A method for preparing tegrazan intermediate

Abstract

The present invention provides a method for synthesizing the compound of formula IX, an intermediate of tegrazan, and the method comprises: A. preparing the compound of formula II by halogenation reaction from the compound of formula I, without separation, and then preparing the compound of formula III by condensation reaction with an amine reagent; B. preparing the compound of formula IV by protecting the group on the compound of formula III; C. preparing the compound of formula V by reduction reaction from the compound of formula IV; D. preparing the compound of formula VI from the compound of formula V under catalyst conditions; E. preparing the compound of formula VII by cyclization reaction from the compound of formula VI; F. preparing the compound of formula VIII by reacting the compound of formula VII with TsCl; G. preparing the compound of formula IX, an intermediate of tegrazan, by deprotection reaction from the compound of formula VIII; The synthesis process of the present invention has low cost, high yield of the compound of formula IX, an intermediate of tegrazan, and strong applicability to industrialized scale-up production.

Description

Background Art

[0001] Tegoprazan, also known as Tegprazan, has the following chemical structural formula:

[0002]

[0003] Tegoprazan is a competitive potassium ion acid blocker (P-CAB) and a hydrogen ion potassium ion exchange ATPase (H+ / K+ ATPase) inhibitor, approved for the treatment of gastroesophageal reflux disease and erosive esophagitis. Tegoprazan was initially developed by Pfizer and licensed to RaQualia Pharma (separated from Pfizer) for co-development in 2008. In 2014, it was licensed by RaQualia Pharma to CJ, and in 2015, CJ HealthCare signed an agreement with Shandong Luoxin Pharmaceutical to jointly develop related diseases in China. Tegoprazan was approved for marketing by the Ministry of Food and Drug Safety (MFDS) of South Korea in July 2018 and is marketed in South Korea by CJ HealthCare.

[0004] Gastroesophageal reflux disease is a very common digestive tract disease with a high incidence in the population. The main symptoms are heartburn, chest pain, acid reflux, and regurgitation, etc. In severe cases, it can lead to esophagitis. Surveys show that about 7% of people experience reflux symptoms almost every day. Currently, the treatment methods for this type of disease include drug treatment and surgical treatment, but both have their own disadvantages. Therefore, it is necessary to develop new drugs for the treatment of such common diseases. Tegoprazan is a potassium-competitive acid blocker and is considered the most advanced drug for the treatment of gastroesophageal reflux disease at present. Since proton pump inhibitors are the most common drugs for the treatment of gastroesophageal reflux disease, and Tegoprazan can just overcome the disadvantages of proton pump inhibitors. Tegporazan provides a new option for the treatment of this type of disease and makes up for the disadvantages of other drugs to a certain extent.

[0005] The Chinese patent CN101341149B applied by RaQualia Pharma Co., Ltd. on December 6, 2006, disclosed the following route:

[0006]

[0007] This route uses 2-(benzyloxy)-4-bromo-6-nitroaniline as the starting material, which is expensive and difficult to prepare. The cost of precious metal catalysts such as tetrakis(triphenylphosphine)palladium and palladium hydroxide used in the route is also very high. In addition, there are two steps in this route that require microwave reactions, and four steps of reaction work-up require column chromatography separation, with complex operations and it is difficult to achieve industrial production.

[0008] The patent WO2008114123 applied by Raqualia Pharma Inc. on March 12, 2008 discloses the following route:

[0009]

[0010] This route also has disadvantages such as difficult availability of raw materials, high reagent prices, complex post-treatment, and dangerous operations, making it difficult to achieve industrial production.

[0011] This route uses inexpensive and easily available 3-hydroxy-4-nitrobenzoic acid as the starting material, and prepares the Tegrazan intermediate of formula IX through seven steps of reactions including amidation, phenolic hydroxyl protection, nitro reduction, acetonitrile amination, cyclization, Ts addition, and deprotection. It has the advantages of low raw material and reagent prices, safe and simple reactions, few by-products, high total yield, good product quality, and simple post-treatment, and is suitable for large-scale industrial production. Summary of the Invention

[0012] The present invention provides a method for synthesizing a Tegrazan intermediate. The synthesis process of the present invention has low cost, high yield of the prepared Tegrazan intermediate, and strong applicability to industrial scale-up production.

[0013] To achieve the technical objectives of the present invention, the following technical solutions are provided:

[0014] First, the present invention provides a method for preparing a compound of the Tegrazan intermediate of formula IX, comprising the following steps:

[0015] A. The compound of formula II is prepared by halogenation reaction from the compound of formula I, and without separation, it is then subjected to a condensation reaction with an amine reagent to prepare the compound of formula III;

[0016] B. The compound of formula IV is prepared by adding a protecting group to the compound of formula III;

[0017] C. The compound of formula V is prepared by reduction reaction from the compound of formula IV;

[0018] D. The compound of formula VI is prepared from the compound of formula V under the condition of a catalyst;

[0019] E. The compound of formula VII is prepared by cyclization reaction from the compound of formula VI;

[0020] F. The compound of formula VIII is prepared by reacting the compound of formula VII with TsCl;

[0021] G. The Tegrazan intermediate of formula IX is prepared by deprotection reaction from the compound of formula VIII;

[0022]

[0023] Wherein, X is a halogen;

[0024] Prot is a protecting group, and the protecting group is benzyl, p-methoxybenzyl, benzyloxyhydroxy, allyl, acetyl, benzoyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropylsilyl;

[0025] The halogenating reagent in the halogenation reaction in step A is thionyl chloride (SOCl2), oxalyl chloride ((COCl)2), phosphorus trichloride (PCl3), phosphorus pentachloride (PCl5) or pivaloyl chloride (tBuCl);

[0026] The base used in step A is triethylamine, diisopropylamine, N-methylmorpholine, N-methylpiperidine, potassium tert-butoxide, sodium ethoxide or sodium hydroxide;

[0027] The amine reagent in step A is dimethylamine, dimethylamine hydrochloride, aqueous solution of dimethylamine;

[0028] The reaction temperature in step A is 0 to 100 °C;

[0029] The reaction solvent in step A is acetonitrile, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, xylene or chlorobenzene;

[0030] The reaction solvent in step B is acetone, acetonitrile, tetrahydrofuran, toluene or xylene;

[0031] The reaction temperature in step B is 0 - 100 °C;

[0032] The feeding ratio of the substrate to the protecting group reagent in the step is 1∶0.8 - 1.5;

[0033] The nitro reduction reagent in step C is Zn powder, Fe powder, SnCl2 or sodium dithionite;

[0034] The acid in step C is HCl, AcOH or NH4Cl;

[0035] The reaction solvent in step C is dichloromethane, chloroform, methanol, ethanol, water, acetonitrile, tetrahydrofuran, toluene or xylene;

[0036] The reaction temperature in step C is 0 to 100 °C;

[0037] The reaction solvent in step D is acetonitrile or a mixed solvent of acetonitrile and other solvents;

[0038] The reaction catalyst in step D is HCl gas, HCl organic solution or aluminum trichloride;

[0039] The reaction temperature in step D is 20 to 80 °C;

[0040] The reaction cyclization reagent in step E is NCS, NBS, NIS, trichloroisocyanuric acid or sodium hypochlorite solution;

[0041] The reaction solution in step E is acetonitrile, acetone, toluene or an alcohol solvent;

[0042] The reaction temperature in step E is -5 to 80 °C;

[0043] The reaction solution in step F is acetonitrile, acetone, dichloromethane, toluene, xylene, tetrahydrofuran or ethyl acetate;

[0044] The reaction temperature in step F is -5 to 80 °C;

[0045] The reaction base in step F is triethylamine, diisopropylethylamine, N-methylpiperidine, N-methylmorpholine, DBU, sodium carbonate, potassium carbonate, sodium hydroxide or sodium hydride;

[0046] The reaction conditions for deprotecting the protecting group in step G are removal under hydrogen atmosphere using Pd / C, palladium hydroxide, palladium black or platinum, and the pressure is 1 to 50 atm;

[0047] The reaction solvent in step G is tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, isopropanol, acetic acid or dichloromethane;

[0048] The reaction temperature in step G is 0 to 80 °C.

[0049] Then, the present invention provides a method for preparing a compound of the structure of formula IX, an intermediate of tegaserod, which includes the following steps:

[0050] A. The compound of formula II' is prepared by halogenating the compound of formula I with thionyl chloride at 70 °C, and without separation, it is then reacted with dimethylamine hydrochloride under the action of triethylamine to prepare the compound of formula III;

[0051] B. The compound of formula IV' is prepared by reacting the compound of formula III with benzyl bromide under the conditions of acetone and sodium carbonate; the feeding ratio of the compound of formula III to benzyl bromide is 1:0.8 to 1.5, preferably 1:1;

[0052] C. The compound of formula V' is prepared by reducing the compound of formula IV' with Zn powder under the conditions of dichloromethane and acetic acid;

[0053] D. The compound of formula VI' is prepared by catalyzing the compound of formula V' with HCl in an acetonitrile solution;

[0054] E. The compound of formula VII' is prepared by cyclizing the compound of formula VI' with NCS in an acetonitrile solution;

[0055] F. The compound of formula VIII’ is prepared by reacting the compound of formula VII’ with TsCl in the presence of a solvent and a base;

[0056] G. The intermediate of tegaserod, the compound of formula IX, is prepared by deprotecting the compound of formula VIII’ under the condition of THF in a hydrogen atmosphere using Pd / C;

[0057]

[0058] The reaction solution in step F is acetonitrile, acetone, dichloromethane, toluene, xylene, tetrahydrofuran or ethyl acetate;

[0059] The reaction temperature in step F is -5 to 80 °C;

[0060] The reaction base in step F is triethylamine, diisopropylethylamine, N-methylpiperidine, DBU, sodium carbonate, potassium carbonate, sodium hydroxide or sodium hydride.

[0061] The intermediate of tegaserod is prepared according to the above method, with low cost, high yield, simple operation and strong applicability to industrialized scale-up production. Detailed Description of the Invention

[0062] To further understand the present invention, a method for synthesizing an intermediate of tegaserod provided by the present invention will be described in detail below with reference to examples. It should be understood that these example descriptions are only for further elaborating the features of the present invention, rather than limiting the scope of the present invention or the scope of the claims of the present invention.

[0063] Example 1: Synthesis of Compound III’

[0064]

[0065] Into a 5L three-necked flask, add 3-hydroxy-4-nitrobenzoic acid (183 g, 1.0 mol), dry acetonitrile (1.0 L), and DMF (3.7 g, 2.0 mol). Start mechanical stirring and slowly heat up to 70 °C. Then, slowly add thionyl chloride (238.0 g, 2.0 mol) dropwise to the reaction solution within 0.5 - 1.0 hours. After dropping, continue the reaction for 2 hours. Then, cool down to 0 °C, add dimethylamine hydrochloride (163.0 g, 2.0 mol) to the reaction solution, continue stirring for 0.5 hours, slowly add triethylamine (405.0 g, 4.0 mol) dropwise within 1.0 hour. After dropping, heat up to room temperature and continue the reaction for 0.5 hours. Evaporate the solvent under reduced pressure at 40 - 50 °C, add 300 mL of water, adjust the pH value to 3 - 4 with 2N dilute hydrochloric acid, extract with dichloromethane twice (500 ml x 3), discard the aqueous phase, combine the organic phases, and concentrate to dryness under reduced pressure at 35 - 40 °C to obtain a pale yellow solid (206.0 g, 0.98 mol), which is the target product compound III with a yield of 93.2%. 1 H NMR (400 MHz, CDCl3) δ 2.96 (s, 3H), 3.12 (s, 3H), 7.00 (d, 2H, J = 8.4 Hz), 7.17 (s, 1H), 8.15 (d, 1H, J = 8.4 Hz), 10.61 (s, 1H). MS (ESI): m / z 211.0683 [M + H] + 。

[0066] Example 2: Synthesis of Compound IV’

[0067]

[0068] Into a 2.0L three-necked flask, add 3-hydroxy-N,N-dimethyl-4-nitrobenzamide (168.2 g, 0.80 mol), acetone (800 mL), and potassium carbonate (221.1 g, 0.016 mol). Start mechanical stirring and keep it at room temperature for 10 minutes. Then, slowly add benzyl bromide (136.8 g, 0.80 mol) dropwise to the reaction solution within 0.5 - 1.0 hours. After dropping, heat up to reflux and react for 4.0 hours. After the reaction is completed, evaporate the solvent under reduced pressure at 40 - 50 °C, add 500 mL of water, extract with isopropyl acetate twice (500 ml x 2), discard the aqueous phase, combine the organic phases, and concentrate to dryness under reduced pressure at 35 - 40 °C to obtain a yellow viscous substance (233.3 g, 0.78 mol), which is the target product compound IV’ with a yield of 97.2%. 11H NMR (400 MHz, CDCl3) δ 2.96 (s, 3H), 3.09 (s, 3H), 5.25 (s, 2H), 7.04 (d, 2H, J = 8.4 Hz), 7.16 (s, 1H), 7.32 - 7.44 (m, 5H), 7.87 (d, 1H, J = 8.0 Hz). MS (ESI): m / z 301.1132 [M+H] + 。

[0069] Example 3: Synthesis of Compound V'

[0070]

[0071] 3-(benzyloxy)-N,N-dimethyl-4-nitrobenzamide (180.2 g, 0.6 mol) and dichloromethane (800 ml) were charged into a 1.0 L three-necked flask, and acetic acid (180.2 g, 1.8 mol) was added. Mechanical stirring was started, and the mixture was stirred at room temperature for 10 minutes. Subsequently, Zn powder (78.5 g, 1.2 mol) was added in batches, in four batches, 19.6 g each time, with an interval of 1.5 h. The reaction progress was monitored by HPLC. The reaction was complete after 7 h. The mixture was filtered, and the filter cake was washed with 200 mL of dichloromethane. The filtrate was added with 500 mL of water, stirred and then separated. The aqueous phase was extracted with dichloromethane twice (500 ml x 2), the aqueous phase was discarded, and the organic phases were combined and concentrated under reduced pressure to dryness at 35 - 40 °C to obtain a yellow viscous substance (150.2 g, 0.56 mol), which was the target product Compound V', with a yield of 92.5%. 1 1H NMR (400 MHz, CDCl3) δ 3.01 (s, 6H), 4.02 (s, 2H), 5.09 (s, 2H), 6.68 (d, 1H, J = 8.0 Hz), 6.96 (d, 1H, J = 8.0 Hz), 7.01 (s, 1H), 7.33 - 7.44 (m, 5H). MS (ESI): m / z 271.1354 [M+H] + 。

[0072] Example 4: Synthesis of Compound VI'

[0073]

[0074] In a 1.0 L three-necked flask, 4-amino-3-(benzyloxy)-N,N-dimethylbenzamide (135.2 g, 0.5 mol) and acetonitrile (200 ml) were added. Mechanical stirring was started, and after mixing evenly, the temperature was lowered to 0 - 5 °C. Then, a 1.0 M acetonitrile hydrochloride solution (1.0 L) was slowly added thereto. After the addition, the temperature was raised to 70 °C for reaction, and the reaction progress was monitored by HPLC. The reaction was complete after 3 h. Filtration was carried out, and the filter cake was washed with 200 mL of acetonitrile. The solid was transferred to be dried at 60 °C for 12 hours, and then mixed evenly with 500 mL of dichloromethane. The pH value was adjusted to 10 - 11 with 40% sodium hydroxide solution. After stirring, liquid separation was carried out. The aqueous phase was extracted with dichloromethane twice (500 ml × 2), the aqueous phase was discarded, and the organic phases were combined and concentrated under reduced pressure to dryness at 35 - 40 °C to obtain a colorless viscous substance (153.2 g, 0.49 mol), which was the target product compound VI', and the yield was 98.3%. 1 1H NMR (400 MHz, CDCl3) δ 1.98 (s, 3H), 2.93 (s, 3H), 3.03 (s, 3H), 5.08 (s, 2H), 6.99 (s, 1H), 7.00 (s, 1H), 7.27 - 7.39 (m, 5H). MS (ESI): m / z 312.1647 [M + H] + 。

[0075] Example 5: Synthesis of compound VII'

[0076]

[0077] In a 250 ml three-necked flask, 4-acetimidamido-3-(benzyloxy)-N,N-dimethylbenzamide (62.3 g, 0.2 mol) and acetonitrile (800 ml) were added. Mechanical stirring was started, and the temperature was lowered to 0 - 5 °C. NCS (26.7 g, 0.2 mol) was added thereto, and stirring was continued for 0.5 hour. Then, a 50% NaOH solution (80 g, 1.0 mol) was slowly added dropwise to the reaction solution. After the addition, stirring was continued for 1.0 hour, and the reaction progress was monitored by TLC. Then, 700 ml of the solvent was distilled off under reduced pressure at 40 - 50 °C. 300 ml of water and 300 ml of EA were added. The pH value was adjusted to 4 - 5 with hydrochloric acid. After stirring, liquid separation was carried out. The organic phase was extracted once more with 300 ml of dilute hydrochloric acid (pH value 4 - 5). The aqueous phases were combined, the pH value was adjusted to 9 - 10 with saturated Na2CO3 solution, and extracted with DCM twice (500 ml × 2). The aqueous phase was discarded, and the organic phases were combined and concentrated under reduced pressure to dryness at 35 - 40 °C to obtain a pale yellow solid (54.8 g, 0.18 mol), which was the target product compound VII', and the yield was 88.6%. 11H NMR (400 MHz, DMSO-d6) δ 2.54 (s, 3H), 2.92 (s, 3H), 3.07 (s, 3H), 5.27 (s, 2H), 6.83 (s, 1H), 7.29 (d, 1H, J = 8.4 Hz), 7.35 (t, 2H, J = 6.8 Hz), 7.49 (t, 2H, J = 7.2 Hz). MS (ESI): m / z 310.1563 [M+H] + 。

[0078] Example 6: Synthesis of Compound VIII’

[0079]

[0080] 4-(Benzyloxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (46.4 g, 0.15 mol) and DCM (500 ml) were added into a 2.0 L three-necked flask. Magnetic stirring was started, and then a DCM solution of p-toluenesulfonyl chloride (28.6 g, 0.15 mol) was slowly added dropwise. After the addition was complete, stirring was continued for 10 minutes, and then triethylamine (45.4 g, 0.45 mol) was added dropwise to the system. After the addition was complete, the temperature was raised to room temperature, and the reaction progress was monitored by HPLC. The reaction was complete after 3 h. 500 ml of water was added, and after stirring, the layers were separated. The aqueous phase was extracted twice with DCM (300 ml x 2). The organic phases were combined and concentrated under reduced pressure to dryness at 35 - 40 °C to obtain a white solid (66.9 g, 0.144 mol), which was the target product Compound VIII’, with a yield of 96.2%. 1 1H NMR (400 MHz, CDCl3) δ 2.40 (s, 3H), 2.81 (s, 3H), 2.87 (s, 3H), 3.11 (s, 3H), 5.32 (s, 2H), 6.86 (s, 1H), 7.28 - 7.36 (m, 5H), 7.43 (s, 1H), 7.45 (s, 1H), 7.69 (s, 1H), 7.78 (d, 2H, J = 8.4 Hz). MS (ESI): m / z 464.1678 [M+H] + 。

[0081] Example 7: Synthesis of Compound IX

[0082]

[0083] Into a 1.0 L three-necked flask was added

[0084] 4-(Benzyloxy)-N,N,2-trimethyl-1-tosyl-1H-benzo[d]imidazole-6-carboxamide (46.4 g, 0.1 mol), THF (400 ml), 10% Pd / C (10 g) were reacted at room temperature for 24 h under a hydrogen (1 atm) atmosphere. Subsequently, 6.5 g of 10% Pd / C was added, and the reaction was continued at room temperature for 6 h under a hydrogen (1 atm) atmosphere. The reaction progress was monitored by HPLC. After the reaction was completed, the mixture was filtered, and the filter cake was washed with 100 ml of THF. The filtrates were combined and concentrated to dryness under reduced pressure at 35 - 40 °C to obtain a white solid (36.1 g, 0.097 mol), which was the target product compound IX with a yield of 96.8%. 1 H NMR (400 MHz, CDCl3) δ 2.41 (s, 3H), 2.79 (s, 3H), 3.02 (s, 3H), 3.15 (s, 3H), 6.92 (s, 1H), 7.32 (d, 2H, J = 8.1 Hz), 7.63 (s, 1H), 7.82 (d, 2H, J = 8.1 Hz). MS (ESI): m / z 374.1210 [M + H] + 。

Claims

1. A method for preparing a compound of formula IX, an intermediate of tegrazan, characterized in that, It includes the following steps: A. The compound of formula II is prepared by the halogenation reaction of the compound of formula I, and without separation, it is then subjected to a condensation reaction with an amine reagent to prepare the compound of formula III; B. The compound of formula IV is prepared by protecting the compound of formula III; C. The compound of formula V is prepared by the reduction reaction of the compound of formula IV; D. The compound of formula VI is prepared from the compound of formula V under the condition of a catalyst; E. The compound of formula VII is prepared by the cyclization reaction of the compound of formula VI; F. The compound of formula VIII is prepared by reacting the compound of formula VII with TsCl; G. The intermediate of tegrazan of formula IX is prepared by the deprotection reaction of the compound of formula VIII; wherein, X is a halogen; Prot is a protecting group, and the protecting group is benzyl, p-methoxybenzyl, benzyloxyhydroxy, allyl, acetyl, benzoyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or triisopropylsilyl, In the halogenation reaction in step A, the halogenating reagent is thionyl chloride (SOCl2), oxalyl chloride ((COCl)2), phosphorus trichloride (PCl3), phosphorus pentachloride (PCl5), or pivaloyl chloride (tBuCl); the base used is triethylamine, diisopropylamine, N-methylmorpholine, N-methylpiperidine, potassium tert-butoxide, sodium ethoxide, or sodium hydroxide; the amine reagent is dimethylamine, dimethylamine hydrochloride, or aqueous dimethylamine; the reaction temperature is 0 - 100 °C; the reaction solvent is acetonitrile, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, xylene, or chlorobenzene, In the reaction solution in step F, the reaction solvent is acetonitrile, acetone, dichloromethane, toluene, xylene, tetrahydrofuran, or ethyl acetate; the reaction temperature is -5 - 80 °C; the reaction base is triethylamine, diisopropylethylamine, N-methylpiperidine, N-methylmorpholine, DBU, sodium carbonate, potassium carbonate, sodium hydroxide, or sodium hydride.

2. A method for preparing a compound of formula IX, an intermediate of tegrazan, characterized in that, It includes the following steps: A. The compound of formula II' is prepared by halogenating the compound of formula I with thionyl chloride at 70 °C, and without separation, it is then subjected to a condensation reaction with dimethylamine hydrochloride in triethylamine to prepare the compound of formula III; B. The compound of formula IV' is prepared by reacting the compound of formula III with benzyl bromide under the conditions of acetone and sodium carbonate; the feeding ratio of the compound of formula III to benzyl bromide is 1:0.8 - 1.5; C. The compound of formula V' is prepared by reducing the compound of formula IV' with Zn powder under the conditions of dichloromethane and acetic acid; D. The compound of formula VI' is prepared from the compound of formula V' by catalysis with HCl in an acetonitrile solution; E. The compound of formula VII' is prepared by cyclizing the compound of formula VI' with NCS in an acetonitrile solution; F. The compound of formula VIII' is prepared by reacting the compound of formula VII' with TsCl in a solvent and triethylamine; G. The intermediate of tegrazan of formula IX is prepared by the deprotection reaction of the compound of formula VIII' with Pd / C in a hydrogen environment under the condition of THF; The reaction temperature is 0 - 100 °C; the reaction solvent is acetonitrile, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, xylene, or chlorobenzene; The reaction solution in step F is acetonitrile, acetone, dichloromethane, toluene, xylene, tetrahydrofuran or ethyl acetate; the reaction temperature is -5 to 80 °C.

3. The preparation method according to claim 1, characterized in that, The reaction solvent in step B is acetone, acetonitrile, tetrahydrofuran, toluene or xylene; the reaction temperature in step B is 0 - 100 °C; the feeding ratio of the substrate to the protecting group reagent in step B is 1:0.8 - 1.

5.

4. The preparation method according to claim 1, characterized in that, The nitro reduction reagent in step C is Zn powder, Fe powder, SnCl2 or sodium dithionite; the acid in step C is HCl, AcOH or NH4Cl; the reaction solvent in step C is dichloromethane, chloroform, methanol, ethanol, water, acetonitrile, tetrahydrofuran, toluene or xylene; the reaction temperature in step C is 0 - 100 °C.

5. The preparation method according to claim 1, characterized in that, The reaction solvent in step D is acetonitrile or a mixed solvent of acetonitrile and other solvents; the reaction catalyst in step D is HCl gas, an organic solution of HCl or aluminum trichloride; the reaction temperature in step D is 20 - 80 °C.

6. The preparation method according to claim 1, characterized in that, The cyclization reagent in step E is NCS, NBS, NIS, trichloroisocyanuric acid or sodium hypochlorite solution; the reaction solution in step E is acetonitrile, acetone, toluene or an alcohol solvent; the reaction temperature in step E is -5 to 80 °C.

7. The preparation method according to claim 1, characterized in that, The conditions for deprotecting in step G are removal under hydrogen atmosphere with Pd / C, palladium hydroxide, palladium black or platinum, and the pressure is 1 - 50 atm; the reaction solvent in step G is tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, isopropanol, acetic acid or dichloromethane; the reaction temperature in step G is 0 - 80 °C.

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