Process for the preparation of a urat1 inhibitor intermediate

Abstract

The application belongs to the field of medicine synthesis, and particularly relates to a preparation method of a URAT1 inhibitor intermediate. The method takes 2,3-diaminopyridine (salt) and 1-bromo-4-bromomethylnaphthalene as raw materials, stirs, monitors by HPLC, filters, paddles, and dries to obtain the product. The application can synthesize the product by only one reaction N 3 -[(4-bromonaphthalen-1-yl)methyl]-2,3-diaminopyridine (salt) is low in cost, simple, efficient, has a product yield of 65%-98%, a purity of 86-98%, and is suitable for industrial large-scale production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a preparation method of an intermediate of a URAT1 inhibitor. BACKGROUND

[0002] Currently, there are mainly two types of drugs for treating gout: one is xanthine oxidase inhibitor for inhibiting uric acid generation, and the other is URAT1 inhibitor for promoting uric acid excretion. From the safety of target points or the efficacy of product clinical trials, the URAT1 inhibitor becomes the only breakthrough point in the development of new drugs in the field. Urate transporter 1 (URAT1) is an important urate transporter, and the reabsorption of uric acid in the proximal tubule is mainly completed by URAT1. URAT1 is not affected by membrane voltage and intracellular and extracellular pH value. Inhibition of URAT1 can inhibit the reabsorption of uric acid in the kidney, increase the excretion of uric acid in urine, and thus achieve the purpose of reducing blood uric acid and controlling the onset of gout. Compared with allopurinol and febuxostat and other xanthine oxidase inhibitors, the mechanism of action of the URAT1 inhibitor is more reasonable, because only 10% of patients have excessive uric acid generation, and the remaining 90% of patients have varying degrees of insufficient kidney excretion.

[0003] The key intermediate of the URAT1 inhibitor contains a structure as shown in the compound of formula 1. The preparation method of the intermediate is disclosed by CN114478522A and reported by Journal of Medicinal Chemistry 2020, 63, 19, 10829-1085. The route has a total of 5 steps, and the total yield is 21.7% (calculated based on 2-nitro-3-hydroxypyridine). The method has many steps, a long period, and high cost. Therefore, in order to meet the future clinical needs, it is urgent to develop a simpler and more efficient synthesis method of the intermediate of the URAT1 inhibitor.

[0004] In order to avoid the generation of pyridine 2-aminoalkylation isomers, the initial attempt of the present application is to use 2-nitro-3-aminopyridine as a starting material, and the nitro group can be reduced to an amino group later. However, it is found through experiments that the 3-amino group of the raw material has low activity, and the reaction needs to be heated to 50-70℃ to proceed. At this temperature, the stability of another raw material 1-bromo-4-bromomethylnaphthalene is poor, resulting in poor purity of the main peak in the reaction solution. After detailed research and comparison, 2,3-diaminopyridine and its salt are finally selected as the starting material. SUMMARY

[0005] To achieve the above purpose, the technical scheme adopted by the present application is as follows:

[0006] A preparation method of an intermediate of a URAT1 inhibitor comprises the following reactions:

[0007]

[0008] The specific process is to react the compound of formula 2 with the compound of formula 3 at a molar ratio of 1:1-1:1.2, to obtain the compound of formula 1.

[0009] Preferably, the Y substituent of the compound of formula 2 is selected from any one of nitro and amino, the number of acid-containing molecules n of the compound of formula 2 is 0-3, and the benzyl substituent Z of the compound of formula 3 is selected from any one of F, Cl, Br, I and O.

[0010] Preferably, when the Y substituent is nitro, the reaction is further followed by reduction, cooling and pH adjustment.

[0011] Preferably, the temperature of the reduction is 50-60°C, the time of the reduction is 3-5 h, the stannous chloride is added during the reduction, the concentration of the stannous chloride is 4-6 mol / L, the temperature of the cooling is 0-5°C, and the pH is 7-9.

[0012] Preferably, the acid-containing group X of the compound of formula 1 is selected from one or more of halide, sulfate, bisulfate, sulfonate, phosphate, formate, acetate and C3-C 18 C4 carboxylic acid derivatives, and the number of acid-containing molecules m of the compound of formula 1 is 0-3.

[0013] Preferably, an organic solvent is added during the reaction, and the organic solvent is selected from one or more of dichloromethane, chloroform, tetrahydrofuran, acetonitrile, ethyl acetate, isopropyl acetate, methanol, ethanol, isopropyl alcohol, butyl alcohol, N,N dimethylformamide, dimethyl sulfoxide, N, N dimethylacetamide and N methyl pyrrolidone, and more preferably, the organic solvent is selected from one or more of tetrahydrofuran, acetonitrile, ethyl acetate, methanol and ethanol.

[0014] Preferably, an acid-binding agent is added after the reaction, and the acid-binding agent is selected from N methyl imidazole, N methyl morpholine, triethylamine, diisopropyl ethylamine, pyridine, 4-dimethyl amino pyridine, 1,8-diazabicycloundec-7-ene, sodium carbonate, potassium carbonate and cesium carbonate.

[0015] Preferably, after the addition of the acid-binding agent, water quenching, extraction, drying, filtration, concentration, elution, crystallization are further performed, the solvent for the extraction is methyl tert-butyl ether, and the eluent for the elution is a mixture of petroleum ether and ethyl acetate at a volume ratio of 80-120:1.

[0016] Preferably, the reaction is stirred for 5-20 h at 20-55℃, and the reaction is monitored by HPLC or TLC, filtered, slurried, and dried.

[0017] Preferably, the TLC monitoring uses a developing agent comprising a mixture of dichloromethane, methanol, and triethylamine in a volume ratio of 150-250:5:1-3, the HPLC monitoring uses sampling and filtering with a needle filter until the content of the compound of formula 2 or the compound of formula 1 in the filtrate is <0.5%, and the HPLC monitoring uses a chromatographic column of the type CHIRALPAK IC, a mobile phase comprising n-hexane, ethanol, and diethylamine in a volume ratio of 100-900:100-900:0.1-10. ®

[0018] More preferably, the TLC monitoring uses a developing agent comprising a mixture of dichloromethane, methanol, and triethylamine in a volume ratio of 40:1:0.4, and the n-hexane:ethanol:diethylamine is in a volume ratio of 880:120:2.

[0019] Preferably, the slurry solvent is selected from one or more of methanol, water, tetrahydrofuran, and ethyl acetate, the drying is performed at a temperature of 40-60℃ for 12-18 h, and more preferably, the drying is performed at a temperature of 50℃ for 16 h.

[0020] Compared with the prior art, the present application has the following advantages:

[0021] The present application only needs one step of reaction to obtain N 3 -[(4-bromonaphthalen-1-yl)methyl]-2,3-diaminopyridine (salt) with high yield and high purity.

[0022] The preparation method of the present application is simple and efficient, low in cost, and suitable for large-scale industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 HPLC spectrum of the raw material 2,3-diaminopyridine;

[0024] Figure 2 HPLC spectrum of the raw material 1-bromo-4-bromomethylnaphthalene;

[0025] Figure 3 Product N 3 HPLC spectrum of the product -[(4-bromonaphthalen-1-yl)methyl]-2,3-diaminopyridine (salt);

[0026] Figure 4 Product N ​3 -[(4-bromonaphth-1-yl)methylene]-2,3-diaminopyridine (salt) 1 H NMR spectrum.

[0027] It is worth noting that the unclear parts of the accompanying drawings do not affect the understanding of the technical solution of the present invention by those skilled in the art. Detailed Implementation

[0028] It is worth noting that the raw materials used in this invention are all commercially available products.

[0029] Example 1

[0030] In a 3 L reactor, 1.10 L of methanol, 110 g (1.00 mol, 1.0 eq) of 2,3-diaminopyridine, and 300 g (1.0 mol, 1.0 eq) of 1-bromo-4-bromomethylnaphthalene were added. Mechanical stirring was started, and the temperature was maintained at 20 °C for 18 h. A sample was taken, filtered through a syringe filter, and the filtrate was mixed with 10% (v / v) [reagent / liquid]. N- The reaction was monitored by HPLC using a methanol solution of methylpyrrolidone and a CHIRALPAK column. ® The reaction mixture was prepared using an IC (inductively coupled plasma) mobile phase consisting of hexane, ethanol, and diethylamine in a volume ratio of 880:120:2, with compound 2 < 0.5%. The reaction solution was filtered to obtain a crude product, a brown solid powder (339 g, purity 86%). The crude product was slurried with methanol (1.10 L) and dried at 50 °C for 16 h to obtain compound 1, with a mass of 280 g, purity 98%, and yield of 65%. The HPLC chromatogram of the starting material 2,3-diaminopyridine in this example is shown below. Figure 1 As shown, the HPLC chromatogram of the raw material 1-bromo-4-bromomethylnaphthalene is as follows. Figure 2 As shown, the product N 3 The HPLC chromatogram of -[(4-bromonaphth-1-yl)methylene]-2,3-diaminopyridine (salt) is shown below. Figure 3 As shown, the product N 3 -[(4-bromonaphth-1-yl)methylene]-2,3-diaminopyridine (salt) 1 H NMR spectrum as follows Figure 4 As shown.

[0031] 1 H NMR (600 MHz, DMSO- d 6) δ 8.25-8.20 (q, J = 8.4 Hz, 2H), 7.86-7.84 (d, J= 7.2 Hz, 1H), 7.74-7.68 (m, 2H), 7.41-7.41 (d, J = 8.2Hz, 1H), 7.30-7.41(d, Ja = 4.8Hz, Jb = 0.6Hz 1H), 6.55-6.53 (dd, Ja = 7.8 Hz, Jb = 4.8 Hz 1H), 5.54(s, 2H), 5.44-5.43 (t, 1H), 4.73-4.72 (d, J = 7.2Hz, 2H). MS(ESI) m / z: 327.9, 329.9 Calculated value: C 16 H 14 BrN3, 327.04, 329.04.

[0032] Example 2

[0033] In a 3 L reactor, 1.10 L of methanol, 1.00 mol of 2,3-diaminopyridine (110 g, 1.00 mol, 1.0 eq), and 360 g of 1.2 mol of 1.2 eq were added. Mechanical stirring was started, and the temperature was maintained at 25 °C for 18 h. A sample was taken, filtered through a syringe filter, and the filtrate was mixed with 10% (v / v) [reagent / liquid]. N- The reaction was monitored by HPLC using a methanol solution of methylpyrrolidone and a CHIRALPAK column. ® The reaction mixture was prepared using an IC (inductively coupled plasma) reactor with a mobile phase consisting of hexane, ethanol, and diethylamine in a volume ratio of 900:900:10. The reactant compound of formula 1 was present in concentrations less than 0.5%. The reaction mixture was filtered to obtain a crude product, which was a brown solid powder. The crude product was then slurried with methanol (1.10 L) and dried at 50 °C for 16 h to obtain compound of formula 1, with a mass of 401 g, a purity of 86%, and a yield of 98%.

[0034] Example 3

[0035] In a 3 L reactor, 1.10 L of methanol, 1.00 mol of 2,3-diaminopyridine hydrochloride (1HCl) (147 g, 1.00 eq), and 360 g of 1.2 mol of 1.2 eq were added. Mechanical stirring was started, and the temperature was maintained at 20 °C for 18 h. A sample was taken, filtered through a syringe filter, and the filtrate was mixed with 10% (v / v) [a specific solution]. N- The reaction was monitored by HPLC using a methanol solution of methylpyrrolidone and a CHIRALPAK column. ®The reaction mixture was prepared using an IC (inductively coupled plasma) reactor with a mobile phase consisting of hexane, ethanol, and diethylamine in a volume ratio of 880:120:2, and compound 2 < 0.5%. The reaction solution was filtered to obtain a crude product, a brown solid powder. This crude product was then slurried with 1.10 L of methanol and dried at 50 °C for 16 h to obtain compound 1, with a mass of 438 g, purity of 97%, and yield of 98%.

[0036] Example 4

[0037] In a 3 L reactor, 1.10 L of methanol, 2,3-diaminopyridine dihydrochloride (2HCl) (183 g, 1.00 mol, 1.0 eq), and 1-bromo-4-bromomethylnaphthalene (360 g, 1.2 mol, 1.2 eq) were added. Mechanical stirring was started, and the temperature was maintained at 25 °C for 18 h. A sample was taken, filtered through a syringe filter, and the filtrate was mixed with 10% (v / v) [amount missing]. N- The reaction was monitored by HPLC using a methanol solution of methylpyrrolidone and a CHIRALPAK column. ® The reaction mixture was prepared using an IC (inductively coupled plasma) reactor with a mobile phase consisting of hexane, ethanol, and diethylamine in a volume ratio of 880:120:2, and compound 2 < 0.5%. The reaction solution was filtered to obtain a crude product, a brown solid powder. This crude product was then slurried with 1.10 L of methanol and dried at 50 °C for 16 h to obtain compound 1, with a mass of 438 g, purity of 98%, and yield of 98%.

[0038] Example 5

[0039] In a 3 L reactor, 1.10 L of tetrahydrofuran, 110 g (1.00 mol, 1.0 eq) of 2,3-diaminopyridine, and 255 g (1.0 mol, 1.0 eq) of 1-bromo-4-chloromethylnaphthalene were added. Mechanical stirring was started, and the temperature was maintained at 20 °C for 18 h. A sample was taken, filtered through a syringe filter, and the filtrate was mixed with 10% (v / v) [reagent / liquid]. N- The reaction was monitored by HPLC using a methanol solution of methylpyrrolidone and a CHIRALPAK column. ® The reaction mixture was prepared using an IC (inductively coupled plasma) reactor with a mobile phase of hexane, ethanol, and diethylamine in a volume ratio of 880:120:2, and compound 2 < 0.5%. The reaction solution was filtered to obtain a crude product, a brown solid powder (339 g, purity 86%). The crude product was slurried with methanol (1.10 L) and dried at 50 °C for 16 h. Compound 1 was then obtained, with a mass of 289 g, purity 98%, and yield of 80%.

[0040] Example 6

[0041] Add to a 3 L reactor N-Methyl pyrrolidine 1.10 L, 2-nitro-3-aminopyridine (139 g, 1.00 mol, 1.0 eq), 1-bromo-4-bromomethylnaphthalene (300 g, 1.0 mol, 1.0 eq), potassium carbonate (138 g, 1.0 mol, 1.0 eq), open mechanical stirring, temperature control 55 °C, stirring for 7 h. Sampling, TLC monitoring. After the reaction is completed, quench with water, methyl tert-butyl ether extraction, sodium sulfate drying, filtration, concentration, column chromatography elution, eluent is a mixture of petroleum ether and ethyl acetate with a volume ratio of 100, crystallization, yellow solid. Add N-methyl pyrrolidine solution and stannous chloride (945 g, 5.00 mol, 5.0 eq), temperature control 55 °C, reaction for 4 h, cool to 0 °C, adjust pH to 8 with aqueous sodium hydroxide solution, a large amount of inorganic salt precipitates, add tetrahydrofuran and ethyl acetate to make a slurry, filter to obtain the crude product. The crude product is slurried with water (1.10 L) and dried at 50 °C for 16 h to obtain the pure product, compound of formula 1, with a mass of 290 g, a purity of 98%, and a yield of 65%.

[0042] Comparative Example 1

[0043] In a 3 L reaction kettle, add water 1.10 L, 2,3-diaminopyridine dihydrochloride (2HCl) (183 g, 1.00 mol, 1.0 eq), 1-bromo-4-bromomethylnaphthalene (360 g, 1.2 mol, 1.2 eq), open mechanical stirring, temperature control 25 °C, stirring for 18 h. Sampling, filter with a needle filter, take the filtrate, mix with 10% (v / v) N- Methanol solution of methyl pyrrolidine, HPLC monitoring reaction, column type CHIRALPAK ® IC, mobile phase is n-hexane, ethanol and diethylamine, the volume ratio of n-hexane, ethanol and diethylamine is 880:120:2, compound 2 <0.5%. Filter the reaction solution to obtain the crude product as a brown solid powder, which is slurried with methanol (1.10 L) and dried at 50 °C for 16 h to obtain the compound of formula 1, with a mass of 290 g, a purity of 55%, and a yield of 65%.

[0044] Comparative Example 2

[0045] In a 3 L reaction kettle, add methanol 1.10 L, 2,3-diaminopyridine dihydrochloride (2HCl) (183 g, 1.00 mol, 1.0 eq), 1-bromo-4-bromomethylnaphthalene (360 g, 1.2 mol, 1.2 eq), open mechanical stirring, temperature control 60 °C, stirring for 18 h. Sampling, filter with a needle filter, take the filtrate, mix with 10% (v / v) N-Methanol solution of methylpyrrolidone, HPLC monitoring reaction, column type CHIRALPAK ® IC, mobile phase is n-hexane, ethanol and diethylamine, the volume ratio of n-hexane, ethanol and diethylamine is 880:120:2, compound 2 <0.5%. The reaction solution is filtered to obtain the product crude product as a brown solid powder, the crude product is slurried in methanol (1.10 L) and dried at 50°C for 16 h to obtain the compound of formula 1, the mass of which is 246 g, the purity is 85%, and the yield is 55%.

[0046] Comparative example 3

[0047] In a 3 L reaction kettle, methanol 2.20 L, 2,3-diaminopyridine dihydrochloride (2HCl) (183 g, 1.00 mol, 1.0 eq), 1-bromo-4-bromomethylnaphthalene (360 g, 1.2 mol, 1.2 eq) were put in, mechanical stirring was started, the temperature was controlled at 25°C, and stirring was carried out for 18 h. Sampling, filtering with a needle filter, taking the filtrate, and adding 10% (v / v) N- Methanol solution of methylpyrrolidone, HPLC monitoring reaction, column type CHIRALPAK ® IC, mobile phase is n-hexane, ethanol and diethylamine, the volume ratio of n-hexane, ethanol and diethylamine is 880:120:2, compound 2 <0.5%. The reaction solution is filtered to obtain the product crude product as a brown solid powder, the crude product is slurried in methanol (1.10 L) and dried at 50°C for 16 h to obtain the compound of formula 1, the mass of which is 246 g, the purity is 85%, and the yield is 55%.

[0048] Finally, it should be noted that the above content is only used to illustrate the technical solutions of the present application, and is not a limitation on the protection scope of the present application. Simple modifications or equivalent replacements of the technical solutions of the present application made by those skilled in the art do not deviate from the essence and scope of the technical solutions of the present application.

Claims

1. A method for preparing a URAT1 inhibitor intermediate, characterized in that, Including the following reactions: The specific process involves reacting compound 2 and compound 3 in a molar ratio of 1:1.2 to obtain... The Y substituent of compound 2 is amino, the number n of acid molecules in compound 2 is 1 or 2, and the Z substituent at the benzylic position of compound 3 is Br. The acid radical X of compound 1 is a chlorine group, and the number of acid molecules m in compound 1 is 1 or 2. An organic solvent, namely methanol, is added during the reaction. The reaction is carried out by stirring for 18 hours at a temperature of 20°C or 25°C.

2. The preparation method according to claim 1, characterized in that, The reaction is followed by HPLC or TLC monitoring, filtration, pulping, and drying.

3. The preparation method according to claim 2, characterized in that, The HPLC monitoring conditions included a CHIRALPAK column. ® The mobile phase of the IC comprises hexane, ethanol, and diethylamine, wherein the volume ratio of hexane, ethanol, and diethylamine is 100-900:100-900:0.1-10. The developing solvent for TLC monitoring is a mixture of dichloromethane, methanol, and triethylamine in a volume ratio of 150-250:5:1-3. The solvent for pulping is selected from one or more of methanol, water, tetrahydrofuran, and ethyl acetate. The drying temperature is 40-60°C, and the drying time is 12-18 h.

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