WO2021214785A1 - Improved process for the preparation of roxadustat - Google Patents

Improved process for the preparation of roxadustat Download PDF

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Publication number
WO2021214785A1
WO2021214785A1 PCT/IN2021/050387 IN2021050387W WO2021214785A1 WO 2021214785 A1 WO2021214785 A1 WO 2021214785A1 IN 2021050387 W IN2021050387 W IN 2021050387W WO 2021214785 A1 WO2021214785 A1 WO 2021214785A1
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WO
WIPO (PCT)
Prior art keywords
morpholine
methyl
roxadustat
acid
group
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PCT/IN2021/050387
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English (en)
French (fr)
Inventor
Santosh Kumar Singh
Ramesh Kumar SABBAM
Sathish Babu KOTHARI
Sreenivasarao PATHURI
Vipin Kumar Kaushik
Sureshbabu JAYACHANDRA
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Mylan Laboratories Limited
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Application filed by Mylan Laboratories Limited filed Critical Mylan Laboratories Limited
Priority to CN202180030203.3A priority Critical patent/CN115867537A/zh
Publication of WO2021214785A1 publication Critical patent/WO2021214785A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present disclosure relates to an improved process for the preparation of Roxadustat by employing novel intermediates.
  • Roxadustat is chemically known as [(4-hydroxy-l-methyl-7-phenoxy-isoquinoline-3- carbonyl)-amino] -acetic acid and is represented by Formula I. Roxadustat is used for the treatment of anemia in patients with chronic kidney disease (CKD). It is in Phase III clinical development in the US.
  • CKD chronic kidney disease
  • the present disclosure provides an improved process for the preparation of Roxadustat by employing novel intermediates.
  • the present disclosure provides a process for the preparation of Roxadustat, the process comprising: a) reacting chloromethyl ester with tosyl morpholine to obtain N-alkyl tosyl morpholine; chloromethyl ester
  • N-alkyl tosyl morpholine or morpholine ester b) cyclizing N-alkyl tosyl morpholine to obtain cyclic morpholine; N-alkyl tosyl morpholine or morpholine ester c) treating cyclic morpholine with N,N,N’,N’-tetramethyldiamino-methane to obtain diamino methyl morpholine; d) treating the diamino methyl morpholine [with or without isolation] with acetic anhydride to obtain a mixture of diacetyl and monoacetyl morpholine compounds, wherein the diacetyl morpholine compound is treated with morpholine in the presence of dichloromethane to obtain the monoacetyl morpholine; e) converting monoacetyl morpholine to methyl morpholine; f) converting methyl morpholine to methyl acid; g) treating methyl
  • an improved process for the preparation of Roxadustat comprising a) reacting chloromethyl ester compound with tosyl morpholine to obtain morpholine ester; b) cyclizing the morpholine ester to obtain cyclic morpholine; c) treating the cyclic morpholine with N, N, N’, N’-tetramethyl- diaminomethane to obtain dimethyl morpholine; d) converting the dimethyl morpholine to methyl morpholine; e) converting the methyl morpholine to obtain methyl acid; f) treating the methyl acid with pivaloyl chloride followed by treatment with glycine methyl ester hydrochloride to obtain Roxadustat diester; and g) converting Roxadustat diester to Roxadustat, or a pharmaceutically acceptable salt thereof.
  • the present disclosure relates to an improved process for the preparation of Roxadustat by employing novel intermediates.
  • an improved process for the preparation of Roxadustat comprising: a) reacting chloromethyl ester with tosyl morpholine to obtain N-alkyl tosyl morpholine; b) cyclizing the N-alkyl tosyl morpholine to obtain cyclic morpholine; N-alkyl tosyl morpholine or morpholine ester c) treating the cyclic morpholine with N,N,N’,N’-tetramethyldiamino-methane to obtain diamino methyl morpholine; d) treating the diamino methyl morpholine [with or without isolation] with acetic anhydride to obtain a mixture of diacetyl and monoacetyl morpholine compounds, wherein the diacetyl morpholine compound is treated with morpholine in
  • reacting chloromethyl ester with tosyl morpholine can be done in the presence of a base selected from the group consisting of potassium carbonate, sodium carbonate, and lithium carbonate, preferably potassium carbonate, a catalyst selected from the group consisting of sodium iodide, potassium iodide, sodium bromide, and potassium bromide, preferably sodium iodide, and/or a solvent selected from the group consisting of N,N-dimethylformamide, dimethylacetamide, dimethylsulfoxide,l,4-dioxane, tetrahydrofuran, dichloromethane and mixtures thereof, preferably N,N-dimethylformamide, to obtain N-alkyl tosyl morpholine.
  • a base selected from the group consisting of potassium carbonate, sodium carbonate, and lithium carbonate, preferably potassium carbonate
  • a catalyst selected from the group consisting of sodium iodide, potassium iodide, sodium bromide, and potassium bro
  • the N-alkyl tosyl morpholine may be cyclized in the presence of a base selected from the group consisting of sodium methoxide, sodium hydride, sodium tertiary butoxide, and potassium tertiary butoxide, preferably sodium methoxide, and a solvent selected from the group consisting of dimethylsulfoxide, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dixoane, and N,N-dimethylacetamide, preferably dimethylsulfoxide, to obtain cyclic morpholine.
  • a base selected from the group consisting of sodium methoxide, sodium hydride, sodium tertiary butoxide, and potassium tertiary butoxide, preferably sodium methoxide
  • a solvent selected from the group consisting of dimethylsulfoxide, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dixoane, and N,N-dimethyl
  • the cyclic morpholine may be treated with N,N,N’,N’-tctramcthyldiamino methane in the presence of a polar solvent selected from the group consisting of acetic acid, 1,4- dioxane, propionic acid, dimethylformamide, and dimethylsulfoxide, preferably acetic acid, to obtain diaminomethyl morpholine.
  • a polar solvent selected from the group consisting of acetic acid, 1,4- dioxane, propionic acid, dimethylformamide, and dimethylsulfoxide, preferably acetic acid
  • the diaminomethyl morpholine, with or without isolation may be treated with acetic anhydride to obtain a mixture of diacetyl morpholine and monoacetyl morpholine.
  • the diacetyl morpholine compound may be treated with morpholine in the presence of dichloromethane to obtain monoacetyl morpholine.
  • the monoacetyl morpholine may be hydrogenated using a palladium catalyst in ethyl acetate/tetrahydrofuran to obtain the methyl morpholine which is then treated with a base selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, preferably sodium hydroxide, in the presence of a mixture of solvents selected from methanol/ 1,4-dioxane to obtain methyl acid.
  • a base selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, preferably sodium hydroxide
  • the methyl acid may be treated with pivaloyl chloride in the presence of a base selected from the group consisting of N,N-diisopropylethylamine, triethylamine, n-butylamine, N,N-diisopropylamine, and l,8-diazabicyclo[5.4.0]undec-7-ene, preferably N,N- diisopropylethylamine, and a solvent selected from the group consisting of tetrahydrofuran, ethyl acetate, dichloromethane, 1,4-dioxane, and acetonitrile, preferably tetrahydrofuran, followed by treating with glycine methyl ester hydrochloride in the presence of N,N-diisopropylethylamine to obtain Roxadustat pivaloyl methyl ester.
  • a base selected from the group consisting of N,N-diisopropylethy
  • Roxadustat pivaloyl methyl ester may be deprotected in the presence of a solvent selected from the group consisting of tetrahydrofuran, methanol, ethanol, dioxane, water, and mixtures thereof, preferably a tetrahydrofuran/water mixture, and a base selected from the group consisting of lithium hydroxide, sodium hydroxide, sodium carbonate, and potassium carbonate, preferably lithium hydroxide, to form Roxadustat which may optionally be converted to a pharmaceutically acceptable salt thereof.
  • a solvent selected from the group consisting of tetrahydrofuran, methanol, ethanol, dioxane, water, and mixtures thereof, preferably a tetrahydrofuran/water mixture
  • a base selected from the group consisting of lithium hydroxide, sodium hydroxide, sodium carbonate, and potassium carbonate, preferably lithium hydroxide, to form Roxadustat which may optionally be converted to a pharmaceutically acceptable salt thereof.
  • an improved process for the preparation of Roxadustat comprising: a) reacting a chloromethyl ester compound with tosyl morpholine to obtain morpholine ester; b) cyclizing the morpholine ester to obtain cyclic morpholine; c) treating the cyclic morpholine with N, N, N’, N’- tetramethyl diaminomethane to obtain dimethyl morpholine; d) converting the dimethyl morpholine to methyl morpholine; e) converting the methyl morpholine to obtain methyl acid; f) treating the methyl acid with pivaloyl chloride followed by treatment with glycine methyl ester hydrochloride to obtain Roxadustat diester; and g) converting the Roxadustat diester to Roxadustat, or a pharmaceutically acceptable salt thereof.
  • chloromethyl ester may be reacted with tosyl morpholine in the presence of a base selected from the group consisting of potassium carbonate, sodium carbonate, and lithium carbonate, preferably potassium carbonate, a catalyst selected from the group consisting of sodium iodide, potassium iodide, sodium bromide, and potassium bromide, preferably sodium iodide, a suitable solvent selected from the group consisting of N,N-dimethylformamide, dimethylacetamide, dimethylsulfoxide, 1,4-dioxane, tetrahydrofuran, dichloromethane, and toluene, and/or a phase transfer catalyst like benzyltriethylammonium chloride to obtain the morpholine ester.
  • a base selected from the group consisting of potassium carbonate, sodium carbonate, and lithium carbonate, preferably potassium carbonate
  • a catalyst selected from the group consisting of sodium iodide, potassium iodide, sodium bromid
  • the morpholine ester may be cyclized in the presence of a base selected from the group consisting of sodium methoxide, sodium hydride, sodium tertiary butoxide, and potassium tertiary butoxide, preferably sodium methoxide, and a solvent selected from the group consisting of dimethylsulfoxide, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dixoane, and N,N-dimethylacetamide, preferably dimethylsulfoxide, to obtain the cyclic morpholine.
  • a base selected from the group consisting of sodium methoxide, sodium hydride, sodium tertiary butoxide, and potassium tertiary butoxide, preferably sodium methoxide
  • a solvent selected from the group consisting of dimethylsulfoxide, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dixoane, and N,N-dimethylacetamide, preferably
  • the cyclic morpholine may be treated with N, N, N’, N’-tetramethyldiaminomethane in the presence of a polar solvent selected from the group consisting of acetic acid, 1,4- dioxane, propionic acid, dimethylformamide, and dimethylsulfoxide, preferably acetic acid, to obtain dimethyl morpholine.
  • a polar solvent selected from the group consisting of acetic acid, 1,4- dioxane, propionic acid, dimethylformamide, and dimethylsulfoxide, preferably acetic acid
  • the dimethyl morpholine may be treated with zinc in the presence of an acid mixture selected from acetic acid/aqueous hydrochloric acid, propionic acid/aqueous hydrochloric acid, and propionic acid/formic acid, preferably acetic acid/aqueous hydrochloric acid, to obtain the methyl morpholine.
  • an acid mixture selected from acetic acid/aqueous hydrochloric acid, propionic acid/aqueous hydrochloric acid, and propionic acid/formic acid, preferably acetic acid/aqueous hydrochloric acid, to obtain the methyl morpholine.
  • the methyl morpholine may be treated with a base such as sodium hydroxide or potassium hydroxide in dioxane/methanol mixture followed by pH adjustment to obtain methyl acid.
  • a base such as sodium hydroxide or potassium hydroxide in dioxane/methanol mixture followed by pH adjustment to obtain methyl acid.
  • the methyl acid may be treated with pivaloyl chloride in the presence of a base selected from the group consisting of N,N-diisopropylethylamine, triethylamine, tri-n- butylamine, and l,8-diazabicyclo[5.4.0]undec-7-ene, preferably N,N- diisopropylethylamine, and a solvent selected from the group consisting of tetrahydrofuran, ethyl acetate, dichloromethane, 1,4-dioxane, and acetonitrile, preferably tetrahydrofuran, followed by treatment with glycine methyl ester hydrochloride in the presence of N,N-diisopropylethylamine to obtain Roxadustat diester.
  • a base selected from the group consisting of N,N-diisopropylethylamine, triethylamine, tri-n- butylamine,
  • Roxadustat diester may be deprotected in the presence of a solvent selected from the group consisting of tetrahydrofuran, methanol, ethanol, dioxane, water and mixtures thereof, preferably a tetrahydrofuran/water mixture, in the presence of a base selected from the group consisting of lithium hydroxide, sodium hydroxide, sodium carbonate, and potassium carbonate, preferably lithium hydroxide, to form Roxadustat, which may optionally be converted to a pharmaceutically acceptable salt.
  • a solvent selected from the group consisting of tetrahydrofuran, methanol, ethanol, dioxane, water and mixtures thereof, preferably a tetrahydrofuran/water mixture
  • a base selected from the group consisting of lithium hydroxide, sodium hydroxide, sodium carbonate, and potassium carbonate, preferably lithium hydroxide, to form Roxadustat, which may optionally be converted to a pharmaceutically acceptable salt.
  • a pharmaceutical composition comprising Roxadustat, or a pharmaceutically acceptable salt thereof, prepared according to the methods disclosed herein, and one or more pharmaceutical excipient.
  • One advantage of the process described in the present disclosure is that all the intermediate compounds can be isolated as solid compounds without using column chromatography, thus making the process industrially feasible and economical with high yields.
  • Phenoxy phthalide (25.0 g, 0.110 mol), trimethyl borate (0.22 g, 0.002 mol) and triphenylphosphine dibromide (0.9 g, 0.002 mol) in thionyl chloride (50 mL) were refluxed (72-75 °C). After the reaction was complete, excess thionyl chloride was distilled off and the residue was cooled to 5-10 °C. Methanol (50 ml) was added and stirring continued at 50-55 °C for 1.0 h. The product was subjected to concentration by solvent removal and product purification by column chromatography to yield methyl 2-(chloromethyl)-4-phenoxybenzoate (23.0 g).
  • Stage-III Preparation of methyl 2-(((4-methyl-N-(2-morpholino-2- oxoethyl)phenyl)sulfonamido)-methyl)-4-phenoxybenzoate or N-alkyl tosyl morpholine
  • Stage-IV Preparation of (4-hydroxy-7-phenoxyisoquinolin-3-yl)(morpholino) methanone or cyclic morpholine N-alkyl tosyl morpholine or morpholine ester
  • Stage- V Preparation of (4-hydroxy-3-(morpholine-4-carbonyl)-7- phenoxyisoquin-olin-l-yl)methyl acetate or Monoacetyl Morpholine
  • the filtrate containing the diacetylated product i.e. (4-acetoxy-3-(morpholine-4- carbonyl)-7-phenoxyisoquinolin-l-yl)methyl acetate was extracted with ethyl acetate, washed with water/brine and concentrated. The obtained residue was dissolved in dichloromethane (25 mL) and cooled to 0-5 °C. Morpholine (0.5g, 0.006 mol) was added, and the reaction mass was stirred at the same temp. After completion, 10% citric acid (15 mL) was added, and the separated organic layer was washed with water. The obtained organic layer was concentrated under vacuum to afford (4-hydroxy-3- (morpholine-4-carbonyl)-7 -phenoxyisoquinolin- 1 -yl)methylacetate (2.0g) .
  • the reaction mass was cooled to 0-5 °C and glycine methyl ester hydrochloride (1.65g, 0.013 mol) and N,N-diisopropylethylamine (2.0 g, 0.015 mol) were added sequentially.
  • water (30 mL) and ethyl acetate (100 mL) were added.
  • the organic layer was separated and washed with water (3 x 50 mL) followed by 5% sodium bicarbonate solution (50 mL) sequentially.
  • the organic layer was subjected to carbon treatment, and the obtained filtrate was concentrated.
  • Stage-XI Preparation of 4-methyl-N-(2-morpholino-2- oxoethyl)benzenesulfonamide or tosyl morpholine tosyl glycine tosyl morpholine
  • reaction mass was filtered through a hyflo bed which was washed with toluene and water sequentially.
  • the toluene layer was separated and washed with water and ⁇ 5% w/w sodium bicarbonate sequentially. It was then concentrated under vacuum.
  • the obtained residue was crystalized with methanol to afford 5-phenoxyisobenzofuran-l(3H)-one (80.0 g) as a light brown solid.
  • Stage-Ill Preparation of methyl 2-(((4-methyl-N-(2-morpholino-2- oxoethyl)phenyl)sulfonamido)methyl)-4-phenoxybenzoate or morpholine ester 4-Methyl-N-(2-morpholino-2-oxoethyl)benzene sulfonamide (100.0 g, 0.335 mol), potassium carbonate (19.8 g, 0.143 mol), methyl 2-(chloromethyl)-4-phenoxybenzoate (60.2 g, 0.436 mol) and sodium iodide (5.0 g, 0.0335 mol) in dimethylsulfoxide (400 mL) were stirred for 4 hrs at 50-55 °C.
  • Stage- V Preparation of [l- ⁇ (dimethylamino)methyl ⁇ -4-hydroxy-7- phenoxyisoquinolin-3-yl](morpholino)methanone or dimethyl morpholine dimethyl morpholine
  • Stage- VII Preparation of 4-Hydroxy-l-methyl-7-phenoxyisoquinoline-3- carboxylic acid or methyl acid
  • Stage-VIII Preparation of 3-((2-methoxy-2-oxoethyl)carbamoyl)-l-methyl-7- phenoxyisoquinolin -4-yl pivalate or Roxadustat diester
  • reaction mass was again cooled to 0-5 °C and glycine methyl ester hydrochloride (1.65g, 0.013 mol) and N,N-diisopropylethylamine (2.0 g, 0.015 mol) were added sequentially.
  • water (30 mL) and ethyl acetate (100 mL) were added.
  • the organic layer was separated and washed with water (3 x 50 mL) followed by 5% sodium bicarbonate solution (50 mL). The obtained organic layer was subjected to carbon treatment, and the obtained filtrate was concentrated.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
PCT/IN2021/050387 2020-04-21 2021-04-19 Improved process for the preparation of roxadustat WO2021214785A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114736157A (zh) * 2022-03-11 2022-07-12 海口市制药厂有限公司 一种罗沙司他的制备方法及其药物组合物和应用
WO2023135499A1 (en) * 2022-01-17 2023-07-20 Optimus Drugs Pvt Ltd Process for roxadustat using novel intermediates

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EP3305769B1 (en) 2016-10-07 2019-06-26 Zentiva K.S. Method for preparation of (7-phenoxy-4-hydroxy-1-methyl-isoquinoline-3-carbonyl)-glycine (roxedustat) and its intermediates based on simultaneous opening of oxazolic ring, fission of ether and creation of imine

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WO2014014834A1 (en) * 2012-07-16 2014-01-23 Fibrogen, Inc. Process for making isoquinoline compounds
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023135499A1 (en) * 2022-01-17 2023-07-20 Optimus Drugs Pvt Ltd Process for roxadustat using novel intermediates
CN114736157A (zh) * 2022-03-11 2022-07-12 海口市制药厂有限公司 一种罗沙司他的制备方法及其药物组合物和应用

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