A preparation method of omeprazole sulfide

Abstract

The present invention provides a method for preparing omeprazole sulfide. The method uses 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride as a raw material and reacts it with thiocyanate to obtain an intermediate, which is then further reacted with p-methoxyphenylhydrazine and post-treated to obtain omeprazole sulfide. The preparation method is novel, simple to operate, and produces a high-purity product, making it suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical synthesis intermediates, and particularly relates to a preparation method of omeprazole sulfide. Background Art

[0002] Proton Pump Inhibitor (PPI) is a class of drugs that inhibit gastric acid secretion. + / K + -ATPase inhibitor, which can act specifically and non-competitively on H + / K + -ATPase, blocking gastric acid secretion. Common proton pump inhibitors are benzimidazole derivatives that can quickly penetrate the gastric wall cell membrane and accumulate in the highly acidic gastric secretion duct. Under acidic conditions, they are catalyzed by acid to generate sulfenamide compounds. The newly generated sulfenamide compounds can covalently bind to the sulfhydryl group of H+ / K+-ATPase to form a disulfide bond, allowing H + / K + -ATPase inactivation, thereby effectively inhibiting peripheral and centrally mediated gastric acid secretion. Currently, esomeprazole sodium, esomeprazole magnesium, and omeprazole are on the market.

[0003] Most of the proton pump inhibitors currently on the market or under development are synthesized using benzimidazole compounds as intermediates. Among them, the compound 5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1-H benzimidazole (omeprazole sulfide) is an important intermediate in the synthesis of esomeprazole sodium, esomeprazole magnesium, and omeprazole. The structural formula is shown below:

[0004]

[0005] There are many reports on the synthesis of the compound 5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1-H benzimidazole (omeprazole sulfide). Generally speaking, the similarities are that they all undergo a substitution reaction between mercaptobenzimidazole and a pyridine derivative. The differences lie in the different leaving groups of the pyridine derivative and the different order of reaction of the groups at the para position of the pyridine ring. The main synthetic routes are as follows: 1.

[0007]

[0008] AM Crowe, RJ Ife et al. first reported the synthesis method of this intermediate in Journal of Labelled Compounds and Radiopharmaceuticals, 1986, 21-33.

[0009] This method uses 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride and 5-methoxy-2-mercapto-1H-benzimidazole as starting materials for the synthesis of omeprazole sulfide. Omeprazole sulfide is obtained through a one-step condensation reaction under alkaline conditions. This method features a simplified synthesis process with few steps, a simple reaction, readily available raw materials, and easy operation, making it relatively suitable for industrial production. However, low yield and purity hinder subsequent reactions. While existing technologies have improved post-processing, the steps involved are complex. 2.

[0011]

[0012] The pyridine derivative used in the synthesis of omeprazole sulfide in CN1233613A is p-methoxypyridine methanesulfonate. The hydroxyl group in the methanesulfonate is a good leaving group, allowing for a smooth substitution reaction with mercaptomethoxybenzimidazole in the presence of a base. However, the synthesis of p-methoxypyridine methanesulfonate requires the use of highly toxic and corrosive methanesulfonyl chloride or methanesulfonic anhydride, which is environmentally unfriendly, and the wastewater post-processing is relatively cumbersome, making it unsuitable for industrial production. 3.

[0014]

[0015] Omeprazole sulfide is obtained by condensing 2-chloromethyl-3,5-dimethyl-4-chloropyridine with 2-mercapto-5-methoxy-1-hydrobenzimidazole, followed by substitution of the chlorine with a methoxy group in the presence of sodium methoxide. This synthetic route is prone to side reactions during the condensation reaction, and the reaction is incomplete when the methoxy group replaces the chlorine. The yield and purity are low, making it unsuitable for industrial production. 4.

[0017]

[0018] Esfandyari, Maryam et al. Iranian Journal of Chemistry & Chemical Engineering, 36(4), 21-29; 2017, published a synthetic route in which the thioether nitro group was treated with a yield of 75%. However, separation and purification are difficult, resulting in severe material loss and high costs, making it unsuitable for industrial production. 5.

[0020]

[0021] CN 109134354A discloses a method of reacting pyridine nitrogen oxide III-1 with trifluoroacetic anhydride in ethyl acetate or dichloromethane as a solvent to obtain II-1. The product is then reacted with 2-mercapto-5-methoxybenzimidazole in toluene or ethyl acetate as a solvent to produce omeprazole sulfide without purification. Although the reaction process is simple, post-treatment with column chromatography yields only 60%, making it unsuitable for industrial production.

[0022] The above-mentioned synthetic routes each have their own advantages, but the reaction conditions and production costs used therein are still relatively harsh, so it is necessary to develop a new synthetic route. Summary of the Invention

[0023] In response to the numerous problems existing in the prior art for preparing omeprazole sulfide compounds, the present invention provides a novel method for preparing omeprazole sulfide compounds. The method has mild reaction conditions, a safe and simple operation process, and the obtained target product has high purity and yield.

[0024] The present invention is specifically implemented through the following technical solutions:

[0025] A method for preparing an omeprazole sulfide compound I comprises reacting SM-1 as a starting material with thiocyanate under alkaline conditions to obtain an intermediate SM-2, and then reacting p-methoxyphenylhydrazine with SM-2 to obtain the target product I. The reaction formula is as follows:

[0026]

[0027] A method for preparing an omeprazole sulfide compound as shown in Formula I comprises the following steps:

[0028] Step 1: Add SM-1 and base to the reaction solvent, control the temperature to T1 and stir, add thiocyanate, keep warm and stir until the reaction is complete, and obtain the intermediate SM-2 through post-treatment. The synthesis route is as follows:

[0029]

[0030] Preferably, the molar ratio of SM-1 to thiocyanate in step 1 is 1:1.0-1.2, more preferably 1:1.05.

[0031] Preferably, the molar ratio of SM-1 to the base in step 1 is 1:1.0-2.0, more preferably 1:1.2.

[0032] Preferably, the base in step 1 is one of NaOH, KOH, Na2CO3, K2CO3, NaHCO3, and KHCO3.

[0033] Preferably, the reaction solvent in step 1 is one of ethanol, methanol and isopropanol.

[0034] Preferably, the thiocyanate in step 1 is one of NaSCN, KSCN and ammonium thiocyanate.

[0035] Preferably, T1 in step 1 is 20-30° C., preferably 25° C. The room temperature in the present invention is 25° C.

[0036] Preferably, the reaction time in step 1 is 1 to 2 hours, more preferably 1.5 hours.

[0037] In a preferred embodiment, the post-treatment step in step 1 is as follows: after the reaction is completed, the feed liquid is added to the extractant, washed with water and saturated brine respectively, the organic phase is dried, and concentrated to dryness to obtain SM-2.

[0038] Preferably, the extractant is one of dichloromethane, chloroform, toluene, ethyl acetate, and butyl acetate, and dichloromethane is more preferred.

[0039] Step 2: Add the intermediate SM-2 and p-methoxyphenylhydrazine to the reaction solvent, control the temperature to T2, and after the reaction is completed, perform post-treatment to obtain the target compound I. The synthesis route is as follows:

[0040]

[0041] Preferably, the reaction solvent in step 2 is one or a combination of tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,4-dioxane, 2-methyltetrahydrofuran, water, ethylene glycol, ethylene glycol dimethyl ether, and ethylene glycol monoether, and the tetrahydrofuran:water volume ratio is further preferably 1:1.

[0042] Preferably, the molar ratio of SM-2 to p-methoxyphenylhydrazine in step 2 is 1:1.0-1.2, more preferably 1:1.05.

[0043] Preferably, the reaction temperature in step 2 is 60-100°C, more preferably 60-80°C.

[0044] Preferably, the reaction time in step 2 is 6 to 10 hours, more preferably 8 hours.

[0045] In a preferred embodiment, the post-treatment step in step 2 is as follows: after the reaction is completed, the temperature is cooled to room temperature, an extractant is added, the organic phase is washed with water, the organic phase is dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to an oily substance. Acetonitrile is added and stirred until no crystals precipitate. The temperature is cooled to 0-5°C for crystallization, filtered, the filter cake is rinsed with acetonitrile, and air-dried to obtain Compound I. Preferably, the extractant is one of dichloromethane, chloroform, and ethyl acetate, more preferably dichloromethane.

[0046] Beneficial effects of the present invention:

[0047] 1. The present invention provides a simple and efficient method for preparing omeprazole sulfide. The target product obtained by this process has a high yield and purity, and is suitable for large-scale industrial production. It also avoids the problem of excessive water content in omeprazole sulfide. Testing shows that the water content is less than 0.01%, or even less. DETAILED DESCRIPTION

[0048] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention based on the method of the present invention fall within the scope of protection claimed by the present invention.

[0049] In the following embodiments, various processes and methods not described in detail are conventional methods well known in the art.

[0050] Example 1

[0051] 100 g (0.45 mol) of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride, 21.6 g (0.54 mol) of sodium hydroxide and 500 ml of ethanol were added to a 1 L three-necked flask and stirred at room temperature for 30 min. 38.3 g (0.47 mol) of sodium thiocyanate was added and the reaction was continued with stirring at room temperature for 1.5 hours. After detection, the reaction was completed, and the feed liquid was transferred to a 2 L separatory funnel, 500 ml of dichloromethane was added, and the mixture was washed twice with 500 ml of water and once with 500 ml of saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness to obtain compound SM-2, which is 92.7 g of (4-methoxy-3,5-dimethylpyridin-2-yl) methyl thiocyanate, with a yield of 98.9% and an HPLC value of 98.5%.

[0052] To a 1L three-necked flask was added 250ml of water, 62g (0.45mol) of p-methoxyphenylhydrazine, and the above SM-2 compound 89.3g (0.43mol) was dissolved in 250ml of tetrahydrofuran and added to the three-necked flask, refluxed for 8 hours, the reaction was completed, cooled to room temperature, 500ml of dichloromethane was added, stirred for 15 minutes, separated, the organic phase was washed twice with 200ml of water, the organic phase was dried over 100g of anhydrous sodium sulfate for 1 hour, evaporated to dryness under reduced pressure to an oil, added to 400ml of acetonitrile and stirred, cooled to 0-5°C and crystallized for 6 hours, filtered, the filter cake was rinsed once with 50ml of acetonitrile, and air-dried to give 135.6g of white solid compound I, i.e., omeprazole sulfide, with a yield of 95.7%, a purity of 99.8%, and a moisture content of less than 0.01%.

[0053] Example 2

[0054] 100 g (0.45 mol) of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride, 21.6 g (0.54 mol) of sodium hydroxide and 500 ml of ethanol were added to a 1 L three-necked flask, stirred at room temperature for 30 min, 43.8 g (0.54 mol) of sodium thiocyanate was added, and the reaction was continued with stirring at room temperature for 2 hours. After detection, the reaction was completed, and the feed liquid was transferred to a 2 L separatory funnel, 500 ml of dichloromethane was added, and the mixture was washed twice with 500 ml of water and once with 500 ml of saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness to obtain compound SM-2, which is (4-methoxy-3,5-dimethylpyridin-2-yl) methyl thiocyanate 91.4 g, with a yield of 97.5% and an HPLC value of 98.0%.

[0055] To a 1L three-necked flask was added 250ml of water, 62g (0.45mol) of p-methoxyphenylhydrazine, and the above SM-2 compound 78.1g (0.38mol) was dissolved in 250ml of tetrahydrofuran and added to the three-necked flask, refluxed for 6 hours, the reaction was completed, cooled to room temperature, 500ml of dichloromethane was added, stirred for 15 minutes, separated, the organic phase was washed twice with 200ml of water, the organic phase was dried over 100g of anhydrous sodium sulfate for 1 hour, evaporated to dryness under reduced pressure to an oil, added to 400ml of acetonitrile and stirred, cooled to 0-5°C and crystallized for 7 hours, filtered, the filter cake was rinsed once with 50ml of acetonitrile, and air-dried to give 121.2g of white solid compound I, i.e., omeprazole sulfide, with a yield of 96.8%, a purity of 99.3%, and a moisture content of less than 0.01%.

[0056] Example 3

[0057] 100 g (0.45 mol) of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride, 21.6 g (0.54 mol) and 500 ml of ethanol were added to a 1 L three-necked flask, stirred at room temperature for 30 min, 36.5 g (0.45 mol) of sodium thiocyanate was added, and the reaction was continued with stirring at room temperature for 1 hour. After detection, the reaction was completed, and the feed liquid was transferred to a 2 L separatory funnel, 500 ml of dichloromethane was added, and the mixture was washed twice with 500 ml of water and once with 500 ml of saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness to obtain compound SM-2, which is 89.6 g of (4-methoxy-3,5-dimethylpyridin-2-yl) methyl thiocyanate, with a yield of 95.6% and an HPLC value of 99.0%.

[0058] To a 1L three-necked flask was added 250ml of water, 55.3g (0.40mol) of p-methoxyphenylhydrazine, and the above SM-2 compound 83.3g (0.40mol) was dissolved in 250ml of tetrahydrofuran and added to the three-necked flask, refluxed for 6 hours, the reaction was completed, cooled to room temperature, 500ml of dichloromethane was added, stirred for 15 minutes, separated, the organic phase was washed twice with 200ml of water, the organic phase was dried over 100g of anhydrous sodium sulfate for 1 hour, evaporated to dryness under reduced pressure to an oil, added to 350ml of acetonitrile and stirred, cooled to 0-5°C for crystallization for 6 hours, filtered, the filter cake was rinsed once with 40ml of acetonitrile, and air-dried to give 123.1g of white solid compound I, i.e., omeprazole sulfide, with a yield of 93.4%, a purity of 99.1%, and a moisture content of less than 0.01%.

[0059] Example 4

[0060] 100 g (0.45 mol) of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride, 57.3 g (0.54 mol) of sodium carbonate and 500 ml of ethanol were added to a 1 L three-necked flask, stirred at room temperature for 30 min, 47.4 g (0.59 mol) of sodium thiocyanate was added, and the reaction was continued with stirring at room temperature for 1 hour. After detection, the reaction was completed, and the feed liquid was transferred to a 2 L separatory funnel, 500 ml of dichloromethane was added, and the mixture was washed twice with 500 ml of water and once with 500 ml of saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness to obtain compound SM-2, which is 89.8 g of (4-methoxy-3,5-dimethylpyridin-2-yl) methyl thiocyanate, with a yield of 95.8% and an HPLC value of 97.8%.

[0061] To a 1L three-necked flask was added 250ml of N, N-dimethylformamide and 62g (0.45mol) of p-methoxyphenylhydrazine. The above SM-2 compound 89.3g (0.43mol) was dissolved in 250ml of N, N-dimethylformamide and added to the three-necked flask. The reaction was carried out at 100°C for 8 hours. After completion of the reaction, the mixture was cooled to room temperature, 500ml of dichloromethane was added, stirred for 15 minutes, separated, and the organic phase was washed twice with 200ml of water. The organic phase was dried over 100g of anhydrous sodium sulfate for 1 hour and evaporated to dryness under reduced pressure to an oily substance. The mixture was added to 400ml of acetonitrile and stirred, cooled to 0-5°C and crystallized for 6 hours. The mixture was filtered, and the filter cake was rinsed once with 50ml of acetonitrile and dried with air to give 133.6g of white solid compound I, i.e., omeprazole sulfide, with a yield of 94.3%, a purity of 98.7%, and a moisture content of less than 0.01%.

[0062] Example 5

[0063] 100 g (0.45 mol) of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride, 57.3 g (0.54 mol) of sodium carbonate and 500 ml of ethanol were added to a 1 L three-necked flask, stirred at 30 ° C for 30 min, 36.0 g (0.47 mol) of ammonium thiocyanate was added, and the reaction was continued with stirring at 30 ° C for 1 hour. After detection, the reaction was completed, and the feed liquid was transferred to a 2 L separatory funnel, 500 ml of dichloromethane was added, and the mixture was washed twice with 500 ml of water and once with 500 ml of saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness to obtain compound SM-2, which is (4-methoxy-3,5-dimethylpyridin-2-yl) methyl thiocyanate 90.8 g, with a yield of 96.9% and an HPLC value of 98.2%.

[0064] To a 1L three-necked flask was added the above SM-2 compound 89.3g (0.43mol), 62g (0.45mol) of p-methoxyphenylhydrazine, and then 500ml of 1,4-dioxane was added, and the reaction was carried out at 80 ° C for 6 hours. After the reaction was completed, the temperature was reduced to room temperature, 500ml of dichloromethane was added, stirred for 15 minutes, and the liquid was separated. The organic phase was washed twice with 200ml of water, and the organic phase was dried over 100g of anhydrous sodium sulfate for 1 hour and evaporated to dryness under reduced pressure to an oil. It was added to 400ml of acetonitrile and stirred, and the temperature was reduced to 0-5 ° C for crystallization for 6 hours. Filter, the filter cake was rinsed once with 50ml of acetonitrile, and air-dried to give 132.7g of white solid compound I, i.e., omeprazole sulfide, with a yield of 93.7%, a purity of 99.4%, and a moisture content of less than 0.01%.

[0065] Example 6

[0066] Step 1. Operate as in Example 1.

[0067] To a 1L three-necked flask was added 250ml of water, 62g (0.45mol) of p-methoxyphenylhydrazine, and the above SM-2 compound 89.3g (0.43mol) was dissolved in 250ml of tetrahydrofuran and added to the three-necked flask, and the reaction was carried out at 50°C for 8 hours. After the reaction was completed, the temperature was reduced to room temperature, 500ml of dichloromethane was added, stirred for 15 minutes, and the liquid was separated. The organic phase was washed twice with 200ml of water, and the organic phase was dried over 100g of anhydrous sodium sulfate for 1 hour and evaporated to dryness under reduced pressure to an oily substance. The mixture was added to 400ml of acetonitrile and stirred, and the temperature was reduced to 0-5°C for crystallization for 6 hours. The filter cake was rinsed once with 50ml of acetonitrile and dried with air to give 129.8g of white solid compound I, i.e., omeprazole sulfide, with a yield of 91.6%, a purity of 95.8%, and a moisture content of less than 0.01%.

Claims

1. A method for preparing omeprazole sulfide, characterized in that: SM-1 is used as the starting material and reacts with thiocyanate under alkaline conditions to obtain the intermediate SM-2, and then p-methoxyphenylhydrazine reacts with SM-2 to obtain the target product I. The reaction formula is as follows: 。 2. The preparation method according to claim 1, characterized in that The steps include: Step 1: Add SM-1 and base to the reaction solvent, control the temperature to T1 and stir, add thiocyanate, keep warm and stir until the reaction is complete, and obtain the intermediate SM-2 through post-treatment. The synthesis route is as follows: ； Step 2: Add the intermediate SM-2 and p-methoxyphenylhydrazine to the reaction solvent, control the temperature to T2, and after the reaction is completed, perform post-treatment to obtain the target compound I. The synthesis route is as follows: 。 3. The preparation method according to claim 1 or 2, characterized in that The molar ratio of the SM-1 to the thiocyanate is 1:1.0-1.2; the molar ratio of the SM-1 to the base is 1:1.0-2.

0.

4. The preparation method according to claim 1 or 2, characterized in that The thiocyanate is one of NaSCN, KSCN and ammonium thiocyanate.

5. The preparation method according to claim 2, characterized in that The T1 described in step 1 is 20 to 30°C.

6. The preparation method according to claim 2, characterized in that T1 described in step 1 is 25°C.

7. The preparation method according to claim 2, characterized in that The reaction solvent in step 1 is one of ethanol, methanol and isopropanol.

8. The preparation method according to claim 2, characterized in that The reaction solvent described in step 2 is tetrahydrofuran, N,N dimethylformamide, N,N One or a combination of dimethylacetamide, dimethyl sulfoxide, 1,4-dioxane, 2-methyltetrahydrofuran, water, ethylene glycol, ethylene glycol dimethyl ether, and ethylene glycol monoether.

9. The preparation method according to claim 2, characterized in that The molar ratio of SM-2 to p-methoxyphenylhydrazine in step 2 is 1:1.0-1.

2.

10. The preparation method according to claim 2, characterized in that The reaction temperature in step 2 is 60-100°C.

11. The preparation method according to claim 2, characterized in that The reaction temperature in step 2 is 60-80°C.

12. The preparation method according to claim 2, characterized in that The post-treatment steps of step 2 are as follows: after the reaction is completed, the temperature is lowered to room temperature, an extractant is added, the organic phase is washed with water, the organic phase is dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure to an oil, acetonitrile is added and stirred until no crystals precipitate, the temperature is lowered to 0-5°C for crystallization, filtered, the filter cake is rinsed with acetonitrile, and air-dried to obtain compound I.

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