CN111943883A - Production process of Orimei chloride - Google Patents
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- CN111943883A CN111943883A CN202010849543.6A CN202010849543A CN111943883A CN 111943883 A CN111943883 A CN 111943883A CN 202010849543 A CN202010849543 A CN 202010849543A CN 111943883 A CN111943883 A CN 111943883A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/68—One oxygen atom attached in position 4
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Abstract
The invention belongs to the field of preparation of omeprazole chloride, and discloses a production process of omeprazole chloride, which comprises the following steps: firstly, carrying out N-oxidation on 2,3, 5-trimethylpyridine to prepare 2,3, 5-trimethylpyridine-N-oxide; secondly, nitrifying the 2,3, 5-trimethylpyridine-N-oxide obtained in the first step to obtain 4-nitro-2, 3, 5-trimethylpyridine-N-oxide; and thirdly, carrying out nucleophilic substitution on the 4-nitro-2, 3, 5-trimethylpyridine-N-oxide obtained in the first step to obtain the 2,3, 5-trimethyl-4-methoxy-pyridine-N-oxide. The production process of the ormea chloride synthesizes the 2-chloromethyl-4-methoxy-3, 5-dimethylpyridine hydrochloride of the ormea chloride through five steps of N-oxidation, nitration, nucleophilic substitution, rearrangement hydrolysis and chloromethylation, optimizes the production process in detail, determines the optimal reaction condition of each step, and the prepared ormea-like chloride has high yield and purity, increases the recovery rate of a solvent, is more economic and environment-friendly, and is worthy of popularization.
Description
Technical Field
The invention relates to the technical field of omeprazole chloride preparation, in particular to a production process of omeprazole chloride.
Background
Orametpyr chloride Chinese alias: 2-chloromethyl-4-methoxyl group-3, 5-dimethyl pyridine hydrochloride, 3, 5-dimethyl-2-chloromethyl-4-methoxyl pyridine hydrochloride, omeprazole chloride, esomeprazole midbody, the finished product of the omeprazole chloride prepared by the existing production process of the omeprazole chloride has low yield and higher impurity.
Disclosure of Invention
Technical problem to be solved
1. Technical problem to be solved
Aiming at the problems in the prior art, the invention aims to provide a production process of an ormea chloride, and solves the problems that the yield of an ormea chloride final product prepared by the existing production process of the ormea chloride is low and the impurities are high.
(II) technical scheme
In order to achieve the purpose, the invention provides the following technical scheme:
a process for the production of omeprazole chloride, comprising the steps of:
firstly, carrying out N-oxidation on 2,3, 5-trimethylpyridine to prepare 2,3, 5-trimethylpyridine-N-oxide;
secondly, nitrifying the 2,3, 5-trimethylpyridine-N-oxide obtained in the first step to obtain 4-nitro-2, 3, 5-trimethylpyridine-N-oxide;
thirdly, nucleophilic substitution is carried out on the 4-nitro-2, 3, 5-trimethylpyridine-N-oxide obtained in the first step to obtain 2,3, 5-trimethyl-4-methoxy-pyridine-N-oxide;
fourthly, carrying out rearrangement hydrolysis on the 2,3, 5-trimethyl-4-methoxy-pyridine-N-oxide obtained in the third step to obtain 2-hydroxymethyl-3, 5-dimethyl-4-methoxy-pyridine:
fifthly, chloromethylating the 2-hydroxymethyl-3, 5-dimethyl-4-methoxy-pyridine obtained in the step three to obtain 2-chloromethyl-4-methoxy-3, 5-dimethyl pyridine hydrochloride.
Preferably, the preparation of the 2,3, 5-trimethylpyridine-N-oxide comprises the following specific steps:
adding 0.6mol of 2,3, 5-trimethylpyridine into a 500mL three-neck flask, refluxing and condensing, stirring uniformly, respectively adding 120mL of glacial acetic acid and 2mL of concentrated sulfuric acid into the solution, heating to 80-110 ℃, and adding 80mL of 30% H2O2Controlling the dripping to be finished within 2h, dripping by using a constant-pressure dropping funnel, and after the dripping is finishedContinuing to perform heat preservation reaction for 6H, and tracking and detecting H which is completely reacted and not completely reacted by TlC2O2Decomposing with appropriate amount of formaldehyde, distilling under reduced pressure to remove acetic acid and water in the reaction to obtain light yellow liquid, standing and solidifying to obtain 2,3, 5-trimethylpyridine-N-oxide.
Preferably, the preparation of the 4-nitro-2, 3, 5-trimethylpyridine-N-oxide comprises the following specific steps:
under the atmosphere of ice-water bath, 30mL of concentrated H is added under stirring2SO4Slowly dripping the mixed acid into the 2,3, 5-trimethylpyridine-N-oxide obtained in the step one, raising the temperature in a reaction bottle to 80-90 ℃, slowly dripping the prepared mixed acid by using a constant-pressure dropping funnel, keeping the temperature in the reaction bottle to be about 85 ℃ after dripping is finished, carrying out heat preservation reaction for 4-5 hours, carrying out TLC tracking detection to complete the reaction, pouring the reaction solution into crushed ice water after the temperature of the reaction solution is reduced to room temperature after the heat preservation reaction is finished, and adding Na into the crushed ice water2CO3Neutralizing the supersaturated aqueous solution until the pH value is 8-10, using dichloromethane or ethyl acetate as an extracting agent, removing water by using anhydrous sodium sulfate, drying, filtering, spin-drying and the like to obtain a yellow solid product, dissolving the yellow solid by using a small amount of ethanol, and recrystallizing at low temperature to obtain a bright yellow needle crystal product 4-nitro-2, 3, 5-trimethylpyridine-N-oxide.
Preferably, the preparation of the 2,3, 5-trimethyl-4-methoxy-pyridine-N-oxide comprises the following specific steps:
dissolving 0.1mol of 4-nitro-2, 3, 5-trimethylpyridine-N-oxide product obtained in the second step into 20mL of methanol, adding a mixed solution of 8.0g of NaOH and 80mL of methanol into the methanol solution under the condition of room temperature while stirring, after dropwise adding, adding 2.0g of tetrabutylammonium bromide into the methanol, raising the temperature for reflux reaction for 3 hours, gradually deepening the color of the reaction solution with generation of precipitates, tracking and detecting by TLC to detect that the reaction is complete, stopping heating when the reaction is complete, cooling the reaction solution to room temperature, filtering the reaction solution, precipitating a filter cake which is most of inorganic salts, removing the reaction solvent methanol from the filtrate through rotary evaporation, extracting the residual substances with dichloromethane, filtering, wherein a filter cake is inorganic salt, obtaining yellow oily matter by spin-drying the filtrate, standing and solidifying to obtain the product 2,3, 5-trimethyl-4-methoxy-pyridine-N-oxide.
Preferably, the preparation of the 2-hydroxymethyl-3, 5-dimethyl-4-methoxy-pyridine comprises the following specific steps:
adding 0.05mol of compound 2, 3.5-trimethyl 4 methoxy-pyridine N-oxide into a 300mL three-neck flask, stirring, dropwise adding a mixed solution prepared from 15mL of acetic anhydride and 10mL of acetic acid in an ice-water bath state, raising the reaction temperature to 90-100 ℃, continuing to perform heat preservation reaction for 7h, performing TLC tracking detection to complete the reaction, distilling under reduced pressure to remove acetic acid and acetic anhydride in the reaction solution, neutralizing the acetic anhydride which is not distilled off with a 5% NaOH aqueous solution until the pH value is 7, adding 40.0g of 15% NaOH aqueous solution into the acetic anhydride, raising the reaction temperature to 60 ℃, continuing to perform heat preservation reaction for 8h, performing TLC tracking detection to complete the reaction, cooling the temperature of the reaction solution to room temperature after the reaction is finished, extracting the reaction solution for 2-3 times with an organic solvent dichloromethane, collecting an organic phase, drying, evaporating to obtain a product 2-hydroxymethyl-3, 5-dimethyl-4-methoxy-pyridine.
Preferably, the preparation method of the 2-chloromethyl-4-methoxy-3, 5-dimethylpyridine hydrochloride comprises the following specific steps:
dissolving 0.03mol of 2-hydroxymethyl-3, 5-dimethyl-4-methoxyl-pyridine obtained in the fourth step in dichloromethane, adding a catalytic amount of N, N-dimethyl amide into the dichloromethane as a catalyst for reaction under the stirring condition, adding a mixed solution consisting of 0.09mol of thionyl chloride and 10mL of dichloromethane into the reaction solution under the ice bath atmosphere, continuing to perform heat preservation reaction for 3-6 h after the dropwise addition is finished, controlling the reaction temperature to be-10 ℃, concentrating the reaction solution to about 5mL under the condition that the temperature is lower than 40 ℃ after the reaction is finished, dropwise adding ethyl acetate into the reaction solution, gradually precipitating white crystals in the bottle, continuously dropwise adding ethyl acetate into the bottle until no white crystals are precipitated in the bottle, performing suction filtration on the mixed solution, washing a filter cake by using a mixed solution prepared from cold acetone and petroleum ether in a ratio of 2:1, obtain white solid powder product, namely 2-chloromethyl-4-methoxyl-3, 5-dimethylpyridine chloride.
Preferably, the mixed acid is prepared from 100mL of concentrated H2SO4And 80mL of 65% concentrated HNO3And (4) forming.
(III) advantageous effects
Compared with the prior art, the invention provides a production process of an ormea chloride, which has the following beneficial effects:
the production process of the ormea chloride synthesizes the 2-chloromethyl-4-methoxy-3, 5-dimethylpyridine hydrochloride of the ormea chloride through five steps of N-oxidation, nitration, nucleophilic substitution, rearrangement hydrolysis and chloromethylation, optimizes the production process in detail, determines the optimal reaction condition of each step, and the prepared ormea-like chloride has high yield and purity, increases the recovery rate of a solvent, is more economic and environment-friendly, and is worthy of popularization.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
A process for the production of omeprazole chloride, comprising the steps of:
firstly, carrying out N-oxidation on 2,3, 5-trimethylpyridine to prepare 2,3, 5-trimethylpyridine-N-oxide;
secondly, nitrifying the 2,3, 5-trimethylpyridine-N-oxide obtained in the first step to obtain 4-nitro-2, 3, 5-trimethylpyridine-N-oxide;
thirdly, nucleophilic substitution is carried out on the 4-nitro-2, 3, 5-trimethylpyridine-N-oxide obtained in the first step to obtain 2,3, 5-trimethyl-4-methoxy-pyridine-N-oxide;
fourthly, carrying out rearrangement hydrolysis on the 2,3, 5-trimethyl-4-methoxy-pyridine-N-oxide obtained in the third step to obtain 2-hydroxymethyl-3, 5-dimethyl-4-methoxy-pyridine:
fifthly, chloromethylating the 2-hydroxymethyl-3, 5-dimethyl-4-methoxy-pyridine obtained in the step three to obtain 2-chloromethyl-4-methoxy-3, 5-dimethyl pyridine hydrochloride.
Further, the preparation of the 2,3, 5-trimethylpyridine-N-oxide comprises the following specific steps:
adding 0.6mol of 2,3, 5-trimethylpyridine into a 500mL three-neck flask, refluxing and condensing, stirring uniformly, respectively adding 120mL of glacial acetic acid and 2mL of concentrated sulfuric acid into the solution, heating to 80-110 ℃, and adding 80mL of 30% H2O2Controlling the dropwise adding within 2H, dropwise adding by using a constant-pressure dropping funnel, continuing the heat preservation reaction for 6H after the dropwise adding is finished, and detecting H which is completely reacted and not completely reacted by TlC tracking2O2Decomposing with appropriate amount of formaldehyde, distilling under reduced pressure to remove acetic acid and water in the reaction to obtain light yellow liquid, standing and solidifying to obtain 2,3, 5-trimethylpyridine-N-oxide.
Further, the preparation of the 4-nitro-2, 3, 5-trimethylpyridine-N-oxide comprises the following specific steps:
under the atmosphere of ice-water bath, 30mL of concentrated H is added under stirring2SO4Slowly dripping the mixed acid into the 2,3, 5-trimethylpyridine-N-oxide obtained in the step one, raising the temperature in a reaction bottle to 80-90 ℃, slowly dripping the prepared mixed acid by using a constant-pressure dropping funnel, keeping the temperature in the reaction bottle to be about 85 ℃ after dripping is finished, carrying out heat preservation reaction for 4-5 hours, carrying out TLC tracking detection to complete the reaction, pouring the reaction solution into crushed ice water after the temperature of the reaction solution is reduced to room temperature after the heat preservation reaction is finished, and adding Na into the crushed ice water2CO3Neutralizing the supersaturated aqueous solution until the pH value is 8-10, using dichloromethane or ethyl acetate as an extracting agent, removing water by using anhydrous sodium sulfate, drying, filtering, spin-drying and the like to obtain a yellow solid product, dissolving the yellow solid by using a small amount of ethanol, and recrystallizing at low temperature to obtain a bright yellow needle crystal product 4-nitro-2, 3, 5-trimethylpyridine-N-oxide.
Further, the preparation of the 2,3, 5-trimethyl-4-methoxy-pyridine-N-oxide comprises the following specific steps:
dissolving 0.1mol of 4-nitro-2, 3, 5-trimethylpyridine-N-oxide product obtained in the second step into 20mL of methanol, adding a mixed solution of 8.0g of NaOH and 80mL of methanol into the methanol solution under the condition of room temperature while stirring, after dropwise adding, adding 2.0g of tetrabutylammonium bromide into the methanol, raising the temperature for reflux reaction for 3 hours, gradually deepening the color of the reaction solution with generation of precipitates, tracking and detecting by TLC to detect that the reaction is complete, stopping heating when the reaction is complete, cooling the reaction solution to room temperature, filtering the reaction solution, precipitating a filter cake which is most of inorganic salts, removing the reaction solvent methanol from the filtrate through rotary evaporation, extracting the residual substances with dichloromethane, filtering, wherein a filter cake is inorganic salt, obtaining yellow oily matter by spin-drying the filtrate, standing and solidifying to obtain the product 2,3, 5-trimethyl-4-methoxy-pyridine-N-oxide.
Further, the preparation of the 2-hydroxymethyl-3, 5-dimethyl-4-methoxyl-pyridine comprises the following specific steps:
adding 0.05mol of compound 2, 3.5-trimethyl 4 methoxy-pyridine N-oxide into a 300mL three-neck flask, stirring, dropwise adding a mixed solution prepared from 15mL of acetic anhydride and 10mL of acetic acid in an ice-water bath state, raising the reaction temperature to 90-100 ℃, continuing to perform heat preservation reaction for 7h, performing TLC tracking detection to complete the reaction, distilling under reduced pressure to remove acetic acid and acetic anhydride in the reaction solution, neutralizing the acetic anhydride which is not distilled off with a 5% NaOH aqueous solution until the pH value is 7, adding 40.0g of 15% NaOH aqueous solution into the acetic anhydride, raising the reaction temperature to 60 ℃, continuing to perform heat preservation reaction for 8h, performing TLC tracking detection to complete the reaction, cooling the temperature of the reaction solution to room temperature after the reaction is finished, extracting the reaction solution for 2-3 times with an organic solvent dichloromethane, collecting an organic phase, drying, evaporating to obtain a product 2-hydroxymethyl-3, 5-dimethyl-4-methoxy-pyridine.
Further, the preparation of 2-chloromethyl-4-methoxyl-3, 5-dimethylpyridine chloride comprises the following steps:
dissolving 0.03mol of 2-hydroxymethyl-3, 5-dimethyl-4-methoxyl-pyridine obtained in the fourth step in dichloromethane, adding a catalytic amount of N, N-dimethyl amide into the dichloromethane as a catalyst for reaction under the stirring condition, adding a mixed solution consisting of 0.09mol of thionyl chloride and 10mL of dichloromethane into the reaction solution under the ice bath atmosphere, continuing to perform heat preservation reaction for 3-6 h after the dropwise addition is finished, controlling the reaction temperature to be-10 ℃, concentrating the reaction solution to about 5mL under the condition that the temperature is lower than 40 ℃ after the reaction is finished, dropwise adding ethyl acetate into the reaction solution, gradually precipitating white crystals in the bottle, continuously dropwise adding ethyl acetate into the bottle until no white crystals are precipitated in the bottle, performing suction filtration on the mixed solution, washing a filter cake by using a mixed solution prepared from cold acetone and petroleum ether in a ratio of 2:1, obtain white solid powder product, namely 2-chloromethyl-4-methoxyl-3, 5-dimethylpyridine chloride.
Further, the mixed acid is prepared from 100mL of concentrated H2SO4And 80mL of 65% concentrated HNO3And (4) forming.
The foregoing is only a preferred embodiment of the present invention; the scope of the invention is not limited thereto. Any person skilled in the art should be able to cover the technical scope of the present invention by equivalent or modified solutions and modifications within the technical scope of the present invention.
Claims (7)
1. The production process of the Orimei chloride is characterized by comprising the following steps of:
firstly, carrying out N-oxidation on 2,3, 5-trimethylpyridine to prepare 2,3, 5-trimethylpyridine-N-oxide;
secondly, nitrifying the 2,3, 5-trimethylpyridine-N-oxide obtained in the first step to obtain 4-nitro-2, 3, 5-trimethylpyridine-N-oxide;
thirdly, nucleophilic substitution is carried out on the 4-nitro-2, 3, 5-trimethylpyridine-N-oxide obtained in the first step to obtain 2,3, 5-trimethyl-4-methoxy-pyridine-N-oxide;
fourthly, carrying out rearrangement hydrolysis on the 2,3, 5-trimethyl-4-methoxy-pyridine-N-oxide obtained in the third step to obtain 2-hydroxymethyl-3, 5-dimethyl-4-methoxy-pyridine:
fifthly, chloromethylating the 2-hydroxymethyl-3, 5-dimethyl-4-methoxy-pyridine obtained in the step three to obtain 2-chloromethyl-4-methoxy-3, 5-dimethyl pyridine hydrochloride.
2. The process for the production of omeprazole chloride according to claim 1, wherein: the preparation method of the 2,3, 5-trimethylpyridine-N-oxide comprises the following specific steps:
adding 0.6mol of 2,3, 5-trimethylpyridine into a 500mL three-neck flask, refluxing and condensing, stirring uniformly, respectively adding 120mL of glacial acetic acid and 2mL of concentrated sulfuric acid into the solution, heating to 80-110 ℃, and adding 80mL of 30% H2O2Controlling the dropwise adding within 2H, dropwise adding by using a constant-pressure dropping funnel, continuing the heat preservation reaction for 6H after the dropwise adding is finished, and detecting H which is completely reacted and not completely reacted by TlC tracking2O2Decomposing with appropriate amount of formaldehyde, distilling under reduced pressure to remove acetic acid and water in the reaction to obtain light yellow liquid, standing and solidifying to obtain 2,3, 5-trimethylpyridine-N-oxide.
3. The process for the production of omeprazole chloride according to claim 1, wherein: the preparation method of the 4-nitro-2, 3, 5-trimethylpyridine-N-oxide comprises the following specific steps:
under the atmosphere of ice-water bath, 30mL of concentrated H is added under stirring2SO4Slowly dripping the mixed acid into the 2,3, 5-trimethylpyridine-N-oxide obtained in the step one, raising the temperature in a reaction bottle to 80-90 ℃, slowly dripping the prepared mixed acid by using a constant-pressure dropping funnel, keeping the temperature in the reaction bottle to be about 85 ℃ after dripping is finished, carrying out heat preservation reaction for 4-5 hours, carrying out TLC tracking detection to complete the reaction, pouring the reaction solution into crushed ice water after the temperature of the reaction solution is reduced to room temperature after the heat preservation reaction is finished, and adding Na into the crushed ice water2CO3Neutralizing the supersaturated aqueous solution until the pH value is 8-10, using dichloromethane or ethyl acetate as an extracting agent, removing water by using anhydrous sodium sulfate, drying, filtering, spin-drying and the like to obtain a yellow solid product, dissolving the yellow solid by using a small amount of ethanol, and recrystallizing at low temperature to obtain a bright yellow needle crystal product 4-nitro-2, 3, 5-trimethylpyridine-N-oxide.
4. The process for the production of omeprazole chloride according to claim 1, wherein: the preparation method of the 2,3, 5-trimethyl-4-methoxy-pyridine-N-oxide comprises the following specific steps:
dissolving 0.1mol of 4-nitro-2, 3, 5-trimethylpyridine-N-oxide product obtained in the second step into 20mL of methanol, adding a mixed solution of 8.0g of NaOH and 80mL of methanol into the methanol solution under the condition of room temperature while stirring, after dropwise adding, adding 2.0g of tetrabutylammonium bromide into the methanol, raising the temperature for reflux reaction for 3 hours, gradually deepening the color of the reaction solution with generation of precipitates, tracking and detecting by TLC to detect that the reaction is complete, stopping heating when the reaction is complete, cooling the reaction solution to room temperature, filtering the reaction solution, precipitating a filter cake which is most of inorganic salts, removing the reaction solvent methanol from the filtrate through rotary evaporation, extracting the residual substances with dichloromethane, filtering, wherein a filter cake is inorganic salt, obtaining yellow oily matter by spin-drying the filtrate, standing and solidifying to obtain the product 2,3, 5-trimethyl-4-methoxy-pyridine-N-oxide.
5. The process for the production of omeprazole chloride according to claim 1, wherein: the preparation method of the 2-hydroxymethyl-3, 5-dimethyl-4-methoxyl-pyridine comprises the following specific steps:
adding 0.05mol of compound 2, 3.5-trimethyl 4 methoxy-pyridine N-oxide into a 300mL three-neck flask, stirring, dropwise adding a mixed solution prepared from 15mL of acetic anhydride and 10mL of acetic acid in an ice-water bath state, raising the reaction temperature to 90-100 ℃, continuing to perform heat preservation reaction for 7h, performing TLC tracking detection to complete the reaction, distilling under reduced pressure to remove acetic acid and acetic anhydride in the reaction solution, neutralizing the acetic anhydride which is not distilled off with a 5% NaOH aqueous solution until the pH value is 7, adding 40.0g of 15% NaOH aqueous solution into the acetic anhydride, raising the reaction temperature to 60 ℃, continuing to perform heat preservation reaction for 8h, performing TLC tracking detection to complete the reaction, cooling the temperature of the reaction solution to room temperature after the reaction is finished, extracting the reaction solution for 2-3 times with an organic solvent dichloromethane, collecting an organic phase, drying, evaporating to obtain a product 2-hydroxymethyl-3, 5-dimethyl-4-methoxy-pyridine.
6. The process for the production of omeprazole chloride according to claim 1, wherein: the preparation method of the 2-chloromethyl-4-methoxyl-3, 5-dimethylpyridine chloride comprises the following specific steps:
dissolving 0.03mol of 2-hydroxymethyl-3, 5-dimethyl-4-methoxyl-pyridine obtained in the fourth step in dichloromethane, adding a catalytic amount of N, N-dimethyl amide into the dichloromethane as a catalyst for reaction under the stirring condition, adding a mixed solution consisting of 0.09mol of thionyl chloride and 10mL of dichloromethane into the reaction solution under the ice bath atmosphere, continuing to perform heat preservation reaction for 3-6 h after the dropwise addition is finished, controlling the reaction temperature to be-10 ℃, concentrating the reaction solution to about 5mL under the condition that the temperature is lower than 40 ℃ after the reaction is finished, dropwise adding ethyl acetate into the reaction solution, gradually precipitating white crystals in the bottle, continuously dropwise adding ethyl acetate into the bottle until no white crystals are precipitated in the bottle, performing suction filtration on the mixed solution, washing a filter cake by using a mixed solution prepared from cold acetone and petroleum ether in a ratio of 2:1, obtain white solid powder product, namely 2-chloromethyl-4-methoxyl-3, 5-dimethylpyridine chloride.
7. The process for the production of omeprazole chloride according to claim 3, wherein: the mixed acid is prepared from 100mL of concentrated H2SO4And 80mL of 65% concentrated HNO3And (4) forming.
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| CN112645873A (en) * | 2021-02-23 | 2021-04-13 | 荆楚理工学院 | Synthetic method of 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide |
| CN114044752A (en) * | 2021-05-28 | 2022-02-15 | 上海卓鼎生物技术有限公司 | Production method of omeprazole drug intermediate 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride |
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