CN102603584A - Preparation method of 2-aminophenyl phenyl sulfide - Google Patents

Abstract

The invention discloses a preparation method of 2-aminodiphenyl sulfide, which uses o-nitroaniline as a raw material, and successively undergoes diazotization reaction, thioetherification-reduction "one-pot" reaction, salt formation, acylation, Monodiazotization, denitrification, and neutralization reactions to obtain 2-aminodiphenyl sulfide; that is, firstly carry out diazotization reaction with sodium nitrite and hydrochloric acid, and then carry out thioetherification-reduction with sodium sulfide "one-pot method" Reaction, that is, after the thioetherification reaction, heat up and carry out the reduction reaction; then react with equimolar hydrochloric acid to form a salt, react with an acylating agent to form an amide, and then carry out a diazotization reaction with sodium nitrite and hydrochloric acid; finally in the reducing agent ( That is, the denitrogenation reaction is carried out under the action of the denitrification reaction reagent), and the alkali solution neutralizes to obtain 2-aminodiphenyl sulfide. The preparation of 2-aminodiphenyl sulfide by the method of the invention has the characteristics of low cost.

Description

The preparation method of 2-aminodiphenyl sulfide

technical field

The invention relates to a method for synthesizing organic compounds, in particular to a method for synthesizing 2-aminodiphenylsulfide (2-Aminodiphenylsulfide).

Background technique

2-Aminodiphenyl sulfide, its molecular formula is C ₁₂ H ₁₁ NS, and its structural formula is shown in S-1; it is soluble in benzene, toluene, etc., and almost insoluble in water. It is an important fine chemical intermediate, mainly used Used in the synthesis of antipsychotic drug quetiapine hemifumarate (CAS: 111974-72-2).

According to comprehensive literature reports, the preparation of 2-aminodiphenyl sulfide mainly adopts the following methods at present:

1. Use o-iodoaniline and thiophenol to react with CuI as a catalyst and K ₂ CO ₃ as a base to generate 2-aminodiphenyl sulfide. The reaction formula is shown in S-2 (Journal of Organic Chemistry, 73 (14): 5625-5628, 2008);

2. Use o-chloronitrobenzene and thiophenol to react under the action of alkali KOH to generate 2-nitrodiphenyl sulfide, and then reduce it with zinc powder to generate 2-aminodiphenyl sulfide. The reaction formula is as S-3 Shown (Organometallics, 25(13): 3259-3266, 2006);

3. Use o-aminothiophenol and iodobenzene to react under the action of catalyst CuBr to generate 2-aminodiphenyl sulfide, the reaction formula is shown in S-4 (Tetrahedron, 65(47): 9737-9741, 2009) .

It can be seen that the essence of the above three processes is to form 2-aminodiphenyl sulfide after condensation reaction of halogenated benzene and thiophenol to remove a molecule of hydrogen halide. Due to the high price of starting materials, 2-aminodiphenylsulfide The production cost of phenylene sulfide is relatively high. In addition, the raw material thiophenol is a substance with a strong odor and pollutes the environment.

Contents of the invention

The technical problem to be solved by the present invention is to provide a preparation method of 2-aminodiphenyl sulfide with high yield, low cost and less pollution.

In order to solve the above-mentioned technical problems, the invention provides a kind of preparation method of 2-aminodiphenyl sulfide, take o-nitroaniline as raw material, carry out following steps successively:

1), diazotization reaction:

The diazotization reaction of o-nitroaniline, sodium nitrite, and hydrochloric acid is carried out, the reaction temperature is -10-20°C, and the reaction time is 2-4 hours; the molar ratio of o-nitroaniline, hydrochloric acid, and sodium nitrite is 1:2.9 ～3.1:1.05～1.4 (the preferred molar ratio is 1:3:1.05～1.4);

2), thioetherification-reduction "one-pot" reaction:

Heat Na ₂ S and NaOH to 40-60°C, then add the diazonium salt solution (all) obtained in step 1) dropwise, keep warm (40-60°C) and react for 0.8-1.2 hours after dropping, then raise the temperature to 75-60°C Carry out the reduction reaction at 85°C for 3 to 5 hours; after the reaction is completed, cool, extract, wash and dry in sequence to obtain 2,2'-diaminodiphenyl sulfide;

The molar ratio of Na ₂ S to o-nitroaniline in step 1) is 2.5 to 6:1;

The molar ratio of NaOH and the o-nitroaniline in step 1) is 2.9～3.1:1 (the preferred molar ratio is 3.0:1);

3), prepare 2,2'-diaminodiphenyl sulfide monodiazonium salt, carry out following steps successively:

①, into salt:

Add hydrochloric acid solution dropwise to 2,2'-diaminodiphenyl sulfide and water at 10-30°C, keep warm (10-30°C) and react for 20-40 minutes;

The mol ratio of 2,2'-diaminodiphenyl sulfide and hydrochloric acid is 1: 1;

②, acylation:

At 10-30°C, add the acylation reagent dropwise to the reaction solution obtained in step ①, and keep warm (10-30°C) for 1-2 hours; the acylation reagent and 2,2'-diaminodiphenyl sulfide The molar ratio is 1～1.1:1 (the preferred molar ratio is 1.04:1);

③. Single diazotization reaction:

Add hydrochloric acid solution to the reaction solution obtained in step ② at 10-30°C; then add sodium nitrite aqueous solution dropwise at 5-10°C, and react at 5-10°C for 20-40 minutes after the dropwise addition; to obtain 2,2 '-diaminodiphenyl sulfide monodiazonium salt solution;

The molar ratio of the hydrochloric acid, sodium nitrite and 2,2'-diaminodiphenyl sulfide is 2.9～3.1:1.05～1.4:1 (the preferred molar ratio is 3:1.05～1.4:1);

4), prepare 2-aminodiphenyl sulfide, carry out the following steps successively:

①, denitrification:

Add a denitrification reagent to the 2,2'-diaminodiphenylsulfide monodiazonium salt solution obtained in step 3), and react at 35-60°C for 1.5-2.5 hours;

The molar ratio of the denitrification reagent to 2,2'-diaminodiphenylsulfide monodiazonium salt is 5-20:1 (the preferred molar ratio is 8.5-10:1);

②, neutralization:

Add an alkaline solution (such as a sodium hydroxide solution with a mass solubility of 20 to 40%) to the reaction solution obtained in step ① until pH=7;

③. After cooling, extraction, washing and drying in sequence, 2-aminodiphenyl sulfide is obtained.

As an improvement to the preparation method of 2-aminodiphenyl sulfide of the present invention: the acylation reagent in step 3) is acetic anhydride, acetic acid or propionic anhydride.

As a further improvement of the preparation method of 2-aminodiphenyl sulfide of the present invention: the denitrification reagent in step 4) is ethanol, hypophosphorous acid or ethyl acetate.

In step 1) of the present invention, hydrochloric acid is selected hydrochloric acid solution (mass solubility is 10～20%) for use; The sodium nitrate aqueous solution controls the dropping speed during the dropping process, so that the reaction temperature remains at 5-10° C., and the dropping time of the sodium nitrite aqueous solution+the reaction time after dropping is 2-4 hours in total.

In step 2) of the present invention, Na ₂ S is selected from Na ₂ S solution (mass concentration is 10-25%), and the dropping time of the diazonium salt solution obtained in step 1) is controlled at 2.5-3.5 hours. Control the temperature at 40-60°C. The specific process parameters of cooling, extraction, washing and drying are as follows: cooling to room temperature, extracting the reaction solution with toluene, washing the extract phase with water-soluble sodium hydroxide with a mass concentration of 7-13%, and then washing with distilled water until neutral; toluene and dried in a vacuum oven.

In step 3) of the present invention, every 0.05mol of 2,2'-diaminodiphenylsulfide is equipped with 30-80ml of water, and the mass concentration of the hydrochloric acid solution is 10-20%. The dropwise addition time of the hydrochloric acid solution is 0.5 to 1.5 hours. The time for dropping the acylation reagent is 20-40 minutes. When adding the aqueous solution of sodium nitrite dropwise, adjust the rate of addition to keep the reaction temperature at 5-10°C; the time for adding the solution is about 3.5-4.5 hours.

In step 4) of the present invention, the specific process parameters of cooling, extraction, washing and drying are as follows: cooling to room temperature, extracting with ethyl acetate, washing the extract phase with distilled water to neutrality; drying the extract phase with anhydrous magnesium sulfate, After filtering out the desiccant (ie, anhydrous magnesium sulfate), ethyl acetate was removed from the extract phase in a rotary evaporator, and the precipitated solid was dried in a vacuum oven.

The preparation method of 2-aminodiphenyl sulfide of the present invention uses o-nitroaniline as a raw material, successively undergoes diazotization reaction, thioetherification-reduction "one-pot" reaction, salt formation, acylation, monodiazo Chemicalization, denitrogenation, and neutralization reactions to obtain 2-aminodiphenyl sulfide. That is, first carry out diazotization reaction with sodium nitrite and hydrochloric acid, and then carry out thioetherification-reduction "one-pot" reaction with sodium sulfide, that is, after thioetherification reaction, heat up for reduction reaction; then react with equimolar hydrochloric acid Salt formation, reaction with acylating reagent to form amide, and then diazotization reaction with sodium nitrite and hydrochloric acid (ie, single diazotization reaction); finally denitrification under the action of reducing agent (ie, denitrification reagent) Reaction, alkali solution (such as sodium hydroxide solution) and neutralization, in 2-amino diphenyl sulfide.

The present invention prepares the reaction equation of 2-aminodiphenyl sulfide as shown in S-5:

The raw materials used in the method of the invention are easy to obtain and low in cost. Therefore, the preparation of 2-aminodiphenyl sulfide by the method of the present invention has the advantage of low cost, and the total yield can reach 55.6%.

Detailed ways

Embodiment 1, a kind of preparation method of 2-aminodiphenyl sulfide, take o-nitroaniline, hydrochloric acid, sodium nitrite, sodium sulfide, acetic anhydride, ethanol, sodium hydroxide etc. as raw material, carry out following steps successively:

Step 1), prepare diazonium salt:

13.8g (0.1mol) o-nitroaniline, 73g mass solubility are 15% hydrochloric acid solution (11g, 0.3mol) drop in the 250ml flask, be cooled to 5 ℃, dropwise add 30ml sodium nitrite aqueous solution ( 7.9g, 0.115mol), adjust the rate of addition so that the reaction temperature is kept at 5-10°C, drop it in 2 hours, continue to stir at 5°C for 30 minutes after the drop, stop the reaction.

Step 2), preparation 2,2'-diaminodiphenylsulfide:

Put 150ml of Na ₂ S solution (0.4mol) with a mass concentration of 17.5% and 12g (0.3mol) of NaOH into a 500ml flask, heat to 45°C, and add dropwise all the diazonium salt solution obtained in step 1) under stirring After 3 hours of dropping, the temperature was controlled at 45-50°C during the dropping. After the dropping, the stirring was continued at 45°C for 1 hour, and then the temperature was raised to 80°C for the reduction reaction, and the reaction was stopped after 4 hours. After the reaction is finished, cool to room temperature, extract the reaction solution with toluene (50ml×3), and wash the extract phase with 10% sodium hydroxide water-soluble (30ml×2), and wash with distilled water until neutral. Toluene was removed, and the precipitated solid was dried to constant weight (about 12h) in a vacuum oven, and the solid 2,2'-diaminodiphenylsulfide quality obtained was 8.5g, and the yield was 78.7% (based on o-nitroaniline count).

Step 3), preparation 2,2'-diaminodiphenyl sulfide monodiazonium salt:

10.8g (0.05mol) 2,2'-diaminodiphenyl sulfide, 50ml water are dropped into the 250ml flask, slowly drip 12.2g mass concentration in the flask at 30 ℃ and be 15% hydrochloric acid (1.8g, 0.05 mol), after 1 hour of dripping, keep warm (30° C.) and continue to stir for 30 minutes after dripping. Then, acetic anhydride (0.052 mol) was added dropwise to the reaction solution at 30° C., and the drop was completed in 30 minutes. After the drop was completed, the mixture was kept warm (30° C.) and stirred for 1 hour. Next, add 36.5g mass concentration to the solution and be 15% hydrochloric acid (5.4g, 0.15mol), add dropwise 20ml sodium nitrite aqueous solution (3.62g, 0.053mol) at 5 ℃, under stirring, adjust the rate of addition so that the reaction temperature Keep it at 5-10°C, drop it for 4 hours, keep it warm (5°C) and continue stirring for 30 minutes after the drop, to obtain 0.05mol of diazonium salt solution (that is, 2,2'-diaminodiphenylsulfide monodiazonium salt solution) .

Step 4):

Put all the diazonium salt solution and 0.46mol (about 30ml) ethanol obtained in step 3) into a 250ml flask, and react at 50°C for 2h; neutralized with sodium hydroxide solution until the pH of the solution was 7, then the reaction solution was cooled to room temperature, extracted with 50 ml of ethyl acetate, and the extract phase was washed with distilled water until neutral. Next, dry the extract phase with anhydrous magnesium sulfate, after filtering out the desiccant (i.e., anhydrous magnesium sulfate), the extract phase removes ethyl acetate in a rotary evaporator, and the precipitated solid is dried in a vacuum oven to constant weight (about 12h), the product 2-aminodiphenyl sulfide was obtained, with a mass of 7.1 g and a yield of 70.6% (calculated as 2,2'-diaminodiphenyl sulfide). The total yield of 2-aminodiphenyl sulfide produced by this method reaches 55.6%.

Embodiment 2～10:

Change the following reaction conditions in step 1)～4) of embodiment 1:

The diazotization reaction temperature (abbreviated as T ₁ ) in step 1), the molar ratio of o-nitroaniline and sodium nitrite in step 1) (abbreviated as R ₁ ), the thioetherification reaction temperature in step 2) (abbreviated as T ₂ ) , the molar ratio of o-nitroaniline and sodium sulfide (abbreviated as R ₂ ) in step 2), the acylation reaction reagent (abbreviated as S ₁ ) in step 3), the denitrification reaction temperature in step 4) (abbreviated as T ₃ ), the step 4) The denitrification reaction reagent (abbreviated as S ₂ ) is obtained in Examples 2-10, and the molar ratio between the rest of the reaction raw materials is the same as in Example 1; thereby obtaining the corresponding yield of 2-aminodiphenyl sulfide (abbreviated as Y) . See Table 1 for details and data results.

Table 1

Finally, it should be noted that the above examples are only some specific embodiments of the present invention. Obviously, the present invention is not limited to the above embodiments, and many variations are possible. All deformations that can be directly derived or associated by those skilled in the art from the content disclosed in the present invention should be considered as the protection scope of the present invention.

Claims (3)

1.2-the preparation method of diaminodiphenyl sulfide is characterized in that: with the o-Nitraniline is raw material, carries out following steps successively:

1), diazotization reaction:

O-Nitraniline and Sodium Nitrite, hydrochloric acid carry out diazotization reaction, and temperature of reaction is-10～20 ℃, and the reaction times is 2～4 hours; The mol ratio of said o-Nitraniline, hydrochloric acid, Sodium Nitrite is 1: 2.9～3.1: 1.05～1.4;

2), thioetherification-reduction " one kettle way " reaction:

With Na ₂S and NaOH are heated to 40～60 ℃, drip the diazonium salt solution of step 1) gained then, drip off back insulation reaction 0.8～1.2 hour, are warming up to 75～85 ℃ then and carry out reduction reaction 3～5 hours; Reaction finishes, and warp cooling successively, extraction, washing and dry get 2,2 '-diaminodiphenyl sulfide;

Said Na ₂The mol ratio of the o-Nitraniline in S and the step 1) is 2.5～6: 1;

The mol ratio of the o-Nitraniline in said NaOH and the step 1) is 2.9～3.1: 1;

3), the preparation 2,2 '-diaminodiphenyl sulfide substance nitrogen salt, carry out following steps successively:

1., salify:

In 10～30 ℃, 2, dripping hydrochloric acid solution in 2 '-diaminodiphenyl sulfide and the water, insulation reaction 20～40min;

2, the mol ratio of 2 '-diaminodiphenyl sulfide and hydrochloric acid is 1: 1;

2., acidylate:

In 10～30 ℃, 1. drip acylation reaction reagent, insulation reaction 1～2 hour in the reaction solution of gained in step; Acylation reaction reagent and 2, the mol ratio of 2 '-diaminodiphenyl sulfide are 1～1.1: 1;

3., substance nitrogenizing reaction:

In 10～30 ℃, 2. add hydrochloric acid soln in the reaction solution of gained in step; In 5～10 ℃, drip sodium nitrite in aqueous solution then, dropwise the back in 5～10 ℃ of reaction 20～40min; Get 2,2 '-diaminodiphenyl sulfide substance nitrogen salt solution;

Said hydrochloric acid, Sodium Nitrite and 2, the mole of 2 '-diaminodiphenyl sulfide is 2.9～3.1: 1.05～1.4: 1;

4), preparation 2-diaminodiphenyl sulfide, carry out following steps successively:

1., denitrogenation:

To 2 of step 3) gained, add denitrification reaction reagent in 2 '-diaminodiphenyl sulfide substance nitrogen salt solution, react 1.5～2.5h down in 35～60 ℃;

Said denitrification reaction reagent and 2, the mol ratio of 2 '-diaminodiphenyl sulfide substance nitrogen salt is 5～20: 1;

2., neutralization:

1. add alkaline solution until pH=7 in the reaction solution of gained in step;

3., warp cools off, extracts, washs and be dry successively, gets the 2-diaminodiphenyl sulfide.

2. the preparation method of 2-diaminodiphenyl sulfide according to claim 1 is characterized in that: the acylation reaction reagent in the said step 3) is diacetyl oxide, acetate or propionic anhydride.

3. the preparation method of 2-diaminodiphenyl sulfide according to claim 1 is characterized in that: the denitrification reaction reagent in the said step 4) is ethanol, Hypophosporous Acid, 50 or ETHYLE ACETATE.