CN118894803B - Indole cloth Synthesis method of Fenne - Google Patents

Abstract

The invention belongs to the technical field of drug synthesis, and specifically discloses a synthetic method of indobufen, wherein the synthetic method of the present invention comprises: in an organic solvent, under the action of a catalyst, a base and a ligand, p-bromoiodobenzene reacts with isoindolin-1-one to obtain an intermediate I; under alkaline conditions, the intermediate I reacts with diethyl malonate to obtain an intermediate II, and the intermediate II directly reacts with bromoethane without separation to obtain an intermediate III, and the intermediate III is decarboxylated, refined and purified to obtain indobufen. The synthetic method of the present invention has a simple process, short preparation steps, is suitable for industrial production, does not need to carry out nitration reaction, overcomes the defect of using a large amount of sulfuric acid and nitric acid mixed acid, reduces the pressure on environmental protection, improves the safety of the reaction, and avoids the use of dangerous hydrogen and hydrogen chloride gas, avoids the excessive reduction or incomplete reduction impurities generated in the final zinc powder reduction process, and improves the product purity.

Description

Indole cloth Synthesis method of Fenne

Technical Field

The field belongs to the technical field of medicine synthesis, and in particular relates to a synthesis method of indobufen.

Background

Indolibufen (Indobufen), a racemate compound developed by the American-type pyroxene company, was first marketed in Italy in 1984 as a new generation of non-steroidal potent anti-platelet aggregation drugs, which selectively act on circulating platelets, block thrombus formation, and exert a platelet aggregation blocking effect by inhibiting the release of platelet factors. The inhibition has reversibility, does not damage the function of platelets, does not change plasma parameters, and can restore abnormal platelets to normal functions. Compared with the similar medicines, the indobufen has the effects of inhibiting platelet factors and resisting platelet aggregation, and the effect is 2-5 times of that of salicylic acid. Clinical researches show that in general, 200-400 mg of the traditional Chinese medicine can be taken by a human body every day, and 100-200 mg of the traditional Chinese medicine is suitable for old patients and renal insufficiency patients every day. The product has no mutagenicity, no teratogenicity, and no toxicity to fetus.

The indobufen synthesis methods reported in the current literature mainly comprise the following steps:

1. in Hangzhou Meihua patent No. CN106631974A, it is reported that organic acid is used as a reaction solvent, 2- [4- (1, 3-dioxo-2-isoindolinyl) phenyl ] butyric acid and zinc powder are added, hydrogen chloride gas is introduced under normal pressure, the reaction temperature is controlled at 82 ℃, the reaction time is 1 hour, and the reaction liquid is totally clear. Filtering, washing filter residues with acetic acid, combining filtrate and washing liquid, recovering solvent under reduced pressure, pouring residual liquid into proper amount of water, stirring, regulating pH to 5.5-6.5 with ammonia water, centrifuging and drying to obtain crude indobufen product, and refining the crude indobufen product with active carbon according to the conventional process to obtain the purified indobufen product with the purity of 99.6%. The method has the advantages that (1) the method has higher requirements on equipment under the condition of high Wen Xiatong hydrogen chloride gas, not only pollutes the environment and has safety risks, (2) zinc powder which is an easily-made and explosive tube product is used for reduction at last in the synthesis reaction, excessive reduction or incomplete reduction impurities are inevitably generated, and are difficult to remove, so that the purity of the final product is lower, and (3) residues are poured into water for crystallization during post-treatment, but the viscosity of the concentrate is large, the transfer is difficult, and the operation is inconvenient. The synthesis reaction is prepared by condensing 2- (4-aminophenyl) butyric acid with o-cyanobenzyl bromide or o-phthalaldehyde, and the used o-cyanobenzyl bromide and o-phthalaldehyde are high in price and are not suitable for industrial production.

2. Gao Xuemin et al in the "synthesis of anti-coagulant Indoprofen" (journal of Chinese medicine industry, 1989,20 (11)), zheng Gengxiu et al in the "preparation of Indoprofen" (journal of Chinese medicine industry, 1991,27 (7)), invention patent CN110229075A, invention patent CN101914055A, australian patent (AT 1977,337173), german patent (Ger Offen,1988,3807595) the synthesis of Indoprofen can be summarized as that 2- (4-nitrophenyl) butyric acid is used as starting material, iron powder is used for reduction, catalytic hydrogenation or hydrazine hydrate is used for reduction to 2- (4-aminophenyl) butyric acid, then condensation reaction is carried out with phthalic anhydride, finally zinc powder and hydrogen chloride gas are used for reduction, and finally ethanol recrystallization is carried out to obtain Indoprofen. (1) The synthesis reaction is finally reduced with zinc powder, inevitably resulting in excessive reduction or incomplete reduction of impurities, and difficult to remove. (2) In addition, the synthetic route of the starting material 2- (4-nitrophenyl) butyric acid involves nitration reaction, so that the industrial production of indobufen is influenced by such factors as safety evaluation, criticism and the like, and the market supply is unstable.

3. The invention patent CN 116554083A of Beijing purple bud medicine is prepared into indobufen by reducing 2- [4- (1, 3-dioxo-2-isoindolinyl) phenyl ] butyric acid, and the adopted reducing agent is a mixture of anhydrous zinc chloride and zinc powder, and excessive reduction or incomplete reduction of impurities are unavoidable.

4. The invention patent CN 114685346A of Shanghai high-precision medicine adopts the methanol solution of 2- (4-nitrophenyl) butyric acid to add reagents such as o-carboxybenzaldehyde, sodium borohydride and the like, and finally reacts to produce the indobufen. Although the excessive reduction or incomplete reduction of impurities generated in the final zinc powder reduction reaction is avoided, the invention uses sodium borohydride which is easy to explosion, and the synthetic route of the used starting material 2- (4-nitrophenyl) butyric acid relates to nitration reaction, so the starting material is easy to be influenced by factors such as safety evaluation, criticism and the like, the market supply is unstable, and the industrial production of indobufen is influenced.

5. The invention patent CN 115850154A of the mountain Tokyo guard medicine is prepared by condensing 2- (4-aminophenyl) butyric acid and 2-formylbenzoic acid to obtain indobufen, then directly adding a reducing agent which is sodium borohydride into a reaction system to obtain indobufen, and further adding an acidic reagent into the reaction system to obtain indobufen through cyclization reaction. The reaction route adopts sodium borohydride which is easy to prepare and explode, so that the safety risk exists, and the industrial production and the amplification are not facilitated.

Therefore, it is very necessary to develop a synthetic method of indobufen which is environment-friendly, high in safety, high in product purity and suitable for industrial production.

Disclosure of Invention

In view of the defects in the prior art, the invention provides a preparation method of indobufen, which is simple in operation, environment-friendly, safe and suitable for industrial production. The invention takes p-bromoiodobenzene as a starting material, and reacts with isoindoline-1-ketone to obtain an intermediate I, the intermediate I reacts with diethyl malonate to obtain an intermediate II, the intermediate II directly reacts with bromoethane without separation to obtain an intermediate III, and the intermediate III is subjected to decarboxylation reaction and refining purification to obtain indobufen. The synthetic route is as follows:

the synthesis route is characterized by comprising the following steps:

In an organic solvent A, reacting p-bromoiodobenzene with isoindoline-1-one under the catalysis of a catalyst, an alkaline substance a and a ligand to obtain an intermediate I;

step two, in an organic solvent B, under the action of an alkaline substance B, reacting the intermediate I with diethyl malonate to obtain an intermediate II, and reacting the intermediate II with bromoethane without separation and purification to obtain an intermediate III;

Step III, hydrolyzing the intermediate III under the condition of an alkaline substance c, and obtaining indobufen after post-treatment and refining operation;

The preparation method of the indobufen is characterized in that the molar ratio of the p-bromoiodobenzene to the isoindoline-1-one in the first step is 1-1.3:1;

The preparation method of the indobufen is characterized in that the catalyst in the first step comprises one of cuprous iodide, cuprous chloride and cuprous oxide, and the molar ratio of the catalyst to the p-bromoiodobenzene is 0.04-0.06:1;

The preparation method of the indobufen is characterized in that the ligand in the first step comprises one of N, N-diethyl ethylenediamine and trans-N, N-dimethyl cyclohexanediamine, and the molar ratio of the ligand to the p-bromoiodobenzene is 0.08-0.12:1;

the preparation method of indobufen is characterized in that the alkaline substance a in the first step comprises one of potassium carbonate and potassium phosphate, and potassium phosphate is further preferred, and the molar ratio of the alkaline substance a to p-bromoiodobenzene is 1.5-3:1;

The preparation method of indobufen is characterized in that the reaction temperature in the first step is 70-90 ℃;

The preparation method of indobufen is characterized in that the reaction solvent A in the first step comprises one of acetonitrile, N-dimethylformamide and dimethyl sulfoxide;

The preparation method of the indobufen is characterized in that the alkaline substance B used in the reaction in the step two comprises one of potassium carbonate, cesium carbonate and sodium hydride, preferably potassium carbonate, the molar ratio of the intermediate I, diethyl malonate and the alkaline substance B is 1.1-2:1.2-5, the preparation method of the indobufen is characterized in that the molar ratio of the bromoethane to the intermediate II in the step two is 1.1-2:1, and the reaction solvent B in the step two comprises one of acetonitrile, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide;

the preparation method of indobufen is characterized in that the reaction temperature of the intermediate II in the second step is 60-95 ℃;

the preparation method of indobufen is characterized in that the reaction temperature of the intermediate III in the second step is 25-35 ℃;

The preparation method of indobufen is characterized in that the alkaline substance c in the step three is one of sodium hydroxide and potassium hydroxide, and the molar ratio of the intermediate III to alkali is 1:3-5;

the preparation method of indobufen is characterized in that the reaction temperature in the step three is 40-60 ℃;

Compared with the prior art, the invention has the following advantages:

1. the preparation process of the invention does not need to carry out nitration reaction to prepare 2- (4-nitrophenyl) butyric acid, overcomes the defect of using a large amount of sulfuric acid and nitric acid to mix acid, lightens the pressure on environmental protection and improves the safety of the reaction.

2. The preparation method of the invention avoids the use of dangerous hydrogen and hydrogen chloride gas and explosive reagent, and avoids excessive reduction or incomplete reduction impurities generated in the final zinc powder reduction process, thereby improving the purity of the product.

3. The new indobufen preparation route is developed, the raw materials used in the route are easy to obtain, the process is simple, the preparation steps are short, the reaction process is easy to control, and the method is suitable for industrial production.

Drawings

FIG. 1 is a synthetic route to indobufen;

FIG. 2 is a liquid spectrum of the product indobufen of example 1;

FIG. 3 is the peak results for the product indobufen of example 1;

FIG. 4 is a liquid spectrum of the product indobufen of example 2;

FIG. 5 is the peak results for the product indobufen of example 2;

FIG. 6 is a liquid spectrum of the product indobufen of example 3;

FIG. 7 is the peak results for the product indobufen of example 3;

FIG. 8 is a liquid spectrum of the product indobufen of example 4;

FIG. 9 is the peak results for the product indobufen of example 4.

Detailed Description

The invention is further described in connection with the following detailed description, which is intended to be merely illustrative of the invention and not to be construed as limiting the scope of the invention, since it will be understood by those skilled in the art that equivalents, or modifications thereof, may be resorted to, falling within the scope of the invention.

The present invention will be described in detail with reference to the following specific examples, but is not limited to the present patent.

Example 1

1. Preparation of intermediate I:

P-bromoiodobenzene (50 g,1.0 eq), isoindoline-1-one (32 g,0.83 eq), potassium phosphate (122 g,2.0 eq) and cuprous iodide (2.72 g,0.05 eq), N-diethyl ethylenediamine (3.25 g,0.10 eq) are placed in a reaction bottle, 300ml acetonitrile is added, stirring is started, nitrogen is replaced, the temperature is raised to 70 ℃, after the thin layer detection reaction is completed, the temperature is reduced to 5-10 ℃, filtration is carried out, purified water is added into the filtrate, off-white solid is separated out, and 74g of intermediate I is obtained through suction filtration and drying, and the yield is 90.0%.

2. Preparation of intermediate II and intermediate III:

Placing the intermediate I (74 g,1.0 eq), diethyl malonate (46 g,1.1 eq) and potassium carbonate (178 g,5.0 eq) obtained in the last step into a reaction bottle, adding 500ml of acetonitrile, starting stirring, heating to 95 ℃ for reaction, after the thin layer detection reaction is finished, preparing the intermediate II, cooling to 25 ℃, adding bromoethane (42 g,1.5 eq) for continuous reaction, after the thin layer detection reaction is finished, adding 2000ml of purified water into the reaction liquid, stirring to precipitate off white solid, drying to obtain 87g of intermediate III, and obtaining the yield of 85.0%.

3. Preparation of indobufen:

placing the intermediate III (87 g,1.0 eq) obtained in the last step and sodium hydroxide (45 g,5.0 eq) into a reaction bottle, adding 800ml of purified water, starting stirring, heating to 40 ℃ for reaction, continuing the reaction after the solid in the reaction liquid is completely dissolved, cooling to 5-10 ℃ after the thin layer detection reaction is completed, carrying out neutralization operation on the reaction liquid by using hydrochloric acid, precipitating a large amount of solid in the reaction liquid, and carrying out suction filtration to obtain a wet product of the indobufen crude product.

And (3) putting the wet product into a reaction bottle again, adding ethanol (9V/W), heating to reflux, adding active carbon after the solid is completely dissolved, refluxing and stirring for 1 hour, filtering while the wet product is hot, cooling the filtrate to 0-5 ℃, gradually precipitating white solid in the filtrate, continuously stirring for 1 hour, filtering, leaching a filter cake with a small amount of ethanol, drying at 60 ℃, and obtaining 62g of indobufen with the yield of 95.0% and the purity of 99.68%.

Example 2

1. Preparation of intermediate I:

P-bromoiodobenzene (50 g,1.0 eq), isoindoline-1-one (39 g,1.0 eq), potassium carbonate (36.8 g,1.5 eq) and cuprous chloride (1.13 g,0.04 eq) are placed in a reaction bottle, 300ml of N, N-dimethylformamide is added, stirring is started, nitrogen is replaced, the temperature is raised to 80 ℃ for reaction, after the thin-layer detection reaction is completed, the temperature is reduced to 5-10 ℃, purified water is added into the filtrate, white-like solid is separated out, and the intermediate I is obtained by suction filtration and drying, wherein the yield is 95.0%.

2. Preparation of intermediate II and intermediate III:

Placing the intermediate I (78 g,1.0 eq), diethyl malonate (53.7 g,1.3 eq) and cesium carbonate (265 g,3 eq) obtained in the last step into a reaction bottle, adding 500ml of dimethyl sulfoxide, starting stirring, heating to 60 ℃ for reaction, after the thin layer detection reaction is completed, preparing the intermediate II, cooling to 35 ℃, adding bromoethane (31 g,1.1 eq) for continuous reaction for 20 hours, after the thin layer detection reaction is completed, adding 2000ml of purified water into the reaction liquid, stirring to separate off white solid, drying to obtain 80g of intermediate III, and obtaining the yield of 75%.

3. Preparation of indobufen:

Placing the intermediate III (80 g,1.0 eq) obtained in the last step and sodium hydroxide (33 g,4.0 eq) into a reaction bottle, adding 800ml of purified water, starting stirring, heating to 40 ℃ for reaction, continuing the reaction after the solid in the reaction liquid is completely dissolved, cooling to 5-10 ℃ after the thin layer detection reaction is completed, carrying out neutralization operation on the reaction liquid by using hydrochloric acid, precipitating a large amount of solid in the reaction liquid, and carrying out suction filtration to obtain a wet product of the indobufen crude product.

And (3) putting the wet product into a reaction bottle again, adding ethanol (9V/W), heating to reflux, adding active carbon after the solid is completely dissolved, refluxing and stirring for 1 hour, filtering while the wet product is hot, cooling the filtrate to 0-5 ℃, gradually precipitating white solid in the filtrate, continuously stirring for 1 hour, filtering, leaching a filter cake with a small amount of ethanol, drying at 60 ℃, and obtaining 56g of indobufen with the yield of 95.0% and the purity of 99.68%.

Example 3

1. Preparation of intermediate I:

P-bromoiodobenzene (50 g,1.0 eq), isoindoline-1-ketone (30 g,0.77 eq), potassium phosphate (183g, 3.0 eq) and cuprous oxide (2.45 g,0.06 eq) are placed in a reaction bottle, 300ml of dimethyl sulfoxide is added, stirring is started, nitrogen is replaced, the temperature is raised to 90 ℃, after the thin layer detection reaction is completed, the temperature is reduced to 5-10 ℃, purified water is added into the filtrate, off-white solid is separated out, and the intermediate I is obtained by suction filtration and drying, wherein the yield is 85.0%.

2. Preparation of intermediate II and intermediate III:

Placing the intermediate I (70 g,1.0 eq), diethyl malonate (78 g,2.0 eq) and sodium hydride (15 g,1.2 eq) obtained in the last step into a reaction bottle, adding 500ml of N, N-dimethylformamide, stirring, heating to 70 ℃ for reaction, preparing the intermediate II after the completion of the thin layer detection reaction, cooling to 30 ℃, continuously reacting, adding bromoethane (56 g,2.0 eq) and sodium hydride (15 g,1.2 eq), adding 2000ml of purified water into the reaction liquid after the thin layer detection reaction is completed, precipitating white-like solid under stirring, drying, and obtaining 87g of intermediate III with the yield of 90.0%.

3. Preparation of indobufen:

Placing the intermediate III (87 g,1.0 eq) obtained in the last step and potassium hydroxide (37.5 g,3.0 eq) into a reaction bottle, adding 800ml of purified water, starting stirring, heating to 40 ℃ for reaction, continuing the reaction after the solid in the reaction liquid is completely dissolved, cooling to 5-10 ℃ after the thin layer detection reaction is completed, carrying out neutralization operation on the reaction liquid by using hydrochloric acid, precipitating a large amount of solid in the reaction liquid, and carrying out suction filtration to obtain a wet product of the indobufen crude product.

And (3) putting the wet product into a reaction bottle again, adding ethanol (9V/W), heating to reflux, adding active carbon after the solid is completely dissolved, refluxing and stirring for 1 hour, filtering while the wet product is hot, cooling the filtrate to 0-5 ℃, gradually precipitating white solid in the filtrate, continuously stirring for 1 hour, filtering, leaching a filter cake with a small amount of ethanol, drying at 60 ℃, and obtaining 62g of indobufen with the yield of 95.0% and the purity of 99.70%.

Example 4

1. Preparation of intermediate I:

p-bromoiodobenzene (500 g,1.0 eq), isoindoline-1-one (320 g,0.83 eq), potassium phosphate (1220 g,2.0 eq) and cuprous iodide (27.2 g,0.05 eq), N-diethyl ethylenediamine (32.5 g,0.10 eq) are placed in a reaction bottle, 3000ml acetonitrile is added, stirring is started, nitrogen is replaced, the temperature is raised to 70-80 ℃ for reaction, after the thin layer detection reaction is completed, the temperature is reduced to 5-10 ℃, purified water is added into the filtrate, and then the white solid is separated out, filtered, dried and 750g of intermediate I is obtained, and the yield is 90.0%.

2. Preparation of intermediate II and intermediate III:

Placing the intermediate I (750 g,1.0 eq), diethyl malonate (540 g,1.3 eq) and potassium carbonate (1100 g,3.0 eq) obtained in the last step into a reaction bottle, adding 5000ml of N, N-dimethylacetamide, stirring, heating to 60 ℃, after the thin layer detection reaction is completed, preparing the intermediate II, cooling to 25-35 ℃, adding bromoethane (420 g,1.5 eq) for continuous reaction, after the thin layer detection reaction is completed, adding 2000ml of purified water into the reaction liquid, stirring to separate out white-like solid, drying, and obtaining 875g of intermediate III, wherein the yield is 85.0%.

3. Preparation of indobufen:

Placing the intermediate III (875 g,1.0 eq) obtained in the last step and sodium hydroxide (360 g,4.0 eq) into a reaction bottle, adding 8000ml of purified water, starting stirring, heating to 60 ℃ for reaction, continuing the reaction after the solid in the reaction liquid is completely dissolved, cooling to 5-10 ℃ after the thin layer detection reaction is completed, carrying out neutralization operation on the reaction liquid by using hydrochloric acid, precipitating a large amount of solid in the reaction liquid, and carrying out suction filtration to obtain a wet product of the indobufen crude product.

And (3) putting the wet product into a reaction bottle again, adding ethanol (9V/W), heating to reflux, adding active carbon after the solid is completely dissolved, refluxing and stirring for 1 hour, filtering while the wet product is hot, cooling the filtrate to 0-5 ℃, gradually precipitating white solid in the filtrate, continuously stirring for 1 hour, filtering, leaching the filter cake with a small amount of ethanol, and drying at 60 ℃ to obtain 621g of indobufen, wherein the yield is 95.0% and the purity is 99.76%.

While the invention has been described in terms of preferred embodiments, it will be understood by those skilled in the art that the invention is not limited to the embodiments, but is capable of modification in various other respects.

Claims (6)

1. A method for synthesizing indobufen, characterized in that the method comprises the following steps: Step 1: In solvent A, p-bromoiodobenzene and isoindolin-1-one react under the catalysis of a catalyst, a basic substance a, and a ligand to obtain an intermediate I. The reaction formula is: ; The reaction temperature is 70~90℃. The reaction solvent A is selected from one of acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide, The catalyst is selected from cuprous iodide, cuprous chloride, and cuprous oxide. The ligand is selected from one of N,N-diethylethylenediamine and trans-N,N-dimethylcyclohexanediamine. The molar ratio of 4-bromoiodobenzene to isoindolin-1-one is 1-1.3:1. The molar ratio of catalyst to p-bromoiodobenzene is 0.04-0.06:1. The molar ratio of ligand to p-bromoiodobenzene is 0.08~0.12:1. The molar ratio of alkaline substance a to p-bromoiodobenzene is 1.5-3:1; Step 2: In solvent B, under the action of alkaline substance b, intermediate I reacts with diethyl malonate to obtain intermediate II, and then ethyl bromide is added to react without separation and purification to obtain intermediate III. The reaction formula is: ; Wherein, the reaction temperature of the intermediate II is 60-95°C, the reaction temperature of the intermediate III is 25-35°C, the molar ratio of the intermediate I, diethyl malonate and the alkaline substance b is 1:1.1-2:1.2-5, and the molar ratio of ethyl bromide to the intermediate II is 1.1-2:1; The reaction solvent B is selected from one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide; Step 3, the intermediate III is hydrolyzed under alkaline substance c, and indobufen is obtained after acid adjustment, crystallization and purification. The reaction formula is: ; The reaction temperature is 40-60° C., and the molar ratio of the intermediate III to the alkaline substance c is 1:3-5. 2. The method for synthesizing indobufen according to claim 1, wherein the alkaline substance a described in step 1 is selected from one of potassium carbonate and potassium phosphate. 3. The method for synthesizing indobufen according to claim 1, wherein the alkaline substance a described in step 1 is potassium phosphate. 4. The method for synthesizing indobufen according to claim 1, wherein the alkaline substance b described in step 2 is selected from one of potassium carbonate, cesium carbonate and sodium hydride. 5. The method for synthesizing indobufen according to claim 1, wherein the alkaline substance b described in step 2 is potassium carbonate. 6. The method for synthesizing indobufen according to claim 1, wherein the alkaline substance c described in step 3 is selected from one of sodium hydroxide and potassium hydroxide.