CN115594639A - A kind of Tegrazan key intermediate synthetic method - Google Patents

Abstract

A method for synthesizing 4-hydroxy-N, 2-trimethylbenzimidazole-6-formamide, wherein the method comprises the following steps:

the 4-hydroxy-N, N, 2-trimethylbenzimidazole-6-formamide synthesized by the method has the advantages of novel process route, total molar yield of more than 70 percent, short route, high chemical purity of products and easy production.

Description

A kind of Tegrazan key intermediate synthetic method

technical field

The invention relates to the field of organic chemical synthesis, in particular to a method for preparing a key intermediate of tergorazan (4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide).

Background technique

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

Currently, there is mainly one synthetic route for this intermediate. as shown in the route below. This route requires relatively complicated group protection, using 2-amino-3-nitro-5-bromophenol as the starting material, first carrying out O-benzyl protection, and then carrying out acetylation protection on the amino group, in iron powder/acetic acid Reduction of the nitro group under certain conditions and condensation and ring closure to obtain the benzimidazole skeleton; conversion of bromine to cyano group under transition metal catalysis; subsequent hydrolysis of cyano group to obtain carboxylic acid, reaction with dimethylamine through a condensation agent to obtain amide; final palladium catalyzed Hydrogenation deO-benzyl to give 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide.

CN 101341149 A

CN113527272A

In addition to the relatively expensive starting materials, the first two steps of this route need to protect oxygen and nitrogen atoms in turn. The use of iron powder/glacial acetic acid system in the process of reducing nitro groups greatly increases the difficulty of post-treatment; the process of introducing carboxyl groups requires bromine The introduction of cyano groups by generation and metal catalysis increases the risk of reagent handling, and the resulting carboxylic acid intermediates are highly polar and difficult to purify.

In summary, the development of the pharmaceutical industry requires pharmaceutical intermediates such as 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide, but there is still much room for improvement in its current synthesis methods .

Contents of the invention

In order to improve the disadvantages of 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide, such as long synthetic route, no bulk supply of raw materials, and high production cost, the present invention develops a new process route. Concretely comprise following reaction steps:

1) The compound of formula I and dimethylamine undergo acid amine condensation under the action of a condensing agent to generate compound II;

2) The compound of formula II undergoes a dibromination reaction with a brominated reagent such as bromine, NBS or dibromohydantoin under acidic conditions to generate compound III;

3) The form of the compound of formula III and acetamidine or its salt undergoes a ring-closing reaction in a high boiling point solvent under the catalysis of alkali and transition metal to generate compound IV;

4) Nucleophilic substitution between the compound of formula IV and benzyl halide in the presence of a base to generate benzyl-protected compound V;

5) The compound of formula V is coupled with a boroester reagent in the presence of a base to generate compound VI under the condition of transition metal catalysis, or activated with an alkyllithium reagent, and then reacted with a boroesterification reagent to generate compound VI;

6) The compound of formula VI reacts with a peroxidation reagent, such as hydrogen peroxide, m-CPBA, etc., in the presence of water to generate compound VII;

7) The compound of formula VII undergoes a debenzylation reaction under acidic conditions or transition metal-catalyzed hydrogenation conditions to generate compound VIII.

The CAS of the final product, compound VIII, is 2168520-25-8.

Preferred embodiment of the present invention:

The condensation reagent described in step 1) is selected from carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 2-(7-azobenzotriazole At least one of )-N,N,N',N'-tetramethyluronium hexafluorophosphate, preferably carbonyldiimidazole, because of its low cost, the by-product is imidazole, which is environmentally friendly compared to other condensing agents friendly reagents.

Step 2) the acid is selected from at least one of acetic acid and trifluoroacetic acid, and the brominated reagent is selected from bromine, N-bromosuccinimide, dibromohydantoin, and pyridinium tribromide At least one of them; preferably, the acid is acetic acid, and the brominating agent is bromine. Compared with trifluoroacetic acid, acetic acid is low in cost, weak in corrosion, easy to operate, and will not affect the environment. Compared with other brominated reagents, bromine is an upstream reagent in the industrial chain.

Step 3) the alkali is selected from at least one of potassium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, and the transition metal catalyst is selected from at least one of cuprous reagent and palladium catalyst; the high boiling point The solvent is selected from at least one of N-methylpyrrolidone, dimethyl sulfoxide, DMAc, and DMF. Preferably, the base is potassium phosphate, the transition metal catalyst is a cuprous catalyst, and the high boiling point solvent is Dimethyl sulfoxide, choosing these reagents can obtain the beneficial effects of fast reaction speed, high conversion rate and low impurity content;

The benzyl halide described in step 4) is benzyl bromide or benzyl chloride, and the base is selected from sodium hydroxide, potassium hydroxide, calcium hydrogen, sodium hydrogen, lithium bistrimethylsilamide, sodium bistrimethylsilamide and n-butyl At least one of base lithium, preferably the higher reactive benzyl bromide and sodium hydrogen are the reaction conditions;

Step 5) The catalyst is selected from transition metal catalysts such as palladium and copper, and the base is selected from at least one of potassium acetate and sodium acetate. Preferably, the catalyst is tris(dibenzylideneacetone) dipalladium, and the base is Potassium acetate, because the reaction selectivity is better;

Step 6) the oxidation reagent is selected from at least one of aqueous hydrogen peroxide solution and m-chloroperoxybenzoic acid, preferably aqueous hydrogen peroxide solution, because of its lower cost and more environmentally friendly;

Step 7) the transition metal catalyst is selected from at least one of palladium carbon, platinum carbon, Raney nickel, ruthenium, rhodium and iridium, and the acid is selected from hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid and At least one of the trifluoromethanesulfonic acid, preferably, the transition metal catalyst is palladium carbon, and the acid is acetic acid, because selecting these reagents is easy to scale up and operate, and the cost is lower.

According to one embodiment of the present invention, the method for synthesizing 4-hydroxyl-N,N,2-trimethylbenzimidazole-6-carboxamide comprises:

1.1) Add methylene chloride, the compound of formula I, 4-dimethylaminopyridine, dimethylamine hydrochloride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide to the reactor Hydrochloride, stirred and reacted at room temperature, reacted for 4 to 6 hours, then added water, stirred and washed, and separated.

1.2) Separate the dichloromethane layer to obtain the dichloromethane layer, concentrate the dichloromethane layer under reduced pressure, dissolve the residue with ethyl acetate/n-heptane system and filter it through silica gel, add n-heptane to the filtrate after concentrating under reduced pressure to make a slurry, filter, Drying yields the compound of formula II.

2.1) Add glacial acetic acid and the compound of formula II to the reaction kettle, stir, cool down to 0-10°C, add liquid bromine dropwise, and react at room temperature for 12-16 hours after the dropwise addition is completed.

2.2) Add sodium thiosulfate aqueous solution to quench, stir, concentrate under reduced pressure to remove glacial acetic acid, add water and stir for 2-4 hours, filter and dry to obtain the compound of formula III.

3.1) Add dimethyl sulfoxide, compound of formula III, acetamidine hydrochloride, cuprous oxide, 8-quinoline-alcohol, potassium phosphate into the reaction kettle, stir, vacuumize, replace with nitrogen for 3 times, and heat to 120°C React for 4 hours.

3.2) Add water to the reaction kettle and stir, add acetic acid to adjust the pH to 7-8, add dichloromethane for extraction, concentrate the dichloromethane layer, add ethyl acetate for beating, filter and dry to obtain the compound of formula IV.

4.1) Add N-methylpyrrolidone and sodium hydride to the reaction kettle, suspend it under the liquid surface and stir, vacuumize, replace with nitrogen for 3 times, dissolve the compound of formula IV in N-methylpyrrolidone and add dropwise to the reaction kettle , and then drop benzyl bromide into the reactor, and react at 20-30°C for 10 hours after the dropwise addition.

4.2) Slowly drop water into the reaction kettle to quench the reaction, stir, centrifugally filter and dry to obtain the compound of formula V.

5.1) Add toluene, compound of formula V, tris(dibenzylideneacetone)dipalladium, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, diboronic acid frequency The alcohol ester and potassium acetate were evacuated, replaced with nitrogen for 3 times, and the temperature was raised to 100° C. for 12 hours.

5.2) Add water to the reaction kettle and stir, separate the layers, concentrate the toluene layer under reduced pressure, add ethyl acetate/n-heptane to crystallize, filter and dry to obtain the compound of formula VI.

6.1) Add tetrahydrofuran and the compound of formula VI to the reaction kettle, vacuumize, replace with nitrogen for 3 times, cool down to 10°C and stir, add hydrogen peroxide dropwise, and then add aqueous sodium hydroxide solution dropwise, and continue the reaction for 4~ 6 hours.

6.2) Add hydrochloric acid dropwise to the reaction liquid, stir, adjust the pH to 6-7, filter, and dry to obtain the compound of formula VII.

7.1) Add methanol, compound of formula VII, 10% palladium carbon, and trifluoroacetic acid into the reaction kettle, vacuumize, replace with nitrogen for 3 times, then replace with hydrogen for 3 times, pressurize the hydrogen to 0.2MPa, and react for 6 hours.

7.2) Filtration, adding sodium carbonate aqueous solution to the filtrate to adjust the pH to 7, filtering, adding ethyl acetate to the crude filter cake, beating, filtering, and drying to obtain the compound of formula VIII.

The method for synthesizing 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide of the present invention has the advantages of novel process route, cheap and easy-to-obtain raw materials, high chemical purity of the product, easy scale-up production and the like.

Synthesizing 4-hydroxy-N, N, 2-trimethylbenzimidazole-6-carboxamide by adopting the synthesis method of the present invention, the process route is novel, the total molar yield is greater than 70%, and the route is short, the product has high chemical purity, Ease of production features.

Description of drawings

In order to illustrate the technical solutions of the embodiments of the present invention more clearly, the drawings of the embodiments will be briefly introduced below. Apparently, the drawings in the following description only relate to some embodiments of the present invention, rather than limiting the present invention.

Figure 1 is the H NMR spectrum of compound VIII prepared in the examples.

detailed description

In order to make the object, technical solution and advantages of the present invention clearer, the present invention will be described in further detail below in conjunction with specific embodiments and with reference to the accompanying drawings. However, those skilled in the art know that the present invention is not limited to the drawings and the following embodiments.

S1: dehydration condensation

500 mL of dichloromethane, 50 g of p-aminobenzoic acid, 39 g of dimethylamine hydrochloride, 91 g of carbonyldiimidazole, and 94 g of 4-dimethylaminopyridine were added to the reaction flask. Under the protection of nitrogen, keep warm at 25°C and stir the reaction. After the reaction was completed, water was added to stir, and the liquid was separated after standing. The dichloromethane layer was filtered through silica gel, the filtrate was concentrated, and n-heptane was added to make a slurry and dried to obtain 54 g of compound II with a yield of 90%. ¹ H NMR (400MHz, DMSO-d6) δ7.17–7.10(m,1H),6.60–6.48(m,1H),5.47(s,1H),2.94(s,3H).

S2: bromo

Add 50 g of compound II and 150 mL of acetic acid into the reaction flask, cool down to 10°C, add 195 g of bromine dropwise, and heat to 25°C for 6 hours after the dropwise addition. Add sodium thiosulfate aqueous solution and stir to quench, add dropwise sodium carbonate aqueous solution to adjust pH = 7, extract with ethyl acetate, pass through silica gel, and concentrate the filtrate to obtain a crude product, add a small amount of n-heptane for slurry, filter, and dry to obtain 81 g of compound III. up to 82%. ¹ H NMR (400MHz, Chloroform-d) δ7.53(s,1H),4.78(s,1H),3.07(s,4H).

S3: Condensation closed loop

Add 20g of compound III, 100mL of dimethyl sulfoxide, 12g of acetamidine hydrochloride, 0.9g of cuprous oxide, 1.8g of 8-quinoline-alcohol, 71.5g of potassium phosphate into the reaction flask, vacuumize, replace with nitrogen three times, and protect with nitrogen Heated to 120°C for 4 hours. Add acetic acid to adjust the pH to 6-7, extract with dichloromethane, and concentrate the dichloromethane layer to obtain a crude product. Slurry with a small amount of ethyl acetate, filter and dry to obtain 15.8 g of compound IV with a yield of 90%. ¹ H NMR (400MHz, DMSO-d6) δ12.72(s, 0H), 7.47(s, 0H), 7.36(d, J=1.4Hz, 0H), 2.97(s, 2H), 2.53(s, 1H ).

S4: N-benzyl protection

Add 130mL of N-methylpyrrolidone and 13g of sodium hydride to the reaction bottle 1, suspend and stir, vacuumize, replace with nitrogen for 3 times, cool down to 0°C, and dissolve 100g of compound IV in 500mL of N-methylpyrrolidone in the reaction bottle 2 , the resulting solution was added dropwise to reaction flask 1, and then 36.4 g of benzyl bromide was added dropwise to reaction flask 1, and after the addition was completed, it was heated to 25° C. for 10 hours of reaction. Water was added dropwise into the reactor to quench, filtered, and the filter cake was washed with water and dried to obtain 48 g of Compound V with a yield of 92%. ¹ H NMR (400MHz, DMSO-d6) δ7.63(d, J=1.3Hz, 1H), 7.42(d, J=1.3Hz, 1H), 7.37–7.31(m, 2H), 7.31–7.25(m ,1H),7.19–7.09(m,2H),5.54(s,2H),2.93(d,J＝26.4Hz,6H),2.57(s,3H).

S5: boroesterification reaction

Add 30g of compound V, 52g of pinacol diboronate, 150mL of toluene, 0.74g of tris(dibenzylideneacetone)dipalladium, 2-dicyclohexylphosphine-2',4',6'-triisopropyl Base biphenyl 0.77g, potassium acetate 12g, vacuumize, replace with nitrogen 3 times, heat to 100 ℃ and react for 12 hours. Add water to the reaction kettle and stir, let stand to separate the liquid, and concentrate the toluene layer to obtain the crude product. The crude product was crystallized from ethyl acetate/n-heptane, filtered, and dried to obtain 28.9 g of the compound of formula VI, with a yield of 85%.

S6: oxidation reaction

Add 0.2g of compound VI and 20mL of tetrahydrofuran to the reaction flask, vacuumize, replace with nitrogen three times, cool to 10°C and stir, add 0.2g of 30% hydrogen peroxide dropwise, and then add 0.08mL of 1M aqueous sodium hydroxide solution dropwise, After the addition was complete, the reaction was continued for 6 hours. Dilute hydrochloric acid was added dropwise into the reaction kettle to quench, adjust the pH to 6-7, filter, wash with water, and dry to obtain 0.15 g of the compound of formula VII with a yield of 82%. ¹ H NMR (400MHz, Methanol-d4) δ7.38–7.25(m,1H),7.17–7.11(m,1H),6.96–6.93(m,0H),6.68(d,J=1.3Hz,0H) ,5.46(s,1H),3.08(s,1H),2.97(s,1H),2.58(s,1H).

S7: Hydrodebenzylation

Add 50 g of compound VII, 500 mL of methanol, 5 g of trifluoroacetic acid, and 2.5 g of 10% palladium on carbon into the reaction flask, vacuumize, replace with nitrogen for 3 times, and then replace with hydrogen for 3 times. The hydrogen gas was pressurized to 0.2MPa, and the reaction was carried out for 6 hours. After filtration, aqueous sodium carbonate solution was added dropwise to the filtrate to adjust the pH to 7, and the crude product was obtained by filtration. A small amount of ethyl acetate was added to make a slurry, filtered and dried to obtain 29.5 g of compound VIII with a yield of 85%. Please refer to accompanying drawing 1 for the H NMR spectrum of compound VIII. ¹ H NMR (400MHz,Methanol-d4)δ7.23(s,1H),6.93(s,1H),3.14(s,3H),3.03(s,3H),2.86(s,3H).)

In summary, this route uses the cheap and easy-to-obtain bulk chemical 4-aminobenzoic acid as the starting material, uses the cheap and easy-to-obtain basic material bromine for double bromination, and then uses the lower-cost cuprous catalyst for close ring, and then build a hydroxyl group on the basis of another bromine site. Compared with the original route, the material cost of this route is lower, the steps are simple, and the process does not involve special reactions that affect industrial production.

Claims (10)

1. A method for synthesizing 4-hydroxy-N, 2-trimethylbenzimidazole-6-formamide, which is characterized in that the route of the method is as follows:

2. method according to claim 1, characterized in that it comprises the following steps:

1) Carrying out acid-amine condensation on the compound shown in the formula I and dimethylamine under the action of a condensing agent to generate a compound shown in a formula II;

2) Carrying out dibromo reaction on the compound of the formula II and a brominating agent in the presence of acid to generate a compound of a formula III;

3) Carrying out a ring closure reaction on a compound shown in a formula III and acetamidine or salt thereof in a high-boiling-point solvent under the catalysis of alkali and a transition metal catalyst to generate a compound shown in a formula IV;

4) Nucleophilic substitution of the compound of formula IV with benzyl halide in the presence of a base to produce a benzyl-protected compound of formula V;

5) Under the condition of catalyst catalysis, the compound of the formula V is coupled with a boron ester reagent in the presence of alkali to generate a compound of a formula VI, or is activated with an alkyl lithium reagent and then reacts with a boron esterification reagent to generate a compound of the formula VI;

6) Carrying out boron-removing oxidation reaction on the compound of the formula VI and a peroxidation reagent in the presence of water to generate a compound of a formula VII;

7) The compound of the formula VII is subjected to debenzylation reaction under acidic condition or hydrogenation condition in the presence of transition metal catalyst to generate the compound of the formula VIII.

3. The method according to claim 2, wherein the condensing agent of step 1) is at least one selected from the group consisting of carbonyldiimidazole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, preferably carbonyldiimidazole.

4. The method according to claim 2, wherein the acid in step 2) is selected from at least one of acetic acid and trifluoroacetic acid, and the brominating agent is selected from at least one of bromine, N-bromosuccinimide, dibromohydantoin and pyridinium tribromide;

preferably, the acid is acetic acid and the brominating agent is bromine.

5. The method of claim 2, wherein the base of step 3) is selected from at least one of potassium carbonate, cesium carbonate, potassium phosphate, and potassium hydroxide, and the transition metal catalyst is selected from at least one of cuprous reagent and palladium catalyst; the high boiling point solvent is at least one selected from N-methyl pyrrolidone, dimethyl sulfoxide, DMAc and DMF;

preferably, the alkali is potassium phosphate, the transition metal catalyst is a cuprous catalyst, and the high-boiling point solvent is dimethyl sulfoxide.

6. The method according to claim 2, wherein the benzyl halide in the step 4) is benzyl bromide or benzyl chloride, and the base is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydrogen, sodium hydrogen, lithium bis-trisilyl amide, sodium bis-trisilyl amide and n-butyl lithium;

preferably, the benzyl halide is benzyl bromide, and the base is sodium hydrogen.

7. The method according to claim 2, wherein the catalyst of step 5) is a transition metal catalyst, preferably, the transition metal catalyst is at least one selected from palladium compounds and copper compounds; the alkali is at least one selected from potassium acetate and sodium acetate, preferably, the catalyst is tris (dibenzylideneacetone) dipalladium, and the alkali is potassium acetate.

8. The process according to claim 2, wherein the oxidizing agent of step 6) is selected from at least one of aqueous hydrogen peroxide and m-chloroperoxybenzoic acid, preferably aqueous hydrogen peroxide.

9. The method according to claim 2, wherein the transition metal catalyst of step 7) is at least one selected from palladium on carbon, platinum on carbon, raney nickel, ruthenium, rhodium and iridium, and the acid is at least one selected from hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid and trifluoromethanesulfonic acid; preferably, the transition metal catalyst is palladium on carbon and the acid is acetic acid.

10. The method according to any one of claims 1-9, characterized in that the method comprises:

1.1 Adding dichloromethane, the compound of the formula I, 4-dimethylaminopyridine, dimethylamine hydrochloride and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride into a reaction kettle, stirring at room temperature for reaction, reacting for 4-6 h, adding water, stirring, washing and separating;

1.2 Separating to obtain a dichloromethane layer, concentrating the dichloromethane layer under reduced pressure, dissolving the residue with ethyl acetate/n-heptane system, filtering with silica gel, concentrating the filtrate under reduced pressure, adding n-heptane, pulping, filtering, and drying to obtain compound of formula II;

2.1 Adding glacial acetic acid and the compound of the formula II into a reaction kettle, stirring, cooling to 0-10 ℃, dropwise adding liquid bromine, and reacting at room temperature for 12-16 hours after dropwise adding;

2.2 Adding sodium thiosulfate aqueous solution for quenching, stirring, decompressing and concentrating to remove glacial acetic acid, adding water for stirring for 2-4 h, filtering and drying to obtain a compound shown in a formula III;

3.1 Adding dimethyl sulfoxide, a compound of a formula III, acetamidine hydrochloride, cuprous oxide, 8-quinol-ol and potassium phosphate into a reaction kettle, stirring, vacuumizing, replacing for 3 times with nitrogen, and heating to 120 ℃ for reaction for 4 hours;

3.2 Adding water into a reaction kettle, stirring, adding acetic acid to adjust the pH value to 7-8, adding dichloromethane for extraction, concentrating a dichloromethane layer, adding ethyl acetate for pulping, filtering and drying to obtain a compound shown in the formula IV;

4.1 Adding N-methyl pyrrolidone and sodium hydride suspended below the liquid level into a reaction kettle, stirring, vacuumizing, replacing with nitrogen for 3 times, dissolving the compound shown in the formula IV into the N-methyl pyrrolidone, dropwise adding benzyl bromide into the reaction kettle, and reacting at 20-30 ℃ for 10 hours after dropwise adding;

4.2 Slowly dropwise adding water into the reaction kettle to quench and react, stirring, centrifugally filtering and drying to obtain a compound shown in the formula V;

5.1 Adding toluene, the compound of formula V, tris (dibenzylideneacetone) dipalladium, 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl, pinacol diboron diboride and potassium acetate into a reaction kettle, vacuumizing, replacing 3 times with nitrogen, and heating to 100 ℃ for reaction for 12 hours;

5.2 Adding water into a reaction kettle, stirring, separating, concentrating a toluene layer under reduced pressure, adding ethyl acetate/n-heptane for crystallization, filtering and drying to obtain a compound shown in a formula VI;

6.1 Adding tetrahydrofuran and a compound shown in a formula VI into a reaction kettle, vacuumizing, replacing for 3 times by nitrogen, cooling to 10 ℃, stirring, dropwise adding hydrogen peroxide, dropwise adding a sodium hydroxide aqueous solution, and continuously reacting for 4-6 hours after dropwise adding;

6.2 Dropwise adding hydrochloric acid into the reaction solution, stirring, adjusting the pH value to 6-7, filtering, and drying to obtain a compound shown in the formula VII;

7.1 Adding methanol, the compound of the formula VII, 10% palladium carbon and trifluoroacetic acid into a reaction kettle, vacuumizing, replacing for 3 times with nitrogen, then replacing for 3 times with hydrogen, pressurizing to 0.2MPa with hydrogen, and reacting for 6 hours;

7.2 Filtering, adding sodium carbonate aqueous solution into the filtrate to adjust the pH value to 7, filtering, adding ethyl acetate into the crude filter cake, pulping, filtering and drying to obtain the compound shown in the formula VIII.

Images