CN114685346A - Method for preparing indobufen - Google Patents

Method for preparing indobufen Download PDF

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Publication number
CN114685346A
CN114685346A CN202210222284.3A CN202210222284A CN114685346A CN 114685346 A CN114685346 A CN 114685346A CN 202210222284 A CN202210222284 A CN 202210222284A CN 114685346 A CN114685346 A CN 114685346A
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compound
indobufen
solvent
acid
reaction
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李维华
华岳庭
王江淮
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Shanghai Gaozhun Pharmaceutical Co ltd
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Shanghai Gaozhun Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

The invention discloses a method for synthesizing indobufen, which comprises the steps of adding reagents such as o-carboxybenzaldehyde and sodium borohydride and the like into a methanol solution of 2- (4-nitrophenyl) butyric acid, and finally reacting to generate the indobufen; the method avoids the impurities which are generated in the final zinc powder reduction reaction and are excessively reduced or incompletely reduced, so that the purification process of the reaction is simpler, the post-treatment is simple, the raw materials are low in price, and the material cost is reduced.

Description

Method for preparing indobufen
Technical Field
The invention relates to a preparation method of a compound, in particular to a preparation method of indobufen.
Background
With the progress of society, the living standard of people is continuously improved, the dietary pattern is improved, the labor intensity is reduced, the aging of society is aggravated, and the high risk group of cardiovascular and cerebrovascular diseases is also continuously increased. The thrombus formation of the goby of most cardiovascular and cerebrovascular diseases and thrombus embolism are closely related, so that the factors causing the thrombus formation are many, such as platelet aggregation, blood flow stasis, the activation of blood coagulation factors to promote the formation of thrombin and the like. Therefore, a high-efficiency and low-toxicity anti-platelet aggregation medicine is searched, and the morbidity and the mortality of cardiovascular and cerebrovascular diseases can be effectively reduced.
Indobufen (Indobufen), chemical name 2- [4- (1-oxo-2-isoindolinyl) phenyl ] butanoic acid, is a racemic mixture developed by the U.S. Perey company, first successfully developed by Farmfalia Carlo Erba, S.P.A., Italy, and first marketed in Italy (ICH Member countries) at 8.1984. Indobufen is used as a new generation of nonsteroidal potent platelet aggregation resistant drugs, can selectively act on circulating platelets, block thrombosis, inhibit platelet factor release to play a role in resisting platelet aggregation, and the inhibition is reversible, does not change plasma parameters, has no damage to platelet functions, and enables abnormal platelet functions to be recovered to be normal. The composition can obviously improve the microcirculation parameters and the walking distance of patients with peripheral vascular diseases and intermittent claudication, and has the same effect as aspirin and dipyridamole on the aspect of preventing obstruction after coronary artery bypass and femoral artery bypass; it can significantly reduce platelet deposits on dialysis membranes during hemodialysis. Compared with the similar medicines, the indobufen inhibits platelet factors, has the platelet aggregation inhibition effect which is 2-5 times that of salicylic acid, and has a slightly shorter bleeding time than the similar medicines.
The preparation routes of indobufen disclosed in "synthesis of indobufen as anticoagulant" (journal of Chinese medical industry, 1989,20(11)), patent CN106631974A, patent CN110229075A and patent CN101914055A by high scholars and the like can be summarized as shown in FIG. 3:
2- (4-nitrophenyl) butyric acid is used as a raw material, reduced into 2- (4-aminophenyl) butyric acid by adopting iron powder, catalytic hydrogenation or hydrazine hydrate, cyclized with phthalic anhydride under an acidic condition, reduced by using zinc powder and hydrogen chloride gas, and recrystallized by using ethanol to obtain the indobufen. However, the final zinc powder reduction reaction inevitably produces over-reduced or incompletely reduced impurities, and is difficult to remove, resulting in low purity of the final product.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a novel synthesis method of indobufen, which has the advantages of simple process route, simple operation, cheap raw materials and the like from the industrial point of view, and the intermediate produced by the method has high purity and can easily obtain the indobufen meeting the requirements of pharmacopoeia.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for synthesizing indobufen, wherein the synthetic route is shown in figure 2.
Further, the method for synthesizing the indobufen comprises the following specific steps:
1. synthesis of Compound 2
Dissolving 2- (4-nitrophenyl) butyric acid (compound 1) in methanol, adding concentrated sulfuric acid, and heating and refluxing for reaction under stirring;
preferably, the ratio of compound 1 to methanol is 1: 10 (W: V); the ratio of concentrated sulfuric acid to compound 1 is 0.1: 1 (V: W).
2. Synthesis of Compound 3
Dissolving the compound 2 in a solvent A, adding a metal reducing agent, adding acid at room temperature, removing the solvent after the reaction is finished, adding water and ethyl acetate, adding a sodium carbonate solid to adjust the pH to about 8, separating liquid, extracting a water layer twice by using ethyl acetate, combining organic phases, drying, filtering, and concentrating a filtrate to obtain a compound 3;
preferably, the ratio of the compound 2 to the solvent A is 1: 10 (W: V); the ratio of acid to compound 2 is 5: 1 (V: W); the amount of the metal reducing agent used was 3.5 eq.
Preferably, the metal reducing agent is: one or more of reduced iron powder, zinc powder and aluminum, preferably reduced iron powder.
Preferably, the acid is: one or more of concentrated hydrochloric acid, dilute hydrochloric acid, acetic acid and sulfuric acid, preferably concentrated hydrochloric acid.
Preferably, the solvent A is: one or more of methanol, ethanol, acetonitrile, acetone and tetrahydrofuran, preferably methanol.
3. Synthesis of Compound 4
Dissolving the compound 3 in a solvent B, adding o-carboxybenzaldehyde and a reaction reagent, after the reaction is finished, concentrating the reaction solution, adding ethyl acetate, stirring and dissolving, adding water for extraction for three times, retaining an organic phase, drying, filtering, and concentrating the filtrate to obtain a white-like solid compound 4;
preferably, the ratio of the compound 3 to the solvent B is 1: 15 (W: V); the dosage of o-carboxybenzaldehyde is 1.1 eq; the amount of the reactants used was 1.2 eq.
Preferably, the solvent B is: one or more of N, N-dimethylformamide, acetonitrile, dichloromethane, methanol, ethanol, tetrahydrofuran and toluene, preferably methanol.
Preferably, the reaction reagent is: one or more of tetrabutylammonium hydrogen sulfate, sodium borohydride, potassium borohydride, carbon monoxide, aluminum trichloride, dihydropyridine and formic acid/triethylamine, and sodium borohydride is preferred.
4. Synthesis of Compound 5
Adding the compound 4 into methanol, adding 1mol/L sodium hydroxide solution at room temperature, removing the solvent after the reaction is finished, adding water and ethyl acetate for extraction, adding activated carbon into a water phase for decolorization, filtering, dropwise adding dilute hydrochloric acid, adjusting the pH value to about 5, precipitating a white-like solid, filtering, and drying in vacuum to obtain the indobufen crude product.
The invention has the advantages that:
1. a new route is developed to synthesize the indobufen, the total yield of the whole route is 77.9 percent, the yield is stable, the reaction process is easy to control, and the industrial production is easy to realize;
2. dangerous hydrogen and chlorine hydride gas are avoided, excessive reduction or incomplete reduction of impurities generated in the final zinc powder reduction reaction is avoided, and the product purity is improved;
3. reaction conditions are optimized, and o-carboxybenzaldehyde and sodium borohydride which are low in price are used, so that material cost is saved;
4. the compound 4 produced by the method has the appearance of a white solid, the purity of the compound reaches 99.6 percent, the indobufen (the compound 5) produced by the method has the appearance of a white solid, the single impurity control is less than 0.10 percent, the total purity of the product reaches 99.9 percent, and the requirements of pharmacopoeia can be completely met.
5. The method adopts the reaction of o-carboxybenzaldehyde and sodium borohydride with the compound 2 to form the skeleton structure of the indobufen, is a major technical breakthrough of the invention, avoids impurities which are generated in the final zinc powder reduction reaction and are excessively reduced or incompletely reduced, simplifies the purification process of the reaction, has simple post-treatment, low raw material price and reduces the material cost.
Drawings
FIG. 1 shows the purity chart of indobufen.
FIG. 2 shows a scheme for the synthesis of indobufen in the process for the preparation of indobufen according to the invention.
Figure 3 is a scheme of the synthesis scheme of indobufen disclosed in the prior art.
Detailed Description
Example 1
1. Synthesis of Compound 2
Dissolving 2- (4-nitrophenyl) butyric acid (50g,1.0eq) in methanol, adding concentrated sulfuric acid, heating and refluxing for 2h under stirring, and after TLC detection reaction, directly putting the reaction solution into the next step.
2. Synthesis of Compound 3
Adding reduced iron powder (46.4g, 3.5eq) into the reaction solution in the previous step, dropwise adding concentrated hydrochloric acid at room temperature, reacting for 3 hours, removing the solvent after TLC detection reaction, adding water and ethyl acetate, adding sodium carbonate solid to adjust the pH to about 8, separating liquid, extracting the water layer twice with ethyl acetate, combining organic phases, drying, filtering, and concentrating the filtrate to obtain the compound 3 with the yield of 85.6%.
3. Synthesis of Compound 4
Dissolving the compound 3(20g,1.0eq), o-carboxybenzaldehyde (17.1g,1.1eq) and sodium borohydride (1.96g, 0.5eq) in methanol, reacting at room temperature for 5 hours, concentrating the reaction solution after the reaction is finished, adding ethyl acetate, stirring and dissolving, adding water for extraction for three times, retaining the organic phase, drying, filtering and concentrating the filtrate to obtain the off-white solid compound 4 with the yield of 93.35%.
4. Synthesis of Compound 5
Adding a compound 4(10g,1.0eq) into methanol, adding 1mol/L sodium hydroxide solution at room temperature, heating to 40 ℃ for reaction for 3 hours, removing the solvent after TLC detection reaction, adding water and ethyl acetate for extraction twice, adding activated carbon into a water phase for decolorization for 1 hour, filtering, dropwise adding dilute hydrochloric acid, adjusting the pH to about 5, precipitating a white-like solid, filtering, and drying in vacuum at 50 ℃ to obtain an indobufen crude product, wherein the yield is 92.15%.
Adding the indobufen crude product (10g,1.0eq) into ethanol (10v/w), heating and refluxing, adding activated carbon after the solid is completely dissolved, refluxing for 30 minutes, carrying out hot filtration, cooling the filtrate to room temperature, gradually dissolving, precipitating a white solid, carrying out ice water bath for 1 hour, filtering, washing a filter cake with a small amount of ethanol, and carrying out vacuum drying on the filter cake at 50 ℃ to obtain the indobufen (the yield is 88.9%, the purity is 99.97%, as shown in figure 1).
Chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent; methanol-water-triethylamine (65: 35: 0.5) (phosphoric acid to adjust the pH value to 3.0) is used as a mobile phase; the detection wavelength was 228 nm.
Example 2:
1. synthesis of Compound 2
Dissolving 2- (4-nitrophenyl) butyric acid (50g,1.0eq) in methanol, adding concentrated sulfuric acid, heating and refluxing for 2h under stirring, and after TLC detection reaction, directly putting the reaction solution into the next step.
2. Synthesis of Compound 3
Adding reduced iron powder (60.1g, 4.5eq) into the reaction solution in the previous step, dropwise adding concentrated hydrochloric acid at room temperature, reacting for 3 hours, removing the solvent after TLC detection reaction, adding water and ethyl acetate, adding sodium carbonate solid to adjust the pH to about 8, separating liquid, extracting the water layer twice with ethyl acetate, combining organic phases, drying, filtering, and concentrating the filtrate to obtain the compound 3 with the yield of 85.3%.
3. Synthesis of Compound 4
Dissolving the compound 3(20g,1.0eq), o-carboxybenzaldehyde (17.1g,1.1eq), formic acid (7.15g, 1.5eq) and triethylamine (15.7g, 1.5eq) in methanol, reacting at room temperature for 5 hours, concentrating the reaction solution after the reaction is finished, adding ethyl acetate, stirring and dissolving, adding water for extraction for three times, keeping the organic phase, drying, filtering, and concentrating the filtrate to obtain the off-white solid compound 4 with the yield of 92.6%.
4. Synthesis of Compound 5
Adding compound 4(10g,1.0eq) into methanol (5v/w), adding 1N sodium hydroxide solution at room temperature, heating to 40 ℃ for reaction for 3 hours, removing the solvent after TLC detection reaction, adding water and ethyl acetate for extraction twice, adding activated carbon into the water phase for decolorization for 1 hour, filtering, dropwise adding dilute hydrochloric acid, adjusting the pH to about 5, precipitating a white-like solid, filtering, and drying in vacuum at 50 ℃ to obtain the crude indobufen product with the yield of 92.15%.
Adding crude indobufen (10g,1.0eq) into ethanol (10v/w), heating and refluxing, adding activated carbon after the solid is completely dissolved, refluxing for 30 minutes, performing hot filtration, cooling the filtrate to room temperature, gradually dissolving, precipitating white solid, performing ice water bath for 1 hour, filtering, washing the filter cake with a small amount of ethanol, and performing vacuum drying on the filter cake at 50 ℃ to obtain indobufen (with the purity of 99.88%, the yield of 88.9%, and the chromatographic conditions are the same as those in example 1)
Example 3
1. Synthesis of Compound 2
Dissolving 2- (4-nitrophenyl) butyric acid (50g,1.0eq) in methanol, adding concentrated sulfuric acid, heating and refluxing for 2h under stirring, and after TLC detection reaction, directly putting the reaction solution into the next step.
2. Synthesis of Compound 3
Adding zinc powder (62.5g, 4eq) into the reaction solution in the previous step, dropwise adding concentrated hydrochloric acid at room temperature, reacting for 3 hours, removing the solvent after TLC detection reaction is finished, adding water and ethyl acetate, adding sodium carbonate solid to adjust the pH to about 8, separating liquid, extracting the water layer twice with ethyl acetate, combining organic phases, drying, filtering, and concentrating the filtrate to obtain the compound 3, wherein the yield is 85.6%.
3. Synthesis of Compound 4
Dissolving the compound 3(20g,1.0eq), o-carboxybenzaldehyde (17.1g,1.1eq) and dihydropyridine (39.2g, 1.5eq) in methanol, reacting at room temperature for 5 hours, concentrating the reaction solution after the reaction is finished, adding ethyl acetate, stirring and dissolving, adding water for extraction for three times, retaining the organic phase, drying, filtering, and concentrating the filtrate to obtain the off-white solid compound 4 with the yield of 87.5%.
4. Synthesis of Compound 5
Adding the compound 4(10g,1.0eq) into methanol (5v/w), adding 1N sodium hydroxide solution (50mL, 5v/w) at room temperature, heating to 40 ℃ for reaction for 3 hours, removing the solvent after TLC detection reaction, adding water and ethyl acetate for extraction twice, adding activated carbon into a water phase for decolorization for 1 hour, filtering, dropwise adding dilute hydrochloric acid, adjusting the pH to about 5, precipitating a white-like solid, filtering, and drying in vacuum at 50 ℃ to obtain an indobufen crude product, wherein the yield is 92.15%.
Adding the indobufen crude product (10g,1.0eq) into ethanol (10v/w), heating and refluxing, adding activated carbon after the solid is completely dissolved, refluxing for 30 minutes, carrying out hot filtration, cooling the filtrate to room temperature, gradually dissolving, precipitating a white solid, carrying out ice water bath for 1 hour, filtering, washing a filter cake with a small amount of ethanol, and carrying out vacuum drying on the filter cake at 50 ℃ to obtain the indobufen (the purity is 99.88%, the yield is 88.9%, and the chromatographic conditions are the same as those of example 1).

Claims (9)

1. The method for synthesizing indobufen is characterized by comprising the following specific steps of:
1) synthesis of Compound 2
Dissolving 2- (4-nitrophenyl) butyric acid in methanol, adding concentrated sulfuric acid, and heating and refluxing for reaction under stirring;
2) synthesis of Compound 3
Dissolving the compound 2 in a solvent A, adding a metal reducing agent, adding acid at room temperature, removing the solvent after the reaction is finished, adding water and ethyl acetate, adding a sodium carbonate solid to adjust the pH to 8, separating liquid, extracting a water layer twice by using ethyl acetate, combining organic phases, drying, filtering, and concentrating the filtrate to obtain a compound 3; the solvent A is one or more of methanol, ethanol, acetonitrile, acetone and tetrahydrofuran;
3) synthesis of Compound 4
Dissolving the compound 3 in a solvent B, adding o-carboxybenzaldehyde and a reaction reagent, after the reaction is finished, concentrating the reaction solution, adding ethyl acetate, stirring and dissolving, adding water for extraction for three times, retaining an organic phase, drying, filtering, and concentrating the filtrate to obtain a white-like solid compound 4; the solvent B is one or more of N, N-dimethylformamide, acetonitrile, dichloromethane, methanol, ethanol, tetrahydrofuran and toluene;
4) synthesis of Compound 5
Adding the compound 4 into methanol, adding 1mol/L sodium hydroxide solution at room temperature, removing the solvent after the reaction is finished, adding water and ethyl acetate for extraction, adding activated carbon into a water phase for decolorization, filtering, dropwise adding dilute hydrochloric acid, adjusting the pH value to 5, precipitating a white-like solid, filtering, and drying in vacuum to obtain the indobufen crude product.
2. The method for synthesizing indobufen as claimed in claim 1, wherein the metal reducing agent is one or more of reduced iron powder, zinc powder and aluminum.
3. A method for the synthesis of indobufen as claimed in claim 1 or claim 2, wherein the acid is one or more of concentrated hydrochloric acid, dilute hydrochloric acid, acetic acid and sulphuric acid.
4. A method for synthesizing indobufen as claimed in claim 1 or 2, wherein solvent a is methanol.
5. A method for synthesizing indobufen according to claim 1 or 2, wherein solvent B is methanol.
6. A method for synthesizing indobufen according to claim 1 or 2, wherein the reaction reagent is one or more of tetrabutylammonium hydrogen sulfate, sodium borohydride, potassium borohydride, carbon monoxide, aluminum trichloride, dihydropyridine and formic acid/triethylamine.
7. A method for synthesizing indobufen according to claim 1 or 2, wherein in step 1), the mass-to-volume ratio of 2- (4-nitrophenyl) butyric acid to methanol is 1: 10; the mass-volume ratio of 2- (4-nitrophenyl) butyric acid to concentrated sulfuric acid is 1: 0.1.
8. The method for synthesizing indobufen according to claim 1 or 2, wherein in the step 2), the mass-to-volume ratio of the compound 2 to the solvent A is 1: 10; the mass-to-volume ratio of the compound 2 to the acid is 5: 1; the amount of the metal reducing agent used was 3.5 eq.
9. The method for synthesizing indobufen according to claim 1 or 2, wherein in the step 3), the mass-to-volume ratio of the compound 3 to the solvent B is 1: 15; the dosage of o-carboxybenzaldehyde is 1.1 eq; the amount of the reactants used was 1.2 eq.
CN202210222284.3A 2022-03-07 2022-03-07 Method for preparing indobufen Pending CN114685346A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115850154A (en) * 2022-12-29 2023-03-28 山东京卫制药有限公司 Preparation method of indobufen

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Publication number Priority date Publication date Assignee Title
US4400520A (en) * 1980-09-10 1983-08-23 Hisamitsu Pharmaceutical Co., Inc. Novel process for preparing isoindoline derivatives
CN106631974A (en) * 2017-02-17 2017-05-10 杭州中美华东制药有限公司 Method for preparing indobufen

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Publication number Priority date Publication date Assignee Title
US4400520A (en) * 1980-09-10 1983-08-23 Hisamitsu Pharmaceutical Co., Inc. Novel process for preparing isoindoline derivatives
CN106631974A (en) * 2017-02-17 2017-05-10 杭州中美华东制药有限公司 Method for preparing indobufen

Non-Patent Citations (3)

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Title
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115850154A (en) * 2022-12-29 2023-03-28 山东京卫制药有限公司 Preparation method of indobufen

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