Preparation method of key intermediate of tigorazan

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a key intermediate for synthesizing tigorasen, which comprises the following steps: # imgabs0, in which R is independently selected from C1-C5 straight-chain alkyl or branched-chain alkyl, phenyl and substituted phenyl; comprising the following steps: (1) carrying out esterification reaction on a compound of formula I to obtain an anhydride intermediate; (2) carrying out amidation reaction on the anhydride intermediate and dimethylamine to obtain a compound shown in a formula II; (3) carrying out hydrogenation reaction on the compound shown in the formula II to prepare a compound shown in a formula III; (4) reacting the compound shown in the formula III with paratoluensulfonyl chloride to obtain a compound shown in a formula IV; and (5) carrying out hydrolysis reaction on the compound as shown in the formula IV under the action of alkali to obtain a compound as shown in a formula Vb. According to the method, phenolic hydroxyl group protection is realized through a one-pot method, an anhydride intermediate is formed at the same time, then dimethylamine is used for amidation reaction, the reaction operation is simple and convenient, three wastes are reduced, the production cost is reduced, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to a preparation method of 4-hydroxy-N,N,2-trimethyl-1-toluenesulfonyl-1H-benzo[D]imidazole-6-carboxamide, belonging to the technical field of medicine and chemistry. Background Art

[0002] Tigorazan is a drug used to treat gastroesophageal reflux disease and erosive esophagitis. On April 8, 2022, Tigorazan tablets were approved for marketing by the China National Medical Products Administration (NMPA) for the treatment of reflux esophagitis (RE). More indications of Tigorazan and bismuth quadruple therapy for the eradication of Helicobacter pylori and duodenal ulcers are under development. As China's first self-developed potassium ion competitive acid blocker (P-CAB), Tigorazan tablets have the characteristics of rapid onset of action in 30 minutes, strong and long-lasting acid suppression, and easy to take. It is not affected by food intake and genotype; it effectively controls nocturnal rupture and other characteristics, bringing a new medication option for the treatment of reflux esophagitis and improving patients' quality of life.

[0003] 4-Hydroxy-N,N,2-trimethyl-1-toluenesulfonyl-1H-benzo[D]imidazole-6-carboxamide is a key intermediate in the synthesis of TEGOPRAZAN. Its chemical structure is shown below:

[0004]

[0005] WO2008114123 reports that 2-(benzyloxy)-4-bromo-6-nitroaniline is used as the starting material and expensive tetrakis(triphenylphosphine palladium) catalyst is used, which faces the problems of complex post-processing, dangerous operation, and low carbonylation reaction yield of only 42%. The reaction route is as follows:

[0006]

[0007] CN101341149B reported that 2-(benzyloxy)-4-bromo-6-nitroaniline was used as the starting material, and expensive metal reagents such as tetrakis(triphenylphosphine palladium) were also used, and microwave reaction and column chromatography purification were included, wherein the hydrogenation yield was only 36%, which was very low, the production cost was high, and it was not suitable for scale-up. The reaction route is as follows:

[0008]

[0009] CN114249694A reports the following reaction route:

[0010]

[0011] This route uses 3-hydroxy-4-nitrobenzoic acid as the starting material, and requires seven steps of reaction to prepare the intermediate of tigolasan, including amidation, phenolic hydroxyl protection, nitro reduction, acetonitrile aminolysis, cyclization, Ts addition, and deprotection. It has problems such as long reaction route and complicated post-processing. In addition, the cyclization step in this route uses chlorosuccinimide, which has many side reactions, resulting in a low yield of the target product.

[0012] Therefore, it is currently necessary to develop a new method for preparing 4-hydroxy-N,N,2-trimethyl-1-tosyl-1H-benzo[D]imidazole-6-carboxamide. Summary of the invention

[0013] In order to solve the technical problems in the above reports, the present invention provides a novel method for synthesizing 4-hydroxy-N, N, 2-trimethyl-1-toluenesulfonyl-1H-benzo [D] imidazole-6-carboxamide, a key intermediate of tigolasen. The method uses 1-benzyl-4-hydroxy-2-methyl-1H-benzo [d] imidazole-6-carboxamide as a starting material, and undergoes esterification, amidation, hydrogenation, Ts protection, and hydrolysis to prepare 4-hydroxy-N, N, 2-trimethyl-1-toluenesulfonyl-1H-benzo [D] imidazole-6-carboxamide. The method realizes hydroxyl protection and amidation by a one-step method, and at the same time, the stability of the post-treatment process is increased by adding HOAc in the post-treatment process, and the de-pivaloyl impurity is avoided. The reaction steps of the method of the present invention are short and the reaction selectivity is high. The preparation process is simple, the "three wastes" are reduced, the production cost is reduced, and it is suitable for industrial production.

[0014] In order to achieve the above technical objectives, the present invention adopts the following preferred technical solutions:

[0015] The first aspect of the present invention provides a method for preparing a compound of formula II, and the reaction formula is as follows:

[0016]

[0017] The steps include:

[0018] (1) subjecting the compound of formula (I) to an esterification reaction to obtain an anhydride intermediate;

[0019] (2) subjecting the acid anhydride intermediate to an amidation reaction with dimethylamine to obtain a compound of formula II;

[0020] wherein R is independently selected from C 1 -C 5 Straight-chain alkyl or branched-chain alkyl, phenyl and substituted phenyl; C 1 -C 5The straight-chain alkyl or branched alkyl is preferably methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or tert-pentyl; the substituted phenyl is selected from methoxy, cyano, nitro, F, Cl, Br or I substituted phenyl.

[0021] As a further improvement of the present invention, the esterification reaction in step (1) is a reaction of the compound of formula I with an acyl chloride or an acid anhydride in an organic solvent in the presence of a base, wherein the acyl chloride is, for example, acetyl chloride, propionyl chloride, isopropionyl chloride, butyryl chloride, sec-butyryl chloride, valeryl chloride, pivaloyl chloride or benzoyl chloride; and the acid anhydride is, for example, acetic anhydride or propionic anhydride;

[0022] As a further improvement of the present invention, in step (1), the molar ratio of the compound of formula I to the acid chloride or acid anhydride is 1:(1.2-8), preferably 1:(2-4);

[0023] As a further improvement of the present invention, the molar ratio of the base to the compound of formula I in step (1) is (2-5):1, preferably (2.5-3.5):1;

[0024] As a further improvement of the present invention, in step (1), the base is selected from an organic base or an inorganic base, the organic base is selected from triethylamine, N,N-diisopropylethylamine, triisopropylamine, etc., preferably triethylamine, N,N-diisopropylethylamine; the inorganic base is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, preferably sodium carbonate;

[0025] As a further improvement of the present invention, the base in step (1) is preferably one of triethylamine, N,N-diisopropylethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and cesium carbonate; more preferably triethylamine or N,N-diisopropylethylamine.

[0026] As a further improvement of the present invention, the organic solvent in step (1) is selected from ethyl acetate, isopropyl acetate, dichloromethane, methyl tert-butyl ether, tetrahydrofuran, dioxane, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone, preferably dichloromethane;

[0027] As a further improvement of the present invention, the temperature of the esterification reaction in step (1) is -40 to 50°C, preferably -20 to 40°C, and more preferably -10 to 40°C.

[0028] As a further improvement of the present invention, the mass amount (g) of the organic solvent in step (1) is 5 to 15 times the mass amount (g) of the compound of formula I, preferably 6 to 8 times.

[0029] As a further improvement of the present invention, in the amidation reaction of step (2), the molar ratio of dimethylamine to the compound of formula 1 is (2-6):1, preferably 2-4.

[0030] As a further improvement of the present invention, the reaction time of the amidation reaction in step (2) is 0.5 to 20 hours, preferably 5 to 6 hours.

[0031] As a further improvement of the present invention, after the amidation reaction in step (2) is completed, an acetic acid stabilizer is added to avoid the production of depivaloyl impurities.

[0032] As a further improvement of the present invention, after the amidation reaction in step (2) is completed, acetic acid stabilizer is added; the molar ratio of acetic acid to the compound of formula I is (1-5):1.

[0033] As a further improvement of the present invention, after the amidation reaction in step (2) is completed, acetic acid stabilizer is added, water is added, the liquids are separated, the organic phases are combined, concentrated, the solid is precipitated, filtered, and dried to obtain a high-purity compound of formula II.

[0034] As a further improvement of the present invention, the present invention has the advantage of providing a high-purity new compound of formula II, which provides quality assurance for further preparation of high-purity products; the structure of the new compound of formula II is as follows:

[0035]

[0036] wherein R is independently selected from C 1 -C 5 Straight-chain alkyl or branched-chain alkyl, phenyl and substituted phenyl; C 1 -C 5 The straight chain alkyl or branched chain alkyl is preferably methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or tert-pentyl; the substituted phenyl is selected from methoxy, cyano, nitro, F, Cl, Br or I substituted phenyl; the following intermediates are preferred:

[0037]

[0038] As a further improvement of the present invention, obtaining the intermediate compound II with high purity is crucial for the quality control of the subsequent pharmaceutical process.

[0039] The second aspect of the present invention provides a method for preparing a compound of formula V, and the reaction formula is as follows:

[0040]

[0041] R 2 Selected from Bn (benzyl) or Ts (toluenesulfonyl)

[0042] The following methods are included:

[0043] Method 1:

[0044] When R 2 When selected from benzyl, the reaction formula is as follows:

[0045]

[0046] The steps include:

[0047] (1) subjecting the compound of formula (I) to an esterification reaction to obtain an anhydride intermediate;

[0048] (2) subjecting the acid anhydride intermediate to an amidation reaction with dimethylamine to obtain a compound of formula II;

[0049] (3) Hydrolyzing the compound of formula II under the action of a base to obtain the compound of formula Va.

[0050] Method 2:

[0051] When R 2 When selected from Ts, the reaction formula is as follows:

[0052]

[0053] wherein R is independently selected from C 1 -C 5 Straight-chain alkyl or branched-chain alkyl, phenyl and substituted phenyl; C 1 -C 5 The straight-chain alkyl or branched alkyl is preferably methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or tert-pentyl; the substituted phenyl is selected from methoxy, cyano, nitro, F, Cl, Br or I substituted phenyl;

[0054] The steps include:

[0055] (1) subjecting the compound of formula (I) to an esterification reaction to obtain an anhydride intermediate;

[0056] (2) subjecting the acid anhydride intermediate to an amidation reaction with dimethylamine to obtain a compound of formula II;

[0057] (3) subjecting the compound of formula II to a hydrogenation reaction to obtain a compound of formula III;

[0058] (4) reacting the compound of formula III with p-toluenesulfonyl chloride to obtain the compound of formula IV;

[0059] (5) The compound of formula IV is hydrolyzed in the presence of a base to obtain the compound of formula Vb.

[0060] The preparation method of steps (1) and (2) of method 1 or method 2 refers to all the technical solutions of the first aspect mentioned above.

[0061] As a further improvement of the present invention, in the hydrolysis reaction in step (3) of the method 1, the compound of formula II is reacted in water or an organic solvent or a mixed solvent of water and an organic solvent; the base is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and ammonia water; and the organic solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and 1,4-dioxane.

[0062] As a further improvement of the present invention, in the hydrolysis reaction in step (3) of the method one, the molar ratio of the compound of formula II to the base is 1:(1-6), preferably 1:(2-4).

[0063] As a further improvement of the present invention, after the hydrolysis reaction in step (3) of the method 1 is completed, crystallization purification can be selectively included, for example, separation, extraction, washing, drying, concentration, and crystallization to obtain a solid compound of formula Va. The solvent used in the step is a conventional reagent, and the product can be separated and purified.

[0064] As a further improvement of the present invention, the hydrogenation reaction in step (3) of the second method is a hydrogenation debenzylation reaction of the compound of formula II in an organic solvent in the presence of a metal catalyst and a hydrogen source; the metal catalyst is selected from palladium carbon, palladium hydroxide, platinum carbon, etc., preferably palladium carbon; the hydrogen source is selected from hydrogen, formic acid, ammonium formate;

[0065] As a further improvement of the present invention, the mass ratio of the metal catalyst to the compound of formula 2 in step (3) of the second method is 1: (5-50), preferably 1: (10-30);

[0066] As a further improvement of the present invention, the organic solvent in step (3) of the second method is selected from ethyl acetate, isopropyl acetate, dichloromethane, methyl tert-butyl ether, tetrahydrofuran, methanol, dioxane, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, preferably tetrahydrofuran, and the mass amount (g) of the organic solvent is 1 to 10 times the mass amount (g) of the compound of formula II, preferably 3 to 6 times;

[0067] As a further improvement of the present invention, the reaction time of step (3) of the second method is 1 to 24 hours, preferably 10 to 18 hours.

[0068] As a further improvement of the present invention, in step (4) of the second method, a compound selected from formula III is reacted with p-toluenesulfonyl chloride in an organic solvent in the presence of a base; the molar ratio of the compound of formula III to p-toluenesulfonyl chloride is 1:(1-3), preferably 1:(1-2);

[0069] As a further improvement of the present invention, the base in step (4) of the second method can be a tertiary amine such as triethylamine, N,N-diisopropylethylamine, triisopropylamine, or an inorganic base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc., preferably triethylamine or N,N-diisopropylethylamine;

[0070] As a further improvement of the present invention, the molar ratio of the base in step (4) of the second method to the compound of formula III is (1-5):1, preferably (1.5-3):1;

[0071] As a further improvement of the present invention, the organic solvent in step (4) of the second method is selected from ethyl acetate, isopropyl acetate, dichloromethane, methyl tert-butyl ether, tetrahydrofuran, methanol, dioxane, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, preferably dichloromethane, and the mass amount (g) of the organic solvent is 1 to 10 times the mass amount (g) of the compound of formula II, preferably 5 to 8 times;

[0072] As a further improvement of the present invention, the reaction temperature of step (4) of the second method is 15 to 45° C.; the reaction time is 1 to 10 h, preferably 2 to 5 h;

[0073] As a further improvement of the present invention, step (4) of the second method includes pulping and purification, for example: liquid separation, extraction, washing, drying, concentration, pulping, and obtaining an off-white solid compound of formula IV. The solvent used in the step is a conventional reagent, which can achieve product separation and purification.

[0074] As a further improvement of the present invention, the hydrolysis reaction in step (5) of the second method is a compound of formula IV, and the reaction is carried out in the presence of a base in an organic solvent; the base can be an organic base such as methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, diisopropylethylamine, triisopropylamine, or an inorganic base such as ammonia water, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.;

[0075] As a further improvement of the present invention, the molar ratio of the compound of formula IV to the base in step (5) of the second method is 1:(1-10), preferably 1:(1-5);

[0076] As a further improvement of the present invention, the organic solvent in step (5) of the second method is selected from ethyl acetate, isopropyl acetate, dichloromethane, methyl tert-butyl ether, tetrahydrofuran, methanol, dioxane, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, preferably tetrahydrofuran, and the mass amount (g) of the organic solvent is 0.5 to 3 times the mass amount (g) of the compound of formula II, preferably 0.5 to 1.5 times;

[0077] As a further improvement of the present invention, the reaction temperature of step (5) of the second method is 10 to 30° C.; the reaction time is 1 to 6 hours, preferably 1 to 3 hours.

[0078] The present invention also provides a compound of formula IIIa, the structure of which is as follows:

[0079]

[0080] The third aspect of the present invention provides a new key intermediate compound of formula IV, the structure of which is shown below:

[0081]

[0082] wherein R is independently selected from C 1 -C 5 Straight-chain alkyl or branched-chain alkyl, phenyl and substituted phenyl; C 1 -C 5 The straight-chain alkyl or branched alkyl is preferably methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or tert-pentyl; the substituted phenyl is selected from methoxy, cyano, nitro, F, Cl, Br or I substituted phenyl.

[0083] As a further improvement of the present invention, preferably the compound

[0084]

[0085] The fourth aspect of the present invention provides the use of the compound of formula II, formula IIIa, or formula IV in the preparation of tegrassen or its intermediates.

[0086] The fifth aspect of the present invention provides a method for preparing tegrassen or an intermediate thereof, including the method for preparing the compound of formula II according to the first aspect of the present invention or the method for preparing the compound of formula I according to the second aspect of the present invention.

[0087] Compared with the prior art, the present invention has the following beneficial effects:

[0088] The present invention provides a new synthesis route of a compound of formula V, which realizes the protection of phenolic hydroxyl groups by a cleverly designed one-pot method while forming an anhydride intermediate, and then performs an amidation reaction with dimethylamine to obtain a compound of formula II very conveniently, and avoids the use of conventional condensing agents such as DCC, EDC, HATU, etc., avoids the generation of condensing agent byproducts in the reaction, shortens the generation cycle, improves production efficiency, reduces "three wastes", reduces production costs, and is suitable for large-scale industrial production. The present invention also unexpectedly increases the stability of the post-treatment process by adding acetic acid, avoids the generation of depivaloyl impurities, and obtains an intermediate II with higher quality and more stability. The method is simple to operate, has good operability, and good reproducibility. The compound of formula II can be obtained in a solid form with high purity, which provides quality assurance for subsequent products. BRIEF DESCRIPTION OF THE DRAWINGS

[0089] Figure 1 HPLC purity spectrum of the product obtained in Example 1 of the present invention DETAILED DESCRIPTION

[0090] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0091] Example 1

[0092] Synthesis of 1-benzyl-N,N,2-trimethyl-4-pivaloyloxy-1H-benzo[d]imidazole-6-carboxamide:

[0093]

[0094] At room temperature, (133g, 0.471mol) 1-benzyl-4-hydroxy-2-methyl-1H-benzo[d]imidazole-6-carboxylic acid and 884g dichloromethane were added to a reaction flask, and (365g, 2.832mol) N,N-diisopropylethylamine and (171g, 1.413mol) pivaloyl chloride were added. After addition, the reaction was continued at room temperature for 6h until the reaction was completed. (785mL, 2mol / L, 1.57mol) dimethylamine tetrahydrofuran solution was added to the reaction flask, and the reaction was continued for 6h after addition. (133g, 2.217mol) acetic acid was added, and 665g water was added. The liquid was separated, and the aqueous phase was extracted once with dichloromethane. The organic phases were combined, concentrated, the precipitated solid was filtered, and dried to obtain 163g of light yellow solid, with a yield of 88%. The HPLC purity spectrum is attached. Figure 1 .

[0095] 1 H NMR (CD 3OD,400MHz)δ:7.41-7.41(d,1H),7.36-7.29(m,3H),7.16-7.14(d,2H),7.01-7.01(d,1 H),5.52(s,2H),3.08(s,3H),2.96(s,3H),2.61(s,3H),1.45(s,9H).MS:[M+1]=394.2.

[0096] Example 2

[0097] Synthesis of 1-benzyl-N,N,2-trimethyl-4-acetoxy-1H-benzo[d]imidazole-6-carboxamide:

[0098]

[0099] At room temperature, (133g, 0.471mol) 1-benzyl-4-hydroxy-2-methyl-1H-benzo[d]imidazole-6-carboxylic acid and 884g dichloromethane were added to a reaction flask, and (286g, 2.832mol) triethylamine and (144g, 1.413mol) acetic anhydride were added. After addition, the reaction was continued at 30-40°C for 6h until the reaction was completed. (785mL, 2mol / L, 1.57mol) dimethylamine tetrahydrofuran solution was added to the reaction flask, and the reaction was continued for 6h after addition. (133g, 2.217mol) acetic acid was added, and 665g water was added. The liquids were separated, and the aqueous phase was extracted once with dichloromethane. The organic phases were combined, concentrated, and the precipitated solid was filtered and dried to obtain 152g of light yellow solid with a yield of 92%.

[0100] 1 H NMR (CD 3 OD,400MHz)δ:7.43-7.43(d,1H),7.37-7.30(m,3H),7.17-7.16(d,2H),7.10-7.10(d,1 H),5.52(s,2H),3.10(s,3H),2.97(s,3H),2.62(s,3H),2.43(s,3H).MS:[M+1]=352.2.

[0101] Example 3

[0102] Synthesis of 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzo[D]imidazole-6-carboxamide:

[0103]

[0104] Add 600g tetrahydrofuran, 300g water, (300g, 0.854mol) N,N,2-trimethyl-4-acetoxy-1H-benzo[d]imidazole-6-carboxamide to the reaction bottle. Add (68.3g, 1.708mol) sodium hydroxide, keep warm at 15-25℃ for 2h until the control is qualified. Add 1500g water, slowly add 1750g 1mol / L hydrochloric acid solution, stir at 10-20℃ for 2h, filter and dry to obtain 250g white solid, with a yield of 95%.

[0105] 1 H NMR (CDCl 3 ,400MHz)δ:7.31-7.26(m,3H),7.08-7.06(dd,2H),6.91-6.91(d,1H),6.87-6.8 7(d,1H),5.29(s,2H),3.08(s,3H),2.97(s,3H),2.62(s,3H),MS:[M+1]=309.2.

[0106] Example 4

[0107] Synthesis of 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzo[D]imidazole-6-carboxamide:

[0108]

[0109] Add 600g 1,4-dioxane, 300g water, (336g, 0.854mol) N,N,2-trimethyl-4-pivaloyloxy-1H-benzo[d]imidazole-6-carboxamide to the reaction bottle. Add (240g, 1.714mol) 25% ammonia water, keep at 15-25℃ for 2h until the control is qualified. Add 1500g water, slowly add 1700g 1mol / L hydrochloric acid solution, stir at 10-20℃ for 2h, filter and dry to obtain 250g white solid, with a yield of 95%.

[0110] 1 H NMR (CDCl 3 ,400MHz)δ:7.31-7.26(m,3H),7.08-7.06(dd,2H),6.91-6.91(d,1H),6.87-6.8 7(d,1H),5.29(s,2H),3.08(s,3H),2.97(s,3H),2.62(s,3H),MS:[M+1]=309.2.

[0111] Example 5

[0112] Synthesis of N,N,2-trimethyl-4-acetoxy-1H-benzo[d]imidazole-6-carboxamide:

[0113]

[0114] Add (100g, 0.285mol) N,N,2-trimethyl-4-acetoxy-1H-benzo[d]imidazole-6-carboxamide and 400g tetrahydrofuran to a reaction bottle, replace with nitrogen three times, add 5g 10% wet palladium carbon, replace with hydrogen three times, and react at room temperature for 16h until the reaction is completed. Replace with nitrogen three times, filter to remove palladium carbon, rinse the filter cake with methanol, concentrate the combined filtrate to a volume of 300-400mL, add 100g water, cool to -10-10℃, stir for 1h, filter, and dry to obtain 64g off-white solid with a yield of 85%.

[0115] 1 H NMR (CD 3 OD,400MHz)δ:7.37-7.36(d,1H),6.95-6.94(d,1H),3.00(s,3H),2.95(s,3H),2.49(s,3H),2.30(s,3H).MS:[M+1]=262.2.

[0116] Example 6

[0117] Synthesis of N,N,2-trimethyl-4-pivaloyloxy-1H-benzo[d]imidazole-6-carboxamide:

[0118]

[0119] Add (100g, 0.254mol) N,N,2-trimethyl-4-pivaloyloxy-1H-benzo[d]imidazole-6-carboxamide and 400g ethanol to a reaction bottle, replace with nitrogen three times, add 5g 10% wet palladium carbon, replace with hydrogen three times, and react at room temperature for 16h until the reaction is completed. Replace with nitrogen three times, filter to remove palladium carbon, rinse the filter cake with ethanol, concentrate the combined filtrate to a volume of 300-400mL, add 100g water, cool to -10-10℃, stir for 1h, filter, and dry to obtain 68g off-white solid with a yield of 88%.

[0120] 1 H NMR (CD 3 OD,400MHz)δ:7.46(s,1H),6.99(s,1H),3.11(s,3H),3.06(s,3H),2.60(s,3H),1.44(s,9H).MS:[M+1]=304.2.

[0121] Example 7

[0122] Synthesis of 1-(4-methylbenzenesulfonyl)-N,N,2-trimethyl-4-acetoxy-1H-benzo[d]imidazole-6-carboxamide:

[0123]

[0124] Add (180g, 0.689mol) N,N,2-trimethyl-4-acetoxy-1H-benzo[d]imidazole-6-carboxamide and 1200g dichloromethane to the reaction bottle, stir for 15 minutes, slowly add (139g, 1.378mol) triethylamine to the reaction bottle, dropwise add (197g, 1.033mol) 4-methylbenzenesulfonyl chloride 480g dichloromethane solution at room temperature, heat to reflux reaction for 3h until the reaction is complete. Cool the reaction solution to room temperature, slowly add 540g water, stir and separate, extract the aqueous phase once with dichloromethane, combine the organic phases, steam twice with n-heptane, cool to 5-15°C, stir for 2-3h, filter, and dry to obtain 258g off-white solid, with a yield of 90%.

[0125] 1 H NMR (CDCl 3 ,400MHz)δ:8.01-8.01(d,1H),7.83-7.80(d,2H),7.33-7.31(d,2H),7.20-7.19(d,2H ),3.14(s,3H),3.04(s,3H),2.80(s,3H),2.41(s,3H),2.40(s,3H).MS:[M+1]=416.2.

[0126] Example 8

[0127] Synthesis of 1-(4-methylbenzenesulfonyl)-N,N,2-trimethyl-4-pivaloyloxy-1H-benzo[d]imidazole-6-carboxamide:

[0128]

[0129] (210g, 0.692mol) N, N, 2-trimethyl-4-pivaloyloxy-1H-benzo [d] imidazole-6-carboxamide and 1200g dichloromethane were added to the reaction bottle, stirred for 15 minutes, (178g, 1.378mol) N, N-diisopropylethylamine was slowly added to the reaction bottle, (197g, 1.033mol) 4-methylbenzenesulfonyl chloride 480g dichloromethane solution was added dropwise at room temperature, and the temperature was raised to reflux reaction for 3h until the reaction was completed. The reaction solution was cooled to room temperature, 540g water was slowly added, stirred and separated, the aqueous phase was extracted once with dichloromethane, the organic phase was combined, and it was steamed twice with n-heptane, stirred for 2-3h, filtered, and dried to obtain 294g off-white solid, with a yield of 93%.

[0130] 1 H NMR (CD 3 OD,400MHz)δ:7.98-7.98(d,1H),7.96-7.94(d,2H),7.45-7.43(d,2H),7.15-7.15(d,1 H),3.14(s,3H),3.03(s,3H),2.82(s,3H),2.41(s,3H),1.40(s,9H).MS:[M+1]=458.1.

[0131] Example 9

[0132] Synthesis of 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzo[D]imidazole-6-carboxamide:

[0133]

[0134] Add 300g of process water and (300g, 0.722mol) 1-(4-methylbenzenesulfonyl)-N,N,2-trimethyl-4-acetoxy-1H-benzo[d]imidazole-6-carboxamide to the reaction bottle. Add (300g, 2.174mol) potassium carbonate, keep warm at 15-25℃ for 2h until the control is qualified. Add 1500g of process water, slowly add 250g of glacial acetic acid, stir at 10-20℃ for 2h, filter and dry to obtain 242g of white solid, with a yield of 90%.

[0135] 1 H NMR (CD 3 OD,400MHz)δ:7.92-7.89(d,2H),7.52-7.51(d,1H),7.43-7.41(d,2H),6.77-6. 76(s,1H),3.13(s,3H),3.00(s,3H),2.80(s,3H),2.40(s,3H).MS:[M+1]=374.1.

[0136] Example 10

[0137] Synthesis of 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzo[D]imidazole-6-carboxamide:

[0138]

[0139] Add 300g of process water and (300g, 0.656mol) 1-(4-methylbenzenesulfonyl)-N,N,2-trimethyl-4-acetoxy-1H-benzo[d]imidazole-6-carboxamide to the reaction bottle. Add (52g, 1.312mol) of sodium hydroxide, and react at 15-25℃ for 2h until the control is qualified. Add 1500g of process water, slowly add 250g of glacial acetic acid, stir at 10-20℃ for 2h, filter and dry to obtain 216g of white solid, with a yield of 88%.

[0140] 1 H NMR (CD 3 OD,400MHz)δ:7.92-7.89(d,2H),7.52-7.51(d,1H),7.43-7.41(d,2H),6.77-6. 76(s,1H),3.13(s,3H),3.00(s,3H),2.80(s,3H),2.40(s,3H).MS:[M+1]=374.1.

Claims

1. A method for preparing a compound of formula II, the reaction formula is as follows: The steps include: (1) subjecting the compound of formula (I) to an esterification reaction to obtain an anhydride intermediate; (2) subjecting the acid anhydride intermediate to an amidation reaction with dimethylamine to obtain a compound of formula II; Wherein R is independently selected from C1-C5 straight chain alkyl or branched chain alkyl, phenyl and substituted phenyl; C1-C5 straight chain alkyl or branched chain alkyl is preferably methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or tert-pentyl; substituted phenyl is selected from methoxy, cyano, nitro, F, Cl, Br or I substituted phenyl.

2. A method for preparing a compound of formula V, the reaction formula is as follows: R2 is selected from benzyl or p-toluenesulfonyl The following methods are included: Method 1: When R2 is selected from benzyl, the reaction formula is as follows: The steps include: (1) subjecting the compound of formula (I) to an esterification reaction to obtain an anhydride intermediate; (2) subjecting the acid anhydride intermediate to an amidation reaction with dimethylamine to obtain a compound of formula II; (3) hydrolyzing the compound of formula II under the action of a base to obtain a compound of formula Va; Method 2: When R2 is selected from p-toluenesulfonyl, the reaction formula is as follows: Wherein R is independently selected from C1-C5 straight chain alkyl or branched chain alkyl, phenyl and substituted phenyl; C1-C5 straight chain alkyl or branched chain alkyl is preferably methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or tert-pentyl; substituted phenyl is selected from methoxy, cyano, nitro, F, Cl, Br or phenyl substituted by I; The steps include: (1) subjecting the compound of formula (I) to an esterification reaction to obtain an anhydride intermediate; (2) subjecting the acid anhydride intermediate to an amidation reaction with dimethylamine to obtain a compound of formula II; (3) subjecting the compound of formula II to a hydrogenation reaction to obtain a compound of formula III; (4) reacting the compound of formula III with p-toluenesulfonyl chloride to obtain the compound of formula IV; (5) The compound of formula IV is hydrolyzed in the presence of a base to obtain the compound of formula Vb.

3. The preparation method according to claim 1 or 2, characterized in that: The esterification reaction in step (1) of claim 1 or step (1) of method 1 or method 2 of claim 2 is a reaction of a compound of formula I in an organic solvent in the presence of a base. reacting with an acyl chloride or an acid anhydride, wherein the acyl chloride is selected from acetyl chloride, propionyl chloride, isopropionyl chloride, butyryl chloride, sec-butyryl chloride, valeryl chloride, pivaloyl chloride or benzoyl chloride; and the acid anhydride is selected from acetic anhydride or propionic anhydride; And / or, preferably, in step (1), the molar ratio of the compound of formula I to the acid chloride or acid anhydride is 1:(1.2-8), preferably 1:(2-4); And / or, preferably, in step (1), the molar ratio of the base to the compound of formula I is (2-5):1, preferably (2.5-3.5):1; And / or, preferably, in step (1), the base is selected from an organic base or an inorganic base, the organic base is selected from triethylamine, N,N-diisopropylethylamine, triisopropylamine, etc., preferably triethylamine, N,N-diisopropylethylamine; the inorganic base is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, preferably sodium carbonate; And / or, preferably, in step (1), the base is preferably one of triethylamine, N,N-diisopropylethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and cesium carbonate; more preferably triethylamine or N,N-diisopropylethylamine; And / or, preferably, in step (1), the organic solvent is selected from ethyl acetate, isopropyl acetate, dichloromethane, methyl tert-butyl ether, tetrahydrofuran, dioxane, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone, preferably dichloromethane; And / or, preferably, the temperature of the esterification reaction in step (1) is -40 to 50°C, preferably -20 to 40°C, more preferably -10 to 40°C; And / or, preferably, the mass amount (g) of the organic solvent in step (1) is 5 to 15 times the mass amount (g) of the compound of formula I, preferably 6 to 8 times.

4. The preparation method according to claim 1 or 2, characterized in that: In the amidation reaction of step (2) of claim 1 or method 1 or method 2 of claim 2, the molar ratio of dimethylamine to the compound of formula 1 is (2 to 6):1, preferably 2 to 4; And / or, preferably, the reaction time of the amidation reaction in step (2) is 0.5 to 20 hours, preferably 5 to 6 hours.

5. The preparation method according to claim 1 or 2, characterized in that: After the amidation reaction of step (2) of claim 1 or step (2) of method 1 or method 2 of claim 2 is completed, an acetic acid stabilizer is added; preferably, the molar ratio of acetic acid to the compound of formula I is (1-5):1; And / or, preferably, after the amidation reaction in step (2) is completed, acetic acid stabilizer is added, water is added, the liquids are separated, the organic phases are combined, concentrated, the solid is precipitated, filtered, and dried to obtain a high-purity compound of formula II.

6. The preparation method according to claim 2, characterized in that: In the hydrolysis reaction of step (3) in the method 1, the compound of formula II is reacted in water or an organic solvent or a mixed solvent of water and an organic solvent; the base is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonia water; the organic solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane; And / or, preferably, in the hydrolysis reaction of step (3) in the method one, the molar ratio of the compound of formula II to the base is 1:(1-6), preferably 1:(2-4).

7. The preparation method according to claim 2, characterized in that: The hydrogenation reaction in step (3) of the second method is to carry out a hydrogenation debenzylation reaction of the compound of formula II in an organic solvent in the presence of a metal catalyst and a hydrogen source; the metal catalyst is selected from palladium carbon, palladium hydroxide, platinum carbon, etc., preferably palladium carbon; the hydrogen source is selected from hydrogen, formic acid, ammonium formate; And / or, preferably, the mass ratio of the metal catalyst to the compound of formula 2 in step (3) of the method 2 is 1:(5-50), preferably 1:(10-30); And / or, preferably, the organic solvent in step (3) of the second method is selected from ethyl acetate, isopropyl acetate, dichloromethane, methyl tert-butyl ether, tetrahydrofuran, methanol, dioxane, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, preferably tetrahydrofuran, and the mass amount (g) of the organic solvent is 1 to 10 times the mass amount (g) of the compound of formula II, preferably 3 to 6 times; And / or, preferably, the reaction time of step (3) of the second method is 1 to 24 hours, preferably 10 to 18 hours.

8. The preparation method according to claim 2, characterized in that: In the second method, step (4) of the method comprises reacting a compound selected from formula III with p-toluenesulfonyl chloride in an organic solvent in the presence of a base; the molar ratio of the compound of formula III to p-toluenesulfonyl chloride is 1:(1-3), preferably 1:(1-2); And / or, preferably, the base in step (4) of the second method can be a tertiary amine such as triethylamine, N,N-diisopropylethylamine, triisopropylamine, or an inorganic base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc., preferably triethylamine or N,N-diisopropylethylamine; And / or, preferably, the molar ratio of the base in step (4) of the method 2 to the compound of formula III is (1-5):1, preferably (1.5-3):1; And / or, preferably, the organic solvent in step (4) of the second method is selected from ethyl acetate, isopropyl acetate, dichloromethane, methyl tert-butyl ether, tetrahydrofuran, methanol, dioxane, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, preferably dichloromethane, and the mass amount (g) of the organic solvent is 1 to 10 times the mass amount (g) of the compound of formula II, preferably 5 to 8 times; And / or, preferably, the reaction temperature of step (4) of the second method is 15 to 45° C.; the reaction time is 1 to 10 h, preferably 2 to 5 h.

9. The preparation method according to claim 2, characterized in that: The hydrolysis reaction of step (5) of the second method is a reaction of the compound of formula IV in an organic solvent in the presence of a base; the base can be an organic base such as methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, diisopropylethylamine, triisopropylamine, or an inorganic base such as ammonia water, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; And / or, preferably, the molar ratio of the compound of formula IV to the base in step (5) of the method 2 is 1:(1-10), preferably 1:(1-5); And / or, preferably, the organic solvent in step (5) of the second method is selected from ethyl acetate, isopropyl acetate, dichloromethane, methyl tert-butyl ether, tetrahydrofuran, methanol, dioxane, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, preferably tetrahydrofuran, and the mass amount (g) of the organic solvent is 0.5 to 3 times the mass amount (g) of the compound of formula II, preferably 0.5 to 1.5 times; And / or, preferably, the reaction temperature of step (5) of the second method is 10 to 30° C.; the reaction time is 1 to 6 hours, preferably 1 to 3 hours.

10. A compound of formula II and a compound of formula IV have the following structures: Wherein R is independently selected from C1-C5 straight chain alkyl or branched chain alkyl, phenyl and substituted phenyl; C1-C5 straight chain alkyl or branched chain alkyl is preferably methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or tert-pentyl; substituted phenyl is selected from methoxy, cyano, nitro, F, Cl, Br or phenyl substituted by I; The following intermediates are preferred: Or a compound of formula IIIa has the following structure:

11. A method for preparing tigolasan, comprising the method of claim 1 or the method of claim 2 of the present invention, or the use of the compound of formula II, the compound of formula IV or the compound of formula IIIa in claim 10 for preparing tigolasan.

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