808118-40-3

Usage

Synthesis

Preparation of roxadustat of formula 1 was described in a patent application WO2004108681, where the roxadustat is prepared in 11 steps from initial chemical compound 4-nitro-1,2-dicarbonitrile of formula 2. Reaction of dicarbonitrile of formula 2 with phenol and potash in the first step leads to preparation of corresponding phenoxy derivate of formula 3, 4-phenoxyphthalic acid of formula 4 is prepared by the following hydrolysis effect of potassium hydroxide in methanol, from which a solid-phase mixture with glycine is created for reaction in a melt with temperature of 210°C to 220°C, which provides corresponding phthalimide of formula 5. After that, phthalimide of formula 5 is esterified to corresponding methyl ester of formula 6. Then, expansion of the ring is performed by the effect of sodium butanolate to butyl-7-phenoxy-1,4-dihydroxy isoquinoline-3-carboxylate of formula 7. Hydroxyl group of derivative of formula 7 in a position 1 is then replaced by bromine using phosphorus oxybromide under the alkaline conditions resulting in creation of isoquinoline derivative of formula 8. Further the alkaline hydrolysis is carried out to provide an acid of formula 9. Then the lithiation is carried out, capture of lithium salt with methyl iodide, and in the second step, the hydroxyl group and carboxyl function are protected by benzyl group resulting in the derivative of formula 10. By the effect of potassium hydroxide the derivative of formula 10 is hydrolyzed to the carboxylic acid of formula 11, from which the derivative 12 is prepared under the conditions of glycine benzyl ester. The final step of synthesis of roxadustat of formula 1 is deprotection of benzyl groups by means of hydrogenation reaction (Diagram 1). A Scalable Synthesis of Roxadustat (FG-4592)

Metabolism

Roxadustat is metabolized by cytochrome P450 (CYP)2C8 and uridine diphosphate-glucuronosyltransferase (UGT)1A9. Roxadustat is primarily metabolized through 2 main metabolic pathways: hydroxylation/oxidation followed by sulfation, producing metabolites 4'-hydroxy roxadustat and 4'-O-sulfate conjugates of 4'-hydroxy roxadustat, together accounting for 20% of the radioactive dose. The O-glucuronidation produces metabolite 4-O-β-glucuronide of roxadustat, representing 28% of the dose. Minor metabolic routes included glucosidation producing 4-O-β-glucoside of roxadustat (8.1% of the dose), acyl glucuronidation producing acyl-1-O-β-glucuronide of roxadustat (0.6% of the dose), and demethylation producing N-descarboxymethyl roxadustat oxide and Ndescarboxymethyl roxadustat (together ~3.6% of the dose).

Current market and forecast

Roxadustat is approved in EU member states, including the EEA countries, as well as in Japan, China, Chile and South Korea for the treatment of anemia of CKD in adult patients on dialysis (DD) and not on dialysis (NDD). Several other licensing applications for roxadustat have been submitted by Astellas and AstraZeneca to regulatory authorities across the globe and are currently in review.Astellas and FibroGen are collaborating on the development and commercialization of roxadustat for the potential treatment of anemia of CKD in territories including Japan, Europe, Turkey, Russia and the Commonwealth of Independent States, the Middle East, and South Africa. FibroGen and AstraZeneca are collaborating on the development and commercialization of roxadustat for the potential treatment of anemia of CKD in the U.S., China, other markets in the Americas, in Australia/New Zealand, and Southeast Asia.

Mode of action

Roxadustat is a novel, orally bioavailable, potent and reversible HIF-PH inhibitor (HIF-PHI) that transiently induces HIF stabilization and leads to a functional HIF transcriptional response that mimics the erythropoietic response associated with exposure of humans to intermittent hypoxia. roxadustat increases hemoglobin levels with a mechanism of action that is different from that of ESAs. Roxadustat activates the body’s natural protective response to reduced oxygen levels in the blood. This response involves the regulation of multiple, complementary processes that promote a coordinated erythropoietic response and increase the blood’s oxygen-carrying capacity.

Clinical claims and research

Roxadustat (FG-4592), an oral medication, is one of the medications currently undergoing Phase 3 studies. In their phase 2a study studying anemic CKD patients, the medication showed increases in erythropoietin and hemoglobin levels as well as a reduction in hepcidin concentrations with 0.7 to 2.0 mg/kg given 2 or 3 times per week compared to controls within 4 weeks of treatment with no adverse events observed. Roxadustat was then studied in hemodialysis and peritoneal dialysis patients and raised hemoglobin by 20 g/L in 7 weeks of treatment with 4.3 mg/kg weekly for 12 weeks. The current phase 3 studies will continue to evaluate Roxadustat compared to epoetin alpha(NCT02174731 ) and epoetin alpha or darbepoetin alpha (NCT02278341) in CKD patients on dialysis.

InChI:InChI=1S/C19H16N2O5/c1-11-15-9-13(26-12-5-3-2-4-6-12)7-8-14(15)18(24)17(21-11)19(25)20-10-16(22)23/h2-9,24H,10H2,1H3,(H,20,25)(H,22,23)

Upstream product

• 1421312-34-6 4-hydroxy-1-methyl-7-phenoxyisoquinolinyl-3-carboxylic acid methyl ester 
• 56-40-6 glycine 
• 1455091-10-7 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester 
• 1509958-19-3 1-((dimethylamino)methyl)-4-hydroxy-7-phenoxyisoquinolinyl-3-carboxylic acid methyl ester 
• 1509958-20-6 1-((acetoxy)methyl)-4-hydroxy-7-phenoxyisoquinolinyl-3-carboxylic acid methyl ester 
• 1537180-08-7 C₂₂H₁₉NO₇ 
• 63720-38-7 3-hydroxy-α-methylbenzylamine 
• 31181-23-4 1-methyl-7-hydroxyisoquinoline 
• 1421312-35-7 4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinecarboxylic acid 
• 60-18-4 L-tyrosine 
• 1080-06-4 L-Tyr-OMe 
• 660844-52-0 2-amino-3-(4-phenoxyphenyl)propionic acid methyl ester 

Relevant academic research and scientific papers

A Scalable Synthesis of Roxadustat (FG-4592)

A scalable five-step protocol for synthesis of roxadustat, an orally administered hypoxia-inducible factor-propyl hydroxylase inhibitor (HIF-PHI), was developed with an emphasis placed on aspects of medicinal chemistry. The isoquinoline core of the molecule was prepared using a purposefully designed cyclocondensation in which both the cyclocondensation and demasking of the groups being condensed is promoted by a common acid agent in one step. Roxadustat was obtained pure in a very competitive overall yield across all reaction steps and in compliance with permissible residual Pd level in API.

Preparation method of isoquinoline derivative

Disclosed is a preparation method of an isoquinoline derivative. A preparation method of a compound represented by a general formula II, i.e., 4-hydroxy-1-methyl-7-phenoxy isoquinoline-3-formate, is provided, wherein substituent definitions are as defined in the specification. The preparation method comprises the following steps of: under an acidic condition, dissolving a compound shown as a structural formula III in dimethyl sulfoxide, catalyzing by a ferrous ion (Fe) catalyst, and oxidizing by H2O2 to obtain the 4-hydroxy-1-methyl- 7-phenoxy isoquinoline-3-formate shown as the structuralformula II. By using the method, the production efficiency can be greatly improved, the production cost is reduced, the product purity can be ensured, and the method is suitable for industrial mass production.

IMPROVED PROCESS FOR THE PREPARATION OF ROXADUSTAT

A synthetic route for the preparation of Roxadustat, or a pharmaceutically acceptable salt thereof. Each route involves several novel intermediates and avoids the use of column chromatography.

PROCESS OF MAKING ROXADUSTAT

The invention relates to a method of manufacturing roxadustat of formula (I), comprising the conversion of a compound of formula (VI) to roxadustat, R being an alkyl group in C1- C20 and PG being a protective group.

Preparation method of bleomycin

The invention discloses a preparation method of Roxadustat, compound 1 and bis(dimethylamino)methane are heated in a mixed solvent of acetic acid and trifluoroacetic acid for reaction to form compound2; acetic anhydride is added to the obtained reaction solution of the compound 2 for completing reaction by heating to form compound 3; the compound 3 is dissolved in ethyl acetate and heated, then is catalyzed by Pd/C, and reduced by hydrogen to obtain compound 4; the compound 4 and glycine are dissolved in a solvent, and heated under the action of an organic base for reaction to obtain compound5; wherein the solvent is one or more of dioxane, ethylene glycol monomethyl ether, toluene, acetonitrile and n-propanol, the organic base is one or more of triethylamine, 1,8-diazabicyclo undecane-7-ene, N,N-diisopropylethylamine, N-methylmorpholine, pyridine, and ethylenediamine; the preparation method has the advantages of shorter reaction time, low reaction temperature, low equipment condition requirements and high crude product purity, is suitable for large-scale industrial production, and has a good industrialization prospect.

PROCESSES FOR THE PREPARATION OF ROXADUSTAT AND INTERMEDIATES THEREOF

The present invention provides new procedure and intermediates for the preparation of Roxadustat (1) comprising: (A) reducing a compound of formula 3', 3 or a mixture thereof: (3'), (3 ) wherein Pg is H or a OH protecting group, Ri is alkyl, aryl, or arylalkyl; R2, R3, R4, and Rs each independently represents alkyl, arylalkyl or alkenyl, or R2 and R3 and/or R4 and Rs, taken together with the nitrogen atom to which they are bonded, each independently form a ring selected from: (I), wherein R6 is H or CI-6 alkyl; R7 is Ci to C6 alkyl and X- is an anion selected from the group consisting of halide, O-SO4 -R7 wherein R7 is Ci to C6 alkyl, or O-SO2 -Rs wherein Rs is phenyl, tolyl, methyl or trifluoromethyl; to form a compound of formula (2') wherein Pg is H or an OH protecting group, Ri is alkyl, aryl, or arylalkyl; and removing the Ri group and where present removing the OH protecting group; or (B) reducing a compound of formula 4', a compound of formula 4 or a mixture thereof: (4'), (4 ) wherein Pg is H or an OH protecting group; Ri is H, alkyl, aryl, or arylalkyl; R2, R3, R4, and R5 each independently represents alkyl, aryl, arylalkyl or alkenyl; or R2 is Ci-4 alkyl and R3 is Ci-4 alkoxy; or R2 and R3 and/or R4 and R5, taken together with the nitrogen atom to which they are bonded, each independently form a group selected from: (I) wherein R6 is H or CI-6 alkyl; and where Ri is not H, removing the Ri group, and, where present removing the OH protecting group.

Method for preparing isoquinolinone compound

The invention provides a method for preparing an isoquinolinone compound. Specifically, the invention provides a method for preparing a compound as shown in a formula 4, and the method comprises the step of carrying out catalytic conversion on a compound as shown in a formula 3 through active metal to obtain the compound as shown in the formula 4. The method disclosed by the invention has the excellent technical effects of reasonable route, convenience, feasibility, high preparation yield and purity, suitability for industrial production and the like.

Method for preparing isoquinolinone compound

The invention relates to a method for preparing an isoquinolinone compound. Specifically, the invention provides a method for preparing a compound as shown in a formula 3, which is characterized by comprising the following steps: a) reacting a compound as shown in a formula 1 with glycine to obtain a compound as shown in a formula 2, and reacting the compound as shown in the formula 2 with alcohol and acyl chloride to obtain the compound as shown in the formula 3, or b) reacting the compound as shown in the formula 1 with glycine ester to obtain the compound as shown in the formula 3. The method disclosed by the invention has the excellent technical effects of reasonable route, convenience, feasibility, high preparation yield and purity, suitability for industrial production and the like.

Method for preparing isoquinolinone compound

The invention provides a method for preparing an isoquinolinone compound. Specifically, the invention provides a method for preparing a compound as shown in a formula 3, which is characterized by comprising the following steps: 1) reacting a compound as shown in a formula 1 with acyl chloride to obtain a compound as shown in a formula 2; and 2) reacting the compound of the formula 2 with an aminolysis reagent selected from glycine, glycine derivatives, or a combination thereof, and then carrying out a hydrolysis reaction to obtain a compound of a formula 3. The method disclosed by the invention has the excellent technical effects of reasonable route, convenience, feasibility, high preparation yield and purity, suitability for industrial production and the like.

Preparation method of isoquinolinone compound

The invention relates to a preparation method of an isoquinolinone compound. Specifically, the method for preparing the compound shown in the formula 2 comprises the step that a compound shown in a formula b reacts with a methylation reagent to obtain the compound shown in the formula 2. The method provided by the invention is used for preparing the isoquinolinone compound (such as Roxadustat), and has the excellent effects of reasonable route, convenience, feasibility, high yield, high purity, suitability for industrial production and the like.