dehydration, got the finished product p-aminobenzaldehyde.

Preferably, the potassium sulfate solution has a mass fraction of 10-16%. Preferably, the mass fraction of the cyclohexane solution is 15-23%

Preferably, the sodium chloride solution has a mass fraction of 10-15%.

Preferably, the diethylene glycol ethyl ether solution has a mass fraction of

30-36%.

Preferably, the mass fraction of butyl ether solution is 40-47%.

Preferably, the cyclooctane solution has a mass fraction of 60-66%.

Throughout the reaction process can be the following reaction formula:

2018101137 12 Aug 2018

CH,DH eno

Compared with the synthesis method disclosed in the background art, the invention provides p-aminobenzaldehyde drug intermediates synthesis method, it is unnecessary to use sodium sulfide, sodium hydroxide, sulfur powder as the reaction of raw materials, avoiding the sodium sulfide explodes on being struck, gives off toxic hydrogen sulfide gas in case of acid, releases toxic sulfur oxide smoke when heated, thereby reducing the production operator health hazards; avoiding the strong stimulation and corrosive of sodium hydroxide, thus avoiding the strong corrosion on the equipments, reducing the cost of manufacturing equipments, help reducing the cost ofthe reaction, avoiding the use of flammable and explosive sulfur powder as the reaction of raw materials, thereby reducing the risk of the reaction process, which is conducive to safe production, reducing intermediate links reaction, decreasing the reaction time and improving the reaction yield, at the same time, the present invention provides a new synthetic route which has laid a good foundation for further enhancing the yield of the reaction.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The following examples with reference to specific embodiments of the present invention are further illustrated:

Embodiment 1

P-aminobenzaldehyde drug intermediates synthesis method, comprises the following steps:

A: 2 mol nitrobenzene methanol and 1.3L potassium sulfate solution with a mass fraction of 10% are added to the reaction vessel, controls the temperature of the solution at 30°C, 4 mol lead dioxide is added, controls the stirring speed at 310 rpm, continues to react for 70 min;

2018101137 12Aug2018

B: then 4 mol cyclohexane solution with a mass fraction of 15% is added, 4 mol nickel chloride powder is added in 3 times in 30 min, raises the temperature of the solution to 50 °C, react for 3 h, reduces the temperature to 5 °C, set static for 30 min, washed with sodium chloride solution with a mass fraction of 10% for 30 min, washed with diethylene glycol ethyl ether solution with a mass fraction of 30% for 40 min, washed with butyl ether solution with a mass fraction of 40% for 60 min, recrystallized in the cyclooctane solution with a mass fraction of 60%, dehydrated with anhydrous magnesium sulfate dehydration, got the finished product p-aminobenzaldehyde 237.402g, yield of 98.1%.

Embodiment 2

A: 2 mol nitrobenzene methanol and 1.3L potassium sulfate solution with a mass fraction of 13% are added to the reaction vessel, controls the temperature of the solution at 34°C, 5 mol lead dioxide is added, controls the stirring speed at 320 rpm, continues to react for 80 min;

B: then 5 mol cyclohexane solution with a mass fraction of 19% is added, 5 mol nickel chloride powder is added in 4 times in 40 min, raises the temperature of the solution to 53 °C, react for 3.5 h, reduces the temperature to 7 °C, set static for 40 min, washed with sodium chloride solution with a mass fraction of 13% for 40 min, washed with diethylene glycol ethyl ether solution with a mass fraction of 33% for 45 min, washed with butyl ether solution with a mass fraction of 44% for 70 min, recrystallized in the cyclooctane solution with a mass fraction of 63%, dehydrated with anhydrous magnesium sulfate dehydration, got the finished product p-aminobenzaldehyde

238.128g, yield of 98.4%.

Embodiment 3

A: 2 mol nitrobenzene methanol and 1.3L potassium sulfate solution with a mass fraction of 16% are added to the reaction vessel, controls the temperature of the

2018101137 12Aug2018 solution at 37°C, 6 mol lead dioxide is added, controls the stirring speed at 330 rpm, continues to react for 90 min;

B: then 6 mol cyclohexane solution with a mass fraction of 23% is added, 6 mol nickel chloride powder is added in 5 times in 50 min, raises the temperature of the solution to 56 °C, react for 4 h, reduces the temperature to 9 °C, set static for 50 min, washed with sodium chloride solution with a mass fraction of 15% for 60 min, washed with diethylene glycol ethyl ether solution with a mass fraction of 36% for 50 min, washed with butyl ether solution with a mass fraction of 47% for 80 min, recrystallized in the cyclooctane solution with a mass fraction of 66%, dehydrated with anhydrous magnesium sulfate dehydration, got the finished product p-aminobenzaldehyde 23.096g, yield of 98.8%.

The embodiments of the present invention are merely preferred embodiments of the present invention, but the range of the present invention is not limited this, and any person who is familiar with those skilled in the arts, within the technical range of the present invention. It is intended that the technical solution and its inventive concept be replaced or modified equivalently with reference to the range of the invention.

2018101137 12Aug2018

Claims

Claims

1. P-aminobenzaldehyde drug intermediates synthesis method, comprises the following steps:

5 A: nitrobenzene methanol and potassium sulfate solution are added to the reaction vessel, controls the temperature of the solution at 30-37°C, lead dioxide is added, controls the stirring speed at 310-330 rpm, continues to react for 70-90 min;

B: then cyclohexane solution is added, nickel chloride powder is added in batches in 30-50 min, raises the temperature of the solution to 50-56 °C, react for 3-4

10 h, reduces the temperature to 5-9 °C, set static for 30-50 min, washed with sodium chloride solution for 30-60 min, washed with diethylene glycol ethyl ether solution for 40-50 min, washed with butyl ether solution for 60-80 min, recrystallized in the cyclooctane solution, dehydrated with dehydration, got the finished product p-aminobenzaldehyde.

15
2. P-aminobenzaldehyde drug intermediates synthesis method according to claim

1 wherein the potassium sulfate solution has a mass fraction of 10-16%.
3. P-aminobenzaldehyde drug intermediates synthesis method according to claim 1 wherein the mass fraction of the cyclohexane solution is 15-23%
4. P-aminobenzaldehyde drug intermediates synthesis method according to claim

20 1 wherein the sodium chloride solution has a mass fraction of 10-15%.
5. P-aminobenzaldehyde drug intermediates synthesis method according to claim 1 wherein the diethylene glycol ethyl ether solution has a mass fraction of 30-36%.