A method for preparing a proton pump inhibitor thioether intermediate compound

Abstract

This invention provides a method for preparing a proton pump inhibitor thioether intermediate. The method involves reacting 3,5-dimethyl-4-methoxy-2-pyridinemethanethiol as a raw material with paraformaldehyde to obtain an intermediate, which is then further reacted with 4-methoxy-o-phenylenediamine, followed by post-treatment to obtain omeprazole thioether. This preparation method is novel, simple to operate, produces a high-purity product, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis intermediates technology, specifically relating to a method for preparing a proton pump inhibitor thioether intermediate compound. Background Technology

[0002] Proton pump inhibitors (PPIs) are a class of drugs that inhibit gastric acid secretion, also known as H2N2 inhibitors. + / K + -ATPase inhibitors can specifically and non-competitively act on H+ on gastric parietal cells. + / K + -ATPase, which blocks gastric acid secretion.

[0003] Currently available proton pump inhibitors include: omeprazole, lansoprazole, pantoprazole, rabeprazole, ilaprazole, and leminoprazole. These proton pump inhibitors are benzimidazole derivatives that can rapidly penetrate the gastric parietal cell membrane and accumulate in the highly acidic gastric secretory ducts. Under acidic conditions, they are catalyzed by acid to form sulfenamide compounds. These newly formed sulfenamide compounds can react with H+. + / K + -The sulfhydryl groups of ATPases covalently bind to form disulfide bonds, allowing H... + / K + - ATPase inactivation effectively inhibits peripheral and centrally mediated gastric acid secretion. Clinical studies have found that proton pump inhibitors have a good relieving effect on gastric acid secretion disorders caused by gastric acid stimulation, dietary stimulation, and pentagastrin stimulation, and are the first-line drugs for treating peptic ulcers, duodenal ulcers, reflux esophagitis, and other diseases related to gastric acid secretion disorders.

[0004] Most of the proton pump inhibitors currently on the market and under development are synthesized using benzimidazole compounds as intermediates. The general structural formula of benzimidazole proton pump inhibitors is shown below:

[0005]

[0006] Currently available proton inhibitors include: omeprazole, lansoprazole, pantoprazole, rabeprazole, ilaprazole, and leminoprazole, with the following chemical structures:

[0007]

[0008] There are many synthetic methods for benzimidazole proton pump inhibitors. The classic synthetic route for omeprazole is as follows: Starting with 3,5-dimethylpyridine, a seven-step reaction yields the key intermediate 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine. Using 4-methoxyaniline as another starting material, a multi-step reaction yields 4-methoxyphenyl-1,2-diamine, which is then reacted with carbon disulfide under alkaline conditions followed by acid reversion to obtain another key intermediate, 5-methoxy-1H-benzo[d]imidazole-2-thiol. The two intermediates are then reacted to obtain the key intermediate for omeprazole sulfide, 5-methoxy-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazole (I). Finally, the sulfide is oxidized to sulfoxide with m-chloroperoxybenzoic acid to obtain the target product. The synthetic route is shown below:

[0009]

[0010] However, the preparation of the key intermediate 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine requires the use of thionyl chloride, which is highly corrosive and irritating; the preparation of the key intermediate 5-methoxy-1H-benzo[d]imidazol-2-thiol requires the use of carbon disulfide, which is highly volatile, flammable, and explosive, resulting in low operational safety; in addition, the preparation of the thioether intermediate compound uses a mixture of water and alcohol as a solvent, and the generated thioether undergoes a series of treatments such as filtration, washing, recrystallization, and drying before entering the second step of the reaction, which leads to long time consumption, waste in intermediate steps, and consequently low overall yield.

[0011] As shown above, 5-methoxy-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazole (I) can serve as a key intermediate in the preparation of omeprazole, directly affecting the quality, production, and sales of this drug. Its structure is shown below:

[0012]

[0013] In addition, another method for preparing proton pump inhibitor thioether-related intermediates is to achieve the docking of the two structural parts through a cyclization reaction between o-phenylenediamine and a mercaptoformic acid derivative. However, the reaction is generally carried out in acidic aqueous solution, and the product is unstable in acidic aqueous solution, resulting in poor product quality. The synthetic route is shown below:

[0014]

[0015] Chinese patent CN1102411A uses o-phenylenediamine and mercaptoformate cyclization to generate benzylimidazole. However, this reaction requires reflux in toluene for 24 hours and heating in a heat-conducting oil bath, resulting in high energy consumption. The synthetic route is shown below:

[0016]

[0017] In summary, given the many shortcomings in the current preparation of proton pump inhibitor thioether intermediates, finding a simple, safe, mild reaction process with high yield and purity suitable for the industrial production of 5-methoxy-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazole (I) proton pump inhibitor thioether intermediates remains a problem that needs to be solved. Summary of the Invention

[0018] To address the numerous problems existing in the preparation of 5-methoxy-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzi[d]imidazole (I) in the prior art, this invention provides a novel method for preparing 5-methoxy-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzi[d]imidazole (I). This method features mild reaction conditions, a safe and simple operation, and yields a target product with high purity and high yield.

[0019] This invention is specifically achieved through the following technical solution:

[0020] A method for preparing a proton pump inhibitor thioether intermediate compound I, comprising: using SM-1 as a starting material to obtain intermediate Int-1, and then reacting it with SM-2 to obtain the target product I, the reaction formula is as follows:

[0021]

[0022] A method for preparing a proton pump inhibitor thioether intermediate compound as shown in Formula I includes the following steps:

[0023] Step 1: Add SM-1, paraformaldehyde, and alkali to reaction solvent A, control the temperature T1 until the reaction is complete, and obtain intermediate Int-1 after post-treatment. The synthetic route is shown below:

[0024]

[0025] Preferably, the alkali mentioned in step 1 is one or a combination of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, triethylamine, sodium methoxide, and sodium ethoxide, with sodium hydroxide being the most preferred.

[0026] Preferably, the reaction solvent A in step 1 is one of water, methanol, and ethanol, with water being the most preferred.

[0027] Preferably, the molar ratio of SM-1 to paraformaldehyde and alkali in step 1 is 1:1.2 to 3.0:5% to 20%, more preferably 1:1.6:10%, and the molar amount of paraformaldehyde is calculated as formaldehyde.

[0028] Preferably, the reaction temperature T1 in step 1 is 10–50°C, more preferably 15–20°C.

[0029] In a preferred embodiment, the post-processing step in step 1 is as follows: after the reaction is complete, the reaction solution is cooled to room temperature, poured into purified water, extracted with dichloromethane or trichloromethane, washed with saturated brine in the organic phase, and concentrated under reduced pressure to dryness to obtain intermediate Int-1.

[0030] Step 2: Intermediate Int-1 and catalyst were added to the reaction solvent and reacted under oxygen protection at a controlled temperature (T2). After Int-1 was detected as having completely reacted, SM-2 was added, and the reaction was continued under air atmosphere at a controlled temperature (T2). After the reaction was detected as complete, post-processing was performed to obtain the target compound I. The synthetic route is shown below:

[0031]

[0032] Preferably, the reaction solvent in step 2 is one or a combination of toluene, xylene, m-trimethylbenzene, and 1,4-dioxane, with toluene being the most preferred.

[0033] Preferably, the catalyst mentioned in step 2 is RuCl3, RuO2, RuCl2(PPh3)3, Ru(acac)3, or Ru3(CO). 12 One or a combination thereof, preferably RuCl3.

[0034] Preferably, the molar ratio of Int-1 to SM-2 and the catalyst in step 2 is 1:1.1 to 1.8:0.5% to 2.0%, more preferably 1:1.2:1.0%, and the molar amount of the catalyst is calculated as Ru.

[0035] Preferably, the reaction temperature T2 in step 2 is 60–100°C, more preferably 75–80°C.

[0036] In a preferred embodiment, the post-processing steps in step 2 are as follows: after the reaction is complete, the reaction solution is cooled to room temperature, filtered, washed with purified water, washed with saturated brine, and the organic phase is concentrated under reduced pressure to dryness. After recrystallization with ethyl acetate, the target product I is obtained.

[0037] In another preferred embodiment, the post-processing steps in step 2 are as follows: after the reaction is complete, the reaction solution is poured into purified water, extracted with ethyl acetate, the organic phase is concentrated under reduced pressure to dryness, and then recrystallized with ethyl acetate to obtain the target product I.

[0038] The beneficial effects of this invention are:

[0039] ①This invention provides a simple and efficient method for preparing proton pump inhibitor thioether intermediate compound I, which can effectively avoid the use of highly volatile, flammable and explosive carbon disulfide.

[0040] ②Furthermore, it eliminates the need for high-temperature reactions, effectively reducing energy consumption;

[0041] ③ The target product obtained by this process has a high yield and purity, making it suitable for large-scale industrial production. Detailed Implementation

[0042] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection of the present invention.

[0043] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0044] The structural confirmation data of the compound Int-1 obtained in this invention are as follows:

[0045]

[0046] ESI-HRMS (m / z): 214.0847; 1 H NMR (400MHz, DMSO-d6) δ: 7.93(s,1H),4.46(s,2H),3.95(s,2H),3.82(s,3H),3.26(s,1H),2.46(s,3H),2.44(s,3H); 13 C NMR (125MHz, DMSO-d6) δ: 159.49, 151.73, 145.60, 127.33, 117.92, 60.26, 55.36, 37.83, 12.17, 10.24.

[0047] Synthesis of Int-1:

[0048]

[0049] Example 1

[0050] SM-1 (18.33 g, 0.10 mol), paraformaldehyde (4.80 g), and sodium hydroxide (0.40 g, 0.01 mol) were added to water (120 ml) and reacted at a controlled temperature of 15–20 °C. After the reaction was completed, the reaction solution was cooled to room temperature and poured into purified water (500 ml). It was extracted with dichloromethane (200 ml × 3), washed with saturated brine (200 ml) on the organic phase, and concentrated under reduced pressure to dryness to obtain intermediate Int-1, with a yield of 95.4% and a purity of 98.8%.

[0051] Example 2

[0052] SM-1 (18.33 g, 0.10 mol), paraformaldehyde (3.60 g), and potassium hydroxide (0.56 g, 0.01 mol) were added to water (120 ml) and reacted at a controlled temperature of 30–35 °C. After the reaction was completed, the reaction solution was cooled to room temperature and poured into purified water (500 ml). It was extracted with dichloromethane (200 ml × 3), washed with saturated brine (200 ml) on the organic phase, and concentrated under reduced pressure to dryness to obtain intermediate Int-1, with a yield of 94.9% and a purity of 98.7%.

[0053] Example 3

[0054] SM-1 (18.33 g, 0.10 mol), paraformaldehyde (3.30 g), and sodium ethoxide (0.68 g, 0.01 mol) were added to ethanol (60 ml) and reacted at a controlled temperature of 35–40 °C. After the reaction was completed, the reaction solution was cooled to room temperature and poured into purified water (500 ml). It was extracted with dichloromethane (200 ml × 3), washed with saturated brine (200 ml) on the organic phase, and concentrated under reduced pressure to dryness to obtain intermediate Int-1, with a yield of 92.5% and a purity of 98.9%.

[0055] Example 4

[0056] SM-1 (18.33 g, 0.10 mol), paraformaldehyde (9.01 g), and potassium carbonate (1.38 g, 0.01 mol) were added to water (120 ml) and reacted at a controlled temperature of 15–20 °C. After the reaction was completed, the reaction solution was cooled to room temperature and poured into purified water (500 ml). It was extracted with dichloromethane (200 ml × 3), washed with saturated brine (200 ml) on the organic phase, and concentrated under reduced pressure to dryness to obtain intermediate Int-1, with a yield of 92.1% and a purity of 97.9%.

[0057] Example 5

[0058] SM-1 (18.33 g, 0.10 mol), paraformaldehyde (9.31 g), and sodium bicarbonate (0.84 g, 0.01 mol) were added to water (120 ml) and reacted at a controlled temperature of 10–15 °C. After the reaction was completed, the reaction solution was cooled to room temperature and poured into purified water (500 ml). It was extracted with dichloromethane (200 ml × 3), washed with saturated brine (200 ml) on the organic phase, and concentrated under reduced pressure to dryness to obtain intermediate Int-1, with a yield of 90.5% and a purity of 98.0%.

[0059] Example 6

[0060] SM-1 (18.33 g, 0.10 mol), paraformaldehyde (4.80 g), and sodium methoxide (0.27 g, 0.005 mol) were added to methanol (80 ml) and reacted at a controlled temperature of 45–50 °C. After the reaction was completed, the reaction solution was cooled to room temperature and poured into purified water (500 ml). It was extracted with dichloromethane (200 ml × 3), washed with saturated brine (200 ml) on the organic phase, and concentrated under reduced pressure to dryness to obtain intermediate Int-1, with a yield of 90.1% and a purity of 97.8%.

[0061] Example 7

[0062] SM-1 (18.33 g, 0.10 mol), paraformaldehyde (4.80 g), and triethylamine (2.02 g, 0.02 mol) were added to water (120 ml) and reacted at a controlled temperature of 10–15 °C. After the reaction was completed, the reaction solution was cooled to room temperature and poured into purified water (500 ml). It was extracted with dichloromethane (200 ml × 3), washed with saturated brine (200 ml) on the organic phase, and concentrated under reduced pressure to dryness to obtain intermediate Int-1, with a yield of 91.6% and a purity of 98.4%.

[0063] Synthesis of I:

[0064]

[0065] Example 8

[0066] Intermediate Int-1 (10.66 g, 0.05 mol) and RuCl3 (104 mg, 0.5 mmol) were added to toluene (200 ml). The reaction mixture was reacted at 75–80 °C under oxygen protection. After Int-1 was detected as having completely reacted, SM-2 (8.29 g, 0.06 mol) was added. The reaction mixture was then reacted at 75–80 °C under air atmosphere. After the reaction was detected as having completely reacted, the reaction solution was cooled to room temperature, filtered, washed with purified water (60 ml × 2), washed with saturated brine (60 ml), and the organic phase was concentrated to dryness under reduced pressure. The product was then recrystallized from ethyl acetate to obtain the target product I, with a yield of 96.7% and a purity of 99.7%.

[0067] Example 9

[0068] Intermediate Int-1 (10.66 g, 0.05 mol) and RuCl3 (104 mg, 0.5 mmol) were added to xylene (200 ml). The reaction mixture was reacted at 75–80 °C under oxygen protection. After Int-1 was detected as having completely reacted, SM-2 (7.60 g, 0.055 mol) was added. The reaction mixture was then reacted at 80–85 °C under air atmosphere. After the reaction was detected as having completely reacted, the reaction solution was cooled to room temperature, filtered, washed with purified water (60 ml × 2), washed with saturated brine (60 ml), and the organic phase was concentrated to dryness under reduced pressure. After recrystallization with ethyl acetate, the target product I was obtained, with a yield of 94.6% and a purity of 99.5%.

[0069] Example 10

[0070] Intermediate Int-1 (10.66 g, 0.05 mol) and Ru3(CO) were added. 12 108.7 mg (0.17 mmol) was added to toluene (200 ml). The reaction mixture was reacted at 75–80 °C under oxygen protection. After Int-1 was detected as complete, SM-2 (7.25 g, 0.0525 mol) was added. The reaction mixture was reacted at 85–90 °C under air atmosphere. After the reaction was detected as complete, the reaction solution was cooled to room temperature, filtered, washed with purified water (60 ml × 2), washed with saturated brine (60 ml), and the organic phase was concentrated to dryness under reduced pressure. After recrystallization with ethyl acetate, the target product I was obtained, with a yield of 91.2% and a purity of 99.6%.

[0071] Example 11

[0072] Intermediate Int-1 (10.66 g, 0.05 mol) and Ru(acac)3 (0.20 g, 0.5 mmol) were added to 1,4-dioxane (200 ml). The reaction mixture was reacted at 75–80 °C under oxygen protection. After Int-1 was detected as having completely reacted, SM-2 (12.44 g, 0.09 mol) was added. The reaction mixture was reacted at 70–75 °C under air atmosphere. After the reaction was detected as having completely reacted, the reaction solution was cooled to room temperature and poured into purified water (1500 ml). It was extracted with ethyl acetate (500 ml × 3), and the organic phase was washed with saturated brine (400 ml). The organic phase was concentrated to dryness under reduced pressure and recrystallized from ethyl acetate to obtain the target product I, with a yield of 95.4% and a purity of 99.4%.

[0073] Example 12

[0074] Intermediate Int-1 (10.66 g, 0.05 mol) and RuCl2(PPh3)3 (0.48 g, 0.5 mmol) were added to toluene (200 ml). The reaction mixture was reacted at 75–80 °C under oxygen protection. After Int-1 was detected to have reacted completely, SM-2 (13.13 g, 0.095 mol) was added. The reaction mixture was reacted at 65–70 °C under air atmosphere. After the reaction was detected to be complete, the reaction solution was cooled to room temperature, filtered, washed with purified water (60 ml × 2), washed with saturated brine (60 ml), and the organic phase was concentrated to dryness under reduced pressure to obtain the target product I, with a yield of 94.8% and a purity of 99.0%.

[0075] Example 13

[0076] Intermediate Int-1 (10.66 g, 0.05 mol) and RuCl3 (52 mg, 0.25 mmol) were added to m-trimethylbenzene (200 ml). The reaction mixture was reacted at 60–65 °C under oxygen protection. After Int-1 was detected as having completely reacted, SM-2 (8.29 g, 0.06 mol) was added. The reaction mixture was then reacted at 95–100 °C under air atmosphere. After the reaction was detected as having completely reacted, the reaction solution was cooled to room temperature, filtered, washed with purified water (60 ml × 2), washed with saturated brine (60 ml), and the organic phase was concentrated to dryness under reduced pressure. The product was then recrystallized from ethyl acetate to obtain the target product I, with a yield of 92.3% and a purity of 99.2%.

[0077] Example 14

[0078] Intermediate Int-1 (10.66 g, 0.05 mol) and RuO2 (133 mg, 1.0 mmol) were added to toluene (200 ml). The reaction mixture was reacted at 75–80 °C under oxygen protection. After Int-1 was detected as having completely reacted, SM-2 (8.29 g, 0.06 mol) was added. The reaction mixture was then reacted at 60–65 °C under air atmosphere. After the reaction was detected as having completely reacted, the reaction solution was cooled to room temperature, filtered, washed with purified water (60 ml × 2), washed with saturated brine (60 ml), and the organic phase was concentrated to dryness under reduced pressure. The product was then recrystallized from ethyl acetate to obtain the target product I, with a yield of 93.1% and a purity of 99.0%.

Claims

1. A method for preparing a proton pump inhibitor thioether intermediate compound, characterized in that, Includes the following steps: Step 1: Add SM-1, paraformaldehyde, and alkali to reaction solvent A, control the temperature T1 until the reaction is complete, and obtain intermediate Int-1 after post-treatment. The synthetic route is shown below: ； Step 2: Intermediate Int-1 and catalyst were added to the reaction solvent and reacted under oxygen protection at a controlled temperature (T2). After Int-1 was detected as having completely reacted, SM-2 was added, and the reaction was continued at a controlled temperature (T2) under air. After the reaction was detected as complete, post-treatment was performed to obtain target compound I. The synthetic route is shown below: ； The T1 mentioned in step 1 is 10–50°C; The catalysts mentioned in step 2 are RuCl3, RuO2, RuCl2(PPh3)3, Ru(acac)3, and Ru3(CO). 12 One or a combination thereof; The reaction temperature T2 mentioned in step 2 is 60-100℃.

2. The preparation method according to claim 1, characterized in that, In step 1, the molar ratio of SM-1 to paraformaldehyde and alkali is 1: 1.2-3.0: 0.05-0.20, and the molar amount of paraformaldehyde is calculated as formaldehyde.

3. The preparation method according to claim 1, characterized in that, In step 1, the molar ratio of SM-1 to paraformaldehyde and alkali is 1:1.6:0.10, and the molar amount of paraformaldehyde is calculated as formaldehyde.

4. The preparation method according to claim 1, characterized in that, The T1 mentioned in step 1 is 15-20℃.

5. The preparation method according to claim 1, characterized in that, The alkali mentioned in step 1 is one or a combination of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, triethylamine, sodium methoxide, and sodium ethoxide.

6. The preparation method according to claim 1, characterized in that, The alkali mentioned in step 1 is sodium hydroxide.

7. The preparation method according to claim 1, characterized in that, The reaction solvent A mentioned in step 1 is one of water, methanol, or ethanol.

8. The preparation method according to claim 1, characterized in that, The reaction solvent A mentioned in step 1 is water.

9. The preparation method according to claim 1, characterized in that, The reaction solvent mentioned in step 2 is one or a combination of toluene, xylene, m-trimethylbenzene, and 1,4-dioxane.

10. The preparation method according to claim 1, characterized in that, The reaction solvent mentioned in step 2 is toluene.

11. The preparation method according to claim 1, characterized in that, The catalyst mentioned in step 2 is RuCl3.

12. The preparation method according to claim 1, characterized in that, In step 2, the molar ratio of Int-1 to SM-2 and the catalyst is 1: 1.1-1.8: 0.005-0.02, and the molar amount of the catalyst is expressed as Ru.

13. The preparation method according to claim 1, characterized in that, In step 2, the molar ratio of Int-1 to SM-2 and the catalyst is 1:1.2:0.01, and the molar amount of the catalyst is expressed in Ru.

14. The preparation method according to claim 1, characterized in that, The reaction temperature T2 mentioned in step 2 is 75-80℃.

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