CN108424388B - Preparation method of medicine for treating chronic anemia - Google Patents
Preparation method of medicine for treating chronic anemia Download PDFInfo
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- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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Abstract
The invention discloses a method for synthesizing a chronic anemia drug of roxasistat, which comprises the steps of hydrolyzing and acidifying a compound shown in a formula 6 under the action of alkali to obtain a key intermediate compound shown in a formula 7; the compound shown as the formula 7 and carbonyldiimidazole are subjected to condensation reaction under proper conditions to obtain an intermediate compoundAnd (4) a formula 8, which can be separated from the system or directly participate in the subsequent reaction without separation, and finally react with glycine to obtain a final product, namely the rosisastat formula 9. The synthetic route improves route efficiency, reduces process cost, reduces the generation of byproducts, and is beneficial to improving the purity of the final finished product.
Wherein, the compound is R in formula 62Represents an alkyl group including, but not limited to, methyl, ethyl, isopropyl, tert-butyl or benzyl.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and relates to a chemical synthesis method of a rosisasetamide intermediate and a raw material medicine for treating chronic anemia.
Background
Rosemastat (Roxadustat, FG-4592) is a small molecule inhibitor of Hypoxia Inducible Factor (HIF) prolyl hydroxylase for oral administration. The medicine is developed by American non-Brougen company, and then is authorized and approved by Ansitai and Alikang, and at present, a phase III clinical test is in development, has obvious effect on treating anemia related to chronic nephropathy and end-stage nephropathy, and has great market prospect.
The chemical name of the roxasistat is as follows: n- [ (4-hydroxy-1-methyl-7-phenoxy-3-isoquinolin) carbonyl ] glycine, the structural formula is as follows:
PCT patent WO2004108681 reports a roxasistat intermediate and a synthetic route for preparing the roxasistat, wherein 4-nitrophthalonitrile is used as a starting material, and is subjected to multi-step reactions such as substitution, hydrolysis, condensation, esterification and rearrangement to obtain 1, 4-dihydroxy-7-phenoxyisoquinoline-3-carboxylic ester, then the key intermediate 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid is obtained through bromination, methylation and hydrolysis reactions, and finally the key intermediate is condensed with tert-butyl glycinate and hydrolyzed to obtain the finished product of the roxasistat.
The invention patent WO2013013609A in Zhejiang Bauda pharmaceutical industry improves the synthesis method of 1, 4-dihydroxy-7-phenoxy isoquinoline-3-carboxylic ester on the basis of reference to the original research route, and reports that the synthesis route of the rasagiline is as follows:
international patent WO2014014834A of the original research company reports a new synthetic route for roxasistat, a new intermediate 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate is synthesized, then the new intermediate reacts with tetramethylmethanediamine, then the new intermediate reacts with acetate to complete a substitution reaction, then the methylation reaction of isoquinoline ring is completed by palladium-carbon hydrogenation to obtain a key intermediate of roxasistat, and finally the key intermediate undergoes an aminolysis reaction with glycine to obtain a product, wherein the route is as follows:
generally, the methods for synthesizing the roxasistat have overlong general routes and low total yield, expensive methylating reagents and noble metal palladium catalysts are needed to be used for introducing methyl to the isoquinoline in the steps, the cost is high, the process amplification is difficult, and methods which have simple process routes and low cost and are suitable for industrial production still need to be found.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a novel synthesis method of the roxasistat and the key intermediate thereof, which has the advantages of simple process route, low cost and suitability for industrial production.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
the synthesis method of the roxasistat comprises the following steps:
(1) hydrolyzing and acidifying the compound shown in the formula 6 under the action of alkali to obtain a key intermediate compound shown in the formula 7;
wherein R2 in compound formula 6 represents alkyl, including but not limited to methyl, ethyl, isopropyl, tert-butyl or benzyl;
(2) carrying out condensation reaction on a compound shown in a formula 7 and carbonyldiimidazole under proper conditions to obtain a compound shown in a formula 8;
(3) reacting the compound shown in the formula 8 with glycine to obtain a final product, namely the rosinestotal shown in the formula 9;
preferably, in the reaction in step (1), the base used is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; the reaction solvent is selected from dichloromethane, 1, 4-dioxane, toluene, tetrahydrofuran, isopropyl acetate, acetone, methanol, ethanol, isopropanol, n-butanol or tert-butanol, etc.; the acid is selected from hydrochloric acid, phosphoric acid, acetic acid or citric acid; the reaction temperature is-20 to 110 ℃.
Preferably, in the condensation reaction of step (2), the base used is selected from organic bases such as triethylamine, diisopropylethylamine, pyridine, DMAP, DBU, DABCO and the like; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene, chlorobenzene or acetone, etc.; the reaction temperature is generally-10 to 50 ℃.
Preferably, in the reaction of step (3), the reaction solvent is selected from dichloromethane, toluene, tetrahydrofuran, acetone, acetonitrile, or the like; the reaction temperature is-10 to 90 ℃.
The invention also relates to a synthesis method of the key intermediate compound of the roxasistat, namely the formula 6, which comprises the following steps:
(1) obtaining a compound shown in the formula 5 by reacting the compound shown in the formula 4 under the action of phosphorus oxychloride;
(2) coupling a compound shown in a formula 5 with a methyl Grignard reagent under the action of a catalyst to obtain an intermediate compound shown in a formula 6;
preferably, the base used in the reaction in the step (1) is an organic base such as triethylamine, diisopropylethylamine, pyridine, 2, 6-lutidine, DBU, or dimethylaniline; the reaction solvent is selected from toluene, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, N-dimethylformamide or N, N-dimethylacetamide; the reaction temperature is 0-110 ℃.
Preferably, in the reaction in step (2), the methyl grignard reagent is selected from methyl magnesium bromide or methyl magnesium chloride; the catalyst is selected from metal salt containing nickel, iron or cobalt salt, such as bis-triphenylphosphine nickel dichloride, ferric trichloride, ferric triacetylacetone or cobalt dichloride; the reaction solvent is selected from benzene, toluene, tetrahydrofuran, 2-methyltetrahydrofuran or 1, 4-dioxane, etc.; the reaction temperature is generally-15 to 120 ℃.
The invention also comprises a synthesis method of the intermediate compound of the roxasistat, namely the formula 4, which comprises the following steps:
(1) converting the compound shown in the formula 1 into acyl chloride under the action of thionyl chloride, and then carrying out condensation and decarboxylation reaction on the acyl chloride and the compound shown in the formula 2 to obtain a compound shown in the formula 3;
wherein, R in the compound formula 11And the compound of formula 2 wherein R2Represents alkyl including but not limited to methyl, ethyl, isopropyl, tert-butyl or benzyl;
(2) the compound shown in the formula 3 is subjected to Boc protection removal under the action of acid, and intramolecular cyclization is carried out to obtain a key intermediate compound 4;
preferably, in the reaction in the step (1), the base used is triethylamine, N-diisopropylethylamine, DBU or the like; selecting magnesium chloride as an additive; the reaction solvent is dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran or toluene, etc.; the reaction temperature is selected from-30 to 110 ℃.
Preferably, in the step (2), the acid is selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, and the like; the base used in the cyclization reaction is selected from triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate or potassium phosphate and the like; the reaction solvent is selected from methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, 1, 2-dichloromethane, 1, 4-dioxane, toluene, ethyl acetate, isopropyl acetate or acetonitrile; the reaction temperature is-15 to 110 ℃.
The invention relates to a synthesis method of rosisastat, which is characterized in that 4-phenoxy phthalic acid monoester derivative compound formula 1 is converted into acyl chloride and then condensed and decarboxylated with aminomalonic acid derivative compound formula 2 under the action of alkali to obtain intermediate compound formula 3, then Boc protection is removed under the action of acid and intramolecular cyclization is carried out to obtain key intermediate compound formula 4, and then chlorinated reagent POCl is used3The compound of formula 5 is obtained by chlorination under the action of the catalyst. The compound formula 5 is reacted with a methyl Grignard reagent through Grignard coupling catalyzed by iron, cobalt or nickel to complete methylation reaction, and finally hydrolyzed to obtain the key intermediate 6 of the Rosemastat, so that the reaction yield is high, and noble metal catalysis is avoided. In the subsequent step, CDI is used as a condensing agent to obtain an intermediate compound shown as a formula 8, which can be separated from a system or directly participate in the subsequent reaction without separation, and finally reacts with glycine to obtain the finished product of the roxasistat 9. These improvements greatly improve the route efficiency and reduce the process cost, and reduce the generation of by-products, which is beneficial to improving the purity of the final product. The route is simple to operate, the total yield is high, the purity of the obtained product is high, and the route is suitable for large-scale production.
The route is as follows:
wherein, R in the compound formula 11And the compound of formula 2 wherein R2Represents an alkyl group including, but not limited to, methyl, ethyl, isopropyl, tert-butyl or benzyl.
Detailed Description
The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
Example 1
Adding the compound 1a (27.23g, 100mmol) and dichloromethane (136mL) into a reaction bottle A, stirring to dissolve, slowly dropping thionyl chloride (17.85g,150mmol), refluxing for 4-6 hours, distilling under reduced pressure until no fraction flows out, adding dichloromethane (136mL) and carrying out swirling twice, and adding tetrahydrofuran (136mL) to dissolve for later use. A three-necked flask B is charged with the compound of formula 2a (27.99g,120mmol), anhydrous magnesium chloride (11.43g,120mmol) and tetrahydrofuran (120mL), stirred uniformly, cooled to-10 to 0 ℃ in an ice salt bath, added with triethylamine (13.15g,130mmol) under nitrogen protection, and stirred at an internal temperature of-10 to 0 ℃ for 60 minutes. And then slowly dripping the acyl chloride solution prepared in the flask A into a reaction bottle B, slowly heating to 25-30 ℃ after dripping, reacting for 6-8 hours, cooling the reaction liquid to 0-5 ℃ after the reaction is finished, slowly adding saturated ammonium chloride to quench the reaction (136mL), adding water (136mL), extracting the water phase for 2 times by using ethyl acetate (272mL), combining organic phases, washing for 2 times (136mL), drying by using sodium sulfate, filtering, concentrating to a small volume, adding petroleum ether to pulp, filtering and drying to obtain an intermediate 3a (38.14g, 86%).
Example 2
Adding the compound 1b (28.63g, 100mmol) and dichloromethane (143mL) into a reaction bottle A, stirring and dissolving, slowly dropping thionyl chloride (17.85g,150mmol), refluxing for 4-6 hours, then performing rotary evaporation until no fraction is separated, adding dichloromethane (143mL), performing rotary reaction twice, and adding acetonitrile (143mL) to dissolve for later use. A three-necked flask B was charged with the compound of formula 2B (29.67g,120mmol), anhydrous magnesium chloride (11.43g,120mmol) and acetonitrile (120mL), stirred well, cooled to-10 to 0 ℃ in an ice salt bath, added with diisopropylethylamine (16.80g,130mmol) under nitrogen protection, and stirred at-10 to 0 ℃ for 60 minutes. And then slowly dripping the acyl chloride solution prepared in the flask A into a reaction bottle B, slowly heating to 25-30 ℃ after dripping, reacting for 6-8 hours, cooling the reaction liquid to 0-5 ℃ after the reaction is finished, slowly adding saturated ammonium chloride to quench the reaction (143mL), adding water (143mL), extracting the water phase for 1 time by using ethyl acetate (143mL), combining organic phases, washing for 2 times (143mL), drying by using sodium sulfate, filtering, concentrating to a small volume, adding petroleum ether to pulp, filtering and drying to obtain an intermediate 3B (41.95g, 89%).
Example 3
Adding the compound 1c (30.03g, 100mmol) and dichloromethane (150mL) into a reaction bottle A, stirring and dissolving, slowly dropping thionyl chloride (17.85g,150mmol), refluxing for 4-6 hours, then performing rotary evaporation until no fraction is discharged, adding dichloromethane (150mL), performing rotary reaction twice, and adding dichloromethane (150mL) to dissolve for later use. A three-necked flask B was charged with the compound of formula 2B (29.67g,120mmol), anhydrous magnesium chloride (11.43g,120mmol) and dichloromethane (150mL), stirred well, cooled to-10 to 0 ℃ in an ice salt bath, added with diisopropylethylamine (16.80g,130mmol) under nitrogen protection, and stirred at-10 to 0 ℃ for 60 minutes. And then slowly dripping the acyl chloride solution prepared in the flask A into a reaction bottle B, slowly heating to 25-30 ℃ after dripping, reacting for 6-8 hours, cooling the reaction liquid to 0-5 ℃ after the reaction is finished, slowly adding saturated ammonium chloride to quench the reaction (150mL), adding water (150mL), separating the liquid, extracting the water phase for 1 time by using dichloromethane (143mL), combining organic phases, washing for 2 times (150mL), drying by using sodium sulfate, filtering, concentrating to a small volume, adding petroleum ether to pulp, filtering and drying to obtain an intermediate 3c (42.24g, 87%).
Here, the methylene chloride may be replaced by tetrahydrofuran, 2-methyltetrahydrofuran or toluene, and N, N-diisopropylethylamine may be triethylamine or DBU.
Example 4
Compound 3a (45.75g,100mmol) and methanol (229mL) were added to a three-necked flask, and a 30% methanol hydrochloride solution (36.46g) was added to the flask to carry out a reaction at room temperature for 4 to 6 hours. And (3) cooling the reaction liquid to 0-5 ℃ after TLC raw materials disappear, slowly adding triethylamine (60.71g,600mmol), refluxing and reacting for 6-8 hours after the addition is finished, cooling to room temperature after the reaction is finished, slowly adding saturated ammonium chloride to quench the reaction (229mL), removing part of methanol, extracting the water phase for 2 times by using dichloromethane (115mL), combining organic phases, washing with saturated salt water for 2 times (229mL), drying with sodium sulfate, filtering, concentrating to a small volume, adding petroleum ether to pulp, filtering, and recrystallizing the crude product by using a mixed solvent of methanol and petroleum ether to obtain a compound 4a (28.02g, 90%).
The triethylamine may be replaced by diisopropylethylamine, potassium carbonate, sodium carbonate or potassium phosphate; the methanol can be ethanol, isopropanol, tetrahydrofuran, dichloromethane, 1, 2-dichloromethane, 1, 4-dioxane, toluene, ethyl acetate, or isopropyl acetate.
Example 5
Compound 3b (47.15g,100mmol) and acetonitrile (235mL) were added to a three-necked flask, and trifluoroacetic acid (34.21g,300mmol) was added thereto to react at room temperature for 4 to 6 hours. And (3) cooling the reaction liquid to 0-5 ℃ after TLC raw materials disappear, slowly adding potassium carbonate (82.92g,600mmol), refluxing and reacting for 6-8 hours after the addition is finished, cooling to room temperature after the reaction is finished, slowly adding saturated ammonium chloride to quench the reaction (235mL), removing part of solvent by spinning, extracting the water phase for 2 times by using dichloromethane (117mL), combining organic phases, washing with saturated common salt water for 2 times (235mL), drying with sodium sulfate, filtering, concentrating to a small volume, adding petroleum ether to pulp, filtering, and recrystallizing the crude product by using a mixed solvent of dichloromethane and petroleum ether to obtain a compound 4b (29.93g, 92%).
Here, the trifluoroacetic acid may be replaced by sulfuric acid or p-toluenesulfonic acid, and the potassium carbonate may be triethylamine, diisopropylethylamine, sodium carbonate or potassium phosphate.
Example 6
Compound 3a (48.55g,100mmol) and ethanol (242mL) were added to a three-necked flask, p-toluenesulfonic acid (38.04g,200mmol) was added, and the mixture was reacted at room temperature for 4 to 6 hours. And (3) cooling the reaction liquid to 0-5 ℃ after TLC raw materials disappear, slowly adding potassium carbonate (69.10g,500mmol), refluxing and reacting for 6-8 hours after the addition is finished, cooling to room temperature after the reaction is finished, slowly adding dilute hydrochloric acid to quench the reaction (2mol/L,242mL), removing part of solvent by spinning, extracting the water phase for 2 times by using ethyl acetate (242mL), combining organic phases, washing for 2 times by using saturated saline solution (242mL), drying by using sodium sulfate, filtering, concentrating to a small volume, adding petroleum ether to pulp, filtering, and recrystallizing the crude product by using a mixed solvent of ethyl diacetate and petroleum ether to obtain a compound 4b (28.63g, 88%).
Example 7
Adding the compound 4a (31.13g,100mmol) and toluene (156mL) into a three-neck flask, adding diisopropylethylamine (38.77g,300mmol), stirring uniformly, slowly adding phosphorus oxychloride (23.00g,150mmol), heating to 75-80 ℃ and reacting for 10-16 hours. And after the reaction is finished, cooling the reaction liquid to 0-5 ℃, slowly adding water to adjust and quench the reaction, separating the liquid, extracting the water phase for 1 time by using toluene (156mL), combining the organic phase, washing the organic phase by using saturated salt water for 2 times (156mL), drying the organic phase by using sodium sulfate, filtering the solution, concentrating the solution to a small volume, adding petroleum ether to the solution, pulping the solution, filtering the solution, and drying the solution to obtain a compound 5a (28.36g, 86%).
The diisopropylethylamine can be replaced by triethylamine, pyridine, 2, 6-dimethylpyridine, DBU or dimethylaniline; the toluene may be replaced by dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, N-dimethylformamide or N, N-dimethylacetamide.
Example 8
Adding the compound 4b (32.53g,100mmol) and acetonitrile (162mL) into a three-neck flask, adding triethylamine (30.36g,300mmol), stirring uniformly, slowly adding phosphorus oxychloride (23.00g,150mmol), heating to 75-80 ℃ and reacting for 10-16 hours. And cooling the reaction liquid to 0-5 ℃ after the reaction is finished, slowly adding water to adjust and quench the reaction, removing part of acetonitrile by spinning, pulping for 1-2 hours, filtering, and recrystallizing the crude product by using a mixed solvent of dichloromethane and petroleum ether to obtain a compound 5b (31.28g, 91%).
Example 9
A three-neck flask was charged with 5a (32.97g, 100mmol), catalyst FeCl3(0.96g) and tetrahydrofuran (165mL), stirring and dissolving, cooling to-10-0 ℃, switching nitrogen in vacuum for 3 times, slowly dripping a methyl magnesium chloride solution (2.0M,55mL) into a reaction bottle under the protection of nitrogen, and heating to room temperature for reacting for 8-10 hours after dripping. After the reaction, 1mol/L diluted hydrochloric acid (200mL) is added to quench the reaction, the aqueous phase is extracted 2 times by ethyl acetate (165mL), the combined organic phases are washed by saturated brine 1 time (165mL), dried by anhydrous sodium sulfate, concentrated and recrystallized by a mixed solvent of petroleum ether and ethyl acetate to obtain compound 6a (23.51g, 76%).
The catalyst ferric trichloride can be replaced by bis triphenylphosphine nickel dichloride, ferric triacetylacetonate or cobalt dichloride; the tetrahydrofuran can be replaced by benzene, toluene, 2-methyltetrahydrofuran or 1, 4-dioxane.
Example 10
A three-necked flask was charged with 5b (34.38g,100mmol), a catalyst Fe (acac) triacetylacetonate3(0.96g) and tetrahydrofuran (171mL), stirring and dissolving, cooling to-10-0 ℃, switching nitrogen for 3 times in vacuum, and adding methyl magnesium chloride solution under the protection of nitrogen(2.0M,55mL) is slowly dripped into a reaction bottle, and after dripping is finished, the temperature is raised to room temperature for reaction for 8-10 hours. After the reaction, 1mol/L diluted hydrochloric acid (200mL) was added to quench the reaction, the aqueous phase was extracted 2 times with ethyl acetate (171mL), the combined organic phases were washed with saturated brine 1 time (171mL), dried over anhydrous sodium sulfate, concentrated and recrystallized from a mixed solvent of petroleum ether and ethyl acetate to give compound 6b (26.84g, 83%).
Example 12
A three-necked flask was charged with compound 6a (30.93g,100mmol), dissolved in methanol (155mL), charged with a lithium hydroxide solution (20%, 80mL), and heated to an internal temperature of 50 to 55 ℃ for reaction for 10 to 16 hours. After the reaction is finished, most methanol is concentrated and removed, dilute hydrochloric acid (2N) is slowly added to adjust the pH value to 4-5, pulping is carried out for 1 hour, filtering and washing are carried out, and the solid is collected and dried to obtain the compound 7(27.76g, the yield is 94%).
The lithium hydroxide can be replaced by sodium hydroxide or potassium hydroxide; the solvent methanol can be replaced by dichloromethane, 1, 4-dioxane, toluene, tetrahydrofuran, isopropyl acetate, acetone, ethanol, isopropanol, n-butanol or tert-butanol.
Example 12
A three-necked flask was charged with the compound 6b (32.33g,100mmol), dissolved in ethanol (161mL), added with a sodium hydroxide solution (20%, 80mL), and heated to an internal temperature of 50 to 55 ℃ for reaction for 10 to 16 hours. After the reaction is finished, most ethanol is removed by concentration and spinning, dilute hydrochloric acid (2N) is slowly added to adjust the pH value to 4-5, pulping is carried out for 1 hour, filtering and washing are carried out, and the solid is collected and dried to obtain the compound 7(26.28g, yield 89%).
Example 13
Adding compound 7(29.53g,100mmol) into a three-neck flask, adding dichloromethane (295mL), stirring and dissolving, adding triethylamine (15.18g,150mmol), stirring for 5-10 minutes, cooling to 0-10 ℃, adding carbonyldiimidazole (19.46g,120mmol) in batches, and heating to room temperature for reaction for 6-8 hours. After the reaction, water (340mL) was added, the mixture was stirred and partitioned, the aqueous phase was extracted with dichloromethane (147mL) 1 time, the organic phases were washed with saturated brine (170mL) 2 times, dried over sodium sulfate, concentrated to remove most of the solvent, and n-heptane (147mL) was added, heated, cooled, slurried, filtered and dried to obtain Compound 8(29.24g, 91% yield) as a white solid.
MS(ESI)m/z＝322.1[M+H]+
The triethylamine can be replaced by diisopropylethylamine, pyridine, DMAP, DBU or DABCO; the solvent dichloromethane can be replaced by N, N-dimethylformamide, N-dimethylacetamide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene, chlorobenzene or acetone.
Example 14
Adding the compound 8(32.13g,100mmol) and toluene (160mL) into a three-neck flask, uniformly stirring, adding glycine (9.01g,120mmol), reacting at room temperature for 4-5 hours, concentrating after the reaction is finished to remove most of the solvent, adding isopropanol (64mL) and n-heptane (160mL), heating to 50-55 ℃, slowly cooling, pulping, filtering and drying to obtain the off-white solid compound 9(31.36g, 89%). MS (ESI) M/z 351.2[ M-H ]]-。
Toluene can be replaced here by methylene chloride, tetrahydrofuran, acetone or acetonitrile.
Claims (8)
1. The method for synthesizing the roxasistat is characterized by comprising the following steps of:
(1) obtaining a compound shown in the formula 5 by reacting the compound shown in the formula 4 under the action of phosphorus oxychloride;
(2) coupling a compound shown in a formula 5 with a methyl Grignard reagent under the action of a catalyst to obtain an intermediate compound shown in a formula 6;
(3) hydrolyzing and acidifying the compound shown in the formula 6 under the action of alkali to obtain a key intermediate compound shown in the formula 7;
wherein the compound is R in formula 62Represents an alkyl group selected from methyl, ethyl, isopropyl, tert-butyl or benzyl;
(4) carrying out condensation reaction on a compound shown in a formula 7 and carbonyldiimidazole under proper conditions to obtain a compound shown in a formula 8;
(5) reacting the compound shown in the formula 8 with glycine to obtain a final product, namely the rosinestotal shown in the formula 9;
the catalyst in the step (2) is selected from bis (triphenylphosphine) nickel dichloride, ferric trichloride, ferric triacetylacetonate or cobalt dichloride.
2. The process for the synthesis of rosxastat according to claim 1, characterized in that in the reaction in step (1), the base used is triethylamine, diisopropylethylamine, pyridine, 2, 6-lutidine, DBU or dimethylaniline; the reaction solvent is selected from toluene, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, N-dimethylformamide or N, N-dimethylacetamide.
3. The process for the synthesis of Rosesastat according to claim 1 characterized in that in the reaction in step (2), the methyl Grignard reagent is selected from methyl magnesium bromide or methyl magnesium chloride; the reaction solvent is selected from benzene, toluene, tetrahydrofuran, 2-methyltetrahydrofuran or 1, 4-dioxane.
4. The process for the synthesis of Rosesastat according to claim 1 characterized in that in said reaction in step (3), the base used is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; the reaction solvent is selected from dichloromethane, 1, 4-dioxane, toluene, tetrahydrofuran, isopropyl acetate, acetone, methanol, ethanol, isopropanol, n-butanol or tert-butanol; the acid is selected from hydrochloric acid, phosphoric acid, acetic acid or citric acid.
5. The process for the synthesis of rosxastat according to claim 1, characterized in that in the condensation reaction of step (4), the base used is selected from triethylamine, diisopropylethylamine, pyridine, DMAP, DBU or DABCO; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene, chlorobenzene or acetone.
6. The process for the synthesis of Rosxastat according to claim 1 characterized by the synthesis of compound formula 4 comprising the steps of:
(1) converting the compound shown in the formula 1 into acyl chloride under the action of thionyl chloride, and then carrying out condensation and decarboxylation reaction on the acyl chloride and the compound shown in the formula 2 to obtain a compound shown in the formula 3;
wherein, R in the compound formula 11And the compound of formula 2 wherein R2Represents an alkyl group selected from methyl, ethyl, isopropyl, tert-butyl or benzyl;
(2) the compound shown in the formula 3 is subjected to Boc protection removal under the action of acid, and intramolecular cyclization is carried out to obtain a key intermediate compound 4;
7. the process for the synthesis of Rosemastat according to claim 6 characterized in that in the reaction in step (1) the base used is triethylamine, N-diisopropylethylamine or DBU; selecting magnesium chloride as an additive; the reaction solvent is dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran or toluene.
8. The process for the synthesis of Rosesastat according to claim 6 characterized in that in said step (2) the acid is selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid or p-toluenesulfonic acid; the base used in the cyclization reaction is selected from triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate or potassium phosphate; the reaction solvent is selected from methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, 1, 2-dichloromethane, 1, 4-dioxane, toluene, ethyl acetate, isopropyl acetate and acetonitrile.
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| CN111566090A (en) * | 2017-12-01 | 2020-08-21 | 雷迪博士实验室有限公司 | Preparation method of roxasistat and intermediate thereof |
| CN109369525A (en) * | 2018-12-29 | 2019-02-22 | 安礼特（上海）医药科技有限公司 | Its novel crystal forms and preparation method thereof of Luo Shasi |
| CN111380993B (en) * | 2018-12-30 | 2022-06-24 | 江苏万邦生化医药集团有限责任公司 | Method for analyzing related substances of roxasistat |
| CN111499572B (en) * | 2019-01-31 | 2022-04-01 | 安徽省庆云医药股份有限公司 | Preparation method of intermediate of roxasistat |
| CN112300073B (en) * | 2019-07-30 | 2023-09-29 | 江西同和药业股份有限公司 | Preparation method of isoquinoline derivative |
| WO2021073623A1 (en) * | 2019-10-18 | 2021-04-22 | 上海迪赛诺化学制药有限公司 | Method for preparing isoquinolinone compounds |
| CN112679429B (en) * | 2019-10-18 | 2023-05-05 | 上海迪赛诺化学制药有限公司 | Method for preparing isoquinolinones compound |
| EP4169906B1 (en) * | 2020-06-19 | 2024-09-04 | Jumpcan (Shanghai) Medical Technology Co., Ltd | Method for synthesis of roxadustat and intermediate thereof, and intermediate thereof |
| CN112194624A (en) * | 2020-11-18 | 2021-01-08 | 江苏豪森药业集团有限公司 | Crystal form of isoquinoline compound and preparation method thereof |
| CN112500344B (en) * | 2020-11-18 | 2022-07-01 | 江苏豪森药业集团有限公司 | Crystalline form of roxasistat and preparation method thereof |
| CN113956199A (en) * | 2021-06-18 | 2022-01-21 | 济川(上海)医学科技有限公司 | Impurity of Rosxastat, preparation method and application thereof |
| CN113956198A (en) * | 2021-06-18 | 2022-01-21 | 济川(上海)医学科技有限公司 | Impurity of roxasistat, preparation method and application thereof |
| CN113831284A (en) * | 2021-09-30 | 2021-12-24 | 江苏正济药业股份有限公司 | Impurity compound of intermediate of roxasistat and preparation method and application thereof |
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| EP2357175A1 (en) * | 2003-06-06 | 2011-08-17 | Fibrogen, Inc. | isoquinoline derivatives AND THEIR USE IN INCREASING ENDOGENEOUS ERYTHROPOIETIN |
| KR102029951B1 (en) * | 2011-07-22 | 2019-11-08 | 베이징 베타 파머수티컬 컴퍼니 리미티드 | Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereof |
| CN103387561B (en) * | 2012-05-10 | 2015-08-19 | 常州市第四制药厂有限公司 | 6,7-dimethoxy-benzo [d] [1,3] dioxine-2,4-diketone and preparation method thereof |
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