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WO2024171717A1 - Procédé de fabrication de sélexipag et son procédé de purification - Google Patents

Procédé de fabrication de sélexipag et son procédé de purification Download PDF

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Publication number
WO2024171717A1
WO2024171717A1 PCT/JP2024/001426 JP2024001426W WO2024171717A1 WO 2024171717 A1 WO2024171717 A1 WO 2024171717A1 JP 2024001426 W JP2024001426 W JP 2024001426W WO 2024171717 A1 WO2024171717 A1 WO 2024171717A1
Authority
WO
WIPO (PCT)
Prior art keywords
isopropylamino
diphenylpyrazin
butyloxy
mixture
selexipag
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/JP2024/001426
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English (en)
Japanese (ja)
Inventor
直登 菊池
隆行 宮奥
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.)
Tokuyama Corp
Original Assignee
Tokuyama Corp
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 Tokuyama Corp filed Critical Tokuyama Corp
Publication of WO2024171717A1 publication Critical patent/WO2024171717A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms

Definitions

  • the present invention relates to a method for producing and purifying selexipag.
  • 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ -N-(methylsulfonyl)acetamide is a drug for treating pulmonary hypertension, also known as Selexipag (SXP).
  • Selexipag is represented by the following formula. Technologies related to Selexipag are disclosed, for example, in Patent Documents 1 and 2.
  • the object of the present invention is to provide a method for producing and purifying selexipag with fewer impurities.
  • a method for producing selexipag includes contacting a first mixture with aluminum oxide particles to obtain a second mixture.
  • the first mixture includes 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ -N-(methylsulfonyl)acetamide, 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ acetic acid, and a solvent.
  • the second mixture includes 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ -N-(methylsulfonyl)acetamide.
  • a method for purifying selexipag includes contacting a first mixture with aluminum oxide particles.
  • the first mixture includes 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ -N-(methylsulfonyl)acetamide, 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ acetic acid, and a solvent.
  • the present invention provides a method for producing and purifying selexipag with fewer impurities.
  • a method for producing or purifying 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ -N-(methylsulfonyl)acetamide is provided.
  • 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ -N-(methylsulfonyl)acetamide is also referred to as selexipag or SXP.
  • the manufacturing method according to the embodiment includes contacting a first mixture containing selexipag and impurities with aluminum oxide particles to obtain a second mixture containing selexipag.
  • This manufacturing method produces selexipag with fewer impurities. The reasons for this are believed to be as follows.
  • selexipag used as a raw material i.e., crude selexipag
  • synthesis method shown below a raw material obtained, for example, by the synthesis method shown below.
  • benzil (SX-A01) and glycinamide hydrochloride (SX-D01) are reacted in refluxing methanol solution in the presence of sodium hydroxide to obtain 2-hydroxy-5,6-diphenylpyrazine (SX-A02).
  • SX-A02 is reacted with refluxing phosphoryl chloride to obtain 2-chloro-5,6-diphenylpyrazine (SX-A03Cl).
  • SX-A03Cl is reacted with 4-(isopropylamino)-1-butanol (SX-E01) in n-methylpyrrolidone to obtain 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol (SX-A04).
  • SX-A04 is reacted with t-butyl bromoacetate to obtain tert-butyl 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ acetate (SX-A05Boc).
  • SX-A05Boc is hydrolyzed to obtain 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ acetic acid (SX-A06).
  • Selexipag (SXP) is obtained by reacting SX-A06 with sulfonamide.
  • the crude selexipag obtained by such a method may contain impurities.
  • impurities include 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ acetic acid (SX-A06), which is a precursor of selexipag.
  • SX-A06 is significantly removed by using aluminum oxide particles, i.e., alumina, as an adsorbent, compared to the case where other types of adsorbents are used. Therefore, according to the method of the embodiment, selexipag is obtained with a reduced amount of the impurity SX-A06.
  • the manufacturing method according to the embodiment includes contacting a first mixture containing selexipag, SX-A06, and a solvent with aluminum oxide particles to obtain a second mixture containing selexipag.
  • the purification method according to the embodiment includes contacting a first mixture containing selexipag, SX-A06, and a solvent with aluminum oxide particles.
  • the aluminum oxide particles may be composed of only aluminum atoms and oxygen atoms, or may contain other atoms. Examples of other atoms include hydrogen, carbon, sodium, silicon, and iron.
  • the aluminum oxide particles may be a composite oxide of Al 2 O 3 and at least one oxide selected from the group consisting of Na 2 O 3 , Fe 2 O 3 , and SiO 2. In the composite oxide, the proportion of Al 2 O 3 is, for example, 90 mass% or more.
  • the aluminum oxide particles may be in any form, such as powder, lump, or sphere.
  • the average particle size of the aluminum oxide particles as measured by the laser diffraction/scattering method is, for example, 0.05 mm or more and 0.3 mm or less.
  • the average particle size is preferably 0.1 mm or more and 0.2 mm or less.
  • activated alumina may be acidic, basic, or neutral.
  • As the activated alumina it is preferable to use basic alumina.
  • the pH of basic alumina is preferably 8 or more and 12 or less.
  • the aluminum oxide particles are porous.
  • the specific surface area of the aluminum oxide particles measured by the BET method is, for example, 100 m 2 /g or more and 300 m 2 /g or less.
  • the specific surface area is preferably 150 m 2 /g or more and 250 m 2 /g or less.
  • the aluminum oxide may be alpha alumina or gamma alumina.
  • the amount of aluminum oxide particles per 1 g of selexipag is, for example, 0.01 g or more and 10 g or less.
  • the amount of aluminum oxide particles is preferably 0.1 g or more and 5.0 g or less, and more preferably 0.2 g or more and 1.0 g or less. If the amount of aluminum oxide particles is large, the concentration of impurities tends to decrease.
  • the amount of aluminum oxide particles per 1 g of the first mixture is, for example, 0.001 g or more and 0.5 g or less.
  • the amount of aluminum oxide particles is preferably 0.01 g or more and 0.1 g or less, and more preferably 0.03 g or more and 0.05 g or less.
  • the solvent contained in the first mixture is water, an organic solvent, or a mixture of these. It is preferable to use an organic solvent as the solvent.
  • the organic solvent preferably contains at least one selected from the group consisting of acetone, ethyl acetate, and acetonitrile, and more preferably contains acetone.
  • the amount of solvent is, for example, 1 mL or more and 60 mL or less per 1 g of the mixture of selexipag and SX-A06.
  • the amount of solvent per 1 g of the mixture is preferably 10 mL or more and 50 mL or less, and more preferably 15 mL or more and 40 mL or less.
  • the contact between the first mixture and the aluminum oxide particles is carried out, for example, within a temperature range of 0°C to 40°C. This contact may also be carried out in a room temperature environment of 20°C to 40°C.
  • the contact between the first mixture and the aluminum oxide particles is carried out, for example, for a period of not less than 10 minutes and not more than 3 hours. This contact time is preferably within a range of not less than 30 minutes and not more than 2 hours. During this contact time, it is preferable that the mixture of the first mixture and the aluminum oxide particles is continuously stirred.
  • the area ratio of selexipag by high performance liquid chromatography is, in one example, 90% or more, and in another example, 95% or more. There is no particular upper limit to this ratio, but in one example, it is 99% or less. The method for calculating this area ratio is described in detail in the Examples.
  • the area ratio of SX-A06 by high performance liquid chromatography is, in one example, 10% or less, and in another example, 5% or less. There is no particular lower limit to this ratio, but in one example, it is 1% or more.
  • the area ratio of selexipag by high performance liquid chromatography is preferably 98% or more, and more preferably 99% or more. There is no particular upper limit to this ratio, but in one example, it is 100%.
  • the area ratio of SX-A06 by high performance liquid chromatography is, in one example, 2% or less, and in another example, 1% or less. There is no particular lower limit to this ratio, but in one example it is 0%, and in another example it is 0.1% or more.
  • the ratio A1/A2 of the peak area A1 of SX-A06 measured by high performance liquid chromatography to the peak area A2 of selexipag measured by high performance liquid chromatography is, in one example, 0.01 or more and 0.05 or less, and in another example, 0.015 or more and 0.03 or less.
  • the ratio A1/A2 of the peak area A1 of SX-A06 measured by high performance liquid chromatography to the peak area A2 of selexipag measured by high performance liquid chromatography is, for example, 0.01 or less.
  • SX-A06 can be selectively removed, so that a second mixture having a low ratio is obtained.
  • This ratio A1/A2 is more preferably 0.007 or less.
  • the lower limit of this ratio A1/A2 is 0 in one example, and 0.001 in another example.
  • Selexipag may be filtered out from the second mixture obtained by the above method.
  • the filtered selexipag may be subjected to a washing treatment, or may further be subjected to an adsorbent treatment.
  • adsorbents used in the adsorbent treatment include activated carbon, porous silica, aluminum hydroxide, hydrotalcite, etc.
  • these adsorbents may be used in combination, or only the aluminum oxide particles may be used. Of these, it is preferable to use aluminum oxide particles in combination with activated carbon, as this can further reduce impurities.
  • Example 1 (Production of Crude Selexipag) A solution was obtained by adding 320 mL of ultra-dehydrated THF to 20 g of 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ acetic acid (SX-A06). 11.6 g of 1,1'-carbonyldiimidazole was added to this solution and stirred for several hours. 6.8 g of methanesulfonamide was added to the stirred solution, followed by 14.5 g of diazabicycloundecene, and stirred for several hours to obtain a reaction solution.
  • SX-A06 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ acetic acid
  • Crude selexipag (1.0 g) was dissolved in acetone (20 mL) to obtain a first mixture.
  • Basic alumina 0.1 g was added to the first mixture, and the mixture was stirred at 25° C. for 1 hour. The first mixture was then filtered to remove dust, to obtain a second mixture.
  • the basic alumina had an average particle size of 0.15 mm as measured by a laser diffraction/scattering method, a specific surface area of 200 m 2 /g as measured by a BET method, and a pH of 10.
  • Example 4 Crude selexipag (1.0 g) was dissolved in acetone (15 mL) to obtain a first mixture.
  • a method for producing 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ -N-(methylsulfonyl)acetamide comprising contacting a first mixture containing 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ acetic acid, and a solvent with aluminum oxide particles to obtain a second mixture containing 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ -N-(methylsulfonyl)acetamide.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Solid-Sorbent Or Filter-Aiding Compositions (AREA)

Abstract

Selon un mode de réalisation, l'invention concerne un procédé de fabrication de sélexipag avec des impuretés légères. Ce procédé de fabrication comprend la mise en contact d'un premier mélange avec des particules d'oxyde d'aluminium pour obtenir un second mélange. Le premier mélange comprend du 2-4-[N-(5,6-diphénylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(méthylsulfonyl)acétamide, de l'acide 2-4-[N-(5,6-diphénylpyrazin-2-yl)-N-isopropylamino]butyloxy}acétique, et un solvant. Le second mélange comprend du 2-4-[N-(5,6-diphénylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(méthylsulfonyl)acétamide.
PCT/JP2024/001426 2023-02-17 2024-01-19 Procédé de fabrication de sélexipag et son procédé de purification Ceased WO2024171717A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2023-023089 2023-02-17
JP2023023089 2023-02-17

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Publication Number Publication Date
WO2024171717A1 true WO2024171717A1 (fr) 2024-08-22

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10507917A (ja) * 1994-10-25 1998-08-04 メルク エンド カンパニー インコーポレーテッド Ｈｉｖプロテアーゼ阻害剤の微生物合成
JP2007284416A (ja) * 2005-09-26 2007-11-01 Sumitomo Chemical Co Ltd 光学活性なピペラジン化合物の製造方法
WO2007138998A1 (fr) * 2006-05-26 2007-12-06 Japan Tobacco Inc. Composition pharmaceutique comprenant un composé azoté cyclique fusionné
JP2008001691A (ja) * 2006-05-26 2008-01-10 Japan Tobacco Inc 窒素含有縮合環化合物の製造方法
JP2008303169A (ja) * 2007-06-07 2008-12-18 Fuji Xerox Co Ltd キノクサリン含有化合物およびその重合体
WO2017121806A1 (fr) * 2016-01-15 2017-07-20 Sandoz Ag Composition pharmaceutique de selexipag
WO2018008042A1 (fr) * 2016-07-05 2018-01-11 Maithri Drugs Private Limited Nouveau procédé de préparation de 2-{4-[(5,6-diphényl pyrazin-2-yl)(isopropyl)amino]butoxy}-n-(méthylsulfonyl)acétamide et nouveaux polymorphes associés
CN108774182A (zh) * 2018-07-11 2018-11-09 湖南华腾制药有限公司 一种赛乐西帕的精制方法

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10507917A (ja) * 1994-10-25 1998-08-04 メルク エンド カンパニー インコーポレーテッド Ｈｉｖプロテアーゼ阻害剤の微生物合成
JP2007284416A (ja) * 2005-09-26 2007-11-01 Sumitomo Chemical Co Ltd 光学活性なピペラジン化合物の製造方法
WO2007138998A1 (fr) * 2006-05-26 2007-12-06 Japan Tobacco Inc. Composition pharmaceutique comprenant un composé azoté cyclique fusionné
JP2008001691A (ja) * 2006-05-26 2008-01-10 Japan Tobacco Inc 窒素含有縮合環化合物の製造方法
JP2008303169A (ja) * 2007-06-07 2008-12-18 Fuji Xerox Co Ltd キノクサリン含有化合物およびその重合体
WO2017121806A1 (fr) * 2016-01-15 2017-07-20 Sandoz Ag Composition pharmaceutique de selexipag
WO2018008042A1 (fr) * 2016-07-05 2018-01-11 Maithri Drugs Private Limited Nouveau procédé de préparation de 2-{4-[(5,6-diphényl pyrazin-2-yl)(isopropyl)amino]butoxy}-n-(méthylsulfonyl)acétamide et nouveaux polymorphes associés
CN108774182A (zh) * 2018-07-11 2018-11-09 湖南华腾制药有限公司 一种赛乐西帕的精制方法

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