A rosuvastatin intermediate and its preparation method

Abstract

The current difficulty in synthesizing rosuvastatin lies in the preparation of the key intermediate, 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (or carboxamide), represented by Formula A. To address this issue, the present invention provides a rosuvastatin intermediate and a preparation method thereof. The preparation method comprises the following steps: (1) reacting a compound represented by Formula C with formaldehyde and a halogen acid in the presence of a solvent to obtain a compound represented by Formula B; and (2) reacting the compound represented by Formula B with metal powder in the presence of a solvent to obtain a compound represented by Formula A. This synthesis method has a reasonable route, high yield, and high purity, and is suitable for industrial production.

Description

Technical Field

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

[0002] The Chinese chemical 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. Developed by FibroGen, Roxadustat is a small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase. It can be used orally to treat anemia associated with end-stage renal disease (ESRD) and chronic kidney disease (CKD) in both dialysis-dependent and non-dialysis-dependent patients, as well as myelodysplastic syndrome (MDS). The drug was successfully launched in China in December 2018. Roxadustat can regulate HIF, increase hemoglobin levels, and increase iron absorption and utilization by reducing hepcidin levels, thereby achieving the purpose of treating anemia. Its structural formula is as follows:

[0003]

[0004] In the prior art, the following methods and routes are available for the large-scale production of rosuvastatin: The following synthesis method (CN102977015B) is published in the compound patent of Yuanyan Company. This route uses highly toxic and dangerous reagents such as phosphorus oxybromide, sodium metal, butyl lithium, methyl iodide, and benzyl bromide. The multi-step reaction time exceeds 18 hours, and the reaction conditions are extremely harsh. The intermediates undergo multiple column chromatography purification steps. The entire route is long, complex, and costly, making it unsuitable for industrial scale-up production.

[0005]

[0006] The original research company subsequently optimized and improved the process synthesis route, publishing the following synthesis method (CN103435546B). This route significantly improves synthesis efficiency compared to the previous generation route, but the acetic anhydride used in the route is a controlled precursor to narcotic drugs, the p-toluenesulfonylglycine may introduce genotoxic impurities such as sulfonates, and the penultimate step requires removal of the acetoxy group under high temperature and pressure, which places high demands on production equipment.

[0007]

[0008] Beijing Biometuo New Drug Development Co., Ltd. has published the following synthetic method (CN104024227B, application date 20120723). This route uses difficult-to-obtain methyl isocyanoacetate to prepare the precursor for the key cyclization step, resulting in a very low yield of only 22% for this crucial step in constructing the isoquinoline core. Phosphorus oxychloride, a hazardous reagent, is used for chlorination, and unstable trimethylborane is used for the construction of the methyl group. The entire route is complex, with long steps, low synthesis efficiency, and high costs, making it unsuitable for industrial scale-up.

[0009]

[0010] Patent CN 107954931 B discloses a method using 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (Compound I) as the starting material, followed by bromination with 1,3-dibromo-5,5-dimethylhydantoin to produce 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (Compound II). Compound II is then coupled with methylboronic acid (CH3B(OH)2) to produce Compound III. Compound III is condensed with glycine methyl ester hydrochloride and then hydrolyzed to produce rosuvastatin. This method completes the synthesis of rosuvastatin in four steps, with an overall yield of 43.8% (Example 1). The synthesis of the rosuvastatin intermediate is completed in two steps, with a two-step reaction yield of 63.6% to 19.4% (Examples 1 to 3). Overall, this synthesis method has a low yield and is not suitable for industrial production.

[0011]

[0012] In summary, the difficulty of the method disclosed in the prior art lies in the preparation of the key intermediate 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (or formamide) A.

[0013]

[0014] Wherein X=O, N; R=C1-C6 alkyl, benzyl. Currently, there are few methods for preparing roxadustat intermediate A, and the yield of the preparation methods provided by the existing technology is low. Therefore, it is necessary to develop a new method for preparing roxadustat intermediate A. Summary of the Invention

[0015] The object of the present invention is to provide a rosuvastatin intermediate B. The present invention also provides a reasonable, efficient, simple, high-yield, high-purity preparation method of the rosuvastatin intermediate that is suitable for industrial production.

[0016] A rosuvastatin intermediate compound represented by formula B has the following structure:

[0017]

[0018] wherein X is selected from N, O, and S; Y is selected from halogen; and R is selected from substituted or unsubstituted alkyl, or substituted or unsubstituted benzyl.

[0019] Further, X is selected from N, O, Y is selected from Cl, Br, I, and R is selected from C1-C10 alkyl, benzyl.

[0020] Furthermore, X is selected from N and O, Y is selected from Cl, Br and I, and R is selected from C1-C6 alkyl and benzyl.

[0021] The Blanc reaction involves the introduction of a chloromethyl group (-CHCl2) onto the aromatic ring of an aromatic hydrocarbon in the presence of reagents such as formaldehyde, hydrogen chloride, and a protic acid. The chloromethyl group introduced into the aromatic hydrocarbon can be converted into groups such as -CH2OH, -CHO, -CH2CN, -CH2NH2, and -CH3. Isoquinolinium also exhibits aromaticity. Taking this as a starting point, the inventors synthesized roxadustat intermediate A by first halomethylating the isoquinolinium ring with formaldehyde, a halogen acid, and a protic acid, and then converting -CH2X (where X is a halogen) to -CH3 using metal powder.

[0022] The preparation method of roxadustat intermediate B and roxadustat intermediate A comprises the following contents:

[0023] (1) In the presence of a solvent, the compound represented by formula C is reacted with formaldehyde and a halogen acid to prepare a compound represented by formula B;

[0024] (2) reacting the compound represented by formula B with metal powder in the presence of a solvent to prepare the compound represented by formula A;

[0025] The specific synthetic route is as follows:

[0026]

[0027] Wherein X is selected from N, O, Y is selected from halogen, and R is selected from C1-C6 alkyl and benzyl.

[0028] Furthermore, X is selected from N and O, Y is selected from Cl, Br, and I, and R is selected from C1-C6 alkyl and benzyl.

[0029] In step (1) of the technical solution of the present invention, the solvent is selected from at least one of C1-C6 aliphatic carboxylic acids, C1-C6 aliphatic alcohols, water, and N,N-dimethylacetamide.

[0030] Furthermore, in step (1), the solvent is selected from at least one of formic acid, acetic acid, methanol, ethanol, water, and N,N-dimethylacetamide, preferably acetic acid or methanol.

[0031] In Examples 1-3 of the present invention, when acetic acid or methanol is used as the solvent, the synthesis yield of step (1) is greater than or equal to 85%, and the purity is greater than 90%.

[0032] In the present invention, formaldehyde compounds and halogen acids are used to carry out halogenation and methylation of the isoquinolinium ring to synthesize a new type of roxadustat intermediate compound B, which provides a new method for the synthesis of roxadustat intermediate A.

[0033] The formaldehyde in step (1) of the technical solution of the present invention is selected from at least one of paraformaldehyde, formalin, and a methanol solution of formaldehyde.

[0034] In step (1) of the technical solution of the present invention, the halogen acid is selected from at least one of hydrochloric acid and hydrobromic acid, and its concentration is between 10% and 40%.

[0035] Furthermore, the solvent in the halogen acid includes but is not limited to at least one of water, methanol, and tetrahydrofuran.

[0036] Wherein, the reaction temperature of step (1) is 80-90° C., and the reaction time is 6-10 h.

[0037] In step (2) of the technical solution of the present invention, the solvent is at least one selected from C1-C6 aliphatic carboxylic acids, C1-C6 aliphatic alcohols, ethyl acetate, and tetrahydrofuran.

[0038] Furthermore, in step (2), the solvent is selected from at least one of formic acid, acetic acid, methanol, ethanol, ethyl acetate, and tetrahydrofuran.

[0039] The metal powder used in step (2) of the technical solution of the present invention is selected from at least one of Pd / C, Pt / C, PtO2, and Rh / C.

[0040] Step (2) is carried out under a hydrogen atmosphere at room temperature, wherein the reaction time is 12 to 36 hours.

[0041] In the technical solution of the present invention, when the solvents of the above two steps are the same, the compound represented by formula A can be prepared from the compound represented by formula C in one pot without separating the intermediate, as shown in specific Examples 11 and 12.

[0042] The beneficial effects of the present invention are:

[0043] 1. The present invention provides a compound represented by the intermediate formula B of rosuvastatin, which provides a synthetic strategy for synthesizing the key intermediate A of rosuvastatin.

[0044] 2. The synthetic method of the present invention has a high yield and the prepared product has a high purity. In Examples 11 and 12, the yield of rosuvastatin intermediate A is above 80% and the purity is above 95%, indicating that the method is suitable for industrial production.

[0045] 3. The present invention first uses formaldehyde and a halogen acid to halogenate and methylate the isoquinuclidine ring, and then uses metal powder to convert the halogenated methyl group into a methyl group. Compared with first chlorinating the isoquinuclidine ring with phosphorus oxychloride and then using trimethylborane and a noble metal catalyst, the reagents used in the technical solution of the present invention are milder and more stable, so it is less dangerous, easier to operate, and more operator-friendly.

[0046] 4. The technical solution of the present invention can prepare the compound represented by formula A from the compound represented by formula C in a one-pot process by controlling the solvent in the reaction. The intermediate does not need to be separated, the steps are simple, and the operation is more convenient. DETAILED DESCRIPTION

[0047] The technical solution of the present invention will be described below in conjunction with specific implementation methods, but the present invention is not limited thereto.

[0048] All reagents and solvents used were commercially available and were not specially treated unless otherwise specified.

[0049] Example 1

[0050]

[0051] Methyl 4-hydroxy-1-(chloromethyl)-7-phenoxyisoquinoline-3-carboxylate

[0052] Dissolve 5 g of methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate and 2.04 g of paraformaldehyde in 12 mL of glacial acetic acid, then add 12 mL of concentrated hydrochloric acid (38%). Heat the reaction mixture to 85°C for 6 h. Concentrate to remove most of the solvent to obtain a crude pale yellow solid. Recrystallize from methanol, filter, and dry to yield 5.3 g (95% purity, 87% yield) of the title compound as a pale yellow solid.

[0053] The reaction products were evaluated by MS, and the MS-(+)-ion M+1 of product 2 was measured to be 343.9 and 345.9. Analysis of reactant 1 using Chembio Office software revealed an m / z of 295.08. The difference in m / z between the reactant and product was approximately 49.82, which is similar to the m / z of chloromethane (49.99). Combined with the Blanc reaction, the reactant was determined to be methyl 4-hydroxy-1-(chloromethyl)-7-phenoxyisoquinoline-3-carboxylate.

[0054] Example 2

[0055]

[0056] Methyl 4-hydroxy-1-(chloromethyl)-7-phenoxyisoquinoline-3-carboxylate

[0057] Dissolve 5 g of methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate and 2.0 mL of a methanol solution of formaldehyde (1 g / mL) in 10 mL of methanol. Add 12 mL of methanolic hydrochloric acid. Heat the reaction mixture to 85°C for 6 h, slowly cool, and crystallize. After filtration and drying, yield 5.2 g (96% purity, 85% yield) of the title compound as a pale yellow solid.

[0058] Example 3

[0059]

[0060] Methyl 4-hydroxy-1-(chloromethyl)-7-phenoxyisoquinoline-3-carboxylate

[0061] Dissolve 5 g of methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate and 5.5 mL of formalin (37% formaldehyde in water) in 12 mL of glacial acetic acid, then add 12 mL of concentrated hydrochloric acid (38%). Heat the reaction mixture to 85°C for 10 h. Concentrate to remove most of the solvent to obtain a crude pale yellow solid. Recrystallize the product from methanol, filter, and dry it to yield 5.3 g (95% purity, 87% yield) of the title compound as a pale yellow solid.

[0062] Example 4

[0063]

[0064] Methyl 4-hydroxy-1-(chloromethyl)-7-phenoxyisoquinoline-3-carboxylate

[0065] Dissolve 5 g of methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate and 2.04 g of paraformaldehyde in 12 mL of N,N-dimethylacetamide, then add 12 mL of concentrated hydrochloric acid (38%). Heat the reaction mixture to 85°C for 6 h. Pour the reaction mixture into cold water to precipitate a pale yellow solid. Filter and dry with suction to yield 4.8 g (92% purity, 76% yield) of the title compound as a pale yellow solid.

[0066] Example 5

[0067]

[0068] 4-Hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester

[0069] A mixture of 5 g of methyl 4-hydroxy-1-(chloromethyl)-7-phenoxyisoquinoline-3-carboxylate, 0.52 g of Pd / C, and 25 mL of glacial acetic acid was stirred at ambient pressure and temperature under an atmosphere of H for 18 h. The mixture was filtered and the filtrate was concentrated to yield 4.2 g (98% purity, 91% yield) of the title compound as an off-white solid.

[0070] The reaction products were evaluated by MS.

[0071] MS-(+)-ion M+1=310.0

[0072] Example 6

[0073]

[0074] 4-Hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester

[0075] A mixture of 5 g of methyl 4-hydroxy-1-(chloromethyl)-7-phenoxyisoquinoline-3-carboxylate, 0.52 g of Pt / C, and 25 mL of methanol was stirred at ambient pressure and temperature under an atmosphere of H for 12 h. The mixture was filtered and the filtrate was concentrated to give 4.2 g (94% purity, 88% yield) of the title compound as an off-white solid.

[0076] Example 7

[0077]

[0078] 4-Hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester

[0079] A mixture of 5 g of methyl 4-hydroxy-1-(chloromethyl)-7-phenoxyisoquinoline-3-carboxylate, 0.52 g of Rh / C, and 25 mL of ethyl acetate was stirred at ambient pressure and temperature under an atmosphere of H for 36 h. The mixture was filtered and the filtrate was concentrated to give 4.0 g (98% purity, 87% yield) of the title compound as an off-white solid.

[0080] Example 8

[0081]

[0082] Ethyl 4-hydroxy-1-(chloromethyl)-7-phenoxyisoquinoline-3-carboxylate

[0083] Dissolve 5 g of ethyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate and 1.94 g of paraformaldehyde in 12 mL of glacial acetic acid, then add 12 mL of concentrated hydrochloric acid (38%). Heat the reaction mixture to 85°C for 6 h. Concentrate to remove most of the solvent to obtain a crude pale yellow solid. Recrystallize from methanol, filter, and dry to yield 5.4 g (96% purity, 90% yield) of the title compound as a pale yellow solid.

[0084] The reaction products were evaluated by MS, and the MS-(+)-ion M+1 of product 5 was measured to be 358.1 and 360.1. Similar to Example 1, analysis of reactant 4 using Chembio Office software revealed an m / z of 309.10. The m / z values ​​of the reactant and product differed by approximately 50, which is similar to the m / z of chloromethane (49.99). Combined with the Blanc reaction, it was determined that the reactant was ethyl 4-hydroxy-1-(chloromethyl)-7-phenoxyisoquinoline-3-carboxylate.

[0085] Example 9

[0086]

[0087] Ethyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate

[0088] A mixture of 5 g of ethyl 4-hydroxy-1-(chloromethyl)-7-phenoxyisoquinoline-3-carboxylate, 0.52 g of Pd / C, and 25 mL of ethanol was stirred at ambient pressure and temperature under an atmosphere of H for 18 h. The mixture was filtered and the filtrate was concentrated to yield 4.5 g (94% purity, 94% yield) of the title compound as an off-white solid.

[0089] The reaction products were evaluated by MS.

[0090] MS-(+)-ion M+1=324.1

[0091] Example 10

[0092]

[0093] Methyl 4-hydroxy-1-(bromomethyl)-7-phenoxyisoquinoline-3-carboxylate

[0094] Dissolve 5 g of methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate and 2.04 g of paraformaldehyde in 12.5 mL of glacial acetic acid, then add 12.5 mL of 40% hydrobromic acid. Heat the reaction mixture to 85°C for 6 h. Concentrate to remove most of the solvent to obtain a crude yellow solid. Recrystallize from methanol, filter, and dry to yield 6.2 g (94% purity, 89% yield) of the title compound as a pale yellow solid.

[0095] The reaction products were evaluated by MS.

[0096] MS-(+)-ion M+1=388.0、390.0

[0097] Example 11

[0098]

[0099] 1-[(Dimethylamino)methyl]-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester

[0100] Dissolve 240 g of methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate and 97.6 g of paraformaldehyde in 600 mL of glacial acetic acid, then add 600 mL of concentrated hydrochloric acid (38%). Heat the reaction mixture to 85°C for 6 h, then cool to ambient temperature. Add 24 g of Pd / C, and continue stirring under a H2 atmosphere at ambient pressure and temperature for 18 h. Filter, and concentrate the filtrate to yield 214 g (97% purity, 83% yield) of the title compound as an off-white solid.

[0101] Example 12

[0102]

[0103] Ethyl 1-[(dimethylamino)methyl]-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate

[0104] Dissolve 240 g of ethyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate and 93.2 g of paraformaldehyde in 600 mL of glacial acetic acid, then add 600 mL of concentrated hydrochloric acid (38%). Heat the reaction mixture to 85°C for 6 h, then cool to ambient temperature. Add 24 g of Pd / C, and continue stirring under a H2 atmosphere at ambient pressure and temperature for 18 h. Filter, and concentrate the filtrate to yield 220 g (98% purity, 86% yield) of the title compound as an off-white solid.

[0105] The above content is a further detailed description of the present invention in conjunction with specific embodiments, and the specific embodiments of the present invention should not be considered to be limited to these descriptions. A person skilled in the art of the present invention may make several deductions or substitutions without departing from the concept of the present invention, and all of these should be considered to fall within the scope of protection of the present invention.

Claims

1. A method for preparing a rosuvastatin intermediate (B), comprising: In the presence of a solvent, the compound represented by formula (C) is reacted with a formaldehyde compound and a halogen acid to prepare a compound represented by formula (B); wherein X is selected from O, Y is selected from halogen, and R is selected from methyl and ethyl; The formaldehyde compound is selected from at least one of paraformaldehyde, formalin and methanol solution of formaldehyde, and the halogen acid is selected from at least one of hydrochloric acid and hydrobromic acid.

2. The preparation method according to claim 1, characterized in that The solvent is selected from at least one of C1-C6 aliphatic carboxylic acids, C1-C6 aliphatic alcohols, water, and N,N-dimethylacetamide.

3. The preparation method according to claim 1, wherein The concentration of the halogen acid is between 10% and 40%, and the solvent in the halogen acid is at least one of water, methanol, and tetrahydrofuran.

4. The preparation method according to any one of claims 1 to 3, characterized in that: The reaction time is 6 to 10 hours, and the reaction temperature is 80 to 90°C.

5. A method for preparing a rosuvastatin intermediate (A), comprising: The compound represented by formula (B) is prepared by the method according to any one of claims 1 to 4, wherein the compound represented by formula (B) is reacted with metal powder in the presence of a solvent to obtain the compound represented by formula (A); Wherein X is selected from O, Y is selected from halogen, and R is selected from methyl and ethyl; and the metal powder used is selected from at least one of Pd / C and Rh / C.

6. The preparation method according to claim 5, wherein The solvent is selected from at least one of C1-C6 aliphatic carboxylic acids, C1-C6 aliphatic alcohols, ethyl acetate, and tetrahydrofuran.

7. The preparation method according to any one of claims 5 to 6, characterized in that: The reaction was carried out at room temperature under a hydrogen atmosphere. It should take 12 to 36 hours.

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