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WO2017033016A1 - Procédé de préparation d'un antagoniste des récepteurs d'endothéline - Google Patents

Procédé de préparation d'un antagoniste des récepteurs d'endothéline Download PDF

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Publication number
WO2017033016A1
WO2017033016A1 PCT/GB2016/052636 GB2016052636W WO2017033016A1 WO 2017033016 A1 WO2017033016 A1 WO 2017033016A1 GB 2016052636 W GB2016052636 W GB 2016052636W WO 2017033016 A1 WO2017033016 A1 WO 2017033016A1
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WO
WIPO (PCT)
Prior art keywords
formula
process according
compound
combination
temperature
Prior art date
Application number
PCT/GB2016/052636
Other languages
English (en)
Inventor
Dharmaraj Ramachandra Rao
Geena Malhotra
Srinivas Laxminarayan Pathi
Ravikumar Puppala
Narayanaswami KOMMULA
Original Assignee
Cipla Limited
King, Lawrence
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 Cipla Limited, King, Lawrence filed Critical Cipla Limited
Publication of WO2017033016A1 publication Critical patent/WO2017033016A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine

Definitions

  • the present invention relates to an improved process for the preparation of substantially pure macitentan and to macitentan prepared from such a process.
  • WO02053557 Al discloses a process for the preparation of macitentan as shown in Scheme 1 :
  • step 1 of the process the compound of formula (III) is reacted with ethylene glycol using potassium tertbutoxide in dimethoxy ethane at 100 °C.
  • the isolated solid is further purified by column chromatography, yielding the compound of formula (II).
  • step 2 the compound of formula (II) is added to sodium hydride (NaH) in tetrahydrofuran (THF), diluted with dimethylformamide (DMF), and then reacted with 5-bromo-2-chloropyridine at 60 °C to obtain macitentan of formula (I).
  • the compound of formula (I) is further crystallized according to the disclosed method.
  • step 1 of Scheme 1 describes an alternative route for step 1 of Scheme 1, wherein the compound of formula (III), is reacted with excess ethylene glycol in the presence of a large quantity of base, such as potassium tert-butoxide (3-4 equivalents), at a high temperature such as 100°C for 70hrs to obtain the compound of formula (II).
  • base such as potassium tert-butoxide (3-4 equivalents)
  • Ethylene glycol is toxic in nature and is a high boiling solvent, rendering it difficult to use on industrial scale and difficult to remove by distillation.
  • WO2015004265 discloses preparation of the intermediate compound of formula (II), N-[5-(4- bromophenyl)-6-(2hydroxyethoxy)-4-pyrimidinyl]-N'-propyl-sulfamide, or a salt thereof (Scheme 1) in the presence of ethylene glycol and a base, which process comprises extracting the compound of formula (II) using methyl iso-butyl ketone (MIBK) as the solvent.
  • MIBK methyl iso-butyl ketone
  • WO2014155304 discloses a process for preparing macitentan as shown in Scheme 2 wherein the compound of formula (III) is reacted with 2-(t-butoxy)ethanol to yield the compound of formula (IIIA), which is selectively deprotected to yield the compound of formula (II).
  • the compound of formula (II) is further reacted with 5-bromo-2-chloropyridine to obtain macitentan of formula (I).
  • the principal object of the present invention is to provide a process for the preparation of macitentan using a green chemistry approach, thereby using a green solvent that is environmentally friendly.
  • Another object of the invention is to provide a process for the preparation of substantially pure macitentan in high yield.
  • Yet another object of the present invention is to provide a process for the preparation of macitentan which is simple, economical and suitable for industrial scale up.
  • the present invention provides a process for preparing macitentan of formula
  • the present invention provides a process for preparing macitentan of formula (I):
  • macitentan prepared according to the process of the present invention is in substantially pure form and may be used without further purification.
  • steps (i) and (ii) as hereinbefore described are carried out without isolation of the intermediate compound of formula (II) in a one pot synthesis to obtain a compound of formula (I).
  • intermediate compound of formula (II) is not isolated from the reaction mixture as a solid.
  • the present invention also provides a one-pot process for preparing macitentan of formula (I):
  • the polar aprotic solvent is selected from 2-methyltetrahydrofuran,
  • the present invention provides a green process for preparation of "substantially pure macitentan" without utilizing hazardous solvents as well as high capital intensive processes.
  • the inventors of the present invention have rationally designed an improved process for preparation of macitentan using a green solvent, making the process eco-friendly, inexpensive and industrially viable.
  • These green solvents are alternatives to dichloromethane and tetrahydrofuran.
  • the product obtained is in high yield and high purity without involving tedious and costly purification processes like column chromatography.
  • the present invention relates to the synthesis of macitentan and employs "green” (i.e. nontoxic) polar aprotic solvents such as 2-methyl THF (2-methyltetrahydrofuran), dialkylcarbonates, including but not limited to dimethylcarbonate and diethylcarbonate and the like, which contribute to green chemistry.
  • 2-methyl THF 2-methyltetrahydrofuran
  • dialkylcarbonates including but not limited to dimethylcarbonate and diethylcarbonate and the like, which contribute to green chemistry.
  • 2-methyl THF which is environmentally friendly and safe, rather than THF, as reported in the prior art, reduces the reaction times and also yields macitentan in high purity.
  • the present invention also provides a process for obtaining substantially pure macitentan of formula (I).
  • the inventors of the present invention observed that macitentan obtained using the process disclosed in the prior art process (WO 2002053557) is 62.52% pure whereas the processes of the present invention described herein advantageously yield macitentan having purity at least about 99.5% as depicted in below Table 1.
  • the present invention describes a practical, economical and efficient synthesis for the preparation of macitentan. This process is particularly advantageous in comparison with known methods because the reaction may be carried out according to a "one-pot" method, i.e. without isolating the intermediates formed.
  • the process of the present invention eliminates the risk of handling hazardous chemicals, the enhanced cost associated with multiple reactors, and it reduces the reaction time and clean-up, thus making the process more industrially viable.
  • an improved process for the synthesis of macitentan as depicted below in reaction Scheme 3 :
  • sulfamide compound of formula (III) refers to the compound N- [5-(4-bromophenyl)-6-chloro-4-pyrimidinyl]-N'-propyl-sulfamide:
  • hydroxy compound of formula (II) refers to the compound N-[5- (4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-N'-propyl- sulfamide:
  • substantially pure and “high purity” refer to macitentan having a purity (measured by HPLC) of at least 99.5%, preferably above about 99.7% and more preferably above about 99. 90%.
  • Green chemistry As used herein, the terms “Green chemistry”, “Green solvent” and “Green approach” refer to a philosophy of chemical research and engineering that encourages the design of products and processes that minimize the use and generation of hazardous substances.
  • suitable “green” solvents which may be employed in the process of the present invention include, but are not limited to, 2-methyltetrahydrofuran, dialkylcarbonates such as dimethylcarbonate and diethyl carbonate and the like.
  • step (i) of the process of the present invention the sulfamide compound of formula (III) is reacted with ethylene glycol in presence of a suitable base, to give the hydroxy compound of formula (II).
  • Suitable bases for use in step (i) of the process of the present invention include, but not limited to, an organic base, such as triethylamine (TEA) and diisopropylethylamine (DIPEA), or any inorganic base, such as sodium hydroxide (NaOH), potassium hydroxide (KOH) or potassium carbonate (K 2 C0 3 ), sodium carbonate (Na 2 C0 3 ) and the like, or any combination thereof.
  • the base is sodium hydroxide.
  • the molar ratio of ethylene glycol to sulfamide compound of formula (III) is suitably in the range of from 1- 10: 1, i.e. from 1 to 10 equivalents of ethylene glycol per equivalent of sulfamide compound of formula (III).
  • the molar ratio is from 6: 1, i.e. 6 equivalents of ethylene glycol to one equivalent of sulfamide compound of formula (III).
  • Step (i) of the process of the present invention is optionally carried out in a suitable solvent.
  • Suitable solvents include, but are not limited to, polar aprotic solvents, such as 2- methyltetrahydrofuran, dialkylcarbonates, such as dimethylcarbonate and diethylcarbonate, or any combination thereof.
  • the solvent is 2-methyltetrahydrofuran.
  • the reaction mass (mixture) formed upon treatment of the sulfamide compound of formula (III) with ethylene glycol in presence of a suitable base is optionally stirred at a temperature ranging from about room (ambient) temperature to about the reflux temperature of solvent used.
  • the reaction mass is heated at a temperature in the range from about 20 °C to about 120 °C.
  • reaction mixture is typically cooled and further quenched using IN HC1.
  • water is also added.
  • suitable solvents include, but are not limited to, 2- methyltetrahydrofuran, dialkylcarbonates, such as dimethylcarbonate and diethylcarbonate, and the like.
  • the solvent is 2-methyltetrahydrofuran.
  • the hydroxy compound of formula (II) is optionally purified using one or more suitable solvents including, but not limited to, C 1 -C4 alcohols, esters such as ethyl acetate, ketones such as acetone, hydrocarbons such as toluene, xylene, heptane and the like or any combination thereof.
  • suitable solvents including, but not limited to, C 1 -C4 alcohols, esters such as ethyl acetate, ketones such as acetone, hydrocarbons such as toluene, xylene, heptane and the like or any combination thereof.
  • purification of the hydroxy compound of formula (II) is carried out using a mixture of methanol and toluene, such as 5% methanol in toluene.
  • step (ii) of the process of the present invention the hydroxy compound of formula (II) is reacted with 5-bromo-2-chloropyrimidine in the presence of a suitable base and an aprotic solvent to obtain macitentan of formula (I).
  • Suitable aprotic solvents for use in step (ii) of the process of the present invention include, but are not limited to, 2-methyltetrahydrofuran, dialkylcarbonates, such as dimethylcarbonate and diethylcarbonate and the like, or any combination thereof.
  • the solvent is 2- methyltetrahydrofuran.
  • Suitable bases for use in step (ii) of the process of the present invention include, but are not limited to, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, potassium tert-butoxide, and sodium tert-butoxide and the like.
  • the base is sodium tert-butoxide.
  • the compound of formula (I) so formed is optionally purified using one or more suitable solvents including, but not limited to, organic solvents such as C1-C4 alcohols, esters such as ethyl acetate, ketones such as acetone and the like, or any combination thereof.
  • suitable solvents including, but not limited to, organic solvents such as C1-C4 alcohols, esters such as ethyl acetate, ketones such as acetone and the like, or any combination thereof.
  • the purification solvent is ethyl acetate.
  • steps (i) and (ii) may optionally be carried out in a "one-pot" synthesis to obtain a compound of formula (I), comprising the steps of:
  • step (a) a) reacting the compound of formula (III) with ethylene glycol in presence of a suitable base; b) extracting the compound of formula (II) obtained in step (a) in a mixture of one or more suitable polar aprotic solvents selected from the group comprising of 2- methyltetrahydrofuran, dialkylcarbonate and the like; c) adding a suitable base and 5-bromo-2-chloropyrimidine to the resulting organic layer; and d) isolating and purifying the compound of formula (I) so formed in one or more suitable solvents.
  • suitable polar aprotic solvents selected from the group comprising of 2- methyltetrahydrofuran, dialkylcarbonate and the like
  • Suitable bases for use in step a) of the one-pot process of the present invention include, but not limited to, organic bases, such as triethylamine (TEA) and diisopropylethylamine (DIPEA), or inorganic bases, such as sodium hydroxide (NaOH), potassium hydroxide (KOH) or potassium carbonate (K 2 C0 3 ), sodium carbonate (Na 2 C0 3 ) and the like.
  • the base is sodium hydroxide.
  • the molar ratio of ethylene glycol to sulfamide compound of formula (III) is suitably in the range of from 1- 10: 1, i.e.
  • the molar ratio is from 6: 1, i.e. 6 equivalents of ethylene glycol to one equivalent of sulfamide compound of formula (III).
  • Step a) of the one-pot process of the present invention is optionally carried out in a suitable solvent.
  • suitable solvents include, but are not limited to polar aprotic solvents, such as 2-methyltetrahydrofuran, dialkylcarbonates and the like, or any combination thereof.
  • the solvent is 2-methyltetrahydrofuran.
  • the reaction mass (mixture) formed upon treatment of the sulfamide compound of formula (III) with ethylene glycol in presence of a suitable base is optionally stirred at a temperature ranging from about room (ambient) temperature to about the reflux temperature of solvent used.
  • the reaction mass is heated at a temperature in the range from about 20 °C to about 120 °C.
  • reaction mixture is typically cooled and further quenched using IN HC1.
  • water is also added.
  • reaction mass is optionally further extracted using one or more suitable solvents, treated with water and dried.
  • a suitable drying agent is sodium sulphate.
  • Suitable solvents include, but are not limited to, organic solvents, such as polar aprotic solvents, including 2-methyltetrahydrofuran, dialkylcarbonates and the like.
  • organic solvents such as polar aprotic solvents, including 2-methyltetrahydrofuran, dialkylcarbonates and the like.
  • the solvent is 2-methyltetrahydrofuran.
  • the compound of formula (II) obtained in step a) of the one-pot process of the present invention is extracted using a mixture of one or more suitable organic solvents and one or more suitable aqueous solvents.
  • the organic layer is preferably cooled to a temperature between about 5 °C to 0 °C, preferably 3 ⁇ 2 °C, and subjected to lotwise (dropwise) addition of suitable base selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, potassium tert-butoxide and sodium tert-butoxide and the like.
  • 5-bromo-2-chloropyrimidine is added to the resulting mixture along with one or more suitable solvents including, but not limited to, one or more suitable polar aprotic solvents, such as 2-methyltetrahydrofuran, dialkylcarbonates and the like.
  • suitable solvents such as 2-methyltetrahydrofuran, dialkylcarbonates and the like.
  • the solvent is 2- methyltetrahydrofuran.
  • the temperature of the reaction mass is subsequently raised to about room (ambient) temperature and maintained at such temperature for about 3-4 hours.
  • the compound of formula (I) is purified using one or more suitable solvents including, but not limited to, organic solvents such as C 1 -C4 alcohols, esters such as ethyl acetate, ketones such as acetone and the like.
  • suitable solvents including, but not limited to, organic solvents such as C 1 -C4 alcohols, esters such as ethyl acetate, ketones such as acetone and the like.
  • the purification solvent is ethyl acetate.
  • Macitentan obtained by present the process of the present invention advantageously has a purity (measured by HPLC) of at least 99.5%, preferably above about 99.7% and more preferably above about 99.90%.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising macitentan prepared in accordance with a process described herein and one or more pharmaceutically acceptable excipients.
  • the sulfamide compound of formula (III) may be prepared by reacting 5-(4-bromophenyl)- 4,6-dichloropyrimidine with an alkaline metal salt of N-propyl sulfomyl amide in accordance with known methods or by any other process known in the art.
  • the solid was filtered, washed with purified water.
  • the water slurry wet material was further subjected to methanol purification, heated at 50 ⁇ 2 °C for 30 mins, cooled at 27 ⁇ 2 °C.
  • the final solid obtained was washed with methanol and dried under vacuum at 43 ⁇ 2 °C for 12 hours.
  • hydroxy 1 compound (II) 600 ml of ethylene glycol was added to 39.5gm of sodium hydroxide followed by 100 g of sulfamide compound (III) maintaining temperature 27 ⁇ 2°C. The reaction mass was heated at 108 ⁇ 2°C and maintained for 6 hours. On completion of reaction (checked by TLC), reaction mass was cooled to 27 ⁇ 2°C and 600 ml of purified water was charged followed by pH adjustment to 6.0 to 7.0 with IN HC1. Solution was heated to 55 ⁇ 2°C and stirred for 30 minutes, further cooled to 27 ⁇ 2°C, filtered and dried. To the dried material was added 400 ml of 5% methanol in toluene and the solution was heated at 63 ⁇ 2°C. The solution was cooled at 27 ⁇ 2°C, further chilled to 3 ⁇ 2°C, filtered, washed with toluene and dried under vacuum at 63 ⁇ 2°C for 12 hours.
  • sulfamide compound (III) prepared according to Example 1 was added 600 ml of ethylene glycol and 39.5 g of sodium hydroxide. The reaction mixture was heated at 96 ⁇ 3 °C and maintained for 6 hours. On completion of the reaction (checked by TLC), the reaction mixture was cooled to 27 ⁇ 2 °C. To the cooled mixture were added 800 ml of 2-methyl THF and 800 ml of purified water. The pH of the solution was adjusted to 1-2 with IN HC1. The layers were separated. Aqueous layer was extracted with 500 ml of 2-methyl THF. Combined organic layer was washed with 800 ml of purified layer followed by washing of 2 x 500 ml 10% sodium chloride.
  • the organic layer was dried over sodium sulphate and distilled under vacuum (up to 5 vol stage).
  • the dried organic layer containing the hydroxy compound (II) was cooled to -5 ⁇ 5 °C under nitrogen atmosphere.
  • To the cooled layer was added drop wise 132 g of sodium tertiary butoxide followed by addition of 120 g of 5- Bromo-2-chloro pyridine.
  • the temperature of the reaction mixture was raised to 5 ⁇ 5 °C and reaction was stirred for 6 hrs. Further, on completion of reaction (checked by TLC), was added 1000 ml of purified water.
  • the pH of the solution was adjusted to 5-6 with IN HC1. The layers were separated.
  • the organic layer was washed with purified water, sodium bicarbonate solution followed by sodium chloride solution.
  • the organic layer was dried over sodium sulphate and subjected to distillation. The resulting residue was given stripping of 200 ml of methanol. Further, 500ml of methanol was added and the mixture was heated to 55 ⁇ 5 °C further cooled to 27 ⁇ 2 °C, further chilled to 13 ⁇ 3 °C. The solid obtained was filtered and washed with 100 ml of methanol. The resulting solid was further treated with 300 ml of ethyl acetate and heated to 63 ⁇ 3 °C to obtain a clear solution which was treated with charcoal. The clear solution was cooled to 27 ⁇ 2 °C and further chilled to 3 ⁇ 2 °C. Solid obtained was filtered and washed with 100 ml of ethyl acetate. The solid was dried under vacuum at 43 ⁇ 2 °C for 12 hours.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation d'un macitentan de Formule (I) : un macitentan préparé selon ledit procédé et un macitentan sous une forme sensiblement pure.
PCT/GB2016/052636 2015-08-26 2016-08-24 Procédé de préparation d'un antagoniste des récepteurs d'endothéline WO2017033016A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3266/MUM/2015 2015-08-26
IN3266MU2015 2015-08-26

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WO2017033016A1 true WO2017033016A1 (fr) 2017-03-02

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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
WO2014155304A1 (fr) 2013-03-27 2014-10-02 Actelion Pharmaceuticals Ltd Préparation d'intermédiaires de pyrimidine utiles pour la production de macitentan
WO2015004265A1 (fr) 2013-07-12 2015-01-15 Actelion Pharmaceuticals Ltd Procédé pour préparer un intermédiaire de pyrimidine
CN104447572A (zh) * 2014-12-15 2015-03-25 南京艾德凯腾生物医药有限责任公司 一种马西替坦的制备方法

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
WO2014155304A1 (fr) 2013-03-27 2014-10-02 Actelion Pharmaceuticals Ltd Préparation d'intermédiaires de pyrimidine utiles pour la production de macitentan
WO2015004265A1 (fr) 2013-07-12 2015-01-15 Actelion Pharmaceuticals Ltd Procédé pour préparer un intermédiaire de pyrimidine
CN104447572A (zh) * 2014-12-15 2015-03-25 南京艾德凯腾生物医药有限责任公司 一种马西替坦的制备方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Process for preparing N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]- 4-pyrimidinyl)-N'-propylsulfamide and intermediates the", IP.COM JOURNAL, IP.COM INC., WEST HENRIETTA, NY, US, 21 January 2014 (2014-01-21), XP013160742, ISSN: 1533-0001 *
BOLLI, J. MED. CHEM., vol. 55, 2012, pages 7849 - 7861
MARTIN H. BOLLI ET AL: "The Discovery of N -[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]- N '-propylsulfamide (Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 17, 13 September 2012 (2012-09-13), pages 7849 - 7861, XP055078934, ISSN: 0022-2623, DOI: 10.1021/jm3009103 *

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