A kind of preparation method of bisacodyl

Abstract

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a method for preparing bisacodyl. The method uses 2-pyridinecarboxaldehyde and 2,2,2-trifluoroethoxybenzene as raw materials, and can perform a condensation reaction with extremely high yield and purity to obtain a key intermediate compound III. Compound III is efficiently subjected to a deprotection reaction under the action of triphenylphosphine diiodide, and then an esterification reaction is performed to prepare bisacodyl. The reaction has not only a short synthesis route but also high yield (three-step yield can reach up to more than 85%) and purity (more than 99.5%).

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a method for preparing bisacodyl. Background Art

[0002] Bisacodyl, Bisacodyl, chemical name is 4,4'-(2-pyridylmethylene)-diphenol diacetate, its structural formula is: , originally developed by Boehringer Ingelheim, is an excellent laxative widely used at home and abroad. It can directly contact the intestinal mucosa, stimulate its sensory nerve endings, cause increased intestinal reflex peristalsis and lead to defecation. There are relevant reports on the research of bisacodyl synthesis method in patents and literature.

[0003] At present, there are reports on the research of the synthesis method of bisacodyl. For example, patent CN101973932B discloses a method for preparing bisacodyl, which uses 2-pyridinecarboxaldehyde and phenol as raw materials to prepare bisacodyl through condensation reaction and acetylation reaction. However, the yield and purity of this method are both low.

[0004] Patent CN108707108A discloses a method for synthesizing 4,4'-(2-pyridylmethylene)diphenol diacetate, which uses phenol and 2-pyridinecarboxaldehyde under the catalysis of sulfuric acid, adopts the inert solvent chloroalkane dilution method, and the auxiliary inclusion material α-dextrin for highly selective condensation alkylation reaction to obtain the important intermediate 4,4'-dihydroxydiphenyl-(2-pyridine)-methane of the target compound. After neutralization, purification, and drying, it is acetylated with acetic anhydride and anhydrous sodium acetate to obtain the target compound. The yield and purity of this method are both low.

[0005] Patent CN113943247A discloses a method for preparing bisacodyl, which uses 4,4'-dimethoxybenzophenone as a raw material and obtains the compound through reduction, halogenation, Friedel-Crafts alkylation and hydrolysis. However, the synthetic route of this method is long and the yield is low.

[0006] Patent US2827465A discloses a method for synthesizing bisacodyl, which uses 4',4"-dimethoxydiphenylacetonitrile and 2-bromopyridine as raw materials, obtains 4',4"-dimethoxydiphenyl-(2-pyridine)-acetonitrile through nucleophilic substitution, adds 48% hydrobromic acid for reflux reaction, hydrolyzes the cyano group and removes the methyl group to obtain 4',4"-dihydroxydiphenyl-(2-pyridine)-acetamide, and then heats and refluxes in a potassium carbonate aqueous solution to obtain 4',4"-dihydroxydiphenyl-(2-pyridine)-methane, adds acetic anhydride and pyridine, and performs acetylation reaction to obtain bisacodyl. This synthetic method is complicated to operate, and the raw materials are not easy to obtain, so it is not suitable for industrial production.

[0007] In summary, the prior art methods for preparing bisacodyl have the problems of long synthesis route, low yield, low purity, etc. Therefore, there is an urgent need to provide a method for preparing bisacodyl with a short synthesis route, high yield and high purity. Summary of the invention

[0008] The purpose of the present invention is to provide a method for preparing bisacodyl with a short synthetic route, high yield and high purity, so as to solve the problems of long synthetic route, low yield and low purity existing in the prior art.

[0009] The present invention is achieved by the following technical scheme, and provides a method for preparing bisacodyl, characterized in that it comprises the following steps:

[0010] 1) A certain amount of compound I and compound II are placed in a pressure bottle, and boron trifluoride monohydrate is slowly added at 0°C. After the addition is completed, the temperature is raised to carry out condensation reaction, and the reaction is monitored by TLC and GC-MS. After the reaction is completed, post-treatment is performed to obtain compound III;

[0011] 2) taking a certain amount of compound III prepared in step 1), and performing a deprotection reaction in the presence of triphenylphosphine diiodide, chlorobenzene and water. After the reaction is completed, post-treatment is performed to obtain compound IV;

[0012] 3) Taking a certain amount of compound IV prepared in step 2), carrying out esterification reaction under the action of acetyl chloride and triethylamine, after the reaction is completed, post-treatment is performed to obtain compound V.

[0013] The specific synthetic route is as follows:

[0014] .

[0015] Further, as a preferred technical solution of the present invention, the molar ratio of compound I, compound II and boron trifluoride monohydrate in step 1) is 1:3-10:25-30; preferably, the molar ratio of compound I, compound II and boron trifluoride monohydrate in step 1) is 1:4-5:25.

[0016] Further, as a preferred technical solution of the present invention, the temperature of the condensation reaction in step 1) is 30-50°C, and the condensation reaction time is 2-8 hours; preferably, the temperature of the condensation reaction in step 1) is 30°C-40°C, and the condensation reaction time is 5-6 hours.

[0017] Furthermore, as a preferred technical solution of the present invention, the post-treatment step in step 1) is: pouring the reaction solution into ice water, neutralizing it with sodium bicarbonate, extracting it with dichloromethane, combining the organic phases, washing the organic phases with water, and then drying them with anhydrous sodium sulfate, filtering, and removing the solvent under reduced pressure. The residue is purified by silica gel column chromatography, and the eluent is n-hexane / ethyl acetate.

[0018] Further, as a preferred technical solution of the present invention, the triphenylphosphine diiodide in step 2) is triphenylphosphine diiodide generated in situ, and the specific in situ generation step is: equimolar amounts of triphenylphosphine and iodine are added to the reaction solution (chlorobenzene and water) in sequence, and triphenylphosphine and iodine react rapidly to generate triphenylphosphine diiodide ;

[0019] Further, as a preferred technical solution of the present invention, the molar ratio of compound III to the in-situ generated triphenylphosphine diiodide in step 2) is 1:2.5-3; preferably, the molar ratio of compound III to the in-situ generated triphenylphosphine diiodide in step 2) is 1:3.

[0020] Furthermore, as a preferred technical solution of the present invention, the volume ratio of chlorobenzene to water in step 2) is 100:1.

[0021] Further, as a preferred technical solution of the present invention, the temperature of the deprotection reaction in step 2) is 100°C-120°C, and the time of the deprotection reaction is 5-10 hours; preferably, the temperature of the deprotection reaction in step 2) is 100°C, and the time of the deprotection reaction is 5-6 hours.

[0022] Furthermore, as a preferred technical solution of the present invention, the post-treatment step in step 2) is: adding sodium thiosulfate pentahydrate aqueous solution to quench the reaction, then extracting with ethyl acetate, standing to separate the layers, combining the organic phases, drying the organic phases with anhydrous Na2SO4, and concentrating under reduced pressure to remove the solvent. The residue is separated and purified by column chromatography, and the eluent is a mixed solvent of ethyl acetate and petroleum ether.

[0023] Further, as a preferred technical solution of the present invention, the molar ratio of compound IV, acetyl chloride and triethylamine in step 3) is: 1:2-3:3-5; preferably, the molar ratio of compound IV to acetyl chloride and triethylamine in step 3) is: 1:2-2.2:3-4.

[0024] Furthermore, as a preferred technical solution of the present invention, the temperature of the esterification reaction in step 3) is 0°C-room temperature, and the time of the esterification reaction is 20-48 hours; preferably, the temperature of the esterification reaction in step 3) is 0°C-room temperature, and the time of the esterification reaction is 20 hours.

[0025] Further, as a preferred technical solution of the present invention, the post-treatment step in step 3) is: quenching the reaction with a 1M hydrochloric acid aqueous solution, then extracting with dichloromethane, combining the organic phases, drying over anhydrous sodium sulfate, filtering, and removing the solvent by rotary evaporation. The residue is then heated and dissolved with ethanol, cooled to 0°C for crystallization, filtered, washed with cold ethanol, and dried.

[0026] The advantages or beneficial effects of the above technical solution include at least:

[0027] The invention provides a method for preparing bisacodyl. 2-pyridinecarboxaldehyde and 2,2,2-trifluoroethoxybenzene are used as raw materials, and a condensation reaction can be performed with extremely high yield and purity to obtain a key intermediate compound III. Compound III is efficiently subjected to a deprotection reaction under the action of triphenylphosphine diiodide, and then bisacodyl is prepared through an esterification reaction. The reaction has not only a short synthesis route but also high yield (three-step yield can reach up to more than 85% at most) and purity (more than 99.5%). DETAILED DESCRIPTION

[0028] The present invention is further described in detail below in conjunction with embodiments, but the content of the invention is not limited to the embodiments.

[0029] Example 1

[0030] Preparation of Bisacodyl (Compound V)

[0031] The specific synthetic route is as follows:

[0032]

[0033] Step A: Preparation of Compound III

[0034] 2.14g of compound I (20mmol) and 14.10g of compound II (80mmol) were placed in a pressure bottle, and 42.9g of boron trifluoride monohydrate (molar ratio 1:1) was slowly added at 0°C. After the addition was completed, the temperature was slowly raised to 30°C, and the reaction was continued to stir for 5 hours. The reaction was monitored by TLC (n-hexane: ethyl acetate = 4:1) and GC-MS. After the reaction was completed, the reaction solution was poured into ice water and neutralized with sodium bicarbonate, and then extracted with dichloromethane (100mL×3), the organic phases were combined, washed with water (50mL×2), and then dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and the eluent was n-hexane / ethyl acetate (volume ratio 4:1), to obtain 8.28g of compound III, with a yield of 93% and a purity of 99.1%. LC-MS: [M+H] + =442.13.

[0035] Step B: Preparation of Compound IV

[0036] Take 4.45g of compound III (10mmol) prepared in step A into a 100mL round-bottom flask, add 50mL of chlorobenzene, then add 500μL of H2O to the round-bottom flask, and add 7.87g of triphenylphosphine (30mmol) and 7.61g of iodine (30mmol) to the flask in batches, stir and react at 100°C for 5h, track and detect by TLC during the reaction, after the reaction is completed, add sodium thiosulfate pentahydrate aqueous solution to quench the reaction, then extract with ethyl acetate (50mL×3), stand and separate, combine the organic phases, and dry the organic phases with anhydrous Na2SO4. Concentrate under reduced pressure to remove the solvent, and separate and purify the residue by column chromatography, the eluent is a mixed solvent of ethyl acetate and petroleum ether, and 2.65g of compound IV is obtained, with a yield of 94.9% and a purity of 99.3%. LC-MS: [M+H] + =278.12.

[0037] Step C: Preparation of Bisacodyl (Compound V)

[0038] Under nitrogen protection, 1.39 g of compound IV (5 mmol) prepared in step B was taken into a 100 mL reaction bottle, and 30 mL of dichloromethane and 1.52 g of triethylamine (15 mmol) were added. The mixture was cooled to 0°C, and 0.76 g of acetyl chloride (10 mmol) was slowly added dropwise. The mixture was kept warm for 8 hours, and then the mixture was heated to room temperature and stirred for 12 hours. After the reaction was completed, the reaction was quenched with aqueous hydrochloric acid (1 M, 20 mL), and then extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The residue was dissolved by heating with 8 mL of ethanol, cooled to 0°C for crystallization, filtered, washed with cold ethanol, and dried to obtain 1.70 g of bisacodyl with a yield of 93.6% and a purity of 99.5%. 1 HNMR (CDCl3, 400MHz), δ8.62(d,1H), 7.62(m,1H), 7.22-7.11(m,6H), 7.04(d,4H), 5.68(s,1H), 2.28(s,6H).

[0039] Example 2

[0040] Preparation of Bisacodyl (Compound V)

[0041] The specific synthetic route is as follows:

[0042]

[0043] Step A: Preparation of Compound III

[0044] 2.14g of compound I (20mmol) and 17.61g of compound II (100mmol) were placed in a pressure bottle, and 51.5g of boron trifluoride monohydrate (molar ratio 1:1) was slowly added at 0°C. After the addition was completed, the temperature was slowly raised to 40°C, and the reaction was continued to stir for 5 hours. The reaction was monitored by TLC (n-hexane: ethyl acetate = 4:1) and GC-MS. After the reaction was completed, the reaction solution was poured into ice water and neutralized with sodium bicarbonate, and then extracted with dichloromethane (100mL×3), the organic phases were combined, washed with water (50mL×2), and then dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and the eluent was n-hexane / ethyl acetate (volume ratio 4:1), to obtain 8.36g of compound III, with a yield of 94% and a purity of 99.3%. LC-MS: [M+H] + =442.13.

[0045] Step B: Preparation of Compound IV

[0046] 4.44 g of compound III (10 mmol) prepared in step A was placed in a 100 mL round-bottom flask, 50 mL of chlorobenzene was added, 500 μL of H2O was added to the round-bottom flask, and 7.87 g of triphenylphosphine (30 mmol) and 7.61 g of iodine (30 mmol) were added to the flask in batches. The mixture was stirred at 120°C for 6 h. TLC was used to track the reaction. After the reaction was completed, sodium thiosulfate pentahydrate was added to quench the reaction, and then extracted with ethyl acetate (50 mL × 3). The mixture was allowed to stand for stratification, and the organic phases were combined and dried over anhydrous Na2SO4. The solvent was removed by concentration under reduced pressure, and the residue was separated and purified by column chromatography. The eluent was a mixed solvent of ethyl acetate and petroleum ether, and 2.67 g of compound IV was obtained. The yield was 95.7% and the purity was 99.4%. LC-MS: [M+H] + =278.12.

[0047] Step C: Preparation of Bisacodyl (Compound V)

[0048] Under nitrogen protection, 1.39 g of compound IV (5 mmol) prepared in step B was taken into a 100 mL reaction bottle, and 30 mL of dichloromethane and 2.02 g of triethylamine (20 mmol) were added. The mixture was cooled to 0°C, and 0.86 g of acetyl chloride (11 mmol) was slowly added dropwise. The mixture was kept warm for 8 hours, and then the mixture was heated to room temperature and stirred for 12 hours. After the reaction was completed, the reaction was quenched with aqueous hydrochloric acid (1 M, 30 mL), and then extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The residue was dissolved by heating with 8 mL of ethanol, cooled to 0°C for crystallization, filtered, washed with cold ethanol, and dried to obtain 1.73 g of bisacodyl with a yield of 95.3% and a purity of 99.6%. 1 HNMR (CDCl3, 400MHz), δ8.62(d,1H), 7.62(m,1H), 7.22-7.11(m,6H), 7.04(d,4H), 5.68(s,1H), 2.28(s,6H).

[0049] Comparative Example 1

[0050] Preparation of Bisacodyl (Compound V)

[0051] The specific synthetic route is as follows:

[0052]

[0053] Step A: Preparation of Compound VII

[0054] 2.14 g of compound I (20 mmol) and 8.65 g of compound VI (80 mmol) were placed in a pressure bottle, and 42.8 g of boron trifluoride monohydrate (molar ratio 1:1) was slowly added at 0°C. After the addition was completed, the temperature was slowly raised to 30°C, and the reaction was continued with stirring for 5 hours. The reaction was monitored by TLC (n-hexane: ethyl acetate = 4:1) and GC-MS. After the reaction was completed, the reaction solution was poured into ice water and neutralized with sodium bicarbonate, and then extracted with dichloromethane (100 mL×3), the organic phases were combined, washed with water (50 mL×2), and then dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and the eluent was n-hexane / ethyl acetate (volume ratio 4:1), to obtain 6.65 g of compound VII, with a yield of 96.5% and a purity of 88.6%. LC-MS: [M+H] + =306.14.

[0055] Step B: Preparation of Compound IV

[0056] 3.45 g of compound VII (10 mmol) prepared in step A was placed in a 100 mL round-bottom flask, and 50 mL of chlorobenzene was added. Then 500 μL of H2O was added to the round-bottom flask, and 7.87 g of triphenylphosphine (30 mmol) and 7.61 g of iodine (30 mmol) were added to the flask in batches. The mixture was stirred at 100 ° C for 4 h. TLC was used to track the reaction. After the reaction was completed, sodium thiosulfate pentahydrate was added to quench the reaction, and then extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and dried over anhydrous Na2SO4. The solvent was removed by concentration under reduced pressure, and the residue was separated and purified by column chromatography. The eluent was a mixed solvent of ethyl acetate and petroleum ether, and 2.73 g of compound IV was obtained, with a yield of 88.1% and a purity of 89.5%. LC-MS: [M+H] + =278.12.

[0057] Step C: Preparation of Bisacodyl (Compound V)

[0058] Under nitrogen protection, 1.55 g of compound IV (5 mmol) prepared in step B was taken into a 100 mL reaction bottle, and 30 mL of dichloromethane and 1.52 g of triethylamine (15 mmol) were added. The mixture was cooled to 0°C, and 0.76 g of acetyl chloride (10 mmol) was slowly added dropwise. The mixture was kept warm for 8 hours, and then the mixture was heated to room temperature and stirred for 12 hours. After the reaction was completed, the reaction was quenched with aqueous hydrochloric acid (1 M, 20 mL), and then extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The residue was dissolved by heating with 8 mL of ethanol, cooled to 0°C for crystallization, filtered, washed with cold ethanol, and dried to obtain 1.66 g of bisacodyl with a yield of 84.7% and a purity of 92.2%.

[0059] It should be understood that the above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. For ordinary technicians in this field, they can be improved or transformed according to the above description, and all these improvements and transformations should fall within the scope of protection of the claims attached to the present invention.

Claims

1. A method for preparing bisacodyl, characterized in that: The following steps are involved: 1) A certain amount of compound I and compound II are placed in a pressure bottle, and boron trifluoride monohydrate is slowly added at 0°C. After the addition is completed, the temperature is raised to carry out condensation reaction, and the reaction is monitored by TLC and GC-MS. After the reaction is completed, post-treatment is performed to obtain compound III; 2) taking a certain amount of compound III prepared in step 1), and performing a deprotection reaction in the presence of triphenylphosphine diiodide, chlorobenzene and water. After the reaction is completed, post-treatment is performed to obtain compound IV; 3) taking a certain amount of compound IV prepared in step 2), and subjecting it to an esterification reaction under the action of acetyl chloride and triethylamine. After the reaction is completed, post-treatment is performed to obtain compound V; In the step 1), the molar ratio of compound I, compound II and boron trifluoride monohydrate is 1:4-5:25; The temperature of the condensation reaction in step 1) is 30°C-40°C, and the time of the condensation reaction is 5-6 hours; The triphenylphosphine diiodide in step 2) is triphenylphosphine diiodide generated in situ. The specific in situ generation step is: equimolar amounts of triphenylphosphine and iodine are added to the reaction solution in sequence, and triphenylphosphine and iodine react rapidly to generate triphenylphosphine diiodide [Ph3P + I]I - ; The molar ratio of compound III to in situ generated triphenylphosphine diiodide is 1:3; In the step 2), the volume ratio of chlorobenzene to water is 100:1; The temperature of the deprotection reaction in step 2) is 100° C., and the deprotection reaction time is 5-6 hours; In the step 3), the molar ratio of compound IV to acetyl chloride and triethylamine is 1:2-2.2:3-4; The temperature of the esterification reaction in step 3) is 0°C to room temperature, and the esterification reaction time is 20 hours; The specific synthetic route is as follows: 。 2. The method for preparing bisacodyl according to claim 1, wherein The post-treatment step in step 1) is as follows: pour the reaction solution into ice water, neutralize with sodium bicarbonate, extract with dichloromethane, combine the organic phases, wash the organic phases with water, dry with anhydrous sodium sulfate, filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography, using n-hexane / ethyl acetate as the eluent.

3. The method for preparing bisacodyl according to claim 1, wherein The post-treatment step in step 2) is as follows: adding sodium thiosulfate pentahydrate aqueous solution to quench the reaction, then extracting with ethyl acetate, standing to separate the layers, combining the organic phases, drying the organic phases with anhydrous Na2SO4, concentrating under reduced pressure to remove the solvent, and separating and purifying the residue by column chromatography, wherein the eluent is a mixed solvent of ethyl acetate and petroleum ether.

4. The method for preparing bisacodyl according to claim 1, wherein The post-treatment steps in step 3) are: quenching the reaction with a 1M hydrochloric acid aqueous solution, then extracting with dichloromethane, combining the organic phases, drying with anhydrous sodium sulfate, filtering, and removing the solvent by rotary evaporation. The residue is then heated and dissolved with ethanol, cooled to 0°C for crystallization, filtered, washed with cold ethanol, and dried.

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