WO2021214785A1 - Procédé amélioré pour la préparation de roxadustat - Google Patents

Procédé amélioré pour la préparation de roxadustat Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
morpholine
methyl
roxadustat
acid
group
Prior art date
Application number
PCT/IN2021/050387
Other languages
English (en)
Inventor
Santosh Kumar Singh
Ramesh Kumar SABBAM
Sathish Babu KOTHARI
Sreenivasarao PATHURI
Vipin Kumar Kaushik
Sureshbabu JAYACHANDRA
Original Assignee
Mylan Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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/fr

Links

Classifications

    • 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.

Landscapes

  • 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)

Abstract

L'invention concerne une voie de synthèse pour la préparation de roxavostat, ou d'un sel pharmaceutiquement acceptable correspondant. Chaque voie implique plusieurs nouveaux intermédiaires et évite l'utilisation de la chromatographie sur colonne.
PCT/IN2021/050387 2020-04-21 2021-04-19 Procédé amélioré pour la préparation de roxadustat WO2021214785A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202180030203.3A CN115867537A (zh) 2020-04-21 2021-04-19 改进的罗沙司他的制备方法

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN202041017057 2020-04-21
IN202041017057 2020-04-21
IN202041050043 2020-11-17
IN202041050043 2020-11-17

Publications (1)

Publication Number Publication Date
WO2021214785A1 true WO2021214785A1 (fr) 2021-10-28

Family

ID=76181183

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2021/050387 WO2021214785A1 (fr) 2020-04-21 2021-04-19 Procédé amélioré pour la préparation de roxadustat

Country Status (2)

Country Link
CN (1) CN115867537A (fr)
WO (1) WO2021214785A1 (fr)

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 (fr) * 2022-01-17 2023-07-20 Optimus Drugs Pvt Ltd Procédé de préparation de roxadustat utilisant de nouveaux intermédiaires

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7323475B2 (en) 2003-06-06 2008-01-29 Fibrogen, Inc. Nitrogen-containing heteroaryl compounds and methods of use thereof
WO2014014834A1 (fr) * 2012-07-16 2014-01-23 Fibrogen, Inc. Procédé de fabrication de composés isoquinoléine
CN104892509A (zh) 2015-06-04 2015-09-09 苏州明锐医药科技有限公司 诺得司他的制备方法
WO2018072662A1 (fr) 2016-10-17 2018-04-26 上海医药集团股份有限公司 Procédé de préparation de roxadustat
EP3305769B1 (fr) 2016-10-07 2019-06-26 Zentiva K.S. Procédé de préparation de (7-phénoxy-4-hydroxy-1-méthyl-isoquinoléine-3-carbonyl)-glycine (roxadustat) et ses intermédiaires sur la base de l'ouverture simultanée du cycle oxazolique, de la fission d'éther et de la création d'imine

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7323475B2 (en) 2003-06-06 2008-01-29 Fibrogen, Inc. Nitrogen-containing heteroaryl compounds and methods of use thereof
WO2014014834A1 (fr) * 2012-07-16 2014-01-23 Fibrogen, Inc. Procédé de fabrication de composés isoquinoléine
US9340511B2 (en) 2012-07-16 2016-05-17 Fibrogen, Inc. Process for making isoquinoline compounds
CN104892509A (zh) 2015-06-04 2015-09-09 苏州明锐医药科技有限公司 诺得司他的制备方法
EP3305769B1 (fr) 2016-10-07 2019-06-26 Zentiva K.S. Procédé de préparation de (7-phénoxy-4-hydroxy-1-méthyl-isoquinoléine-3-carbonyl)-glycine (roxadustat) et ses intermédiaires sur la base de l'ouverture simultanée du cycle oxazolique, de la fission d'éther et de la création d'imine
WO2018072662A1 (fr) 2016-10-17 2018-04-26 上海医药集团股份有限公司 Procédé de préparation de roxadustat

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023135499A1 (fr) * 2022-01-17 2023-07-20 Optimus Drugs Pvt Ltd Procédé de préparation de roxadustat utilisant de nouveaux intermédiaires
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

Also Published As

Publication number Publication date
CN115867537A (zh) 2023-03-28

Similar Documents

Publication Publication Date Title
US9233966B2 (en) Preparation of ticagrelor
JP7100125B2 (ja) リボシクリブおよびその塩の改善された調製のためのプロセス
WO2021214785A1 (fr) Procédé amélioré pour la préparation de roxadustat
AU2018102141A4 (en) Method for preparing Baricitinib
CN110891947B (zh) 制备艾乐替尼或其药学上可接受的盐的方法
KR20130038258A (ko) 삭사글립틴 중간체, 삭사글립틴 다형 및 이들의 제조 방법
EP3934758A1 (fr) Formes à l'état solide de baloxavir marboxil
JP2020528433A (ja) アリピプラゾールラウロキシルの調製方法
WO2020194115A1 (fr) Procédé de préparation d'élagolix sodique et d'intermédiaires correspondants
CN114478690A (zh) 一种6,6-二甲基-3-氮杂双环[3.1.0]己烷衍生物的制备方法
US20230128975A1 (en) Process for the preparation of bromodomain inhibitor
JP6276894B2 (ja) キナゾリン誘導体作製方法
WO2020051014A1 (fr) Procédés pour la préparation de ténapanor et d'intermédiaires de ceux-ci
US20240010632A1 (en) Solid state forms of erdafitinib salts and processes for preparation of erdafitinib
CN111100042B (zh) 一种2-甲氧基-5-磺酰胺基苯甲酸的制备方法
JP2004528380A (ja) ゾルピデムの製造方法
WO2023001299A1 (fr) Forme cristalline du composé représenté par la formule i, sa préparation et son application
CN113105385B (zh) 一种左布比卡因的制备方法
US20240124461A1 (en) Processes for the preparation of zanubrutinib and intermediates thereof
CN111499575B (zh) 一种制备氯卡色林的方法
WO2020136671A1 (fr) Procédé perfectionné pour la préparation d'une base de lapatinib et de son sel de ditosylate anhydre
WO2023160541A1 (fr) Procédé de préparation d'un composé hétérocyclique contenant de l'azote
US20100174073A1 (en) Process for the preparation of alfuzosin and salts thereof
JP2010526126A (ja) バルサルタンの製造方法
KR20050062944A (ko) 디이소프로필((1-((2-아미노-6-클로로-9ｈ-퓨린-9-일)메틸)사이클로프로필)옥시)-메틸포스포네이트의 새로운 제조방법

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21728656

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21728656

Country of ref document: EP

Kind code of ref document: A1