Preparation method of rosaxostat intermediate

Abstract

The invention discloses a preparation method of a rosaxostat intermediate, which comprises the following steps: taking an m-phenoxyacetophenone oxime derivative and a propiolic acid ester compound as initial raw materials, and carrying out cyclization reaction on the m-phenoxyacetophenone oxime derivative and the propiolic acid ester compound under the catalysis of a catalyst to synthesize 1-methyl-7-phenoxy-3-isoquinoline methyl formate, the method comprises the following steps of: preparing the rosaxostat intermediate 4-hydroxyl-1-methyl-7-phenoxy-3-isoquinoline formate by using 4-hydroxyl-1-methyl-7-phenoxy-3-isoquinoline formate as a raw material and then using an oxidation rearrangement method. According to the synthetic route, the introduction mode of isoquinoline C-1 methylation is simplified, all raw material reagents used are easy to obtain or prepare, high-risk and high-pollution reagents are not used, safety and environment friendliness are achieved, reaction conditions are mild, operation is convenient and controllable, and the prepared rosaxostat intermediate is good in purity, high in yield, obvious in cost advantage and suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of drug preparation, and in particular to a method for preparing a roxadustat intermediate. Background Art

[0002] Anemia is a very common disease in patients with chronic kidney disease (CKD). The morbidity and mortality rates are very high for both dialysis and non-dialysis CKD patients. CKD can occur at any age and is more common in the elderly. There are approximately 120 million CKD patients in China. There are more than 400,000 CKD people receiving dialysis in China, and the number is growing rapidly at a double-digit rate. Therefore, the number of patients who need anti-anemia therapy is increasing. The current anti-anemia therapy for CKD patients is mainly injection of erythropoietin. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor that can provide a more convenient (oral) and safer treatment option.

[0003] Roxadustat, chemically named [(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)amino]acetic acid and trade name Areltra, was developed by FibroGen in the United States and has been licensed to Astellas in Japan and AstraZeneca in the United Kingdom. It is a new oral hypoxia-inducible factor prolyl hydroxylase inhibitor that can induce erythropoiesis and treat renal anemia. On December 18, 2018, a domestically produced Class 1 original new drug jointly developed by FibroGen China and AstraZeneca China, and the world's first oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), was approved for marketing by the National Medical Products Administration (NMPA). Roxadustat is approved for the treatment of anemia in CKD dialysis patients, including hemodialysis and peritoneal dialysis patients. At present, there are several main routes for the synthesis of roxadustat:

[0004] Synthesis route 1 is world patent WO2004108681, which is the patent of Yuanyan Company. It uses 3,4-dicyanonitrobenzene as the starting material and sequentially undergoes 11 steps of reactions, including phenol etherification, potassium hydroxide hydrolysis, glycine cyclization, methanol esterification, metal sodium and tert-butanol cyclization, phosphorus tribromide bromination, sodium hydroxide hydrolysis, n-butyl lithium and methyl iodide methylation, sodium hydroxide hydrolysis, glycine benzyl ester amidation and palladium carbon debenzylation, to obtain rosuvastatin. This route has a long number of steps and a low yield, especially the use of the hazardous reagent n-butyl lithium in the methylation reaction, which limits its large-scale industrial production.

[0005]

[0006] Synthetic route 1

[0007] The second synthetic route is the optimization of the process route of the original drug by Zhejiang Beida Pharmaceutical's world patent WO2013013609. This route also uses 3,4-dicyanonitrobenzene as the starting material, and successively undergoes phenol etherification, potassium hydroxide hydrolysis, acetic anhydride dehydration, cyanoacetic acid methyl oxazolinylation, hydrochloric acid cyclization, phosphorus oxychloride chlorination, palladium-catalyzed methylation, hydrolysis and amidation to obtain rosuvastatin. Compared with the original research route, this route has one less reaction, but the reaction steps are still more. The starting material 2-cyano-4-nitrobenzonitrile needs to be prepared through multiple steps of reaction, which is very costly and there is no commercial product supply; in particular, the expensive palladium is used to catalyze the methylation and the yield of the methylation reaction is only 33%, which greatly increases the cost of the route, making it difficult to achieve large-scale industrial production.

[0008]

[0009] Synthetic route 2

[0010] The third synthetic route is the further optimization and improvement of the synthetic route by the original research company's world patent WO2014014834. This route uses 2-bromophthalide as the starting material, and successively undergoes phenol etherification, dichlorothionyl ring-opening chlorination, substituted amino acid docking, cyclization, hydroxyl alkylation, acetic anhydride acylation, and palladium carbon deprotection to obtain rosuvastatin. This route has many steps, the entry of the methyl group is more complicated and it undergoes multiple protections and deprotections. In particular, the use of palladium carbon catalytic deprotection requires the use of special pressurized equipment, which is not conducive to industrial production. Therefore, this route is difficult to achieve industrial production and has high costs.

[0011]

[0012] Synthesis route 3

[0013] Synthesis route 4 is a new route disclosed by Shanghai Xunhe Pharmaceutical in Chinese patent CN106478504A. This route uses m-bromoacetophenone as the starting material, and is successively subjected to phenol etherification, hydroxylamine hydrochloride and sodium borohydride reduction amination, 2-carbonylmalonate to Schiff base, and finally cyclization to obtain the intermediate rosuvastatin intermediate 4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinecarboxylate. The starting materials of this route are difficult to obtain and are expensive, and the cyclization reaction temperature is high and the reaction conditions are harsh. At the same time, the selectivity of the reaction is poor, and ortho-cyclization by-products are easily produced, so the product cost is high and difficult to purify.

[0014]

[0015] Synthetic route 4

[0016] Synthesis route 5 is a novel route of Suzhou Mingrui Company in Chinese patent CN104892509. This route uses tyrosine as the starting material, and successively undergoes alcohol esterification, halogenated benzene etherification, acetaldehyde cyclization, base-catalyzed dehydrogenation, hydrogen peroxide-catalyzed hydroxylation, and finally amidation to obtain rosuvastatin. Compared with the previous route, this method has greatly shortened the steps, but the etherification reaction is prone to side reactions with amino groups, making the product difficult to purify, and the yield of hydrogen peroxide hydroxylation reaction is low, so the industrial production of this route still needs to be improved and optimized.

[0017]

[0018] Synthetic route 5

[0019] In summary, there are many synthetic methods for roxadustat at present, and most of these synthetic methods are to first synthesize the intermediate 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester, and then obtain roxadustat through reactions such as cyclization. In the above preparation route of the intermediate, it is difficult to industrialize the above route on a large scale because of the long synthetic route and low yield, the use of expensive catalysts, the use of dangerous reagents, or the difficulty in purification due to many side reactions. Therefore, it is urgent to develop a process route for the roxadustat intermediate 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester that is green, environmentally friendly, high in yield, low in cost, and good in selectivity, and has broad prospects. Summary of the invention

[0020] Based on the above technical problems existing in the prior art, the purpose of this application is to provide a method for preparing a rosuvastatin intermediate.

[0021] The technical solution adopted by the present invention is as follows:

[0022] A method for preparing a rosuvastatin intermediate comprises the following steps:

[0023] S1: In an organic solvent A, a phenoxyacetophenone oxime derivative represented by formula (1) (synthesis method see Org Lett, 2019, 21, 2863-2866) is used as a starting material, and under the action of additives and catalysts, a cyclization reaction is carried out with a propiolate compound represented by formula (2) to obtain 1-methyl-7-phenoxyisoquinoline-3-carboxylate represented by formula (3);

[0024] S2: Subsequently, the compound of formula (3) is subjected to oxidation and rearrangement reactions to obtain a rosuvastatin intermediate, namely 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate as shown in formula (5), and the reaction equation is as follows:

[0025]

[0026] In formula (2), formula (3) and formula (5), the substituent R is a C1-C4 alkyl group, preferably a methyl group, an ethyl group or a tert-butyl group;

[0027] The reaction route of the invention simplifies the method for introducing methylation at the C-1 position of isoquinoline and avoids the use of noble metal catalysts, and has the characteristics of simple process, convenient operation, no need for column chromatography purification, and high yield.

[0028] The catalyst of the present invention is one or more of a divalent copper compound, a divalent nickel compound, a divalent cobalt compound, a trivalent cobalt compound, and a trivalent iron compound, and is further selected from at least one of copper (II) acetate, cobalt acetate tetrahydrate, nickel (II) chloride, nickel nitrate hexahydrate (II), cobalt (II) acetylacetonate, cobalt (III) acetylacetonate, iron (III) acetylacetonate, cobalt nitrate hexahydrate, cobalt chloride hexahydrate, cobalt (II) fluoride, and cobalt (III) fluoride, and is preferably cobalt acetate tetrahydrate, cobalt nitrate hexahydrate, or cobalt (II) fluoride.

[0029] The additive of the present invention is one or more of acetic acid, trifluoroacetic acid, adamantanecarboxylic acid, pivalic acid, oxalic acid, 2,2,6,6-tetramethyl-3,5-heptanedione, sodium oxalate, and acetylacetone, preferably pivalic acid, 2,2,6,6-tetramethyl-3,5-heptanedione or sodium oxalate.

[0030] Furthermore, the molar ratio of the compound of formula (1) to the catalyst is 1:0.01-0.5, preferably 1:0.1-0.5; the molar ratio of the compound of formula (1) to the compound of formula (2) is 1:0.7-2.5, preferably 1:1-2; the molar ratio of the compound of formula (1) to the additive is 1:0.5-2.0, preferably 1:1.

[0031] Furthermore, in step S1, the organic solvent A is at least one of acetonitrile, dichloroethane, methanol, tetrahydrofuran, hexafluoroisopropanol, N,N-dimethylformamide, dimethylacetamide, isopropyl ether, toluene, and dimethyl sulfoxide, preferably at least one of methanol, dimethylacetamide, and toluene; and the dispersion concentration of the compound of formula (1) in the organic solvent A is 0.1-0.5 mol / L.

[0032] Furthermore, in step S1, the reaction temperature of the cyclization reaction is 30-150°C, preferably 40-110°C.

[0033] Further, after the reaction of step S1 is completed, the following post-treatment steps are also included: directly cooling to room temperature, or concentrating the reaction solution to remove the solvent and then cooling to room temperature, adding water, and adding ethyl acetate or dichloromethane to extract the liquid, the organic phase is first washed with a saturated sodium bicarbonate solution or a saturated sodium chloride solution, then washed with water, dried over anhydrous sodium sulfate, concentrated, and the obtained concentrate is recrystallized with ethyl acetate and normal hexane, and dried. The volume ratio of the recrystallized ethyl acetate: normal hexane is 1:1-5, preferably 1:2-3.

[0034] Furthermore, in step S2, the compound of formula (3) undergoes an oxidation reaction with an oxidant in an organic solvent B, the oxidant is at least one of meta-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, and ozone, preferably meta-chloroperbenzoic acid, and the molar ratio of the oxidant to the compound of formula (3) is 1.4-3.5:1.

[0035] Furthermore, in step S2, the organic solvent B is dichloromethane, acetic acid, chloroform or 1,2-dichloroethane, preferably dichloromethane or 1,2-dichloroethane, and the dispersion concentration of the compound of formula (3) in the organic solvent B is 0.1-0.5 mol / L.

[0036] Furthermore, the rearrangement reaction in step S2 comprises the following steps: adding the product of the oxidation of the compound of formula (3) to a mixture of acetic acid and acetic anhydride, adding acetate, heating to 75-85°C for reaction, monitoring the reaction until completion by TLC, concentrating under reduced pressure, adding water and alkalizing to pH 11-12 with aqueous ammonia, extracting with ethyl acetate, separating the liquids, washing the organic phase with water, drying, filtering, concentrating, and then refluxing in an acidic solution for reaction, monitoring the reaction completion by TLC, adjusting the pH to 7-8 with alkali, filtering, and recrystallizing with isopropanol to obtain the target product.

[0037] Furthermore, the volume ratio of acetic acid to acetic anhydride is 1:1.5-3, the acetate is sodium acetate, potassium acetate or ammonium acetate, preferably sodium acetate, and the molar ratio of acetate to the compound of formula (3) is 1.5-3:1.

[0038] Furthermore, the acidic solution is one of a hydrochloric acid-methanol mixed solution, a hydrochloric acid-ethanol mixed solution, a sulfuric acid-methanol mixed solution, and a sulfuric acid-ethanol mixed solution, and the acid concentration is 2%-10%, preferably 3%-7%; the temperature of the rearrangement reaction in step S2 is 65-75°C.

[0039] The beneficial effects achieved by the present invention are:

[0040] The present invention uses the m-phenoxyacetophenone oxime derivative shown in formula (1) and the propiolate compound shown in formula (2) as starting materials to prepare the rosuvastatin intermediate shown in formula (3) of 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester, and then prepares the 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester shown in formula (5) through an oxidative rearrangement reaction. Compared with the content of the existing public technology, the synthesis route disclosed in the present invention has short steps, uses cheap cobalt metal catalysis, avoids harsh reaction conditions, does not require column chromatography purification, and realizes 1-position methylation while constructing the isoquinoline mother nucleus. The present invention focuses on the influence of catalysts, additives, organic solvents, molar equivalents, etc. on the reaction. The selection of catalysts, additives, and organic solvents in the present invention greatly improves the reaction effect. DETAILED DESCRIPTION

[0041] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0042] The raw materials used in the present invention are the m-phenoxyacetophenone oxime derivative represented by formula (1) (the synthesis method is shown in Org Lett, 2019, 21, 2863-2866.), m-phenoxyacetophenone, the propiolate compound represented by formula (2), etc., which are all commercially available.

[0043] Example 1

[0044] In a 50 mL three-necked flask with a magnetic stirrer and a thermometer, m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), cobalt chloride hexahydrate (0.19 g), adamantanecarboxylic acid (5 mmol), methyl propiolate (12.5 mmol), and toluene (15 mL) were added respectively. After the addition was completed, the temperature was raised to 90°C and the reaction was continued for 16 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated to remove toluene, the reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, and it was extracted with ethyl acetate three times. The organic phases were combined, washed with saturated sodium bicarbonate solution and water in turn, dried over anhydrous sodium sulfate, and concentrated. The concentrate obtained was recrystallized with ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v), and dried to obtain 1.28 g of roxadustat intermediate 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester, with a yield of 87.85% and a HPLC purity of 99.7%.

[0045] Example 2

[0046] In a 50 mL three-necked flask with a magnetic stirrer and a thermometer, m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), cobalt acetate tetrahydrate (0.49 g), trifluoroacetic acid (5 mmol), tert-butyl propiolate (10 mmol), and hexafluoroisopropanol (15 mL) were added respectively. After the addition was completed, the temperature was raised to 40°C and the reaction was continued for 15 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated, the reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, and it was extracted with ethyl acetate three times. The organic phases were combined, washed with saturated sodium bicarbonate solution and water in turn, dried over anhydrous sodium sulfate, and concentrated. The concentrate obtained was recrystallized with ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v), and dried to obtain 1.49 g of roxadustat intermediate 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid tert-butyl ester, with a yield of 89.31% and a HPLC purity of 99.3%.

[0047] Example 3

[0048] Into a 50 mL three-necked flask equipped with a magnetic stirrer and a thermometer, add m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), acetylacetonate iron (III) (0.71 g), 2,2,6,6-tetramethyl-3,5-heptanedione (10 mmol), methyl propiolate (10 mmol), and isopropyl ether (15 mL). After the addition, raise the temperature to 120 °C and reflux for 15 h. After the reaction was completed as monitored by TLC, the reaction solution was concentrated and cooled to room temperature. 20 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride and water in turn, dried over anhydrous sodium sulfate, and concentrated. The concentrate was recrystallized with ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v), and dried to obtain 0.93 g of rosuvastatin intermediate 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester with a yield of 63.15% and a HPLC purity of 93.4%.

[0049] Example 4

[0050] In a 50 mL three-necked flask with a magnetic stirrer and a thermometer, m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), cobalt chloride hexahydrate (0.03 g), sodium oxalate (2.5 mmol), ethyl propiolate (10 mmol), and N,N-dimethylformamide (15 mL) were added respectively. After the addition was completed, the temperature was raised to 110°C and the reaction was continued for 16 hours. After the reaction was completed by TLC monitoring, the reaction solution was cooled to room temperature, 40 mL of water was added to the reaction solution, and it was extracted with dichloromethane three times. The organic phases were combined, washed with saturated sodium chloride and water in turn, dried over anhydrous sodium sulfate, filtered and concentrated, and the concentrate obtained was recrystallized with ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v), and dried to obtain 0.81 g of roxadustat intermediate 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid ethyl ester, with a yield of 52.89% and a HPLC purity of 95.5%.

[0051] Example 5

[0052] In a 50 mL three-necked flask with a magnetic stirrer and a thermometer, m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), nickel (II) chloride (0.06 g), acetic acid (7.5 mmol), methyl propiolate (5 mmol), and toluene (15 mL) were added respectively. After the addition was completed, the temperature was raised to 120°C and the reaction was refluxed for 17 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated, the reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, and it was extracted with ethyl acetate for 3 times. The organic phases were combined, washed with saturated sodium bicarbonate solution and water in turn, dried over anhydrous sodium sulfate, and concentrated. The concentrate obtained was recrystallized with ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v), and dried to obtain 0.93 g of roxadustat intermediate 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester, with a yield of 63.49% and a HPLC purity of 99.3%.

[0053] Example 6

[0054] In a 50 mL three-necked flask with a magnetic stirrer and a thermometer, m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), cobalt (II) acetylacetonate (0.18 g), trifluoroacetic acid (7.5 mmol), tert-butyl propiolate (5 mmol), and tetrahydrofuran (15 mL) were added respectively. After the addition was completed, the temperature was raised to 40°C and the reaction was continued for 17 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated, the reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, and it was extracted with ethyl acetate three times. The organic phases were combined, washed with saturated sodium bicarbonate solution and water in turn, dried over anhydrous sodium sulfate, and concentrated. The concentrate obtained was recrystallized with ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v), and dried to obtain 1.34 g of roxadustat intermediate 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid tert-butyl ester, with a yield of 80.10% and a HPLC purity of 98.5%.

[0055] Example 7

[0056] In a 50 mL three-necked flask with a magnetic stirrer and a thermometer, m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), cobalt nitrate hexahydrate (0.22 g), acetylacetone (2.5 mmol), ethyl propiolate (6 mmol), and dimethylacetamide (15 mL) were added respectively. After the addition was completed, the temperature was raised to 90°C and the reaction was continued for 14 h. After the reaction was completed by TLC monitoring, the reaction solution was cooled to room temperature, 40 mL of water was added to the reaction solution, and ethyl acetate was extracted 3 times, the organic phases were combined, washed with saturated sodium chloride and water in turn, dried over anhydrous sodium sulfate, and concentrated. The concentrate obtained was recrystallized with ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v), and dried to obtain 1.37 g of roxadustat intermediate 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid ethyl ester, with a yield of 89.13% and a HPLC purity of 92.1%.

[0057] Example 8

[0058] In a 50 mL three-necked flask with a magnetic stirrer and a thermometer, add m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), cobalt (II) fluoride (0.24 g), sodium oxalate (10 mmol), tert-butyl propiolate (10 mmol), and dichloroethane (15 mL), respectively. After the addition, heat to 60 ° C and continue to react for 16 hours. After the reaction is completed by TLC monitoring, the reaction solution is concentrated, 20 mL of water is added to the concentrated solution, and ethyl acetate is used to extract 3 times. The organic phases are combined, washed with saturated sodium chloride and water in turn, dried over anhydrous sodium sulfate, and concentrated. The concentrate obtained is recrystallized with ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v), and dried to obtain 1.38 g of roxadustat intermediate 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid tert-butyl ester, with a yield of 82.33% and a HPLC purity of 98.2%.

[0059] Example 9

[0060] In a 50 mL three-necked flask with a magnetic stirrer and a thermometer, m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), cobalt acetate tetrahydrate (0.06 g), adamantanecarboxylic acid (2.5 mmol), ethyl propiolate (12.5 mmol), and DMSO (15 mL) were added respectively. After the addition was completed, the temperature was raised to 90°C and the reaction was continued for 17 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated, 40 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate for 3 times. The organic phases were combined, washed with saturated sodium bicarbonate solution and water in turn, dried over anhydrous sodium sulfate, and concentrated. The obtained concentrate was recrystallized with ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v), and dried to obtain 1.31 g of roxadustat intermediate 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid ethyl ester, with a yield of 85.54% and a HPLC purity of 92.2%.

[0061] Example 10

[0062] In a 50 mL three-necked flask with a magnetic stirrer and a thermometer, add m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), copper (II) acetate (0.10 g), trifluoroacetic acid (2.5 mmol), methyl propiolate (7.5 mmol), acetonitrile (15 mL), and after the addition, heat to 40 ° C and continue to react for 15 hours. After the reaction is completed by TLC monitoring, the reaction solution is cooled to room temperature, the reaction solution is concentrated, 20 mL of water is added to the concentrated solution, and it is extracted with ethyl acetate three times, the organic phases are combined, washed with sodium bicarbonate solution and water in turn, dried over anhydrous sodium sulfate, and concentrated. The obtained concentrate is recrystallized with ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v), and dried to obtain 0.88 g of roxadustat intermediate 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester, with a yield of 60.29% and a HPLC purity of 94.9%.

[0063] Embodiment 11

[0064] In a 50 mL three-necked flask with a magnetic stirrer and a thermometer, m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), nickel nitrate hexahydrate (II) (1.5 g), sodium oxalate (7.5 mmol), tert-butyl propiolate (5 mmol), and N,N-dimethylformamide (15 mL) were added respectively. After the addition was completed, the temperature was raised to 120°C and refluxed for 15 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated, the reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, and it was extracted with dichloromethane three times. The organic phases were combined, washed with saturated sodium bicarbonate solution and water in turn, dried over anhydrous sodium sulfate, and concentrated. The concentrate obtained was recrystallized with ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v), and dried to obtain 0.87 g of roxadustat intermediate 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid tert-butyl ester, with a yield of 52.89% and a HPLC purity of 99.3%.

[0065] Example 12

[0066] In a 50 mL three-necked flask with a magnetic stirrer and a thermometer, m-phenoxyacetophenone derivative 1 (1.57 g, 5 mmol), cobalt (III) fluoride (0.07 g), acetylacetone (2.5 mmol), ethyl propiolate (6 mmol), and dimethylacetamide (15 mL) were added respectively. After the addition was completed, the temperature was raised to 150°C and the reaction was continued for 14 h. After the reaction was completed by TLC monitoring, the reaction solution was cooled to room temperature, 40 mL of water was added to the reaction solution, and it was extracted with ethyl acetate three times. The organic phases were combined, washed with saturated sodium chloride and water in turn, dried over anhydrous sodium sulfate, and concentrated. The concentrate obtained was recrystallized with ethyl acetate and n-hexane (ethyl acetate: n-hexane = 1:2.5, v / v), and dried to obtain 1.35 g of roxadustat intermediate 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid ethyl ester, with a yield of 88.00% and a HPLC purity of 92.1%. 1 H NMR (400MHz, DMSO-d6) δ8.45(s,1H),8.20(d,J=8.8Hz,1H),7.65(d,J=2.4Hz,1H),7.57(m 1H),7.47(m,2H),7.24(m,1H),7.20–7.08(m,2H),3.90(s,3H),2.77(s,3H). 13C NMR (101MHz, DMSO-d6) δ166.2,158.1,157.8,156.1,139.4,131.9,131.8,130.8,129.9,124.9,124.4,122.6,119.8,112.0,52.6,22.5.

[0067] Embodiment 13

[0068] In a 50 mL two-necked flask equipped with a magnetic stirrer and a thermometer, add 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (1.47 g, 5 mmol) and chloroform (15 mL), cool the system to 0°C, add perbenzoic acid (7.5 mmol) in batches, and after the addition, warm the temperature to room temperature for reaction. Monitor the completion of the reaction by TLC (12 h). The mixture was quenched by adding saturated sodium thiosulfate solution, washed with saturated brine, dried by adding anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and the remaining concentrated solution was dissolved in a mixture of acetic acid (7.5 mL) and acetic anhydride (15 mL). Sodium acetate (15 mmol) was added and the temperature was raised to 80°C. The reaction was monitored by TLC (2 h). The mixture was concentrated under reduced pressure, 10 mL of water was added and the pH was alkalized to 11-12 with aqueous ammonia, extracted with ethyl acetate (10 mL×2), the organic phase was washed with water, dried, filtered, concentrated, and then heated to 70°C in a 7% mixed solution of hydrochloric acid and methanol for reflux reaction. The reaction was monitored by TLC (2 h), the pH was adjusted to 7-8 with sodium bicarbonate solution, filtered, and recrystallized from isopropanol to obtain 0.93 g of 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester as an off-white solid with a yield of 60.1% and a purity of 98.2% by HPLC.

[0069] Embodiment 14

[0070] In a 50mL two-necked flask equipped with a magnetic stirrer and a thermometer, add 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid ethyl ester (1.54g, 5mmol) and glacial acetic acid (20mL), add 30% hydrogen peroxide (1.0mL, 10mmol) dropwise under stirring at room temperature, and raise the temperature to 65-70℃ for reaction. After the addition is completed, continue the reaction and monitor the completion of the reaction by TLC (14h). After concentration under reduced pressure, the product was dissolved in a mixture of acetic acid (7.5 mL) and acetic anhydride (15 mL), potassium acetate (10 mmol) was added, the temperature was raised to 75-85°C, the reaction was monitored by TLC (2 h), and the product was concentrated under reduced pressure. Water was added and the pH of the solution was alkalized to 11-12 with aqueous ammonia, and the product was extracted with ethyl acetate (10 mL×2). The organic phase was washed with water, dried, filtered, and concentrated, and then heated to 70°C in a 10% mixed solution of hydrochloric acid and ethanol for reflux reaction. The reaction was monitored by TLC (2 h). The pH was adjusted to 7-8 with sodium bicarbonate solution, filtered, and recrystallized from isopropanol to obtain 1.11 g of 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid ethyl ester as an off-white solid with a yield of 68.5% and a purity of 98.1% by HPLC.

[0071] Embodiment 15

[0072] In a 50 mL two-necked flask equipped with a magnetic stirrer and a thermometer, add tert-butyl 1-methyl-7-phenoxyisoquinoline-3-carboxylate (1.68 g, 5 mmol) and dichloromethane (30 mL), cool the system to 0°C, add m-chloroperbenzoic acid (7 mmol) in batches, and after the addition, warm the temperature to room temperature for reaction. Monitor the completion of the reaction by TLC (11 h). The mixture was quenched by adding saturated sodium thiosulfate solution, washed with saturated brine, dried, filtered, concentrated, dissolved in a mixture of acetic acid (7.5 mL) and acetic anhydride (15 mL), added with sodium acetate (10 mmol), heated to 75-85°C, and the reaction was completed after TLC monitoring (2 h). The mixture was concentrated under reduced pressure, 10 mL of water was added, and the pH value of the solution was alkalized to 11-12 with aqueous ammonia, extracted with ethyl acetate (10 mL×2), and the organic phase was washed with water, dried, filtered, concentrated, and then heated to 70°C in a 6% mixed solution of hydrochloric acid and methanol for reflux reaction. The reaction was completed after TLC monitoring (2 h). The pH value was adjusted to 7-8 with sodium bicarbonate solution, filtered, and recrystallized with isopropanol to obtain 1.18 g of off-white solid 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid tert-butyl ester with a yield of 67.2% and a purity of 98.7% by HPLC. 1 H NMR (400MHz, DMSO-d6) δ12.53–9.36(s,1H),8.25(m,1H),7.52–7.46(m,4H),7.32–7.09(m,3H),3.97(s,3H),2.59(s,3H). 13C NMR(101MHz,DMSO-d6)δ170.9,158.9,155.8,154.6,148.2,132.0,130.9,1 26.0,125.1,123.3,122.6,120.1,118.9,112.1,52.9,21.8.HRMS(ESI):m / z calcd for C 18 H 16 NO4[M+H] + :310.1072,found:310.1057.

[0073] The contents described in this specification are merely an enumeration of implementation forms of the inventive concept, and the protection scope of the present invention should not be regarded as being limited to the specific forms described in the embodiments.

Claims

1. A method for preparing a rosuvastatin intermediate, characterized in that The following steps are involved: S1: In an organic solvent A, a phenoxyacetophenone oxime derivative represented by formula (1) and a propiolate compound represented by formula (2) undergo a cyclization reaction under the action of an additive and a catalyst to obtain 1-methyl-7-phenoxyisoquinoline-3-carboxylate represented by formula (3); S2: Subsequently, the compound of formula (3) is subjected to oxidation and rearrangement reactions to obtain a rosuvastatin intermediate, namely 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate as shown in formula (5), and the reaction equation is as follows: In formula (2), formula (3) and formula (5), the substituent R is a C1-C4 alkyl group; The catalyst is one or more of a divalent copper compound, a divalent nickel compound, a divalent cobalt compound, a trivalent cobalt compound, and a trivalent iron compound; The additive is one or more of acetic acid, trifluoroacetic acid, adamantanecarboxylic acid, pivalic acid, oxalic acid, 2,2,6,6-tetramethyl-3,5-heptanedione, sodium oxalate and acetylacetone.

2. The method for preparing a rosuvastatin intermediate according to claim 1, characterized in that The molar ratio of the compound of formula (1) to the catalyst is 1:0.01-0.5, preferably 1:0.1-0.5; the molar ratio of the compound of formula (1) to the compound of formula (2) is 1:0.7-2.5, preferably 1:1-2; the molar ratio of the compound of formula (1) to the additive is 1:0.5-2.0, preferably 1:

1.

3. The method for preparing a rosuvastatin intermediate according to claim 1, characterized in that The catalyst is at least one of copper (II) acetate, cobalt acetate tetrahydrate, nickel (II) chloride, nickel (II) nitrate hexahydrate (II), cobalt (II) acetylacetonate, cobalt (III) acetylacetonate, iron (III) acetylacetonate, cobalt nitrate hexahydrate, cobalt chloride hexahydrate, cobalt (II) fluoride, and cobalt (III) fluoride, preferably cobalt acetate tetrahydrate, cobalt nitrate hexahydrate, or cobalt (II) fluoride; the additive is pivalic acid, 2,2,6,6-tetramethyl-3,5-heptanedione, or sodium oxalate.

4. The method for preparing a rosuvastatin intermediate according to claim 1, characterized in that In step S1, the organic solvent A is at least one of acetonitrile, dichloroethane, methanol, tetrahydrofuran, hexafluoroisopropanol, N,N-dimethylformamide, dimethylacetamide, isopropyl ether, toluene, and dimethyl sulfoxide, preferably at least one of methanol, dimethylacetamide, and toluene; the dispersion concentration of the compound of formula (1) in the organic solvent A is 0.1-0.5 mol / L.

5. The method for preparing a rosuvastatin intermediate according to claim 1, characterized in that In step S1, the reaction temperature of the cyclization reaction is 30-150° C., preferably 40-110° C.; after the reaction in step S1 is completed, the following post-treatment steps are further included: directly cooling to room temperature, or concentrating the reaction solution to remove the solvent and then cooling to room temperature, adding water, and adding ethyl acetate or dichloromethane to extract the liquid, washing the organic phase with a saturated sodium bicarbonate solution or a saturated sodium chloride solution, then washing with water, drying over anhydrous sodium sulfate, and concentrating. The obtained concentrate is recrystallized with ethyl acetate and n-hexane, and dried, and the volume ratio of ethyl acetate to n-hexane in the recrystallization is 1:1-5, preferably 1:2-3.

6. The method for preparing a rosuvastatin intermediate according to claim 1, characterized in that In step S2, the compound of formula (3) and the oxidant undergo an oxidation reaction in an organic solvent B, the oxidant is at least one of meta-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, and ozone, preferably meta-chloroperbenzoic acid, and the molar ratio of the oxidant to the compound of formula (3) is 1.4-3.5:

1.

7. The method for preparing a rosuvastatin intermediate according to claim 6, characterized in that In step S2, the organic solvent B is dichloromethane, acetic acid, chloroform or 1,2-dichloroethane, preferably dichloromethane or 1,2-dichloroethane, and the dispersion concentration of the compound of formula (3) in the organic solvent B is 0.1-0.5 mol / L.

8. The method for preparing a rosuvastatin intermediate according to claim 1, characterized in that The rearrangement reaction in step S2 comprises the following steps: adding the product of the oxidation of the compound of formula (3) to a mixed solution of acetic acid and acetic anhydride, adding acetate, heating to 75-85° C. for reaction, monitoring the reaction until completion by TLC, concentrating under reduced pressure, adding water and alkalizing to pH 11-12 with aqueous ammonia, extracting with ethyl acetate, separating the liquids, washing the organic phase with water, drying, filtering, concentrating, and then refluxing in an acidic solution for reaction, monitoring the reaction completion by TLC, adjusting the pH to 7-8 with alkali, filtering, and recrystallizing with isopropanol to obtain the target product.

9. The method for preparing a roxadustat intermediate according to claim 8, characterized in that The volume ratio of acetic acid to acetic anhydride is 1:1.5-3, the acetate is sodium acetate, potassium acetate or ammonium acetate, preferably sodium acetate, and the molar ratio of acetate to the compound of formula (3) is 1.5-3:

1.

10. The method for preparing a rosuvastatin intermediate according to claim 8, characterized in that The acidic solution is one of a hydrochloric acid-methanol mixed solution, a hydrochloric acid-ethanol mixed solution, a sulfuric acid-methanol mixed solution, and a sulfuric acid-ethanol mixed solution, and the acid concentration is 2%-10%, preferably 3%-7%; the temperature of the rearrangement reaction in step S2 is 65-75°C.

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