WO2014098410A1 - Procédé de préparation de monohydrate de bosentan, nouvel intermédiaire utilisé, et son procédé de préparation - Google Patents

Procédé de préparation de monohydrate de bosentan, nouvel intermédiaire utilisé, et son procédé de préparation Download PDF

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Publication number
WO2014098410A1
WO2014098410A1 PCT/KR2013/011488 KR2013011488W WO2014098410A1 WO 2014098410 A1 WO2014098410 A1 WO 2014098410A1 KR 2013011488 W KR2013011488 W KR 2013011488W WO 2014098410 A1 WO2014098410 A1 WO 2014098410A1
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WIPO (PCT)
Prior art keywords
acid
bosentan
sodium
benzenesulfonamide
scheme
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PCT/KR2013/011488
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English (en)
Korean (ko)
Inventor
전종수
이성룡
김백중
강석원
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제일약품주식회사
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Publication of WO2014098410A1 publication Critical patent/WO2014098410A1/fr

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    • 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
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C07F1/06—Potassium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table

Definitions

  • the present invention relates to a process for preparing bosentan monohydrate, novel intermediates used therein and a process for producing the same.
  • Bosentane represented by the following [Formula 1] is a sulfonamide compound useful for the treatment of cardiovascular diseases such as hypertension, ischemia, vasospasm and angina by having endothelin inhibitory activity.
  • bosentane monohydrate having a moisture content of about 3 to 5% is sold under the trade name Tracleer ® by Actelion Pharmaceuticals.
  • the bosentan was first disclosed in US Pat. No. 5,292,740.
  • US Patent No. 5,292,740 discloses a monochloro compound of Compound 4 by reacting the sulfonamide potassium salt of Compound 3 with 4,6-dichlorobipyrimidine compound of Compound 2 as shown in Scheme 1 below.
  • a method of preparing bosentan of compound 6 by reacting monochloro compound of compound 4 with ethylene glycol and sodium.
  • reaction of [Scheme 1] is characterized in that using sodium.
  • sodium has a risk of explosion upon contact with moisture, making it difficult to use industrially.
  • US Patent No. 6,136,971 discloses a method for synthesizing high purity bosentan monohydrate 1 using Compound 9 in which one hydroxyl group is protected, as shown in Scheme 2, in order to prevent impurities.
  • the manufacturing method has to go through the protection step and the deprotection step of ethylene glycol, thereby causing a problem of generating additional labor, time, cost. Therefore, the manufacturing method is not suitable on an industrial scale.
  • An object of the present invention is to provide a production method capable of mass production of high purity bosentan monohydrate in high yield and economical.
  • Another object of the present invention is to provide a benzenesulfonamide sodium salt dihydrate intermediate compound useful for preparing bosentan monohydrate in high yield and high purity, and a method for preparing the same.
  • the present invention provides a method for producing bosentan monohydrate.
  • Method for preparing bosentan monohydrate according to the present invention is 1) by the following [Scheme I], 4,6-dichloro-5- (2-methoxyphenoxy) -2,2 in the presence of the first base in an organic solvent.
  • '-Bipyrimidine reacts with 4- (tert-butyl) benzenesulfonamide to give 4- (tert-butyl) -N- [6-chloro-5- (2-methoxyphenoxy)-(2,2' -Bipyrimidin) -4-yl] benzenesulfonamide alkali metal salt;
  • ⁇ M is lithium, sodium, potassium ⁇
  • the organic solvent used in the process for preparing bosentan monohydrate according to the present invention is dimethyl sulfoxide, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide, xylene, toluene, 1,4-dioxane and these It may be selected from the group consisting of a mixed solvent of, preferably dimethyl sulfoxide may be used.
  • the first base used in the first step of the method for producing bosentan monohydrate according to the present invention may be selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate and potassium carbonate.
  • Sodium carbonate can be used.
  • reaction of the first step may be performed for 2 to 10 hours at 60 to 120 °C. Preferably it may be carried out at 60 to 100 °C for 4 to 10 hours, more preferably at 70 to 80 °C may be performed for 5 to 10 hours.
  • the alkali metal salt prepared in the first step according to the present invention may be a dihydrate, preferably a sodium salt dihydrate having the structure [I].
  • the alkali metal salt dihydrate according to the present invention may be obtained by adding purified water after the reaction of the first step.
  • the second base used in the second step of the method for producing bosentan monohydrate according to the present invention may be selected from the group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide, preferably sodium hydroxide. Therefore, in the present invention, since sodium is not used as the second base, the explosion risk can be eliminated.
  • the crude (crude) in the second step is preferably carried out for 2 to 8 hours at 40 to 80 °C. More preferably, it is performed for 3 to 6 hours at 40 to 60 °C, most preferably at 4 to 5 hours at 40 to 50 °C. Since the reaction does not proceed at a high temperature, it is possible to reduce the generation of impurities by side reactions.
  • the bosentane acid addition salt prepared in the second step according to the present invention is separated into a stable solid phase (crystalline or amorphous), which is useful for purification, and the acid used in the second step is a bosentane acid moiety when pKa is less than 3 Salting can be prepared in high yield and high purity.
  • the acid used in the second step is hydrochloric acid, hydrobromic acid, methane sulfonic acid, benzenesulfonic acid, sulfuric acid, p -toluenesulfate. It may be selected from the group consisting of p- toluenesulfonic acid, oxalic acid and maleic acid.
  • the beam ambrisentan acid addition salts according to the invention are p-toluene sulfonate is most preferred that the-toluenesulfonic acid (p -toluenesulfonic acid) and the mixture to the prepared [formula II] of the structural beam ambrisentan p.
  • the water-soluble solvent used in the third step may be water, acetone, alcohol or a mixture thereof, the alcohol is preferably C1 ⁇ C4 alcohol.
  • the production method of the present invention is very suitable for the production of bosentan monohydrate.
  • the present invention provides a benzenesulfonamide sodium salt dihydrate having the following structure [Formula I] usefully used in the production of bonded carbon monohydrate.
  • the benzenesulfonamide sodium salt dihydrate compound is a novel compound, it can be produced in high yield and high purity through a simple manufacturing process.
  • bosentane acid addition salts and bosentan monohydrate can be prepared in high purity and high yield through a simple manufacturing process.
  • the present invention provides a method for preparing benzenesulfonamide sodium salt dihydrate which is usefully used for the preparation of bosentan monohydrate.
  • the benzenesulfonamide sodium salt dihydrate is 4,6-dichloro-5- (2-methoxyphenoxy) -2,2'-bipyrimidine in the presence of a base in an organic solvent by the following [Scheme I-1]. It can be prepared by reacting with 4- (tert-butyl) benzenesulfonamide and adding purified water.
  • the organic solvent used in Scheme [I-1] is made of dimethyl sulfoxide, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide, xylene, toluene, 1,4-dioxane, and a mixed solvent thereof. It may be selected from the group, the base may be used sodium hydroxide or sodium carbonate.
  • reaction of [Scheme I-1] is preferably carried out at 60 to 120 °C for 2 to 10 hours. More preferably, it may be performed at 60 to 100 ° C. for 4 to 10 hours, and most preferably at 70 to 80 ° C. for 5 to 10 hours.
  • Benzenesulfonamide sodium salt dihydrate prepared through the reaction can be prepared in high yield and high purity.
  • the production method of the present invention exhibits the effect of economically mass-producing high purity bosentan monohydrate in high yield.
  • the benzenesulfonamide sodium salt dihydrate intermediate of the present invention is easily prepared in high yield and high purity, and has the effect of producing bosentan monohydrate in high yield and high purity.
  • FIG. 1 is a DSC graph of benzenesulfonamide sodium salt dihydrate obtained in Example 1.
  • FIG. 1 is a DSC graph of benzenesulfonamide sodium salt dihydrate obtained in Example 1.
  • FIG. 2 is an MS graph of benzenesulfonamide sodium salt dihydrate obtained in Example 1.
  • Mobile phase A Dissolve 1.36 g of potassium dihydrogen phosphate in 750 mL of purified water, bring the pH to 2.5 with phosphoric acid, and mix with 250 mL of acetonitrile.
  • Mobile phase B Dissolve 1.36 g of potassium dihydrogen phosphate in 300 mL of purified water, bring the pH to 2.5 with phosphoric acid, and mix with 700 mL of acetonitrile.
  • the benzenesulfonamide sodium salt dihydrate intermediate of the present invention is easily prepared in high yield and high purity and can be economically mass-produced in high yield using high purity bosentane monohydrate.

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

Abstract

Cette invention concerne un procédé de préparation de monohydrate de bosentan, un nouvel intermédiaire utilisé, et son procédé de préparation. La nouvelle composition intermédiaire selon l'invention est produite à un rendement élevé et à une pureté élevée, et son utilisation permet de produire économiquement en masse et à un rendement élevé un monohydrate de bosentan de grande pureté.
PCT/KR2013/011488 2012-12-20 2013-12-11 Procédé de préparation de monohydrate de bosentan, nouvel intermédiaire utilisé, et son procédé de préparation WO2014098410A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020120149541A KR102004422B1 (ko) 2012-12-20 2012-12-20 보센탄 일수화물의 제조방법, 이에 사용되는 신규 중간체 및 이의 제조방법
KR10-2012-0149541 2012-12-20

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WO2014098410A1 true WO2014098410A1 (fr) 2014-06-26

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JP6047247B2 (ja) * 2013-02-14 2016-12-21 エルジー エレクトロニクス インコーポレイティド 無線通信システムにおけるｍｂｍｓ情報報告方法及びそれをサポートする装置

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2072503B1 (fr) * 2007-12-18 2011-10-26 Dipharma Francis S.r.l. Procédé de préparation de bosentan
WO2012056468A1 (fr) * 2010-10-13 2012-05-03 Matrix Laboratories Ltd Procédé pour la préparation de bosentan
US20120136015A1 (en) * 2009-04-13 2012-05-31 Sandoz Ag Process for preparation of endothelial receptor antagonist (bosentan)

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2086544C1 (ru) 1991-06-13 1997-08-10 Хоффманн-Ля Рош АГ Бензолсульфонамидные производные пиримидина или их соли, фармацевтическая композиция для лечения заболеваний, связанных с активностью эндотелина
US5883254A (en) * 1996-11-08 1999-03-16 Hoffmann-La Roche Inc. Process for making pyrimidine derivatives
US6136971A (en) 1998-07-17 2000-10-24 Roche Colorado Corporation Preparation of sulfonamides
EP1254121B1 (fr) * 2000-01-25 2006-02-01 F. Hoffmann-La Roche Ag Preparation de sulfonamides
AU2009203174B2 (en) 2008-01-01 2014-01-30 Cipla Limited Method of synthesis of bosentan, its polymorphic forms and its salts

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2072503B1 (fr) * 2007-12-18 2011-10-26 Dipharma Francis S.r.l. Procédé de préparation de bosentan
US20120136015A1 (en) * 2009-04-13 2012-05-31 Sandoz Ag Process for preparation of endothelial receptor antagonist (bosentan)
WO2012056468A1 (fr) * 2010-10-13 2012-05-03 Matrix Laboratories Ltd Procédé pour la préparation de bosentan

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SANJAY A. JADHAV ET AL.: "Stability-Indicating Gradient RP-LC Method for th e Determination of Process and Degradation Impurities in Bosentan Monohydrat e: An Endothelin Receptor Antagonist", CHROMATOGRAPHY RESEARCH INTERNATION, vol. 1, 2011 *

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KR20140080103A (ko) 2014-06-30

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