CN111233835A - Preparation and purification method of 5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde - Google Patents
Preparation and purification method of 5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde Download PDFInfo
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- CN111233835A CN111233835A CN202010185435.3A CN202010185435A CN111233835A CN 111233835 A CN111233835 A CN 111233835A CN 202010185435 A CN202010185435 A CN 202010185435A CN 111233835 A CN111233835 A CN 111233835A
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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Abstract
The invention provides a preparation and purification method for preparing a key intermediate 5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde compound (I) of a chemical drug of pinapran for treating gastric ulcer, duodenal ulcer and reflux esophagitis, and is particularly suitable for removing and purifying a raw material compound (III) which is remained in a target compound (I) and is not completely reacted; the method has the advantages of stable process, simple operation, easy control of process conditions, simple and convenient post-treatment, less three wastes, continuous and cyclic use of mother liquor, good product quality, high yield and low production cost, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of chemical synthesis and preparation, and particularly relates to a preparation and purification method of 5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde (I).
Background
The prior literature reports on the preparation of 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde (I) include: in a high-purity vonoPrazan Fumarate compound, an intermediate and impurities thereof and a preparation method thereof disclosed in the application of CN 1O492679OA, a benign solvent haloalkane and a poor solvent are used for refining a crude product of 5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde, the refining method has an undesirable effect, the purity of the obtained refined product is low, the HPLC content is less than 98%, and the contents of known impurities and unknown impurities are high. The synthesis method reported in patent WO2007026916 uses 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde, sodium hydride and 15-crown-5 as raw materials, reacts with a tetrahydrofuran solvent, reacts with pyridine-3-sulfonyl chloride hydrochloride, is diluted by saturated saline, is extracted by ethyl acetate, is washed by saline, is dried by anhydrous magnesium sulfate, is concentrated under reduced pressure, and is purified by silica gel column chromatography, and then is recrystallized by a mixed solvent of diisopropyl ether and ethyl acetate to obtain the target compound. Therefore, the method has the defects that a large amount of 15-crown-5 is needed in the reaction, the 15-crown-5 is remained in the mother solution and cannot be recovered, and the 15-crown-5 can only be discarded, so that certain resource waste and environmental pollution are caused; and the post-reaction treatment is complex, reaction byproducts are more, a large amount of saturated saline solution is needed for washing, a solvent ethyl acetate is used for extraction, and finally a target compound can be obtained through silica gel column chromatography purification, mixed solvent crystallization and the like, so that the product yield is low, the production efficiency is low, the energy consumption is high, the three wastes are more, the production cost is high, and the industrial production is difficult to realize.
Disclosure of Invention
The invention provides a preparation and purification method for preparing a key intermediate 5- (2-fluorophenyl) -1- (pyridine-3-yl sulfonyl) -1H-pyrrole-3-formaldehyde compound (I) of a chemical drug of pinapranoprazan for treating gastric ulcer, duodenal ulcer and reflux esophagitis, which comprises two steps:
A. reacting the 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde compound (III) with strong base under the protection of organic solvent and nitrogen to generate a 5- (2-fluorophenyl) -1 sodium-pyrrole-3-formaldehyde compound (II), reacting with pyridine-3-sulfonyl chloride without separation, carrying out pressure filtration after the reaction is finished, distilling the filtrate to recover the solvent, adding a mixed solvent for dissolving, decoloring by using active carbon, carrying out pressure filtration, crystallizing, centrifuging and drying to obtain a crude product of the 5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde compound (I);
B. and D, recrystallizing the crude compound (I) obtained in the step A by using an organic solvent to obtain a refined compound (I).
The reaction of the invention is as follows:
the preparation and purification method of the 5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde is characterized by comprising the following steps: the preparation process of the crude product of the compound (I) in the step A is completed by maintaining nitrogen positive pressure salt formation and substitution after nitrogen replacement; the solvent is acetonitrile which is a conventional solvent; the strong base is potassium hydroxide powder with the granularity of more than 100 meshes; the molar ratio of compound (iii) to potassium hydroxide and pyridine-3-sulfonyl chloride ═ 1: 1.5-3.5: 1.5 to 3.5; the mass ratio of the compound (III) to the solvent acetonitrile is 1: 15-30; the reaction temperature of salifying is 10-20 ℃, and the reaction time is 1-2 hours; the substitution reaction process is to add pyridine-3-sulfonyl chloride, control the reaction temperature to be 30 +/-2 ℃ and carry out the reaction for 0.5 to 1.5 hours; and (4) after the reaction is finished, performing pressure filtration, concentrating the filtrate, and recovering the solvent to be dry to obtain an oily substance.
The preparation and purification method of the 5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde is characterized by comprising the following steps: and B, dissolving the oily substance obtained by concentration in a mixed solvent, decoloring by using activated carbon, performing pressure filtration, crystallizing, centrifuging, and drying in vacuum to obtain a crude product of the 5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde compound (I).
The preparation and purification method of the 5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde is characterized by comprising the following steps: the mixed solvent is a conventional solvent of ethyl acetate and n-hexane; the mass ratio of ethyl acetate to n-hexane was 1: 3-8; the mass ratio of the compound (iii) to the mixed solvent and the activated carbon is 1: 10-20: 0.05 to 0.1; the dissolving and decoloring temperature is 60-75 ℃, and the time is 0.5-1 hour; the crystallization temperature is 0-5 ℃, and the heat preservation crystallization time is 1-2 hours.
The preparation and purification method of the 5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde is characterized by comprising the following steps: in the step B, the organic solvent used in the recrystallization process of the crude compound (I) is conventional solvent methanol, and the mass ratio of the crude compound (I) to the methanol is as follows: 1: 3-6; heating to 50-65 ℃ to dissolve for 15-30 min, filter-pressing, cooling the filtrate to crystallize, centrifuging, and vacuum-drying to obtain the refined compound (I).
The preparative purification method is particularly suitable for the purification of the incompletely reacted starting compound (III) which remains in the target compound (I). In the target compound (I), when the content of the compound (III) is more than 0.2%, the reaction product in the subsequent process is an impurity which is difficult to remove by a conventional purification method because the impurity is similar to the structure, the property and the like of the target drug, and the content in the target drug is still more than 0.1%, so that the quality of the target drug product is unqualified. After the purification and recrystallization method is adopted, the unreacted raw material compound (III) in the target compound (I) is effectively removed, the content of the unreacted raw material compound (III) in the obtained compound (I) is less than 0.1 percent, and the quality of the subsequent target drug product is ensured to reach the standard, so that the preparation and purification method of the key intermediate 5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrole-3-formaldehyde compound (I) for preparing the high-purity target drug is provided.
The invention aims to provide a preparation and purification method of a 5- (2-fluorophenyl) -1- (pyridine-3-yl sulfonyl) -1H-pyrrole-3-formaldehyde compound (I). The preparation and purification method effectively reduces the impurity content and improves the quality of subsequent target products.
Compared with the prior art, the invention has the following beneficial effects:
the method has the advantages of stable process, simple operation, easy control of process conditions, simple and convenient post-treatment, less three wastes, continuous and cyclic use of mother liquor, good product quality, high yield and low production cost, and is suitable for industrial production.
Detailed Description
The present invention is further described below with reference to examples.
Example 1
A. 4725g of acetonitrile and 189g of compound (III) were added to a 10L glass-lined reactor equipped with a stirrer, a thermometer, a vacuum pressure gauge, etc. while stirring, the temperature was lowered to 15 ℃ and 140g of potassium hydroxide powder was added, and after replacing the air with nitrogen, the mixture was stirred and reacted for 1.5 hours while maintaining the temperature. 397.7g of pyridine-3-sulfonyl chloride is added into the reaction solution dropwise, the reaction temperature is controlled to be 30 +/-2 ℃, and the reaction is carried out for 1 hour under the condition of heat preservation and stirring. And (3) filter-pressing the reaction mixed liquid into a distillation kettle, carrying out reduced pressure distillation to recover the solvent until no distillate exists, controlling the internal temperature below 50 ℃, controlling the vacuum degree to be more than or equal to-0.07 MPa, adding 472.5g of ethyl acetate and 2362.5g of n-hexane after the concentration is finished, adding 13g of activated carbon while stirring, heating to 70 ℃, decoloring for 0.5 hour, carrying out filter pressing, cooling to crystallize to 3 ℃, carrying out heat preservation and crystallization for 1.5 hours, centrifuging, and carrying out vacuum drying to obtain 308.1g of a crude product of the compound (I).
B. Adding 1232.4g of methanol into a recrystallization kettle, starting stirring, adding the crude product of the compound (I) obtained in the step (2), closing a feeding port, heating to 55 ℃, dissolving for 25min until the crude product is clear, performing filter pressing, cooling the filtrate to crystallize to 3 ℃, performing heat preservation crystallization for 1.5 hours, centrifuging, washing a filter cake with methanol, performing spin-drying, discharging, and putting the wet product into a double-cone dryer to obtain 294.5g of the finished product of the compound (1) in vacuum. HPLC compound (1) content 99.82%, single maximum impurity 0.07%.
Example 2
A. 4725g of acetonitrile and 189g of compound (III) were added to a 10L glass-lined reaction vessel equipped with a stirrer, a thermometer, a vacuum pressure gauge, etc. while stirring, the temperature was lowered to 10 ℃ and 168g of potassium hydroxide powder was added, and after replacing the air with nitrogen, the reaction was stirred for 2 hours while maintaining the temperature. Dropwise adding 477.2g of pyridine-3-sulfonyl chloride into the reaction liquid, controlling the reaction temperature to be 30 +/-2 ℃, keeping the temperature and stirring for reaction for 0.5 hour, press-filtering the reaction mixed liquid into a distillation kettle, carrying out reduced pressure distillation to recover the solvent until no distillate exists, controlling the internal temperature to be below 50 ℃, controlling the vacuum degree to be more than or equal to-0.07 MPa, adding 405g of ethyl acetate and 2430g of n-hexane after the concentration is finished, adding 11.3g of activated carbon while stirring, heating to 70 ℃, decoloring for 0.5 hour, carrying out press-filtering, cooling to crystallize to 3 ℃, keeping the temperature and crystallizing for 1.5 hours, centrifuging, and carrying out vacuum drying to obtain 315.3g of a crude product of the compound (I.
B. Adding 1576.5g of methanol into a recrystallization kettle, starting stirring, adding the crude product of the compound (I) obtained in the step (2), closing a feeding port, heating to 60 ℃, dissolving for 20min until the mixture is clear, performing filter pressing, cooling the filtrate to 2 ℃, performing heat preservation crystallization for 1.5 hours, centrifuging, washing a filter cake with methanol, performing spin-drying, discharging, and putting the wet product into a double-cone dryer for vacuum drying to obtain 304.3g of the finished product of the compound (1). HPLC compound (1) content 99.76%, single maximum impurity 0.06%.
Example 3
A. 2835g of acetonitrile and 189g of compound (III) are added into a 10L glass lining reaction kettle provided with a stirrer, a thermometer, a vacuum pressure gauge and the like under stirring, the temperature is reduced to 12 ℃, 84g of potassium hydroxide powder is added, air is replaced by nitrogen, and then the reaction is carried out for 2 hours under heat preservation and stirring. And then adding 238.6g of pyridine-3-sulfonyl chloride dropwise into the reaction, controlling the reaction temperature to be 30 +/-2 ℃, keeping the temperature and stirring for reaction for 1.5 hours, carrying out pressure filtration on the reaction mixed solution to a distillation kettle, carrying out reduced pressure distillation to recover the solvent until no distillate exists, controlling the internal temperature to be below 50 ℃, controlling the vacuum degree to be not less than-0.07 MPa, after the concentration is finished, adding 472.5g of ethyl acetate and 1417.5g of n-hexane, adding 9.5g of activated carbon while stirring, heating to 75 ℃, decolorizing for 0.5 hour, carrying out pressure filtration, cooling to crystallize to 0 ℃, keeping the temperature and crystallizing for 1 hour, centrifuging, and carrying out vacuum drying to obtain 307.5g of a crude compound (I).
B. Adding 922.5g of methanol into a recrystallization kettle, starting stirring, adding the crude product of the compound (I) obtained in the step (2), closing a feeding port, heating to 65 ℃, dissolving for 30min until the crude product is clear, performing filter pressing, cooling the filtrate to 5 ℃, performing heat preservation crystallization for 2 hours, centrifuging, washing a filter cake with methanol, spin-drying, discharging, and putting the wet product into a double-cone dryer for vacuum drying to obtain 295.1g of the finished product of the compound (1). HPLC compound (1) content 99.81%, single maximum impurity 0.05%.
Example 4
A. 5670g of acetonitrile and 189g of compound (III) were added to a 10L glass-lined reactor equipped with a stirrer, a thermometer, a vacuum pressure gauge, etc., while stirring, the temperature was lowered to 13 ℃ and 196g of potassium hydroxide powder was added, and after replacing the air with nitrogen, the mixture was stirred and reacted for 1 hour while maintaining the temperature. And adding 556.7g of pyridine-3-sulfonyl chloride dropwise into the reaction, controlling the reaction temperature to be 30 +/-2 ℃, keeping the temperature and stirring for reaction for 0.5 hour, carrying out pressure filtration on the reaction mixed solution to a distillation kettle, carrying out reduced pressure distillation to recover the solvent until no distillate exists, controlling the internal temperature to be below 50 ℃, controlling the vacuum degree to be more than or equal to-0.07 MPa, after the concentration is finished, adding 420g of ethyl acetate and 3360g of n-hexane, adding 18.9g of activated carbon while stirring, heating to 60 ℃, decolorizing for 1 hour, carrying out pressure filtration, cooling to crystallize to 5 ℃, keeping the temperature and crystallizing for 2 hours, centrifuging, and carrying out vacuum drying to obtain 311.7g of a crude compound (I.
B. Adding 1870.2g of methanol into a recrystallization kettle, starting stirring, adding the crude product of the compound (I) obtained in the step (2), closing a feeding port, heating to 50 ℃, dissolving for 15min until the crude product is clear, performing filter pressing, cooling the filtrate to 0 ℃, performing heat preservation crystallization for 1 hour, centrifuging, washing a filter cake with methanol, spin-drying, discharging, and putting the wet product into a double-cone dryer for vacuum drying to obtain 298.8g of the finished product of the compound (1). HPLC compound (1) content 99.59%, single maximum impurity 0.07%.
Claims (5)
- A process for the preparation and purification of 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde characterized by the fact that it comprises two steps:A. reacting the 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde compound (III) with strong base under the protection of organic solvent and nitrogen to generate a 5- (2-fluorophenyl) -1 sodium-pyrrole-3-formaldehyde compound (II), reacting with pyridine-3-sulfonyl chloride without separation, carrying out pressure filtration after the reaction is finished, distilling the filtrate to recover the solvent, adding a mixed solvent for dissolving, decoloring by using active carbon, carrying out pressure filtration, crystallizing, centrifuging and drying to obtain a crude product of the 5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde compound (I);B. and D, recrystallizing the crude compound (I) obtained in the step A by using an organic solvent to obtain a refined compound (I).
- 2. The process for the preparation and purification of 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde as claimed in claim 1, wherein: the preparation process of the crude product of the compound (I) in the step A is completed by maintaining nitrogen positive pressure salt formation and substitution after nitrogen replacement; the solvent is acetonitrile which is a conventional solvent; the strong base is potassium hydroxide powder with the granularity of more than 100 meshes; the molar ratio of compound (iii) to potassium hydroxide and pyridine-3-sulfonyl chloride ═ 1: 1.5-3.5: 1.5 to 3.5; the mass ratio of the compound (III) to the solvent acetonitrile is 1: 15-30; the reaction temperature of salifying is 10-20 ℃, and the reaction time is 1-2 hours; the substitution reaction process is to add pyridine-3-sulfonyl chloride, control the reaction temperature to be 30 +/-2 ℃ and carry out the reaction for 0.5 to 1.5 hours; and (4) after the reaction is finished, performing pressure filtration, concentrating the filtrate, and recovering the solvent to be dry to obtain an oily substance.
- 3. The process for producing and purifying 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde according to claim 1 or 2, wherein: and B, dissolving the oily substance obtained by concentration in a mixed solvent, decoloring by using activated carbon, performing pressure filtration, crystallizing, centrifuging, and drying in vacuum to obtain a crude product of the 5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde compound (I).
- 4. The process for the preparation and purification of 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde as claimed in claim 1, wherein: the mixed solvent is a conventional solvent of ethyl acetate and n-hexane; the mass ratio of ethyl acetate to n-hexane was 1: 3-8; the mass ratio of the compound (iii) to the mixed solvent and the activated carbon is 1: 10-20: 0.05 to 0.1; the dissolving and decoloring temperature is 60-75 ℃, and the time is 0.5-1 hour; the crystallization temperature is 0-5 ℃, and the heat preservation crystallization time is 1-2 hours.
- 5. The process for the preparation and purification of 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde as claimed in claim 1, wherein: in the step B, the organic solvent used in the recrystallization process of the crude compound (I) is conventional solvent methanol, and the mass ratio of the crude compound (I) to the methanol is as follows: 1: 3-6; heating to 50-65 ℃ to dissolve for 15-30 min, filter-pressing, cooling the filtrate to crystallize, centrifuging, and vacuum-drying to obtain the refined compound (I).
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| CN202010185435.3A CN111233835A (en) | 2020-03-17 | 2020-03-17 | Preparation and purification method of 5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde |
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| CN202010185435.3A CN111233835A (en) | 2020-03-17 | 2020-03-17 | Preparation and purification method of 5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115850238A (en) * | 2022-11-29 | 2023-03-28 | 山东新华制药股份有限公司 | Post-treatment method of fluoro pranoprazan intermediate |
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- 2020-03-17 CN CN202010185435.3A patent/CN111233835A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115850238A (en) * | 2022-11-29 | 2023-03-28 | 山东新华制药股份有限公司 | Post-treatment method of fluoro pranoprazan intermediate |
| CN115850238B (en) * | 2022-11-29 | 2024-06-11 | 山东新华制药股份有限公司 | Post-treatment method of fluarprazan intermediate |
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