- IMPROVED PROCESS FOR THE PREPARATION OF ROXADUSTAT
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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.
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- Preparation method of isoquinoline derivative
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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.
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- A Scalable Synthesis of Roxadustat (FG-4592)
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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.
- ?erňa, Igor,?embera, Filip,Pí?a, Ond?ej,Rádl, Stanislav
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- PROCESS OF MAKING ROXADUSTAT
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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.
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Paragraph 0062
(2021/12/30)
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- Intermediate compound and preparation method and application thereof
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The invention provides an intermediate compound shown as a formula 5, and provides a method for preparing the intermediate through carbonyl insertion reaction. The invention particularly provides a process for the preparation of an intermediate formula 6 through an intermediate formula 5 , and further provides a process for the preparation of Noxasta through the intermediate formula 5. The preparation method has the advantages of easily available raw materials and controllable cost, and is suitable for industrial production.
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- Preparation method of rosaxostat
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The invention belongs to the field of medicine preparation, and particularly relates to a preparation method of rosaxostat, thepreparation method comprises the following steps: reacting SM1 with glycine ester to generate a compound B; reacting the compound B with tetraR3-group methane diamine to generate a compound C1; reacting the compound C1 to generate a compound E1; hydrolyzing and converting the compound E1 into a target compound rosaxostat; preferably, the compound B can also be generated through an esterification reaction of the compound A and alcohol, or the compound A is generated through an amidation reaction of SM1 and glycine or glycine salt, and the compound A is generated through an esterification reaction of the compound A and alcohol; the compound E1 can also be generated through the reaction of the compound D1, or the compound D1 is generated through the reaction of the compound C1, and the compound D1 is generated through the reaction of the compound C1.
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- Preparation method of isoquinolinone compound
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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.
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- Method for preparing isoquinolinone compound
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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.
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- Method for preparing isoquinolinone compound
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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.
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Paragraph 0238-0239; 0243
(2021/04/21)
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- Method for preparing isoquinolinone compound
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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.
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Paragraph 0228-0229; 0231
(2021/04/21)
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- PROCESSES FOR THE PREPARATION OF ROXADUSTAT AND INTERMEDIATES THEREOF
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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.
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Paragraph 00206
(2021/02/12)
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- Preparation method of bleomycin
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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.
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- CO-CRYSTALS OF ROXADUSTAT AND PROCESS THEREOF
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The present invention relates to a process for the preparation of roxadustat a compound of Formula I. More particularly the present invention relates to a process for the preparation of co-crystal of roxadustat and further more particularly the present invention relates to process for preparation of co-crystal of roxadustat with gentisic acid.
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Page/Page column 4
(2021/07/02)
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- PROCESS FOR THE PURIFICATION OF ROXADUSTAT
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The present invention provides a process for the preparation of crystalline Roxadustat Form-δ and pharmaceutical composition thereof. The present invention also provides a purification process of Roxadustat. Another aspect of the present invention also provides a process for the preparation of Roxadustat Form A and its purification. The present invention also provides a process for the preparation of co-crystal of Roxadustat with L-Proline.
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Page/Page column 12
(2020/11/03)
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- Preparation method of Roxadustat
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The invention provides a preparation method of Roxadustat. The preparation process provided by the invention has the advantages of cheap and easily available initial raw materials, short synthetic route, short reaction period, no environmental pollution, simple operation, avoidance of harsh reaction conditions, simple operation and post-treatment, high yield and product purity, easy purifying of intermediates in each step, low production cost, suitability for industrial large-scale production, and accordance with the principle of green chemistry.
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- Preparation method of roxadustat
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The invention relates to a preparation method of roxadustat. In the method, methyl 4-hydroxy-7-phenoxyisoquinoline-3-formate and N,N,N',N'-tetramethyldiaminomethane as raw materials are reacted in glacial acetic acid and methyl 1-((dimethylamino) methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate is obtained after the reaction is finished; the obtained methyl 1-((dimethylamino) methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate is dissolved into glacial acetic acid, zinc is added, diluted hydrochloric acid is added, and after the reaction is finished, methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate is obtained; the obtained methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate is mixed with glycine, and dissolved into methanol, sodium methoxide is added, and after the reaction is finished, the target product roxadustat is obtained. The method is mild in reaction condition, simple and controllable in operation, low in preparation cost and suitable for large-scale industrial production, the obtained target product is high in purity, and the production requirements of enterprises are met.
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- PROCESS FOR THE PREPARATION OF ROXADUSTAT AND ITS INTERMEDIATES
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The present invention provides the process for the preparation of Roxadustat and its intermediates. Another aspect of the present invention provides a process for preparation of ethyl-5-(2-butoxycarbonyl)-4-phenoxyphenyl) oxazole-4-carboxylate of the formula (X) and its use in the preparation of Roxadustat. Another aspect of the present invention provides a process for the preparation of ethyl-4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate of the formula (XIII) and its use in the preparation of Roxadustat.
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- Preparation method of isoquinolinone compound
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The invention provides a preparation method of an isoquinolinone compound, which creatively uses a condensation agent composition of HOBT-EDCI in a specific ratio and the optimal acid binding agent dosage, so that the yield of a compound F is improved; and the reaction solvent is a dichloromethane-water mixture, so that after the reaction is finished, the high-purity compound F can be obtained only by standing and layering a reaction solution and then spin-drying an organic layer. According to the method, complex post-treatment steps in the prior art are avoided and the layered water layer canbe continuously used for preparing the compound F, so that materials are greatly saved, the production operation is facilitated, the economic cost is reduced, and the environmental pollution is reduced. Besides, in the preparation process of the compound C, tetramethyl ethylenediamine is skillfully used, so that the yield of the compound C is greatly improved compared with that in the prior art.
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- Synthesis method of roxadustat
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The invention provides a synthesis method of roxadustat. The roxadustat is prepared from 2-amino-3-hydroxyl-3-(4-phenoxyphenyl)propionic acid through the steps of acetic anhydride protection, esterification, cyclization, aromatic ring oxidation, hydrolysi
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- Preparation method of drug for chronic anemia
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The invention discloses a synthesis method for a drug Roxadustat for chronic anemia. The synthesis method comprises the following steps: hydrolyzing and acidifying a compound shown as a formula 6 under the action of alkali to obtain a key intermediate compound shown as a formula 7; carrying out condensation reaction on the compound shown as the formula 7 and carbonyl diimidazole under suitable conditions to obtain an intermediate compound shown as a formula 8, and separating or not separating the compound shown as the formula 8 from a system to directly take part in subsequent reaction; and finally, reacting the product with glycine to obtain a final product Roxadustat shown as a formula 9. The preparation method has the advantages that the route efficiency is improved, the process cost isreduced, side products are reduced and the purity of a final product is favorably improved (The formula is shown in the description), wherein R2 in the compound shown as the formula 6 represents alkyl, and includes but not limited to methyl, ethyl, isopropyl, tertiary butyl or benzyl.
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- [...] his preparation method
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The invention discloses a preparation method of Roxadustat. The preparation steps are as follows: the Roxadustat is prepared from tyrosine through esterification, etherification, cyclization, dehydrogenation, oxidative rearrangement and acylation reaction. The preparation method has the advantages that the raw materials are easily obtained; the process is simple; and the preparation method is economic and environmental-friendly, and is suitable for industrialized production.
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- A [...] his preparation method (by machine translation)
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The invention discloses a method for preparing [...] he, [...] he the chemical name is N - [(4 - hydroxy - 1 - methyl - 7 - phenoxy - 3 - isoquinoline) carbonyl] glycine; the process of the invention has simple process, raw materials are easy, economic and environmental protection, help to realize industrialization, [...] he raw material can promote the economic and technological development, and reduces the production cost, high yield, low environmental pollution, is suitable for mass production. (by machine translation)
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- Isoquinolone compound and application thereof
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The invention relates to an isoquinolone compound and application thereof. The invention in particular relates to an isoquinolone compound used as a HIF prolyl hydroxylase inhibitor (HIF-PHI) and a pharmaceutical composition thereof. Moreover, the present invention provides the application of the isoquinolinone compound or the pharmaceutical composition thereof in the preparation of a medicament for preventing or treating HIF-associated or HIF-mediated diseases as anemia or ischemia, local ischemia or hypoxia.
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- Synthetic method of roxadustat and intermediate compounds of roxadustat
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The invention provides a synthetic method of roxadustat. The synthetic method comprises the following steps: 2-bromo-4-methylfluorobenzoate is taken as a raw material, and the raw material reacts withphenol, butyl vinyl ether, acid and hydroxylamine, and
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Paragraph 0060; 0061
(2018/12/05)
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- CRYSTAL TYPES OF COMPOUNDS INHIBITING ACTIVITY OF PROLYL HYDROXYLASE AND USE THEREOF
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The invention relates to crystal types of compound shown as structural formula I, methods of preparing the compound, intermediate, pharmaceutical composition, and use of treating disease or pharmaceutical preparations for treating disease.
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Paragraph 0145; 0165; 0166
(2017/10/27)
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- A substituted heteroaryl compounds and compositions containing such compounds and use thereof (by machine translation)
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The present invention provides a substituted heteroaryl compounds and compositions containing such compounds and its use, the invention discloses a formula (I) indicated by the heteroaryl compound, or its crystalline form, a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate or compound solvent. The invention of monocyclic the base states compounds and compositions containing such compounds may be used to modulate hypoxia inducible factor (HIF) and/or endogenous erythropoietin (EPO), but also has good pharmacokinetic parameter characteristic, can improve the compound in animal drug concentration, in order to improve the effect of drugs and safety. (by machine translation)
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- POLYMORPHIC FORMS OF COMPOUNDS AS PROLYL HYDROXYLASE INHIBITOR, AND USES THEREOF
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The present invention relates to the polymorphic forms of the compound of Formula (I), preparation thereof including the preparation of intermediates and pharmaceutical compositions, and use of a polymorph above in the treatment of a disease, a disorder o
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Paragraph 0153
(2015/02/19)
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- PROCESS FOR MAKING ISOQUINOLINE COMPOUNDS
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The present invention relates to methods for making isoquinoline compounds and the intermediate compounds achieved thereby. Such compounds can be used to prepare compounds and compositions capable of decreasing HIF hydroxylase enzyme activity, thereby increasing the stability and/or activity of hypoxia inducible factor (HIF).
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- POLYMORPHIC FORMS OF COMPOUNDS AS PROLYL HYDROXYLASE INHIBITOR, AND USES THEREOF
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The present invention relates to the polymorphic forms of the compound of Formula (I), preparation thereof including the preparation of intermediates and pharmaceutical compositions, and use of a polymorph above in the treatment of a disease, a disorder o
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Page/Page column 17
(2013/03/26)
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- Novel nitrogen-containing heteroaryl compounds and methods of use thereof
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The present invention relates to compounds suitable for use in mediating hypoxia inducible factor and for treating erythropoietin-associated conditions by increasing endogenous erythropoietin in vitro and in vivo.
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