A method for synthesizing 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide

Abstract

A method for synthesizing 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide, the method route is as follows: The method for synthesizing 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide of the present invention has the characteristics of novel process route, cheap and readily available raw materials, high chemical purity (>99.0%), and easy production and scale-up.

Description

Technical Field

[0001] The invention relates to the field of organic chemical synthesis, and in particular to a method for synthesizing 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide. Background Art

[0002] 4-Hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide is a key intermediate in the synthesis of the proton pump inhibitor tegoprazan.

[0003] Currently, there is one main synthetic route for this intermediate. As shown in the following route map. This route requires relatively cumbersome group protection. Using 2-amino-3-nitro-5-bromophenol as the starting material, the O-benzyl group is first protected, and then the amino group is acetylated. The nitro group is reduced under iron powder / acetic acid conditions and condensed to obtain the benzimidazole skeleton; the bromine is converted to a cyano group under transition metal catalysis; the cyano group is then hydrolyzed to obtain a carboxylic acid, which reacts with dimethylamine via a condensing agent to obtain an amide; finally, palladium-catalyzed hydrogenation is used to remove the O-benzyl group to obtain 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide.

[0004]

[0005] In addition to the relatively expensive starting materials, the first two steps of this route require the protection of oxygen and nitrogen atoms in sequence, and the use of an iron powder / glacial acetic acid system in the reduction of the nitro group greatly increases the difficulty of post-processing. The introduction of the carboxyl group requires the introduction of the cyanide group through bromination and metal catalysis, which increases the risk of reagent handling, and the resulting carboxylic acid intermediate has high polarity and is difficult to purify.

[0006] In summary, the development of the pharmaceutical industry requires pharmaceutical intermediates such as 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide, but its current synthesis method still has much room for improvement. Summary of the invention

[0007] The invention aims to solve the problems of great difficulty in post-processing, low yield and difficulty in obtaining high-purity products in the existing synthesis route of 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide, and provides a new method for synthesizing a 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide intermediate.

[0008] In order to solve the problems of difficult post-processing, low yield, and difficulty in obtaining high-purity products in the existing route, the embodiment of the present invention provides a new method for synthesizing 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide. The method comprises the following reaction steps:

[0009] 1) The compound of formula I reacts with dimethylamine hydrochloride in the presence of a condensing agent to obtain an amide to generate a compound of formula II;

[0010] 2) The compound of formula II undergoes amino substitution under ammonia alkaline conditions to obtain a compound of formula III;

[0011] 3) The compound of formula III undergoes reduction and condensation ring-closing reaction with glacial acetic acid in the presence of a metal reducing agent such as iron or zinc to obtain a compound of formula IV;

[0012] 4) The compound of formula IV undergoes diazotization and hydrolysis under acidic conditions to obtain a compound of formula V.

[0013]

[0014] According to one embodiment of the present invention, the method for synthesizing 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide comprises the following steps:

[0015] 1.1) Add dichloromethane, the compound of formula I, 4-dimethylaminopyridine, dimethylamine hydrochloride, triethylamine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (using EDCI condensation agent, the by-product can be washed away with water in the post-treatment process to avoid residual urea impurities) to a reaction kettle, stir the reaction at room temperature, add water, stir and wash after reacting for 4 to 6 hours, and separate the liquids.

[0016] 1.2) The dichloromethane layer is concentrated under reduced pressure, and n-heptane is added to the residue after concentration to slurry, filter, and dry to obtain a compound of formula II.

[0017] 2.1) Add methanol and the compound of formula II to the reaction kettle with stirring, cool to -20 to -10°C, slowly dropwise add ammonia methanol solution (the reaction is exothermic, if the temperature is higher than the above range, a large amount of ammonia will escape and the reaction cannot be completed), react at room temperature for 2 to 6 hours after the addition is completed, and monitor the complete conversion of the raw materials (<1.0%).

[0018] 2.2) Add water to quench the reaction while stirring, concentrate under reduced pressure to remove methanol, add water again and stir for 2-4 hours, filter and dry to obtain a compound of formula III.

[0019] 3.1) Add glacial acetic acid and the compound of formula III to the reaction kettle under the protection of nitrogen, stir, add reduced iron powder, raise the temperature to 100-110°C (if the temperature is lower than the above range, the intermediates in the reaction cannot be completely converted and the reaction rate decreases), control the temperature to react for 12-16 hours, and cool to room temperature and stir after the reaction is completed.

[0020] 3.2) Filter to remove insoluble matter, concentrate the filtrate under reduced pressure to remove glacial acetic acid, add ethyl acetate to the concentrated residue, filter and dry to obtain a compound of formula IV.

[0021] 4.1) Add dilute hydrochloric acid and the compound of formula IV to the reaction kettle, stir and dissolve, cool to -10 to 0°C, and dropwise add sodium nitrite aqueous solution (the diazotization reaction is significantly exothermic, and side reactions can be effectively suppressed and the reaction purity can be improved by cooling and controlling the dropwise addition speed). After the dropwise addition is completed, continue to stir and react for 2 to 6 hours until the reaction is completed.

[0022] 4.2) Add sodium bicarbonate aqueous solution to the reaction kettle with stirring, adjust the pH to 7, filter to obtain a crude product, add ethyl acetate to the crude product for pulping, filter and dry to obtain the compound of formula V.

[0023] According to one embodiment of the present invention,

[0024] The condensation reagent in step (1) is selected from at least one of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-propyl phosphoric anhydride, and N,N'-carbonyldiimidazole, preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0025] According to one embodiment of the present invention, the source of ammonia in step (2) is selected from at least one of ammonia gas, ammonia water, an alcoholic solution of ammonia, a 1,4-dioxane solution of ammonia, sodium amide, and potassium amide, preferably an alcoholic solution of ammonia.

[0026] According to one embodiment of the present invention, the condensing agent in step (3) is selected from at least one of acetic acid, acetaldehyde, acetal, orthoacetic acid esters (trimethyl orthoacetate, triethyl orthoacetate, etc.), preferably acetic acid; the transition metal reducing agent is selected from at least one of iron powder, zinc powder, stannous chloride compounds, platinum carbon, palladium carbon, preferably reduced iron powder.

[0027] According to one embodiment of the present invention, the diazotizing agent in step (4) is selected from at least one of sodium nitrite, isopentyl nitrite, and tert-butyl nitrite, preferably sodium nitrite; and the acid is selected from at least one of hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, and trifluoromethanesulfonic acid, preferably hydrochloric acid.

[0028] The method for synthesizing 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide in the embodiment of the present invention has the characteristics of novel process route, inexpensive and readily available raw materials, high chemical purity (>99.0%), and easy production scale-up (because the method of the present invention has a short synthesis route and simple reaction conditions, it is easy to scale up production and can be scaled up to hundreds of kilograms for production). DETAILED DESCRIPTION

[0029] To make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments and with reference to the accompanying drawings. However, those skilled in the art will appreciate that the present invention is not limited to the accompanying drawings and the following embodiments.

[0030] Example 1

[0031] S1: Dehydration condensation

[0032] Add 500mL of dichloromethane, 100g of 4-chloro-3,5-dinitrobenzoic acid, 44g of dimethylamine hydrochloride, 101g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 104g of 4-dimethylaminopyridine to the reaction bottle. Stir and react at 25°C under nitrogen protection. After the reaction is completed, add water and stir, let stand and separate the liquids, filter the separated dichloromethane layer through silica gel, concentrate the filtrate, add n-heptane to pulp, and dry to obtain 102g of compound II with a yield of 92%.

[0033] ( 1 H NMR (400MHz, DMSO-d6) δ8.94–8.92(s,2H),2.93(s,6H).

[0034] S2: Aminolysis Substitution

[0035] Add 50 g of compound II and 250 mL of methanol to the reaction bottle, cool to -20°C, slowly drop 460 mL of ammonia methanol solution (4M), and keep warm for 2 hours after the addition is complete. Concentrate under reduced pressure to remove methanol, add n-heptane to the residue, slurry, filter, and dry to obtain 39 g of compound III, with a yield of 85%. 1 H NMR (400MHz, DMSO-d6) δ7.53(s,1H),8.18(s,2H),2.95(s,6H).

[0036] S3: Restore the closed loop

[0037] Add 50 g of compound III, 500 mL of glacial acetic acid, and 45 g of reduced iron powder to the reaction bottle, heat to 115°C and react for 6 hours. Cool to room temperature, stir, filter, and rinse the filter cake with glacial acetic acid; the filtrate is concentrated under reduced pressure, ethyl acetate is added to the residue for pulping, filtered, and dried to obtain 41 g of compound IV, with a yield of 95%. 1 H NMR (400MHz, DMSO-d6) δ12.20(s,1H),7.29(s,1H),6.91(s,1H),5.52(s,1H),2.95(s,6H),2.63(s,3H).

[0038] S4: Diazo Hydrolysis

[0039] Add 300 mL of dilute hydrochloric acid (6M) to the reaction flask, add 25 g of compound IV and stir to dissolve, cool to 0-10°C and stir, slowly add 80 g of 20% sodium nitrite aqueous solution, continue stirring for 2 h after the addition is complete, heat to 50-55°C and react for 6 hours. Add saturated sodium bicarbonate to the reaction kettle to quench, adjust pH to 7, stir, filter, wash the filter cake with water, and dry to obtain 21 g of compound V, with a yield of 84%.

[0040] 1 HNMR (400MHz, Methanol-d4): δ7.23(s,1H),6.93(s,1H),3.14(s,3H),3.03(s,3H),2.86(s,3H).

Claims

1. A method for synthesizing a compound of formula V, characterized in that: The method route is as follows: ； The method comprises the following reaction steps: (1) The compound of formula I reacts with dimethylamine hydrochloride in the presence of a condensing agent to obtain an amide to generate a compound of formula II; (2) The compound of formula II undergoes amino substitution under ammonia alkaline conditions to obtain a compound of formula III; (3) The compound of formula III undergoes reduction and condensation ring-closing reaction with glacial acetic acid under the condition of a metal reducing agent to obtain a compound of formula IV; (4) The compound of formula IV undergoes diazotization and hydrolysis under acidic conditions to obtain a compound of formula V; The ammonia alkaline condition in step (2) is selected from at least one of ammonia gas, ammonia water, an alcohol solution of ammonia, a 1,4-dioxane solution of ammonia, sodium amide, and potassium amide; The metal reducing agent in step (3) is selected from at least one of iron powder, zinc powder and stannous chloride.

2. The method according to claim 1, characterized in that: The condensing agent in step (1) is at least one selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, and N,N'-carbonyldiimidazole.

3. The method according to claim 1, characterized in that The diazotization in step (4) is carried out in the presence of a diazotizing agent, wherein the diazotizing agent is selected from at least one of sodium nitrite, isopentyl nitrite, and tert-butyl nitrite; and the acid is selected from at least one of hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, and trifluoromethanesulfonic acid.

4. A method for synthesizing a compound of formula V, characterized in that: The method route is as follows: , the method comprising: 1.1) Add dichloromethane, the compound of formula I, 4-dimethylaminopyridine, dimethylamine hydrochloride, triethylamine, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to a reaction kettle, stir and react at room temperature, add water, stir and wash after reacting for 4 to 6 hours, and separate the liquids; 1.2) The dichloromethane layer is concentrated under reduced pressure, and n-heptane is added to the residue after concentration for slurrying, filtering, and drying to obtain a compound of formula II; 2.1) Add methanol and the compound of formula II to the reaction kettle and stir, cool to -20 ~ -10 °C, slowly drop ammonia methanol solution, react at room temperature for 2 ~ 6 hours after the dropwise addition is complete, and monitor the complete conversion of the raw materials; 2.2) Add water to quench the reaction while stirring, concentrate under reduced pressure to remove methanol, add water again and stir for 2 to 4 hours, filter and dry to obtain a compound of formula III; 3.1) Add glacial acetic acid and the compound of formula III to the reaction kettle under the protection of nitrogen, stir, add reduced iron powder, heat to 100-110°C, control the temperature and react for 12-16 hours, cool to room temperature and stir after the reaction is completed; 3.2) Filter to remove insoluble matter, concentrate the filtrate under reduced pressure to remove glacial acetic acid, add ethyl acetate to the concentrated residue for slurrying, filter and dry to obtain a compound of formula IV; 4.1) Add dilute hydrochloric acid and the compound of formula IV to the reaction kettle and stir to dissolve, cool to -10 ~ 0℃, add sodium nitrite aqueous solution dropwise, and continue stirring to react for 2 ~ 6 hours after the addition is complete until the reaction is complete; 4.2) Add sodium bicarbonate aqueous solution to the reaction kettle with stirring, adjust the pH to 7, filter to obtain a crude product, add ethyl acetate to the crude product for slurrying, filter and dry to obtain the compound of formula V.

5. The method according to claim 1, characterized in that The condensation agent in step (1) is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

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