A method for preparing a 5-HT3 receptor modulator

Abstract

The present invention provides a method for preparing a 5-HT3 receptor modulator, belonging to the field of pharmaceutical synthesis. The structure of the 5-HT3 receptor modulator is shown in Formula I. The synthesis method of the present invention utilizes readily available raw materials, mild reaction conditions, and achieves a total yield of up to 45.1% and a product purity of up to 97%, making it suitable for industrial production. #imgabs0#

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and particularly relates to a method for preparing a 5-HT3 receptor modulator. Background Art

[0002] Irritable bowel syndrome (IBS) is a functional intestinal disorder characterized by persistent or intermittent episodes of abdominal pain, bloating, and changes in bowel habits and / or stool consistency. It lacks structural or biochemical abnormalities in the gastrointestinal tract. Rome III classifies IBS as a functional bowel disorder. It primarily affects young and middle-aged individuals, with onset typically occurring between the ages of 20 and 50. It is more common in women than in men, tends to run in families, and often coexists with other gastrointestinal disorders, such as functional dyspepsia. The prevalence of IBS in adults is 10% to 20%, and currently, few effective treatments are available.

[0003] Research indicates that 5-hydroxytryptamine (5-HT) is a key neurotransmitter in the gastrointestinal tract, and the 5-hydroxytryptamine 3 (5-HT3) receptor is an important target for the development of drugs for irritable bowel syndrome, carcinoid syndrome, and vomiting. Example 23 of the Chinese patent with authorization publication number CN102046176B discloses a compound and its preparation method: (S)-7-(quinin-3-yl)-2,7,8,9-tetrahydro-6H-azaheterocyclo[5,4,3-cd]indazol-6-one (structure shown below). This compound can act as a 5-HT3 receptor modulator and can be used to treat a variety of conditions, including chemotherapy-induced nausea and vomiting, postoperative nausea and vomiting, and irritable bowel syndrome, with broad application prospects. However, the method for preparing (S)-7-(quinin-3-yl)-2,7,8,9-tetrahydro-6H-azacyclo[5,4,3-cd]indazol-6-one in this patent is relatively expensive and has a total yield as low as less than 10%, making it unsuitable for large-scale promotion.

[0004]

[0005] It is of great significance to develop a method for synthesizing (S)-7-(quinin-3-yl)-2,7,8,9-tetrahydro-6H-azacyclo[5,4,3-cd]indazol-6-one with higher yield. Summary of the Invention

[0006] The object of the present invention is to provide a new method for preparing (S)-7-(quinin-3-yl)-2,7,8,9-tetrahydro-6H-azacyclo[5,4,3-cd]indazol-6-one.

[0007] The present invention provides a method for synthesizing the compound represented by formula I, comprising the following steps:

[0008] (1) Compound 5 reacts with an acid to obtain compound 6;

[0009] (2) Compound 6 reacts with compound 7 or a salt thereof to obtain compound 8;

[0010] (3) Compound 8 reacts with lithium hydroxide or its hydrate to obtain compound 9;

[0011] (4) Compound 9 reacts in the presence of a base and a dehydrating agent to obtain compound 10;

[0012] (5) Compound 10 reacts with a deprotection reagent to obtain a compound represented by Formula I;

[0013]

[0014] R1 is an amino protecting group.

[0015] Furthermore, in step (1), the acid is hydrochloric acid, the molar ratio of the compound 5 to the acid is 1:(5-20), the reaction solvent is an organic solvent, the reaction temperature is 40-60° C., and the reaction time is 2-6 hours;

[0016] In step (2), the reaction is carried out in the presence of an acid and a reducing agent, the molar ratio of compound 6, compound 7 or a salt thereof, the acid, and the reducing agent is 1:(1-4):(1-4):(1-4), the reaction solvent is an organic solvent, the reaction temperature is 20-40° C., and the reaction time is 12-22 hours;

[0017] In step (3), the molar ratio of compound 8 and lithium hydroxide or its hydrate is 1:(1-4), the reaction solvent is water, an organic solvent or a mixture of the two, the reaction temperature is 50-90° C., and the reaction time is 0.5-3 hours;

[0018] In step (4), the mass ratio of compound 9 to the base is 1:(1-3), the molar ratio of the base to the dehydrating agent is (1-3):1, the base is an organic base, the dehydrating agent is 1-propyl phosphoric anhydride, the solvent of the reaction is an organic solvent, the reaction temperature is 20-40°C, and the reaction time is 6-20 hours;

[0019] In step (5), the deprotection reagent is trifluoroacetic acid, the mass volume ratio of compound 10 to trifluoroacetic acid is 50-70 mg / mL, the reaction solvent is an organic solvent, the reaction temperature is 60-100° C., and the reaction time is 6-20 hours.

[0020] Furthermore, in step (1), the concentration of the hydrochloric acid is 5-7 mol / L, the molar ratio of the compound 5 to the acid is 1:12, the organic solvent is tetrahydrofuran, the reaction temperature is 50° C., and the reaction time is 4 hours;

[0021] In step (2), the reducing agent is sodium triacetoxyborohydride, the salt of compound 7 is the dihydrochloride of compound 7, the molar ratio of compound 6, compound 7 or its salt, acid, and reducing agent is 1:2:1:2, the organic solvent is acetonitrile, the reaction temperature is room temperature, and the reaction time is 16-18 hours;

[0022] In step (3), the molar ratio of compound 8 and lithium hydroxide or its hydrate is 1:2, the lithium hydroxide hydrate is lithium hydroxide monohydrate, the solvent of the reaction is methanol, water or a mixture of the two, the reaction temperature is 70° C., and the reaction time is 1 hour;

[0023] In step (4), the mass ratio of compound 9 to the base is 1:1.5, the molar ratio of the base to the dehydrating agent is 1.6:1, the organic base is N,N-diisopropylethylamine, the organic solvent is one or a mixture of tetrahydrofuran and ethyl acetate, the reaction temperature is room temperature, and the reaction time is 8-12 hours;

[0024] In step (5), the mass volume ratio of compound 10 to trifluoroacetic acid is 62.5 mg / mL, the organic solvent is anisole, the reaction temperature is 80° C., and the reaction time is 8-12 hours.

[0025] Furthermore, in step (1), after the reaction is completed, the following purification step is further included: the reaction solution is added to ice water, the pH is adjusted to 9-11 with a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, the organic phase is retained, and dried to obtain compound 6;

[0026] In step (2), after the reaction is completed, the following purification step is further included: the reaction solution is added to ice water, extracted with dichloromethane, the aqueous phase is adjusted to pH 9-11 with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, the organic phase is retained, and dried to obtain compound 8;

[0027] In step (4), after the reaction is completed, the following purification step is further included: the reaction solution is added to water, extracted with dichloromethane, the organic phase is retained, and dried to obtain compound 10;

[0028] In step (5), after the reaction is completed, the following purification step is further included: adding hydrochloric acid to the reaction solution, extracting with methyl tert-butyl ether, adjusting the pH of the aqueous phase to 9-11, extracting with dichloromethane solution, retaining the organic phase, and drying to obtain the compound shown in Formula I.

[0029] Furthermore, the preparation method of the compound 5 comprises the following steps: reacting compound 3 with compound 4 to obtain compound 5;

[0030]

[0031] R1 is an amino protecting group, and X is a halogen.

[0032] Furthermore, the reaction is carried out in the presence of a palladium catalyst and a phase transfer catalyst, the molar ratio of compound 3, compound 4, palladium catalyst and phase transfer catalyst is 1:(1-3):(0.01-0.1):(1-3), the reaction solvent is water, an organic solvent or a mixture of two, the reaction temperature is 40-60°C, and the reaction time is 12-20h.

[0033] Furthermore, the palladium catalyst is dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II), the phase transfer catalyst is cesium carbonate, the molar ratio of compound 3, compound 4, palladium catalyst and phase transfer catalyst is 1:1.5:0.05:2, the reaction solvent is water, 1,4-dioxane or a mixture of two, the reaction temperature is 50°C, and the reaction time is 16 hours;

[0034] Preferably, after the reaction is completed, the following purification step is further included: the reaction solution is concentrated and then subjected to column chromatography to obtain compound 5; the eluent for the column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 6:1.

[0035] Furthermore, the preparation method of compound 3 comprises the following steps:

[0036] (a) Compound 1 reacts with a halogenating agent to obtain Compound 2;

[0037] (b) Compound 2 reacts with an amino protecting agent to obtain compound 3;

[0038]

[0039] X is a halogen, and R1 is an amino protecting group.

[0040] Furthermore, in step (a), the halogenating agent is a brominating agent, and the reaction is carried out in the presence of a base; the molar ratio of compound 1, the brominating agent, and the base is 1:(0.8-1.2):(2-6), the reaction solvent is an organic solvent, the reaction temperature is 20-40° C., and the reaction time is 0.5-3 hours;

[0041] In step (b), the amino protecting reagent is p-methoxybenzyl chloride, the mass volume ratio of compound 2 to p-methoxybenzyl chloride is 0.1-0.5 g / mL, the reaction temperature is 40-60 ° C, and the reaction time is 5-9 hours;

[0042] X is bromine, and R1 is p-methoxybenzyl.

[0043] Further, in step (a), the brominating agent is N-bromosuccinimide, the base is an inorganic base, preferably potassium hydroxide; the molar ratio of compound 1, the brominating agent, and the base is 1:1:4, the organic solvent is N,N-dimethylformamide, the reaction temperature is room temperature, and the reaction time is 1 hour;

[0044] Preferably, after the reaction in step (a) is completed, the following purification step is further included: concentrating and filtering the reaction solution, adding the filtrate to ice water, extracting with ethyl acetate, and washing the retained organic phase with saturated brine and drying to obtain compound 2;

[0045] In step (b), the mass volume ratio of compound 2 to p-methoxybenzyl chloride is 0.2 g / mL, the reaction temperature is 50° C., and the reaction time is 7 hours;

[0046] Preferably, after the reaction in step (b) is completed, the following purification step is further included: adding petroleum ether to the reaction solution, stirring and then filtering, washing the filter cake with petroleum ether, and drying to obtain compound 3.

[0047] In the present invention, room temperature refers to 25±5°C.

[0048] The present invention provides a novel method for preparing (S)-7-(quinin-3-yl)-2,7,8,9-tetrahydro-6H-azacyclo[5,4,3-cd]indazol-6-one. The method utilizes readily available raw materials, mild reaction conditions, and achieves a total yield of up to 45.1% and a product purity of up to 97%, making it suitable for industrial production.

[0049] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0050] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1: The NMR spectrum of (S)-7-(quinin-3-yl)-2,7,8,9-tetrahydro-6H-azacyclo[5,4,3-cd]indazol-6-one obtained in Example 1. DETAILED DESCRIPTION

[0052] The raw materials and equipment used in the present invention are all known products and are obtained by purchasing commercially available products.

[0053] Example 1. Preparation of (S)-7-(quinin-3-yl)-2,7,8,9-tetrahydro-6H-azacyclo[5,4,3-cd]indazol-6-one

[0054]

[0055] Step 1: Preparation of methyl 3-bromo-1H-indazole-4-carboxylate

[0056]

[0057] Methyl 1H-indazole-4-carboxylate (45.0 g, 255.6 mmol) was dissolved in dry N,N-dimethylformamide (0.9 L), and potassium hydroxide (57.0 g, 1022.7 mmol) was added. N-bromosuccinimide (NBS, 45.5 g, 255.7 mmol) was added portionwise to the reaction system with stirring, and the reaction was allowed to proceed at room temperature for 1 h. After completion of the reaction, the residual potassium hydroxide was removed by filtration under reduced pressure, and the filtrate was poured into 3 L of ice water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain methyl 3-bromo-1H-indazole-4-carboxylate (59.8 g, 92.4% yield) as a yellow solid.

[0058] MS m / z(ESI):255.0,257.0[M+H] + .

[0059] 1 H NMR (400MHz, CDCl3) δ7.80 (dd, J=8.5, 0.7Hz, 1H), 7.69 (dd, J=7.2, 0.7Hz, 1H), 7.49 (dd, J=8.5, 7.2Hz, 1H), 4.04 (s, 3H).

[0060] Step 2: Preparation of methyl 3-bromo-2-(4-methoxybenzyl)-2H-indazole-4-carboxylate hydrochloride

[0061]

[0062] Methyl 3-bromo-1H-indazole-4-carboxylate (30.0 g, 117.6 mmol) was added to p-methoxybenzyl chloride (PMB-Cl, 150 mL) and reacted at 50°C for 7 h. After the reaction was completed and cooled to room temperature, 1 L of petroleum ether was added to the system, stirred for 1 h, and filtered under reduced pressure. The filter cake was washed with 0.4 L of petroleum ether and dried to obtain methyl 3-bromo-2-(4-methoxybenzyl)-2H-indazole-4-carboxylate hydrochloride (39.7 g, 82% yield) as a white solid.

[0063] MS m / z(ESI):374.0,376.0[M+H] + .

[0064] 1 H NMR (400MHz, CDCl3) δ7.88 (dd, J=8.9, 0.8Hz, 1H), 7.77–7.59 (dd, J=8.9, 0.8Hz, 1H), 7 .37–7.16(m,3H),6.90–6.64(m,2H),5.66(d,J=24.0Hz,2H),3.97(s,3H),3.77(s,3H).

[0065] Step 3: Preparation of methyl (E)-3-(2-ethoxyvinyl)-2-(4-methoxybenzyl)-2H-indazole-4-carboxylate

[0066]

[0067] Mix 3-bromo-2-(4-methoxybenzyl)-2H-indazole-4-carboxylic acid methyl ester hydrochloride (5.5 g, 13.3 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxolane (4.0 g, 20.0 mmol), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (0.5 g, 0.7 mmol), cesium carbonate (abbreviated as Cs2CO3, 8.6 g, 26.6 mmol), 1,4-dioxane (55 mL), and water (11 mL) in a 100 mL single-necked bottle and react at 50°C for 16 h. After the reaction, the mixture was cooled to room temperature, concentrated under reduced pressure, and then filtered through silica gel for column chromatography (eluent: petroleum ether / ethyl acetate, volume ratio = 6 / 1) to give methyl (E)-3-(2-ethoxyvinyl)-2-(4-methoxybenzyl)-2H-indazole-4-carboxylate (4.00 g, yield: 82.0%) as a white solid.

[0068] MS m / z(ESI):367.2[M+H] + .

[0069] 1H NMR (400MHz, CDCl3) δ7.87(dd,J=8.6,0.7Hz,1H),7.65(dd,J=6.9,0.7Hz,1H),7.27(dd,J=6.9,8.3Hz,1H),7.14–7.12(m,2H),6.94–6.66(m, 2H),6.42(d,J=13.2Hz,1H),6.12(d,J=13.2Hz,1H),5.62(s,2H),3.93(q,7.0Hz,2H),3.93–3.88(s,3H),3.77(s,3H),1.36(t,J=7.0Hz,3H).

[0070] Step 4: Preparation of methyl 2-(4-methoxybenzyl)-3-(2-oxoethyl)-2H-indazole-4-carboxylate

[0071]

[0072] Methyl (E)-3-(2-ethoxyvinyl)-2-(4-methoxybenzyl)-2H-indazole-4-carboxylate (3.7 g, 10.1 mmol), tetrahydrofuran (40 mL), and hydrochloric acid (20 mL, 6N) were added to a 100 mL vial and reacted at 50°C for 4 h. After the reaction was completed and cooled to room temperature, the system was poured into ice water and the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The solution was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain methyl 2-(4-methoxybenzyl)-3-(2-oxoethyl)-2H-indazole-4-carboxylate (3.1 g, 90.6% yield) as a white solid.

[0073] MS m / z(ESI):339.1[M+H] + .

[0074] 1 H NMR (400MHz, DMSO-d6) δ9.58 (s, 1H), 7.92 (dd, J=8.6, 0.8Hz, 1H), 7.72 (dd, J=8.6, 0.8Hz, 1H), 7.34 (dd, J= 8.6,7.1Hz,1H),7.17–7.15(m,2H),6.98–6.66(m,2H),5.62(s,2H),4.53(s,2H),3.79(s,3H),3.71(s,3H).

[0075] Step 5: Preparation of methyl (S)-2-(4-methoxybenzyl)-3-(2-(quinin-3-ylamino)ethyl)-2H-indazole-4-carboxylate

[0076]

[0077] To a solution of methyl 2-(4-methoxybenzyl)-3-(2-oxoethyl)-2H-indazole-4-carboxylate (310.0 mg, 0.92 mmol) and S-3-aminoquinuclidine dihydrochloride (360.0 mg, 1.84 mmol) in acetonitrile (6 mL) was added glacial acetic acid (60.0 mg, 1 mmol), and the mixture was stirred at room temperature for 16 hours. Sodium triacetoxyborohydride (390.0 mg, 1.84 mmol) was then added to the reaction solution, and the mixture was stirred at room temperature. After the reaction, the reaction solution was poured into water and extracted once with dichloromethane. The aqueous phase was adjusted to pH = 8 with a saturated aqueous sodium bicarbonate solution and extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily product, methyl (S)-2-(4-methoxybenzyl)-3-(2-(quinin-3-ylamino)ethyl)-2H-indazole-4-carboxylate (374.0 mg, yield 91.4%).

[0078] MS m / z(ESI):449.2[M+H] +

[0079] Step 6: Preparation of lithium (S)-2-(4-methoxybenzyl)-3-(2-(quinin-3-ylamino)ethyl)-2H-indazole-4-carboxylate

[0080]

[0081] To a solution of methyl (S)-2-(4-methoxybenzyl)-3-(2-(quinin-3-ylamino)ethyl)-2H-indazole-4-carboxylate (310.0 mg, 0.7 mmol) in methanol (5 mL) was added a solution of lithium hydroxide monohydrate (58.0 mg, 1.4 mmol) in water (1 mL), and the mixture was allowed to react at 70°C for 1 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain lithium (S)-2-(4-methoxybenzyl)-3-(2-(quinin-3-ylamino)ethyl)-2H-indazole-4-carboxylate (crude product), which was used in the next step without further purification.

[0082] MS m / z(ESI):435.2[M+H] + .

[0083] Step 7: Preparation of (S)-2-(4-methoxybenzyl)-7-(quinin-3-yl)-2,7,8,9-tetrahydro-6H-azacyclo[5,4,3-cd]indazol-6-one

[0084]

[0085] To a solution of lithium (S)-2-(4-methoxybenzyl)-3-(2-(quinin-3-ylamino)ethyl)-2H-indazole-4-carboxylate (320.0 mg, crude) and N,N-diisopropylethylamine (DIEA, 469.0 mg, 3.6 mmol) in tetrahydrofuran (6 mL) was added 1-propylphosphonic anhydride (50 wt% in ethyl acetate) (T3P, 1.4 g, 2.2 mmol) and stirred overnight at room temperature. After completion of the reaction, the reaction mixture was poured into water and extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (S)-2-(4-methoxybenzyl)-7-(quinin-3-yl)-2,7,8,9-tetrahydro-6H-azacyclo[5,4,3-cd]indazol-6-one (250.0 mg, crude product), which was used in the next step without further purification.

[0086] MS m / z(ESI):417.2[M+H] + .

[0087] Step 8: Preparation of (S)-7-(quinin-3-yl)-2,7,8,9-tetrahydro-6H-azacyclo[5,4,3-cd]indazol-6-one

[0088]

[0089] Compound (S)-2-(4-methoxybenzyl)-7-(quinin-3-yl)-2,7,8,9-tetrahydro-6H-azacyclo[5,4,3-cd]indazol-6-one (250 mg, crude), trifluoroacetic acid (4 mL), and anisole (1 mL) were mixed and heated to 80°C overnight. After the reaction was completed and cooled to room temperature, 50 mL of 1 M hydrochloric acid was added. The mixture was extracted twice with methyl tert-butyl ether. The aqueous phase was adjusted to pH 10 with 6 M sodium hydroxide solution and extracted twice with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield (S)-7-(quinin-3-yl)-2,7,8,9-tetrahydro-6H-azacyclo[5,4,3-cd]indazol-6-one (156.0 mg, 87.6% yield, 97% HPLC purity).

[0090] MS m / z(ESI):297.2[M+H] + .

[0091] 1H NMR (400MHz, DMSO) δ7.45(d,J=8.1Hz,1H),7.27(d,J=6.9Hz,1H),6.80(dd,J=8.0,7.2Hz,1H),4.52–4.28(m,1H),4.16–3.8 8(m,1H),3.71–3.47(m,1H),3.33–2.87(m,5H),2.84–2.65(m,3H),2.06–1.87(m,1H),1.81–1.49(m,3H),1.50–1.30(m,1H).

[0092] The total yield of (S)-7-(quinin-3-yl)-2,7,8,9-tetrahydro-6H-azacyclo[5,4,3-cd]indazol-6-one prepared in Example 1 of the present invention is as high as 45.1%.

[0093] In summary, the present invention provides a method for preparing the 5-HT3 receptor modulator of formula I. The synthetic method of the present invention has readily available raw materials, mild reaction conditions, a total yield of up to 45.1%, and a product purity of up to 97%, and is suitable for industrial production.

Claims

1. A method for synthesizing a compound of formula I, characterized in that: The method comprises the following steps: (1) Compound 5 reacts with acid to obtain compound 6; (2) Compound 6 reacts with a salt of Compound 7 to obtain Compound 8; the reaction is carried out in the presence of an acid and a reducing agent, the reducing agent is sodium triacetoxyborohydride, the salt of Compound 7 is dihydrochloride of Compound 7, the molar ratio of Compound 6, the salt of Compound 7, the acid, and the reducing agent is 1:2:1:2, the solvent of the reaction is an organic solvent, the organic solvent is acetonitrile, the reaction temperature is room temperature, and the reaction time is 16-18 hours; (3) Compound 8 reacts with lithium hydroxide or its hydrate to obtain compound 9; (4) Compound 9 reacts in the presence of a base and a dehydrating agent to obtain compound 10; (5) Compound 10 reacts with a deprotection reagent to obtain a compound represented by Formula I; R1 is p-methoxybenzyl; The preparation method of the compound 5 comprises the following steps: (1) reacting compound 3 with compound 4 to obtain compound 5; X is a halogen; The preparation method of compound 3 comprises the following steps: (a) Compound 1 reacts with a halogenating agent to obtain compound 2; (b) Compound 2 reacts with an amino protecting agent to obtain Compound 3; the amino protecting agent is p-methoxybenzyl chloride, the mass volume ratio of Compound 2 to p-methoxybenzyl chloride is 0.2 g / mL, the reaction temperature is 40-60°C, and the reaction time is 5-9 hours; 。 2. The method according to claim 1, wherein: In step (1), the acid is hydrochloric acid, the molar ratio of the compound 5 to the acid is 1:(5-20), the solvent of the reaction is an organic solvent, the reaction temperature is 40-60°C, and the reaction time is 2-6 hours; In step (3), the molar ratio of compound 8 and lithium hydroxide or its hydrate is 1:(1-4), the solvent of the reaction is water, an organic solvent or a mixture of the two, the reaction temperature is 50-90°C, and the reaction time is 0.5-3 hours; In step (4), the mass ratio of compound 9 to the base is 1:(1-3), the molar ratio of the base to the dehydrating agent is (1-3):1, the base is an organic base, the dehydrating agent is 1-propylphosphoric anhydride, the reaction solvent is an organic solvent, the reaction temperature is 20-40°C, and the reaction time is 6-20 hours; In step (5), the deprotection reagent is trifluoroacetic acid, the mass volume ratio of compound 10 to trifluoroacetic acid is 50-70 mg / mL, the reaction solvent is an organic solvent, the reaction temperature is 60-100° C., and the reaction time is 6-20 hours.

3. The method according to claim 2, wherein: In step (1), the concentration of the hydrochloric acid is 5-7 mol / L, the molar ratio of the compound 5 to the acid is 1:12, the organic solvent is tetrahydrofuran, the reaction temperature is 50°C, and the reaction time is 4 hours; In step (3), the molar ratio of compound 8 and lithium hydroxide or its hydrate is 1:2, the lithium hydroxide hydrate is lithium hydroxide monohydrate, the solvent of the reaction is methanol, water or a mixture of the two, the reaction temperature is 70°C, and the reaction time is 1 hour; In step (4), the mass ratio of compound 9 to the base is 1:1.5, the molar ratio of the base to the dehydrating agent is 1.6:1, the organic base is N,N-diisopropylethylamine, and the organic solvent is tetrahydrofuran, ethyl acetate, or a mixture of the two. The reaction time is 8-12 hours; In step (5), the mass volume ratio of compound 10 to trifluoroacetic acid is 62.5 mg / mL, the organic solvent is anisole, the reaction temperature is 80° C., and the reaction time is 8-12 hours.

4. The method according to claim 3, wherein: In step (1), after the reaction is completed, the following purification step is further included: adding the reaction solution to ice water, adjusting the pH to 9-11 with a saturated sodium bicarbonate aqueous solution, extracting with ethyl acetate, retaining the organic phase, and drying to obtain compound 6; In step (2), after the reaction is completed, the following purification step is further included: the reaction solution is added to ice water, extracted with dichloromethane, the aqueous phase is adjusted to pH 9-11 with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, the organic phase is retained, and dried to obtain compound 8; In step (4), after the reaction is completed, the following purification step is further included: the reaction solution is added to water, extracted with dichloromethane, the organic phase is retained, and dried to obtain compound 10; In step (5), after the reaction is completed, the following purification step is further included: adding hydrochloric acid to the reaction solution, extracting with methyl tert-butyl ether, adjusting the pH of the aqueous phase to 9-11, extracting with dichloromethane solution, retaining the organic phase, and drying to obtain the compound represented by formula I.

5. The method according to claim 1, wherein: In step (1), the reaction is carried out in the presence of a palladium catalyst and a phase transfer catalyst, the molar ratio of compound 3, compound 4, palladium catalyst and phase transfer catalyst is 1: (1-3): (0.01-0.1): (1-3), the reaction solvent is water, an organic solvent or a mixture of two, the reaction temperature is 40-60 ° C, and the reaction time is 12-20 h.

6. The method according to claim 5, characterized in that: In step (1), the palladium catalyst is dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II), the phase transfer catalyst is cesium carbonate, the molar ratio of compound 3, compound 4, palladium catalyst and phase transfer catalyst is 1:1.5:0.05:2, the reaction solvent is water, 1,4-dioxane or a mixture of two, the reaction temperature is 50 ° C, and the reaction time is 16 h.

7. The method according to claim 6, characterized in that: In step (1), after the reaction is completed, the following purification step is further included: the reaction solution is concentrated and then subjected to column chromatography to obtain compound 5; the eluent for the column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 6:

1.

8. The method according to claim 1, wherein: In step (a), the halogenating agent is a brominating agent, and the reaction is carried out in the presence of a base; the molar ratio of compound 1, the brominating agent, and the base is 1:(0.8-1.2):(2-6), the reaction solvent is an organic solvent, the reaction temperature is 20-40° C., and the reaction time is 0.5-3 hours; X is bromine.

9. The method according to claim 8, characterized in that: In step (a), the brominating agent is N-bromosuccinimide, the base is an inorganic base; the molar ratio of compound 1, the brominating agent, and the base is 1:1:4, the organic solvent is N,N-dimethylformamide, and the reaction time is 1 hour; In step (b), the reaction temperature is 50° C. and the reaction time is 7 hours.

10. The method according to claim 9, characterized in that: The inorganic base is potassium hydroxide.

11. The method according to claim 1, wherein: After the reaction in step (a) is completed, the following purification step is further included: the reaction solution is concentrated and filtered, the filtrate is added to ice water, extracted with ethyl acetate, the retained organic phase is washed with saturated brine, and dried to obtain compound 2.

12. The method according to claim 1, wherein: After the reaction in step (b) is completed, the following purification step is further included: adding petroleum ether to the reaction solution, stirring and filtering, washing the filter cake with petroleum ether, and drying to obtain compound 3.

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