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WO2013171767A1 - Procédé amélioré de préparation d'aliskiren - Google Patents

Procédé amélioré de préparation d'aliskiren Download PDF

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Publication number
WO2013171767A1
WO2013171767A1 PCT/IN2013/000320 IN2013000320W WO2013171767A1 WO 2013171767 A1 WO2013171767 A1 WO 2013171767A1 IN 2013000320 W IN2013000320 W IN 2013000320W WO 2013171767 A1 WO2013171767 A1 WO 2013171767A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
process according
aliskiren
give
Prior art date
Application number
PCT/IN2013/000320
Other languages
English (en)
Inventor
Shankar Rama
Lakshmana Rao Vadali
Seshadri Rao Manukonda
Venkata Srinivas Rao Potla
Mohana Vamsi Krishna VADLAMUDI
Srinivasa Rao Dasari
Original Assignee
Mylan Laboratories Limited
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 Mylan Laboratories Limited filed Critical Mylan Laboratories Limited
Publication of WO2013171767A1 publication Critical patent/WO2013171767A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups

Definitions

  • the present invention relates to an improved process for the preparation of renin inhibitor Aliskiren intermediates and further conversion into Aliskiren and its pharmaceutically acceptable salts.
  • Aliskiren is marketed by Novartis as TEKTURNA® in the form of its hemifumarate salt in a once-daily formulation.
  • U.S. pat. No. 5,559,1 1 1 discloses Aliskiren and related compounds along with the synthesis of Aliskiren. Further US 7132569, US 7009078, US 6730798 and US 6800769 claims novel intermediates used in the preparation of Aliskiren and process for the preparation of Aliskiren, which are incorporated here for reference. US 5,559,1 1 1 discloses compound of Formula-II, which is used as an intermediate in the preparation of Aliskiren.
  • the synthesis of the enantiomerically pure compound is quite demanding. Therefore, novel routes of synthesis needed for the preparation of Aliskiren.
  • the intermediates are commercially important in the synthesis of Aliskiren. Therefore an improved process for the preparation of Aliskiren intermediates is needed.
  • the present invention provides an improved process for the preparation of Aliskiren intermediates and further process for the preparation of Aliskiren.
  • Principle object of the present invention is to provide an improved process for the preparation of intermediate compounds of Formula-II and Formula-XIII of Aliskiren.
  • One more object of the present invention is to provide further conversion of intermediate compounds of Formula-II and Formula-XIII into Aliskiren or its pharmaceutically acceptable salts.
  • One aspect of the present invention provides, an improved process for the preparation of compound of Formula-XIII comprising the steps of
  • Another aspect the present invention provides, an improved process for the preparation of compound of Formula-II comprising the steps of: N
  • the present invention relates to an improved process for the preparation of intermediate compounds of Formula-II and Formula-XIII of Aliskiren.
  • the present invention also relates to further conversion of intermediate compounds of Formula-II and Formula-XIII into Aliskiren or its pharmaceutically acceptable salts.
  • the main aspect of the present invention provides an improved process for the preparation of compound of Formula-XIII comprising the steps of a) reacting the compound of Formula-II with magnesium in presence of Grignard reagents, and
  • the Grignard reagent used in this reaction is alkyl magnesium halide preferably Ci -4 alkyl magnesium halide like methyl magnesium chloride or methyl magnesium bromide.
  • the usage of the Grignard reagent as a primer initiates the reaction at lower temperature and kills the moisture present in the system and also minimizes the formation of methyl, hydroxyl, desmethoxy and phenoxy impurities.
  • Another aspect of the present invention provides an improved process for the preparation of compound of Formula-II comprising the steps of:
  • the compound of Formula-IV is prepared by condensing compound of Formula-Ill with l-Bromo-3-methoxy-propane in presence of a base.
  • the base is selected from alkaline metal hydroxides or alkaline metal carbonates such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, preferably potassium carbonate.
  • the reaction is carried out in solvents such as hydrocarbon like toluene.
  • the compound of Formula-IV in toluene layer is reduced by using reducing agent to give compound of Formula-V.
  • the suitable reducing agent is selected from sodium borohydride, Lithium borohydride, Lithium aluminum hydride, Tetrabutyl ammonium borohydride, potassium borohydride, preferably sodium borohydride.
  • the obtained compound of Formula-V is chlorinated in the presence of suitable chlorinating agent selected from . thionyl chloride, phosphoursoxychloride, oxalylch!oride, preferably thionyl chloride.
  • suitable chlorinating agent selected from . thionyl chloride, phosphoursoxychloride, oxalylch!oride, preferably thionyl chloride.
  • Prior art process provides bromination of compound of formula V in which for isolation of bromo compound, aqueous work up is required. As bromo compound is unstable due to aqueous work up, yield of the bromo compound is very less.
  • Present invention provides nonaqueous work up condition for isolation of chloro compound due to this yield of chloro compound (compound of formula VI) is higher when compared to its corresponding bromo compound.
  • the compound of Formula- VI is optionally reacted with sodium iodide to get the corresponding iodo compound of formula VII.
  • compound of formula VI or compound of formula VII is condensed with the Evans amide compound of Formula- VIII in presence of Lithium -diisopropylamide (LDA) to give compound of Formula-IX in an organic solvent.
  • LDA Lithium -diisopropylamide
  • the preferable organic solvent is tetrahydrofuran.
  • the compound of Formula-IX hydrolyzed to give compound of Formula-X by using procedures known in the prior art for example as disclosed in US 5659065 in presence of Lithium hydroxide and hydrogen peroxide.
  • the compound of Formula-X is reduced by using reducing agent such as sodium borohydride in the presence of an acid such as sulfuric acid, hydrochloric acid, methane sulfonic acid, trifluoro acetic acid, preferably sulfuric acid to give compound of Formula-XL
  • the alcohol compound of Formula-XI is chlorinated in the presence of chlorinating agent such as thionyl chloride in presence of N,N-dimethyl acetamide to give compound of Formula-II.
  • One more aspect of the present invention provides an improved process for the preparation of compound of Evans amide compound of Formula-VIII comprising, reacting 4-Benzyl-oxazolidin-2-one with Isovalerylchloride in presence of sodium hydride and toluene.
  • the compound of Formula-XIII is further converted into Aliskiren or its pharmaceutically acceptable salts as disclosed in prior art US 7009078 or our co-pending application WO 2012052829 for example as shown in the following scheme-Ill.
  • aqueous lithium hydroxide monohydrate solution (23g in 180 ml DM water) was added slowly and reaction mixture was stirred at 20-25°C for 6-8h. Then, aq. Na 2 S0 3 (290g in 1.5 liter water) was added drop wise within lh and organic layer was separated and aqueous layer was extracted with ethyl acetate. Combined organic layers were dried and evaporated under reduced pressure to give a residue. This residue was dissolved in dichloromethane and extracted the required product in aqueous lithium hydroxide monohydrate solution. Aqueous lithium hydroxide solution pH was adjusted to 2-5-3.0 dilute hydrochloric acid and extracted the aqueous layer with dichloromethane. Combined organic layers were dried and evaporated under reduced pressure to give compound Formula-X as residue.

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

Abstract

La présente invention concerne un procédé amélioré de préparation d'intermédiaires d'aliskiren, un inhibiteur de la rénine, de formule II, puis de conversion ultérieure de ceux-ci en aliskiren et en ses sels pharmaceutiquement acceptables.
PCT/IN2013/000320 2012-05-18 2013-05-17 Procédé amélioré de préparation d'aliskiren WO2013171767A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1976CH2012 2012-05-18
IN1976/CHE/2012 2012-05-18

Publications (1)

Publication Number Publication Date
WO2013171767A1 true WO2013171767A1 (fr) 2013-11-21

Family

ID=48832971

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2013/000320 WO2013171767A1 (fr) 2012-05-18 2013-05-17 Procédé amélioré de préparation d'aliskiren

Country Status (1)

Country Link
WO (1) WO2013171767A1 (fr)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5559111A (en) 1994-04-18 1996-09-24 Ciba-Geigy Corporation δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amides
US5659065A (en) 1994-04-18 1997-08-19 Novartis Corporation Alpha-aminoalkanoic acids and reduction products
US6730798B2 (en) 2000-07-05 2004-05-04 Speedel Pharma Ag Process for the preparation of substituted octanoyl amides
US6800769B2 (en) 2000-07-25 2004-10-05 Speedel Pharma Ag Process for the preparation of substituted octanoyl amides
US7009078B1 (en) 1999-07-29 2006-03-07 Speedel Pharma Ag Production of N-substituted 2,7-dialkyl-4-hydroxy-5-amino-8-arly-octanoylamides
WO2007137799A1 (fr) * 2006-05-31 2007-12-06 Schwarz Pharma Ltd. Nouvelle synthèse d'hydroxyméthylphénols substitués
WO2011148392A1 (fr) * 2010-05-28 2011-12-01 Msn Laboratories Limited Procédé pour préparer un hémifumarate du composé (2s,4s,5s,7s)-n-(2-carbamoyl-2- méthylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-méthoxy-3-(3- méthoxypropoxy)phényl]-octanamide et produits intermédiaires correspondants
WO2012052829A1 (fr) 2010-10-19 2012-04-26 Matrix Laboratories Ltd Synthèse d'aliskirène

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5559111A (en) 1994-04-18 1996-09-24 Ciba-Geigy Corporation δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amides
US5659065A (en) 1994-04-18 1997-08-19 Novartis Corporation Alpha-aminoalkanoic acids and reduction products
US7009078B1 (en) 1999-07-29 2006-03-07 Speedel Pharma Ag Production of N-substituted 2,7-dialkyl-4-hydroxy-5-amino-8-arly-octanoylamides
US7132569B2 (en) 1999-07-29 2006-11-07 Speedel Pharma Ag Preparation of N-substituted 2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amides
US6730798B2 (en) 2000-07-05 2004-05-04 Speedel Pharma Ag Process for the preparation of substituted octanoyl amides
US6800769B2 (en) 2000-07-25 2004-10-05 Speedel Pharma Ag Process for the preparation of substituted octanoyl amides
WO2007137799A1 (fr) * 2006-05-31 2007-12-06 Schwarz Pharma Ltd. Nouvelle synthèse d'hydroxyméthylphénols substitués
WO2011148392A1 (fr) * 2010-05-28 2011-12-01 Msn Laboratories Limited Procédé pour préparer un hémifumarate du composé (2s,4s,5s,7s)-n-(2-carbamoyl-2- méthylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-méthoxy-3-(3- méthoxypropoxy)phényl]-octanamide et produits intermédiaires correspondants
WO2012052829A1 (fr) 2010-10-19 2012-04-26 Matrix Laboratories Ltd Synthèse d'aliskirène

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