WO2017191565A1 - Procédé de préparation de macitentan - Google Patents

Procédé de préparation de macitentan Download PDF

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Publication number
WO2017191565A1
WO2017191565A1 PCT/IB2017/052553 IB2017052553W WO2017191565A1 WO 2017191565 A1 WO2017191565 A1 WO 2017191565A1 IB 2017052553 W IB2017052553 W IB 2017052553W WO 2017191565 A1 WO2017191565 A1 WO 2017191565A1
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WO
WIPO (PCT)
Prior art keywords
macitentan
pyrimidinyl
bromophenyl
preparation
impurity
Prior art date
Application number
PCT/IB2017/052553
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English (en)
Inventor
Sanjay HIRPARA
Chandresh Kumar TRIPATHI
Rajavardhan GOUD
Chaturvedi AKSHAY KANT
Original Assignee
Shilpa Medicare 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 Shilpa Medicare Limited filed Critical Shilpa Medicare Limited
Publication of WO2017191565A1 publication Critical patent/WO2017191565A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a process for the preparation of N-[5-(4- Bromophenyl)-6- [2- [(5 -bromo-2-pyrimidinyl)oxy] ethoxy] -4-pyrimidinyl] -N'propylsulfamide or Macitentan of Formula (I).
  • Macitentan is an endothelin receptor antagonist that prevents the binding of ET-1 to both ETA and ETB receptors. Macitentan displays high affinity and sustained occupancy of the ET receptors in human pulmonary arterial smooth muscle cells. One of the metabolites of Macitentan is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent as the parent drug in vitro.
  • Macitentan was approved by USFDA in 2013 and is marketed under the brand name OPSUMIT ® , is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression.
  • Disease progression included: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment).
  • OPSUMIT also reduced hospitalization for PAH.
  • Macitentan was chemically known as N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2- pyrimidinyl)oxy] ethoxy] -4-pyrimidinyl]-N'propylsulfamide (I).
  • Macitentan is a crystalline powder with the empirical formula C19H20Br2N6O4S and a molecular weight of 588.27. Macitentan is achiral and insoluble in water. In the solid state Macitentan is very stable, is not hygroscopic, and is not light sensitive.
  • Macitentan is generically and specifically claimed in US7094781 B2. This patent disclosed a generalized process for the preparation of Macitentan and its analogs. Macitentan was generically disclosed in Formula I-V of this patent. Further, this patent also disclosed active metabolites of Macitent which is shown below:
  • US 8324232 disclosed an active metabolite of Macitentan. As described above US '781 generically disclosed the active metabolites of Macitentan. The person skilled in the art will know how to prepare this active metabolite of Macitentan using the process as disclosed in US '781. IPCOM000235526 published on March 06, 2014 disclosed crystalline Macitentan. IPCOM00236886 published on May 21, 2014 disclosed crystalline Form-A, Form-B and amorphous form of Macitentan.
  • WO 2014173805 discloses crystalline Form -I of Macitentan. This patent disclosed that the crystalline Form-I of Macitentan was obtained as per Journal of Medicinal Chemistry 2012 by crystallization using methanol solvent.
  • WO 2014198178 disclosed crystalline Form II of Macitentan and a process for the preparation of Form II of Macitentan.
  • WO2016009322 discloses crystalline Form-Ill, Form-IV, Form-V and amorphous forms of Macitentan.
  • EP2907811 discloses a process for the preparation of Macitentan. The process disclosed in EP '81 lis as disclosed below:
  • WO2014155304 discloses a process for the preparation of Macitentan. The process disclosed in WO '304 is as disclosed below:
  • WO2015004265 discloses a process for the preparation of Macitentan. The process disclosed in WO '265 is as disclosed below:
  • the main objective of the invention relates to aprocess for the preparation of N-[5-(4- Bromophenyl)-6- [2- [(5-bromo-2-pyrimidinyl)oxy] ethoxy] -4-pyrimidinyl] -N'propylsulfamide or Macitentan(I).
  • Yet another objective of the invention relates to a process for the preparation of substantially pure N-[5 -(4-Bromophenyl)-6- [2- [(5 -bromo-2-pyrimidinyl)oxy] ethoxy] -4- pyrimidinylj-N'propylsulfamide or Macitentan (I)
  • the present invention relates to a process for the preparation of Macitentan (I)
  • the present invention further relates substantially pure Macitentan having purity of greater than 99.5% (By HPLC) and total impurities A to D and unknown impurities collectively less than 0.5% by HPLC.
  • Fig. 1 is an example of X-ray powder diffraction ("XRPD") pattern of crystallineN-[5-(4- Bromophenyl)-6- [2- [(5 -bromo-2-pyrimidinyl)oxy] ethoxy] -4-pyrimidinyl] -N'propylsulfamide or Macitentan obtained according to the process of the present invention.
  • XRPD X-ray powder diffraction
  • DSC Differential Scanning Calorimetry
  • the present invention relates to a process for the preparation of Macitentan (I)comprising preparing potassium salt of N-propyl sulfamide (III), which was prepared in- situ comprises of dissolving N-Propyl-sulfamide in a solvent selected from Dimethyl sulfoxide, Dimethyl acetamide, dimethyl formamide, N-Methyl pyrrolidine, 1,4-dioxane, tetrahydrofuran; and then adding a potassium source selected from potassium tertiary butoxide, potassium carbonate, potassium hydride.
  • a solvent selected from Dimethyl sulfoxide, Dimethyl acetamide, dimethyl formamide, N-Methyl pyrrolidine, 1,4-dioxane, tetrahydrofuran
  • the prior art process also involves the condensation potassium salt of N-propyl sulfamide with 5-(4-bromophenyl)-4,6-dichloropyrimidine.
  • the present inventors found that these prior art process requires 48 hours for completion of the reaction, which is not industrially feasible and yields in the formation of impurities and by products in the final Macitentan and quality of Macitentan obtained by the prior art process not meeting the ICH guidelines.
  • the present inventors surprisingly found that the condensation of 5-(4-bromophenyl)-4,6-dichloropyrimidine with potassium salt of N-propyl sulfamide, which was formed in-situ completes the reaction within 5 to 6 hours, which is industrially viable. Further, the product obtained as per the process meets the quality of ICH guidelines.
  • N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propyl sulfamide was added slowly to a Potassium tert-butoxide solution in Ethylene glycol at 10-15 °C and stirred the solution for 30 min to 1 hour at 25-30°C.
  • the contents of the reaction mass were raised to 90-130°C for about 12-14 hrs.
  • the obtained reaction mass was cooled to room temperature and then water and methanol was added.
  • Reaction mixture was cooled to 15-20 °C and added Citric acid solution for a period of about 1 hour to 2 hours and the reaction mass was maintained for 2-3 hrs at room temperature. Filter the solid and washed with water, suck dried the material for 30 min.
  • the product was dried under vacuum at 50-55 °C for 20- 24 hrs to obtain N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propyl s
  • the prior art process also involves the condensation N-5-(4-Bromophenyl)-6-chloro- 4-pyrimidinyl-N'-propylsulfamide with ethylene glycol in presence of a 1,2-dimethoxyethane solvent.
  • the present inventors found that these prior art process requires 70 hours for completion of the reaction, which is not industrially feasible and yields in the formation of impurities and by products in the final Macitentan and quality not meeting the ICH guidelines. Further, these processes involve cumbersome workup to remove the impurities.
  • the present inventors surprisingly found that the use of ethylene glycol as a reactant and as a solvent not only completes the reaction in 12 hours. But also, yield in highly pure N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'- propylsulfamide, which does not involves extra purification.
  • the process developed by the present inventors is industrially feasible and yields in highly pure Macitentan.
  • N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'- propylsulfamide was dissolved in a non-polar solvent selected from toluene, xylene, n- hexane, n-heptane or mixtures thereof.
  • a non-polar solvent selected from toluene, xylene, n- hexane, n-heptane or mixtures thereof.
  • sodium hydride was added slowly at 10-15°C and the stirred the contents for 20 minutes to 1 hour at 10-15°C.
  • Sodium hydride is commercially available in the mineral oil (wherein 55-60 % sodium hydride and 40-45% mineral oil).
  • the prior art process involves removal of mineral oil by washing with hexane to increase the reactivity of sodium hydride, which is very difficult to handle in the industrial scale due to highly explosiveness and quickly catches fire in air.
  • the obtained Macitentan was purified to obtain substantially pure Macitentan comprising the steps of:
  • the obtained Macitentan was purified using a polar solvent selected from selected from nitrile solvents such as acetonitrile, propionitrile; ketone solvents such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone (MIBK); amide solvents such as formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinylacetamide, N-vinyl pyrrolidone, 2- pyrrolidone; alcohols, such as methanol, ethanol, isopropanol, n-butanol, tert-butanol; ethers such as tetrahydrofuran, dioxane; water or mixtures thereof; at a temperature ranging from 60-90°C, by stirring the reaction mixture for 15 to 45 minutes to get clear solution, cooling to 50-60°C and then crystallizing at room temperature or adding precipitating
  • the obtained Macitentan was purified using column chromatography using polar/non-polar solvents to yield pure Macitentan. If the desired purity is not achieved, it is recommended to perform the same purification process operation by using same/different solvent as disclosed above to obtain the substantially pure Macitentan having a purity of greater than 99.5%.
  • Drying may be also be performed by any conventional process not limited to spray drying or distillation to remove the solvent. Drying may be performed under reduced pressure conditions also. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material.
  • the drying may be performed at a temperature ranging from 50-65°C for a time ranging from 12 to 16 hours depending upon the physical attributes of the end product obtained i.e. Pure Macitentan.
  • N-[5-(4-Bromophenyl)-6-[2-[(5- bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'propylsulfamide (I) or Macitentan obtained according to the present invention is having purity greater than 99.5%.
  • Macitentan obtained according to the present invention is having purity of greater than 99.5% and substantially free from process related impurities.
  • Macitentan obtained according to the present invention is analyzed by PXRD and obtained PXRD pattern appears to be crystalline.
  • the process related impurities that appear in the impurity profile of the N-[5-(4- Bromophenyl)-6- [2-[(5 -bromo-2-pyrimidinyl)oxy] ethoxy] -4-pyrimidinyl] -N'propylsulfamide (I) or Macitentan may be substantially removed by the process of the present invention resulting in the formation of highly pure material.
  • the process of the present invention is as summarized below:
  • the present invention relates to a substantially pure Macitentan having a purity of greater than 99.5 %(By HPLC) and total impurities A to D and unknown impurities collectively less than 0.5% by HPLC.
  • the present invention relates to a substantially pure Macitentan having a purity of greater than 99.6%(By HPLC) and total impurities A to D and unknown impurities collectively less than 0.4% by HPLC.
  • the present invention relates to a substantially pure Macitentan having a purity of greater than 99.7%(By HPLC) and total impurities A to D and unknown impurities collectively less than 0.3% by HPLC.
  • the present invention relates to a substantially pure Macitentan having a purity of greater than 99.8%(By HPLC) and total impurities A to D and unknown impurities collectively less than 0.2% by HPLC.
  • the present invention relates to a substantially pure Macitentan having a purity of greater than 99.9%(By HPLC) and total impurities A to D and unknown impurities collectively less than 0.1% by HPLC.
  • the N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2- pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'propylsulfamide (I) or Macitentanobtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules.
  • the active product is mixed with one or more pharmaceutically acceptable excipients.
  • the drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.
  • the compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions.
  • a solvent or vehicle propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed.
  • These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents.
  • the sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
  • compositions comprising N-[5-(4- Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'propylsulfamide (I) or Macitentanobtained as per the present application process- include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, macrocrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearic acid, magnesium stearate
  • compositions derived from N-[5- (4-Bromophenyl)-6- [2- [(5-bromo-2-pyrimidinyl)oxy] ethoxy]-4-pyrimidinyl] - N'propylsulfamide (I) or Macitentan of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
  • Reaction mixture was cooled to 15-20 °C and added 20% Citric acid solution (4.5 lit) for a period of about 1 hour to 2 hours and the reaction mass was maintained for 2-3 hrs at room temperature. Filter the solid and washed with water (700.0 ml), suck dried the material for 30 min. The product was dried under vacuum at 50-55 °C for 20-24 hrs to obtain title product.
  • the reaction mixture was allowed to room temperature and stirred for 5-6 hrs.
  • 10% citric acid solution (1020.0 ml) was added at 10-15 °C and allow the reaction mixture at 25-30°C and filter the reaction mass through Celite bed.
  • the organic layer was separated and washed with 10% NaCl solution (170 ml).
  • the organic layer was separated and distilled out under vacuum at 60-65 °C to obtain residue.
  • Methanol (68.0 ml) was added to the residue and stirred for 1 hr at 10-15 °C to obtain solid.
  • the precipitated solid was filtered and washed with chilled methanol (10 ml) and suck dried for 30 min. The solid was dried under vacuum at 55-60°C for 20-24 hrs to obtain title product.
  • Macitentan 142.0 gm was charged into a reaction flask containing Acetonitrile (1420.0 ml) and heated to 70-75 °C for 15 min to get clear solution, the reaction mixture was cooled to 50-55 °C and DM water (1420.0 ml) was added in 30 min. The reaction mixture was allowed to cool to room temperature and stirred for 1 hr to obtain solid. The precipitated solid was filtered and washed with water (284 ml) to yield pure Macitentan.
  • Macitentan (80.0 gm) was charged into a reaction flask containing Acetonitrile (640.0 ml) and heated to 70-75 °C for 15 min to get clear solution, the reaction mixture was cooled to 50-55 °C and DM water (640.0 ml) was added in 30 min. The reaction mixture was allowed to cool to room temperature and stirred for 1 hr to obtain solid. The precipitated solid was filtered and washed with water (160.0 ml). The product was dried under vacuum for 24 hrs at 55-60 °C to obtain pure Macitentan.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation de N-[5-(4-bromophényl))-6-[2-[(5-bromo-2-pyrimidinyl)oxy]éthoxy]-4-pyrimidinyl]-N'-propylsulfamide ou macitentan de formule (I). La présente invention concerne en outre un procédé de préparation de N-[5-(4-bromophényl))-6-[2-[(5-bromo-2-pyrimidinyl)oxy]éthoxy]-4-pyrimidinyl]-N'-propylsulfamide ou macitentan de formule (I) hautement pur. Ledit macitentan sensiblement pur est utile dans la préparation d'une composition pharmaceutique pour le traitement de troubles cardiaques.
PCT/IB2017/052553 2016-05-04 2017-05-03 Procédé de préparation de macitentan WO2017191565A1 (fr)

Applications Claiming Priority (2)

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IN201641015598 2016-05-04
IN201641015598 2016-05-04

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108727279A (zh) * 2018-07-27 2018-11-02 南京正大天晴制药有限公司 马昔腾坦有关物质d、其制备方法及用途
CN108732276A (zh) * 2018-07-27 2018-11-02 南京正大天晴制药有限公司 马昔腾坦有关物质的高效液相色谱分析方法
EP4154873A1 (fr) * 2021-09-22 2023-03-29 Sanovel Ilac Sanayi Ve Ticaret A.S. Comprimé comprenant du macitentan

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002053557A1 (fr) * 2000-12-18 2002-07-11 Actelion Pharmaceuticals Ltd Nouveaux sulfamides et leur utilisation comme antagonistes du recepteur de l'endotheline
WO2009024906A1 (fr) * 2007-08-17 2009-02-26 Actelion Pharmaceuticals Ltd Dérivé de 4-pyrimidinesulfamide
WO2014155304A1 (fr) * 2013-03-27 2014-10-02 Actelion Pharmaceuticals Ltd Préparation d'intermédiaires de pyrimidine utiles pour la production de macitentan
CN105461639A (zh) * 2015-12-10 2016-04-06 合肥久诺医药科技有限公司 一种高纯度马西替坦的精制方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002053557A1 (fr) * 2000-12-18 2002-07-11 Actelion Pharmaceuticals Ltd Nouveaux sulfamides et leur utilisation comme antagonistes du recepteur de l'endotheline
WO2009024906A1 (fr) * 2007-08-17 2009-02-26 Actelion Pharmaceuticals Ltd Dérivé de 4-pyrimidinesulfamide
WO2014155304A1 (fr) * 2013-03-27 2014-10-02 Actelion Pharmaceuticals Ltd Préparation d'intermédiaires de pyrimidine utiles pour la production de macitentan
CN105461639A (zh) * 2015-12-10 2016-04-06 合肥久诺医药科技有限公司 一种高纯度马西替坦的精制方法

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108727279A (zh) * 2018-07-27 2018-11-02 南京正大天晴制药有限公司 马昔腾坦有关物质d、其制备方法及用途
CN108732276A (zh) * 2018-07-27 2018-11-02 南京正大天晴制药有限公司 马昔腾坦有关物质的高效液相色谱分析方法
CN108732276B (zh) * 2018-07-27 2021-06-04 南京正大天晴制药有限公司 马昔腾坦有关物质的高效液相色谱分析方法
CN108727279B (zh) * 2018-07-27 2022-03-08 南京正大天晴制药有限公司 马昔腾坦有关物质d、其制备方法及用途
EP4154873A1 (fr) * 2021-09-22 2023-03-29 Sanovel Ilac Sanayi Ve Ticaret A.S. Comprimé comprenant du macitentan

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