A preparation method of tergorazan intermediate and its derivatives

Abstract

The present invention discloses a method for preparing a tergorazan intermediate and its derivatives. The preparation method of Formula VII comprises the following steps: step (1), hydrolyzing a compound of Formula V to produce a compound of Formula VI; step (2), reducing and cyclizing the compound of Formula VI to obtain a compound of Formula VII. The synthesis route is as follows: wherein R and R1 are as defined in the specification. The present invention also provides a method for preparing a compound of Formula VIII, comprising synthesizing the compound of Formula VII with a nitrogen atom protecting reagent to prepare a compound of Formula VII; the synthesis route is as follows: wherein R and R2 are as defined in the specification. The process route of the present invention has the advantages of being safe, environmentally friendly, and having low production costs.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical organic synthesis and relates to a method for preparing a key intermediate of tergolactam. Background Art

[0002] Tegorazan, also known as Tegoprazan, was approved for marketing by the Korean Ministry of Food and Drug Safety in July 2018 for the treatment of gastroesophageal reflux disease and erosive esophagitis.

[0003] Tigorapen is a potassium-competitive acid blocker (P-CAB) that competes with potassium ions to reversibly bind to H+ / K+-ATPase, inhibiting both its resting and activated states, thereby sustainably suppressing gastric acid secretion. With a rapid onset of action within 30 minutes, potent and long-lasting acid suppression, and ease of administration, it offers a new medication option for the treatment of reflux esophagitis and improving patients' quality of life.

[0004] 4-Hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide is a key intermediate in the synthesis of the proton pump inhibitor tergolactam.

[0005] At present, the main processes for synthesizing the intermediate 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide are:

[0006] 1) Using 2-amino-3-nitrophenol as the starting material, an intermediate is obtained through benzyl bromide protection and bromination, as described in CN113527272A. This synthetic route involves expensive raw materials, requires sequential protection of oxygen and nitrogen atoms in the first two steps, and uses an iron powder / glacial acetic acid system during nitro group reduction, significantly increasing the difficulty of post-processing. Furthermore, the introduction of a carboxyl group requires bromination and metal-catalyzed introduction of a cyano group, increasing the risk of reagent handling. Furthermore, the resulting carboxylic acid intermediate is highly polar and difficult to purify.

[0007]

[0008] 2) Using 4-nitro-3-hydroxybenzoic acid as the starting material, an intermediate is synthesized through steps such as amination and hydroxyl protection, as shown in CN114249694A. This route still has high raw material costs, requires protection of oxygen atoms, and uses a zinc powder / glacial acetic acid system during the nitro group reduction process, which increases the difficulty of post-processing.

[0009]

[0010] 3) Using 4-aminobenzoic acid as a raw material, an intermediate is obtained through steps such as amination and bromination, as shown in CN115594639A. This route uses cheap raw materials, but requires transition metal catalysis, coupling with a boron ester reagent in the presence of a base or activation with an alkyl lithium reagent, and then reacting with a boron esterification reagent to produce the intermediate. Furthermore, nitrogen atom protection is required, the route is long, the yield is low, and industrialization is difficult.

[0011]

[0012] 4) Using 4-amino-3-nitrobenzoic acid as the raw material, the intermediate is obtained through bromination and amination, etc. (see CN114805317A); this route has low yield and produces a lot of hydrolysis tar;

[0013]

[0014] In summary, the existing methods for preparing intermediates have disadvantages such as high cost, harsh production environment, and unsuitability for industrial production. Summary of the Invention

[0015] In view of the defects in the prior art for synthesizing 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide, the present invention provides a synthetic route for 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide and its derivatives. The synthetic route of the present invention reduces the cost of raw materials, simplifies the process route, reduces the three wastes, improves the reaction yield, and realizes green industrial production.

[0016] The present invention adopts the following technical solutions:

[0017] A method for preparing a compound of formula VIII: the method comprises the following steps:

[0018] Step (1), hydrolyzing the compound of formula V to produce the compound of formula VI;

[0019] Step (2), the compound of formula VI is subjected to reduction cyclization to obtain the compound of formula VII;

[0020] Its synthetic route is as follows:

[0021]

[0022] Wherein, R is selected from halogen, -ORa, -SRa, -NR b Rc, wherein Ra is H, C1-C6 alkyl and optionally substituted aryl, R b , Rc is selected from hydrogen, C1-C6 alkyl;

[0023] R1 is selected from fluorine, chlorine, bromine or iodine, preferably chlorine and bromine.

[0024] The present invention also provides a method for preparing a compound of formula V, which is prepared from a compound of formula IV. The synthetic route is as follows:

[0025] in,

[0026] R is selected from halogen, -ORa, -SRa, -NR b Rc, wherein Ra is H, C1-C6 alkyl and optionally substituted aryl, R b , Rc is selected from hydrogen, C1-C6 alkyl;

[0027] R1 is selected from fluorine, chlorine, bromine or iodine, preferably chlorine and bromine.

[0028] The present invention also provides a method for preparing a compound of formula IV, which is prepared by halogenation reaction of a compound of formula III with a halogenating agent. The synthetic route is as follows:

[0029] in,

[0030] R is selected from halogen, -ORa, -SRa, -NR b Rc, wherein Ra is H, C1-C6 alkyl and optionally substituted aryl, R b , Rc is selected from hydrogen, C1-C6 alkyl;

[0031] R1 is selected from fluorine, chlorine, bromine or iodine, preferably chlorine and bromine.

[0032] The present invention also discloses a method for preparing a compound of formula III, comprising 1) preparing the compound from formula I as a raw material; or 2) preparing the compound from formula II as a raw material:

[0033] Wherein, R is selected from halogen, -ORa, -SRa, -NR b Rc, wherein Ra is H, C1-C6 alkyl and optionally substituted aryl, R b , Rc is selected from hydrogen, C1-C6 alkyl;

[0034] X is fluorine, chlorine, bromine or iodine;

[0035] Y is methyl or trifluoromethyl.

[0036] The present invention also provides a method for preparing a compound of formula VIII: the method comprises the following steps: synthesizing a compound of formula VIII by reacting a compound of formula VII with a nitrogen atom protecting reagent;

[0037] Its synthetic route is as follows:

[0038]

[0039] Wherein, R is selected from halogen, -ORa, -SRa, -NRb Rc, wherein Ra is H, C1-C6 alkyl and optionally substituted aryl, R b , Rc is selected from hydrogen, C1-C6 alkyl;

[0040] R2 is selected from any one of p-toluenesulfonyl, benzyl, acetyl, propionyl, trifluoromethanesulfonyl, trifluoroacetyl, formyl, benzenesulfonyl, methylsulfonyl, trimethylsilyl and tert-butyl.

[0041] Beneficial effects

[0042] The method provided by the present invention has low raw material cost, less three wastes, high reaction yield and improved market competitiveness. DETAILED DESCRIPTION

[0043] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0044] The following is a detailed description of the specific embodiments of the present invention. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present invention and are not intended to limit the present invention.

[0045] The present invention C n -C m The subscripts n and m in each case indicate the number of carbon atoms in the group. For example, C1-C6 indicates a group containing 1 to 6 carbon atoms. The alkyl groups mentioned in the definitions of substituents may be straight-chain or branched and are, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, sec-butyl, isobutyl or tert-butyl. Alkoxy groups are derived from the alkyl groups mentioned.

[0046] Alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy; preference is given to methoxy and ethoxy.

[0047] Halogen is typically fluorine, chlorine, bromine or iodine in the present invention, preferably fluorine, bromine or chlorine. Accordingly, this also applies to halogens combined with other structures, such as haloalkyl. Haloalkyl preferably has a chain length of 1 to 6 carbon atoms, more preferably a chain length of 1 to 4 carbon atoms. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1,1-difluoro-2,2,2-trichloroethyl, 2,2,3,3-tetrafluoroethyl and 2,2,2-trichloroethyl; preferably fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, difluorochloromethyl and dichlorofluoromethyl.

[0048] In the present invention, "aryl" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 ring atoms, such as phenyl or naphthyl, but is not limited thereto.

[0049] The term "optionally substituted" means that the relevant group may be substituted by a substituent or may not be substituted.

[0050] When the relevant group (such as alkyl) is substituted with a substituent, the substituent may include hydroxyl, cyano, nitro, halogen, alkyl, alkoxy, haloalkyl and haloalkoxy, etc., but is not limited thereto.

[0051] The present invention provides a method for preparing a compound of formula VIII, which comprises the following steps:

[0052] Step (1), hydrolyzing the compound of formula V to produce the compound of formula VI;

[0053] Step (2), the compound of formula VI is reduced and cyclized to obtain the compound of formula VII;

[0054] Its synthetic route is as follows:

[0055]

[0056] Wherein, R is selected from halogen, -ORa, -SRa, -NR b Rc, wherein Ra is H, C1-C6 alkyl and optionally substituted aryl, R b , Rc is selected from hydrogen, C1-C6 alkyl;

[0057] R1 is selected from fluorine, chlorine, bromine or iodine, preferably chlorine and bromine.

[0058] Preferably, in step (1), the hydrolysis reaction is a hydrolysis reaction of the compound of formula V in the presence of a catalyst and an acidifying agent in a solvent, the hydrolysis temperature is 0-150°C, preferably 30-80°C; the hydrolysis time is 6-15h, preferably 8-12h.

[0059] Preferably, the acid binding agent is selected from an inorganic base, preferably at least one of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, and sodium bicarbonate, particularly preferably sodium carbonate and / or sodium hydroxide; the molar ratio of the compound to the acid binding agent is 1:1-1.8, preferably 1:1.2-1.5.

[0060] Preferably, the catalyst is a copper salt and a compound capable of forming a ligand with the copper salt; the copper salt is selected from at least one of copper powder, copper chloride, copper acetate, cuprous chloride, cuprous iodide, cuprous bromide, copper acetylacetonate, copper acetate, cupric bromide, copper iodide, copper trifluoroacetate, copper trifluoromethanesulfonate, copper phenylacetate, copper trifluoroacetylacetonate, copper hexafluoroacetylacetonate, copper ethylacetoacetate, triphenylphosphine cuprous bromide and copper benzoylacetonate, preferably cuprous chloride; the compound capable of forming a ligand with the copper salt is selected from ethylenediamine, tetramethylethylenediamine, dimethylpropanediol, Amine, tetramethylpropylenediamine, N,N'-dimethylethylenediamine, N,N-diisopropylethylamine, N-methylmorpholine, morpholine, 2-picolinic acid, glycine, N,N-dimethylaniline and diisopropylethylamine, 8-hydroxyquinoline, ethylene glycol, ethanolamine, salicylaldehyde oxime, 6,7-dihydro-5-H-quinolinone, N,N-dimethylglycine, 2,6-picolinic acid; preferably 2-picolinic acid; the mass ratio of the compound to the catalyst is 1:0.2%-10% w / w, preferably 1:0.5%-2% w / w.

[0061] Preferably, the hydrolysis reaction in step (1) is carried out in a solvent selected from at least one of methanol, ethanol, n-butanol, isopropanol, tert-butanol, water, acetone, N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone. The preferred reaction solvent is a combination of at least one of methanol, ethanol, n-butanol, isopropanol, tert-butanol, acetone, N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone and water, particularly preferably N,N-dimethylformamide and water. Studies have found that the presence of water in the solvent is conducive to the hydrolysis reaction.

[0062] Preferably, the reduction and cyclization reaction of the compound of formula VI in step (2) above is carried out in the presence of an organic acid, and the organic acid can be one of formic acid, acetic acid, and propionic acid, preferably acetic acid.

[0063] Preferably, the reaction temperature in the above step (2) is 60-150° C., preferably 80-100° C.; the reaction pressure is 1-3 MPa, preferably 1.5-2.5 MPa.

[0064] Preferably, a hydrogen reduction catalyst is added in the above step (2), and the catalyst is selected from palladium carbon or Raney nickel, preferably palladium carbon; the mass ratio of formula VI, palladium carbon and acetic acid is 1:0.02-0.05:1.0-1.5.

[0065] Preferably, the reaction in step (2) is carried out in an organic solvent selected from the group consisting of methanol, ethanol, acetonitrile, dichloromethane, dichloroethane, water, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone.

[0066] The present invention also provides a method for preparing a compound of formula V, wherein the compound of formula V is prepared from a compound of formula IV, and the synthetic route is as follows:

[0067]

[0068] Wherein, R is selected from halogen, -ORa, -SRa, -NR b Rc, wherein Ra is H, C1-C6 alkyl and optionally substituted aryl, R b , Rc is selected from hydrogen, C1-C6 alkyl;

[0069] R1 is selected from fluorine, chlorine, bromine or iodine, preferably chlorine and bromine.

[0070] In a preferred embodiment, the compound of formula IV reacts with acetic anhydride in acetic acid at a reaction temperature of 70-85° C., and the molar ratio of the compound of formula IV to acetic anhydride is 1:1.0-1.5.

[0071] Preferably, the compound of formula IV is prepared by halogenation reaction of the compound of formula III with a halogenating agent, and its synthesis route is as follows:

[0072] Wherein, R is selected from halogen, -ORa, -SRa, -NR b Rc, wherein Ra is H, C1-C6 alkyl and optionally substituted aryl, R b , Rc is selected from hydrogen, C1-C6 alkyl;

[0073] R1 is selected from fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.

[0074] Preferably, the halogenating agent in the above step is at least one selected from a combination of sodium bromate and hydrogen peroxide, chlorine, sulfuryl chloride, thionyl chloride, N-chlorosuccinimide, dichlorohydantoin, dibromohydantoin, N-bromosuccinimide and bromine, preferably chlorine or bromine.

[0075] Preferably, the conditions for the halogenation reaction in the above step include: a halogenation temperature of 0-60°C, more preferably, when the halogenation is chlorination, the reaction temperature is 40-50°C, and when the halogenation is bromination, the reaction temperature is 5-15°C; the halogenation time is 1-6h, preferably 3-4h; and the molar ratio of the compound to the halogenation reagent is 1:1-3;

[0076] Preferably, the preparation method of the compound of formula III in the above steps includes 1) preparing the compound of formula I as a raw material; or 2) preparing the compound of formula II as a raw material:

[0077] Wherein, R is selected from halogen, -ORa, -SRa, -NR b Rc, wherein Ra is H, C1-C6 alkyl and optionally substituted aryl, R b , Rc is selected from hydrogen, C1-C6 alkyl, X is fluorine, chlorine, bromine, iodine; Y is methyl, trifluoromethyl.

[0078] Preferably, the step of preparing the compound of formula III from the compound of formula I as a raw material in the above steps comprises an amination, oxidation or hydrolysis step.

[0079] Preferably, the step of preparing the compound of formula III from the compound of formula II as a raw material includes an amination step.

[0080] Preferably, the oxidation reaction is carried out under the catalysis of a cobalt salt and oxygen oxidation, the oxidation temperature is 50-150°C, preferably 100-120°C, and the cobalt salt is preferably cobalt acetate; the hydrolysis reaction is carried out under the action of concentrated sulfuric acid, the hydrolysis temperature is 70-150°C, preferably 80-90°C; the amination reaction temperature is 10-180°C, preferably 70-100°C; preferably 3-4h; the amination reagent is ammonia water, an alcoholic solution of ammonia, and the molar ratio of compound I to the amination reagent is 1:1.0-4.5, preferably 1:2-2.2.

[0081] The present invention also provides a method for preparing a compound of formula VIII: the method comprises the following steps: synthesizing a compound of formula VIII by reacting a compound of formula VII with a nitrogen atom protecting reagent;

[0082] Its synthetic route is as follows:

[0083]

[0084] Wherein, R is selected from halogen, -ORa, -SRa, -NR b Rc, wherein Ra is H, C1-C6 alkyl and optionally substituted aryl, R b , Rc is selected from hydrogen, C1-C6 alkyl;

[0085] R2 is selected from any one of p-toluenesulfonyl, benzyl, acetyl, propionyl, trifluoromethanesulfonyl, trifluoroacetyl, formyl, benzenesulfonyl, methylsulfonyl, trimethylsilyl, and tert-butyl;

[0086] The nitrogen atom protecting reagent is a reagent that reacts with a nitrogen atom to protect the nitrogen atom. For example, the nitrogen atom can be protected during the reaction. Common protecting agents react with nitrogen atoms to form protecting groups, such as toluenesulfonyl, benzyl, acetyl, propionyl, trifluoromethanesulfonyl, trifluoroacetyl, formyl, benzylsulfonyl, methanesulfonyl, trimethylsilyl, and tert-butyl compounds, such as toluenesulfonyl chloride, benzyl bromide, acetyl chloride, acetic anhydride, propionyl chloride, trifluoromethanesulfonyl chloride, trifluoroacetyl chloride, formyl chloride, benzylsulfonyl chloride, methanesulfonyl chloride, trimethylsilyl chloride, di-tert-butyl dicarbonate, and the like. Protecting groups are not limited thereto.

[0087] Preferably, the above reaction is carried out in an organic solvent at a reaction temperature of -10-100°C, preferably 10-40°C; the molar ratio of compound VII to the nitrogen atom protecting agent is 1:1.0-2.1; the reaction in the above steps is carried out in an organic solvent, and the organic solvent is preferably one of toluene, acetonitrile, tetrahydrofuran, dioxane, and xylene.

[0088] The present invention will be described in detail below by way of examples. In the following examples:

[0089] The amounts of reactants and products were determined by liquid chromatography (Agilent HPLC 1260).

[0090] The conversion and selectivity of the reaction were calculated using the following formula:

[0091] Conversion rate = (molar amount of raw material input - molar amount of raw material remaining in the product) / molar amount of raw material input × 100%.

[0092] Selectivity = actual molar amount of target product / theoretical molar amount of target product × 100%

[0093] Yield = actual mass of target product / theoretical mass of target product × 100%

[0094] Unless otherwise specified, all raw materials used were commercially available products.

[0095] Example 1 Synthesis of 4-amino-3-nitrobenzoic acid

[0096]

[0097] In an autoclave, 17.2 g (0.1 mol, 99%, purchased from Aladdin) of 4-chloro-3-nitrotoluene, 0.2 g of cobalt acetate, and acetic acid were added, oxygen was introduced, and the mixture was reacted at 100°C for 6 h. After extraction and desolvation, 26 g of ammonia water was directly added, the mixture was kept at 105°C, and the reaction was continued for 6 h. After extraction and desolvation with ethyl acetate, 15.5 g of 4-amino-3-nitrobenzoic acid was obtained, with a yield of 85%.

[0098] Example 2 Synthesis of 4-amino-3-nitrobenzoic acid

[0099]

[0100] In a four-necked flask, add 22.6g (0.1mol, 99%, purchased from Aladdin) of 4-chloro-3-nitrotrifluorotoluene and 60g of concentrated sulfuric acid, react at 100°C for 6h, pour into water, filter and dry, then directly add to an autoclave, add 26g of ammonia water, keep warm at 105°C, react for 6h, and extract and desolventize with ethyl acetate to obtain 16.0g of 4-amino-3-nitrobenzoic acid with a yield of 88%.

[0101] Example 3 Synthesis of 4-hydroxy-N,N,2-trimethyl-1-(p-toluenesulfonyl)-1H-benzimidazole-6-carboxamide

[0102] 3.1 Synthesis of 4-Hydroxy-N,N,2-Trimethylbenzimidazole-6-carboxamide

[0103]

[0104] In an autoclave, 22.9 g (0.1 mol, 99%, purchased from Aladdin) of 3-nitro-4-chloro-N,N-dimethylbenzoyl was added, 28 g of ammonia water was added, the mixture was kept at 100 ° C, the reaction was carried out for 6 h, ethyl acetate was added for extraction and desolvation, 60 g of dichloroethane was added, the mixture was kept at 5 ° C, 16 g of bromine was added dropwise, the reaction was carried out for 2 h, the mixture was washed with water and alkali, and 23.6 g of 3-nitro-4-amino-5-bromo-N,N-dimethylbenzoyl was obtained by extraction and desolvation, with a yield of 82%; 0.1 mol of 3-nitro-4-amino-5-bromo-N,N-dimethylbenzoyl was added to a four-necked flask, 60 g of acetic acid and 14.8 g of acetic anhydride were added, the mixture was kept at 85 ° C for 8 h, and after the reaction of the raw materials was completed, the mixture was desolvated to obtain 31.4 g of the compound 3-nitro-4-acetylamino-5-bromo-N,N-dimethylbenzamide, with a yield of 95%;

[0105] In a four-necked flask, 0.1 mol of 3-nitro-4-acetylamino-5-bromo-N,N-dimethylbenzamide, 120 g of water, 40 g of DMF, 16 g of sodium carbonate, 0.33 g of cuprous chloride, and 0.33 g of 2-picolinic acid were added. The reaction was kept warm for 10 h. After HPLC detection of the complete raw material, the temperature was lowered to 0°C and filtered to obtain 24.0 g of 3-nitro-4-acetylamino-5-hydroxy-N,N-dimethylbenzamide, with a yield of 90%. Then, all the solid from the previous step was added with 60 g of methanol, 26 g of acetic acid, and 0.5 g of palladium carbon. The mixture was kept warm at 85°C and filled with hydrogen at 1.8 MPa. The reaction was continued for 10 h. After HPLC detection of the complete raw material, the mixture was filtered and desolvated to obtain 17.0 g of 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide, with a yield of 86%.

[0106] 3.2 Synthesis of 4-hydroxy-N,N,2-trimethyl-1-(p-toluenesulfonyl)-1H-benzimidazole-6-carboxamide

[0107]

[0108] In a four-necked flask, add 0.1 mol of 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide, 60 g of acetonitrile, and 21.0 g of p-toluenesulfonyl chloride. Keep the temperature at 30°C and react for 3 h. HPLC detection shows that the raw material is complete. Wash with water, extract with ethyl acetate, and remove the solvent to obtain 35.5 g of 4-hydroxy-N,N,2-trimethyl-1-(p-toluenesulfonyl)-1H-benzimidazole-6-carboxamide, with a yield of 95%.

[0109] Example 4 Synthesis of 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide

[0110] The difference from Example 3 is that bromine is replaced by chlorine. The other molar ratios remain unchanged. The reaction yields 18.2 g of 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide with a yield of 83%.

[0111] Example 5 Synthesis of 4-hydroxy-N,N,2-trimethyl-1-(methylsulfonyl)-1H-benzimidazole-6-carboxamide

[0112]

[0113] The difference from Example 3 is that p-toluenesulfonyl chloride is replaced by methanesulfonyl chloride, and the other molar ratios remain unchanged. The reaction yields 27.6 g of 4-hydroxy-N,N,2-trimethyl-1-(methylsulfonyl)-1H-benzimidazole-6-carboxamide with a yield of 93%.

[0114] Example 6 Synthesis of methyl 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxylate

[0115] The difference from Example 3 is that 3-nitro-4-chloro-N,N-dimethylbenzamide is replaced by 3-nitro-4-chloro-benzoic acid methyl ester, and the other molar ratios remain unchanged. The reaction yields 16.5 g of 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxylic acid methyl ester with a yield of 80%.

[0116] Example 7 Synthesis of 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxylic acid

[0117] The difference from Example 3 is that 3-nitro-4-chloro-N,N-dimethylbenzamide is replaced by 3-nitro-4-chloro-benzoic acid, and the other molar ratios remain unchanged. The reaction yields 15.6 g of 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxylic acid with a yield of 81%.

[0118] Example 8 Synthesis of 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide

[0119] The difference from Example 3 is that the catalysts cuprous chloride and N,N'-dimethylethylenediamine replace the combination of cuprous chloride and 2-picolinic acid, and the other molar ratios remain unchanged. 18.6 g of 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide is obtained with a yield of 85%.

[0120] Example 9 3-Nitro-4-acetylamino-5-hydroxy-N,N-dimethylbenzamide

[0121] The difference from Example 3 is that the catalyst is cuprous chloride, 2-picolinic acid is not added, and other molar ratios remain unchanged. 14.7 g of 3-nitro-4-acetylamino-5-hydroxy-N,N-dimethylbenzamide is obtained, with a yield of 55%.

[0122] Example 10 3-Nitro-4-acetylamino-5-hydroxy-N,N-dimethylbenzamide

[0123] The difference from Example 3 is that no water is added, and other molar ratios remain unchanged, to obtain 6.9 g of 3-nitro-4-acetylamino-5-hydroxy-N,N-dimethylbenzamide, with a yield of 26%.

[0124] Example 11 Preparation of 3-nitro-4-acetylamino-5-hydroxy-N,N-dimethylbenzamide

[0125] Add 0.1 mol of 3-nitro-4-acetylamino-5-bromo-N,N-dimethylbenzamide, 10 g of water, 40 g of DMF, 16 g of sodium carbonate, 0.33 g of cuprous chloride, and 0.33 g of 2-picolinic acid. Keep the mixture warm for 10 h. HPLC detection shows that the raw materials are complete. Cool the mixture to 0°C and filter to obtain 20.0 g of 3-nitro-4-acetylamino-5-hydroxy-N,N-dimethylbenzamide in a yield of 75%.

[0126] The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, various simple variations of the technical solution of the present invention may be made, including combining the various technical features in any other appropriate manner. These simple variations and combinations should also be regarded as disclosed in the present invention and fall within the scope of protection of the present invention.

Claims

1. A method for preparing a compound of formula VII: characterized in that, The method comprises the following steps: Step (1), hydrolysis of the compound of formula V to generate the compound of formula VI, Step (2), the compound of formula VI is reduced and cyclized to obtain the compound of formula VII, Its synthetic route is as follows: Wherein, R is selected from halogen, -ORa, -SRa, -NR b Rc, wherein Ra is H, C1-C6 alkyl and optionally substituted aryl, R b , Rc is selected from hydrogen, C1-C6 alkyl; R1 is selected from fluorine, chlorine, bromine or iodine; In step (2), the reduction and cyclization reaction of the compound of formula VI is carried out in an organic acid; A catalyst is added in step (2), wherein the catalyst is selected from palladium carbon or Raney nickel.

2. The method for preparing according to claim 1, characterized in that The organic acid is acetic acid; a catalyst is added in step (2), and the catalyst is palladium carbon.

3. The preparation method according to claim 2, characterized in that The mass ratio of Formula VI, palladium carbon and acetic acid in step (2) is 1:0.02-0.05:1.0-1.

5.

4. The preparation method according to claim 1, wherein in step (1), the hydrolysis reaction is a hydrolysis reaction of the compound of formula V in the presence of a catalyst and an acid binding agent in a solvent, the hydrolysis temperature is 0-150°C, and the hydrolysis time is 6-15h.

5. The preparation method according to claim 4, wherein in step (1), the hydrolysis temperature is 30-80°C and the hydrolysis time is 8-12 hours.

6. The preparation method according to claim 4, characterized in that The acid-binding agent is selected from inorganic bases; the molar ratio of the compound to the acid-binding agent is 1:1-1.

8.

7. The preparation method according to claim 4, characterized in that The acid binding agent is selected from at least one of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, and sodium bicarbonate, and the molar ratio of the compound to the acid binding agent is 1:1.2-1.

5.

8. The preparation method according to claim 4, characterized in that The acid binding agent is selected from sodium carbonate and / or sodium hydroxide.

9. The preparation method according to claim 4, characterized in that The catalyst is a copper salt and a compound that can form a ligand with the copper salt; the copper salt is selected from at least one of copper powder, copper chloride, copper acetate, cuprous chloride, cuprous iodide, cuprous bromide, copper acetylacetonate, copper acetate, cupric bromide, copper iodide, copper trifluoroacetate, copper trifluoromethanesulfonate, copper phenylacetate, copper trifluoroacetylacetonate, copper hexafluoroacetylacetonate, copper ethylacetoacetate, triphenylphosphine cuprous bromide and copper benzoylacetonate; the compound that can form a ligand with the copper salt is selected from ethylenediamine, tetramethylethylenediamine, Dimethylpropylenediamine, tetramethylpropylenediamine, N,N'-dimethylethylenediamine, N,N-diisopropylethylamine, N-methylmorpholine, morpholine, 2-picolinic acid, glycine, N,N-dimethylaniline and diisopropylethylamine, 8-hydroxyquinoline, ethylene glycol, ethanolamine, salicylaldehyde oxime, 6,7-dihydro-5-H-quinolinone, N,N-dimethylglycine, 2,6-picolinic acid; the mass ratio of the compound of formula V to the catalyst is 1:0.2%-10% w / w.

10. The preparation method according to claim 9, characterized in that The copper salt is selected from cuprous chloride; the compound forming a ligand with the copper salt is selected from 2-pyridinecarboxylic acid; the mass ratio of the compound of formula V to the catalyst is 1:0.5%-2% w / w.

11. The preparation method according to claim 4, characterized in that The hydrolysis reaction in step (1) is carried out in a solvent selected from at least one of methanol, ethanol, n-butanol, isopropanol, tert-butanol, water, acetone, N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone.

12. The preparation method according to claim 4, characterized in that The hydrolysis reaction in step (1) is carried out in a solvent selected from N,N-dimethylformamide and water.

13. The preparation method according to any one of claims 1 to 12, characterized in that: The reaction temperature of step (2) is 60-150° C.; and the reaction pressure is 1-3 MPa.

14. The preparation method according to claim 13, characterized in that The reaction temperature of step (2) is 80-100° C.; and the reaction pressure is 1.5-2.5 MPa.

15. The preparation method according to claim 13, characterized in that The reaction of step (2) is carried out in an organic solvent, and the organic solvent is selected from one of methanol, ethanol, acetonitrile, dichloromethane, dichloroethane, water, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone.

16. The preparation method according to claim 1, characterized in that The compound of formula V is prepared from the compound of formula IV, and its synthetic route is as follows: wherein, R and R1 are as defined in claim 1.

17. The preparation method according to claim 16, characterized in that The compound of formula IV reacts with acetic anhydride in acetic acid at a reaction temperature of 70-85° C., and the molar ratio of the compound of formula V to acetic anhydride is 1:1.0-1.

5.

18. The preparation method according to claim 16, characterized in that The compound of formula IV is prepared by halogenation reaction of the compound of formula III with a halogenating agent, and its synthesis route is as follows: wherein, R and R1 are as defined in claim 16.

19. The preparation method according to claim 18, characterized in that R1 is chlorine and bromine.

20. The preparation method according to claim 18, wherein The halogenating agent is selected from at least one of a combination of sodium bromate and hydrogen peroxide, chlorine, sulfuryl chloride, thionyl chloride, N-chlorosuccinimide, dichlorohydantoin, dibromohydantoin, N-bromosuccinimide and bromine.

21. The preparation method according to claim 18, wherein The halogenating agent is selected from chlorine or bromine.

22. The preparation method according to claim 18, characterized in that The halogenation reaction temperature is 0-60° C.; the halogenation time is 1-6 h; and the molar ratio of the compound of formula III to the halogenation reagent is 1:1-3.

23. The preparation method according to claim 22, characterized in that When the halogenation is chlorination, the reaction temperature is 40-50°C; when the halogenation is bromination, the reaction temperature is 5-15°C; the halogenation time is 3-4h.

24. The preparation method according to claim 18, characterized in that The preparation of the compound of formula III comprises: 1) Prepared from the compound of formula I as raw material; or 2) Prepared from the compound of formula II as raw material: wherein R is as defined in claim 18, X is fluorine, chlorine, bromine, or iodine, and Y is methyl or trifluoromethyl.

25. The preparation method according to claim 24, characterized in that in, The preparation of the compound of formula III from the compound of formula I includes amination, oxidation or hydrolysis steps, The aminating agent is aqueous ammonia or an alcoholic ammonia solution, and the molar ratio of compound I to the aminating agent is 1:1.0-4.5; The amination reaction temperature is 10-180°C; The oxidation reaction is carried out under the catalysis of cobalt salt and oxygen oxidation, and the oxidation temperature is 50-150°C; The hydrolysis reaction is carried out under the action of concentrated sulfuric acid at a temperature of 70-150°C.

26. The preparation method according to claim 25, characterized in that The molar ratio of the compound I to the aminating agent is 1:2-2.2; The amination reaction temperature is 70-100°C; Oxidation temperature is 100-120℃; The cobalt salt is cobalt acetate; The hydrolysis temperature is 80-90℃.

27. A method for preparing a compound of formula VIII, characterized in that: The method comprises the following steps: synthesizing a compound of formula VIII with a compound of formula VII and a nitrogen atom protecting reagent; Its synthetic route is as follows: Wherein, R is selected from halogen, -ORa, -SRa, -NR b Rc, wherein Ra is H, C1-C6 alkyl and optionally substituted aryl, R b , Rc is selected from hydrogen, C1-C6 alkyl; R2 is selected from any one of p-toluenesulfonyl, benzyl, acetyl, propionyl, trifluoromethanesulfonyl, trifluoroacetyl, formyl, benzenesulfonyl, methylsulfonyl, trimethylsilyl, and tert-butyl; Wherein, the compound of formula VII is prepared by the method according to any one of claims 1-15.

28. The preparation method according to claim 27, characterized in that The reaction temperature is -10-100° C.; the molar ratio of the compound of formula VII to the nitrogen atom protecting agent is 1:1.0-2.1; the reaction in the above steps is carried out in an organic solvent, and the organic solvent is selected from one of toluene, acetonitrile, tetrahydrofuran, dioxane, and xylene.

29. The preparation method according to claim 28, characterized in that The reaction temperature is 10-40°C.

Images