CN118652185A - A kind of preparation method of p-methoxybenzylamine - Google Patents

Abstract

The invention relates to the technical field of drug intermediate synthesis, and discloses a method for preparing p-methoxybenzylamine, comprising the following steps: S1) adding p-methoxybenzaldehyde to a reaction container, and then sequentially adding a methanol solution, sodium borohydride and glacial acetic acid, stirring, filtering and washing with water after the reaction is completed, to obtain p-methoxybenzyl alcohol; S2) adding p-methoxybenzyl alcohol to a reaction container, then adding methanol to dissolve the methoxybenzyl alcohol, then adding ammonia water and titanium dioxide, heating and refluxing, after the reaction is completed, cooling the reaction system to stand to room temperature, and then distilling under reduced pressure to obtain p-methoxybenzylamine. Compared with the prior art, the above preparation method of the invention is lower in cost and safer.

Description

A kind of preparation method of p-methoxybenzylamine

Technical Field

The invention relates to the technical field of pharmaceutical intermediate synthesis, and in particular to a method for preparing p-methoxybenzylamine.

Background Art

p-Methoxybenzylamine, also known as 4-methoxybenzylamine, is an important intermediate in drug synthesis.

The prior art discloses the following methods for preparing p-methoxybenzylamine:

Method 1: Using p-methoxybenzonitrile and hydrogen as raw materials, methanol as reaction solvent, and palladium-containing activated carbon as catalyst, the product is obtained by catalytic hydrogenation with a yield of 100%.

The disadvantages of this method are that the raw materials are expensive and difficult to obtain; and the palladium catalyst is flammable and irritating.

Method 2: Using oxybenzyl azide and hydrogen as raw materials, methanol as reaction solvent, nickel as catalyst, catalytic hydrogenation was performed to obtain the product with a yield of 89%.

The disadvantage of this method is that sodium azide needs to be used in the synthesis process of azide, which is highly dangerous.

Method 3: dissolve p-methoxybenzaldehyde in a solvent, add a nickel catalyst, introduce liquid ammonia and hydrogen to carry out catalytic hydrogenation, and after the reaction, separate by desolventizing and distillation to obtain p-methoxybenzylamine.

This method not only requires the use of multiple catalysts, but also requires the use of liquid ammonia and hydrogen at the same time, which is highly dangerous and environmentally unfriendly.

Method 4: Under strong alkaline conditions, 1 equivalent of p-methoxybenzaldehyde undergoes a disproportionation reaction to generate 0.5 equivalent of p-methoxybenzyl alcohol and 0.5 equivalent of p-methoxybenzoic acid.

The above method for obtaining p-methoxybenzyl alcohol is the Cannizzaro reaction, which has very harsh reaction conditions and requires a strong base with a high concentration to react. It is very dangerous for production and application, and the post-treatment and separation process of the reaction byproduct p-methoxybenzoic acid is extremely complicated.

Summary of the invention

In view of the above-mentioned shortcomings, the object of the present invention is to provide a new method for preparing p-methoxybenzylamine to improve the production safety of synthesizing p-methoxybenzylamine.

To achieve this object, the present invention adopts the following technical solutions:

A method for preparing p-methoxybenzylamine comprises the following steps:

S1) adding p-methoxybenzaldehyde into a reaction container, and then adding methanol solution, sodium borohydride and glacial acetic acid in sequence, stirring, filtering and washing with water after the reaction is completed, to obtain p-methoxybenzyl alcohol;

S2) adding p-methoxybenzyl alcohol to a reaction vessel, then adding methanol to dissolve the methoxybenzyl alcohol, then adding ammonia water and titanium dioxide, heating to reflux, and after the reaction is completed, cooling the reaction system to room temperature, and then distilling under reduced pressure to obtain p-methoxybenzylamine.

Preferably, in step S1), the reaction temperature is room temperature, the reaction time is 4-6 hours, and glacial acetic acid is used as a catalyst.

More preferably, in step S1), the reaction temperature is 35-45°C, the reaction time is 3-4h, and the amount of glacial acetic acid added is a catalytic amount.

Preferably, in step S1), the molar ratio of p-anisaldehyde to sodium borohydride is 1:1.1.

Preferably, in step S2), the molar ratio of p-methoxybenzyl alcohol, ammonia water and titanium dioxide is 1:1.2:0.05; and the effective ammonia content of the ammonia water is 25wt%.

Preferably, in step S2), the reaction temperature is 100-110° C., and the reflux time is 2-3 h.

The beneficial effect of the technical solution of the present invention is that the preparation method of p-methoxybenzylamine uses ammonia water as a nitrogen source, utilizes sodium borohydride for reduction, starts from the raw material p-methoxybenzaldehyde, passes through the intermediate state of p-methoxybenzyl alcohol, and obtains the final product p-methoxybenzylamine. The present invention introduces a new strategy for synthesizing p-methoxybenzylamine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a hydrogen nuclear magnetic resonance spectrum of the final product p-methoxybenzylamine I of Example 1 of the present invention;

FIG2 is a carbon-1NMR spectrum of the final product p-methoxybenzylamine I of Example 1 of the present invention;

FIG3 is a hydrogen nuclear magnetic resonance spectrum of the intermediate p-methoxybenzyl alcohol M2 of Example 1 of the present invention;

FIG. 4 is a carbon NMR spectrum of the intermediate p-methoxybenzyl alcohol M2 of Example 1 of the present invention.

DETAILED DESCRIPTION

The technical solution of the present invention is further described below with reference to the accompanying drawings and through specific implementation methods.

In the description of this specification, the description with reference to the terms "embodiment", "example", etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner.

Although the embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the claims and their equivalents.

A method for preparing p-methoxybenzylamine comprises the following steps:

S1) adding p-methoxybenzaldehyde into a reaction container, and then adding methanol solution, sodium borohydride and glacial acetic acid in sequence, stirring, filtering and washing with water after the reaction is completed, to obtain p-methoxybenzyl alcohol;

S2) adding p-methoxybenzyl alcohol to a reaction vessel, then adding methanol to dissolve the methoxybenzyl alcohol, then adding ammonia water and titanium dioxide, heating to reflux, and after the reaction is completed, cooling the reaction system to room temperature, and then distilling under reduced pressure to obtain p-methoxybenzylamine.

Compared with the prior art that uses metal catalysts such as palladium and nickel to perform catalytic hydrogenation to obtain p-methoxybenzylamine, the above preparation method of the present invention is more cost-effective and safer; compared with the use of azide to synthesize intermediates, the above preparation method of the present invention is safer; liquid ammonia is mostly stored in pressure-resistant steel cylinders or steel tanks, is corrosive and easily volatile, and has a high incidence of chemical accidents. Compared with the prior art that uses liquid ammonia as a nitrogen source, the volatilization rate of ammonia water is relatively slow and the toxicity and corrosiveness are relatively small, which is safer overall, and the price of ammonia water is also lower than that of liquid ammonia; compared with the prior art that uses the Cannizzaro reaction with a high concentration of strong alkali, the reaction conditions of the present invention do not involve a high concentration of strong alkali, and the ammonia water used is more mild and controllable.

In some embodiments, in step S1), the reaction temperature is room temperature, the reaction time is 4-6 hours, and glacial acetic acid is used as a catalyst.

During the reaction process of step S1), it can be observed that the reaction solution gradually becomes turbid and presents a slurry state; after the reaction is completed, it is subjected to reduced pressure distillation to obtain a p-methoxybenzyl alcohol compound as a slightly yellow liquid.

In other embodiments, in step S1), the reaction temperature is 35-45° C., the reaction time is 3-4 h, and the amount of glacial acetic acid added is a catalytic amount.

By appropriately increasing the reaction temperature of step S2) from room temperature to 35-45°C, the reaction time can be shortened from 4-6 hours to 3-4 hours, which is beneficial to improving production efficiency.

Preferably, in step S1), the molar ratio of p-anisaldehyde to sodium borohydride is 1:1.1.

Adding sodium borohydride in an amount 1.1 times the molar amount of p-methoxybenzaldehyde can not only make the reaction in step S1) more complete, but also avoid excessive water consumption for filtration and washing, thereby reducing waste of production materials.

Preferably, in step S2), the molar ratio of p-methoxybenzyl alcohol, ammonia water and titanium dioxide is 1:1.2:0.05; and the effective ammonia content of the ammonia water is 25wt%.

Preferably, in step S2), the reaction temperature is 100-110° C., and the reflux time is 2-3 h.

In a preferred embodiment of the present invention, the reaction temperature is 110° C., the molar ratio of the feed is p-methoxybenzyl alcohol: ammonia water (effective ammonia content 25%): titanium dioxide = 1:1.2:0.05, and the reaction is heated to reflux for 2 hours. After the reaction is completed, the reaction system is cooled and allowed to stand to room temperature, and after reduced pressure distillation, a p-methoxybenzylamine compound is obtained as a slightly yellow liquid.

Example 1

Compound I of p-methoxybenzylamine was synthesized according to the following steps:

S1) Synthesis of compound M2: Add p-methoxybenzaldehyde (10 g, 73.4 mmol) M1 into a round-bottom flask, add methanol solution to the system, add sodium borohydride (3.33 g, 88.1 mmol) at low temperature, and then slowly add a catalytic amount of glacial acetic acid. Stir at room temperature for 4-6 hours (slightly heat can be used to shorten the stirring time). During the reaction, it can be observed that the solution gradually becomes turbid and presents a slurry state. After the reaction is completed, filter and wash with water to obtain compound M2 (8.71 g, 63.1 mmol, yield 85%) as a slightly yellow liquid.

S2) Synthesis of compound I: Compound M2 (8.71 g, 63.1 mmol) was added to a round-bottom flask, methanol was added to dissolve it, and then aqueous ammonia (effective ammonia content 25%) (2.87 g, 82 mmol) and titanium dioxide (0.25 g, 3.15 mmol) were added to the system and heated to reflux for 2 h. After the reaction was completed, the reaction system was cooled and allowed to stand to room temperature. After reduced pressure distillation, the resulting product was a slightly yellow liquid compound I (7.87 g, 57.4 mmol, yield 90%).

The chemical reaction formula of the above step S1) and step S2) is:

;

For the above compounds, the present invention uses nuclear magnetic resonance spectra including 1H and 13C NMR nuclear magnetic spectra to determine their structures; the 1H and 13C NMR nuclear magnetic spectra of the compound M2 synthesized in step S2) of the above embodiment 1, which is p-methoxybenzylamine, are (see Figures 1 and 2 for details):

The 1H, 13C NMR spectrum of the compound I of p-methoxybenzyl alcohol synthesized in step S1) of Example 1 above is (see Figures 3 and 4 for details):

The yield of the above step S1) is 85%, and the yield of step S2) is 90%, which has good production efficiency.

In summary, the preparation method of p-methoxybenzylamine of the present invention is a new strategy for synthesizing p-methoxybenzylamine in a green, safe and low-cost manner.

The above content is a further detailed description of the present invention in combination with specific optimized implementation methods, and it cannot be determined that the specific implementation of the present invention is limited to these descriptions. For ordinary technicians in the technical field to which the present invention belongs, under the premise of the core concept of the present invention, several simple deductions and substitutions can also be made, which should all be deemed to belong to the protection scope of the present invention. As ordinary technicians in the technical field to which the present invention belongs, based on the present invention, several simple inferences can also be made to obtain other field applications of the compounds of the present invention, which should all be deemed to belong to the protection scope of the present invention.

Claims (6)

1. The preparation method of the p-methoxybenzylamine is characterized by comprising the following steps of:

s1) adding p-methoxybenzaldehyde into a reaction vessel, sequentially adding a methanol solution, sodium borohydride and glacial acetic acid, stirring, filtering and washing after the reaction is finished to obtain p-methoxybenzyl alcohol;

S2) adding the p-methoxybenzyl alcohol into a reaction vessel, adding methanol to dissolve the methoxybenzyl alcohol, adding ammonia water and titanium pigment, heating and refluxing, cooling and standing the reaction system to room temperature after the reaction is completed, and then distilling under reduced pressure to obtain the p-methoxybenzyl amine.

2. The process for preparing p-methoxybenzylamine according to claim 1, wherein in step S1), the reaction temperature is room temperature, the reaction time is 4 to 6 hours, and glacial acetic acid is used as a catalyst.

3. The process for preparing p-methoxybenzylamine according to claim 1, wherein in step S1), the reaction temperature is 35 to 45 ℃, the reaction time is 3 to 4 hours, and the glacial acetic acid is added in a catalytic amount.

4. The process for preparing p-methoxybenzylamine according to claim 1, wherein in step S1), the molar ratio of p-methoxybenzaldehyde to sodium borohydride is 1:1.1.

5. The method for preparing p-methoxybenzylamine according to claim 1, wherein in step S2), the molar ratio of p-methoxybenzyl alcohol, ammonia water and titanium pigment is 1:1.2:0.05; the effective ammonia content of the aqueous ammonia is 25wt%.

6. The process for preparing p-methoxybenzylamine according to claim 5, wherein in step S2), the reaction temperature is 100 to 110℃and the reflux time is 2 to 3 hours.