WO2013118138A1 - Nouveau procédé de préparation d'inhibiteurs de rénine - Google Patents

Nouveau procédé de préparation d'inhibiteurs de rénine Download PDF

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Publication number
WO2013118138A1
WO2013118138A1 PCT/IN2012/000815 IN2012000815W WO2013118138A1 WO 2013118138 A1 WO2013118138 A1 WO 2013118138A1 IN 2012000815 W IN2012000815 W IN 2012000815W WO 2013118138 A1 WO2013118138 A1 WO 2013118138A1
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WIPO (PCT)
Prior art keywords
formula
compound
alkoxy
alkyl
preparation
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PCT/IN2012/000815
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English (en)
Inventor
Laboratories Ltd Mylan
Shankar Rama
Lakshmana Rao Vadali
Sarat Chandra Srikanth Gorantla
Seshadri Rao Manukonda
Venkata Srinivas Rao Potla
Mohana Vamsi Krishna VADLAMUDI
Jayaram POTHANI
Raja Reddy ANUPATI
Original Assignee
Laboratories Ltd Mylan
Shankar Rama
Lakshmana Rao Vadali
Sarat Chandra Srikanth Gorantla
Seshadri Rao Manukonda
Venkata Srinivas Rao Potla
Vadlamudi Mohana Vamsi Krishna
Pothani Jayaram
Anupati Raja Reddy
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Application filed by Laboratories Ltd Mylan, Shankar Rama, Lakshmana Rao Vadali, Sarat Chandra Srikanth Gorantla, Seshadri Rao Manukonda, Venkata Srinivas Rao Potla, Vadlamudi Mohana Vamsi Krishna, Pothani Jayaram, Anupati Raja Reddy filed Critical Laboratories Ltd Mylan
Publication of WO2013118138A1 publication Critical patent/WO2013118138A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups

Definitions

  • the present invention relates to novel process for the preparation of 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. 5,559,11 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 11 discloses compound of Formula-II, which is used as an intermediate in the preparation of Aliskiren.
  • Ri and R 2 are independently of one another H, Ci-C 6 alkyl, Q- Q halogenalkyl, C]-C 6 alkoxy, Ci-C 6 alkoxy-Ci-C 6 alkyl, or Ci-C 6 alkoxy-Ci- C 6 alkyloxy, and X is CI, Br and I.
  • the Aiiskiren comprises, 4 chiral carbon atoms
  • the synthesis of the enantiomerically pure compound is quite demanding. Therefore, novel routes of synthesis needed for the preparation of Aiiskiren.
  • the intermediate of Formula-II is having commercially important in the synthesis of Aiiskiren. Therefore novel route of synthesis is needed for that intermediate.
  • the present invention provides novel compounds used in the preparation of Aiiskiren intermediate and further process for the preparation of Aiiskiren.
  • Principle object of the present invention is to provide a novel process for the preparation of intermediate of Formula-II of Aiiskiren.
  • Another object of the present invention is to provide novel intermediate (Formula- V) used in the preparation of Aiiskir
  • Ri and R 2 are independently of one another H, Ci-C 6 alkyl, Ci- C 6 halogenalkyl, Ci-C 6 alkoxy, Ci-C 6 alkoxy-Ci-C alkyl, or Ci-C alkoxy-Ci- C 6 alkyloxy.
  • One more object of the present invention is to provide further conversion of intermediate of Formula-II into Aliskiren or its pharmaceutically acceptable salts.
  • One aspect of the present invention provides, novel process for the preparation of compound of Formula-II comprising the steps of:
  • Ri and R 2 are independently of one another H, Ci-C alkyl, Q- C 6 halogenalkyl, C
  • R ⁇ and R 2 are as defined above.
  • the present invention relates to novel process for the preparation of intermediate of Formula-II of Aliskiren.
  • the present invention further relates to novel intermediate (Formula-V) used in the preparation of Aliskiren.
  • the present invention also relates to further conversion of compound of Formula-II into Aliskiren or its pharmaceutically acceptable salts.
  • the main aspect of the present invention provides novel process for preparation of compound of Formula-II comprising the steps of:
  • Ri and R 2 are independently of one another H, Ci-C 6 alkyl, C ⁇ - C 6 halogenalkyl, C]-C 6 alkoxy, C]-C 6 alkoxy-Ci-C 6 alkyl, or C t -Ce alkoxy-Ci- C 6 alkyloxy and X is halogen selected from fluoro, chloro, bromo and iodo
  • the compound of Formula-V is prepared by condensing compound of Formula-Ill with the compound of Formula-IV in presence of a base.
  • the base is selected from LiHMDS (Lithium bis(trimethylsilyl)amide), NaHMDS (sodium hexamethyldisilazide), KHMDS (potassium hexamethyldisilazide), LDA (Lithium diisopropylamide), n-BuLi (n-Butyl lithium).
  • the reaction is carried out in inert solvents such as ether, hydrocarbons, selected from tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentyl methyl ether, diethyl ether , dioxane, diglyme, tetrahydropyran, diisopropyl ether, methyl tertiary butyl ether and their mixtures, aliphatic and aromatic hydrocarbons such as cyclohexane, toluene, heptanes, hexanes, methyl cyclohexane etc. and their mixtures, preferably tetrahydrofuran or mixture of tetrahydrofuran with hexanes, heptanes to give the compound of Formula-V.
  • solvents such as ether, hydrocarbons, selected from tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentyl methyl ether, diethyl ether
  • compound of Formula-V is converted into compound of Formula-VI by reducing the compound of Formula-V.
  • the reduction of the compound of Formula-V is carried out with suitable reducing agents such as transition metal catalysts and hydride reagents, preferably using hydride reagents.
  • suitable reducing agents such as transition metal catalysts and hydride reagents, preferably using hydride reagents.
  • the reducing reagent is selected from sodium borohydride, sodium cyano borohydride, lithium aluminium hydride, lithium tri-tert-butoxy aluminium hydride, diborane and vitride, preferably sodium borohydride.
  • Ri and R 2 are independently of one another H, Ci-C 6 alkyl, Cj- C 6 halogenalkyl, Ci-C 6 alkoxy, C C alkoxy-Ct-Ce alkyl, or C C6 alkoxy-Ci-C 6 alkyloxy, and R 3 is C]-C 6 alkyl or aryl.
  • the compound of Formula-V is reacted with a base such as alkali-metal alkoxide in a solvent such as aromatic/aliphatic hydrocarbon solvents, preferably toluene, cyclohexane, tetrahydrofuran, methanol or mixture there of, to obtain alkyl or aryl ester of compound of Formula-VII.
  • a base such as alkali-metal alkoxide in a solvent such as aromatic/aliphatic hydrocarbon solvents, preferably toluene, cyclohexane, tetrahydrofuran, methanol or mixture there of, to obtain alkyl or aryl ester of compound of Formula-VII.
  • Alkalimetal alkoxide used in this reaction is selected from sodium, alkoxide, potassium alkoxide, preferably sodium methoxide. This reaction is carried out in presence of alkyl carbonate such as dimethylcarbonate and diethyl carbonate etc.
  • reduction of compound of Formula-VII to compound of Formula-VI is carried out in the presence of hydride reagents selected from sodium borohydride and lithium aluminium hydride, lithium tri-tert-buotoxy aluminium hydride, diborane and vitride.
  • hydride reagents selected from sodium borohydride and lithium aluminium hydride, lithium tri-tert-buotoxy aluminium hydride, diborane and vitride.
  • Ri and R 2 are independently of one another H, Ci-C 6 alkyl, C ⁇ - C 6 halogenalkyl, CrQalkoxy, Ci-Qalkoxy-CrQalkyl, or Ci-C 6 alkoxy-Ci- C 6 alkyloxy.
  • hydrolysis of compound of Formula-V is carried out with a base in presence of hydrogen peroxide in suitable polar aprotic solvents.
  • the base used in this reaction is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide, preferably lithium hydroxide.
  • the polar aprotic solvents used in the reaction are tetrahydrofuran, methyl tetrahydrofuran, cyclopentyl methyl ether, methanol, ethanol etc.
  • Mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid etc., or bases such as potassium hydroxide, sodium hydroxide, lithium hydroxide etc., can be used for hydrolysis to get compound of Formula-VIII.
  • reduction of the compound of Formula-VIII is carried out as such or optionally converting into corresponding acid chloride/anhydride and subjecting to reduction with suitable reducing agents such as transition metal catalysts and hydride reagents, preferably using hydride reagents selected from sodium borohydride, sodium cyano borohydride, lithium aluminium hydride, diborane and vitride, most preferably with in-situ generated diborane.
  • suitable reducing agents such as transition metal catalysts and hydride reagents, preferably using hydride reagents selected from sodium borohydride, sodium cyano borohydride, lithium aluminium hydride, diborane and vitride, most preferably with in-situ generated diborane.
  • Diborane can be generated using sodium borohydride in combination with iodine, sulfuric acid, hydrochloric acid, lewis acids such as boron trifluoride diethyl etharate etc.
  • One more aspect of the present invention provides, process for the preparation of compound of Formula-IIa comprising the steps of:
  • X is halogen selected from fluoro, chloro, bromo and iodo a) condensing the compound of Formula-IIIa with compound of Formula- IVa in presence of a base to give compound of Formula- Va, b) compound of formula Va to compound of formula Via, and
  • L is halogen selected from fluoro, chloro, bromo and iodo.
  • One more aspect of the present invention provides novel intermediate of compound of Formula-IV, i.e. (S)-N-Isovaleryl c
  • One more aspect of the present invention provides novel intermediate of compound of Formula- V.
  • Ri and R 2 are independently of one another H, Ci-C alkyl, C ⁇ - C 6 halogenalkyl, Ci-C alkoxy, Ci-C 6 alkoxy-Ci-C 6 alkyl, or Ci-C 6 alkoxy-Ci- C 6 alkyloxy.
  • the preferred compound of Formula-V is as shown below.
  • alcoholic compound compound of Formula- VI
  • compound of Formula-II compound of Formula-II
  • suitable reagents such as thionyl chloride, thionyl bromide, trimethyl silyl bromide trimethyl silyl iodide etc.
  • One more aspect of the present invention provides further conversion of Compound VI or compound of Formula-II into Aliskiren by conventional methods as disclosed in US 5,559,11 1, US 7009078 and WO 2012052829 for example as depicted in scheme-II.
  • the compound of Formula-V obtained from example-3 (lOgm, 19.7mol) was dissolved in THF (60ml) and water (20ml). The reaction mixture was cooled to 0°C. To this 30% hydrogen peroxide (13.5ml, 30%solution) was added followed by lithium hydroxide (2.07gm,50 mol), while the temperature was maintained at 0 °C. Temperature was slowly raised to 20-25° and the reaction mixture was stirred at this temperature for 10-12h. The reaction was quenched by the addition of a cold aqueous solution of sodium sulfite. The temperature of the reaction mixture was raised to 20 °C and stirred at this temperature for 30 min. The solution was concentrated under reduced pressure.
  • the concentrate was extracted with dichloromethane and then acidified with 3 N HCl to a final pH of 3-4.
  • the product was extracted into ethyl acetate, and the extracts were combined and washed with water.
  • the combined dichloromethane layers were concentrated under vacuum to give 5g of compound of Formula-VIII.

Abstract

La présente invention concerne un procédé amélioré pour la préparation du composé de Formule-II, qui est un intermédiaire dans la préparation d'Aliskirène et la conversion ultérieure du composé de Formule II en Aliskirène ou de ses sels pharmaceutiquement acceptables. Formule-II dans laquelle R1 et R2 représentent, indépendamment l'un de l'autre, H, C1-C6 alkyle, C1- C6 halogenalkyle, C1-C6 alcoxy, C1-C6 alcoxy-C1-C6 alkyle, ou C1-C6 alcoxy-C1- C6 alkyloxy et X représente halogène sélectionné parmi fluoro, chloro, bromo et iodo.
PCT/IN2012/000815 2011-12-13 2012-12-12 Nouveau procédé de préparation d'inhibiteurs de rénine WO2013118138A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN4342/CHE/2011 2011-12-13
IN4342CH2011 2011-12-13

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WO2013118138A1 true WO2013118138A1 (fr) 2013-08-15

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11925651B2 (en) 2019-05-31 2024-03-12 Ikena Oncology, Inc. TEAD inhibitors and uses thereof

Citations (6)

* 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
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
WO2008006394A1 (fr) * 2006-07-14 2008-01-17 F.I.S. Fabbrica Italiana Sintetici S.P.A Procédé de préparation d'acides (4e)-5-halo-2-alkylpent-4-énoïques optiquement actifs et de leurs dérivés ester
WO2012052829A1 (fr) 2010-10-19 2012-04-26 Matrix Laboratories Ltd Synthèse d'aliskirène

Patent Citations (7)

* 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
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
WO2008006394A1 (fr) * 2006-07-14 2008-01-17 F.I.S. Fabbrica Italiana Sintetici S.P.A Procédé de préparation d'acides (4e)-5-halo-2-alkylpent-4-énoïques optiquement actifs et de leurs dérivés ester
WO2012052829A1 (fr) 2010-10-19 2012-04-26 Matrix Laboratories Ltd Synthèse d'aliskirène

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MEALY N E ET AL: "ALISKIREN FUMARATE ANTIHYPERTENSIVE", DRUGS OF THE FUTURE, PROUS SCIENCE, ES, vol. 26, no. 12, 1 January 2001 (2001-01-01), pages 1139 - 1148, XP009017211, ISSN: 0377-8282, DOI: 10.1358/DOF.2001.026.12.648490 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11925651B2 (en) 2019-05-31 2024-03-12 Ikena Oncology, Inc. TEAD inhibitors and uses thereof

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