Preparation method of tergorazan intermediate and derivative thereof

Abstract

The invention discloses a preparation method of a tergorazan intermediate and a derivative thereof. Wherein the preparation method of the formula VII comprises the following steps: step (1), carrying out hydrolysis reaction on a compound of a formula V to generate a compound of a formula VI; and step (2), carrying out reduction and cyclization on the compound of the formula VI to obtain a compound of the formula VII. The synthesis route is as follows: # imgabs0 #, wherein R and R1 are defined in the specification. The invention also provides a preparation method of the compound as shown in the formula VIII. The method comprises the following steps: synthesizing a compound as shown in the formula VII and a nitrogen atom protection reagent to prepare a compound as shown in the formula VII; the synthesis route is as follows: # imgabs1 #, wherein R and R2 are defined in the specification. The process route has the advantages of safety, greenness, low production cost and the like.

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 tergolan 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] Tegolasen is a potassium ion competitive acid blocker (P-CAB), which reversibly binds to H+ / K+-ATPase by competing with potassium ions, and can simultaneously inhibit both its resting and activated states, thereby permanently inhibiting gastric acid secretion. It has the characteristics of rapid onset of action within 30 minutes, strong and long-lasting acid suppression, and easy to take, bringing a new medication option for the treatment of reflux esophagitis and improving the quality of life of patients.

[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 processes for synthesizing the intermediate 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide mainly include:

[0006] 1) 2-amino-3-nitrophenol is used as a raw material, and an intermediate is obtained through benzyl bromide protection and bromination, etc., refer to CN113527272A; the raw materials of this synthetic route are expensive, and the first two steps of this route need to protect oxygen and nitrogen atoms in sequence. The iron powder / glacial acetic acid system is used in the process of reducing the nitro group, which greatly increases the difficulty of post-processing; in the process of introducing the carboxyl group, bromination and metal catalysis are required to introduce the cyano group, which increases the risk of reagent handling, and the obtained carboxylic acid intermediate has a large polarity and is difficult to purify.

[0007]

[0008] 2) Using 4-nitro-3-hydroxybenzoic acid as a raw material, an intermediate is synthesized through steps such as amination and hydroxyl protection, see CN114249694A; this route still has high raw material costs, requires protection of oxygen atoms, and uses a zinc powder / glacial acetic acid system in the process of reducing the nitro group, 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 ammoniation and bromination, see CN115594639A; this route has 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 generate an intermediate; and requires protection of the nitrogen atom, a long route, a low yield, and is not easy to industrialize;

[0011]

[0012] 4) Using 4-amino-3-nitrobenzoic acid as a raw material, the intermediate is obtained through bromination, amination and other steps, refer to CN114805317A; this route has a low yield and produces a lot of hydrolyzed tar;

[0013]

[0014] In summary, the existing methods have the disadvantages of high cost, harsh production environment, and unsuitability for industrial production when preparing intermediates. 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 three wastes, improves the reaction yield, and realizes green industrialized production.

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

[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 generate 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, and 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, and 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 of formula I as a raw material; or 2) preparing the compound of 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 and any values ​​of the ranges disclosed in this article 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 endpoint values ​​of each range, the endpoint values ​​of each range and the 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 as specifically disclosed in this article.

[0044] The specific embodiments of the present invention are described in detail below. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present invention, and are not used 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 means that it contains 1 to 6 carbon atoms. The alkyl groups appearing 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 usually 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. Haloalkyl examples, such as 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. The method comprises the following steps:

[0052] Step (1), hydrolyzing the compound of formula V to generate 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 that can form a ligand with the copper salt; the copper salt is selected from at least one of copper powder, cupric chloride, cupric acetate, cuprous chloride, cuprous iodide, cuprous bromide, copper acetylacetonate, cupric acetate, cupric bromide, cupric iodide, copper trifluoroacetate, copper trifluoromethanesulfonate, copper phenylacetate, copper trifluoroacetylacetonate, copper hexafluoroacetylacetonate, copper ethylacetoacetate, triphenylphosphine cuprous bromide and copper benzoylacetonate, preferably cuprous chloride; the compound that can form a ligand with the copper salt is selected from ethylenediamine, tetramethylethylenediamine, dimethylmalonate, 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 the above step (1) is carried out in a solvent, and the solvent is 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, and N,N-dimethylformamide and water are particularly preferred. 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 the above step (2) is carried out in the presence of an organic acid, and the organic acid may 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 1-3MPa, preferably 1.5-2.5MPa.

[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, 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.

[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, sulfonyl chloride, thionyl chloride, N-chlorosuccinimide, dichlorohydantoin, dibromohydantoin, N-bromosuccinimide and bromine, preferably chlorine or bromine.

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

[0076] Preferably, the method for preparing the compound of formula III in the above steps comprises 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 in the above step comprises an amination step.

[0080] Preferably, the oxidation reaction is carried out under the catalysis of a cobalt salt, with oxygen oxidation at an oxidation temperature of 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, with a hydrolysis temperature of 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, benzenesulfonyl, methanesulfonyl, trimethylsilyl, and tert-butyl compounds, such as toluenesulfonyl chloride, benzyl bromide, acetyl chloride, acetic anhydride, propionyl chloride, trifluoromethanesulfonyl chloride, trifluoroacetyl chloride, formyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, trimethylsilyl chloride, di-tert-butyl dicarbonate, and the like protecting groups, but are not limited thereto.

[0087] Preferably, the above reaction is carried out in an organic solvent, the reaction temperature is -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 by 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, add 17.2 g (0.1 mol, 99%, purchased from Aladdin) of 4-chloro-3-nitrotoluene, 0.2 g of cobalt acetate, acetic acid, introduce oxygen, react at 100°C for 6 h, extract and desolventize, then directly add 26 g of ammonia water, keep warm at 105°C, react for 6 h, extract and desolventize with ethyl acetate to obtain 15.5 g of 4-amino-3-nitrobenzoic acid, with a yield of 85%.

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

[0099]

[0100] In a four-necked bottle, 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 into an autoclave, add 26g of ammonia water, keep warm at 105°C, react for 6h, 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, add 22.9g (0.1mol, 99%, purchased from Aladdin) of 3-nitro-4-chloro-N,N-dimethylbenzoyl, add 28g of ammonia water, keep warm at 100°C, react for 6h, add ethyl acetate for extraction and desolventization, add 60g of dichloroethane, keep warm at 5°C, add 16g of bromine dropwise, react for 2h, wash with water and alkali, extract and desolventize to obtain 23.6g of 3-nitro-4-amino-5-bromo-N,N-dimethylbenzoyl, with a yield of 82%; add 0.1mol of 3-nitro-4-amino-5-bromo-N,N-dimethylbenzoyl in a four-necked bottle, add 60g of acetic acid and 14.8g of acetic anhydride, keep warm at 85°C for 8h, wait until the raw materials react, desolventize, and obtain 31.4g of compound 3-nitro-4-acetylamino-5-bromo-N,N-dimethylbenzamide, with a yield of 95%;

[0105] In a four-necked flask, add 0.1mol 3-nitro-4-acetylamino-5-bromo-N,N-dimethylbenzamide, 120g water and 40g DMF, 16g sodium carbonate, 0.33g cuprous chloride, 0.33g 2-picolinic acid, and keep warm for 10h. HPLC detects that the raw materials are complete, cool to 0°C, filter, and obtain 24.0g 3-nitro-4-acetylamino-5-hydroxy-N,N-dimethylbenzamide, with a yield of 90%; then add all the solids in the previous step to 60g methanol, 26g acetic acid, and 0.5g palladium carbon, keep warm at 85°C, charge with hydrogen at 1.8MPa, react for 10h, HPLC detects that the raw materials are complete, filter and desolventize, and obtain 17.0g 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 bottle, add 0.1 mol 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide, 60 g acetonitrile, and 21.0 g p-toluenesulfonyl chloride. Keep warm at 30°C 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 4-hydroxy-N,N,2-trimethyl-1-(p-toluenesulfonyl)-1H-benzimidazole-6-carboxamide. The yield is 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, and 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 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 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxylic acid methyl ester

[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 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 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, to obtain 18.6 g of 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide 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, to obtain 14.7 g of 3-nitro-4-acetylamino-5-hydroxy-N,N-dimethylbenzamide, 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 113 Preparation of 4-nitro-5-hydroxy-N,N-dimethylbenzamide

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

[0126] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope 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), hydrolyzing 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.

2. 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 a solvent in the presence of a catalyst and an acidifying agent, the hydrolysis temperature is 0-150° C., preferably 30-80° C.; the hydrolysis time is 6-15 h, preferably 8-12 h.

3. The preparation method according to claim 2, characterized in that: The acid binding agent is selected from inorganic bases, 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.

4. The preparation method according to claim 2 or 3, 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, preferably cuprous chloride; the compound that can form a ligand with the copper salt is selected from ethylenediamine, tetramethylethylenediamine, dimethylpropylenediamine, tetramethyl The catalyst comprises the following: propylene diamine, 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 of formula V to the catalyst is 1: 0.2%-10% w / w, preferably 1: 0.5%-2% w / w.

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

6. The preparation method according to any one of claims 1 to 5, characterized in that: In step (2), the reduction and cyclization reaction of the compound of formula VI is carried out in an organic acid, and the organic acid is preferably acetic acid.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The reaction temperature of step (2) is 60-150° C., preferably 80-100° C.; the reaction pressure is 1-3 MPa, preferably 1.5-2.5 MPa.

8. The preparation method according to any one of claims 1 to 7, characterized in that: A catalyst is added in step (2), wherein 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.

9. The preparation method according to any one of claims 1 to 8, 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.

10. The preparation method according to any one of claims 1 to 9, 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.

11. The preparation method according to claim 10, 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.

12. The preparation method according to any one of claims 1 to 11, 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, R1 are as defined in claim 1, and R1 is preferably chlorine or bromine.

13. The preparation method according to claim 12, wherein: The halogenating agent is selected from at least one of a combination of sodium bromate and hydrogen peroxide, chlorine, sulfonyl chloride, thionyl chloride, N-chlorosuccinimide, dichlorohydantoin, dibromohydantoin, N-bromosuccinimide and bromine, preferably chlorine or bromine.

14. The preparation method according to claim 13, characterized in that: The halogenation reaction temperature is 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; the molar ratio of the compound of formula III to the halogenation agent is 1:1-3.

15. The preparation method according to any one of claims 1 to 14, 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 claims 1-4, X is fluorine, chlorine, bromine, iodine, and Y is methyl, trifluoromethyl.

16. The preparation method according to claim 15, characterized in that: in, The preparation of the compound of formula III from the compound of formula I as a raw material includes an amination, oxidation or hydrolysis step, 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, preferably 1:2-2.2; The amination reaction temperature is 10-180°C, preferably 70-100°C; The oxidation reaction is carried out under the catalysis of cobalt salt and oxygen oxidation, and the oxidation temperature is 50-150°C, preferably 100-120°C; the cobalt salt is preferably cobalt acetate; The hydrolysis reaction is carried out under the action of concentrated sulfuric acid at a temperature of 70-150°C, preferably 80-90°C.

17. The preparation method according to claim 15, characterized in that: The preparation of the compound of formula III from the compound of formula II comprises an amination step; The amination reaction temperature is 10-180°C, preferably 70-100°C; The aminating agent is aqueous ammonia or an alcoholic ammonia solution. The molar ratio of compound II to the aminating agent is 1:1.0-4.5, preferably 1:2-2.

2.

18. 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.

19. The preparation method according to claim 18, characterized in that: The reaction temperature is -10-100°C, preferably 10-40°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 preferably selected from one of toluene, acetonitrile, tetrahydrofuran, dioxane, and xylene.

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