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WO2012056468A1 - Procédé pour la préparation de bosentan - Google Patents

Procédé pour la préparation de bosentan Download PDF

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Publication number
WO2012056468A1
WO2012056468A1 PCT/IN2011/000231 IN2011000231W WO2012056468A1 WO 2012056468 A1 WO2012056468 A1 WO 2012056468A1 IN 2011000231 W IN2011000231 W IN 2011000231W WO 2012056468 A1 WO2012056468 A1 WO 2012056468A1
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Prior art keywords
formula
bosentan
process according
compound
solvent
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Ceased
Application number
PCT/IN2011/000231
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English (en)
Inventor
Vinayak Gore
Manojkumar Bindu
Dattatraya Shinde
Dattatrey Kokane
Sushant Ghrat
Ramesh Dandala
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Mylan Laboratories Ltd
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Matrix Laboratories Ltd
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Publication of WO2012056468A1 publication Critical patent/WO2012056468A1/fr
Anticipated expiration legal-status Critical
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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

Definitions

  • the present invention relates to an improved process for the preparation of Bosentan or its salt.
  • the present invention also relates to an improved process for the deprotection of hydroxy protected Bosentan.
  • the present invention further relates to a pharmaceutical composition comprising Bosentan of formula I with excipients.
  • Bosentan is found to be a potential inhibitor of endothelin receptors. Endothelin has recently been shown to play a pivotal role in the development of pulmonary hypertension and elevated endothelin concentrations have been found to be strongly correlated with disease severity. Endothelin antagonists especially bosentan, are therefore considered to represent a new approach to the treatment of pulmonary hypertension.
  • the selective nonpeptide mixed endothelin ETA and ETB receptor antagonist bosentan (Tracleer®) has become the first endothelin antagonist to reach the market for pulmonary hypertension. It has a greater significance because until now only few drugs have been specifically approved for the indication of pulmonary hypertension. Bosentan can also be used for treatment of circulatory disorders such as ischemia, vasospasms and angina pectoris.
  • Bosentan is chemically known as 4-(1 ,1-Dimethylethyl)-N-[6-(2-hydroxyethoxy)-5-(2- methoxyphenoxy) [2,2'-bipyrimidin]-4-yl] benzene sulfonamide, having structural formula I. ⁇
  • Bosentan and its analogues as potential endothelin inhibitors have been first disclosed in US patent No. 5292740.
  • the patent also disclosed the methods for preparing these compounds.
  • One of the methods involves the dichloro derivative is reacted with 4-tert- butylbenzenesulfonamide and one of the chlorine is replaced by 4-tert- butylbenzenesulfonamide.
  • the sulfonamide derivative thus formed is reacted with ethylene glycol in presence of sodium to provide bosentan sodium salt (Scheme 1).
  • the 740 patent describes the use of sodium metal for the preparation of sodium ethylene glycolate.
  • Sodium metal is an explosive and hazardous reagent and vigorously reacts with water.
  • the bosentan obtained by the process described in the 740 patent using sodium metal is not satisfactory from a purity perspective. Unacceptable amount of impurities are formed along with Bosentan.
  • the present invention encompassed herein an improved, commercially viable and industrially advantageous process for the preparation of Bosentan.
  • the current processes solve the drawbacks associated with the prior processes and it is commercially viable for preparing Bosentan.
  • US 6136971 discloses a process for the preparation of Bosentan wherein 4,6-dichloro- 5-(2- methoxyphenoxy)-2,2'-bipyrimidine reacted with 4-tert-butylbenzenesulfonamide in the presence of anhydrous potassium carbonate and a phase transfer catalyst (e.g., benzyltriethylammonium chloride) in toluene, provides p-tert-butyl-N-[6-chloro-5-(2- methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide potassium salt.
  • a phase transfer catalyst e.g., benzyltriethylammonium chloride
  • the potassium salt is then reacted with ethylene glycol mono-tert-butyl ether in toluene in the presence of sodium hydroxide to . produce p-tert- butyl-N- [6-(2-tert-butyl-ethoxy)-5-(2- methoxyphenoxy) [2,2 '-bipyrimidin] -4-yl]benzenesulfonamide (Bosentan tert-butyl ether). The Bosentan tert-butyl ether is then subjected to deprotection with formic acid afford formyl derivative of Bosentan.
  • This formyl derivative is reacted with sodium hydroxide in mixture of ethanol and water followed by acidification with hydrochloric acid to give crude Bosentan.
  • the crude Bosentan is further purified in mixture of ethanol and water to give Bosentan monohydrate (Scheme 2).
  • protecting groups are performed using suitable deprotecting agents by known methods, for example as disclosed in "Protecting Groups in Organic Synthesis,” T.W. Greene, John Wiley & Sons, New York, N.Y., 1981.
  • Phosphoric acid is considered a green reagent as it is environmental benign worker friendly for the deprotection of tert-butyl carbamates, esters and ethers.
  • the reaction conditions are mild and offer good selectivity in the presence of other acid sensitive-groups.
  • the present invention encompassed herein an improved, simple, commercially viable, eco-friendly and industrially advantageous process over the prior art process for preparation of Bosentan.
  • the present invention encompassed herein an improved, simple, commercially viable, eco- friendly and industrially advantageous process over the prior art process for preparation of Bosentan.
  • the present invention relates to an improved process for the preparation of Bosentan or its salt thereof.
  • One aspect of the present invention is to provide an improved process for the preparation of Bosentan of formula I or its salt comprising the steps of: a) reacting dichloro compound of formula VII with ethylenegycol in a solvent in the presence of base to produce monochloro derivative of formula VI, b) reacting monochloro derivative of formula VI with propionyl reagent in a solvent in the presence of base to produce propionyl protected monochloro derivative of formula V, c) reacting the compound of formula V with 4- tertbutyl benzene sulfonamide in a solvent in the presence of a base to produce propionyl protected Bosentan of formula IV, d) hydrolyzing the compound of formula IV to give Bosentan salt of formula III, and e) converting Bosentan salt to Bosentan.
  • Another aspect of the present invention is to provide novel crystalline Bosentan lithium.
  • Yet another aspect of the present invention is to provide a process for the preparation of Lithium salt of Bosentan of formula III comprising the steps of: a) reacting hydroxy! protected bosentan with lithium source, and b) isolating crystalline lithium salt of Bosentan formula I.
  • Yet another aspect of the present invention is to provide a process for the purification of Bosentan from the crude Bosentan comprising the steps of: a) reacting crude Bosentan with pivaloyl chloride in a solvent to obtain pivaloyl derivative of compound of formula Va, b) optionally purify the compound of formula Va, c) hydrolyzing the compound of formula Va, and d) isolating Bosentan formula I.
  • In another aspect of present invention is to provide a novel 2,2-Dimethyl-propionic acid 2-[6- (4-tert-butyl-benzenesulfonylamino)-5-(2-methoxy-phenoxy)-[2,2']bipyrimidinyl-4-yloxy]-ethyl ester compound of formula Va.
  • Yet another aspect of the present invention is to provide an improved process for the preparation of Bosentan comprising the steps of: a) dissolving hydroxy protected Bosentan in a solvent, b) reacting with phosphoric acid, c) treating the compound obtained in step b) with a base, and d) isolating Bosentan.
  • the present invention is schematically represented by the following scheme 3.
  • Figure-1 Illustrates the powder X-Ray diffractogram of crystalline Form of Bosentan lithium salt.
  • Figure-2 Illustrates the TGA of crystalline Form of Bosentan lithium salt.
  • Figure -3 Illustrates the DSC of crystalline Form of Bosentan lithium salt.
  • Present invention relates to an improved process for the preparation of Bosentan or its salt, wherein dichloro compound is reacted with ethyleneglycol in a solvent to produce monochloro derivative.
  • the monochloro derivative is reacted with propionyl reagent in a solvent to produce propionyl protected monochloro derivative.
  • One embodiment of the present invention is to provide an improved process for the preparation of Bosentan of formula I or its salt comprising the steps of: a. reacting dichlorocompound of formulaVII
  • M + is Li, Na, K
  • dichloro compound of formula VII is reacted with ethylene glycol in a solvent selected form tetrahydrofuran, dimethylformamide, dimethylacetamide or methyl tert-butyl ether, preferably tetrahydrofuran in the presence of base selected from sodium hydroxide potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate or calcium carbonate, preferably sodium hydroxide.
  • base selected from sodium hydroxide potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate or calcium carbonate, preferably sodium hydroxide.
  • the reaction is optionally carried out by lot wise addition of base at a temperature ranging from 0- 35°C, preferably 20-35°C.
  • protection of monochloro derivative of formula VI is done with propionyl reagent selected from propionic anhydride or propionyl chloride in a solvent selected from toluene, xylene, acetonitrile, acetone, dimethylformamide, dimethylacetamide, tetrahydrofuran or methyl isobutyl ketone, preferably dimethyl acetamide.
  • the reaction is carried out in the presence of base selected from organic bases such as triethylamine or inorganic base such as sodium hydroxide.
  • the reaction temperature is ranging from 25- 90°C and duration of the reaction is about 6-7 hours.
  • the compound of formula V is isolated by saturating the reaction mass with water and the separating the solid by filtration to get compound of formula V.
  • compound of formula V is reacted with 4-tert-butyl benzene sulfonamide in a solvent selected from dimethyl acetamide, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran or methyl isobutyl ketone, preferably dimethyl acetamide in the presence of base is selected from alkaline earth metal hydroxides such as sodium hydroxide, alkaline earth metal carbonate such as sodium carbonate or alkaline earth metal phosphate such as potassium phosphate.
  • a solvent selected from dimethyl acetamide, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran or methyl isobutyl ketone, preferably dimethyl acetamide in the presence of base is selected from alkaline earth metal hydroxides such as sodium hydroxide, alkaline earth metal carbonate such as sodium carbonate or alkaline earth metal phosphate such as potassium phosphate.
  • hydrolysis reaction of formula IV is carried out in a solvent selected from tetrahydrofuran, methanol, ethanol, isopropanol, acetone, acetonitrile, toluene or xylene, preferably tetrahydrofuran.
  • Hydrolysis is carried out with acid or base.
  • the acid is selected from phosphoric acid, trifluoroacetic acid, formic acid or hydrochloric acid and the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or lithium carbonate to get its corresponding Bosentan salt of formula III.
  • the bosentan salt of compound formula III is converted to Bosentan by treating with acid such as hydrochloric acid in a solvent selected from methanol ethanol, isopropanol, acetone, acetonitrile, ethyl acetate or dichloromethane.
  • acid such as hydrochloric acid in a solvent selected from methanol ethanol, isopropanol, acetone, acetonitrile, ethyl acetate or dichloromethane.
  • Another embodiment of the present invention is to provide Bosentan salt as a crystalline solid.
  • M + is Li, Na, K
  • Yet another aspect of the present invention is to provide a novel crystalline form-M of Bosentan lithium salt, characterized by an X-Ray diffraction pattern having the 2 ⁇ values at 6.30, 10.11 , 12.61 , 14.44, 18.92, 23.23 and 25.29 ⁇ 0.2.
  • Yet another aspect of the present invention is to provide novel crystalline form-M of Bosentan lithium, characterized by a DSC comprising an endothermic peak at about T19°C and an endothermic peak at about 203°C.
  • Yet another embodiment of the present invention is to provide a process for the preparation of crystalline Bosentan lithium salt comprising the steps of:
  • hydroxyprotected bosentan is reacted with lithium source selected from lithium hydroxide or lithium carbonate in a solvent selected form methanol, ethanol, isopropanol, tetrahydrofuran, acetone or acetonitrile.
  • a solvent selected form methanol, ethanol, isopropanol, tetrahydrofuran, acetone or acetonitrile.
  • the obtained solid is filtered.
  • Another embodiment of the present invention is to provide a process for the purification of Bosentan, which comprising the steps of:
  • Bosentan is reacted with pivaloyl chloride in a solvent at 15-35°C, preferably 20-25X for about 12-20 hours.
  • hydrocarbon solvent is added and the solid is separated by filtration.
  • This solid is refluxed in a solvent, cooled to 0-10°C and the obtained pure solid of formula Va is isolated by filtration.
  • Compound of formula Va is hydrolyzed in the presence of aqueous base in a solvent and finally the obtained Bosentan is treated with aqueous alcohol to get Bosentan.
  • Bosentan is reacted with pivolyol chloride in a solvent selected from halogenated hydrocarbon such as dichlormethane, aromatic hydrocarbon such as toluene.
  • a solvent selected from halogenated hydrocarbon such as dichlormethane, aromatic hydrocarbon such as toluene.
  • the hydrocarbon solvent used for the isolation of compound of formula Va is selected from cyclohexane, n-hexane, heptane or pentane.
  • the solvent used in the purification of compound of formula Va is selected from methanol, ethanol, isopropanol or butanol, acetone, methyl isobutyl ketone, methyl ethyl ketone or mixture thereof.
  • base used for the hydrolysis is selected from metal hydroxides such as sodium hydroxide, metal carbonates such as sodium carbonate or metal bicarbonates such as sodium bicarbonate.
  • Yet another embodiment of present invention is to provide novel 2,2-Dimethyl-propionic acid 2-[6-(4-tert-butyl-benzenesulfonylamino)-5-(2-methoxy-phenoxy)-[2,2'] bipyrimidinyl-4-yloxy]- ethyl ester compound of formula Va, which is characterized by 1 H-NMR.
  • step b) treating the compound obtained in step b) with a base
  • hydroxy protected Bosentan of formula II is dissolved in a solvent and phosphoric acid is added slowly at room temperature.
  • the resulting solution is heated to reflux for about 3 to 8 hours, preferably about 5 to 7 hours.
  • the solution is cooled to about 5 to 10°C and water is added, stirred and obtained solid is filtered to afford Bosentan.
  • a hydroxy protecting group is selected from the group consisting of C1-C4 alkyl, acetyl, tert-butyl, silyl and formyl, in particular tert-butyl.
  • the solvent used for the dissolution of hydroxy protected Bosentan is selected from methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, toluene, xylene, tetrahydrofuran, water or mixture thereof, preferably acetonitrile and the base is selected from alkali or alkaline earth metal hydroxide, carbonate and bicarbonate.
  • the phosphoric acid used for the reaction is about 5-20 equivalents with respect to hydroxy protected Bosentan of formula II, more preferably 10-15 equivalents.
  • the obtained Bosentan is purified by converting the crude Bosentan to alkaline salt such as sodium or potassium salt, followed by neutralization to get Bosentan.
  • crude Bosentan may be having the purity up to 98.5%.
  • Bosentan having the purity more than 99.0%, preferably more than 99.5%, more preferably more than 99.95%.
  • Yet another embodiment of the present invention is to provide pharmaceutical composition
  • pharmaceutical composition comprising: (a) a therapeutically effective amount of Bosentan of formula-1 or pharmaceutically acceptable salt; and (b) at least one pharmaceutically acceptable carrier.
  • Lithium salt of Bosentan obtained by hydrolysis using Lithium hydroxide is highly pure and need not be crystallized; it is used as such for converting Bosentan.
  • the present invention does not involve explosive chemicals like sodium metal.
  • Example 2 preparation of Propionic acid 2-[6-chloro-5-(2-methoxy-phenoxy)-[2,2'] bipyrimidinyl-4-yloxy]-ethyl ester compound of formula V.
  • Example 3 Preparation of propionic acid 2-[6-(4-tert-butyl-benzenesulfonylamino)-5- (2-methoxy-phenoxy)-[2, 2'] bipyrimidinyl-4-yloxy]-ethyl ester compound of formula IV.
  • Example 7 p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl] benzene sulfonamide formula Via.
  • the compound of formula VII (500g, 1.0eq), 4-tert butyl benzene sulfonamide (305.2g, 1.0eq) and potassium carbonate (237.24g, 1.2eq) was heated in dimethylsulfoxide (2500.0ml, 5.0vol) at 120°C for 10-12 hours. After completion of reaction, the reaction mixture was cooled to 20°C-25°C and filtered. Filtrate was added to a mixture of water (6000.0ml, 12.0vol) and concentrated hydrochloric acid (100ml, 0.2vol) at 5°C-10°C. After completion of addition the reaction mixture was maintained at 5°C-10°C for 1 hour. Precipitated solid was filtered and washed with water (5000ml, 10.0vol). Dried the solid at 55°C-60°C for 20Hrs under vacuum to get title compound (Yield: 742.0g, 98.67%, HPLC purity 87.39).
  • the dried solid (742.0g, 1eq) was heated in ethyl acetate (7420.0ml, 10.0vol) at 75°C-80°C for 1 hour. Cooled to 5-10°C and filtered. Washed with ethyl acetate (371.0ml, 0.5vol) and dried the solid under vacuum at 55-60°C for 15hrs.
  • Example 9 Preparation of 2,2-Dimethyl-propionic acid 2-[6-(4-tert-butyl- benzenesulfonylamino)-5-(2-methoxy-phenoxy)-[2,2']bipyrimidinyl-4-yloxy]-ethyl ester compound of formula Va.
  • Example 11 Purification processes of pivaloyl derivative of formula Va.
  • Example 12 Purification processes of pivaloyl derivative of formula Va.
  • Example 13 Preparation of Bosentan from compound of formula Va.
  • Compound of formula Va (50.0g,1.0eq) and ethanol (850.0ml,17.0vol) slurry was cooled to 10-15°C and sodium hydroxide (22.0gJ.0eq) in water (100.0ml,2.0vol) solution was added. Allowed to attain 20-25°C and stirred at that temperature for 7-10 hours, till completion of reaction.
  • Bosentan of formula II (10g, 1 eq) was taken in Acetonitrile (100ml, 10 vol) and phosphoric acid (24.21g, 15 eq) was added in three lots at 25-35°C. Refluxed for about 5-7 hours till completion of reaction. After completion of reaction, cooled the reaction mixture to 5-10°C and water (100ml, 10vol) was added slowly. Stirred for 1 hour at 5-10°C and filtered the precipitated solid. Washed the solid with water and dried under vacuum to get Bosentan (Yield: 9g; HPLC purity: 98.5%).
  • Bosentan of formula II (10g, 1 eq) was taken in Acetonitrile (100ml, 10 vol) and phosphoric acid was added in three lots at reflux temperature in different intervals. Maintained the reaction for 5-7 hours at reflux temperature till completion of reaction, after completion of reaction, cooled the reaction mixture to 5-10°C and water (100ml, 10vol) was added slowly. Stirred for 1 hour at 5-10°C and filtered the precipitated solid. Washed the solid with water and dried under vacuum to get Bosentan (Yield: 9g; HPLC purity: 98.5%).
  • Example 16 Purification of Bosentan.
  • Bosentan (9g, 1eq obtained from Example 15) was taken in Ethanol (99ml, 11 vol) and the slurry was cooled to 10-15°C.
  • Solution of Sodium hydroxide (1.89g,3eq) in water (9ml,1vol) was added slowly at 10-15°C and the solution was stirred at 20-25°C for 2-3 hours.
  • the precipitated solid was filtered, washed with ethanol (27ml, 3vol) and suck dried.
  • the solid was suspended in ethanol (63ml, 7vol) and cooled to 10-15°C.

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

Abstract

La présente invention porte sur un procédé perfectionné pour la préparation de Bosentan ou de son sel. La présente invention porte également sur un procédé perfectionné pour la déprotection de Bosentan à hydroxy protégé. La présente invention porte en outre sur une composition pharmaceutique comprenant du Bosentan de formule (I) à excipients.
PCT/IN2011/000231 2010-10-13 2011-04-01 Procédé pour la préparation de bosentan Ceased WO2012056468A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN3030/CHE/2010 2010-10-13
IN3030CH2010 2010-10-13
IN3920CH2010 2010-12-22
IN3920/CHE/2010 2010-12-22

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WO2012056468A1 true WO2012056468A1 (fr) 2012-05-03

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014033758A1 (fr) 2012-08-31 2014-03-06 Rao Davuluri Ramamohan Sodium de 4-tert-butyl-n-[6-(2-hydroxyéthoxy)-5-(2-méthoxyphénoxy)-2(2-pyrimidinyl)-pyrimidine-4-yl)-benzènesulfonamide
WO2014098410A1 (fr) * 2012-12-20 2014-06-26 제일약품주식회사 Procédé de préparation de monohydrate de bosentan, nouvel intermédiaire utilisé, et son procédé de préparation
CN114907275A (zh) * 2022-04-29 2022-08-16 武汉工程大学 一种波生坦的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5292740A (en) 1991-06-13 1994-03-08 Hoffmann-La Roche Inc. Sulfonamides
EP0743307A1 (fr) * 1995-05-16 1996-11-20 Tanabe Seiyaku Co., Ltd. Dérivés de sulfonamide et procédé pour leur préparation
US6136971A (en) 1998-07-17 2000-10-24 Roche Colorado Corporation Preparation of sulfonamides
EP2072503A2 (fr) * 2007-12-18 2009-06-24 Dipharma Francis S.r.l. Procédé de préparation de bosentan

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5292740A (en) 1991-06-13 1994-03-08 Hoffmann-La Roche Inc. Sulfonamides
EP0743307A1 (fr) * 1995-05-16 1996-11-20 Tanabe Seiyaku Co., Ltd. Dérivés de sulfonamide et procédé pour leur préparation
US6136971A (en) 1998-07-17 2000-10-24 Roche Colorado Corporation Preparation of sulfonamides
EP2072503A2 (fr) * 2007-12-18 2009-06-24 Dipharma Francis S.r.l. Procédé de préparation de bosentan

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 6, 2002, pages 120 - 124
T.W. GREENE: "Protecting Groups in Organic Synthesis", 1981, JOHN WILEY & SONS

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014033758A1 (fr) 2012-08-31 2014-03-06 Rao Davuluri Ramamohan Sodium de 4-tert-butyl-n-[6-(2-hydroxyéthoxy)-5-(2-méthoxyphénoxy)-2(2-pyrimidinyl)-pyrimidine-4-yl)-benzènesulfonamide
WO2014098410A1 (fr) * 2012-12-20 2014-06-26 제일약품주식회사 Procédé de préparation de monohydrate de bosentan, nouvel intermédiaire utilisé, et son procédé de préparation
KR20140080103A (ko) * 2012-12-20 2014-06-30 제일약품주식회사 보센탄 일수화물의 제조방법, 이에 사용되는 신규 중간체 및 이의 제조방법
KR102004422B1 (ko) 2012-12-20 2019-07-26 제일약품주식회사 보센탄 일수화물의 제조방법, 이에 사용되는 신규 중간체 및 이의 제조방법
CN114907275A (zh) * 2022-04-29 2022-08-16 武汉工程大学 一种波生坦的制备方法

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