Preparation method of rosaxostat intermediate

Abstract

The invention provides a rosaxostat intermediate and a preparation method thereof, and relates to the technical field of organic synthesis. The preparation method comprises the following steps: condensing m-phenoxybenzaldehyde and amino acid under the catalysis of alkali to generate imine, reducing to obtain amine, and carrying out hydrolysis, substitution, Friedel-Crafts acylation, substitution and aromatization to obtain the target product. The method has the advantages of no use of high-risk and high-pollution reagents, safety, environmental protection, mild reaction conditions, convenient and controllable operation, good purity of the prepared rosaxostat intermediate, and suitableness for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a rosuvastatin intermediate and a preparation method thereof. Background Art

[0002] The Chinese name of Roxadustat is N-[(4-hydroxy-1-methyl-7-phenoxyisoquinolin-3-yl)carbonyl]glycine, and its molecular formula is C 19 H 16 N2O5. Roxadustat is a small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase developed by FibroGen. It can be used for oral treatment of dialysis-dependent and non-dialysis-dependent end-stage renal disease (ESRD), anemia associated with chronic kidney disease (CKD), and myelodysplastic syndrome (MDS). The drug was successfully launched in China in December 2018. Roxadustat can regulate HIF, increase hemoglobin content, and increase iron absorption and utilization by reducing hepcidin levels. It is well tolerated. Therefore, roxadustat is used to treat anemia caused by chronic kidney disease (CKD) in patients undergoing dialysis treatment.

[0003] In the prior art, roxadustat is generally prepared by organic synthesis, and there are multiple synthetic routes. Among them, the following compounds of formula A and formula B are important intermediates for the synthesis of roxadustat.

[0004]

[0005] At present, there are mainly the following routes for the synthesis of compounds of formula A and formula B:

[0006] Synthesis Route 1: Zhejiang Beida Company disclosed the following preparation method in WO2013013609 and CN104024227A. When preparing the compound of formula B, phosphorus oxychloride is used for chlorination, and the safety risk of scaled-up production is high; the methylation method uses a palladium catalyst and methyl borane for preparation (trimethylboron, tetrakistriphenylphosphine palladium, potassium carbonate, 1,4-dioxane as solvent), the yield is low, and trimethylborane is a dangerous substance, which is prone to spontaneous combustion, and is not conducive to industrial scale-up.

[0007]

[0008] Synthesis Route 2: CN106083720A reports that compound A is obtained by esterification, coupling, bromination, amination and cyclization using 4-bromo-2-methylbenzoic acid as raw material. The raw material 4-bromo-2-methylbenzoic acid used in this route is expensive, and carbon tetrachloride is used in the reaction solvent, which is a controlled product. The post-processing of the entire route uses a column chromatography purification method, which is time-consuming and labor-intensive and is not suitable for industrial production.

[0009]

[0010] Synthesis Route 3: Suzhou Mingrui Pharmaceutical Technology Co., Ltd. reported in CN104892509A that tyrosine was used as a raw material, and compound B was obtained through esterification, etherification, cyclization, dehydrogenation, and oxidative rearrangement. The amino acid ring-closing method was used to prepare compound B. In this method, during the process of introducing phenolic hydroxyl group into phenyl group, amino substitution by-products were easily generated, which brought difficulties to the purification of the final product. In addition, the introduction of 4-hydroxyl group on the isoquinoline ring adopted hydrogen peroxide oxidation method, which had great hidden dangers in the industrial production process.

[0011]

[0012] Synthesis Route 4: CN103435546 reported that 5-bromophthalide was used as a raw material, and the target product A was obtained through coupling with phenol, ring opening, amination, and cyclization. The raw material 5-bromophthalide used in this route, the reaction materials including trimethyl borate and dichlorotriphenylphosphorane are expensive, among which the reaction material trimethyl borate is flammable, explosive, toxic, and has a high safety risk factor. The entire route is expensive and is not suitable for industrial production.

[0013]

[0014] In summary, the above routes are not suitable for industrial production due to high cost, time-consuming and labor-intensive post-treatment column chromatography, high safety risk coefficient of the materials used, and difficulty in final product purification. Therefore, it is particularly important to find a route with low safety risk coefficient, green environmental protection, good reaction selectivity and suitable for industrial production. Summary of the invention

[0015] 1. Technical issues to be resolved

[0016] In view of the deficiencies in the prior art, the present invention provides a rosuvastatin intermediate and a preparation method thereof, which solves the technical problems of high cost and high safety risk factor of the existing synthesis method of rosuvastatin intermediate.

[0017] (II) Technical solution

[0018] To achieve the above objectives, the present invention is implemented through the following technical solutions:

[0019] A method for preparing a rosuvastatin intermediate, the synthetic route is as follows:

[0020]

[0021] The preparation method comprises the following steps:

[0022] S1, adding the compound of formula 1 and the glycine derivative to solvent 1, reacting at room temperature under the catalysis of base and solvent 2, adding a reducing agent at low temperature after the reaction, quenching, concentrating, extracting, drying and concentrating to obtain a compound of formula 2;

[0023] S2, adding the compound of formula 2 to water, then adding a base to heat the reaction, extracting with extractant 1 after the reaction, acidifying the water layer at low temperature, then extracting with extractant 2, drying and concentrating to obtain the compound of formula 3;

[0024] S3, adding the compound of formula 3 into water, then adding alkali, heating until dissolved, then adding p-toluenesulfonyl chloride, cooling after the reaction, acidifying, extracting, drying, concentrating, and crystallizing to obtain the compound of formula 4;

[0025] S4, adding the compound of formula 4 to solvent 1, adding a catalytic amount of DMF, then adding an acylating agent, heating the reaction, concentrating the solvent, dissolving the oil in solvent 2, protecting the mixture with N2 in a low temperature environment, adding a Lewis acid, and after the reaction, quenching, alkali washing, water washing, drying, and concentrating the mixture to obtain a compound of formula 5;

[0026] S5, adding the compound of formula 5 and sodium hydrogen to dimethyl carbonate under a nitrogen atmosphere, heating the reaction, evaporating the solvent after the reaction, quenching with methanol at low temperature, adding water, extracting with an extractant, washing with water, drying, and concentrating to obtain a compound of formula 6;

[0027] S6, adding the compound of formula 6 to a solvent, adding a catalyst and a base, heating the reaction, cooling the reaction, extracting with an extractant, drying, and concentrating to obtain a compound of formula A;

[0028] Furthermore, the S1 specifically includes the following steps:

[0029] The reaction equation is as follows:

[0030]

[0031] Furthermore, the glycine derivative in S1 is glycine methyl ester, glycine methyl ester hydrochloride, glycine ethyl ester, glycine ethyl ester hydrochloride, glycine isopropyl ester, glycine isopropyl ester hydrochloride, and preferably, the amino acid is glycine methyl ester hydrochloride.

[0032] Further, the compound of formula 1 in S1 is m-phenoxybenzaldehyde, and the molar ratio of m-phenoxybenzaldehyde to the glycine derivative is 1:1-3.5, preferably 1:1-1.4;

[0033] Furthermore, the solvent 1 in S1 is any one of tetrahydrofuran, dichloromethane, chloroform, and ethyl acetate, preferably dichloromethane;

[0034] Further, the base in S1 is any one of sodium bicarbonate, sodium carbonate, triethylamine, diethylamine, pyridine, and 4-N,N-dimethylaminopyridine, preferably triethylamine;

[0035] Further, the molar ratio of the compound of formula 1 (m-phenoxybenzaldehyde) to the base in S1 is 1:1-3.0, preferably 1:1-2.5;

[0036] Further, the room temperature reaction time in S1 is 16-30h, preferably 18-22h;

[0037] Furthermore, the solvent 2 in S1 is any one of tert-butanol, methanol, and ethanol, preferably methanol;

[0038] Further, the reducing agent in S1 is any one of sodium borohydride, zinc borohydride, and sodium cyanoborohydride, preferably sodium borohydride;

[0039] Further, the molar ratio of the compound of formula 1 (m-phenoxybenzaldehyde) to the reducing agent in S1 is 1:1-2.0, preferably 1:1-1.5;

[0040] Further, the low temperature reaction temperature in S1 is -5°C-10°C, preferably 0°C-5°C;

[0041] Furthermore, the extraction reagent in S1 is one of ethyl acetate, dichloromethane and chloroform, preferably dichloromethane.

[0042] Furthermore, after step S1, post-treatment is also included: specifically including the following steps: quenching, extraction, drying, concentration, and column chromatography to obtain the compound of formula 2.

[0043] Furthermore, the S2 specifically includes the following steps:

[0044] The reaction equation is as follows:

[0045]

[0046] Further, the base in S2 is any one of sodium carbonate, sodium hydroxide, and potassium hydroxide, preferably sodium hydroxide;

[0047] Further, the molar ratio of the compound of formula 2 to the base in S2 is 1:1.1-2.5, preferably 1:1.5-2.0;

[0048] Further, the extractant 1 in S2 is any one of ethyl acetate, dichloromethane, and methyl tert-ether, preferably methyl tert-ether;

[0049] Further, the acid used for acidification in S2 is one of hydrochloric acid, sulfuric acid, and acetic acid, preferably acetic acid;

[0050] Furthermore, the extractant 2 in S2 is one of ethyl acetate, dichloromethane and chloroform, preferably ethyl acetate.

[0051] Furthermore, the step S2 further includes post-processing: drying and concentrating to obtain the compound of formula 3.

[0052] Furthermore, the S3 specifically includes the following steps:

[0053] The reaction equation is as follows:

[0054]

[0055] Further, the base in S3 is any one of sodium carbonate, sodium hydroxide, and potassium hydroxide, preferably sodium carbonate;

[0056] Further, the molar ratio of the compound of formula 3 to p-toluenesulfonyl chloride in S3 is 1:1-2.0, preferably 1:1.1-1.4;

[0057] Further, the molar ratio of the compound of formula 3 to the base in S3 is 1:1-2.5, preferably 1:1.2-1.6;

[0058] Further, the acid used for acidification in S3 is one of hydrochloric acid, sulfuric acid, and acetic acid, preferably hydrochloric acid;

[0059] Furthermore, the extraction reagent used in S3 is one of ethyl acetate, dichloromethane and chloroform, preferably ethyl acetate.

[0060] Furthermore, step S3 further includes post-processing: drying, concentration, and crystallization to obtain the compound of formula 4.

[0061] Furthermore, the S4 specifically includes the following steps:

[0062] The reaction equation is as follows:

[0063]

[0064] Further, the solvent 1 in S4 is any one of toluene, dichloromethane and chloroform, preferably dichloromethane;

[0065] Further, the volume ratio of the compound of formula 4 in S4 to DMF is 1 g: 0.01-0.05 mL, preferably 1 g: 0.03 mL;

[0066] Further, the acylating agent in S4 is any one of oxalyl chloride, thionyl chloride, and phosphorus oxychloride, preferably thionyl chloride;

[0067] Further, the molar ratio of the compound of formula 4 to the acylating agent in S4 is 1:1.5-4.0, preferably 1:1.5-2.5;

[0068] Further, the solvent 2 in S4 is any one of toluene, dichloromethane, and chloroform, preferably dichloromethane;

[0069] Further, the Lewis acid in S4 is any one of zinc chloride, ferric chloride, aluminum chloride, and boron trifluoride, preferably aluminum chloride;

[0070] Further, the molar ratio of the compound of formula 4 to the Lewis acid in S4 is 1:2.0-4.0, preferably 1:2.0-2.5;

[0071] Further, the alkali used in the alkali washing in S4 is any one of sodium bicarbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide, preferably sodium hydroxide;

[0072] Furthermore, step S4 further includes post-treatment: washing, drying, and concentrating to obtain the compound of formula 5.

[0073] Furthermore, the S5 specifically includes the following steps:

[0074] The reaction equation is as follows:

[0075]

[0076] Further, the base in S5 is any one of lithium tert-butoxide, LDA, and sodium hydrogen, preferably sodium hydrogen;

[0077] Furthermore, the molar ratio of the compound of formula 5 to the base in S5 is 1:2-5, preferably 1:2-4;

[0078] Further, the reaction temperature of the temperature-raising reaction in S5 is 80-95° C., preferably 85-90° C.;

[0079] Further, the extractant in S5 is one of ether, ethyl acetate, dichloromethane and chloroform, preferably ethyl acetate;

[0080] Furthermore, the step S5 further includes post-treatment: cooling, quenching with methanol, washing with water, drying, and concentrating to obtain a compound of formula 6;

[0081] Furthermore, the S6 specifically includes the following steps:

[0082] The reaction equation is as follows:

[0083]

[0084] Further, the catalyst in S6 is one of CuI and Pd2(dba)3, preferably CuI;

[0085] Further, the solvent in S6 is one of 1,4-dioxane, 1,4-dioxane, and acetonitrile, preferably 1,4-dioxane;

[0086] Further, the base in S6 is one of sodium bicarbonate, cesium carbonate, sodium carbonate, and potassium carbonate, preferably potassium carbonate;

[0087] Further, the molar ratio of the compound of formula 6 to the catalyst in S6 is 1:0.05-0.5, preferably: 1:0.05-0.1;

[0088] Further, the reaction temperature of the temperature-raising reaction in S6 is 50-80°C, preferably 65-75°C;

[0089] Furthermore, the reaction time of the temperature-raising reaction in S6 is 30-40 hours, preferably 34-38 hours;

[0090] Furthermore, the extractant in S6 is any one of ethyl acetate, dichloromethane and chloroform, preferably ethyl acetate.

[0091] Furthermore, the step S6 further includes post-processing: drying and concentrating to obtain the compound of formula A.

[0092] (III) Beneficial effects

[0093] The present invention provides a rosuvastatin intermediate and a preparation method thereof. Compared with the prior art, the present invention has the following beneficial effects:

[0094] The invention provides a rosuvastatin intermediate and a preparation method thereof. The preparation method comprises the following steps: condensing m-phenoxybenzaldehyde and a glycine derivative under the catalysis of a base to generate an imine, then reducing the imine to obtain an amine, and then hydrolyzing, substituting, Friedel-Crafts acylation, substituting and aromatizing the target product. The synthesis route of the invention is novel, all raw materials and reagents used are easy to obtain or prepare, and no highly dangerous and highly polluting reagents are used. The invention is safe and environmentally friendly, has mild reaction conditions, is convenient and controllable in operation, and the prepared rosuvastatin intermediate has good purity and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0095] Figure 1 The present invention is a flow chart of the method for preparing the roxadustat intermediate. DETAILED DESCRIPTION

[0096] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are clearly and completely described. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0097] In order to better understand the above technical solution, the above technical solution will be described in detail below in conjunction with specific implementation methods.

[0098] See also Figure 1 The present invention provides two technical solutions: a method for preparing a rosuvastatin intermediate specifically includes the following embodiments:

[0099] Embodiment 1:

[0100] A method for preparing rosuvastatin intermediate 4-hydroxy-7-phenoxy-3-isoquinolinecarboxylic acid methyl ester (Formula A), comprising the following steps:

[0101]

[0102] S1. Synthesis of compound of formula 2

[0103] At room temperature, 3-phenoxybenzaldehyde (49.6 g, 0.25 mol) and glycine methyl ester hydrochloride (31.4 g, 0.25 mol) were added to 250 ml of dichloromethane, and triethylamine (50.6 g, 0.5 mol) was added. The reaction was carried out at room temperature for 18 h, and the reaction was monitored by TLC (EA: PE = 1:5). After the reaction of the raw materials was complete, the reaction solution was concentrated to dryness, and 300 ml of methanol was added to the obtained oily substance. The temperature was lowered to 0 ° C, and sodium borohydride ( 9.5g, 0.25mol), after the addition, turn off the cooling source, stir the reaction for 1h, monitor by TLC (EA:PE=1:1), after the imine reaction is complete, add water to quench the reaction, after the quenching is completed, concentrate most of the solvent, add 200ml of water, extract with 200ml*2 of dichloromethane, combine the organic phases, wash once with 200ml of saturated brine, dry, and concentrate to obtain 61g of red oily liquid with a purity of 98.4% and a yield of 90%, which is directly used in the next step;

[0104] 1H NMR (CDCl3, 400MHz): δ = 7.40 (d, J = 7.2Hz, 1H), 7.30 (t, J = 8.0Hz, 2H), 7.24 (t, J = 7.2Hz, 1H), 7.18–7.05 (m ,2H),6.94(d,J=8.0Hz,2H),6.83(d,J=8.0Hz,1H),3.82(s,2H),3.74(s,3H),3.40(s,2H),2.12(bs,1H). 13 C NMR (CDCl3, 150MHz): δ=170.51,157.54,155.07,130.54,129.89,128.76,125.85,123.91,123.12,119.17,118.24,54.19,51.97,49.87.

[0105] S2, Synthesis of Formula 3:

[0106] At room temperature, the compound of formula 2 (71.6 g, 0.264 mol) was put into 430 ml of water, and then sodium hydroxide (15.8 g, 0.396 mol) was added, and the temperature was raised to 60°C for reaction for 2 h, and TLC monitoring (EA: PE = 1: 1) was performed until the raw material reaction was complete, and the temperature was lowered to room temperature, and extracted with 400 ml of tertiary methyl ether, and the pH value of the water layer was adjusted to 4 with acetic acid, and then the water layer was extracted with 400 ml*2 ethyl acetate, and the organic phases were combined, dried, and concentrated to obtain 64.5 g of white solid with a purity of 99.4% and a yield of 95%;

[0107] 1 H NMR (CDCl3, 400MHz): δ = 11.8 (s, 1H), 7.62 (d, J = 7.6Hz, 1H), 7.50 (t, J = 8.4Hz, 2H), 7.34 (t, J = 7.6Hz, 1H), 7.28–7.12(m,2H),7.04(d,J=8.4Hz,2H),6.95(d,J=8.4Hz,1H),3.87(s,2H),3.43(s,2H),1.94(bs,1H). 13 C NMR (CDCl3, 150MHz): δ=171.21,157.50,157.18,138.80,129.93,129.83,124.45,121.96,121.86,118.77,117.88,53.07,48.64.

[0108] S3, Synthesis of compounds of formula 4:

[0109] At room temperature, the compound of formula 3 (53 g, 0.206 mol) was put into 560 ml of water, sodium carbonate (26.2 g, 0.247 mol) was added, the temperature was raised to 60°C and stirred to dissolve, and then p-toluenesulfonyl chloride (43.19 g, 0.226 mol) was added, and TLC monitoring (EA: PE = 1: 1) was performed until the raw materials reacted completely, the reaction solution was cooled to room temperature, ethyl acetate 500 ml was added, and the pH was adjusted to 2 with 3 mol / L hydrochloric acid, the organic layer was separated, the aqueous layer was extracted with ethyl acetate 500 ml, the organic layers were combined, dried, and concentrated to obtain an orange-yellow oil, 200 mL of petroleum ether was added, stirred, and crystallized to obtain 72.9 g of a white solid with a purity of 99.1% and a yield of 86%;

[0110] 1 H NMR (CDCl3, 400MHz): δ = 11.8 (s, 1H), 7.95 (d, J = 8.4Hz, 2H), 7.64 (d, J = 7.4Hz, 1H), 7.48 (t, J = 8.1Hz, 2H), 7.43 (d, J = 8.4Hz, 2H) ,7.32(t,J=7.4Hz,1H),7.28–7.15(m,2H),7.09(d,J=8.1Hz,2H),6.99(d,J=8.1Hz,1H),3.92(s,2H),3.87(s,3H),3.32(s,2H).

[0111] 13 C NMR (CDCl3, 150MHz): δ=172.72,158.60,156.35,144.85,137.66,136.76,132.24,13 0.13,129.55,127.62,124.54,123.43,121.73,119.17,118.54,51.48,50.63,24.36.

[0112] S4, Synthesis of compounds of formula 5:

[0113] At room temperature, the compound of formula 4 (50.6 g, 0.123 mol) and 1.5 ml DMF were added to 254 ml dichloromethane, replaced with nitrogen 3 times, and thionyl chloride (29.3 g, 0.246 mol) was added dropwise. After the addition was completed, the temperature was raised to reflux and monitored by TLC (EA: PE = 1: 1) until the raw material reaction was complete. The solvent was concentrated, and 250 ml of dichloromethane was added under nitrogen protection and cooled to -10 ° C. Anhydrous aluminum chloride (32.8 g, 0.246 mol) was added and monitored by TLC (EA: PE = 1: 1) until the raw material reaction was basically complete. The reaction solution was slowly added to 300 ml of ice water to quench, and the layers were separated. The organic layer was adjusted to pH = 9 with 20% sodium hydroxide aqueous solution, separated, and the organic layer was washed once with 300 ml of water. The organic layer was dried and concentrated to obtain 44.1 g of a yellow solid with a purity of 98.6% and a yield of 91.2%.

[0114] 1 H NMR (400MHz, CDCl3) δ=8.49 (d, J=8.6Hz, 1H), 8.15 (d, J=8.4Hz, 2H), 7.95 (d, J=8.6&2.2Hz, 1H), 7.75 (d, J=8.4Hz, 2H), 7.61 (m, J=7.5, 3H), 7.34 (t, J=7.3, 1H), 7.26 (d, J=7.5Hz, 2H), 4.83 (s, 2H), 3.82 (dd, J=10.4, 1.0Hz, 1H), 3.73 (dd, J=10.4, 1.3Hz, 1H), 2.53 (s, 3H); 13 C NMR (150MHz, CDCl3) δ=183.14,158.24,157.78,143.34,138.35,137.60,129.95,129 .91,129.82,127.49,127.14,124.54,118.58,118.17,117.87,54.34,49.83,21.34.

[0115] S5, Synthesis of compound of formula 6:

[0116] Under nitrogen atmosphere, compound 5 (26.6 g, 0.05 mol) and 60% NaH (6 g, 0.15 mol) were added to 80 ml of dimethyl carbonate, the temperature was raised to 90°C, and TLC was monitored (EA: PE = 1: 1) until the raw materials were basically reacted, the solvent was evaporated, the temperature was lowered to room temperature, 6 ml of methanol was added to quench, 40 ml of water was added, the aqueous layer was extracted with 50 ml*2 of ethyl acetate, the organic layers were combined and washed once with 20 ml of water, the organic layers were dried, and concentrated to dryness to obtain 13.2 g, purity 98.7%, yield 89.1%;

[0117] 1H NMR (400MHz, CDCl3) δ=8.39 (d, J=8.6Hz, 1H), 7.85 (d, J=8.6&2.2Hz, 1H), 7.52 (m, J=7.5, 3H), 7.30 (t, J=7.3, 1H), 7.21 (d, J=7.5Hz, 2H), 4.86 (s, 1H), 3.85 (dd, J=10.4, 1.0Hz, 1H), 3.83 (dd, J=10.4, 1.3Hz, 1H), 3.29 (s, 3H), 1.94 (bs, 1H); 13 C NMR (150MHz, CDCl3) δ = 185.43, 170.22, 160.13, 158.24, 137.47, 130.38, 130.24, 129.29, 124.54, 118.29, 117.53, 115.42, 61.70, 52.32, 47.16.

[0118] S6. Synthesis of Formula A:

[0119] At room temperature, compound 6 (10 g, 33.6 mmol), CuI (0.64 g, 3.36 mmol) and K2CO3 (13.9 g, 100.8 mmol) were added to 50 ml of 1,4-dioxane, and the temperature was raised to 70°C. After reacting for 34 hours, TLC monitoring (EA: PE = 1:1) showed that the raw materials were basically reacted. 100 ml of water was added, and the reactants were extracted with 50 ml*3 of ethyl acetate. The organic layers were combined, dried, and concentrated to obtain 8.95 g of a powdery solid with a purity of 98.6% and a yield of 90.2%.

[0120] 1H NMR (400MHz, CDCl3) δ = 11.61 (s, 1H), 8.73 (s, 1H), 8.31 (d, J = 9.0Hz, 1H), 7.60 (dd, J = 9.0, 2 .4Hz, 1H), 7.50 (t, J=7.9Hz, 3H), 7.29 (t, J=7.4Hz, 1H), 7.21 (d, J=7.9Hz, 2H), 3.97 (s, 3H), 13 C NMR (150MHz, CDCl3) δ=171.16, 158.30, 155.81, 154.83, 142.82, 129.93, 128.67, 124.45, 124.26, 124.17, 122.51, 119.65, 118.81, 112.30, 52.53.

[0121] Embodiment 2:

[0122] A method for preparing rosuvastatin intermediate 4-hydroxy-7-phenoxy-3-isoquinolinecarboxylic acid methyl ester (Formula A), comprising the following steps:

[0123]

[0124] S1. Synthesis of compounds of formula 2

[0125] At room temperature, m-phenoxybenzaldehyde (49.6 g, 0.25 mol) and glycine ethyl ester hydrochloride (41.9 g, 0.30 mol) were added to 250 ml of ethyl acetate, and sodium carbonate (53 g, 0.5 mol) was added. The mixture was reacted at room temperature for 21 h and monitored by TLC (EA: PE = 1:5). After the reaction of the raw materials was complete, the mixture was filtered and the reaction solution was concentrated to dryness. 300 ml of ethanol was added to the obtained oily substance, and the temperature was lowered to 0 ° C. Cyanoborane was added in batches. Sodium hydride (23.6 g, 0.375 mol) was added, and the cooling source was turned off. The reaction was stirred for 1 h and monitored by TLC (EA: PE = 1:1). After the imine reaction was complete, water was added dropwise to quench the reaction. After quenching, most of the solvent was concentrated, 200 ml of water was added, and 150 ml of chloroform was used for extraction. The organic phases were combined, washed once with 200 ml of saturated brine, dried, and concentrated to obtain 62.9 g of a red oily liquid with a purity of 98.6% and a yield of 88.2%.

[0126] S2, Synthesis of compounds of formula 3:

[0127] At room temperature, the compound of formula 2 (52.8 g, 0.185 mol) was put into 300 ml of water, potassium hydroxide (20.8 g, 0.37 mol) was added, the temperature was raised to 60°C for reaction for 2 h, TLC monitoring (EA: PE = 1: 1) until the raw material reaction was complete, the temperature was lowered to room temperature, extracted with 300 ml of ethyl acetate, the pH value of the water layer was adjusted to 4 with hydrochloric acid, and the water layer was extracted with 300 ml*2 of ethyl acetate, the organic phases were combined, dried, and concentrated to obtain 43.3 g of white solid with a purity of 99.2% and a yield of 91%;

[0128] S3, Synthesis of compounds of formula 4:

[0129] At room temperature, the compound of formula 3 (40.1 g, 0.156 mol) was put into 400 ml of water, sodium hydroxide (8.7 g, 0.218 mol) was added, the temperature was raised to 60°C and stirred to dissolve, and then p-toluenesulfonyl chloride (35.7 g, 0.187 mol) was added, and TLC monitoring (EA: PE = 1: 1) was performed until the raw materials reacted completely, the reaction solution was cooled to room temperature, 400 ml of dichloromethane was added, the pH was adjusted to 2 with acetic acid, the organic layer was separated, the aqueous layer was extracted with 400 ml of dichloromethane, the organic layers were combined, dried, and concentrated to obtain an orange-yellow oil, 200 mL of petroleum ether was added, stirred, and crystallized to obtain 52.6 g of a white solid with a purity of 98.7% and a yield of 82%;

[0130] S4, Synthesis of compounds of formula 5:

[0131] At room temperature, the compound of formula 4 (36 g, 87.6 mmol) and 1 ml of DMF were added to 180 ml of toluene, and the mixture was replaced with nitrogen three times. Oxalyl chloride (22.2 g, 0.175 mol) was added dropwise. After the addition was completed, the mixture was heated to 40°C and monitored by TLC (EA: PE = 1: 1) until the reaction of the raw materials was complete. The solvent was concentrated. 180 ml of toluene was added under nitrogen protection and the temperature was lowered to -10°C. Anhydrous ferric chloride (35.5 g, 0.219 mol) was added and monitored by TLC (EA: PE = 1: 1) until the reaction of the raw materials was basically complete. The reaction solution was slowly added to 200 ml of ice water to quench, the mixture was separated, the organic layer was adjusted to pH = 9 with a 20% aqueous potassium hydroxide solution, the organic layer was separated, the organic layer was washed once with 200 ml of water, the organic layer was dried, and concentrated to obtain 30.8 g of a yellow solid with a purity of 97.6% and a yield of 89.3%.

[0132] S5. Synthesis of compound of formula 6

[0133] Under nitrogen atmosphere, compound 5 (30 g, 0.076 mol) and LDA (25 g, 0.229 mol) were added to 120 ml of dimethyl carbonate, the temperature was controlled at 0°C, the reaction was carried out for 2 h, the temperature was raised to room temperature, the reaction was continued, and TLC monitoring (EA: PE = 1: 1) was performed until the raw materials were basically reacted completely, the solvent was evaporated, the temperature was lowered to room temperature, an aqueous solution of ammonium chloride was added to quench, 60 ml of water was added, the aqueous layer was extracted with 60 ml*2 of dichloromethane, the organic layers were combined and washed once with 30 ml of water, the organic layers were dried, and concentrated to dryness to obtain 19.2 g, with a purity of 97.4% and a yield of 85%;

[0134] S6. Synthesis of compound of formula A:

[0135] At room temperature, the compound of formula 6 (10 g, 33.6 mmol), Pd2(dba)3 (3.1 g, 3.36 mmol) and Cs2CO3 (32.8 g, 100.8 mmol) were added to 50 ml of 1,4-dioxane, and the temperature was raised to 70°C. After reacting for 38 hours, TLC monitoring (EA: PE = 1:1) was performed until the raw materials were basically reacted. 100 ml of water was added, and the reactants were extracted with 50 ml*3 of dichloromethane. The organic layers were combined, dried, and concentrated to obtain 8.7 g of a powdery solid with a purity of 98% and a yield of 87.6%.

[0136] Meanwhile, the contents not described in detail in this specification belong to the prior art known to those skilled in the art.

[0137] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device.

[0138] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a rosuvastatin intermediate, characterized in that: The synthetic route is as follows: Wherein, R in the compound of formula 2 is one of methyl, ethyl, and isopropyl; The preparation method of the roxadustat intermediate comprises the following steps: S1, the compound of formula 1 reacts with a glycine derivative under the action of a base, and then is reduced with sodium borohydride to obtain a compound of formula 2; S2, the compound of formula 2 is hydrolyzed under the action of a base, and then acidified to obtain a compound of formula 3; S3, the compound of formula 3 is substituted under the action of an acid-binding agent, and then acidified to obtain a compound of formula 4; S4, the compound of formula 4 is subjected to Friedel-Crafts acylation to obtain the compound of formula 5; S5, the compound of formula 5 is substituted under the action of a base to obtain a compound of formula 6; S6. The compound of formula 6 is aromatized to obtain the compound of formula A.

2. The method for preparing a rosuvastatin intermediate according to claim 1, characterized in that: The S1 specifically includes the following steps: The compound of formula 1 and a glycine derivative are added to solvent 1, and reacted at room temperature under the catalysis of a base and solvent 2. After the reaction is completed, a reducing agent is added at low temperature. After the reaction is completed, the compound of formula 2 is obtained through quenching, concentration, extraction, drying and concentration.

3. The method for preparing a rosuvastatin intermediate according to claim 1, characterized in that: The S2 specifically includes the following steps: The compound of formula 2 is added into water, and then a base is added to react at a high temperature. After the reaction is completed, extraction is performed with extractant 1. The water layer is acidified at low temperature, and then extracted with extractant 2. The mixture is dried and concentrated to obtain the compound of formula 3.

4. The method for preparing a rosuvastatin intermediate according to claim 1, characterized in that: The S3 specifically includes the following steps: The compound of formula 3 is added into water, and then a base is added, and the temperature is raised until it is dissolved, and then p-toluenesulfonyl chloride is added. After the reaction is completed, the temperature is lowered, and the compound of formula 4 is obtained through acidification, extraction, drying, concentration, and crystallization.

5. The method for preparing a rosuvastatin intermediate according to claim 1, characterized in that: The S4 specifically comprises the following steps: Add the compound of formula 4 to solvent 1, add a catalytic amount of DMF, then add an acylating agent, heat the reaction, concentrate the solvent, dissolve the oil in solvent 2, protect with N2 in a low temperature environment, add Lewis acid, and after the reaction is completed, quench, wash with alkali, wash with water, dry, and concentrate to obtain the compound of formula 5.

6. The method for preparing a roxadustat intermediate according to claim 1, characterized in that: The S5 specifically includes the following steps: Under a nitrogen atmosphere, sodium hydrogen is added to dimethyl carbonate, the temperature is increased, and the compound of formula 5 of dimethyl carbonate is added to the reaction solution, the temperature is increased to react, and after the reaction is completed, the temperature is lowered to a low temperature, quenched with methanol, acidified, extracted with an extractant, washed with alkaline water, washed with brine, washed with water, dried, and concentrated to obtain a compound of formula 6.

7. The method for preparing a roxadustat intermediate according to claim 1, characterized in that: The S7 specifically comprises the following steps: The compound of formula 6 is added to a solvent, a catalyst and a base are added, the temperature is raised for reaction, the temperature is lowered after the reaction is completed, extraction is performed with an extractant, drying is performed, and concentration is performed to obtain the compound of formula A.

8. A rosuvastatin intermediate, characterized in that: Including the compound of formula 2, the compound of formula 4, and the compound of formula 5 prepared by the preparation method according to any one of claims 1 to 8, wherein R in the compound of formula 2 is independently selected from one of methyl, ethyl, and isopropyl; The structural formulas of the compound of formula 4 and the compound of formula 5 are shown below:

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