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WO2012101648A1 - Nouveau procédé de synthèse de 2-méthoxy-5-[(2r)-2-(4-alkylpipérazin-l-yl)propyl]-benzènesulfonamide énantiomériquement pur - Google Patents

Nouveau procédé de synthèse de 2-méthoxy-5-[(2r)-2-(4-alkylpipérazin-l-yl)propyl]-benzènesulfonamide énantiomériquement pur Download PDF

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Publication number
WO2012101648A1
WO2012101648A1 PCT/IN2011/000051 IN2011000051W WO2012101648A1 WO 2012101648 A1 WO2012101648 A1 WO 2012101648A1 IN 2011000051 W IN2011000051 W IN 2011000051W WO 2012101648 A1 WO2012101648 A1 WO 2012101648A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
synthesis
novel process
benzenesulfonamide
Prior art date
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Ceased
Application number
PCT/IN2011/000051
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English (en)
Inventor
Freddy H. HAVALDAR
Bhushan Vasant DABHOLKAR
Ganesh Baban MULE
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Individual
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Individual
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Priority to PCT/IN2011/000051 priority Critical patent/WO2012101648A1/fr
Publication of WO2012101648A1 publication Critical patent/WO2012101648A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups

Definitions

  • the present invention is more particularly relates to a process for the preparation of enantiomerically pure (R)-(2-methoxy-5- [(2R)-2-(4-alkyl piperazin-l-yl) propyl] benzenesulfonamide.
  • the present invention is most particularly relates to an optically pure (2-methoxy-5-[(2R)-2-(4- akylpiperazin-l-yl)propyl]benzenesulfonamide of formula I is a key intermediate for the -preparation of Tamsulosin which ' is is a ala-selective alpha blocker used in the symptomatic treatment of benign prostatic hyperplasia (BPH).
  • BPH benign prostatic hyperplasia
  • R.sub.l represents, an amino group or a mono- or di-lower alkylamino group
  • R.sub.2 represents, a hydroxyl group, a lower alkyl group, or a lower alkoxy group
  • R.sub.3 represents, hydrogen atom, halogen atom, a lower alkyl group, a lower alkoxy group, a phenylthio group, or a phenylsulfinyl group
  • R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 each represents, hydrogen atom or a lower alkyl group
  • sub.10 represents, hydrogen atom, a lower alkyl group, or a lower alkoxy group
  • Y represents oxygen atom or a methylene group; said Y being, however, an oxygen atom when R.sub.2 is a hydroxyl group.
  • lower used in the above-described formula means a straight or branched carbon chain having 1 to 5 carbon atoms. Therefore, for example, a lower alkyl group includes a methyl group, ethyl group, propyl group, butyl group, pentyl group, isobutyl group, etc., and a lower alkoxy group includes a methoxy group, ethoxy group, propoxy group, butoxy group, etc.
  • R.sub.10 which is substituents of the benzene ring may be disposed at any position of which is ortho, meta or para to the side chain.
  • the compounds of this invention shown by formula can readily form the salts thereof and contain asymmetric carbon atom(s), the compounds of this invention include the salts thereof, the racemic compounds thereof, a mixture of the racemic compounds, and each optically active substance.
  • the compounds of formula above mentioned and the acid addition salts thereof provided by the present invention exhibit an .alpha. -adrenergic blocking action and thus they can be utilized for various treatments., they can be used as useful agents for the treatments of hypertension, congestive heart failure, angina pectoris, lower urinary tract dysfunction, prostatic hypertrophy, pheochromocytoma and peripheral vascular disorders.
  • optically pure (R) or (S)-5-(2-aminopropyl)-2- methoxybenzenesulfonamide which comprises resolving (R, S)-5-(2-aminopropyl)- 2-methoxybenzene-sulfonamide with D- or L-tartaric acid to form a mixture of diastereomeric salts, and separating the diastereomeric salts in two stage process in a mixture of solvent systems to obtain methoxybenzenesulfonamide in optically pure form.
  • An object of this invention is to provide the novel alkyl benzenesulfonamide derivatives.
  • Another object of the invention is to provide an optically pure (R)-2-methoxy-5- [(2R)-2-(4-ethyl piperazin-l-yl) propyl] benzenesulfonamide
  • Yet another object of the R-alkyl group invention is to provide
  • Formula I pharmaceutical composition comprising an optically pure (2-methoxy-5-[(2R)-2-(4- methylpiperazin-l-yl)propyl]benzenesulfonamide of formula I for the treatment of benign prostatic hyperplasia (BPH).
  • the present invention provides a process for the manufacture of optically pure (R)-5-[(lR)-l-(4-alkylpiperazin-l-yl) ethyl]-2- methoxybenzenesulfonamide (I), via intermediate (R)-(-)-5-(2-aminopropyl)-2- methoxybenzenesulfonamide (II) in optically pure form.
  • the present invention includes substantially pure compound (I) in its substantially pure form optical purity is greater than 99 %, preferably 99.5 %, and more preferably 99.8% w/w.
  • Compound (I) described herein and/or prepared in accordance with the processes described herein may contain less than about 0.5 %, or less than about 0.1 %, by weight of process, optical, or structural impurities as characterized by high performance liquid chromatography (HPLC) and chiral HPLC of Formula I determined by HPLC method having a column LICROSPHER(R) silica, 250x4.0 mm ID, 5 [mu]m or equivalent.
  • HPLC high performance liquid chromatography
  • Compound of Formula I is second HPLC method using a column IIMERTSIL(R) silica 250x4.6 mm ID, 5 [mu]m particle size or equivalent.
  • the optical purity of compound (I) of Formula I may be analyzed by chiral HPLC using a column CHIRALPAK(R) AD (4.6x250 mm).
  • the present invention includes pharmaceutical compositions comprising a
  • the resulting formulation/ composition includes pharmaceutically effective amount of compound of formula I along with carrier excipients.
  • N,N-diisopropylethylamine (22 g), R- (-)-5-[-2- aminopropyl]-2-methoxybenzenesulfonamide (12.5 g), and IM,N-dichloroethyl-4- methoxybenzenesulfonamide (19.8 g) are charged under stirring and the reaction mixture is heated to about 125 C to about 130 C.
  • the reaction mass is maintained under reflux at the same temperature for about 10 hours.
  • the reaction mass is cooled from about 80C to about 90C.
  • Methanol (5ml) is charged into the vessel and cooled to about 0C to about 5 C, and the reaction mass is maintained at the same temperature for about 30 to about 60 minutes.
  • the separated solid is then filtered and the wet material is washed with methanol (12.5 L). The material is suck-dried for about 30 for about 60 minutes. The wet cake is further dried at about 60 C to about 70 C for about 3 to about 4 hours to afford 23.8 g of the title compound. Yield : 90.83%, Purity by HPLC: 99.0%.
  • benzenesulfonamide (22.0kg) is slowly added to a solution of hydrobromic acid in glacial acetic acid (91.0 g) in a clean and dry reactor, and the contents are heated to about 70-75 C and maintained at the same temperature for about 3 hours. After completion of the reaction, the reaction mass is cooled to about 25-35 C. Water (115 L) is slowly charged into the reactor at a temperature of about 25 C to about 30 C and stirred for about 10-15 minutes. The reaction mass is washed with toluene (2X45 L) at room temperature followed by cooling of the aqueous layer to 0-5 C and then the pH of the aqueous layer is adjusted to about 12.0 to about 14.0 at below 35 C using 40 % sodium hydroxide (67 L).
  • reaction mass is then extracted with toluene (3*70 L) at about 40C to about 45C.
  • the combined organic layer is washed with water (2*25 L) and distilled off completely.
  • water (115 L) is charged at about 25C to about 35 C and stirred at the same temperature for about 2-4 hours.
  • the separated solid is then centrifuged and the wet material in the centrifuge is washed with water (25 L).
  • the material is spin-dried for about 30 to about 60 minutes.
  • the cake is further dried at about 30 C to about 35 C for about 10 hours to afford 12.8 kg of the title compound. Yield : 92.7%, Purity by HPLC: 98.9%, Chiral purity by HPLC: 99.87.

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

Abstract

L'invention concerne un nouveau procédé de synthèse d'un composé de formule 1, dans laquelle R représente alkyle en C1-C3, alcényle, qui comprend la réduction catalytique stéréosélective d'un composé de formule IV sous une pression d'hydrogène gazeux pour obtenir un composé intermédiaire de formule II, qui est couplé en présence d'un agent de couplage et d'une base en présence d'un solvant organique pour obtenir un composé de formule X, Formule X, qui est mis en réaction avec un agent de déprotection en présence d'un solvant organique pour former un composé de formule XI, la condensation du composé de formule XI avec un halogénure d'alkyle pour former un composé de formule I.
PCT/IN2011/000051 2011-01-24 2011-01-24 Nouveau procédé de synthèse de 2-méthoxy-5-[(2r)-2-(4-alkylpipérazin-l-yl)propyl]-benzènesulfonamide énantiomériquement pur Ceased WO2012101648A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IN2011/000051 WO2012101648A1 (fr) 2011-01-24 2011-01-24 Nouveau procédé de synthèse de 2-méthoxy-5-[(2r)-2-(4-alkylpipérazin-l-yl)propyl]-benzènesulfonamide énantiomériquement pur

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2011/000051 WO2012101648A1 (fr) 2011-01-24 2011-01-24 Nouveau procédé de synthèse de 2-méthoxy-5-[(2r)-2-(4-alkylpipérazin-l-yl)propyl]-benzènesulfonamide énantiomériquement pur

Publications (1)

Publication Number Publication Date
WO2012101648A1 true WO2012101648A1 (fr) 2012-08-02

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PCT/IN2011/000051 Ceased WO2012101648A1 (fr) 2011-01-24 2011-01-24 Nouveau procédé de synthèse de 2-méthoxy-5-[(2r)-2-(4-alkylpipérazin-l-yl)propyl]-benzènesulfonamide énantiomériquement pur

Country Status (1)

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WO (1) WO2012101648A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005080323A1 (fr) * 2004-02-23 2005-09-01 Cadila Healthcare Limited Procede de production de (r) ou (s)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide optiquement pur
WO2009062036A2 (fr) * 2007-11-09 2009-05-14 Dr. Reddy's Laboratories Ltd. Procédés de préparation de lévocétirizine et de ses sels pharmaceutiquement acceptables

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005080323A1 (fr) * 2004-02-23 2005-09-01 Cadila Healthcare Limited Procede de production de (r) ou (s)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide optiquement pur
WO2009062036A2 (fr) * 2007-11-09 2009-05-14 Dr. Reddy's Laboratories Ltd. Procédés de préparation de lévocétirizine et de ses sels pharmaceutiquement acceptables

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