Preparation method of key intermediate of tigorazan

Abstract

The invention relates to the field of organic chemical synthesis, in particular to a method for preparing a key intermediate (7-bromo-N, N, 2-trimethylbenzimidazole-5-formamide) of tigorazan, and the route of the method is shown in the specification. The method has the advantages that the process route is novel, the raw materials are cheap and easy to obtain, the cost is low, the operation is safe and simple, the large-scale production is easy, and the like. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of organic chemical synthesis, and particularly relates to a method for preparing a key intermediate of tigolacine (i.e., 7-bromo-N,N,2-trimethylbenzimidazole-5-carboxamide). Background Art

[0002] Tigolacine, a potassium ion competitive acid blocker, is mainly used for the treatment of gastroesophageal reflux disease and erosive esophagitis. As shown in the following route, 7-bromo-N,N,2-trimethylbenzimidazole-5-carboxamide (Compound of Formula I) is a key intermediate in the synthesis of tigolacine.

[0003]

[0004] Chinese Invention CN115594639A discloses a synthesis method of the Compound of Formula I. As shown in the following route, 4-aminobenzoic acid is subjected to amidation, bromination and then reacts with acetamidine hydrochloride under the catalysis of a copper reagent to obtain the Compound of Formula I. The copper-catalyzed reaction reported in this route requires alkaline and high temperature conditions of 120 °C, while the boiling point of acetamidine liberated from acetamidine hydrochloride under alkaline conditions is 62.8 °C. Therefore, this reaction needs to be carried out in a closed system, which is very dangerous and not suitable for industrial production.

[0005]

[0006] In the route reported in Chinese Invention CN116375650A, the Compound of Formula 4 benzoic acid is subjected to amidation, bromination and then cyclized with acetic acid under the catalysis of reduced iron powder to obtain the Compound of Formula I. Chinese Invention CN116375650A also reports that the Compound of Formula 7 methyl benzoate is brominated and then cyclized with acetic acid under the catalysis of stannous chloride to obtain the Compound of Formula 9 benzimidazole, and finally the Compound of Formula I can be obtained through amine-ester exchange. The starting materials and intermediates of these two routes both contain nitro functional groups with potential explosion risks; the reduction of nitro uses an iron powder / acetic acid or stannous chloride / acetic acid system, and the post-treatment is difficult; moreover, the strongly reducing reagents zinc powder or stannous chloride have safety risks during transportation, storage and use.

[0007]

[0008] In summary, the development of the pharmaceutical industry requires pharmaceutical intermediates such as 7-bromo-N,N,2-trimethylbenzimidazole-5-carboxamide (Compound of Formula I), and there is an even greater need to provide a route with low-cost raw materials and reagents, safe and simple reactions, few by-products, high overall yield, simple post-treatment and conducive to large-scale industrial production to synthesize this compound. Summary of the Invention

[0009] Object of the Invention: The technical problem to be solved by the present invention is to provide a new preparation method of 7-bromo-N,N,2-trimethylbenzimidazole-5-carboxamide, a key intermediate of tigolaciclib, aiming at the problems of difficult post-treatment, safety risks, high production costs, and low yields in the existing synthetic route of 7-bromo-N,N,2-trimethylbenzimidazole-5-carboxamide.

[0010] To solve the above technical problems, the present invention discloses the following technical solutions:

[0011] A method for synthesizing the intermediate 7-bromo-N,N,2-trimethylbenzimidazole-5-carboxamide of tigolaciclib, the method comprising:

[0012] 1) The compound of formula II undergoes a bromination reaction under the catalysis of a brominating reagent to form a compound of formula III;

[0013] 2) The compound of formula III undergoes an addition reaction with acetonitrile under the catalysis of a catalyst to form a compound of formula IV;

[0014] 3) The compound of formula IV undergoes a cyclization reaction under the action of a chlorinating reagent and an aqueous alkali solution to form a compound of formula I (CAS: 2476762-63-5);

[0015]

[0016] In step 1), the bromination reaction is carried out in an organic solvent; the organic solvent is dichloromethane.

[0017] In step 1), the concentration of the compound of formula II in the organic solvent is 100-160 g / L, such as 130-140 g / L, 133 g / L.

[0018] In step 1), the brominating reagent is selected from bromine, N-bromosuccinimide, dibromohydantoin, pyridinium tribromide, or a combination of any of the foregoing; preferably N-bromosuccinimide. Compared with other brominating reagents, N-bromosuccinimide is relatively safe and has fewer by-product dibromo compounds; when the brominating reagent is bromine, acetic acid needs to be added to the reaction system; the molar ratio of acetic acid to bromine is 1-1.8:1, such as 1.2-1.6:1, 1.4:1.

[0019] In step 1), the molar ratio of the compound of formula II to the brominating reagent is 1:0.8-1.7, such as 1:0.9-1.5, 1:1.

[0020] In step 1), the temperature of the bromination reaction is 20-30 °C.

[0021] In step 1), before adding the brominating reagent, the reaction system is cooled to 0-10°C. After adding the brominating reagent, the temperature is raised to 20-30°C for the bromination reaction; the reaction system is a mixture of an organic solvent and a compound of formula II; or a mixture of an organic solvent, a compound of formula II and acetic acid.

[0022] In step 1), after the reaction ends, the reaction solution is quenched, layered, the organic layer is filtered through silica gel, the obtained filtrate is concentrated, n-heptane is added for pulping, filtered, and the filter cake is dried to obtain the compound of formula III. In some embodiments, when acetic acid is added to the reaction system, after the reaction solution is quenched, the pH is adjusted to 6.5-7.5, and then layered.

[0023] In step 2), the catalyst is selected from HCl gas, acetonitrile hydrochloride solution and dioxane hydrochloride solution, aluminum trichloride, or any combination of the foregoing; the concentration of hydrochloric acid in the acetonitrile hydrochloride solution and dioxane hydrochloride solution is 0.2-2 mol / L, such as 0.5-1.5 mol / L, 0.8-1.2 mol / L, 1 mol / L. Compared with HCl gas and aluminum trichloride, the acetonitrile hydrochloride solution is easier to operate and safer; acetonitrile serves as both a solvent and a reaction reagent, and the post-treatment is more convenient; at the same time, acetonitrile as a solvent does not introduce other solvents.

[0024] In step 2), the solvent for the reaction is acetonitrile.

[0025] In step 2), the mixed solution of the solvent and the compound of formula III is cooled to 0-5°C, the catalyst is added, and an addition reaction is carried out. Among them, in the mixed solution, the volume-mass ratio of the solvent to the compound of formula III is 0.5-2 mL / g, such as 0.8-1.5 mL / g, 1 mL / g; the molar ratio of the compound of formula III to the acid in the catalyst is 1:1.5-2.5, such as 1:2-2.2.

[0026] In step 2), the temperature of the reaction is 60-80°C.

[0027] In step 2), after the reaction ends, it is filtered, the filter cake is rinsed with acetonitrile, the obtained solid is dissolved in dichloromethane, the pH value is adjusted to 10-11, stirred and layered, the aqueous phase is extracted with dichloromethane 1-3 times, the organic phases are combined, and concentrated under reduced pressure to obtain the compound of formula IV.

[0028] In step 3), the mixed solution of acetonitrile and the compound of formula IV is cooled to 0-5°C, a chlorinating reagent is added, stirred, and an aqueous alkali solution is added for a cyclization reaction. Among them, in the mixed solution, the mass-volume ratio of the compound of formula IV to acetonitrile is 180-220 g / L, such as 190-210 g / L, 200 g / L; the stirring time is 0.4-0.6 h, such as 0.5 h.

[0029] In step 3), the chlorinating agent is selected from N-chlorosuccinimide, trichloroisocyanuric acid, calcium hypochlorite, sodium hypochlorite, or a combination of any several of the foregoing, preferably N-chlorosuccinimide. Compared with other chlorinating agents, N-chlorosuccinimide has low cost, convenient and safe operation. In some embodiments, the calcium hypochlorite and sodium hypochlorite are added in the form of an aqueous solution of calcium hypochlorite and an aqueous solution of sodium hypochlorite; the mass concentration of the aqueous solution of calcium hypochlorite and the aqueous solution of sodium hypochlorite is 20%-40%, such as 25%-35%, 30%.

[0030] In step 3), the aqueous alkali solution is an aqueous solution of sodium hydroxide, and the mass concentration of the aqueous alkali solution is 10%-30%, such as 15%-25%, 20%.

[0031] In step 3), the molar ratio of the compound of formula IV to the chlorinating agent is 1:0.2-2, such as 1:0.5-1.5, 1:0.5-1.

[0032] In step 3), the mass ratio of the aqueous alkali solution to the compound of formula IV is 0.85-1.25:1, such as 0.95-1.15:1, 1.05:1.

[0033] In step 3), after the reaction is completed, water and ethyl acetate are added after concentration under reduced pressure, the pH is adjusted to 3-5, and then the aqueous phase is separated; the pH value of the aqueous phase is adjusted to 9-10, and extracted with dichloromethane for 1-3 times. The dichloromethane organic phases are combined and concentrated under reduced pressure to obtain the compound of formula I. The volume ratio of the water to the ethyl acetate is 1:0.5-1.5, such as 1:1.

[0034] In some embodiments, the method includes:

[0035] 1) Add dichloromethane and the compound of formula II to a reaction flask, stir, cool down to 0-10 °C, add N-bromosuccinimide, and react at room temperature for 1-16 hours after addition. After the reaction is completed, add an aqueous solution of sodium thiosulfate to quench, stir, separate to obtain the dichloromethane layer, filter through silica gel, concentrate the filtrate under reduced pressure, add n-heptane for pulping, filter, and dry to obtain the compound of formula III.

[0036] 2) Add acetonitrile and the compound of formula III to a reaction flask, cool down to 0-5 °C, then add a hydrochloric acid acetonitrile solution, and react at 70 °C for 2-8 hours after addition. After the reaction is completed, filter, wash the filter cake with acetonitrile, dissolve the solid in dichloromethane, adjust the pH value to 10-11 with an aqueous solution of sodium hydroxide, stir and then separate the layers. The aqueous phase is extracted with dichloromethane for 2 times, the organic phases are combined and concentrated under reduced pressure to obtain the compound of formula IV.

[0037] 3) Add acetonitrile and the compound of Formula IV to the reaction flask. After cooling the temperature to 0 - 5 °C, add N-chlorosuccinimide. Stir for 0.5 hour and then add the NaOH solution. After adding, continue to stir for 1 - 4 hours. After the reaction is completed, concentrate under reduced pressure, add water and ethyl acetate, adjust the pH to 4 - 5 with hydrochloric acid, and then separate the aqueous phase. Adjust the pH value of the aqueous phase to 9 - 10 with saturated aqueous Na2CO3 solution, extract twice with DCM, combine the organic phases, and concentrate under reduced pressure to obtain the compound of Formula I.

[0038] Beneficial effects:

[0039] The method for synthesizing the key intermediate of tigolacine, 7-bromo-N,N,2-trimethylbenzimidazole-5-carboxamide, of the present invention has the advantages of novel process route, inexpensive and easily available raw materials, low cost, safe and simple operation, and easy scale-up production. Description of the drawings

[0040] The following further specifically describes the present invention in conjunction with the drawings and specific embodiments, and the above and / or other advantages of the present invention will become clearer.

[0041] Figure 1 1H-NMR spectrum of the compound of Formula III obtained in Example 1 of the present invention 1 1H-NMR spectrum.

[0042] Figure 2 13C-NMR spectrum of the compound of Formula III obtained in Example 1 of the present invention 13 13C-NMR spectrum.

[0043] Figure 3 1H-NMR spectrum of the compound of Formula IV obtained in Example 1 of the present invention 1 1H-NMR spectrum.

[0044] Figure 4 13C-NMR spectrum of the compound of Formula IV obtained in Example 1 of the present invention 13 13C-NMR spectrum. Specific embodiments

[0045] According to the following examples, the present invention can be better understood. However, those skilled in the art can easily understand that the content described in the examples is only used to illustrate the present invention and should not and will not limit the present invention described in detail in the claims.

[0046] In the following examples, the experimental methods are all conventional methods unless otherwise specified; the reagents and materials can be obtained from commercial sources unless otherwise specified.

[0047] Example 1:

[0048] 1) Synthesis of the compound of Formula III:

[0049] Add 1.5 L of dichloromethane and 200 g of the compound of formula II to the reaction flask, cool the temperature to 0 - 10 °C, slowly add 238 g of N-bromosuccinimide. After the addition, heat to 25 °C and react for 6 hours. Quench with an aqueous sodium thiosulfate solution, stir, separate to obtain the dichloromethane layer, filter through silica gel. The filtrate is concentrated under reduced pressure and then slurried with 600 mL of n-heptane, filtered, and the filter cake is dried to obtain 272 g of the compound of formula III, yield: 92%.

[0050] The NMR of the compound of formula III is as Figure 1-2 shown, 1 H NMR(400MHz,CDCl3)δ8.12(d,J=1.9Hz,1H),7.78(dd,J=8.4,1.9Hz,1H),6.73(d,J=8.4Hz,1H),4.35(brs,2H),3.05(s,6H); 13 CNMR(100MHz,Chloroform-d)δ166.16,148.36,134.55,130.29,120.58,114.29,107.86,34.90.

[0051] 2) Synthesis of the compound of formula IV:

[0052] Add 200 mL of acetonitrile and 200 g of the compound of formula III to the reaction flask, cool the temperature to 0 - 5 °C, and then slowly add 1.0 mol / L hydrochloric acid acetonitrile solution (1.8 L). After the addition, heat to 70 °C and react. Monitor the reaction progress by HPLC. After 5 hours, the reaction is complete. Filter, wash the filter cake with 200 mL of acetonitrile. Dissolve the solid in 1 L of dichloromethane, adjust the pH value to 10 - 11 with 20% aqueous sodium hydroxide solution, stir and then separate the layers. Extract the aqueous phase with 300 mL of dichloromethane twice. Combine all the dichloromethane organic phases and concentrate under reduced pressure to obtain 222 g of the compound of formula IV, yield: 95%.

[0053] The NMR of the compound of formula IV is as Figure 3-4 shown, 1 H NMR(400MHz,Chloroform-d)δ8.11(d,J=1.9Hz,1H),7.77(dd,J=8.4,1.9Hz,1H),6.72(d,J=8.4Hz,1H),4.39(brs,2H),3.05(s,6H),2.05(s,3H); 13 C NMR(100MHz,Chloroform-d)δ167.14,153.72,148.36,131.64,131.19,124.80,122.09,113.82,34.90,22.23.

[0054] 3) Synthesis of the compound of formula I:

[0055] Add 1 L of acetonitrile and 200 g of the compound of formula IV to a reaction flask. After cooling the temperature to 0 - 5 °C, add 103 g of N-chlorosuccinimide. Stir for 0.5 hour, then add 210 g of 20% aqueous NaOH solution. After addition, continue stirring for 1 hour. After the reaction is completed, concentrate the reaction solution under reduced pressure to remove acetonitrile. Add 500 mL of water and 500 mL of ethyl acetate. Adjust the pH to 3 - 5 with hydrochloric acid, then separate the aqueous phase. The organic phase is extracted once more with 300 mL of dilute hydrochloric acid (pH value 3 - 5), and the aqueous phases are combined. Adjust the pH value of the combined aqueous phase to 9 - 10 with saturated aqueous Na2CO3 solution, extract 2 times with 500 mL of dichloromethane, combine the dichloromethane organic phases, and concentrate under reduced pressure to obtain 179 g of the compound of formula I, yield: 90%. 1 H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 7.47 (s, 1H), 7.36 (d, J = 1.4 Hz, 1H), 2.97 (s, 6H), 2.53 (s, 3H).

[0056] Example 2:

[0057] 1) Synthesis of the compound of formula III:

[0058] Add 1.5 L of dichloromethane, 200 g of the compound of formula II, and 100 g of acetic acid to a reaction flask. Cool the temperature to 0 - 10 °C, and slowly add 195 g of bromine. After addition, heat to 25 °C and react for 6 hours. Quench with aqueous sodium thiosulfate solution, add aqueous sodium carbonate solution dropwise to adjust the pH = 7, stir, separate to obtain the dichloromethane layer, filter through silica gel. After concentrating the filtrate under reduced pressure, add 600 mL of n-heptane for pulping, filter, and dry the filter cake to obtain 269 g of the compound of formula III, yield: 91%.

[0059] 2) Synthesis of the compound of formula IV:

[0060] Add 200 mL of acetonitrile and 200 g of the compound of formula III to a reaction flask. After cooling the temperature to 0 - 5 °C, slowly add 1.0 mol / L dioxane hydrochloride solution (1.8 L). After addition, heat to 70 °C for reaction, and monitor the reaction progress by HPLC. After 5 hours, the reaction is complete. Filter, wash the filter cake with 200 mL of acetonitrile. Dissolve the solid in 1 L of dichloromethane, adjust the pH value to 10 - 11 with 20% aqueous sodium hydroxide solution, stir and then separate the layers. Extract the aqueous phase 2 times with 300 mL of dichloromethane, combine all the dichloromethane organic phases, and concentrate under reduced pressure to obtain 217 g of the compound of formula IV, yield: 93%.

[0061] 3) Synthesis of the compound of formula I:

[0062] Add 1 L of acetonitrile and 200 g of the compound of Formula IV to a reaction flask. After cooling the temperature to 0 - 5 °C, add 192 g of 30% calcium hypochlorite aqueous solution. After stirring for 0.5 hour, add 210 g of 20% NaOH aqueous solution, and continue stirring for 1 hour after addition. After the reaction is completed, concentrate the reaction solution under reduced pressure to remove acetonitrile. Add 500 mL of water and 500 mL of ethyl acetate. Adjust the pH to 3 - 5 with hydrochloric acid, then separate the aqueous phase. The organic phase is extracted once again with 300 mL of dilute hydrochloric acid (pH value is 3 - 5), and the aqueous phases are combined. Adjust the pH value of the combined aqueous phase to 9 - 10 with saturated Na2CO3 aqueous solution, extract twice with 500 mL of dichloromethane, combine the dichloromethane organic phases, and concentrate under reduced pressure to obtain 173 g of the compound of Formula I, with a yield of 87%.

[0063] The above embodiments only represent several implementation manners of the present invention. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the patent of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the appended claims.

Claims

1. A method for synthesizing the intermediate of tigolacine, 7-bromo-N,N,2-trimethylbenzimidazole-5-carboxamide, which is characterized in that, The described method includes: 1) The compound of formula II undergoes a bromination reaction under the catalysis of a brominating reagent to form a compound of formula III; 2) The compound of formula III undergoes an addition reaction with acetonitrile under the catalysis of a catalyst to form a compound of formula IV; 3) The compound of formula IV undergoes a cyclization reaction under the action of a chlorinating reagent and an aqueous alkali solution to form a compound of formula I; 2. The method according to claim 1, wherein In step 1), the bromination reaction is carried out in an organic solvent; the organic solvent is dichloromethane, and / or the concentration of the compound of formula II in the organic solvent is 100 - 160 g / L.

3. The method according to claim 1, characterized in that, In step 1), the brominating reagent is selected from bromine, N-bromosuccinimide, dibromohydantoin, pyridinium tribromide, or any combination of the foregoing; and / or the molar ratio of the compound of formula II to the brominating reagent is 1:0.8 - 1.

7.

4. The method according to any one of claims 1 to 3, characterized in that In step 1), before adding the brominating reagent, the reaction system is cooled to 0 - 10 °C, and after adding the brominating reagent, it is heated to 20 - 30 °C for the bromination reaction; and / or after the reaction is completed, the reaction solution is quenched, layered, the organic layer is filtered through silica gel, the obtained filtrate is concentrated, n-heptane is added for slurrying, filtration, and drying to obtain the compound of formula III.

5. The method according to claim 1, wherein In step 2), the catalyst is selected from HCl gas, an acetonitrile solution of HCl, a dioxane solution of HCl, aluminum trichloride, or any combination of the foregoing; and / or the solvent for the reaction is acetonitrile.

6. The method according to claim 1 or 5, characterized in that In step 2), the mixed solution of the solvent and the compound of formula III is cooled to 0 - 5 °C, and the catalyst is added for the addition reaction; the solvent is acetonitrile; Preferably, the volume-mass ratio of the solvent to the compound of formula III is 0.5 - 2 mL / g; the molar ratio of the compound of formula III to the acid in the catalyst is 1:1.5 - 2.

5.

7. The method according to claim 6, wherein In step 2), the temperature of the reaction is 60 - 80 °C; and / or after the reaction is completed, filtration is carried out, the filter cake is rinsed with acetonitrile, the obtained solid is dissolved in dichloromethane and the pH value is adjusted to 10 - 11, stirred and layered, the aqueous phase is extracted with dichloromethane 1 - 3 times, the organic phases are combined, and concentrated under reduced pressure to obtain the compound of formula IV.

8. The method according to claim 1, wherein In step 3), the mixed solution of acetonitrile and the compound of formula IV is cooled to 0 - 5 °C, the chlorinating reagent is added, stirred, and then the aqueous alkali solution is added for the cyclization reaction.

9. The method according to claim 8, wherein In step 3), in the mixed solution, the mass-volume ratio of the compound of formula IV to acetonitrile is 180 - 220 g / L; the stirring time is 0.4 - 0.6 h.

10. The method according to claim 1 or 8, characterized in that, In step 3), the chlorinating reagent is selected from N-chlorosuccinimide, trichloroisocyanuric acid, calcium hypochlorite, sodium hypochlorite, or any combination of the foregoing; and / or the aqueous alkali solution is an aqueous sodium hydroxide solution; and / or the molar ratio of the compound of formula IV to the chlorinating reagent is 1:0.2 - 2; and / or the mass ratio of the aqueous alkali solution to the compound of formula IV is 0.85 - 1.25:1; and / or after the reaction is completed, it is concentrated under reduced pressure, water and ethyl acetate are added, the pH is adjusted to 3 - 5, and then the aqueous phase is separated; the pH value of the aqueous phase is adjusted to 9 - 10, and it is extracted with dichloromethane 1 - 3 times, the dichloromethane organic phases are combined, and concentrated under reduced pressure to obtain the compound of formula I.

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