[go: up one dir, main page]

WO2017122139A1 - Procédé perfectionné de préparation de pirfénidone - Google Patents

Procédé perfectionné de préparation de pirfénidone Download PDF

Info

Publication number
WO2017122139A1
WO2017122139A1 PCT/IB2017/050141 IB2017050141W WO2017122139A1 WO 2017122139 A1 WO2017122139 A1 WO 2017122139A1 IB 2017050141 W IB2017050141 W IB 2017050141W WO 2017122139 A1 WO2017122139 A1 WO 2017122139A1
Authority
WO
WIPO (PCT)
Prior art keywords
pirfenidone
methyl
solvent
formula
isolating
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2017/050141
Other languages
English (en)
Inventor
Ravindra Babu Bollu
Venkata Pramod Kumar MANDADAPU
Venkata Sunil Kumar Indukuri
Satyanarayana Chava
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Laurus Labs Pvt Ltd
Original Assignee
Laurus Labs Pvt Ltd
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 Laurus Labs Pvt Ltd filed Critical Laurus Labs Pvt Ltd
Publication of WO2017122139A1 publication Critical patent/WO2017122139A1/fr
Priority to US16/032,210 priority Critical patent/US11066368B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6

Definitions

  • the present invention relates to an improved process for the preparation of pure pirfenidone.
  • the present invention also relates to a crystalline form of pirfenidone and is pharmaceutical composition thereof.
  • Pirfenidone is an anti-fibrotic drug for the treatment of idiopathic pulmonary fibrosis (IPF). It works by reducing lung fibrosis through down regulation of the production of growth factors and procollagens I and II. Pirfenidone was approved by USFDA for the treatment of idiopathic pulmonary fibrosis on Oct 15, 2014. Pirfenidone is chemically known as 5- methyl-l-phenyl-2-l(H)-pyridone and represented by the following structural formula (I)
  • Idiopathic pulmonary fibrosis is a rare disease of unknown etiology that is characterized by progressive fibrosis of the interstitium of the lung, leading to decreasing lung volume and progressive pulmonary insufficiency.
  • PCT publication WO 2002/085858 disclosed the purification process for pirfenidone, which involves dissolution of pirfenidone in 5% aqueous acetic acid at 90°C and adding 25% aqueous sodium hydroxide followed by isolating pure pirfenidone.
  • PCT publication WO 2003/014087 disclosed an improved process of pirfenidone, which involves the reaction of 5-methyl-2(lH)-pyridinone with bromobenzene in the presence of cuprous oxide and potassium carbonate at 156°C followed by isolation and purification of pirfenidone by acid-base treatment.
  • US patent No. US8519140 (“the ⁇ 40 patent”) disclosed an improved process for the preparation of pure pirfenidone, which involves the reaction of 5-methyl-2(lH)-pyridinone with bromobenzene having less than 0.15 % by weight dibromobenzene in presence of a cuprous oxide, potassium carbonate in dimethylsulfoxide followed by crystallization of obtained pirfenidone by acid-base treatment.
  • purity of dibromobenzene is important, as amount of dibromobenzene impurity in the bromobenzene can lead to dimer type byproducts, which complicate the purification of pirfenidone and difficult to remove from final pirfenidone.
  • bromobenzene with less that 0.15% of dibromobenzene is not readily available and moreover expensive when compared with the regular bromobenzene.
  • PCT publication WO2016/122420 disclosed an improved process for the preparation of pirfenidone, which involves the reaction of 5-methyl-2-pyridone with low quantity of bromobenzene in a low quantity of solvent, in presence of copper catalyst such as Cu(l) or Cu(ll) salts and a base.
  • This publication Further disclosed the purification of pirfenidone by formation of pirfenidone acid adducts with strong acids followed by recovery of pirfenidone from the adduct.
  • the present invention provides an improved process for the preparation of pure pirfenidone. More specifically, provides an improved process for pirfenidone which comprise of reacting the 5 -methyl- lH-pyridin-2-one of formula- II with bromobenznene, wherein the bromobenzene contain about 0.2% or more by weight dibromobenzene.
  • the present invention provides an improved process for the preparation of pirfenidone of formula (I),
  • bromobenzene in the presence of a suitable copper catalyst and a base in a suitable organic solvent under sufficient conditions to provide pirfenidone, wherein the bromobenzene contain about 0.2% or more by weight dibromobenzene.
  • the present invention provides an improved process for the preparation of pirfenidone, which comprises the reaction of 5-methyl-lH-pyridin-2-one with bromobenzene in presence of copper chloride and potassium carbonate in dimethylformamide under sufficient conditions to provide pirfenidone, wherein the bromobenzene contain about 0.2% or more by weight dibromobenzene.
  • the present invention provides crystalline pirfenidone characterized by its Powder X-ray diffractogram having one or more peaks at about 8.76, 14.22, 14.90, 18.36, 18.72, 19.86, 20.90, 21.92, 22.52, 22.86, 24.22, 26.96, 27.20, 28.16, 28.80, 29.50, 30.20, 31.42, 32.32, 37.02, 39.40 and 43.38 ⁇ 0.2 °2 ⁇ or by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 1.
  • PXRD powder X-Ray diffraction
  • the present invention provides crystalline pirfenidone characterized by a differential scanning calorimetry (DSC) substantially in accordance with Figure 2.
  • the present invention provides a process for the purification of pirfenidone, comprising:
  • the present invention provides a process for preparation of pirfenidone having less than 0.1% by HPLC of dimer impurity of Formula IV comprising: dissolving pirfenidone in an ester solvent or aromatic hydrocarbon solvent and isolating the pirfenidone.
  • the present invention provides a process for preparing pirfenidone having a particle size with D90 from 50 microns to 500 microns, comprising:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising pirfenidone prepared by the process of the invention and at least one pharmaceutically acceptable excipient.
  • Figure 1 illustrates the characteristic powder X-ray diffraction (XRD) pattern of crystalline pirfenidone.
  • Figure 2 illustrates the characteristic differential scanning calorimetric (DSC) thermogram of crystalline pirfenidone.
  • the present invention provides an improved process for the preparation of pure pirfenidone using the commercially available bromobenzene having about 0.2% or more by weight dibromobenzene.
  • the purity of the bromobenzene is more important for the preparation of pirfenidone, as amount of dibromobenzene impurity in the bromobenzene leads to produce dimer-type byproducts, which are difficult to remove from final pirfenidone using regular purification techniques.
  • the ⁇ 40 patent utilizes bromobenzene having less than 0.15% by weight dibromobenzene.
  • the present invention provides an improved process for preparation of pure pirfenidone utilizing commercially available bromobenzene having about 0.2% or more by weight dibromobenzene. Thereby avoiding the sourcing difficulties and cost associated with sourcing of bromobenzene with particular purity level.
  • the present invention provides an improved process for the preparation of pirfenidone of formula (I)
  • the another starting material bromobenzene of formula (III) is commercially available and having dibromobenzene isomer content such as 1,4-dibromobenzene, 1,3-dibromobenzene and 1 ,2-dibromobenzene, is in the range of about 0.2% to about 1% w/w.
  • the suitable copper catalyst used herein for the reaction of formula (II) with formula (III) is selected from copper (I)chloride, copper (I) bromide, copper(I)iodide and the like. Preferably copper(I)chloride.
  • the suitable base used herein is selected from alkali metal carbonates such as potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate and the like; alkali metal hydroxide such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like, or mixtures thereof; organic base such as triethylamine, diisopropylethylamine and the like.
  • alkali metal carbonates such as potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate and the like
  • alkali metal hydroxide such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like, or mixtures thereof
  • organic base such as triethylamine, diisopropylethylamine and the like.
  • the suitable base is potassium carbonate.
  • the suitable organic solvent used herein is selected from hydrocarbon solvents such as benzene, chlorobenzene, toluene, xylene, heptane, hexane, cyclohexane, methyl cyclohexane, cyclopentane and the like; amide solvents such as dimethylacetamide, dimethylformamide, N-methylformamdide, dimethylimidazolidinone, N-methyl pyrrolidinone and the like; dimethylsulfoxide; and mixtures thereof.
  • the suitable solvent is dimethylformamide.
  • the reaction of formula (II) with formula (III) can be suitably carried out at a temperature of about 30°C to about 180°C, preferably at about 100°C to about 160°C for sufficient period of time to complete the reaction, preferably for 1 to 24 hrs, more preferably for 8-12 hrs.
  • the product formed can be isolated by the techniques known in the art; preferably by filtration.
  • the present invention provides a process for the purification of pirfenidone, comprising:
  • the starting pirfenidone and alkaline base is taken in a flask at about 25°C to about 35°C and raising the reaction mass temperature at about 70 to about 90°C to completely dissolving the reactants. Then, isolating the pure pirfenidone by methods known in the art, for example, cooling the reaction mass to below about 20°C followed by filtration and drying at suitable temperature.
  • the suitable alkaline base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like, and mixtures thereof; preferably aqueous sodium hydroxide solution.
  • the present invention provides crystalline pirfenidone characterized by its Powder X-ray diffractogram having one or more peaks at about 8.76, 14.22, 14.90, 18.36, 18.72, 19.86, 20.90, 21.92, 22.52, 22.86, 24.22, 26.96, 27.20, 28.16, 28.80, 29.50, 30.20, 31.42, 32.32, 37.02, 39.40 and 43.38 ⁇ 0.2 °2 ⁇ or by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 1.
  • PXRD powder X-Ray diffraction
  • the present invention provides crystalline pirfenidone characterized by a differential scanning calorimetry (DSC) substantially in accordance with Figure 2.
  • DSC differential scanning calorimetry
  • the present invention provides a process for preparation of pirfenidone having less than 0.1% by HPLC of dimer impurity of Formula IV, comprising: dissolving pirfenidone in an ester solvent or aromatic hydrocarbon solvent and isolating the pirfenidone.
  • the process of dissolving pirfenidone in an ester solvent or aromatic hydrocarbon solvent is carried out at a temperature of about 25°C to about reflux, preferably at reflux temperature.
  • the esters include, but are not limited to ethyl acetate, methyl acetate, isopropyl acetate and the like; aromatic hydrocarbons such as toluene, xylene and the like; preferably ethyl acetate or toluene.
  • the contents may be stirred for sufficient period of time, preferably for about 10 min to about 30 min for complete dissolution.
  • the solution may be optionally concentrated to partially reduce the solvent volume and cooled to a temperature from about 25 °C or less such that the pirfenidone can be isolated by conventional techniques, for example by filtration.
  • the present invention provides a process for preparing pirfenidone having a particle size with D90 from 50 microns to 500 microns, comprising:
  • Step a) of the forgoing process involves the dissolution of pirfenidone in an organic solvent, wherein the organic solvent includes but are not limited to aromatic hydrocarbons such as toluene, xylene and the like; esters such as isopropyl acetate, methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; ethers such as methyl tertiary butyl ether, tetrahydrofuran, dimethyl ether, diisopropyl ether, 1,4-
  • aromatic hydrocarbons such as toluene,
  • reaction mixture may be heated to complete dissolution of the contents in the solvent.
  • the suitable temperature may be selected from 35 °C to about reflux temperature of the solvent used; preferably at about 50°C to about 65 °C.
  • the anti-solvent used for step b) includes but are not limited to water, hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, cyclohexane, methyl cyclohexane, cycloheptane or mixture thereof.
  • antisolvent at different temperatures leads to formation of pirfenidone particles with different sizes; for instance: anti solvent addition at 0 to -10°C, preferably at - 5 ⁇ 2°C temperature forms small particles (D90: 50-100 ⁇ ), at 0 to 10°C, preferably at 7 ⁇ 3°C temperature forms particles of D90 at 100-150 ⁇ and at below 45 °C forms particles of D90 at 250-500 ⁇ .
  • step c) of the foregoing process involves the isolation of pirfenidone.
  • the isolation can be carried out by conventional techniques known in the art, for example filtration.
  • the step c) of the isolation of the pirfenidone is particularly carried out by stirring the step b) reaction solution at less than about 30°C, preferably at about 0-5°C, at about 5-10°C and at about room temperature for about 10 minutes to about 4 hours and the precipitated crystals can be isolated by methods known in the art, filtration, followed by drying the resultant crystals at temperature below 65 °C under vacuum.
  • the pirfenidone prepared according to the present invention is having purity of at least about 98% as measured by HPLC, preferably at least about 99% as measured by HPLC; more preferably at least about 99.5% as measured by HPLC.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising pirfenidone prepared by the process of the invention and at least one pharmaceutically acceptable excipient.
  • DM water 800 ml was added to concentrated sulfuric acid (227 g) at 0-5°C and stirred for 15 mins.
  • 2-amino-5-methyl pyridine 100 g
  • aqueous sodium nitrite 83 g of sodium nitrite dissolved in 200 ml of water
  • the reaction mass was stirred for an hour at 0-5°C.
  • reaction mass temperature was raised to 25-35°C and stirred for 4 hrs.
  • Aqueous sulphamic acid 26.9 g of sulphamic acid dissolved in 100 ml of water was added to the reaction mass and stirred for 60 mins at 25-35°C.
  • reaction mass was cooled to 10-15°C and pH was adjusted to 7 with aqueous sodium hydroxide solution.
  • the reaction mass was heated to 55-65°C and extracted with ethyl acetate (6 X 500 ml). The solvent from the extract was distilled off completely under mild vacuum at below 60°C. Ethyl acetate (200 ml) was added to the obtained residue and the reaction mixture was cooled to 25-35°C then stirred for an hour. The precipitated solid was filtered, washed with ethyl acetate and dried at 45-55°C.
  • Example-2 Preparation of pirfenidone: A mixture of 5 -methyl- lH-pyridin-2-one (100 g), bromo benzene (259 g, comprising greater than 0.2% by weight dibromobenzene isomers) and dimethylformamide (200 ml) were added in to a round bottom flask and stirred up to complete dissolution. Potassium carbonate (254 g) and copper (I) chloride (18.2 g) was added to the above reaction mass and then heated to 130-140°C. The reaction mass was stirred at 130-140°C for 10 hrs. After the reaction completion, the reaction mass was cooled to 25-35°C.
  • Toluene (500 ml), aqueous sodium chloride (75 g of sodium chloride in 500 ml of water) was added to the reaction mass and stirred for 15-30 mins at 25-35°C. The reaction mass was filtered and the filtrate was allowed to settle. Organic and aqueous layers were separated and the aqueous layer was extracted with toluene. Organic layers combined and was washed with aqueous sodium chloride, treated with carbon and filtered through hyflo. The solvent from the filtrate was distilled off completely under vacuum at below 60°C. Toluene (300 ml) was added to the obtained residue and stirred for 30 mins. The reaction mass was heated to 77-83°C and stirred for 45 mins.
  • the reaction mass was cooled to 25-35°C over 60 mins. The reaction mass was further cooled to 0-6°C. The solid obtained was filtered, washed with toluene and dried under vacuum. DM water (500 ml) was added to the above obtained wet compound followed by 50% aqueous sodium hydroxide solution (10 g of sodium hydroxide in 20 ml of water) at 25-35°C. The reaction mass was heated to 75-85°C and stirred for 30-60 mins. The reaction mass was then gradually cooled to 25-35°C and stirred for 60 mins. The reaction mass was further cooled to 0-5 °C and stirred for 3 hrs. The obtained solid was filtered, washed with water and dried to provide the title compound.
  • the XRPD is set forth in Figure 1 ;
  • the DSC is set forth in Figure 2.
  • Example-3 Purification of pirfenidone (from ethyl acetate).
  • Example-4 Purification of pirfenidone (from toluene).
  • Pirfenidone (83g) was dissolved in ethyl acetate (425 mL), at 55-65°C, and then added to pre-cooled (-5 ⁇ 2°C) n-Heptane (425 mL), over a period of 15-20 min, while maintaining temperature below 20°C.
  • the suspension was stirred, at 0-5°C, for l-2h; filtered the product washed with chilled ethyl acetate (50 mL).
  • the wet material was dried, at 60°C, under vacuum, for 6-8h, to afford Pirfenidone as white colored powder. Yield: 65 g, HPLC purity 99.9%, PSD: (D 90 ) 50-100 ⁇ .
  • Pirfenidone (81g) was dissolved in ethyl acetate (425 mL), at 55-65°C, and then added to pre-cooled (7 ⁇ 3°C) n-Heptane (425 mL), over a period of 15-20 min, while maintaining temperature below 20°C.
  • the suspension was stirred, at 0-5°C, for l-2h; filtered the product washed with chilled ethyl acetate (50 mL).
  • the wet material was dried, at 60°C, under vacuum, for 6-8h, to afford Pirfenidone as white colored powder Yield: 61 g, HPLC purity 99.9%, PSD: (D 90 ) 100-150 ⁇ .
  • Example 7 Example 7:
  • Pirfenidone (81g) was dissolved in ethyl acetate (500 mL), at 50-55°C, and then added to pre-cooled (8 ⁇ 3°C) n-Heptane (500 mL), over a period of 15-20 min, while maintaining temperature below 25°C.
  • the suspension was stirred, at 5-10°C, for l-2h; filtered the product washed with chilled ethyl acetate (50 mL).
  • the wet material was dried, at 60°C, under vacuum, for 6-8h, to afford Pirfenidone as white colored powder Yield: 57 g, HPLC purity 99.9%, PSD: (D 90 ) 150-250 ⁇ .
  • Pirfenidone (80g) was dissolved in ethyl acetate (400 mL), at 55-65°C, and then added to n- Heptane (400 mL), over a period of 5-10 min, while maintaining temperature below 45 °C.
  • the suspension was stirred, at 25-30°C, for l-2h; filtered the product washed with chilled ethyl acetate (50 mL).
  • the wet material was dried, at 60°C, under vacuum, for 6-8h, to afford Pirfenidone as white colored powder, Yield: 55 g, HPLC purity 99.9%, PSD: (D 90 ) 250-500 ⁇ .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pyridine Compounds (AREA)

Abstract

La présente invention concerne un procédé perfectionné de préparation de pirfénidone pure. Elle concerne également une forme cristalline de pirfénidone, et une composition pharmaceutique la comprenant.
PCT/IB2017/050141 2016-01-14 2017-01-12 Procédé perfectionné de préparation de pirfénidone Ceased WO2017122139A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US16/032,210 US11066368B2 (en) 2016-01-14 2018-07-11 Process for the preparation and particle size reduction of pirfenidone

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201641001390 2016-01-14
IN201641001390 2016-01-14

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/032,210 Continuation-In-Part US11066368B2 (en) 2016-01-14 2018-07-11 Process for the preparation and particle size reduction of pirfenidone

Publications (1)

Publication Number Publication Date
WO2017122139A1 true WO2017122139A1 (fr) 2017-07-20

Family

ID=59311970

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2017/050141 Ceased WO2017122139A1 (fr) 2016-01-14 2017-01-12 Procédé perfectionné de préparation de pirfénidone

Country Status (1)

Country Link
WO (1) WO2017122139A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3494965A1 (fr) 2017-12-11 2019-06-12 Laurus Labs Limited Procédé amélioré pour la préparation de pirfénidone
CN112409246A (zh) * 2019-08-21 2021-02-26 北京凯因科技股份有限公司 一种新型吡非尼酮的晶型及其制备方法
CN114195708A (zh) * 2021-11-30 2022-03-18 岳阳新华达制药有限公司 一种吡非尼酮的纯化方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010141600A2 (fr) * 2009-06-03 2010-12-09 Intermune, Inc. Procédé de synthèse amélioré de la pirfénidone

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010141600A2 (fr) * 2009-06-03 2010-12-09 Intermune, Inc. Procédé de synthèse amélioré de la pirfénidone

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3494965A1 (fr) 2017-12-11 2019-06-12 Laurus Labs Limited Procédé amélioré pour la préparation de pirfénidone
CN112409246A (zh) * 2019-08-21 2021-02-26 北京凯因科技股份有限公司 一种新型吡非尼酮的晶型及其制备方法
CN112409246B (zh) * 2019-08-21 2023-04-07 北京凯因科技股份有限公司 一种吡非尼酮的晶型及其制备方法
CN114195708A (zh) * 2021-11-30 2022-03-18 岳阳新华达制药有限公司 一种吡非尼酮的纯化方法

Similar Documents

Publication Publication Date Title
JP5535082B2 (ja) ボセンタン、その多形形態及びその塩の合成方法
WO2013026391A1 (fr) Procédé de synthèse d'azoxystrobine et intermédiaire exclusif utilisé dans sa synthèse
EP2094665A2 (fr) Préparation de montélukast et de ses sels
US8962832B2 (en) Process for the preparation of ambrisentan and novel intermediates thereof
JP2015107976A (ja) 結晶形態のテノホビルジソプロキシル及びその製造方法
JP6081450B2 (ja) アセナピンの結晶塩
US20210002275A1 (en) Process for preparation of palbociclib
WO2010103362A2 (fr) Procédé pour la préparation du bosentan
JP4262920B2 (ja) 置換シクロペンタン誘導体の調製方法及びその新規結晶構造
JP7622338B2 (ja) ２－（３，５－ジクロロフェニル）－６－ベンズオキサゾールカルボン酸１－デオキシ－１－メチルアミノ－ｄ－グルシトールの製造方法
WO2024228133A1 (fr) Nouveaux sels de tegoprazan et ses polymorphes
WO2017122139A1 (fr) Procédé perfectionné de préparation de pirfénidone
WO2013024492A2 (fr) Procédé de préparation d'asénapine et nouveaux sels de celle-ci
US20190284197A1 (en) Pharmaceutically acceptable salts and polymorphic forms of hydrocodone benzoic acid enol ester and processes for making same
JP2019108351A (ja) モリンドン及びその塩の製造方法
CN113880819B (zh) 立他司特的制备方法及其中间体化合物
WO2012103105A1 (fr) Procédés de préparation du raltégravir et de ses intermédiaires dans lesdits procédés
US20130109865A1 (en) Methods of preparing 1-(4-((1r,2s,3r)-1,2,3,4-tetrahydroxybutyl)-1h-imidazol-2-yl)ethanone
EP3374349A1 (fr) Procédé de préparation d'eltrombopag olamine
WO2005100367A1 (fr) Intermediaires utiles dans la synthese de cephalosporines (vinyle substitue en 2)-3
US20120165527A1 (en) process for the preparation of pure paliperidone
WO2015104602A2 (fr) Procédé de préparation d'anagliptine et de ses intermédiaires
US20140275535A1 (en) Acid addition salts of bosentan
KR100963520B1 (ko) 이르베사르탄의 개선된 제조방법
TW202539676A (zh) 製備ｎ－［（１ｓ，２ｅ）－１－環丙基－３－（甲磺醯基）丙－２－烯－１－基］－２－（１，１－二氟乙基）－４－苯氧基嘧啶－５－甲醯胺之方法

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: 17738264

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: 17738264

Country of ref document: EP

Kind code of ref document: A1