Preparation method of rabeprazole chloride and intermediate thereof

Abstract

According to an existing method, acetic anhydride is adopted for a reaction when a formula III is synthesized from a formula IV, the reaction temperature is high, the reaction time is long, a large number of isomer byproducts can be generated in the reaction process, and the product purity is low. When the compound shown in the formula I is synthesized from free alkali of a compound shown in a formula II, halogenated alkane is used as a solvent and thionyl chloride is used as a chlorination reagent for reaction, alkali quenching, water washing extraction and salt formation after concentrationare needed for aftertreatment, the operation is complex, and the production period is long. According to the invention, p-toluenesulfonic acid is added for catalysis when the compound shown as the formula III is prepared, so that the reaction can be carried out at a relatively low temperature, the side reaction is greatly reduced, and the purity of the product is improved. When the compound shownin the formula I is prepared, ethyl acetate is used as a solvent, a product is gradually separated out along with the reaction, the product can be obtained through direct filtration after the reactionis completed, aftertreatment is simple, the product purity is high, and the method is suitable for industrial production.

Description

technical field

[0001] The invention belongs to the field of drug synthesis, and relates to a preparation method of rabeprazole chloride and an intermediate thereof. Specifically, the chemical name of rabeprazole chloride is 2-chloromethyl-3-methyl-4- (3-methoxypropoxy)pyridine hydrochloride, the chemical name of the intermediate is 3-methyl-2-acetoxymethyl-4-(3-methoxypropoxy)pyridine. Background technique

[0002] Rabeprazole chloride, chemically named 2-chloromethyl-3-methyl-4-(3-methoxypropoxy)pyridine hydrochloride, (CAS No.: 153259-31-5), is the raw material The key intermediate of the drug rabeprazole sodium, most of which are reported in the literature is 2,3-lutidine as the starting raw material, which is oxidized, nitrated, chlorinated, etherified, esterified, rearranged, hydrolyzed, Chlorine 2 and salt preparation.

[0003]

[0004] Esterification rearrangement can be obtained by reacting 2,3-dimethyl-4-(3-methoxypropoxy)pyridine nitrogen oxide (formula IV) w...

Examples

Embodiment 13

[0048] Preparation of embodiment 13-methyl-2-hydroxymethyl-4-(3-methoxypropoxy)pyridine

[0049]Add 50g of 2,3-dimethyl-4-(3-methoxypropoxy)pyridine nitrogen oxide, 48.5g of acetic anhydride, and 4g of p-toluenesulfonic acid into the reaction flask, stir evenly and then raise the temperature, and control the temperature at 50±5 After reacting at ℃ for 3 hours, TLC showed that the reaction of the raw materials was complete (the reaction solution was detected by HPLC, and the purity of the target product was 93.6%), and the excess acetic anhydride was concentrated under negative pressure. Add 10% sodium hydroxide aqueous solution, adjust the pH to 14, then raise the temperature to 80°C for 1 hour, TLC confirms that the reaction is complete, then lowers to room temperature, extracts with toluene and concentrates to dryness to obtain the compound shown in the title, with a molar yield of 90.1 %, purity 94.71%.

Embodiment 23

[0050] The preparation of embodiment 23-methyl-2-hydroxymethyl-4-(3-methoxypropoxy)pyridine

[0051] Add 50g of 2,3-dimethyl-4-(3-methoxypropoxy)pyridine nitrogen oxide, 48.5g of acetic anhydride, and 8g of p-toluenesulfonic acid into the reaction flask, stir evenly and then raise the temperature, and control the temperature at 60±5 After reacting at ℃ for 3 hours, TLC showed that the reaction of the raw materials was complete (the reaction solution was detected by HPLC, and the purity of the target product was 95.1%), and the excess acetic anhydride was concentrated under negative pressure. Add 10% sodium hydroxide aqueous solution, adjust the pH to 14, then raise the temperature to 80 ° C for 1 hour, TLC confirms that the reaction is complete, then lowers to room temperature, extracts with toluene and concentrates to dryness to obtain the compound shown in the title, with a molar yield of 91.6 %, purity 95.35%.

Embodiment 33

[0052] Preparation of Example 33-methyl-2-hydroxymethyl-4-(3-methoxypropoxy)pyridine

[0053] Add 50g of 2,3-dimethyl-4-(3-methoxypropoxy)pyridine nitrogen oxide, 97g of acetic anhydride, and 4g of p-toluenesulfonic acid into the reaction flask, stir well and then raise the temperature, and control the temperature at 50±5°C After 3 hours of reaction, TLC showed that the reaction of the raw materials was complete (the reaction solution was detected by HPLC, and the purity of the target product was 94.9%), and the excess acetic anhydride was concentrated under negative pressure. Add 10% sodium hydroxide aqueous solution, adjust the pH to 14, then raise the temperature to 80°C for 1 hour, TLC confirms that the reaction is complete, then lowers to room temperature, extracts with toluene, and concentrates to dryness to obtain the compound shown in the title, with a molar yield of 92.1 %, purity 95.52%.

technical field

[0001] The invention belongs to the field of drug synthesis, and relates to a preparation method of rabeprazole chloride and an intermediate thereof. Specifically, the chemical name of rabeprazole chloride is 2-chloromethyl-3-methyl-4- (3-methoxypropoxy)pyridine hydrochloride, the chemical name of the intermediate is 3-methyl-2-acetoxymethyl-4-(3-methoxypropoxy)pyridine. Background technique

[0002] Rabeprazole chloride, chemically named 2-chloromethyl-3-methyl-4-(3-methoxypropoxy)pyridine hydrochloride, (CAS No.: 153259-31-5), is the raw material The key intermediate of the drug rabeprazole sodium, most of which are reported in the literature is 2,3-lutidine as the starting raw material, which is oxidized, nitrated, chlorinated, etherified, esterified, rearranged, hydrolyzed, Chlorine 2 and salt preparation.

[0003]

[0004] Esterification rearrangement can be obtained by reacting 2,3-dimethyl-4-(3-methoxypropoxy)pyridine nitrogen oxide (formula IV) w...

Examples

Embodiment 13

[0048] Preparation of embodiment 13-methyl-2-hydroxymethyl-4-(3-methoxypropoxy)pyridine

[0049]Add 50g of 2,3-dimethyl-4-(3-methoxypropoxy)pyridine nitrogen oxide, 48.5g of acetic anhydride, and 4g of p-toluenesulfonic acid into the reaction flask, stir evenly and then raise the temperature, and control the temperature at 50±5 After reacting at ℃ for 3 hours, TLC showed that the reaction of the raw materials was complete (the reaction solution was detected by HPLC, and the purity of the target product was 93.6%), and the excess acetic anhydride was concentrated under negative pressure. Add 10% sodium hydroxide aqueous solution, adjust the pH to 14, then raise the temperature to 80°C for 1 hour, TLC confirms that the reaction is complete, then lowers to room temperature, extracts with toluene and concentrates to dryness to obtain the compound shown in the title, with a molar yield of 90.1 %, purity 94.71%.

Embodiment 23

[0050] The preparation of embodiment 23-methyl-2-hydroxymethyl-4-(3-methoxypropoxy)pyridine

[0051] Add 50g of 2,3-dimethyl-4-(3-methoxypropoxy)pyridine nitrogen oxide, 48.5g of acetic anhydride, and 8g of p-toluenesulfonic acid into the reaction flask, stir evenly and then raise the temperature, and control the temperature at 60±5 After reacting at ℃ for 3 hours, TLC showed that the reaction of the raw materials was complete (the reaction solution was detected by HPLC, and the purity of the target product was 95.1%), and the excess acetic anhydride was concentrated under negative pressure. Add 10% sodium hydroxide aqueous solution, adjust the pH to 14, then raise the temperature to 80 ° C for 1 hour, TLC confirms that the reaction is complete, then lowers to room temperature, extracts with toluene and concentrates to dryness to obtain the compound shown in the title, with a molar yield of 91.6 %, purity 95.35%.

Embodiment 33

[0052] Preparation of Example 33-methyl-2-hydroxymethyl-4-(3-methoxypropoxy)pyridine

[0053] Add 50g of 2,3-dimethyl-4-(3-methoxypropoxy)pyridine nitrogen oxide, 97g of acetic anhydride, and 4g of p-toluenesulfonic acid into the reaction flask, stir well and then raise the temperature, and control the temperature at 50±5°C After 3 hours of reaction, TLC showed that the reaction of the raw materials was complete (the reaction solution was detected by HPLC, and the purity of the target product was 94.9%), and the excess acetic anhydride was concentrated under negative pressure. Add 10% sodium hydroxide aqueous solution, adjust the pH to 14, then raise the temperature to 80°C for 1 hour, TLC confirms that the reaction is complete, then lowers to room temperature, extracts with toluene, and concentrates to dryness to obtain the compound shown in the title, with a molar yield of 92.1 %, purity 95.52%.

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