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CAS No. : | 1421312-34-6 | MDL No. : | MFCD30489347 |
Formula : | C18H15NO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WJGPMRFWBJZJOQ-UHFFFAOYSA-N |
M.W : | 309.32 | Pubchem ID : | 71244895 |
Synonyms : |
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Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.42 g | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane at 20℃; for 51h; Inert atmosphere; Reflux; | 1 Synthesis of Compound 7 Under N2 atmosphere, Compound 6 (1 .41 g), dioxane (20 mL), rdj Pii ).Π )φ (0.49 g), .2CO3 (1.78 g) and trimethyl borane (0.54 g) were stirred mixed and heated to reflux for 3 hrs., then stirred at room temperature for 48 hrs. After concentration, the resulting mixture was extracted with ethyl acetate, washed with water, dried and filtered, then distilled on a rotary evaporator, followed by further purification through chromatography, to obtain 0.42 g of Compound 7. |
0.42 g | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane at 20℃; for 51h; Inert atmosphere; Reflux; | 1 Synthesis of Compound 7 Under N2 atmosphere, Compound 6 (1.41 g), dioxane (20 mL), Pd[P(C6H5)3]4 (0.49 g), K2CO3 (1.78 g) and trimethyl borane (0.54 g) were stirred mixed and heated to reflux for 3 hrs., then stirred at room temperature for 48 hrs. After concentration, the resulting mixture was extracted with ethyl acetate, washed with water, dried and filtered, then distilled, on a rotary evaporator, followed by further purification through chromatography, to obtain 0.42 g of Compound 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: acetic anhydride; acetic acid / 3 h / Resolution of racemate 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / tetrahydrofuran / 1 h / 20 °C 3: hydrogenchloride / methanol; water / 4 h / 60 °C 4: trichlorophosphate / 3 h / 70 °C 5: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 51 h / 20 °C / Inert atmosphere; Reflux | ||
Multi-step reaction with 5 steps 1: acetic anhydride / acetic acid / 3 h / Reflux 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / tetrahydrofuran / 1 h / 20 °C 3: hydrogenchloride / methanol; water / 4 h / 60 °C 4: trichlorophosphate / 3 h / 70 °C 5: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 51 h / 20 °C / Inert atmosphere; Reflux | ||
Multi-step reaction with 5 steps 1: acetic acid; acetic anhydride / 3 h / Reflux 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / tetrahydrofuran / 1 h / 20 °C 3: hydrogenchloride / methanol; water / 4 h / 60 °C 4: trichlorophosphate / 3 h / 70 °C 5: tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 48 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: trichlorophosphate / 3 h / 70 °C 2: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 51 h / 20 °C / Inert atmosphere; Reflux | ||
Multi-step reaction with 2 steps 1: trichlorophosphate / 3 h / 70 °C 2: tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 48 h / 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: trichlorophosphate; N-ethyl-N,N-diisopropylamine / toluene / 75 - 80 °C 2: iron halide / tetrahydrofuran / -10 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: sodium hydroxide / ethanol / 1.5 h / Reflux 2: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / 20 °C 3: sodium hydroxide / tetrahydrofuran / 1 h / 20 °C | ||
Multi-step reaction with 3 steps 1: sodium hydroxide; ethanol / 1.5 h / Reflux 2: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; bis(isopropyl)ethylamine / dichloromethane / 3 h / 20 °C 3: sodium hydroxide / tetrahydrofuran / 1 h / 20 °C | ||
Multi-step reaction with 3 steps 1: sodium hydroxide; ethanol / 1.5 h / Reflux 2: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / 20 °C 3: sodium hydroxide / tetrahydrofuran / 1 h / 20 °C |
Multi-step reaction with 3 steps 1: ethanol; sodium hydroxide / 30 - 55 °C 2: triethylamine; N-ethyl-N,N-diisopropylamine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 3: hydrogenchloride / water | ||
Multi-step reaction with 3 steps 1.1: lithium hydroxide / methanol / 50 - 55 °C 2.1: triethylamine / dichloromethane 2.2: 0 - 20 °C 3.1: toluene / 20 °C | ||
Multi-step reaction with 3 steps 1: lithium hydroxide; methanol / 50 - 55 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; triethylamine / dichloromethane; water / 40 °C 3: sodium hydroxide; water / methanol / 6 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With methanol; lithium hydroxide at 50 - 55℃; | 3 Example 3 Preparation of Compound D Weigh 3.1 g of Compound C in a three-necked flask containing methanol solution.8 ml of a 20% lithium hydroxide solution was added, and the mixture was heated to 50 to 55 ° C for 10 to 16 hours.At the end of the reaction, concentrate and swirl off most of the methanol, slowly add dilute hydrochloric acid (2N) to adjust the pH to 4-5, and beat for 1 hour.Filtration, washing with water, and collecting solid were dried to give Compound D (yield: 95.0%, purity 97.9%). |
94% | With lithium hydroxide In methanol at 50 - 55℃; | 12 Example 12 Compound 6a (30.93 g, 100 mmol) was added to a three-necked flask. Add methanol (155 mL) to dissolve, Add lithium hydroxide solution (20%, 80 mL), The mixture is heated to an internal temperature of 50 to 55 ° C for 10 to 16 hours. At the end of the reaction, concentrate and vortex off most of the methanol. Slowly add dilute hydrochloric acid (2N) to adjust the pH to 4-5.Beat for 1 hour, filter, wash, The solid was collected to give Compound 7 (27.76 g, yield 94%). |
0.5 g | With sodium hydroxide In ethanol for 1.5h; Reflux; | 1 Synthesis of Compound 8 Compound 7 (1.02 g) was added into the mixture of etiianol (10 mL) and 2N of NaOH (10 mL), and refluxed for 1.5 hrs. After removing the impurities by filtration, the resulting mixture was distilled to remove ethanol on a rotary evaporator. The resulting pale yellow precipitate was then filtered, washed with water, and dried to obtain 0.5 g of Compound 8. |
0.5 g | With ethanol; sodium hydroxide for 1.5h; Reflux; | 1 Synthesis of Compound 8 Compound 7 (1.02 g) was added into the mixture of ethanol (10 mL) and 2N of NaOH (10 mL), and refluxed for 1.5 hrs. After removing the impurities by filtration, the resulting mixture was distilled to remove ethanol on a rotary evaporator. The resulting pale yellow precipitate was then filtered, washed with water, and dried to obtain 0.5 of Compound 8. |
0.5 g | With ethanol; sodium hydroxide for 1.5h; Reflux; | 1 Synthesis of Compound 8 1.02 g of compound 7 was added to a mixture of 10 ml of ethanol and 10 ml of 2 mol / L of sodium hydroxide and refluxed for 1.5 hours. After filtering off a small amount of impurities, ethanol was removed to give a pale yellow solid which was filtered and washed with water to give 0.5 g of compound 8. |
17.3 g | With ethanol; sodium hydroxide at 30 - 55℃; | 1.5 Example 1 In step (4), 19.6 g of (1-methyl-7-phenoxy-3,4-hydroxy-3-isoquinoline)carbonyl methyl ester 6 is added to 600 ml of an ethanol solution of sodium hydroxide. Heated to 30-55°C, hydrolysis reaction occurs.(1-methyl-7-phenoxy-4-hydroxy-3-isoquinoline)carboxylic acid 717.3 g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sodium hydroxide / ethanol / 1.5 h / Reflux 2: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / 20 °C | ||
Multi-step reaction with 2 steps 1: sodium hydroxide; ethanol / 1.5 h / Reflux 2: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; bis(isopropyl)ethylamine / dichloromethane / 3 h / 20 °C | ||
Multi-step reaction with 2 steps 1: sodium hydroxide; ethanol / 1.5 h / Reflux 2: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / 20 °C |
Multi-step reaction with 2 steps 1: ethanol; sodium hydroxide / 30 - 55 °C 2: triethylamine; N-ethyl-N,N-diisopropylamine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate | ||
Multi-step reaction with 2 steps 1: dmap / methanol / 100 °C / Sealed tube 2: sulfuric acid / Reflux | ||
Multi-step reaction with 2 steps 1: lithium hydroxide; methanol / 50 - 55 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; triethylamine / dichloromethane; water / 40 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium methylate In methanol at 120℃; for 0.5h; Microwave irradiation; | 108.b 3-[(4-Hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-propionic acid 3-[(4-Hydroxy-l-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino] '-propionic acid [0394] A mixture of 4-hydroxy-l-methyl-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (120 mg, 0.39 mmol) and beta-alanine (242 mg, 2.72 mmol) in 0.5 M NaOMe / MeOH solution (4.5 mL, 2.25 mmol) was microwaved at 120 °C for 30 min. Reaction mixture was concentrated and dissolved in water (100 mL). It was acidified by 1 N HC1 to pH = 3-4. Gummy precipitate was collected by filtration and dissolved in EtOAc. It was dried over MgS04, filtered and concentrated to provide the title compound 1 16 mg (0.32 mmol) in 81% yield. LC-MS ESI-: 365.16 (M-l) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With resin-bound Pd(PPh3)2Cl2 In 1-methyl-pyrrolidin-2-one at 130℃; for 3h; | 108.a 4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester To a mixture of l-bromo-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (500 mg, 1.34 mmol) in N-methylpyrrolidone (NMP) (7 mL) was added SnMe4 (358 mg, 2.0 mmol) and resin-bound-Pd(PPh3)2Cl2 (Sigma-Aldrich) (1-2 mmol/g) (40 mg, ca. 0.03 mmol). The resultant mixture was stirred in a 130 °C oil bath for 3 h. Reaction mixture was filtered and rinsed with NMP (1 mL). Filtrate was poured into water (120 mL) and stirred at room temperature until good precipitate formed. Solid was collected and rinsed with water (100 mL) and then hexanes (50 mL). Solid was dried and purified by silica gel chromatography, eluting with 2-50% EtOAc / hexanes, to provide the title compound 240 mg (0.78 mmol) in 58% yield. H NMR (200 MHz) CDC13, δ in ppm: 1 1.68 (s, 1 H), 8.37 (d, J = 9.3 Hz, 1 H), 7.48-7.08 (m, 7 H), 4.07 (s, 3 H), 2.75 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: copper(l) chloride; 2,2,6,6-tetramethylheptane-3,5-dione; caesium carbonate / 1-methyl-pyrrolidin-2-one / 64 h / 130 °C 2.1: Triphenylphosphine oxide; thionyl chloride; boric acid / Reflux 2.2: 1 h / Reflux 3.1: potassium carbonate; sodium iodide / N,N-dimethyl-formamide / 50 °C 4.1: sodium methylate / dimethyl sulfoxide; methanol / 0.5 h / 20 °C 5.1: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / 1 h / Reflux 6.1: resin-bound Pd(PPh3)2Cl2 / 1-methyl-pyrrolidin-2-one / 3 h / 130 °C | ||
Multi-step reaction with 4 steps 1.1: copper(I) bromide; acetylacetone; potassium carbonate / N,N-dimethyl-formamide / 7 h / 120 °C 2.1: hydroxylamine hydrochloride; sodium hydroxide / ethanol / 3 h / 60 °C 2.2: 4 h / 20 °C 3.1: toluene-4-sulfonic acid / toluene / 8 h / Reflux 4.1: ethylene glycol / 5 h / 190 °C | ||
Multi-step reaction with 6 steps 1.1: copper(I) bromide; potassium carbonate; acetylacetone / 1,4-dioxane / 24 h / 80 °C / Inert atmosphere 2.1: N-benzyl-N,N,N-triethylammonium chloride; boron trifluoride diethyl etherate / 5,5-dimethyl-1,3-cyclohexadiene / 0.5 h / 110 °C 2.2: 10 h / 120 °C 3.1: 1 h / 60 °C 4.1: potassium carbonate; sodium iodide / N,N-dimethyl-formamide / 2 h / 60 °C 5.1: methanol; sodium methylate / 2 h 6.1: iron(II) chloride; trifluoroacetic acid; dihydrogen peroxide / 3 h / 40 °C / Inert atmosphere |
Multi-step reaction with 4 steps 1.1: potassium carbonate; copper(I) bromide / N,N-dimethyl-formamide / 6 h / 80 - 90 °C / Inert atmosphere 2.1: acetic acid / methanol / 6 h / 35 - 50 °C 3.1: hydrogenchloride / methanol; water / 4.33 h / 30 - 40 °C 4.1: dihydrogen peroxide / acetic acid / 2.5 h / 25 °C 4.2: 1 h / 20 °C | ||
Multi-step reaction with 3 steps 1: copper(I) bromide; acetylacetone; potassium carbonate / N,N-dimethyl-formamide / 7 h / 120 °C 2: magnesium chloride / ethylene glycol / Reflux 3: N,N-dimethyl-formamide / 153 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene at 45 - 85℃; for 3h; | 1 Example 1 Preparation of the roxadustat crude product (II): add 150 ml of toluene in a 500 ml three-necked flask, and start stirring; then add 25 g of compound (I), 17.97 g of glycine; 42.27 g of DBU are added dropwise below 45°C; the temperature was raised to 80°C to 85°C and the reaction was incubated for 3 h, and the reaction end was monitored by TLC. After the reaction was completed, the temperature was lowered to 30°C to 40°C, followed by 150 ml of water, and stirred for 15 min. Separation, discarding the toluene phase, washing the aqueous phase with 100 ml of ethyl acetate once again, and separating the aqueous phase; adding 19.17 g of glacial acetic acid to the aqueous phase rapidly under stirring, adjusting pH=4, precipitation of solids, and continuing to stir for 2 hours; filtering, the filter cake was washed with purified water to pH ≈ 6, and then drained; the filter cake was transferred to a vacuum drying oven at 55°C to 60°C for vacuum drying for 12 hours to obtain crude roxadustat (II), (purity: 99.7%; yield: 95%). |
93.84% | With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 85℃; for 2h; | 1-3; 2-3 Preparation of compound 5 Compound 4 (100g, 0.323mol) and glycine (72.78g, 0.969mol) were dissolved in dioxane (500mL), and then N,N-diisopropylethylamine (DIEA) (83.49g, 0.646mol) was added , The above mixture was heated to 85°C for 2h, and the TLC plate detected that the reaction was complete. The reaction solution was lowered to room temperature and the solvent was concentrated. The solution was cleared by adding 1L of water and extracted three times with ethyl acetate. The aqueous phase was collected and adjusted with dilute hydrochloric acid to adjust the pH. The solid precipitated out slowly and filtered. 106.8g of compound 5 was obtained by drying, the total yield was 93.84%, and the HPLC purity was 99.58% |
92% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 65℃; for 6h; | 5 Example 5 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester(10g, 32.3mmol) was added to acetonitrile, DBU (65mmol) was slowly added dropwise, and then glycine (3.64g, 48.5 mmol), heated to 65°C and reacted for 6h, TLC plate detected that the reaction was complete, cooled to room temperature, adjusted the pH to weak acidity, stirred and crystallized, filtered the baking material [(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)amino]acetic acid10.5g, yield 92%, purity 99.3%. |
86.1% | Stage #1: 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester; glycine With sodium methoxide In methanol at 110℃; Sealed tube; Stage #2: With glacial acetic acid at 20℃; | |
85% | With methanol; sodium methoxide at 110℃; for 24h; | 1 Preparation of 2-(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamido)acetic acid of structural formula I Put 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (5.3g, 17mmol) of structural formula II-1 into the reaction flask,Glycine (3.83g),Methanol (30ml), methanol solution of sodium methoxide (6.12g),Warm up to 110°C,Reaction for 24h.After the reaction is over,Cool the reaction solution to room temperature,filter,Wash the filter cake once with 30ml methanol;The filter cake was dissolved in 100 ml water and washed twice with ethyl acetate (40 ml×2). Stand for layering,Remove the ethyl acetate layer,Add 5.0ml acetic acid to the water layer,Stir at room temperature for 1h,filter,The filter cake is washed once with 20ml of water,30ml acetone beating once,Vacuum filtration under reduced pressure,After drying, the target product I (5.08 g, 85%, purity 99.8%) was obtained. |
82% | With sodium methoxide In methanol Reflux; | 7 Example 7. Preparation of Rosacetita Add methanol (3 ml) to a 100 ml reaction vial.Stir,Adding compound (VII) or its tautomer or a mixture thereof (1.00 g),Glycine (0.73g),Sodium methoxide (0.38g),Warming reflux reaction,Until the reaction is complete.The reaction solution was cooled to room temperature.Filtering,Rinse with methanol,Dry in vacuum.The filter cake was dissolved in water and washed with ethyl acetate. Acetic acid was added to the aqueous layer, crystals were precipitated, stirred at room temperature, suction filtered, washed with water, washed with cold acetone, and dried in vacuo to give rosartane, yield 82%. |
70.2% | With sodium methoxide; glacial acetic acid In methanol for 16h; Reflux; | 5 Preparation of Roxadustat (Formula 4), the reaction formula is as follows: Take 20 g of 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (Formula 3) and 13 g of glycine, dissolve them in 200 ml of methanol, and add 100 g of sodium methoxide methanol solution dropwise. Warm up to reflux reaction. The reaction of the raw materials in the liquid phase is basically completed, and the time is about 16 hours. The filter cake is cooled and filtered. After drying, the filter cake is placed in a mixture of water and ethyl acetate and stirred, separated into layers, and the water phase is added dropwise. , The filter cake was refined with acetone to obtain 16g of roxadustat (formula 4), with a yield of 70.2%. The liquid chromatogram is shown in Figure 1, which shows that the purity of the target product rosastat is 99% the above, |
68.2% | With 4-dimethylaminopyridine In methanol at 100℃; Sealed tube; | 12.1; 20.1 1st step:N-aminoacetic acid-4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamide(12b) Compound 12a (300 mg, 0.97 mmol) was dissolved in methanol (5 mL)Glycine (220 mg, 2.91 mmol) was added to the above system, and after mixing, DMAP (710 mg, 5.82 mmol) was added to the above system. Seal overnight at 100 °C. LC-MS traces the completion of the reaction. After the system was cooled to room temperature, methanol was evaporated to dryness, and 10 mL of water was added, and extracted three times with DCM (10 mL). Combine the organic phases and spin dry. The title compound 12b (240 mg, 68.2%) was obtained. |
18.3% | With sodium methoxide In methanol at 110℃; Sealed tube; | 6.1 Synthesis of N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinyl)carbonyl]glycine (Compound 35). At room temperature,Sodium methoxide (1.05 g, 19.4 mmol)add to4-hydroxy-1-methyl-7-phenoxyisoquinolinyl-3-carboxylate(600 mg, 1.94 mmol)And glycine (437 mg, 5.80 mmol) in methanol (4 mL)The reaction solution was sealed at 110 ° C overnight.The reaction solution was cooled to room temperature, solid filtered, washed with methanol (cold, 5 mL) and solid dried.The solid was dissolved in 5 mL of water and extracted with ethyl acetate (5 mL).The aqueous phase was adjusted to pH with acetic acid, and the suspension was stirred at room temperature until a large amount of solid was precipitated and filtered.The filter cake was washed with water (3 x 2 mL), acetone (cold, 2 x 2 mL)Dried in vacuo to give 125 mg of a white solid in 18.3% yield, |
In methanol at 110 - 115℃; | 1 Example 1: Preparation of Roxadustat (I) 3-isoquinolinecarboxylic acid-4-hydroxy-l-methyl-7-phenoxy methyl ester (lOgm) and glycine (7.28gm) was charged in methanol. The reaction mixture was stirred for about 6 hours to about 8 hours at about 110°C to about 115°C. After completion of reaction, reaction mixture was cooled to about 25°C to about 30°C, filtered, washed with methanol and dried under vacuum to give Roxadustat disodium salt (13. lgm). The solid was dissolved in water and washed with ethyl acetate. Aqueous layer was treated with activated carbon and pH was adjusted to about 4.50 to about 5.0 using acetic acid. The solid was filtered, washed with water and air dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.7% | With hydrogenchloride; acetic acid; zinc In water at 50 - 60℃; | 2-4 The preparation of 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester, the reaction formula is as follows: Add 25g of glacial acetic acid solution containing methyl 1-((dimethylamino)methyl)-4-hydroxy-7-phenoxyisoquinolyl-3-carboxylate (Formula 2) into a 1L four-necked flask, 13g Zinc powder, stir,Then add 7.5g of 5% dilute hydrochloric acid and raise the temperature to 5060,When the raw materials in the liquid phase have basically reacted, the temperature is lowered, filtered, and the filtrate is rotary evaporated.Obtain 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (Formula 3),Its purity was 96.9%, and its yield was 87.7%. |
Multi-step reaction with 2 steps 1: 25 - 100 °C 2: palladium on activated charcoal; sodium carbonate; hydrogen / ethyl acetate / 60 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: acetic acid / 100 °C 2: sodium carbonate; palladium 10% on activated carbon; hydrogen / ethyl acetate / 80 °C |
2 g | With acetic acid; zinc at 60℃; for 4h; | 42.2 2nd step: methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (42c) Add to the acetic acid solution of methyl 1-((dimethylamino)methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (42a) (first reaction solution) at room temperature Zinc powder (7.5g, 110mmol), at this time, the heat is very strong. The reaction was then stirred at 60 ° C for 4 hours. The acetic acid was concentrated under reduced pressure, and then a mixture of ethanol/water = 1:5 was applied and then filtered to give the title compound 42c (2.0 g, yield of 60% in two steps). |
Multi-step reaction with 2 steps 1.1: 8 h / 20 - 100 °C 1.2: 0 - 20 °C 2.1: sodium carbonate; palladium on activated charcoal / ethyl acetate / 7 h / 60 °C | ||
Multi-step reaction with 2 steps 1: 12 h / 90 °C 2: sodium carbonate; hydrogen; palladium on activated charcoal / ethyl acetate / 15 h / 40 °C / 7500.75 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.23% | With palladium on activated charcoal; hydrogen; sodium carbonate In ethyl acetate at 40℃; for 15h; | 1-2 Preparation of compound 4 Add compound 3 (90g, 0.246mol), 500ml ethyl acetate, sodium carbonate (14.52g, 0.132mol), Pd/C (13.5g) into the hydrogenation reactor in sequence, and pressurize the hydrogen to 1.0MPa after nitrogen replacement. The reaction solution was heated to 40°C and reacted for 15 hours. TLC plate detected that the reaction was completed. The reaction solution was filtered and concentrated to obtain 72 g of crude compound 4, with a total yield of 95.23% and an HPLC purity of 99.61%. |
90% | With palladium on activated charcoal; hydrogen; sodium carbonate In ethyl acetate at 60℃; Inert atmosphere; | 3.f 1) Preparation of methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (3e) 102411 A reactor was charged with 3c (16.0 g), Pd/C (2.08 g), anhydrous Na2CO3 (2.56 g) and ethyl acetate (120 mL). The flask was vacuum-purged with nitrogen (3X) and vacuum-purged with hydrogen(3X). The flask was then pressurized with hydrogen and stirred at about 60 °C until completion of reaction. The flask was cooled to 20-25 °C, the pressure released to ambient, the head space purged with nitrogen three times and mixture was filtered. The filtrate was concentrated. Methanol was added. The mixture was stirred and then cooled. Product precipitated and was filtered and dried in an oven (Yield:90%, HPLC: 99.7%). |
74.3% | With palladium on activated charcoal; sodium carbonate In ethyl acetate at 60℃; for 7h; | 2.6 6th step: Methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (2h) Add methyl 1-(acetoxymethyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (2g) to the reaction flask(320 mg, 0.87 mmol),Ethyl acetate (10 mL), sodium carbonate (180 mg, 1.7 mmol),Palladium on carbon (400mg), protected by hydrogen, stirred at 60 ° C for 7 hours,After the reaction was monitored by thin layer chromatography, suction filtration and the filtrate was concentrated to dryness.The title compound (2h) (200 mg, 74.3%) was obtained. |
55.4% | With palladium 10% on activated carbon; hydrogen; sodium carbonate In ethyl acetate at 80℃; | 1.8 Synthesis of 4-hydroxy-1-methyl-7-phenoxyisoquinolinyl-3-carboxylic acid methyl ester A mixture of 1-((acetoxymethyl)methyl)-4-hydroxy-7-phenoxyisoquinolinyl-3-carboxylate(1.30 g, 3.50 mmol)Was dissolved in anhydrous ethyl acetate (26 mL)Sodium carbonate (186 mg, 1.80 mmol)And Pd / C (10%, 170 mg),The reaction solution was stirred under hydrogen at 80 ° C overnight.Cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure.The crude product was subjected to column separation to give 600 mg of a white solid in a yield of 55.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium methoxide In methanol at 40℃; for 5h; | 15 Preparation of methyl 4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinecarboxylate (VI) 2L reaction flask, methyl 2-(1-(N-methoxycarbonylmethyl(toluene-4-sulfonyl)amino)ethyl)-4-phenoxybenzoate (V, 300 g, 0.6 mol) ,Methanol (1.5 L),Stir,5 parts of sodium methoxide (65 g, 1.2 mol) was added.Heated to 40 ° C for 5 h.Concentrate the solvent to dry,Add water (1L) / glacial acetic acid (0.5L)Stir at room temperature for 1 h.filter,Washed (0.5L),Dried in vacuo (55 ° C) to afford product VI (149 g, yield 80%), |
70% | With methanol; sodium methoxide at 50℃; | 5A Synthesis of methyl 1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate: Methyl 2-(1-((N-(2-methoxy-2-oxoethyl)-4-methylphenyl)sulfonamido)ethyl)-4-phenoxybenzoate (4.88 g, 9.8 mmol) was added to the reaction flask,Then add methanol 20mL and sodium methoxide (1.59g, 29.4mmol),The temperature was raised to 50 °C and the reaction was completed by TLC detection.2N hydrochloric acid and saturated NaHCO3 aqueous solution were successively added, filtered, and the filter cake was dried to obtain the target product with a yield of 70%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.2% | With sodium methylate In deuteromethanol at 110℃; Sealed tube; | 1.9 Synthesis of N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinyl)carbonyl]-2,2-d2-glycine At room temperature,Sodium methoxide (220 mg, 4.00 mmol)Was added to a solution of methyl 4-hydroxy-1-methyl-7-phenoxyisoquinolinyl-3-carboxylate ((120 mg, 0.39 mmol)And deuterated glycine-d5 (100 mg, 1.20 mmol)Of deuterated methanol-d4 (3 mL)The reaction solution was sealed at 110 ° C overnight.The reaction solution was cooled to room temperature, solid filtered, washed with methanol (cold, 10 mL)Solid dry. The solid was dissolved in 5 mL of water and extracted with ethyl acetate (5 mL).The aqueous phase was adjusted to pH with 0.5 mL of acetic acid,The suspension was stirred at room temperature until a large amount of solid was precipitated,filter. The filter cake was washed with water (3 x 1 mL)Acetone (cold, 2 x 0.5 mL) and dried in vacuo to give 60 mg of an off-white solid in a yield of 45.2% |
Yield | Reaction Conditions | Operation in experiment |
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0.42 g | With tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane at 20℃; for 48h; Inert atmosphere; | 1 Synthesis of Compound 7 Under nitrogen protection, 1.41 g of compound 6 was added,Dioxane 20ml,0.49 g of tetrakis (triphenylphosphine) palladium,And the mixture was stirred at room temperature for 48 hours. After column chromatography, 0.42 g of compound 7 was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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85% | In ethylene glycol at 190℃; for 5h; | 7 Example 7 Preparation of methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (IV) 2L reaction flask was charged with dimethyl 2-(1-(3-phenoxyphenyl)ethylimino)malonate (III, 270 g, 0.79 mol), ethylene glycol (1L), stirring, heated to 190 ° C for 5h, the reaction was distilled off the methanol generated. After the reaction was completed, the temperature was lowered to room temperature, stirred with water (1 L) for 30 min, filtered and washed with water (0.5 L). The crude product was recrystallized from absolute ethanol (0.5 L) and dried under vacuum (55 ° C) to give the product IV (208 g, 85% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22.6 g | With hydrogenchloride; potassium iodide In water | 1.5 Example 1 21.2 g of methyl chloroformate was added to 531.2 g of 1-methyl-7-phenoxy-3,4-dihydroxy-isoquinoline produced in step (4), and 15 g of potassium iodide and hydrochloric acid solution were added thereto. 280ml, condensation reaction occurs(1-methyl-7-phenoxy-3,4-hydroxy-3-isoquinoline)Carbonyl methyl ester622.6g; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With iron halide In tetrahydrofuran at -10 - 20℃; Inert atmosphere; | 9 Example 9 into a three-necked flask added Compound 5a (32.97g, 100mmol), catalyst FeCl3 (0.96g) and tetrahydrofuran (165mL), Stir and dissolve, cool at-10~0 °C and switch nitrogen three times in vacuum, under nitrogen protection the methyl magnesium chloride solution (2.0 M, 55mL) is slowly dropped into the reaction flask, after the completion of the drop-wise addition, the temperature is raised at room temperature for 8-10 hours. At the end of the reaction, 1 mol/L dilute hydrochloric acid (200mL) is added to quench the reaction, the aqueous phase is extracted twice with ethyl acetate (165mL), and the organic phase is washed once with saturated brine (165mL), dry over anhydrous sodium sulfate, after concentration re-crystallized from petroleum ether ethyl acetate mixed solvent and then obtained compound 6a (23.51 g, 76%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia In methanol at 60℃; | 22.1 1st step: Synthesis of 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamide (22b) Compound 22a (575 mg, 1.86 mmol) was dissolved in MeOH (5 mL)Ammonia (10 mL) was added and the reaction was carried out at 60 °C. LC-MS traces the completion of the reaction. methanol was spun off, extracted with DCM (10 mL) three times, dried |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With sodium methylate In methanol Sealed tube; Heating; | 21.1; 42.3 1st step:2-(1-Methyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)propionic acid (21a) Add the starting material 1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester to a 25 mL sealed tube(300 mg, 0.97 mmol), alanine (400 mg, 3.9 mmol), 5M sodium methoxide in methanol (0.97 mL, 4.85 mmol), and methanol (6.0 mL), followed by heating to 100 ° C for 4 h. After completion of the reaction to be monitored, silica gel was added and the residue was purified by column chromatography to give the desired product (280 mg, 79%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With sodium methylate In methanol at 110℃; Sealed tube; | 2.7 7th step: N-((2H-tetrazol-5-yl)methyl)-4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamide(2) At room temperature,Methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (2h) (200mg, 0.64mmol),(2H-tetrazol-5-yl)methylamine (500mg, 3.68mmol), methanol 2mL, sodium methoxide methanol solution (1mL) was added to the sealed tube, sealed at 110 ° C overnight, and the reaction was monitored by thin layer chromatography. Filtration, the filtrate was added to DCM to precipitate a solid, and the obtained solid was purified by silica gel column chromatography.The title compound 2 (65 mg, 27%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With sodium methylate In methanol at 110℃; Sealed tube; | 3 Example 3: N-((2H-tetrazol-5-yl)methyl)-4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamide At room temperature,Methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (200 mg, 0.65 mmol),(1H-1,2,3-triazol-4-yl)methylamine (500mg, 3.68mmol), methanol 2mL, sodium methoxide methanol solution 1mL was added to the sealed tube, sealed at 110 ° C overnight, suction filtration, filtrate added A solid precipitated from DCM, and the obtained solid was purified by silica gel column chromatography.The title compound 3 (75 mg, 30%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With dmap In methanol at 100℃; Sealed tube; | 7 Example 7: N-(2-cyanopropyl)-4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamide (Compound 7) Compound 7a (120 mg, 0.39 mmol) was dissolved in methanol (3 mL)2-Cyanopropylamine (98 mg, 1.95 mmol) was added to the above system, and after mixing, DMAP (285 mg, 2.34 mmol) was added to the above system. Sealed at 100 ° C overnight. LC-MS traces the completion of the reaction.The reaction solution was concentrated and separated by column chromatography to give the title compound 7(60 mg, 43%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.2% | With dmap In methanol at 100℃; Sealed tube; | 5 Example 5: N-(2-oxoaminoethyl)-4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamide(Compound 5) Compound 5a (120 mg, 0.39 mmol) was dissolved in MeOH (3 mL).0.79 mmol) was added to the above system, and after mixing, DMAP (568 mg, 4.66 mmol) was added to the above system. Sealed at 100 ° C overnight. LC-MS traces the completion of the reaction. After the system was cooled to room temperature, methanol was removed by rotary evaporation, 10 mL of water was added, and extracted three times with DCM (10 mL). The organic phases were combined and evaporated to dryness. The title compound 5 (36 mg, 26.2%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | In methanol at 100℃; for 4h; Sealed tube; | 9.1 1st step: N-(2-Aminoethyl)-4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamide (9a) Add the starting material 1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester to a 25 mL sealed tube(80 mg, 0.32 mmol), ethylenediamine (250 mg, 5.2 mmol), methanol 15.0 mL, then heated to 100 ° C for 4 h. After completion of the reaction to be monitored, silica gel was added and the mixture was purified by column chromatography to give the objective product (50 mg, 57%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.2% | With sodium methylate In methanol at 100℃; Sealed tube; | 6 Example 6: N-(2-hydroxypropyl)-4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamide (Compound 6) Compound 6a (150 mg, 0.49 mmol) was dissolved in MeOH (3 mL).After the above system was added, after mixing, sodium methoxide (324 mg, 6.00 mmol) was added to the above system. Sealed at 100 ° C overnight. LCMS followed up to detect the completion of the reaction. After the system was cooled to room temperature, methanol was removed by rotary evaporation, 10 mL of water was added, pH was adjusted to 3-4 with diluted hydrochloric acid, and extracted three times with DCM (10 mL). The organic phases were combined and evaporated to dryness. The title compound 6 (40 mg, 23.2%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap In methanol at 100℃; Sealed tube; | 10.1 1st step: N-(5-amino-4H-1,2,4-triazol-3-methyl)-4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamide Compound 10a (150 mg, 0.49 mmol) was dissolved in methanol (3 mL) amine(364 mg, 2.43 mmol) After the above system was added, after mixing, DMAP (711 mg, 5.83 mmol) was added to the above system. Sealed at 100 ° C overnight reaction. LC-MS traces the completion of the reaction. After cooling the system to room temperature, the methanol was removed by rotary evaporation and taken twice with DCM (10 mL).The concentrate is ready for use. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With triethylamine In toluene for 48h; Reflux; Inert atmosphere; | 5 Example 5. Preparation of Formula (VII) or Its Tautomers or Mixtures thereof Add dry toluene (10 ml) to a 100 ml reaction vial.Under stirring, the compound (V) (2.00 g), the compound (VI) (2.90 g), and triethylamine (0.40 g) were added, and the reaction was refluxed for 2 days under nitrogen. After cooling to room temperature, it was added to silica gel for adsorption for 1 hour. After suction filtration, the filtrate was concentrated to dryness, and then, 10 ml of methanol was added, and the mixture was stirred and crystallized to give a white solid (1.81 g, yield: 74%). Column chromatography (methylene chloride / n-hexane 3/7) gave compound (VII). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: glycine ethyl ester hydrochloride With triethylamine In toluene at 20℃; Stage #2: C16H14O4 With boron trifluoride In tetrahydrofuran at 0 - 20℃; | 1.5 (5) Synthesis of Compound A Glycine methyl ester hydrochloride (1.5 g, 12.0 mmol) and 30 ml of toluene were added to the reaction flask.Triethylamine (4 ml) was added with stirring and stirred at room temperature overnight.Filtration, the filtrate was transferred to another reaction vial and compound IV (1.6 g, 6.0 mmol) was added.The mixture was cooled to 0 ° C, and a solution of 0.5 ml of boron trifluoride in tetrahydrofuran was added, followed by stirring at room temperature overnight.Add water to quench the reaction,The organic phase was washed with a saturated aqueous solution of sodium bicarbonate, water and brine and dried over anhydrous sodium sulfate.Filtration and removal of the solvent under reduced pressure gave the residue in 15 ml of methanol.After cooling to 0 ° C, sodium methoxide (0.5 g, 9 mmol) was added portionwise, and the mixture was stirred at room temperature overnight.It was concentrated to dryness under reduced pressure, and a mixture solution of water and acetic acid was added and stirred for 2 hours.Filtration, washing with water and drying in vacuo gave Compound A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.3% | With N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | 2 Example 2 Preparation of Compound C: Weigh 1.0 g of compound B, 0.1 g of ferric chloride, and 0.1 g of a ligand catalyst (TMEDA) into a three-necked flask.Add 10 mL of anhydrous tetrahydrofuran solution, replace with argon three times, and cool the ice salt bath to below 0 °C.1.25 ml of 3 mol/L methyl magnesium chloride solution was slowly added dropwise, and the reaction was allowed to shift to room temperature for 8 to 10 hours. At the end of the reaction, 1 mol/L of dilute hydrochloric acid was added to quench the reaction.The aqueous phase was extracted twice with ethyl acetate.After concentration, it was recrystallized from petroleum ether ethyl acetate mixed solvent to give Compound C (0.85 g, yield: 91.3%, purity 99.1%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.01% | With potassium phosphate tribasic heptahydrate; palladium diacetate; tricyclohexylphosphine In toluene at 90 - 110℃; for 8h; Inert atmosphere; | 2.1; 2.3; 2.6 Method 1: Add toluene (5.2L) to the reaction bottle, start stirring, and after deoxygenation under nitrogen for 30min,Under nitrogen protection, methyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (200.0g, 0.53mol) was added in sequence.Palladium acetate (12.0g, 0.053mol), tricyclohexylphosphorus (29.9g, 0.10mol), potassium phosphate heptahydrate (904.0g, 2.65mol) and trimethylcyclotriboroxane (300ml, 1.06mol), feed After the end, the reaction was carried out at 90-110 ° C for 8h.After the reaction is completed, the temperature is lowered to 0-10 ° C, 5.2L of isopropyl acetate is added, 3.3L of 1mol / L hydrochloric acid is added, the pH is adjusted to 6.0-8.0, and the extraction operation is performed.The aqueous phase was extracted once with dichloromethane (5.2L), the organic phases were combined and concentrated under reduced pressure,After column purification (eluent: n-heptane / dichloromethane / ethyl acetate volume ratio is 1: 1: 2),1-Methyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (145.4 g, yield 88.01%, purity 99.83%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.01% | With potassium phosphate tribasic heptahydrate; palladium diacetate; tricyclohexylphosphine In toluene at 90 - 110℃; for 8h; Inert atmosphere; | 2.2; 2.4-2.5 Method 2: Add toluene (104mL) to the reaction bottle, start stirring,Under nitrogen protection, methyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (4.00 g, 10.60 mmol) was added in sequence,Palladium acetate (0.24g, 1.06mmol), tricyclohexyl phosphorus (0.60g, 2.12mmol), potassium phosphate heptahydrate (18.08g, 53.00mmol) and methylboronic acid (3.81g, 63.60mmol) Reaction at 90 110 for 8h.After the reaction is completed, the temperature is lowered to 0-10 ° C, 104 mL of isopropyl acetate is added, 1 mol / L hydrochloric acid is added, the pH is adjusted to 6.0-8.0, and the extraction operation is performed.The aqueous phase was extracted once with 104 mL of dichloromethane, and the organic phases were combined and concentrated under reduced pressure.After column purification (eluent: n-heptane / dichloromethane / ethyl acetate volume ratio is 1: 1: 2),1-Methyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (2.89 g, yield 85.01%, purity 99.82%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: methyl 2-amino-3-oxo-3-(4-phenoxyphenyl)propionate; acetyl chloride With triethylamine In toluene at 0 - 50℃; for 3h; Stage #2: With trichlorophosphate In toluene for 6h; Reflux; | 2 Synthesis of methyl 4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinecarboxylate (Formula I) In a round bottom flask equipped with mechanical stirring, 80g (0.28mol, 1.0eq) of methyl 2-amino-3-oxo-3-(4-phenoxyphenyl)propionate participating in the reaction was sequentially added,43g of triethylamine (0.42mol, 1.5eq), 800mL of toluene, lower the temperature of the reaction system to 0°C, slowly add dropwise a solution of 200mL of toluene with 23g of acetyl chloride dissolved, and control the temperature of the reaction to not exceed 10°CAfter the addition, the temperature was raised to 50°C and refluxed for 3 hours, the triethylamine hydrochloride was removed by filtration, and 218g (1.4mol, 5.0eq) of phosphorus oxychloride was slowly removed.Heat to reflux and react for 6 hours, cool to room temperature, remove the solvent under reduced pressure, collect the filter cake, add 500 mL of 2.0M sodium hydroxide to the filter cake, stir for 15 minutes, filter, and wash the filter cake twice with water 500 mL*2 to get wet The product was dried by blowing at 40°C to obtain an off-white methyl 4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinecarboxylate solid 61g, with a yield of 71% and a purity of 99.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.9% | With trichlorophosphate In N,N-dimethyl-formamide for 6h; Reflux; | 1 Synthesis of methyl 4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinecarboxylate (Formula I) In a round-bottom flask equipped with mechanical stirring, 120 g (0.36mol, 1.0eq) of methyl 2-acetamido-3-oxo-3-(4-phenoxyphenyl)propionate, N,N- Dimethylformamide 1000mL, phosphorus oxychloride 112g (0.72mol, 2.0eq), heated to reflux for 6 hours, cooled to room temperature, the solvent was removed under reduced pressure, the filter cake was collected, and 2.0M hydroxide was added to the filter cake Stir 500mL of sodium for 15 minutes, filter, and wash the filter cake twice with 1000mL*2 of water to obtain a wet product.It was dried by blowing at 40°C to obtain an off-white methyl 4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinecarboxylate solid 105g, with a yield of 92.9% and a purity of 98.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester With dihydrogen peroxide In acetic acid at 25℃; for 2.5h; Stage #2: With sodium sulfite In water; acetic acid at 20℃; for 1h; | 10; 11 A preparation process of rosarestat intermediate 1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (compound 1 in formula III, hereinafter referred to as compound 1), details as follows: Compound 14 (29.3 g, 0.1 mol) was added to 150 mL of acetic acid,Stir, add 30% hydrogen peroxide (18g, 0.16mol) dropwise at 25°C,After 30min, react at 25 for 2h;Add 30 mL of 40% sodium sulfite aqueous solution dropwise to the reaction solution,Stir at room temperature for 1 hour; concentrate and dry the reaction solution under reduced pressure to obtain a brown oil;Add 40mL of isopropanol and stir for 15min at 40-50,Stir and cool to room temperature to precipitate a solid, filter with suction, and bake at 50°C for 3h,The off-white solid compound 1 (26.8 g, 87%) was obtained. |
42.4% | Stage #1: 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0℃; Stage #2: With sodium acetate; acetic anhydride; acetic acid In dichloromethane at 75℃; | 21-22 Example 21 Preparation of methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (I-a) Add methyl 1-methyl-7-phenoxyisoquinoline-3-carboxylate (2.933g, 10mmol) and 30mL of dichloromethane into a 100mL two-necked flask with magnetic stirring and a thermometer to reduce the system At 0° C. m-chloroperoxybenzoic acid (2.07 g, 12 mmol) was added in batches. After the addition, the temperature was raised to room temperature for reaction, and the reaction was monitored by TLC. It was quenched by adding saturated sodium thiosulfate solution, washed with saturated brine, dried, filtered and concentrated, dissolved in a mixture of acetic acid (15mL) and acetic anhydride (30mL), sodium acetate (984mg, 12mmol) was added, and the temperature was raised to 75°C , TLC monitors the completion of the reaction. Concentrate under reduced pressure, add 20 mL of water and basify with ammonia, extract with ethyl acetate (2×20 mL), take the organic phase, wash with water, dry, filter, concentrate and mix with 2% hydrochloric acid and methanol In the solution, reflux the reaction, TLC monitors the end of the reaction, Adjust the pH to neutral with sodium bicarbonate solution, filter, and recrystallize with isopropanol to obtain a white solid The methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (I-a) was 1.311 g, the yield was 42.4%, and the product purity was 98.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With dihydrogen peroxide; trifluoroacetic acid; iron(II) chloride at 40℃; for 3h; Inert atmosphere; | 1 Preparation of 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester of structural formula II-1 Under N2 protection, add 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (12g, 40mmol), FeCl2 (2.5g), trifluoroacetic acid (7g) and DMSO ( Dimethyl sulfoxide, 200 mL). After the temperature of the reaction mixture rises to 40°C, 30% H2O2 (18g) is slowly added dropwise. After reaction for 2h, 18gH2O2 is added and the reaction is continued for 1h. After the reaction is completed, the above mixture is cooled to room temperature, and triethylamine is slowly added to the above reaction flask to adjust the pH to neutral. The above reaction solution was diluted by adding H2O (100mL), and then extracted three times with ethyl acetate (50mLx3), combined the organic layers, added activated carbon and stirred for 30 minutes, filtered, the filtrate was evaporated to dryness under reduced pressure, the residue was slurried with methanol, filtered and dried The target product II-1 (10.6 g, yield 85%, purity 99.5%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In methanol; water; toluene at 100℃; for 5h; Inert atmosphere; Large scale; | 1-3 In a 30L double-layer glass reactor, 7kg of toluene, 3kg of methanol, 3kg of purified water,405g compound 5 , 200g Methyl boronic acid pinacol ester and 250g anhydrous potassium carbonate.Add 40 g of tetrakis (triphenylphosphine) palladium under the protection of nitrogen, increase the temperature to 100°C±5°C, and react for 5 hours.Oil and water were separated, the organic phase was filtered with 400 g of diatomaceous earth, and toluene in the organic phase was recovered under reduced pressure to obtain a crude product of the concentrate compound 6.Add 7kg methanol, 2kg purified water, 30L double-layer glass reactorThe crude compound 6 is heated and refluxed until it is clear and filtered while it is hot.The filtrate was slowly cooled to 0°C±5°C for crystallization overnight, filtered and washed, and the filter cake was air-dried to obtain 295g of compound 6 fine product.The yield was 77%, the maximum single impurity was 0.06%, the total impurity was 0.4%, the purity was 99.6%, and the heavy metal content was not detected. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.7% | With sulfuric acid; dihydrogen peroxide; iron(II) sulfate; acetic acid In water at -25 - -5℃; for 3h; | 1 Example 1 Mix 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (compound of formula 1a-1) (10g, 33.9mmol) and acetic acid (100ml), slowly add ferrous sulfate (68mmol) in sulfuric acid Aqueous solution (dissolve ferrous sulfate with 100ml of water, add 50ml of concentrated sulfuric acid dropwise under ice bath to obtain ferrous sulfate aqueous solution of sulfuric acid), then cool to -25°C and add acetaldehyde (340mmol), control temperature from -25°C ~ -15°C After adding hydrogen peroxide (68mmol), the temperature was controlled at -15°C ~-5°C and reacted for 3h. TLC plate detected that the reaction was completed. Add sodium thiosulfate aqueous solution and stir, add dichloromethane for extraction, and concentrate the organic phase to obtain 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (compound of formula 2a-1) was 9.5 g, yield was 90.7%, and purity determined by HPLC was 98.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.3% | In N,N-dimethyl-formamide at 153℃; | 7 Preparation of 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline methyl carboxylate Add (E) 2-((1-(3-phenoxyphenyl)ethylene)amino) dimethyl malonate (240g, 0.7mol), DMF (1.5L), and stir in a 2L reaction flask. The temperature was raised to 153°C and the reaction was completed.Cool to room temperature, add water (2.4L) and stir for 30min, filter with suction to obtain the crude product, add absolute ethanol (0.72L) to recrystallize the crude product, and vacuum dry to obtain the product (185.5g, yield 85.3%)HPLC: 99.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With hydrogen bromide; acetic acid; phenol for 3h; | 6 Example 6: Synthesis of compound 13 To a round-bottom flask were added compound 12 (0.13 g), 33% HBr-AcOH solution (1 mL) and phenol (26 mg). The reaction mixture was stirred for 3 h. EtOAc (20 mL) was added, and the layers were separated. The organic phase was washed with 20% potassium carbonate aqueous solution. The organic phase was concentrated to dryness. The crude product was purified by silica gel column chromatography eluting with EtOAc/heptane=l/5 to give compound 13 as a light-yellow solid (10 mg, 11% yield, 98.0% purity). NMR (400 MHz, CDCh) d 11.71 (s, 1H), 8.42-8.40 (m, 1H), 7.52-7.42 (m, 4H), 7.28-7.23 (m, 1H), 7.16-7.13 (m, 2H), 4.10 (s, 3H), 2.77 (s, 3H).Mass: [M+H]+: 310.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.1 g | With potassium hydroxide In methanol; water Reflux; | 1-3 Preparation of compounds of formula I: Methyl 1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate 10.0g(II) was added to a 100ml reaction bottle, methanol 20ml was added, and a previously configured aqueous potassium hydroxide solution (potassium hydroxide 8.65g dissolved in 20ml water) was heated to reflux, insulation overnight, TLC detected that there was no raw material left; added 5.6g hydrochloric acid to adjust the pH to 7-8. Concentrated reaction solution, add 30ml of ethyl acetate, add 15ml of water to extract layering, concentrate ethyl acetate phase, give Compound I crude product 5.8g, yield 84.9%, HPLC purity: 75.2%; Compound I crude product 5.8g was added to a 100ml three-mouth bottle, added 10ml tetrahydrofuran, heated to 65 degrees, stirred to dissolve, dropwise add n-heptane 20ml, cooled to 0 ° C; filtration, concentration, to give Compound I purified product 4.1g, recovery rate of 70.6%, HPLC purity: 95.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With methanol; sodium methoxide at 50℃; | 5D Synthesis of methyl 1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate: Methyl 2-(1-((N-(2-methoxy-2-oxoethyl)-4-chlorophenyl)sulfonamido)ethyl)-4-phenoxybenzoate (5.06g , 9.77mmol) was added to the reaction flask, then 20mL of methanol and sodium methoxide (1.58g, 29.31mmol) were added, the temperature was raised to 50°C and the reaction was completed until TLC detected that the reaction was complete, followed by adding 2N hydrochloric acid and saturated NaHCO Aqueous solution, filtered, and the filter cake was dried to obtain The target product, the yield is 70%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.6% | In methanol at 105 - 115℃; for 8h; Sealed tube; | 1.1.6 1.6 Synthesis of Roxadustat Add 15.0 g (about 0.05 mol) of intermediate 9 to methanol (150 g), then add 14.1 g of sodium glycinate, seal and heat to 105°C-115°C in a pressure-resistant container, and stir for 8 hours. The reaction solution was cooled to room temperature, filtered with suction, washed with a small amount of methanol, and then drained to obtain a crude roxadustat sodium salt product. The crude product of roxadustat sodium salt was dissolved in 90 mL of water, and the aqueous phase was washed with 40 mL of ethyl acetate. Slowly add acetic acid to the aqueous phase, adjust pH<7, a large amount of solid is precipitated, suction filtration, wash the filter cake, and vacuum dry the baking material to obtain 14.1 g of roxadustat finished product with a yield of 82.6% and a purity of 99.47%. |
78% | With methanol at 60℃; | 6 Synthesis of Noshasta: 1-Methyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (2.00 g, 6.47 mmol) was added to the reaction flask,Then add methanol 10mL and sodium glycinate (1.88g, 19.40mmol),The temperature was raised to 60 °C and the reaction was completed until TLC detected that the reaction was complete.The pH was adjusted to about 4 with hydrochloric acid, and the target product was obtained by filtration with a yield of 78% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.4% | With glacial acetic acid; zinc powder at 50 - 60℃; for 3h; | 2.2.3 2.3 Synthesis of Intermediate 9 1.5 g (about 0.0046 mol) of intermediate M2-2 was dissolved in acetic acid (15 mL), 0.81 g of zinc powder was added, heated to 50°C-60°C, and stirred for 3 hours. The completion of the reaction was monitored by TLC, the reaction solution was filtered, and the filter cake was washed twice with a mixed solvent of dichloromethane (10 mL) and methanol (5 mL). The filtrates were combined and concentrated to a volume of about 2-3mL of the concentrated solution. The added isopropanol (3mL) and water (6mL) were filtered with suction after stirring. The filter cake was in methanol/water (1:3/v:v, 9mL). ), and suction filtration to obtain 1.1 g of intermediate 9 with a yield of 74.4% and a purity of 96.23%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.3% | With glacial acetic acid; zinc powder at 50 - 60℃; for 6h; | 1.1.5 1.5 Synthesis of Intermediate 9 Dissolve 25.0 g (about 0.074 mol) of intermediate M2-1 with acetic acid (250 g), add 26.1 g of zinc powder, heat to 50°C-60°C, and stir for 6 hours. TLC monitored the completion of the reaction, the reaction solution was filtered, and the filter cake was washed twice with a mixed solvent of dichloromethane (50 mL) and methanol (25 mL). After the filtrates were combined, the concentrated solution was concentrated to a volume of about 10-15mL, isopropanol (25mL) and water (50mL) were added, and after stirring, suction filtration was performed, and the filter cake was in methanol/water (1:3/v:v, 75mL) Medium beating, suction filtration, and vacuum drying of the filter cake to obtain 15.6 g of a brown solid with a yield of 75.3% and a purity of 96.57%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In 2-methoxy-ethanol at 110℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.6% | With potassium carbonate; copper(II) bromide In N,N-dimethyl-formamide at 90 - 100℃; for 16h; Inert atmosphere; | 16-18 Preparation of methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (B): DMF (500mL) was put into a 1L reaction flask, followed by 4-hydroxy-1-methyl-7-bromo-isoquinoline-3-carboxylate methyl ester (59.2g, 0.2mol), phenol (20.7g, 0.22mol), cuprous bromide (5.7g, 0.04mol), and potassium carbonate (82.8g, 0.6mol), replaced by nitrogen three times, heated to 90~100 for 16h, after the reaction was completed, water was added to the reaction solution and stirred After 1 h, filter, the filter cake was dissolved in ethyl acetate under reflux, decolorized by activated carbon, and filtered with suction. The filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by tetrahydrofuran to obtain B (45.5 g, 73.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.7% | With ammonium peroxodisulphate; silver(I) nitrate; trifluoroacetic acid In tetrahydrofuran; lithium hydroxide monohydrate at 60℃; for 5h; Inert atmosphere; | 1-6 (a) Take 100g of 4-hydroxy-7-phenoxyisoquinoline-3-carboxymethyl ester (Compound I) dissolved in 1kg of tetrahydrofuran, under nitrogen protection, add 17g of silver nitrate, 16.5g of trifluoroacetic acid, 50g of water and 81g of acetic acid, heated to 60 ° C, and then add ammonium persulfate solution dropwise (385g of ammonium persulfate dissolved in 700g of water), drip after stirring, stirring for 5 hours, so that the reaction system temperature control at about 5 °C.(b) Add 500g of 20% sodium carbonate solution dropwise to terminate the reaction, then add 1kg of ethyl acetate, and after 20 minutes of resting, separate the aqueous phase.(c) Wash the organic phase with 150g of saturated brine once, separate the aqueous phase, concentrate 150g of organic solvent under reduced pressure, then add 100g of ethyl acetate to heat and dissolve, slowly cool down to 20 °C, filter, dry under reduced pressure at 45 °C, and produce 95g of compound II., yield 90.7%. |
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