Rosaxostat intermediate and preparation method thereof

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 cyclization, hydrolysis, Friedel-Crafts acylation, ring opening, oxidation and esterification to obtain the target product. 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 organic synthesis, and in particular to a rosuvastatin intermediate and a preparation method thereof. Background Art

[0002] Roxadustat is a 4-hydroxyisoquinoline derivative and a small molecule HIF-PH enzyme inhibitor. HIF is an important transcription factor that adapts to oxygen changes in the body. Under normal oxygen-containing conditions, HIF-PH enzymes will promote HIF degradation; when the body is hypoxic, the activity of HIF-PH enzymes is inhibited, and the accumulation of HIF increases, thereby inducing the expression of corresponding genes and allowing the body to adapt to the changes of hypoxia. Roxadustat stabilizes HIF, inhibits its degradation, activates the transcription of related genes, produces corresponding physiological responses, moderately increases the concentration of erythropoietin, increases the sensitivity of erythropoietin (EPO) receptors, coordinates the production of red blood cells, reduces hepcidin levels, increases the content and activity of transferrin receptors, promotes the absorption and utilization of iron, and 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 compound of formula A below is an important intermediate for the synthesis of roxadustat.

[0004]

[0005] At present, there are mainly the following routes for the synthesis of Ⅰ:

[0006] Synthesis route 1: CN106083720A reported that 4-bromo-2-methylbenzoic acid was used as a raw material, and compound I was obtained through esterification, coupling, bromination, amination, and cyclization. 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-treatment of the entire route uses a column chromatography purification method, which is time-consuming and labor-intensive and is not suitable for industrial production.

[0007]

[0008] Synthesis route 2: CN103435546 reported that 5-bromophthalide was used as a raw material, and the target product 1 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.

[0009]

[0010] In summary, the above routes are not suitable for industrial production due to high cost, time-consuming and labor-intensive post-treatment column chromatography, and high safety risk factors of the materials used. Therefore, it is particularly important to find a route with appropriate cost, green and environmental protection, good reaction selectivity, high yield, and suitable for industrial production. Summary of the invention

[0011] 1. Technical issues to be resolved

[0012] 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.

[0013] (II) Technical solution

[0014] To achieve the above objectives, the present invention is implemented through the following technical solutions:

[0015] A method for preparing a rosuvastatin intermediate, the synthetic route is as follows:

[0016]

[0017] The preparation method comprises the following steps:

[0018] S1, adding the compound of formula 1 and the amino acid to solvent 1, reacting at room temperature under base catalysis, and concentrating to dryness after the reaction. The oily substance is dissolved in solvent 2, and a reducing agent is added, reacting at low temperature, and after the reaction is completed, quenching, extraction, drying, and concentration are performed to obtain the compound of formula 2;

[0019] S2, adding the compound of formula 2 to a solvent, then adding a condensing agent, N2 protection, heating to react, concentrating to dryness after the reaction, extracting, drying, and concentrating to obtain a compound of formula 3;

[0020] S3, adding the compound of formula 3 into water, then adding a base, reacting, 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 4;

[0021] 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 in a low temperature environment with N2, adding Lewis acid, and after the reaction, quenching, alkali washing, water washing, drying, and concentrating to obtain a compound of formula 5;

[0022] S5. Add the compound of formula 5 to solvent and water, add a base, and heat to react. After the reaction is completed, cool to room temperature and filter to obtain the compound of formula 6;

[0023] S6, adding the compound of formula 6 and the catalyst into water, adding an oxidant, and then adding a base to the reaction system, heating the reaction, and after the reaction is completed, acidifying, extracting with an extractant, drying, and concentrating to obtain a compound of formula 7;

[0024] S7, adding the compound of formula 7 to a solvent, adding an acid, heating the mixture, cooling the mixture for crystallization after the reaction is completed, filtering the mixture, and drying the mixture to obtain compound A;

[0025] Furthermore, the S1 specifically includes the following steps:

[0026] The reaction equation is as follows:

[0027]

[0028] Furthermore, the amino acid in S1 is serine methyl ester, serine methyl ester hydrochloride, serine ethyl ester, serine ethyl ester hydrochloride, serine isopropyl ester, serine isopropyl hydrochloride, preferably, the amino acid is serine methyl ester hydrochloride.

[0029] Further, the molar ratio of m-phenoxybenzaldehyde to amino acid in S1 is 1:1-3.5, preferably 1:1-1.4;

[0030] Furthermore, the solvent 1 in S1 is any one of tetrahydrofuran, dichloromethane, chloroform, and ethyl acetate, preferably dichloromethane;

[0031] Further, the base in S1 is any one of sodium bicarbonate, sodium carbonate, triethylamine, diethylamine, pyridine, and 4-N,N-dimethylaminopyridine, preferably triethylamine;

[0032] Further, the molar ratio of m-phenoxybenzaldehyde to base in S1 is 1:1-3.0, preferably 1:1-2.5;

[0033] Further, the room temperature reaction time in S1 is 16-30h, preferably 18-22h;

[0034] Furthermore, the solvent 2 in S1 is any one of tert-butanol, methanol, and ethanol, preferably methanol;

[0035] Further, the reducing agent in S1 is any one of sodium borohydride, zinc borohydride, and lithium borohydride, preferably sodium borohydride;

[0036] Further, the molar ratio of m-phenoxybenzaldehyde to the reducing agent in S1 is 1:1-2.0, preferably 1:1-1.5;

[0037] Further, the low temperature reaction temperature in S1 is -5°C-10°C, preferably 0°C-5°C;

[0038] Furthermore, the extraction solvent in S1 is one of ethyl acetate, dichloromethane and chloroform, preferably dichloromethane.

[0039] Furthermore, after step S1, post-treatment is also included: specifically including the following steps: quenching, extraction, drying, and concentration to obtain the compound of formula 2.

[0040] Furthermore, the S2 specifically includes the following steps:

[0041] The reaction equation is as follows:

[0042]

[0043] Further, the solvent in S2 is one of tetrahydrofuran, ethyl acetate and acetonitrile, preferably acetonitrile;

[0044] Further, the condensing agent in S2 is carbonyldiimidazole (CDI), N,N'-diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), preferably CDI;

[0045] Further, the molar ratio of the compound of formula 2 to the condensing agent in S2 is 1:1.2-3.5, preferably 1:1-1.5;

[0046] Further, the reaction temperature in S2 is 50-100°C, preferably 75-90°C, and the reaction time is 2-28h, preferably 2-12h;

[0047] Further, the extraction solvent is one of ethyl acetate, dichloromethane and chloroform, preferably ethyl acetate;

[0048] Furthermore, step S2 further includes post-treatment: drying and concentration to obtain the compound of formula 3.

[0049] Furthermore, the S3 specifically includes the following steps:

[0050]

[0051] Further, the base in S3 is any one of sodium carbonate, sodium hydroxide, and potassium hydroxide, preferably sodium hydroxide;

[0052] Further, the molar ratio of the compound of formula 3 to the base in S3 is 1:1.2-3.5, preferably 1:1.5-2.0;

[0053] Further, the extractant 1 in S3 is any one of ethyl acetate, dichloromethane, and chloroform, preferably ethyl acetate;

[0054] Further, the acid used for acidification in S3 is one of hydrochloric acid and sulfuric acid, preferably hydrochloric acid;

[0055] Furthermore, the extractant 2 in S3 is one of ethyl acetate, dichloromethane and chloroform, preferably ethyl acetate.

[0056] Furthermore, the step S3 further includes post-processing: drying and concentrating to obtain the compound of formula 3.

[0057] Furthermore, the S4 specifically includes the following steps:

[0058]

[0059] Further, the solvent 1 in S4 is any one of toluene, dichloromethane and chloroform, preferably dichloromethane;

[0060] 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;

[0061] Further, the acylating agent in S4 is any one of oxalyl chloride, thionyl chloride, and phosphorus oxychloride, preferably thionyl chloride;

[0062] 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;

[0063] Further, the solvent 2 in S4 is any one of toluene, dichloromethane, and chloroform, preferably dichloromethane;

[0064] Further, the Lewis acid in S4 is any one of zinc chloride, ferric chloride, aluminum chloride, and boron trifluoride, preferably aluminum chloride;

[0065] Further, the molar ratio of the compound of formula 4 to the Lewis acid in S4 is 1:1.5-4.0, preferably 1:1.5-2.5;

[0066] 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;

[0067] Furthermore, step S4 further includes post-treatment: washing, drying, and concentrating to obtain the compound of formula 5.

[0068] Furthermore, the S5 specifically includes the following steps:

[0069]

[0070] Further, the solvent in S5 is any one of tetrahydrofuran, acetone, acetonitrile, and 1,4-dioxane, preferably 1,4-dioxane;

[0071] Furthermore, the base in S5 is any one of cesium carbonate, potassium hydroxide, sodium hydroxide, sodium carbonate, and sodium bicarbonate, preferably sodium bicarbonate.

[0072] Further, the molar ratio of the compound of formula 5 to the base in S5 is 1:4-8, preferably 1:4-6;

[0073] Further, the reaction temperature in S5 is 40-80°C, preferably 50-60°C;

[0074] Furthermore, the step S5 further includes post-treatment: cooling to room temperature and filtering to obtain the compound of formula 6.

[0075] Furthermore, the S6 specifically includes the following steps:

[0076]

[0077] Further, the catalyst in S6 is any one of sodium chloride, potassium chloride, NCS, and sodium bromide, preferably sodium chloride;

[0078] Further, the molar ratio of the compound of formula 6 to the catalyst in S6 is: 1:0.15-0.35, preferably: 1:0.20-0.25;

[0079] Further, the oxidant in S6 is any one of 30% hydrogen peroxide and 30% TBHP, preferably 30% TBHP;

[0080] Furthermore, the molar ratio of the compound of formula 6 to the oxidant in S6 is 1:3-8, preferably 1:4-6;

[0081] Further, the base in S6 is any one of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, and potassium acetate; preferably sodium hydroxide;

[0082] Further, the molar ratio of the compound of formula 6 to the base in S6 is 1:3-8, preferably 1:4-6;

[0083] Further, the reaction temperature in S6 is 40-90°C, preferably 70-80°C;

[0084] Further, the reaction time in S6 is 10-26h, preferably 12-14h;

[0085] Furthermore, the extractant in S6 is any one of ethyl acetate, dichloromethane and chloroform, preferably ethyl acetate.

[0086] Furthermore, the step S6 further includes post-processing: drying and concentrating to obtain the compound of formula 7.

[0087] Furthermore, the S7 specifically includes the following steps:

[0088]

[0089] Further, the solvent in S7 is any one of methanol, ethanol, and isopropanol, preferably methanol;

[0090] Further, the acid in S7 is concentrated sulfuric acid, concentrated hydrochloric acid, or thionyl chloride, preferably concentrated sulfuric acid;

[0091] Further, the reaction time in S7 is 6-14h, preferably 8-10h;

[0092] Furthermore, the crystallization temperature in S7 is -10-0°C, preferably -5-0°C.

[0093] Furthermore, the step S6 further includes post-processing: filtering and drying to obtain compound A.

[0094] (III) Beneficial effects

[0095] 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:

[0096] The invention provides a rosuvastatin intermediate and a preparation method thereof. The preparation method comprises the following steps: condensing m-phenoxybenzaldehyde with an amino acid under the catalysis of a base to generate an imine, then reducing the imine to obtain an amine, and then performing cyclization, hydrolysis, Friedel-Crafts acylation, ring opening, oxidation and esterification to obtain a 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 high yield, has obvious cost advantages, and is suitable for industrial production. DETAILED DESCRIPTION

[0097] 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.

[0098] 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.

[0099] Example 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, m-phenoxybenzaldehyde (50 g, 0.25 mol) and serine methyl ester hydrochloride (38.9 g, 0.25 mol) were added to 250 ml of dichloromethane, and triethylamine (63.2 g, 0.63 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 ( 10g, 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 of dichloromethane*2, combine the organic phases, wash once with 200ml of saturated brine, dry, and concentrate to obtain 70.1g of red oily liquid with a purity of 99.2% and a yield of 93.1%; Formula 2 is C 17 H 19 NO4, LC-MS measured the molecular ion peak m / z as 302.1, [M+H]+ was consistent with the theoretical value, elemental analysis C.67.74; H.6.35; N.4.65; O.21.26; 1 HNMR (400MHz, CDCl3) δ7.39 (m, 3H), 7.30 (t, J=8.0Hz, 1H), 7.10 (d, J=7.3Hz, 2H), 7.04 (d, J=8.0, 1H), 6.92 (d, J=8.0, 1H), 6.83 (m, 1H), 6.25 (s, 1H), 4.92 (s, 1H), 3.88 (m, 2H), 3.74 (m, 1H), 3.66 (m, 2H), 3.25 (s, 3H); 13 CNMR (150MHz, CDCl3) δ173.07, 157.50, 157.14, 139.26, 129.93, 129.84, 124.45, 121.96, 121.50, 118.77, 117.65, 69.79, 62.20, 52.17, 52.07.

[0104] S2, Synthesis of Formula 3:

[0105] At room temperature, the compound of formula 2 (60.2 g, 0.20 mol) and CDI (48.65 g, 0.3 mol) were added to 360 ml of acetonitrile, heated to 80 ° C for 2 h, monitored by TLC (EA: PE = 1: 1) until the reaction of the raw materials was complete, the solvent was concentrated to dryness, 250 ml of water was added, and 250 ml*2 ethyl acetate was extracted. The organic phases were combined, washed once with 250 ml of saturated brine, dried, and concentrated to obtain 62.2 g of light red oil with a purity of 99.4% and a yield of 95%; Formula 3 is C 18 H 17 NO5, LC-MS measured the molecular ion peak m / z as 328.2, [M+H]+ was consistent with the theoretical value, elemental analysis C.66.04; H.5.24; N.4.28; O.24.44; 1 HNMR (400MHz, CDCl3δ7.32 (m, 3H), 7.30 (t, J=8.1Hz, 1H), 7.10 (d, J=7.9Hz, 2H), 7.04 (d, J=8.1, 1H), 6.96 (d, J=8.1, 1H), 6.92 (t, J=7. 3Hz, 1H), 4.67 (t, J=4.0Hz, 1H), 4.54 (dt, J=1.9, 1.0Hz, 2H), 4.35 (dd, J=12.3, 3.9Hz, 1H), 4.31 (dd, J=12.3, 3.9Hz, 1H), 3.68 (s, 3H).; 13 CNMR (150MHz, CDCl3) δ171.24, 160.13, 157.50, 156.96, 137.18, 130.06, 12 9.93, 124.45, 121.93, 121.78, 118.77, 118.01, 64.46, 60.36, 52.26, 47.35.

[0106] S3, Synthesis of compounds of formula 4:

[0107] At room temperature, the compound of formula 3 (65.5 g, 0.2 mol) was put into 300 ml of water, sodium hydroxide (12 g, 0.3 mol) was added, and the reaction was stirred and monitored by TLC (EA: PE = 1: 1) until the raw material reaction was complete. The reaction solution was cooled to room temperature, 300 ml*2 of ethyl acetate was added for extraction, the water layer was cooled to 0°C, the pH was adjusted to 2 with hydrochloric acid, and 200 ml*2 of ethyl acetate was used for extraction. The organic layers were combined, dried, and concentrated to obtain 59 g of yellow oil with a purity of 99.1% and a yield of 94.3%. Formula 4 is C 17 H 15NO5, LC-MS measured the molecular ion peak m / z as 314.1, [M+H]+ was consistent with the theoretical value, elemental analysis C.65.16; H.4.84; N.4.46; O.25.54; 1 HNMR (400MHz, CDCl3) δ13.25 (s, 1H), 7.39 (m, 3H), 7.31 (t, J=8.2Hz, 1H), 7.10 (d, J=7.9Hz, 2H), 7.02 (d, J=8.2Hz, 1H), 6.96 (J=8.2Hz, 1H ), 6.92 (t, J=7.4Hz, 1H), 4.71 (t, J=4.0Hz, 1H), 4.58 (dt, J=1.9, 1.0Hz, 2H), 4.38 (dd, J=12.3, 4.0Hz, 1H), 4.30 (dd, J=12.3, 4.0Hz, 1H).; 13 CNMR (125MHz, CDCl3) δ173.52, 158.37, 157.50, 156.96, 137.19, 130.06, 129.93, 124.45, 121.93, 121.78, 118.77, 118.01, 64.64, 60.89, 47.46.

[0108] S4, Synthesis of compounds of formula 5:

[0109] At room temperature, the compound of formula 4 (62.7 g, 0.2 mol) and 1.9 ml DMF were added to 450 ml dichloromethane, replaced with nitrogen 3 times, and thionyl chloride (35.7 g, 0.3 mol) was added dropwise. After the addition was completed, the temperature was raised to reflux, and TLC was monitored (EA: PE = 1: 1) until the raw material reaction was complete. The solvent was concentrated, and 450 ml dichloromethane was added under nitrogen protection to cool to -10 ° C. Anhydrous aluminum chloride (75.7 g, 0.5 mol) was added, and TLC was monitored (EA: PE = 1: 1) until the raw material reaction was basically complete. The reaction solution was slowly added to 400 ml ice water to quench, and the layers were separated. The organic layer was adjusted to pH = 9 with 20% sodium hydroxide aqueous solution, and the layers were separated. The organic layer was washed once with 400 ml water. The organic layer was dried and concentrated to obtain 54.5 g of an oily substance with a purity of 99% and a yield of 92.2%. Formula 5 is C 17 H 13 NO4, LC-MS measured the molecular ion peak m / z as 296.2, [M+H]+ was consistent with the theoretical value, elemental analysis C.69.14; H.4.46; N.4.75; O.21.65; 1HNMR (400MHz, CDCl3) δ7.99 (d, J=8.6Hz, 1H), 7.65 (d, J=8.6Hz, 1H), 7.32 (m, J=7.5, 3H), 7.10 (t, J=7.3, 1H), 6.97 (m, 2H), 6.95 (d, J= 2.0Hz, 1H), 4.86 (dd, J=12.4, 1.0Hz, 1H), 4.64 (dd, J=12.4, 1.0Hz, 1H), 4.37 (dd, J=12.5, 3.3Hz, 1H), 4.29 (dd, J=12.5, 3.5Hz, 1H).; 13 CNMR (125MHz, CDCl3) δ192.62, 159.59, 157.78, 156.87, 135.39, 129.93, 129.89, 129.17, 124.45, 118.92, 117.92, 117.37, 64.56, 58.71, 42.34.

[0110] S5, Synthesis of compound of formula 6:

[0111] At room temperature, the compound of formula 5 (11.8 g, 40 mmol) was added to a system of 50 ml 1,4-dioxane and 120 ml water, and then sodium bicarbonate (13.4 g, 160 mmol) was added. The temperature was raised to 60°C and monitored by TLC (EA: PE = 1:1) until the raw materials were basically reacted. The mixture was filtered and the filter cake was rinsed with a small amount of ice methanol to obtain 9.3 g of solid with a purity of 99.5% and a yield of 87%. Formula 6 is C 16 H 13 NO3, LC-MS measured the molecular ion peak m / z as 268.3, [M+H]+ was consistent with the theoretical value, elemental analysis C.71.92; H.4.90; N.5.22; O.17.96; 1 HNMR (400MHz, CDCl3) δ11.94 (s, 1H), 8.59 (s, 1H), 7.91 (d, J = 8.0Hz, 1H), 7.63 (d, J = 8.0, 1H), 7 .32 (t, J=7.4, 3H), 6.97 (d, J=7.4, 2H), 6.87 (t, J=7.2, 1H), 5.39 (s, 1H), 4.76 (d, J=5.6Hz, 2H); 13 CNMR (125MHz, CDCl3) δ158.30, 155.85, 147.78, 143.46, 142.52, 129.93, 127.32, 124.45, 123.67, 123.22, 118.88, 118.81, 111.36, 59.71.

[0112] S6, Synthesis of Formula 7:

[0113] At room temperature, the compound of formula 6 (20 g, 75 mmol) and sodium chloride (0.87 g, 15 mmol) were added to 30% TBHP (90.1 g, 0.3 mol), and then sodium hydroxide (12 g, 0.3 mol) was added to the reaction mixture. The temperature was raised to 70°C and kept warm for 14 h. TLC monitoring (EA: PE = 1: 1) was performed until the reaction of the raw materials was complete. The reaction solution was cooled to 0°C, acidified with hydrochloric acid to pH = 2, and 100 ml*2 of ethyl acetate was added for extraction. The organic layers were combined, dried, and concentrated to obtain 18.8 g of solid with a purity of 98.8% and a yield of 89%. Formula 7 is C 16 H 11 NO4, LC-MS measured the molecular ion peak m / z as 282.1, [M+H]+ was consistent with the theoretical value, elemental analysis C.68.35; H.3.95; N.4.97; O.22.73, 1 HNMR (400MHz, CDCl3) δ13.4 (s, 1H), 11.9 (s, 1H), δ8.70 (s, 1H), 8.20 (d, J=8.3Hz, 1H), 7. 95 (d, J=8.3Hz, 1H), 7.30 (t, J=7.5Hz, 3H), 7.03 (d, J=7.2Hz, 2H), 6.89 (t, J=7.4Hz, 1H).; 13 CNMR (125MHz, CDCl3) δ171.21, 164.01, 158.30, 155.81, 142.23, 129.93, 128.54, 125.35, 124.45, 124.18, 121.88, 119.63, 118.81, 112.30.

[0114] S7, Synthesis of compound of formula A:

[0115] At room temperature, the compound of formula 7 (16.9 g, 60 mmol) was added to 80 ml of methanol, and then 0.6 g of concentrated sulfuric acid was added. The temperature was raised to reflux and kept warm for 8 h. TLC monitoring (EA: PE = 1: 1) was performed until the reaction of the raw materials was complete. The reaction solution was cooled to -5 ° C for crystallization, filtered and dried to obtain 15.4 g of a white powdery solid with a purity of 99.4% and a yield of 87%. Formula A is C 17 H 13NO4, LC-MS measured the molecular ion peak m / z as 296.1, [M+H]+ was consistent with the theoretical value, elemental analysis C.69.16; H.4.43; N.4.73; O.21.68; 1HNMR (400MHz, CDCl3) δ11.61 (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 CNMR (125MHz, CDCl3) δ171.16, 158.30, 155.81, 154.83, 142.82, 129.93, 1 28.67, 124.45, 124.26, 124.17, 122.51, 119.65, 118.81, 112.30, 52.53.

[0116] Example 2

[0117] A method for preparing rosuvastatin intermediate 4-hydroxy-7-phenoxy-3-isoquinolinecarboxylic acid methyl ester (Formula A), comprising the following steps:

[0118]

[0119] S1. Synthesis of compounds of formula 2

[0120] At room temperature, m-phenoxybenzaldehyde (50 g, 0.25 mol) and serine isopropyl ester (38.9 g, 0.35 mol) were added to 200 ml of ethyl acetate, and sodium carbonate (26.5 g, 0.25 mol) was added. The mixture was reacted at room temperature for 22 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. Lithium borohydride was added in batches. (8.3g, 0.38mol), 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 150ml of water, extract with 100ml*2 of chloroform, combine the organic phases, wash once with 200ml of saturated brine, dry, and concentrate to obtain 79.16g of red oily liquid with a purity of 98.9% and a yield of 92.2%. Formula 2 is C 20 H 25 NO4, LC-MS measured the molecular ion peak m / z as 344.2, [M+H]+ was consistent with the theoretical value, elemental analysis C.69.94; H.7.35; N.4.06; O.18.65; 1HNMR (400MHz, CDCl3) δ7.39 (m, 3H), 7.30 (t, J=8.0Hz, 1H), 7.10 (d, J=7.2Hz, 2H), 6.96 (d, J=8.0Hz, 1H), 6.83 (m, 1H), 6.92 (d, J=8.0Hz, 1H), 6.23 (s, 1H), 4.95 (s, 1H), 3.84 (m, 2H), 3.79 (m, 1H), 3.56 (m, 2H), 3.27 (s, 9H); 13 CNMR (125MHz, CDCl3) δ170.50, 157.50, 157.14, 139.26, 129.93, 129.84, 12 4.45, 121.96, 121.50, 118.77, 117.65, 82.77, 62.77, 62.01, 52.07, 28.38.

[0121] S2, Synthesis of compounds of formula 3:

[0122] At room temperature, the compound of formula 2 (68.7 g, 0.20 mol) and DIC (25.24 g, 0.2 mol) were added to 200 ml THF, heated to 80 ° C and reacted for 5 h. TLC monitoring (EA: PE = 1: 1) was performed until the raw materials reacted completely. The solvent was concentrated to dryness, 350 ml of water was added, and 200 ml*2 dichloromethane was used for extraction. The organic phases were combined, washed once with 300 ml of saturated brine, dried, and concentrated to obtain 69.2 g of a light red oil with a purity of 99.1% and a yield of 93.7%. Formula 3 is C 21 H 23 NO5, LC-MS measured the molecular ion peak m / z as 370.1, [M+H]+ was consistent with the theoretical value, elemental analysis C.68.27; H.6.28; N.3.80; O.21.65; 1 HNMR (400MHz, CDCl3) δ7.36 (m, 3H), 7.31 (t, J=8.2Hz, 1H), 7.10 (d, J=7.2, Hz, 2H), 7.07 (d, J=8.2Hz, 1H), 6.96 (d, J=8.2Hz, 1H), 6.9 2 (m, 1H), 4.71 (t, J=3.8Hz, 1H), 4.58 (dt, J=1.8, 1.2Hz, 2H), 4.56 (dd, J=12.0, 0.9Hz, 1H), 4.33 (dd, 12.0, 0.9Hz, 1H), 3.25 (s, 9H); 13CNMR (125MHz, CDCl3) δ169.11, 160.13, 157.50, 156.96, 137.19, 130.06, 129.93 , 124.45, 121.93, 121.78, 118.77, 118.01, 82.09, 64.30, 61.19, 47.33, 27.59.

[0123] S3, Synthesis of compounds of formula 4:

[0124] At room temperature, the compound of formula 3 (73.9 g, 0.2 mol) was put into 200 ml of water, potassium hydroxide (22.4 g, 0.4 mol) was added, the reaction was stirred, and TLC was monitored (EA: PE = 1: 1) until the raw material reaction was complete. The reaction solution was cooled to room temperature, and 200 ml*2 of dichloromethane was added for extraction. The water layer was cooled to 0°C, the pH was adjusted to 2 with sulfuric acid, and extracted with 200 ml*2 of dichloromethane. The organic layers were combined, dried, and concentrated to obtain 57.6 g of a yellow oil with a purity of 98.8% and a yield of 92.0%.

[0125] S4, Synthesis of compounds of formula 5:

[0126] At room temperature, the compound of formula 4 (62.7 g, 0.2 mol) and 3.2 ml DMF were added to 300 ml toluene, replaced with nitrogen three times, and oxalyl chloride (63.5 g, 0.5 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, 450 ml toluene was added under nitrogen protection, the temperature was lowered to -10 ° C, anhydrous zinc chloride (40.9 g, 0.3 mol) was added, and TLC was monitored (EA: PE = 1: 1) until the raw material reaction was basically complete. The reaction solution was slowly added to 500 ml ice water to quench, the layers were separated, the organic layer was adjusted to pH = 9 with sodium carbonate aqueous solution, the layers were separated, the organic layer was washed twice with 300 ml water, the organic layer was dried and concentrated to obtain 53.8 g of an oily substance with a purity of 98.5% and a yield of 91%.

[0127] S5. Synthesis of compound of formula 6

[0128] At room temperature, the compound of formula 5 (11.8 g, 40 mmol) was added to a system of 150 ml tetrahydrofuran (THF) and 120 ml water, and cesium carbonate (78 g, 240 mmol) was added. The temperature was raised to 50 ° C. TLC monitoring (EA: PE = 1: 1) was performed until the raw materials were basically reacted. The mixture was filtered and the filter cake was rinsed with a small amount of ice methanol to obtain 9.15 g of solid with a purity of 99.0% and a yield of 85.5%.

[0129] S6, Synthesis of compounds of formula 7:

[0130] At room temperature, the compound of formula 6 (20 g, 75 mmol) and sodium bromide (1.95 g, 19 mmol) were added to 30% hydrogen peroxide (51 g, 0.45 mol), and sodium carbonate (47.69 g, 0.45 mol) was added to the reaction mixture. The temperature was raised to 80°C and kept warm for 22 h. TLC monitoring (EA: PE = 1: 1) was performed until the reaction of the raw materials was complete. The reaction solution was cooled to 0°C, acidified with hydrochloric acid to pH = 2, and 100 ml*2 of dichloromethane was added for extraction. The organic layers were combined, dried, and concentrated to obtain 18.5 g of solid with a purity of 98.5% and a yield of 88%.

[0131] S7, synthesis of compound of formula A:

[0132] At room temperature, the compound of formula 7 (16.9 g, 60 mmol) was added to 100 ml of isopropanol, and then 1.0 g of concentrated hydrochloric acid was added. The temperature was raised to reflux and kept warm for 8 h. TLC monitoring (EA: PE = 1: 1) was performed until the raw materials reacted completely. The reaction solution was cooled to 0 ° C for crystallization, filtered and dried to obtain 15.1 g of a white powdery solid with a purity of 99.2% and a yield of 85%.

[0133] Example 3

[0134] A method for preparing rosuvastatin intermediate 4-hydroxy-7-phenoxy-3-isoquinolinecarboxylic acid methyl ester (Formula A), comprising the following steps:

[0135]

[0136] S1. Synthesis of compounds of formula 2

[0137] At room temperature, m-phenoxybenzaldehyde (50 g, 0.25 mol) and ethyl serine (39.9 g, 0.3 mol) were added to 200 ml of tetrahydrofuran, and N, N-dimethylaminopyridine (76.9 g, 0.63 mol) was added. The reaction was carried out at room temperature for 22 h and monitored by TLC (EA: PE = 1:5). After the reaction of the raw materials was complete, the reaction solution was filtered and concentrated to dryness. 200 ml of tert-butyl alcohol was added to the obtained oily substance, the temperature was lowered to 0 ° C, and borohydride was added in batches. Zinc (28.52 g, 0.3 mol), after addition, turn off the cooling source, stir the reaction for 1 h, monitor by TLC (EA: PE = 1: 1), after the imine reaction is complete, add water to quench the reaction, after quenching, concentrate most of the solvent, add 350 ml of water, extract with 150 ml of ethyl acetate * 2, combine the organic phases, wash once with 200 ml of saturated brine, dry, and concentrate to obtain 78.56 g of red oily liquid with a purity of 99.0% and a yield of 91.5%. Formula 2 is C 19 H 23NO4, LC-MS measured the molecular ion peak m / z as 330.2, [M+H]+ was consistent with the theoretical value, elemental analysis C.69.28; H.7.04; N.4.25; O.19.43; 1 HNMR (400MHz, CDCl3) δ7.37 (m, 3H), 7.32 (d, J = 8.0Hz, 1H), 7.10 (d, J = 7.2Hz, 2H ), 7.00 (d, J = 8.0Hz, 1H), 6.92 (d, J = 8.0Hz, 1H), 6.83 (m, 1H), 6.23 (s, 1H), 5.01 ( s, 1H), 3.88 (ddt, J=5.3, 4.0, 0.9Hz, 2H), 3.77 (ddt, J=6.2, 5.3Hz, 1H), 3.66 (m, 2H), 3.55 (dt, J=8.5, 4.4Hz, 1H), 1.29 (d, J=5.7Hz, 3H), 1.24 (d, J=5.7Hz, 3H).; 13 CNMR (125MHz, CDCl3) δ171.91, 157.50, 157.14, 139.26, 129.93, 129.84, 12 4.45, 121.96, 121.50, 118.77, 117.65, 70.09, 62.88, 62.22, 52.07, 21.77.

[0138] S2, Synthesis of compounds of formula 3:

[0139] At room temperature, the compound of formula 2 (65.9 g, 0.20 mol) and EDCl (25.24 g, 0.3 mol) were added to 300 ml of ethyl acetate, and the temperature was raised to 75°C for reaction for 15 h. TLC monitoring (EA: PE = 1:1) was performed until the reaction of the raw materials was complete. The solvent was concentrated to dryness, 250 ml of water was added, and 100 ml*2 of chloroform was extracted. The organic phases were combined, washed once with 300 ml of saturated brine, dried, and concentrated to obtain 64.8 g of a light red oil with a purity of 98.5% and a yield of 91.2%. Formula 3 is C 20 H 21 NO5, LC-MS measured the molecular ion peak m / z as 356.1, [M+H]+ was consistent with the theoretical value, elemental analysis C.67.59; H.5.96; N.3.94; O.22.5; 1HNMR (400MHz, CDCl3) δ7.34 (m, 3H), 7.30 (t, J=8.1Hz, 1H), 7.10 (d, J=7.2, 2H ), 7.05 (d, J=8.1Hz, 1H), 7.00 (d, J=8.1Hz, 1H), 6.92 (m, 1H), 5.03 (m, 1H), 4.6 8(t, J=4.1Hz, 1H), 4.54 (dt, J=1.7, 1.2Hz, 2H), 4.42 (dd, J=12.4, 1.1Hz, 1H) , 4.34 (dd, J=12.4, 1.1Hz, 1H), 1.29 (d, J=1.9Hz, 3H), 1.24 (d, J=1.7Hz, 3H).; 13 CNMR (125MHz, CDCl3)) δ170.34, 160.13, 157.50, 156.96, 137.19, 130.06, 129.9 3, 124.45, 121.93, 121.78, 118.77, 118.01, 69.31, 64.48, 60.51, 47.35, 21.32.

[0140] S3, Synthesis of compounds of formula 4:

[0141] At room temperature, the compound of formula 3 (71 g, 0.2 mol) was put into 200 ml of water, sodium carbonate (21.2 g, 0.36 mol) was added, and the reaction was stirred and monitored by TLC (EA: PE = 1: 1) until the raw material reaction was complete. The reaction solution was cooled to room temperature, 100 ml*2 of chloroform was added for extraction, the water layer was cooled to 0°C, the pH was adjusted to 2 with hydrochloric acid, and extracted with 200 ml*2 of chloroform. The organic layers were combined, dried, and concentrated to obtain 57.6 g of a yellow oil with a purity of 98.8% and a yield of 92.0%.

[0142] S4, Synthesis of compounds of formula 5:

[0143] At room temperature, the compound of formula 4 (62.7 g, 0.2 mol) and 2.6 ml DMF were added to 200 ml chloroform, nitrogen was replaced 3 times, phosphorus oxychloride (61.3 g, 0.4 mol) was added dropwise, and after the addition, the temperature was raised to reflux, and TLC was monitored (EA: PE = 1: 1) until the raw material reaction was complete, the solvent was concentrated, 250 ml chloroform was added under nitrogen protection, the temperature was lowered to -10 ° C, ferric chloride (81.1 g, 0.5 mol) was added, and TLC was monitored (EA: PE = 1: 1) until the raw material reaction was basically complete, the reaction solution was slowly added to 400 ml ice water to quench, the layers were separated, the organic layer was adjusted to pH = 9 with potassium hydroxide aqueous solution, the layers were separated, the organic layer was washed twice with 300 ml water, the organic layer was dried and concentrated to obtain 52.9 g of an oily substance with a purity of 98.9% and a yield of 89.5%.

[0144] S5, Synthesis of compound of formula 6:

[0145] At room temperature, the compound of formula 5 (11.8 g, 40 mmol) was added to a system of 250 ml of acetonitrile and 220 ml of water, and then sodium hydroxide (8 g, 200 mmol) was added. The temperature was raised to 60°C and monitored by TLC (EA: PE = 1: 1) until the raw materials were basically reacted. The mixture was filtered and the filter cake was rinsed with a small amount of ice methanol to obtain 9.17 g of solid with a purity of 99.2% and a yield of 85.8%.

[0146] S6, Synthesis of compounds of formula 7:

[0147] At room temperature, the compound of formula 6 (20 g, 75 mmol) and NCS (2.3 g, 17.3 mmol) were added to 30% TBHP (114 g, 0.38 mol), and sodium acetate (31.2 g, 0.38 mol) was added to the reaction mixture. The temperature was raised to 90°C and kept warm for 12 h. TLC monitoring (EA: PE = 1: 1) was performed until the reaction of the raw materials was complete. The reaction solution was cooled to 0°C, acidified with hydrochloric acid to pH = 2, and 150 ml * 2 of chloroform was added for extraction. The organic layers were combined, dried, and concentrated to obtain 18.4 g of solid with a purity of 98.9% and a yield of 87%.

[0148] S7, synthesis of compound of formula A:

[0149] At room temperature, the compound of formula 7 (16.9 g, 60 mmol) was added to 100 ml of ethanol, and then 5.0 g of thionyl chloride was added. The temperature was raised to reflux and kept warm for 8 h. TLC monitoring (EA: PE = 1: 1) was performed until the raw materials reacted completely. The reaction solution was cooled to 0 ° C for crystallization, filtered and dried to obtain 15.1 g of a white powdery solid with a purity of 99.0% and a yield of 85.5%.

[0150] 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. In the absence of further restrictions, the elements defined by the sentence "comprise a ..." do not exclude the existence of other identical elements in the process, method, article or device including the elements.

[0151] 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 compounds of Formula 2 and Formula 3 is one of methyl, ethyl, and isopropyl; The preparation method comprises the following steps: S1, the compound of formula 1 reacts with an amino acid 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 protected by cyclization to obtain the compound of formula 3; S3, the compound of formula 3 is hydrolyzed under the action of a base 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 ring-opened under the action of a base to obtain a compound of formula 6; S6, the compound of formula 6 is oxidized to obtain the compound of formula 7; S7. The compound of formula 7 is esterified 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 amino acid are added to solvent 1, reacted at room temperature under base catalysis, concentrated to dryness after the reaction, the oily substance is dissolved in solvent 2, a reducing agent is added, reacted at low temperature, and after the reaction is completed, quenched, extracted, dried and concentrated to obtain the compound of formula 2.

3. The method for preparing a roxadustat intermediate according to claim 1, characterized in that: The S2 specifically includes the following steps: The compound of formula 2 is added to a solvent, and then a condensing agent is added, and the temperature is raised under the protection of N2 to react. After the reaction is completed, the mixture is concentrated to dryness, and the compound of formula 3 is obtained through extraction, drying and concentration.

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 for reaction. 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 4.

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: The compound of formula 5 is added into a solvent and water, and a base is added, and the temperature is raised to react. After the reaction is completed, the temperature is lowered to room temperature, and the compound of formula 6 is obtained by filtration.

7. The method for preparing a roxadustat intermediate according to claim 1, characterized in that: The S6 specifically comprises the following steps: The compound of formula 6 and the catalyst are added into water, and then an oxidant is added. Then, a base is added into the reaction system, and the temperature is raised to react. After the reaction is completed, the mixture is acidified with an acid, extracted with an extractant, dried, and concentrated to obtain the compound of formula 7.

8. 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 7 is added to a solvent, an acid is added, the temperature is raised to react, and after the reaction is completed, the temperature is lowered to crystallize, and the compound of formula A is obtained by filtration.

9. A rosuvastatin intermediate, characterized in that: Including compounds of formula 2, formula 3, formula 4, formula 5, formula 6 and formula 7 prepared by the preparation method according to any one of claims 1 to 8, wherein R in the compounds of formula 2 and formula 3 is independently selected from one of methyl, ethyl and isopropyl; The structural formulas of the compound of formula 2, the compound of formula 3, the compound of formula 4, the compound of formula 5, the compound of formula 6 and the compound of formula 7 are shown below:

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