ROKSADUSTAT? A NEW STABLE CRYSTAL FORM AND PREPARATION METHOD

Abstract

The present invention relates to a novel crystalline form of Roxadustat, with the chemical name 2-[(4-Hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid, and to a method for preparing the stable crystalline polymorph of the said compound, "Form X".

Description

1 ROKS FORM AND PREPARATION Technical Area Existing -[(4-Hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-5 Roxadustat, a new crystalline form of acetic acid. crystalline Roxadustat (b prolyl hydroxylases or HIF-10 Roxadustat is chemically 2-[(4-Hydroxy-l-methyl-7-phenoxy- isoquinoline-3-carbonyl)-amino]- I Arend et al., character - - process Witschi et al., patent WO2014014835, b20 crystalline Roxadustat Form A, Form B (hemihydrate), Form C (hexafluoropropan-2-ol solvate), Form D (DMSO: Water co-solvate), Sodium salt, Potassium salt, L-arginine salt, L-lysine salt, Ethanolamine salt, diethanolamine salt, tromethamine salt, hydrochloric acid salt, S M Amorphous form, bis-TEA (triethylamine) salt, hemi Calcium and 25 M Li et al., in patent WO2020135058A1, described 12 crystals from b-A to ARZ-L. 2 ARZ-L crystal form, b process Kallem et al., number WO2019030711, b - - Formic acid: Water co- in 5 - numa Jinchao et al., in the patent -proline co- crystal form (E, F, G, H). 10 Chen et al., WO2021077994A1, b anhydrous crystalline form (form Due to the remote processes, These matters are Roksadustat Therefore, the current 20 ks ks ks Roksadustat 25 Technical Problem 3 Polymorphism, to possess in physical A specific It is necessary. It is preferred. 15 ks20 The problem ks anhydrous anhydrous Form X, 3..2, 6..2, 11..2, 12..2, 13.02 .2, 16. .2, 16. .2, 18. .2, 24. .2 and 26.89 .2 degrees 2-theta 4 b in b 10 -propanol, 1-propanol, 1-b tanol, 2- b tanol, tert- -pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, β-tanone, 2-pentanone, 3- acetate, ethyl acetate, propyl acetate, tert-15 diisopropyl ether, tert- -dioxane, 2- methoxyethanol, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), N-methylpyrrolidone reflex (b), 16 hours .00 2. 25 cost-effective Suitable. 30 of b in 5 of Stability, closing system. limit10 of In this context, crystalline in 25 The crystalline element is referred to here. hydration or dehydration, na Roks' stability X- 6 of crystalline in in stability of -5 - Crystalline of Table 1, and 60% . 0.14% and Form . Table 1. Roxadustat Test Acceptance Criteria* Form X Form A** 6 Months* 6 Months* White, k white K white K white K white PXRD Suitable Suitable Suitable Suitable Determination (HPLC) (on anhydrous basis) 98.0-102% 99.90% 99.86% 99.76% 99.71% * % . ** . decomposition decomposition 25 7 Thermal . It was determined to be 0.46%. . . 10 . .34 a little more Table 2. Stress Parameters Stress Wait Form X : 99.90% Form A* 99.76% Thermal Decomposition 15% 99.81% 99.54% in decomposition sine (At least ) 99.86% 99.70% UV I Decomposition ICH Q1B sine (at least 200) watt hours / square meter UV energy) 99.88% 99.66% * 15 n 8 this air It can remain. ideal storage : b -I Dust K b -I Dust K b10 b Z Total YDK (ATR- b - b - 15 b -I Dust K % Device parameters: NMR: to protons (DMSO-d6) and (DMSO-d6) , , . FTIR: 25 4000 cm 1 1 Prestige IR Spectrometer plan DSC: - 30 9 : : : 5 min : Atmosphere: Nitrogen. 5 PXRD: -ID Radiation: CuKal (1.5406 A) : 50% 10 Voltage: 40.0 kV : 30.0 mA : Divergence: : 15 : .30 mm Movement axis: Theta-2Theta : 2.00 Scanning mode: 20 min : : 0.60 s -1: Rox Org. Process Res. Dev. 2022, -hydroxy-1-methyl-7-5 fenoksiizokinolin-3- .12 g, 0.155 mol, 1. III, 14 g, 0.186 mol, 1. N,N-dimethylformamid (250 mL) ile -diazabisiklo(5.4.0)undek-7-en (DBU, 34.7 mL, 0.233 mol, 1.50 izin 10 ; (1 500 mL to 2 250 mL). .8 g, 0.17 mol, 1. ilave .45 mikronluk pH, 1N HCl damla ilave edilerek ila ila 6. meydana 15 Elde edilen k (50.5 g, %92. , KF(%): 0.80. 1H NMR (400 MHz, DMSO-d6 (ppm) = 8.89 (t, J = 5.3 Hz, 1H), 8.28 (dd, J = 9.0, 0.5 Hz, 1H), 7.60 (dd, J = 2.4, 20 0.5 Hz, 1H), 7.54 7.44 (m, 3H), 7.28 7.22 (m, 1H), 7.20 7.15 (m, 2H), 3.86 (d, J = 5.4 Hz, 2H), 2.69 (s, 3H). 13C NMR (100 MHz, DMSO-d6 (ppm) = 171.07 (C), 169.66 (C), 158.21 (C), 156.17 (C), 153.34 (C), 147.16 (C), 131.86 (C), 130.90 (CH), 125.75 (CH), 125.03 (CH), 124.22 (C), 122.93 (CH), 120.27 (C), 119.99 (CH), 112.70 (CH), 42.60 (CH2), 22.03 (CH3). Roxadustat 11 -2: 2-[(4-benzyloxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]acetic acid benzyl ester Hydrogenolysis of benzyl esters, however, takes even longer (5 years). with his machine. .6 g, 33.0 mmol, 1 l acetate 10 palladium (1.05 g, 10% w / w Pd), positive N2 captured More Selit and filter cake, EtOAc (4 x 150 mL) 15 thoroughly (1.02 g, 97%). -3: Ethyl 4- hydroxy-1-methyl-7-phenoxyisoquinoline-3- .02 g, 0.031 mol, 1.00 20 .8 g, 0.037 mol, 1.-diazabicyclo(5.4.0)undec-7- en (DBU, 6.94 mL, 0.047 mol, 1. N,N- (100 mL and 2 50 mL) The extracted pH was adjusted by adding 6N HCl dropwise to a level between 3 and 3.25. One Roxadustat 12 and EtOH obtained The substance is Roxadustat Form A (10.5 g, 96%). 0.68 g, 0.017 mol, 1. .5 1N HCl is added dropwise, between 6 and 6 minutes. The obtained k 0.65 g, 93%). 10

Claims

13 1. It is a Rox Form form, and 3. . . . . . . . . . . . . .

18. . . . . . - 2. - 3. Up, IR spectrum pattern 4. -10 5.

6. being done, 5 6.

7. It is a process involving water, methanol, and ethanol.

8. 9.

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