CN114805192B - Tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid and preparation method and application thereof - Google Patents

Abstract

The invention discloses a tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid and a preparation method and application thereof, belonging to the field of XOR/URAT1 dual inhibitors. The structure of the tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid is shown as a formula (A): wherein X is O or NH, R ₁ Is hydrogen, alkyl, alkoxy, halogen or cyano, R ₂ Is hydrogen, alkyl, alkoxy, halogen or cyano. The tricyclic XOR/URAT1 dual inhibitors containing 2-hydroxybenzoic acid of the present invention have a different chemical structure than the known XOR/URAT1 dual inhibitors; the inhibitor has excellent inhibition effect on two key action targets, namely XOR and URAT1, related to gout, and can be applied to preparation of anti-hyperuricemia or gout drugs.

Description

A tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid and its preparation Preparation method and application

technical field

The invention belongs to the field of XOR/URAT1 dual inhibitors, and specifically relates to a tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid and its preparation method and application.

Background technique

Epidemiological studies from different countries have shown that the prevalence and incidence of gout are increasing, causing a huge economic burden on people. Hyperuricemia is an important risk factor for gout, and it is related to renal insufficiency, cardiovascular disease, hypertension, hyperlipidemia, cancer, diabetes, etc. loss, or a combination of both. In patients with hyperuricemia, 90% are due to inefficient renal excretion. In the human body, 90% of uric acid is reabsorbed back into the blood by the renal proximal tubule in large quantities. This reabsorption process mainly depends on the human urate transporter 1 (hURAT1, SLC22A12), whose function is to regulate blood uric acid levels. By inhibiting the activity of this transporter, uric acid excretion can be promoted. On the other hand, in about 10% of cases it is due to overproduction of endogenous uric acid. In the pathway of endogenous uric acid production, the key enzyme is xanthine oxidoreductase (XOR), which can oxidize hypoxanthine to xanthine and then to uric acid. XOR is one of the important targets for early research on the pathological mechanism and drug action of hyperuricemia and gout.

In the past 40 years, the development of uric acid-lowering drugs has mainly focused on XOR and URAT1. The most representative three new drugs are listed: febuxostat (launched in the United States in 2009, XOR inhibitor), topinastat (launched in Japan in 2013, XOR inhibitor), and lesinurad (launched in the United States in 2015, URAT1 inhibitor ). However, febuxostat, which has received the most attention, has not yet solved the problem of poor efficacy of XOR inhibitors in some patients (about 20-30% of patients with hyperuricemia do not respond to febuxostat), and it is possible In 2019, the FDA requested a black box warning to increase the risk of cardiovascular events; on the other hand, although lesinurad used alone has a significant effect on lowering uric acid, the safety window is narrow and it is easy to cause kidney damage, while lesinurad (lesinurad+ Allopurinol) compound has excellent clinical performance, and it has achieved good response rate and curative effect for patients with allopurinol intolerance and poor curative effect. Therefore, uric acid-lowering drugs that can both inhibit uric acid production and promote uric acid excretion may become a hot spot in this research field, with more significant clinical effects and application prospects. The XOR/URAT1 dual inhibitor PF-06743649 developed by Pfizer has IC ₅₀ of 1.6nM and 0.237μM for the two targets, respectively. In the Phase I clinical trial, the patient took 40 mg/day orally, and the uric acid level decreased by 69% after two weeks, further confirming that the combined inhibition of XOR and URAT1 is an effective strategy for rapidly reducing uric acid in the body. The XOR/URAT1 dual inhibitor KUX-1151 developed by Japan Orange Pharmaceutical Company has entered phase II clinical trials. The XOR/URAT1 dual inhibitor RLBN-1001 and its series of analogues developed by Relburn-Metabolomics are in Phase I clinical and preclinical research stages respectively. RLBN1001 is a prototype of a cancer drug, which was found to cause hypouricemia during the use of patients. A clinical study of 50 cases of hypouricemia caused by taking RLBN1001 and its analogues found that this type of drug inhibits URAT1/ XOR increases uric acid excretion.

At present, the overall research on XOR/URAT1 dual inhibitors is still in the early stages of development, requiring a lot of preliminary exploration and accumulation. In particular, the in vitro activity of PF-06743649 is significantly higher than that of febuxostat and benzbromarone, two single-target inhibitors, and the clinical effect is stronger than the currently available clinical combination administration, and the time for uric acid to reach the target is shorter. However, this may also be the reason for the kidney injury found in its phase I clinical trial. In conclusion, the development of new structural types of XOR/URAT1 dual inhibitors has important practical significance for alleviating the need for clinical medication.

Contents of the invention

Aiming at the shortcomings and deficiencies of the above prior art, the primary purpose of the present invention is to provide a tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid.

Another object of the present invention is to provide a preparation method of the above-mentioned tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid.

Another object of the present invention is to provide the application of the above-mentioned tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid in the preparation of medicines for preventing and treating diseases related to XOR/URAT1.

The purpose of the present invention is achieved through the following technical solutions.

A tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid, the structure of which is shown in formula (A):

Wherein, X is O or NH, R ₁ is alkyl, alkoxy, halogen or cyano, R ₂ is alkyl, alkoxy, halogen or cyano.

Preferably, X is O or NH, R ₁ is C1-C7 alkyl, OCH ₃ , F, Cl, Br or CN, R ₂ is C1-C7 alkyl, OCH ₃ , F, Cl, Br or CN.

Preferably, the inhibitor is any one of the following compounds:

4-(5-phenoxypyridin-3-yl)2-hydroxybenzoic acid

4-(5-(4-chlorophenoxy)pyridin-3-yl)-2-hydroxybenzoic acid

4-(5-(p-Tolyloxy)pyridin-3-yl)2-hydroxybenzoic acid

4-(5-(4-(tert-butyl)phenoxy)pyridin-3-yl)-2-hydroxybenzoic acid

4-(5-(3-chlorophenoxy)pyridin-3-yl)-2-hydroxybenzoic acid

4-(5-(m-methylphenoxy)pyridin-3-yl)2-hydroxybenzoic acid

4-(5-(phenylamino)pyridin-3-yl)2-hydroxybenzoic acid

4-(5-((4-chlorophenyl)amino)pyridin-3-yl)-2-hydroxybenzoic acid

4-(5-((4-methoxyphenyl)amino)pyridin-3-yl)2-hydroxybenzoic acid

4-(5-(p-Tolylamino)pyridin-3-yl)2-hydroxybenzoic acid

4-(5-((4-(tert-butyl)phenyl)amino)pyridin-3-yl)-2-hydroxybenzoic acid

4-(5-((3-chlorophenyl)amino)pyridin-3-yl)-2-hydroxybenzoic acid

4-(5-((3,4-dichlorophenyl)amino)pyridin-3-yl)-2-hydroxybenzoic acid

4-(5-((3-fluoro-4-methylphenyl)amino)pyridin-3-yl)-2-hydroxybenzoic acid.

A method for preparing a tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid described in any one of the above, comprising the following steps:

(1) Dissolve 3-hydroxy-5-bromopyridine and compound I in an organic solvent, add an organic base, copper acetate, and stir at room temperature to obtain compound II, or dissolve 3-amino-5-bromopyridine and compound I in In an organic solvent, add an organic base and copper acetate, and stir at room temperature to obtain compound III;

(2) Compound II and 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl) methyl benzoate were dissolved in 1,4 -In the mixed solvent of dioxane and water, add palladium catalyst, inorganic base, argon protection, reflux reaction obtains 4-(5-substituted-pyridine-3-phenoxy)-2-hydroxybenzoic acid compound, Or compound III and 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)methyl benzoate were dissolved in 1,4-bis In the mixed solvent of oxane and water, add palladium catalyst, inorganic base, argon protection, and reflux reaction to obtain 4-(5-substituted-pyridine-3-phenylamino)-2-hydroxybenzoic acid compounds.

Preferably, the organic solvent described in the step (1) refers to dichloromethane, and the organic base is pyridine; the inorganic base described in the step (2) refers to potassium carbonate; the palladium catalyst used in the step (2) is (1 , 1-bis(diphenylphosphino)ferrocene)palladium dichloride.

Preferably, the molar equivalent ratio of 3-hydroxyl-5-bromopyridine, compound I, organic base, and copper acetate in step (1) is 1:2:2-3:0.5-1, and the 3-amino-5 The molar equivalent ratio of bromopyridine, compound I, organic base and copper acetate is 1:2:2-3:0.5-1.

Preferably, the compound II described in step (2), 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxylbenzaldehyde-2-yl)benzoic acid methyl The molar equivalent ratio of ester, inorganic base and palladium catalyst is 1:1.5:3:0.03, the compound III, 2-hydroxyl-4-(4,4,5,5-tetramethyl-1,3,2- The molar equivalent ratio of dioxybenzaldehyde-2-yl) methyl benzoate, inorganic base and palladium catalyst is 1:1.5:3:0.03.

The use of a tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid described in any one of the above in the preparation of medicines for preventing and treating diseases related to XOR/URAT1.

Preferably, the drug is an anti-hyperuricemia or gout drug.

Preferably, the anti-hyperuricemia or gout drug comprises, as an active ingredient, a tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Compared with the prior art, the present invention has the following advantages and beneficial effects:

The tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid of the present invention has a novel chemical structure different from the known XOR/URAT1 dual inhibitor; Both key targets showed excellent inhibition. Therefore, they can be used to prevent and treat diseases related to XOR/URAT1, for example, hyperuricemia, heart failure, cardiovascular disease, hypertension, kidney disease, inflammation, arthropathy and the like.

Description of drawings

Fig. 1 is a synthetic route diagram of a tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid of the present invention.

Detailed ways

The present invention will be further described in detail below in conjunction with examples, but the embodiments of the present invention are not limited thereto.

A synthetic route diagram of a tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid of the present invention is shown in FIG. 1 .

Example 1

Synthesis of 4-(5-phenoxypyridin-3-yl)2-hydroxybenzoic acid (A1)

3-Hydroxy-5-bromopyridine (1.4g, 8.2mmol) and phenylboronic acid (2.0g, 16.4mmol) were dissolved in dichloromethane, pyridine (2.0mL, 24.6mmol), copper acetate (0.4g, 2.2mmol) were added ), stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate:petroleum ether (volume ratio 1:5) column chromatography, obtained 0.5g of white solid 3-bromo-5-phenoxypyridine, Yield 22%.

3-Bromo-5-phenoxypyridine (0.5g, 1.6mmol) and 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2- base) methyl benzoate (0.5g, 1.9mmol) was dissolved in a mixture of 1,4-dioxane and water (volume ratio was 3:1), potassium carbonate (0.7g, 4.8mmol), ( 1,1-bis(diphenylphosphino)ferrocene)palladium dichloride (0.04g, 0.05mmol), replaced by argon, refluxed and stirred. Filtration with celite, acidification with dilute hydrochloric acid, and recrystallization from ethanol gave 0.2 g of 4-(5-phenoxypyridin-3-yl) 2-hydroxybenzoic acid A1 as a white solid, with a yield of 33%.

The structural characterization data of the product are as follows:

¹ H NMR (400MHz, DMSO-d ₆ )δ7.11-7.17(d, J=8.0Hz, 2H), 7.18-7.25(t, J=7.4Hz, 1H), 7.26-7.34(m, 2H), 7.41-7.49(t, J=7.8Hz, 2H), 7.75-7.80(t, J=2.2Hz, 1H), 7.84-7.91(d, J=8.2Hz, 1H), 8.36-8.44(d, J= 2.7Hz,1H),8.73-8.78(s,1H).

¹³ C NMR (151MHz, DMSO-d ₆ )δ172.09, 161.91, 156.49, 153.90, 143.55, 143.26, 141.01, 136.01, 131.51, 130.76, 124.67, 124.44, 119.19, 118.41, 115 .84, 113.31.

Example 2

Synthesis of 4-(5-(4-chlorophenoxy)pyridin-3-yl)-2-hydroxybenzoic acid (A2)

3-Hydroxy-5-bromopyridine (0.5g, 2.9mmol) and 4-chloro-phenylboronic acid (0.9g, 5.7mmol) were dissolved in dichloromethane, added pyridine (0.5mL, 5.8mmol), copper acetate (0.2 g, 0.7mmol), stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate:petroleum ether (volume ratio 1:5) column chromatography, obtained white solid 3-bromo-5-(4- Chlorophenoxy)pyridine 0.3g, yield 34%.

3-Bromo-5-(4-chlorophenoxypyridine) (0.3g, 1mmol) and 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxobenzene Formaldehyde-2-yl)methyl benzoate (0.3g, 1.2mmol) was dissolved in a mixture of 1,4-dioxane and water (3:1 by volume), and potassium carbonate (0.4g, 2.9 mmol), (1,1-bis(diphenylphosphino)ferrocene)palladium dichloride (0.02g, 0.03mmol), replace argon, and stir at reflux for 6h. Filtration with diatomaceous earth, acidification with dilute hydrochloric acid, and recrystallization from ethanol gave 20.1 g of 4-(5-phenoxypyridin-3-yl) 2-hydroxybenzoic acid A as a white solid, with a yield of 25%.

The structural characterization data of the product are as follows:

¹ H NMR (400MHz,DMSO-d ₆ )δ7.15-7.21(m,2H),7.28-7.33(dd,J=1.9,8.2Hz,1H),7.33-7.37(d,J=1.8Hz,1H ),7.45-7.52(m,2H),7.82-7.86(t,J=2.3Hz,1H),7.86-7.91(d,J=8.2Hz,1H),8.41-8.47(d,J=2.6Hz, 1H), 8.74-8.82(d, J=1.9Hz, 1H).

¹³ C NMR (151MHz, DMSO-d ₆ ) δ172.06, 161.90, 155.55, 153.54, 143.69, 143.45, 141.26, 136.06, 131.51, 130.58, 128.40, 124.78, 120.88, 118.48, 115 .90, 113.34.

Example 3

Synthesis of 4-(5-(p-methylphenoxy)pyridin-3-yl)2-hydroxybenzoic acid (A3)

3-Hydroxy-5-bromopyridine (1g, 5.5mmol) and 4-methylphenylboronic acid (1.5g, 11.1mmol) were dissolved in dichloromethane, pyridine (1.4mL, 16.5mmol), copper acetate (0.3g , 1.4mmol), stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate:petroleum ether (volume ratio 1:5) column chromatography, obtained white solid 3-bromo-5-p-methylphenoxy Pyridine 0.3g, yield 22%.

3-Bromo-5-p-tolyloxypyridine (0.3g, 1.2mmol) and 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2 -yl) methyl benzoate (0.4g, 1.5mmol) was dissolved in a mixture of 1,4-dioxane and water (3:1 by volume), potassium carbonate (0.5g, 3.6mmol) was added, (1,1-bis(diphenylphosphino)ferrocene)palladium dichloride (0.03g, 0.04mmol), replaced with argon, and stirred at reflux for 6h. Filtration with celite, acidification with dilute hydrochloric acid, and recrystallization from ethanol gave 30.1 g of 4-(5-phenoxypyridin-3-yl) 2-hydroxybenzoic acid A as a white solid, with a yield of 22%.

The structural characterization data of the product are as follows:

¹ H NMR (400MHz, DMSO-d ₆ ) δ2.28-2.35(s, 3H), 7.02-7.08(d, J=7.9Hz, 2H), 7.21-7.32(m, 4H), 7.67-7.71(s ,1H),7.84-7.90(d,J=8.2Hz,1H),8.33-8.38(d,J=2.7Hz,1H),8.68-8.73(s,1H).

¹³ C NMR (151MHz, DMSO-d ₆ )δ172.04, 161.89, 154.41, 153.96, 143.58, 142.84, 140.54, 135.94, 133.98, 131.53, 131.13, 123.75, 119.43, 118.39, 115 .80, 113.36, 20.77.

Example 4

Synthesis of 4-(5-(4-(tert-butyl)phenoxy)pyridin-3-yl)-2-hydroxybenzoic acid (A4)

3-Hydroxy-5-bromopyridine (0.9g, 5mmol) and 4-tert-butylphenylboronic acid (1.8g, 10mmol) were dissolved in dichloromethane, pyridine (1.2mL, 15mmol), copper acetate (0.2g, 1.3mmol), stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate:petroleum ether (volume ratio 1:5) column chromatography, obtained white solid 5-(4-(tert-butyl)benzene Oxypyridine 0.4 g, yield 27%.

5-(4-(tert-butyl)phenoxypyridine (0.4g, 1.4mmol) and 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxobenzene Formaldehyde-2-yl)methyl benzoate (0.5g, 1.6mmol) was dissolved in a mixture of 1,4-dioxane and water (3:1 by volume), and potassium carbonate (0.6g, 4.1 mmol), (1,1-bis(diphenylphosphino)ferrocene)palladium dichloride (0.03g, 0.04mmol), replace argon, and stir at reflux for 6h. Diatomaceous earth filtration, acidification with dilute hydrochloric acid, ethanol weight Crystallized to obtain 40.1 g of white solid 4-(5-phenoxypyridin-3-yl) 2-hydroxybenzoic acid A with a yield of 19%.

The structural characterization data of the product are as follows:

¹ H NMR (400MHz,DMSO-d ₆ )δ1.20-1.38(s,9H),7.04-7.11(m,2H),7.27-7.32(dd,J＝1.8,8.2Hz,1H),7.34-7.37 (d,J=1.8Hz,1H),7.41-7.48(m,2H),7.84-7.91(m,2H),8.37-8.41(d,J=2.6Hz,1H),8.74-8.79(d,J =1.8Hz,1H).

¹³ C NMR (151MHz, DMSO-d ₆ )δ171.97, 161.83, 154.29, 154.02, 147.13, 143.29, 142.41, 140.02, 136.33, 131.55, 127.45, 125.14, 118.73, 118.52, 115 .94, 113.41, 34.59, 31.68.

Example 5

Synthesis of 4-(5-(3-chlorophenoxy)pyridin-3-yl)-2-hydroxybenzoic acid (A5)

3-Hydroxy-5-bromopyridine (1.7g, 9.6mmol) and 3-chloro-phenylboronic acid (3.0g, 19.2mmol) were dissolved in dichloromethane, added pyridine (2.3mL, 28.8mmol), copper acetate (0.4 g, 2.2mmol), stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate:petroleum ether (volume ratio 1:5) column chromatography, obtained white solid 3-bromo-5-(3- Chlorophenoxy)pyridine 0.4g, yield 16%.

3-Bromo-5-(3-chlorophenoxy)pyridine (0.4g, 1.3mmol) and 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxo Benzaldehyde-2-yl)methyl benzoate (0.4g, 1.5mmol) was dissolved in a mixture of 1,4-dioxane and water (3:1 by volume), and potassium carbonate (0.5g, 3.8mmol), (1,1-bis(diphenylphosphino)ferrocene)palladium dichloride (0.03g, 0.04mmol), replace argon, and stir at reflux for 6h. Filtration with celite, acidification with dilute hydrochloric acid, and recrystallization from ethanol gave 0.1 g of 4-(5-phenoxypyridin-3-yl) 2-hydroxybenzoic acid A5 as a white solid, with a yield of 17%.

The structural characterization data of the product are as follows:

¹ H NMR (400MHz,DMSO-d ₆ )δ7.14-7.19(m,1H),7.27-7.33(m,2H),7.34-7.40(dd,J＝1.8,8.3Hz,1H),7.42-7.44 (d, J=1.8Hz, 1H), 7.44-7.51(t, J=8.0Hz, 1H), 7.86-7.93(d, J=8.2Hz, 1H), 8.18-8.24(d, J=2.2Hz, 1H), 8.57-8.62(d, J=2.5Hz, 1H), 8.92-8.97(d, J=1.8Hz, 1H).

¹³ C NMR (151MHz, DMSO-d ₆ ) δ171.94, 161.82, 157.33, 154.00, 142.28, 141.43, 138.72, 137.29, 134.70, 132.20, 131.57, 128.14, 124.95, 119.35, 118 .60, 117.84, 116.19, 113.75.

Example 6

Synthesis of 4-(5-(m-methylphenoxy)pyridin-3-yl)2-hydroxybenzoic acid (A6)

3-Hydroxy-5-bromopyridine (1.54g, 8.8mmol) and 3-methylphenylboronic acid (2.4g, 17.7mmol) were dissolved in dichloromethane, added pyridine (2.1mL, 26.4mmol), copper acetate (0.4 g, 2.2mmol), stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate:petroleum ether (volume ratio 1:5) column chromatography, obtained white solid 3-bromo-5-m-tolyloxy Based pyridine 0.4g, yield 17%.

3-Bromo-5-m-tolyloxypyridine (0.4g, 1.5mmol) and 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2 - Base) methyl benzoate (0.5g, 1.8mmol) was dissolved in a mixture of 1,4-dioxane and water (3:1 by volume), potassium carbonate (0.6g, 4.5mmol) was added, (1,1-bis(diphenylphosphino)ferrocene)palladium dichloride (0.03g, 0.04mmol), replaced with argon, and stirred at reflux for 6h. Filtrate with diatomaceous earth, acidify with dilute hydrochloric acid, and recrystallize from ethanol to obtain 60.1 g of white solid 4-(5-phenoxypyridin-3-yl) 2-hydroxybenzoic acid A, with a yield of 20%.

The structural characterization data of the product are as follows:

¹ H NMR (400MHz, DMSO-d ₆ ) δ2.29-2.33(s, 3H), 6.88-6.99(m, 2H), 6.99-7.05(d, J=7.7Hz, 1H), 7.24-7.36(m ,3H),7.73-7.79(t,J=2.3Hz,1H),7.82-7.91(d,J=8.2Hz,1H),8.33-8.40(d,J=2.6Hz,1H),8.71-8.76( d,J=1.9Hz,1H).

¹³ C NMR (151MHz, DMSO-d ₆ ) δ172.07, 161.88, 156.45, 154.00, 143.57, 143.08, 140.89, 140.60, 136.00, 131.53, 130.44, 125.42, 124.48, 119.72, 118 .45, 116.21, 115.83, 113.25, 21.37.

Example 7

Synthesis of 4-(5-(phenylamino)pyridin-3-yl)2-hydroxybenzoic acid (A7)

3-Amino-5-bromopyridine (0.8g, 4.6mmol) and phenylboronic acid (1.1g, 9.2mmol) were dissolved in dichloromethane, added pyridine (2.0mL, 19.2mmol), copper acetate (0.4g, 2.2mmol ), stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate: sherwood oil (volume ratio 1:5) column chromatography, got white solid 3-bromo-5-aminopyridine 0.4g, yield 38%.

3-Bromo-5-aminopyridine (0.4g, 1.8mmol) and 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl) Methyl benzoate (0.6g, 2.1mmol) was dissolved in a mixture of 1,4-dioxane and water (3:1 by volume), potassium carbonate (0.7g, 5.3mmol), (1, 1-bis(diphenylphosphino)ferrocene)palladium dichloride (0.04g, 0.05mmol), replaced with argon, and stirred under reflux. Filtration with celite, acidification with dilute hydrochloric acid, and recrystallization from ethanol gave 0.1 g of 4-(5-aminopyridin-3-yl) 2-hydroxybenzoic acid A7 as a yellow solid, with a yield of 18%.

The structural characterization data of the product are as follows:

¹ H NMR(400MHz,DMSO-d6)δ9.05(s,1H),8.43(dd,J＝11.2,2.2Hz,2H),7.94-7.86(m,2H),7.38-7.32(m,2H) ,7.31(d,J=1.7Hz,1H),7.26(td,J=8.5,1.6Hz,3H),7.00(td,J=7.3,1.2Hz,1H).

¹³ C NMR (151MHz, DMSO-d ₆ ) δ171.56, 162.23, 145.10, 143.72, 140.65, 140.64, 140.13, 134.08, 132.44, 129.45, 122.20, 120.63, 119.01, 117.54, 115 .25, 114.24.

Example 8

Synthesis of 4-(5-((4-chlorophenyl)amino)pyridin-3-yl)-2-hydroxybenzoic acid (A8)

3-Amino-5-bromopyridine (1.0g, 5.8mmol) and 4-chloro-phenylboronic acid (1.8g, 11.6mmol) were dissolved in dichloromethane, pyridine (0.9mL, 11.6mmol), copper acetate (0.3 g, 1.4mmol), stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate:petroleum ether (volume ratio 1:5) column chromatography, obtained white solid 3-bromo-5-(4- Chlorophenyl)aminopyridine 0.4g, yield 24%.

3-Bromo-5-aminopyridine (0.4g, 1.4mmol) and 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl) Methyl benzoate (0.5g, 1.7mmol) was dissolved in a mixture of 1,4-dioxane and water (3:1 by volume), potassium carbonate (0.6g, 4.1mmol), (1, 1-bis(diphenylphosphino)ferrocene)palladium dichloride (0.03g, 0.04mmol), replaced with argon, and stirred at reflux for 6h. Filtrate with diatomaceous earth, acidify with dilute hydrochloric acid, and recrystallize from ethanol to obtain 0.1 g of yellow solid 4-(5-((4-chlorophenyl)amino)pyridin-3-yl)-2-hydroxybenzoic acid A8, yield 18 %.

The structural characterization data of the product are as follows:

¹ H NMR (400MHz, DMSO-d6) δ9.57(s, 1H), 8.59(d, J=1.7Hz, 1H), 8.45(d, J=2.5Hz, 1H), 8.16(t, J=2.1 Hz,1H),7.93(d,J=8.2Hz,1H),7.45-7.38(m,3H),7.36-7.30(m,3H).

¹³ C NMR (151MHz, DMSO-d ₆ )δ171.89, 161.82, 143.11, 142.03, 139.80, 137.85, 132.20, 131.72, 130.38, 129.97, 126.78, 125.94, 121.22, 118.52, 116 .17, 114.07.

Example 9

Synthesis of 4-(5-((4-methoxyphenyl)amino)pyridin-3-yl)2-hydroxybenzoic acid (A9)

3-Amino-5-bromopyridine (0.2g, 1.1mmol) and 4-methoxyphenylboronic acid (0.3g, 2.2mmol) were dissolved in dichloromethane, added pyridine (0.2mL, 2.2mmol), copper acetate ( 0.1g, 0.6mmol), stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate:petroleum ether (volume ratio 1:5) column chromatography, to give white solid 3-bromo-5-(4 -Methoxyphenyl)aminopyridine 0.1 g, yield 37%.

3-Bromo-5-(4-methoxyphenyl)aminopyridine (0.1g, 0.4mmol) and 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2- Dioxybenzaldehyde-2-yl)methyl benzoate (0.12g, 0.5mmol) was dissolved in a mixture of 1,4-dioxane and water (3:1 by volume), and potassium carbonate (0.2 g, 1.3mmol), (1,1-bis(diphenylphosphino)ferrocene)palladium dichloride (0.01g, 0.02mmol), replace argon, and stir at reflux for 6h. Filtrate with diatomaceous earth, acidify with dilute hydrochloric acid, and recrystallize from ethanol to obtain 0.1 g of yellow solid 4-(5-((4-methoxyphenyl)amino)pyridin-3-yl)2-hydroxybenzoic acid A9, the yield 28%.

The structural characterization data of the product are as follows:

¹ H NMR (600MHz, DMSO-d ₆ )δ9.31(s, 1H), 8.49(d, J=1.7Hz, 1H), 8.24(d, J=2.5Hz, 1H), 8.01(t, J= 2.0Hz, 1H), 7.93(d, J=8.2Hz, 1H), 7.35(d, J=1.8Hz, 1H), 7.31-7.24(m, 3H), 7.03-6.97(m, 2H), 3.77( s,3H).

¹³ C NMR (151MHz, DMSO-d ₆ ) δ171.86, 161.78, 156.53, 145.34, 141.86, 138.14, 132.66, 131.76, 129.35, 127.03, 124.63, 123.54, 118.43, 116.11, 115 .43, 114.14, 55.75.

Example 10

Synthesis of 4-(5-(p-tolylamino)pyridin-3-yl)2-hydroxybenzoic acid (A10)

3-Amino-5-bromopyridine (1.0g, 5.8mmol) and 4-methylphenylboronic acid (1.6g, 11.6mmol) were dissolved in dichloromethane, pyridine (0.9mL, 11.6mmol), copper acetate (0.5 g, 2.9 mmol), stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate:petroleum ether (volume ratio 1:5) column chromatography, and obtained 3-bromo-5-p-toluidine as a white solid Pyridine 0.3g, yield 22%.

3-Bromo-5-p-tolylaminopyridine (0.3g, 1.3mmol) and 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2- Base) methyl benzoate (0.4g, 1.6mmol) was dissolved in the mixed solution of 1,4-dioxane and water (volume ratio was 3:1), potassium carbonate (0.5g, 3.9mmol) was added, ( 1,1-bis(diphenylphosphino)ferrocene)palladium dichloride (0.03g, 0.04mmol), replaced with argon, and stirred at reflux for 6h. Filtration with celite, acidification with dilute hydrochloric acid, and recrystallization from ethanol gave 0.1 g of 4-(5-phenoxypyridin-3-yl) 2-hydroxybenzoic acid A10 as a yellow solid, with a yield of 18%.

The structural characterization data of the product are as follows:

¹ H NMR (400MHz, DMSO-d6) δ9.43(s, 1H), 8.54(d, J=1.7Hz, 1H), 8.34(d, J=2.5Hz, 1H), 8.11(dd, J=2.5 ,1.7Hz,1H),7.93(d,J=8.2Hz,1H),7.37(d,J=1.8Hz,1H),7.30(dd,J=8.2,1.9Hz,1H),7.22(s,4H ),2.30(s,3H).

¹³ C NMR (151MHz, DMSO-d ₆ )δ171.86, 161.80, 144.41, 141.87, 138.10, 137.55, 133.26, 131.77, 130.64, 130.28, 128.21, 125.35, 120.82, 118.45, 116 .13, 114.18, 20.93.

Example 11

Synthesis of 4-(5-((4-(tert-butyl)phenyl)amino)pyridin-3-yl)-2-hydroxybenzoic acid (A11)

3-Amino-5-bromopyridine (0.8g, 4.6mmol) and 4-tert-butylphenylboronic acid (1.2g, 6.9mmol) were dissolved in dichloromethane, added pyridine (0.8mL, 9.2mmol), copper acetate ( 0.4g, 2.2mmol), stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate:petroleum ether (volume ratio 1:5) column chromatography, and obtained white solid 3-bromo-5-(( 0.5 g of 4-(tert-butyl)phenyl)amino)pyridine, yield 37%.

3-bromo-5-((4-(tert-butyl)phenyl)amino)pyridine (0.5g, 1.4mmol) and 2-hydroxy-4-(4,4,5,5-tetramethyl-1, 3,2-Dioxybenzaldehyde-2-yl)methyl benzoate (0.5g, 1.7mmol) was dissolved in a mixture of 1,4-dioxane and water (3:1 by volume), and added Potassium carbonate (0.6g, 4.3mmol), (1,1-bis(diphenylphosphino)ferrocene)palladium dichloride (0.03g, 0.04mmol) was replaced by argon, and stirred at reflux for 6h. Filtration with diatomaceous earth, acidification with dilute hydrochloric acid, and recrystallization from ethanol gave 0.2 g of 4-(5-phenoxypyridin-3-yl) 2-hydroxybenzoic acid A11 as a yellow solid, with a yield of 45%.

The structural characterization data of the product are as follows:

¹ H NMR (400MHz, DMSO-d6) δ9.35(s, 1H), 8.54-8.49(m, 1H), 8.38(d, J=2.5Hz, 1H), 8.09(d, J=3.2Hz, 1H ),7.93(d,J=8.2Hz,1H),7.42(d,J=2.0Hz,1H),7.40-7.34(m,2H),7.31(dd,J=8.2,1.8Hz,1H),7.27 -7.20(m,2H).

¹³ C NMR (151MHz, DMSO-d ₆ ) δ171.88, 161.79, 146.14, 144.07, 142.02, 137.85, 131.72, 130.44, 126.78, 125.23, 119.94, 118.47, 116.11, 114.08, 34. 55,31.67.

Example 12

Synthesis of 4-(5-((3-chlorophenyl)amino)pyridin-3-yl)-2-hydroxybenzoic acid (A12)

3-Amino-5-bromopyridine (1.0g, 5.8mmol) and 3-chloro-phenylboronic acid (2.0g, 11.6mmol) were dissolved in dichloromethane, pyridine (1.0mL, 11.6mmol), copper acetate (0.32 g, 1.7mmol), stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate:petroleum ether (volume ratio 1:5) column chromatography, obtained white solid 3-bromo-5-((3 -Chlorophenyl)amino)pyridine 0.4g, yield 22%.

3-bromo-5-((3-chlorophenyl)amino)pyridine (0.4g, 1.3mmol) and 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2- Dioxybenzaldehyde-2-yl)methyl benzoate (0.4g, 1.5mmol) was dissolved in a mixture of 1,4-dioxane and water (3:1 by volume), and potassium carbonate (0.5 g, 3.9mmol), (1,1-bis(diphenylphosphino)ferrocene)palladium dichloride (0.03g, 0.04mmol), replace argon, and stir at reflux for 6h. Filtrate with diatomaceous earth, acidify with dilute hydrochloric acid, and recrystallize from ethanol to obtain 0.1 g of yellow solid 4-(5-((3-chlorophenyl)amino)pyridin-3-yl)-2-hydroxybenzoic acid A12, yield 20 %.

The structural characterization data of the product are as follows:

¹ H NMR (400MHz, DMSO-d6) δ9.61(s, 1H), 8.63(d, J=1.7Hz, 1H), 8.51(d, J=2.4Hz, 1H), 8.20(t, J=2.1 Hz,1H),7.94(d,J=8.2Hz,1H),7.43-7.36(m,2H),7.35-7.30(m,2H),7.28(td,J=8.1,2.2,1.0Hz,1H) ,7.09(td,J=7.9,2.0,0.9Hz,1H).

¹³ C NMR (151MHz, DMSO-d ₆ )δ171.89, 161.81, 142.96, 142.50, 141.71, 138.06, 134.40, 131.74, 131.72, 129.78, 127.23, 122.88, 118.89, 118.52, 117 .63, 116.24, 114.13.

Example 13

Synthesis of 4-(5-((3,4-dichlorophenyl)amino)pyridin-3-yl)-2-hydroxybenzoic acid (A13)

3-Amino-5-bromopyridine (1.0g, 5.8mmol) and 3,4-dichloro-phenylboronic acid (2.2g, 11.6mmol) were dissolved in dichloromethane, pyridine (0.9mL, 11.6mmol), acetic acid Copper (0.3g, 1.7mmol), stirred at room temperature overnight, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate:petroleum ether (volume ratio 1:5) column chromatography, to give white solid 3-bromo-5- (3,4-dichlorophenyl)amino)pyridine 0.4 g, yield 23%.

3-bromo-5(3,4-dichlorophenyl)amino)pyridine (0.4g, 1.4mmol) and 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2 -Dioxybenzaldehyde-2-yl)methyl benzoate (0.5g, 1.7mmol) was dissolved in a mixture of 1,4-dioxane and water (3:1 by volume), and potassium carbonate ( 0.5g, 4.1mmol), (1,1-bis(diphenylphosphino)ferrocene)palladium dichloride (0.03g, 0.04mmol), replace argon, and stir at reflux for 6h. Filtration with celite, acidification with dilute hydrochloric acid, and recrystallization from ethanol gave 0.1 g of 4-(5-phenoxypyridin-3-yl) 2-hydroxybenzoic acid A13 as a yellow solid, with a yield of 24%.

The structural characterization data of the product are as follows:

¹ H NMR (400MHz, DMSO-d6) δ9.74(s, 1H), 8.65(d, J=1.8Hz, 1H), 8.53(d, J=2.5Hz, 1H), 8.23(t, J=2.1 Hz,1H),7.93(d,J=8.2Hz,1H),7.58(d,J=8.7Hz,1H),7.51(d,J=2.6Hz,1H),7.41(d,J=1.8Hz, 1H),7.34(dd,J=8.3,1.8Hz,1H),7.30(dd,J=8.8,2.7Hz,1H).

¹³ C NMR (151MHz, DMSO-d ₆ )δ171.89, 161.81, 142.74, 141.57, 141.28, 138.10, 132.25, 132.01, 131.78, 131.71, 130.02, 127.55, 124.31, 120.61, 119 .27, 118.53, 116.27, 114.14.

Example 14

Synthesis of 4-(5-((3-fluoro-4-methylphenyl)amino)pyridin-3-yl)-2-hydroxybenzoic acid (A14)

3-Amino-5-bromopyridine (1.0g, 5.8mmol) and 3-fluoro4-methylphenylboronic acid (1.8g, 11.6mmol) were dissolved in dichloromethane, added pyridine (0.9mL, 11.6mmol), acetic acid Copper (0.5g, 2.9mmol), stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate:petroleum ether (volume ratio 1:5) column chromatography, 3-bromo-5- ((3-fluoro-4-methylphenyl)amino)pyridine 0.4 g, yield 22%.

3-bromo-5-((3-fluoro-4-methylphenyl)amino)pyridine (0.4g, 1.7mmol) and 2-hydroxy-4-(4,4,5,5-tetramethyl-1 , 3,2-Dioxybenzaldehyde-2-yl)methyl benzoate (0.4g, 1.5mmol) was dissolved in a mixture of 1,4-dioxane and water (volume ratio 3:1), Potassium carbonate (0.5g, 3.8mmol) and (1,1-bis(diphenylphosphino)ferrocene)palladium dichloride (0.03g, 0.04mmol) were added, argon was replaced, and stirred at reflux for 6h. Filtration with celite, acidification with dilute hydrochloric acid, and recrystallization from ethanol gave 0.1 g of 4-(5-phenoxypyridin-3-yl) 2-hydroxybenzoic acid A14 as a yellow solid, with a yield of 20%.

The structural characterization data of the product are as follows:

¹ H NMR (400MHz, DMSO-d6) δ9.35(s, 1H), 8.51(s, 1H), 8.47-8.39(m, 1H), 8.00(d, J=2.2Hz, 1H), 7.91(d ,J=8.2Hz,1H),7.33(d,J=1.8Hz,1H),7.28(dd,J=8.2,1.8Hz,1H),7.24(t,J=8.5Hz,1H),7.08-6.99 (m,2H),2.19(d,J=1.8Hz,3H).

¹³ C NMR (151MHz, DMSO-d ₆ ) δ171.89, 162.28-160.68 (fluorine splitting), 161.82, 160.68, 142.83, 142.57, 140.62, 137.31, 132.72, 132.68, 131.67, 124.81, 118.4 5,118.28,116.03,115.25, 113.91, 106.31, 106.15, 14.11.

The activity evaluation of above embodiment gained product:

1. In vitro inhibitory activity evaluation of compound A1-14 on XOR:

Dilute 10×PBS (pH=7.4) to 1×PBS, and the PBS in the following reaction systems are all 1×PBS. Weigh 15.2mg of xanthine, add 250mL PBS and 1mL NaOH solution (1mmol/L) for sonication to induce dissolution, and obtain a 0.4mmol/L substrate solution. Take 20 μL of XOR master solution and add 20 mL of PBS to dilute and store in ice bath to obtain 0.5 μg/100 μL enzyme solution. Set up a blank group, a control group, and an experimental group. The blank group only adds inhibitors and xanthine solutions, the control group only adds xanthine solutions and enzyme solutions, and the experimental group adds compound A1-14. Carry out in a 96-well plate, PBS buffer Solution, 100 μL of enzyme solution, and 50 μL of inhibitors of various concentrations were incubated at 37°C for 3 minutes, then removed and immediately added with 30 μL of substrate to start. The total volume of the reaction system was 200 μL, readings were made every 30 s at 295 nm for a total of 5 min, and each experiment was measured 4 times in parallel. The absorbance values obtained at different times for each concentration of the compound were converted into the initial velocity of the test compound, and compared with the control group, the IC ₅₀ value of each compound was obtained by calculation. See Table 1.

Table 1. In vitro inhibitory activity of compounds A1-14 on XOR

2. In vitro inhibitory activity evaluation of compound A1-14 on URAT1

The self-built fluorescence detection method for measuring the activity of URAT1 was used to measure the activity of the compounds to be tested. Using 6-carboxyfluorescein as the substrate for URAT1 transport, the inhibitory effect of the test compound on URAT1 in vitro was determined according to the change of the fluorescence value before and after adding the test compound in the reaction system. Self-constructed HEK293T/hURAT1 stably transfected cells, prepared a cell suspension with a density of 2×10 ⁵ cells/mL, added 200 μL/well in a 96-well fluorescent plate, and set up a blank group, a control group, and an experimental group, with 5 cells in each group Duplicate wells, in which HEK293T/hURAT1 cells were added to the control group and the experimental group, and cells were not added to the blank group. After culturing for 48 hours, add 100 μL of HBSS (without Cl ^- ) solution to the blank group, add 100 μL 6-carboxyfluorescein solution (final concentration 239.48 μmol/L) to the control group, and add 100 μL 6-carboxyfluorescein solution (239.48 μmol/L) to the experimental group. ) of each concentration gradient of the test compound solution. After 1 h, the working solution was sucked off, and 100 μL of NaOH solution (0.5 mol/L) was added to each well for lysis for 30 min. In the microplate reader, set the excitation wavelength to 490nm and the emission wavelength to 525nm, and read after shaking. The results are shown in Table 2.

Table 2. In vitro inhibitory activity of compounds A1-14 on URAT1

From the results in Tables 1 and 2, it can be seen that the compound A1-14 obtained in the present invention has the following unexpected but relatively clear structure-activity relationship. 1. Substituting X with -NH- is more effective than connecting with -O-. Whether it is the inhibitory activity of XOR or URAT1, compound A7-14 has a more obvious improvement than compound A1-6; 2. R ₂ is fixed as hydrogen, and when R ₁ is substituted with different alkyl groups, as the carbon number of the substituted alkyl group increases, the inhibitory activity of the compound on XOR and URAT1 is weakened, such as A1 and A4, A7 and A11; 3. Compound A12, X is When -NH-, R ₁ is H, and when R ₂ is replaced by Cl, its in vitro activity has the best inhibitory activity on the two targets, surpassing febuxostat and benzbromarone respectively. In conclusion, the tricyclic XOR/URAT1 dual inhibitors containing 2-hydroxybenzoic acid of the present invention have shown strong inhibitory effects on the two key drug targets in the uric acid metabolic pathway, and have potential clear uric acid-lowering effects. treatment effect.

The above-mentioned embodiment is a preferred embodiment of the present invention, but the embodiment of the present invention is not limited by the above-mentioned embodiment, and any other changes, modifications, substitutions, combinations, Simplifications should be equivalent replacement methods, and all are included in the protection scope of the present invention.

Claims (9)

1. The tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid is characterized in that the structure is shown in a formula (A):

wherein X is O or NH, R ₁ Is hydrogen, C1-C7 alkyl, OCH ₃ F, cl, br or CN, R ₂ Is hydrogen, C1-C7 alkyl, OCH ₃ F, cl, br or CN.

2. A tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid according to claim 1, wherein the inhibitor is a compound of any one of:

4- (5-Phenoxypyridin-3-yl) 2-hydroxybenzoic acid

4- (5- (4-chlorophenoxy) pyridin-3-yl) -2-hydroxybenzoic acid

4- (5- (p-tolyloxy) pyridin-3-yl) 2-hydroxybenzoic acid

4- (5- (4- (tert-butyl) phenoxy) pyridin-3-yl) -2-hydroxybenzoic acid

4- (5- (3-chlorophenoxy) pyridin-3-yl) -2-hydroxybenzoic acid

4- (5- (Methanophenoxy) pyridin-3-yl) 2-hydroxybenzoic acid

4- (5- (Phenylamino) pyridin-3-yl) 2-hydroxybenzoic acid

4- (5- ((4-chlorophenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid

4- (5- ((4-methoxyphenyl) amino) pyridin-3-yl) 2-hydroxybenzoic acid

4- (5- (p-toluylamino) pyridin-3-yl) 2-hydroxybenzoic acid

4- (5- ((4- (tert-butyl) phenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid

4- (5- ((3-chlorophenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid

4- (5- ((3, 4-dichlorophenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid

4- (5- ((3-fluoro-4-methylphenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid.

3. A process for the preparation of a tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid as claimed in any one of claims 1 to 2, comprising the steps of:

(1) Dissolving 3-hydroxy-5-bromopyridine and the compound I in an organic solvent, adding an organic base and copper acetate, and stirring at normal temperature to obtain a compound II, or dissolving 3-amino-5-bromopyridine and the compound I in the organic solvent, adding the organic base and copper acetate, and stirring at normal temperature to obtain a compound III;

(2) Dissolving the compound II and 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) methyl benzoate in a mixed solvent of 1, 4-dioxanone and water, adding a palladium catalyst, inorganic alkali and argon protection, and carrying out reflux reaction to obtain an A-1 compound, or dissolving the compound III and 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) methyl benzoate in a mixed solvent of 1, 4-dioxanone and water, adding the palladium catalyst, inorganic alkali and argon protection, and carrying out reflux reaction to obtain the A-2 compound.

4. A process according to claim 3, wherein the organic solvent in step (1) is methylene chloride and the organic base is pyridine; the inorganic base in the step (2) refers to potassium carbonate; the palladium catalyst used in the step (2) is (1, 1-bis (diphenylphosphine) ferrocene) palladium dichloride.

5. The method according to claim 3, wherein the molar equivalent ratio of 3-hydroxy-5-bromopyridine, compound I, organic base, copper acetate in step (1) is 1:2:2-3:0.5-1, wherein the molar equivalent ratio of the 3-amino-5-bromopyridine to the compound I to the organic base to the copper acetate is 1:2:2-3:0.5-1.

6. The process according to claim 3, wherein the molar equivalent ratio of the compound II, 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) benzoate, the inorganic base and the palladium catalyst in the step (2) is 1:1.5:3:0.03, wherein the molar equivalent ratio of the compound III to the methyl 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxybenzaldehyde-2-yl) benzoate to the inorganic base to the palladium catalyst is 1:1.5:3:0.03.

7. use of a tricyclic XOR/URAT1 dual inhibitor comprising 2-hydroxybenzoic acid as claimed in any one of claims 1 to 2 in the manufacture of a medicament for the prophylaxis and treatment of XOR/URAT 1-related disorders.

8. The use according to claim 7, wherein the medicament is an antihyperlipidemic or gout medicament.

9. The use according to claim 8, wherein the anti-hyperuricemia or gout drug comprises as an active ingredient a tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

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